Legend
| Annovar Function | Annovar: Function prediction |
| Annovar Mutation type | Annovar: Mutation type prediction |
| Annovar Region type | Annovar: Region type prediction |
| ccdsGene name | Consensus Coding Sequence Database (CCDS): gene name |
| CosmicCodingMuts gene | Catalogue of Somatic Mutations in Cancer (COSMIC): gene name |
| cytoBand name | Cytoband location of gene |
| dbNSFP KGp1 AF | dbNSFP: Alternative allele frequency in the whole 1000Gp1 data. |
| dbNSFP KGp1 Afr AF | dbNSFP: Alternative allele frequency in the 1000Gp1 African descendent samples. |
| dbNSFP KGp1 Amr AF | dbNSFP: Alternative allele frequency in the 1000Gp1 American descendent samples. |
| dbNSFP KGp1 Asn AF | dbNSFP: Alternative allele frequency in the 1000Gp1 Asian descendent samples. |
| dbNSFP KGp1 Eur AF | dbNSFP: Alternative allele frequency in the 1000Gp1 European descendent samples. |
| dbNSFP LR score | dbNSFP: logistic regression (LR) based ensemble prediction score, which incorporated 10 scores (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy, PhyloP) and the maximum frequency observed in the 1000 genomes populations. Larger value means the SNV is more likely to be damaging. The threshold seperationg 'T(olerated)' and 'D(amaging)' is 0.5. |
| dbNSFP Uniprot Acc | dbNSFP: Uniprot accession number |
| dbNSFP Uniprot ID | dbNSFP: Uniprot ID number |
| dbSNP Clinical Significance | dbSNP: Variant Clinical Significance, 0 - unknown, 1 - untested, 2 - non-pathogenic, 3 - probable-non-pathogenic, 4 - probable-pathogenic, 5 - pathogenic, 6 - drug-response, 7 - histocompatibility, 255 - other |
| dbSNP GMAF | dbSNP: Global Minor Allele Frequency [0, 0.5]; global population is 1000Gp1 |
| dbSNP name | dbSNP: rsID |
| EntrezGene Description | Entrez Gene: Description (a descriptive name for this gene) |
| EntrezGene GeneID | Entrez Gene: ID (unique identifier for a gene) |
| EntrezGene Symbol | Entrez Gene: Symbol (default symbol for the gene) |
| EntrezGene Type of gene | Entrez Gene: Type, given by http://www.ncbi.nlm.nih.gov/IEB/ToolBox/CPP_DOC/lxr/source/src/objects/entrezgene/entrezgene.asn |
| ESP Afr MAF | NHLBI GO Exome Sequencing Project (ESP): The African American minor-allele frequency in percent. |
| ESP All MAF | NHLBI GO Exome Sequencing Project (ESP): The minor-allele frequency in percent for all populations. |
| ESP ClinicalLink | NHLBI GO Exome Sequencing Project (ESP): The potential clinical implications associated with a SNP |
| ESP Eur/Amr MAF | NHLBI GO Exome Sequencing Project (ESP): The European American minor-allele frequency in percent. |
| ExAC AF | Exome Aggregation Consortium (ExAC): Alternate Allele Freq |
| gene | refGene: gene name |
| OMIM Clinical Significance | Online Mendelian Inheritance in Man (OMIM): Clinical Significance |
| OMIM Description | Online Mendelian Inheritance in Man (OMIM): Description |
| OMIM Title | Online Mendelian Inheritance in Man (OMIM): Title |
| snpEff Effect | snpEff: predicted highest-impact effect resulting from the current variant (or one of the highest-impact effects, if there is a tie) |
| snpEff Functional Class | snpEff: predicted functional class of the highest-impact effect resulting from the current variant (none, silent, missense, or nonsense) |
| snpEff Gene Biotype | snpEff: predicted gene biotype for the highest-impact effect resulting from the current variant |
| snpEff Gene Name | snpEff: Gene name prediction |
| snpEff Impact | snpEff: predicted impact of the highest-impact effect resulting from the current variant (high, moderate, low, or modifier) |
FAM87B
| dbSNP name | rs3131967(T,C); rs3115859(G,A) |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 400728 |
| EntrezGene Description | family with sequence similarity 87, member B |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3168 |
LINC00115
| dbSNP name | rs2286139(C,T) |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 79854 |
| snpEff Gene Name | NCRNA00115 |
| EntrezGene Description | long intergenic non-protein coding RNA 115 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3875 |
TNFRSF4
| dbSNP name | rs17568(C,T) |
| ccdsGene name | CCDS11.1 |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 7293 |
| EntrezGene Description | tumor necrosis factor receptor superfamily, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TNFRSF4:NM_003327:exon5:c.G534A:p.E178E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbNSFP KGp1 AF | 0.45467032967 |
| dbNSFP KGp1 Afr AF | 0.469512195122 |
| dbNSFP KGp1 Amr AF | 0.475138121547 |
| dbNSFP KGp1 Asn AF | 0.756993006993 |
| dbNSFP KGp1 Eur AF | 0.207124010554 |
| dbSNP GMAF | 0.4559 |
| ESP Afr MAF | 0.379452 |
| ESP All MAF | 0.264224 |
| ESP Eur/Amr MAF | 0.205236 |
| ExAC AF | 0.354 |
OMIM Clinical Significance
Cardiac:
Atrioventricular septal defect (AVSD);
Ostium primum atrial septal defect;
Ventricular septum inlet defect;
Tricuspid and mitral valves are replaced by a single inlet valve;
Congestive failure;
Lower left sternal thrill and pansystolic murmur;
Poorly localized midsystolic murmur
Skin:
Cyanosis
Lung:
Pulmonary hypertension
Misc:
Characteristic feature of Down syndrome
Lab:
Superior axis and first-degree heart block on EKG;
Chararacteristic 4-chamber echocardiogram
Inheritance:
Autosomal dominant with variable expression and incomplete penetrance
OMIM Title
*600315 TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 4; TNFRSF4
;;TAX-TRANSCRIPTIONALLY ACTIVATED GLYCOPROTEIN 1 RECEPTOR; TXGP1L;;
OX40 ANTIGEN;;
LYMPHOID ACTIVATION ANTIGEN ACT35; ACT35;;
CD134
OMIM Description
DESCRIPTION
TNFRSF4 encodes a transmembrane protein belonging to the TNF receptor
superfamily (see 191190). The TNFRSF4 protein is a costimulatory
molecule implicated in long-term T-cell immunity (summary by Byun et
al., 2013).
CLONING
The ACT35 antigen is a cell surface glycoprotein that was discovered
through the production of a monoclonal antibody raised against the
HUT-102 cell line. Its expression can be induced on lymphocytes by
mitogen stimulation or viral stimulation. Because the cell and tissue
distribution resembles the pattern of the IL2 receptor, CD25 (147730),
it was speculated that a relationship between the ACT35 antigen and the
CD25 antigen exists. Latza et al. (1994) cloned a cDNA for the ACT35
antigen and showed its strong homology with the previously described rat
OX40 antigen. It is therefore another member of the tumor necrosis
factor/nerve growth factor receptor family. Birkeland et al. (1995)
cloned cDNA and genomic DNA for the mouse homolog.
Byun et al. (2013) reported that the 277-amino acid human OX40 protein
contains an N-terminal signal peptide, followed by 4 cysteine-rich
domains, a transmembrane domain, and a C-terminal cytosolic domain.
GENE STRUCTURE
Birkeland et al. (1995) determined the gene structure of mouse OX40,
which showed that there are several intron/exon bodies shared between
OX40 and CD27 (186711), CD40 (109535), TNFR1 (191190), and CD95
(134637).
MAPPING
By fluorescence in situ hybridization, Latza et al. (1994) mapped the
ACT35 gene to 1p36, where the genes for TNFR2 (191191) and the lymphoid
activation antigen CD30 (153243) are located.
Gross (2014) mapped the TNFRSF4 gene to chromosome 1p36.33 based on an
alignment of the TNFRSF4 sequence (GenBank GENBANK BC105070) with the
genomic sequence (GRCh37).
Birkeland et al. (1995) mapped the gene encoding murine OX40 to
chromosome 4 in an area that contains the gene for TNFR2 and shows
homology of synteny with the region of human chromosome 1 that contains
the genes for TNFR2, OX40, and CD30.
GENE FUNCTION
Song et al. (2004) showed that OX40 engagement sustains activation of
protein kinase B (PKB; 164730) and intermediates of PKB signaling
pathways, including PI3K (see 601232), GSK3 (see 606784), and FKHR
(FOXO1A; 136533). T cells from mice lacking Ox40 were unable to maintain
PKB activity over time, and this loss of activity coincided with cell
death. Expression of active PKB in responding Ox40 -/- cells reversed
the survival defect. Song et al. (2004) concluded that the duration of
signaling needed for long-term survival is much longer than that needed
for proliferation.
Munks et al. (2004) found that stimulation of 4-1BB (TNFRSF9; 602250) in
mice at the time of a DNA prime, poxvirus vaccine, increased the number
of functional memory CD8 (see 186910) T cells that responded, while
stimulation of OX40 increased the number of antigen-specific CD4
(186940) T cells that responded. Stimulating both of these TNFRs
enhanced the CD8 response more than stimulating 4-1BB alone. Munks et
al. (2004) suggested that stimulating these receptors can improve the
response to a powerful virus vector and may be useful in vaccine
development.
BIOCHEMICAL FEATURES
Using a single dose of agonistic antibody against OX40, Bansal-Pakala et
al. (2001) were able to prevent tolerance induction and to break
existing tolerance or augment the reactivity of hyporesponsive T cells.
Bansal-Pakala et al. (2001) proposed that targeting OX40 and possibly
other members of the TNFR family might have benefits as adjuvants.
MOLECULAR GENETICS
Byun et al. (2013) studied a 19-year-old Turkish woman with a primary
immunodeficiency (IMD16; 615593) presenting as childhood-onset classic
Kaposi sarcoma who had previously been reported as Case 3 by Sahin et
al. (2010). Homozygosity mapping and whole-exome sequencing identified a
homozygous arg65-to-cys (R65C; 600315.0001) mutation in the OX40 gene.
The patient's consanguineous parents, a younger sister, and a younger
brother were all heterozygous for R65C and HHV-8 seropositive, but they
were free of Kaposi sarcoma. Byun et al. (2013) noted that the
immunologic phenotype of the patient largely overlapped with that of
mice lacking Ox40. Flow cytometric analysis demonstrated that OX40 with
the R65C mutation was poorly expressed on T cells. Immunoblot analysis
of activated control T cells showed expression of a 50-kD OX40 protein,
with a minor fraction of 35 kD. However, in R65C heterozygotes and the
homozygous patient, the 35-kD form, which was associated with immature
carbohydrates and was exclusively intracellular, was predominant. The
patient's T cells were unable to bind or respond to OX40L, indicating
complete functional OX40 deficiency. All family members had a history of
BCG vaccination, but only the patient's T cells failed to respond to
tuberculin stimulation with IFNG (147570) production. Although
seropositive for a number of recall antigens, the patient did not make a
T-cell response to these antigens. Byun et al. (2013) proposed that the
patient's high susceptibility to Kaposi sarcoma may have resulted from
an inability to interact with OX40L, which is highly expressed on
HHV-8-infected endothelial cells.
ANIMAL MODEL
Using Ox40 -/- mice and a mouse model of asthma, Jember et al. (2001)
found that wildtype mice had significantly higher eosinophilic
infiltrate in the bronchial fluid than did Ox40 -/- mice. The
Ox40-deficient mice also had significantly reduced levels of the Th2
cytokines IL4 (147780) and IL5 (147850), but no elevation in IFNG
(147570), in bronchial fluid, and antigen-specific and total IgE was
reduced in serum. Functional analysis indicated that wildtype mice had
pronounced airway hyperreactivity compared with Ox40 -/- mice.
Histologic analysis revealed marked cellular infiltrate around the
bronchioles of wildtype mice and a near absence of mucus production by
Ox40 -/- mice. Jember et al. (2001) concluded that OX40/OX40L
interactions are integral to the development of the asthmatic phenotype.
They proposed that strategies targeting both OX40 and CD28 (186760) may
be most effective in preventing the development of allergen-specific T
cells.
OX40 is not expressed on naive T cells, but it is upregulated within 2
days of antigen activation. Humphreys et al. (2003) showed that
influenza virus-induced weight loss and T-cell inflammation in mice
could be reduced by an Ox40-Ig fusion protein. Flow cytometric and
intracellular cytokine analysis demonstrated that the number and
proportion of Cd8-positive T cells producing Tnf were reduced in treated
mice. Delayed treatment also inhibited weight loss in mice with
established illness without affecting viral clearance or antigen recall
responses. Reduced proliferation and enhanced apoptosis of lung cells
accompanied the improved clinical phenotype. Humphreys et al. (2003)
concluded that interference with the late costimulatory pathway has
potential for the treatment of dysregulated immune responses in lung.
Shimojima et al. (2004) found that CD134 is the primary receptor for
feline immunodeficiency virus. CD134 expression promotes viral binding
and renders cells permissive for viral entry, productive infection, and
syncytium formation. Infection is CXCR4 (162643)-dependent, analogous to
infection with X4 strains of HIV.
B3GALT6
| dbSNP name | rs144527217(T,G); rs45578847(G,A); rs45591840(G,T); rs56852924(G,A); rs114208940(C,T); rs61353980(C,T) |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 126792 |
| snpEff Gene Name | SDF4 |
| EntrezGene Description | UDP-Gal:betaGal beta 1,3-galactosyltransferase polypeptide 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Scapular winging (in some patients)
SKELETAL:
[Spine];
Hyperlordosis (in some patients);
[Pelvis];
Hip dysplasia (in some patients);
Hip contractures (in some patients);
[Limbs];
Knee contractures (in some patients);
[Feet];
Foot deformities;
Pes equinovarus;
Achilles tendon contractures
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal and distal (predominant lower limb involvement);
Muscle atrophy, proximal and distal (predominant lower limb involvement);
Gower sign;
Axial muscle weakness;
Fasciculations (in some patients);
Neurogenic abnormalities seen on EMG;
Groups of atrophic fibers seen on muscle biopsy (type I fiber predominance)
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Waddling gait;
Difficulty running;
Toe-walking;
Spasticity (in some patients);
Hyperreflexia (in some patients);
Upper motor signs (in some patients);
Loss of motor neurons in the anterior horn of the spinal cord;
[Peripheral nervous system];
Hyporeflexia, distal;
Areflexia, distal
MISCELLANEOUS:
Onset in early first decade, although some patients have onset at
birth or early in infancy;
Variable severity;
Slowly or non-progressive
MOLECULAR BASIS:
Caused by mutation in the homolog of the Drosophila bicaudal D, 2
gene (BICD2, 609797.0001)
OMIM Title
*615291 UDP-GAL:BETA-GAL BETA-1,3-GALACTOSYLTRANSFERASE POLYPEPTIDE 6; B3GALT6
;;GALACTOSYLTRANSFERASE II; GALTII;;
BETA-1,3-GALACTOSYLTRANSFERASE 6;;
BETA-3-GALT6
OMIM Description
DESCRIPTION
Glycosaminoglycan biosynthesis initiates with the formation of a linkage
tetrasaccharide that serves as a primer, followed by sequential transfer
of monosaccharide residues from the corresponding nucleotide sugars
starting at the reducing end. B3GALNT6 (EC 2.4.1.134) forms a galactose
(Gal)-beta-1,3-Gal linkage via the transfer of Gal from UDP-Gal to a
terminal beta-linked Gal residue and functions in the synthesis of
heparan sulfate and chondroitin sulfate (Bai et al., 2001).
CLONING
By searching an EST database for sequences similar to mouse
beta-1,3-galactosyltransferases (see B3GALT1, 603093), followed by
screening a human fetal brain cDNA library and a newborn mouse brain
cDNA library, Bai et al. (2001) cloned human and mouse B3GALT6, which
they designated GALTII. The deduced human and mouse proteins contain 329
and 325 amino acids, respectively. GALTII is a typical type II
transmembrane protein, with a transmembrane domain near the N terminus
and a C-terminal galactosyltransferase domain containing a conserved
cysteine residue. Northern blot analysis detected variable expression of
transcripts of about 1.6, 2.4, and 3.3 kb in all 16 human tissues
examined. Fluorescence-tagged GALTII colocalized with alpha-mannosidase
II (MAN2A1; 154582), a marker of the medial Golgi. Bai et al. (2001)
noted that the sequence and expression pattern of B3GALT6 had
erroneously been reported as that of B3GNT2 (605581) in a previous
publication (Zhou et al., 1999) due to a clerical error. The correct
B3GNT2 sequence and expression pattern were provided in an erratum.
GENE FUNCTION
Bai et al. (2001) found that human GALTII expressed in insect cells
showed strict requirement for UDP-Gal as a Gal donor. For a substrate,
it reacted strongly with Gal-beta-1,4-xylosyl-beta-O-benzyl, which is
found in the linkage region of glycosaminoglycans. It also used simple
beta-galactosides and other glycans with terminal beta-linked Gal
residues. Knockdown of GALTII in HeLa cells inhibited synthesis of both
heparan sulfate and chondroitin sulfate.
GENE STRUCTURE
Bai et al. (2001) determined that B3GALT6 is a single-exon gene.
MAPPING
By genomic sequence analysis, Bai et al. (2001) mapped the B3GALT6 gene
to chromosome 1p36.3. They mapped the mouse B3galt6 gene to a region of
chromosome 4E2 that shares homology of synteny with human chromosome
1p36.3.
MOLECULAR GENETICS
- Spondyloepimetaphyseal Dysplasia with Joint Laxity, Type
1, with or without Fractures
By next-generation sequencing in 7 individuals, including 2 sibs, with
spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1;
271640) from 5 unrelated Japanese families and a Singapore/Japanese
family, Nakajima et al. (2013) identified possible mutations in the
B3GALT6 gene. By direct sequencing of this gene in these 7 patients and
an additional patient with JEMDJL1 from a Vietnamese family, they
identified compound heterozygous missense mutations in all but 1 in whom
a second mutation was not found (615291.0001-615291.0006). One of the
mutations (M1?; 615291.0001) was found in 5 of the 7 families. None of
the mutations were found in 200 ethnically matched controls or in public
databases, including the 1000 Genomes Database. Immunocytochemical
studies of mutant proteins showed subcellular mislocalization of all but
2 (D156N, 615291.0003 and C300S, 615291.0004). Galt-II activities of all
mutant proteins were significantly decreased compared to wildtype,
indicating loss of function. There were no significant differences in
GALT-II activities between wildtype and a common B3GALT6 polymorphism
(dbSNP rs12085009). Biochemical studies using patient lymphoblastoid
cells showed a decrease of heparan sulfate and a paradoxical increase of
chondroitin sulfate and dermatan sulfate on the cell surface.
By homozygosity mapping and candidate gene sequence analysis in 3
unrelated Iranian families segregating SEMDJL1 with fractures, Malfait
et al. (2013) identified homozygous or compound heterozygous mutations
in the B3GALT6 gene (615291.0012-615291.0014), which segregated with the
disorder in each family. Patient fibroblasts exhibited a large decrease
in ability to prime glycosaminoglycan synthesis together with impaired
glycanation of the small chondroitin/dermatan sulfate proteoglycan
decorin, confirming B3GALT6 loss of function. Dermal electron microscopy
showed abnormalities in collagen fibril organization. A strong reduction
in heparan sulfate level was also observed, indicating that B3GALT6
deficiency alters synthesis of both main types of glycosaminoglycans. An
in vitro wound healing assay revealed a significant delay in fibroblasts
from 2 index individuals, pointing to a role for glycosaminoglycan
defect in impaired wound repair in vivo.
- Ehlers-Danlos Syndrome, Progeroid Type, 2
Because some of the patients with SEMDJL1 in whom they had identified
mutations in the B3GALT6 gene had some overlapping features with the
progeroid form of Ehlers-Danlos syndrome (615349), Nakajima et al.
(2013) performed Sanger sequencing of the B3GALT6 gene in 4 EDSP
patients from 3 families who did not have a mutation in the B4GALT7 gene
(604327). All 4 patients were found to be compound heterozygous for a
frameshift and a missense mutation in the B3GALT6 gene
(615291.0007-615291.0011). A missense mutation that was common in 2 EDSP
families (S309T; 615291.0008) was found to have significantly decreased
GalT-II activities compared to wildtype, indicating loss of function.
None of the mutations were found in 200 ethnically matched controls or
in public databases, including the 1000 Genomes Database.
ANKRD65
| dbSNP name | rs143038747(G,A); rs1781132(C,T); rs904589(C,G); rs3766165(A,G); rs12089560(A,G) |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 441869 |
| snpEff Gene Name | RP4-758J18.6 |
| EntrezGene Description | ankyrin repeat domain 65 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04224 |
ATAD3A
| dbSNP name | rs151027309(A,T); rs140927356(C,A); rs150199746(T,G); rs6669795(A,C); rs9439458(T,C); rs141627726(G,C); rs150520639(T,C); rs113751252(G,T); rs1077906(A,G); rs146756261(G,C); rs9439441(G,A); rs189196817(T,A); rs183883762(C,T); rs61226390(G,A); rs138757840(G,A); rs3813216(A,G); rs3737714(C,T); rs112869160(T,C); rs201275592(G,A); rs10796394(C,T); rs3128345(A,G); rs116279124(C,T); rs6684212(C,T); rs9439462(C,T); rs78493114(G,C); rs11260608(C,A); rs9439443(C,T); rs114845849(G,A); rs182958394(C,T); rs112624192(G,C); rs149348995(G,A); rs144698654(G,A); rs12032637(A,G); rs115990140(G,A); rs6683520(C,T); rs6688404(A,G); rs1987191(T,C); rs6677993(G,A); rs145341309(C,T) |
| ccdsGene name | CCDS53260.1 |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 55210 |
| EntrezGene Description | ATPase family, AAA domain containing 3A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ATAD3A:NM_018188:exon16:c.C1865T:p.A622V,ATAD3A:NM_001170536:exon16:c.C1484T:p.A495V,ATAD3A:NM_001170535:exon16:c.C1721T:p.A574V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5571 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | D2K8Q1 |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.008398 |
| ESP All MAF | 0.002999 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 9.760e-04,4.067e-05 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature;
[Other];
Growth retardation, pre- and postnatal
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
High forehead;
Frontal bossing;
Midface hypoplasia;
Small mandible;
Long face;
Hypotonic face;
Smooth philtrum;
[Ears];
Low-set ears;
[Eyes];
Downslanting palpebral fissures;
[Nose];
Prominent nasal bridge;
Thin nose;
Long nose;
Bulbous nasal tip;
[Mouth];
High-arched palate;
Cleft palate;
Small mouth;
[Teeth];
Delayed primary dentition;
Crowded teeth;
Oligodontia;
Peg-shaped teeth
ABDOMEN:
[External features];
Inguinal hernia
SKELETAL:
[Hands];
Camptodactyly;
Arachnodactyly;
[Feet];
Pes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Thin skin;
[Nails];
Dysplastic nails;
[Hair];
Thin, sparse hair
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Poor speech development;
Broad-based gait;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Aggression;
Happy demeanor
LABORATORY ABNORMALITIES:
Some patients carry a deletion of minimum of 8.1 Mb on 2q32-q33
MISCELLANEOUS:
Variable manifestations
MOLECULAR BASIS:
Caused by mutation in the special AT-rich sequence-binding protein
2 gene (SATB2, 608148.0001)
OMIM Title
*612316 ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3A; ATAD3A
OMIM Description
DESCRIPTION
ATAD3A and ATAD3B (612317) are mitochondrial membrane proteins that
contribute to the stabilization of large mitochondrial DNA
(mtDNA)-protein complexes called nucleoids (He et al., 2007).
CLONING
Using mass spectroscopy to identify cell surface antigens on myeloid
cell lines, followed by RT-PCR of promyelocytic cell line RNA, Geuijen
et al. (2005) cloned ATAD3A. Western blot analysis detected ATAD3A at an
apparent molecular mass of 75 kD in transfected human embryonic kidney
(HEK293T) cells. Flow cytometry revealed ATAD3A on the cell surface of a
promyelocytic cell line, on 77% of AML (601626) samples, on half of
monocytes, and on a subpopulation of dendritic cells, but not on other
lymphocytes. ATAD3A was not expressed on the surface of transfected
HEK293T cells.
By searching for sequences similar to rat Atad3, He et al. (2007)
identified human ATAD3A and ATAD3B. In its C-terminal half, the deduced
587-amino acid ATAD3A protein contains Walker A and B motifs, followed
by ATP-binding sensor-1 and sensor-2 motifs. An alpha helix is located
N-terminal to the Walker A motif, and an arginine finger separates the
sensor motifs. An antibody that did not differentiate between ATAD3A and
ATAD3B detected ATAD3 in a punctate pattern within mitochondria of human
osteosarcoma cells. The pattern frequently coincided with
mtDNA-containing nucleoids, but not all nucleoids contained ATAD3.
Bogenhagen et al. (2008) stated that ATAD3A contains a central
transmembrane domain. Using immunofluorescence and protease
susceptibility studies, they found that ATAD3A was embedded in the inner
membrane of HeLa cell mitochondria, with the C-terminal AAA domain
directed toward the matrix and the N terminus exposed to the cytoplasm.
GENE FUNCTION
He et al. (2007) found that depletion of ATAD3 via small interfering RNA
in human osteosarcoma cells led to increased negative supercoiling of
mtDNA, although mitochondria maintained essentially normal morphology.
Bogenhagen et al. (2008) found that, although both ATAD3A and ATAD3B
were present in native HeLa cell nucleoids, neither ATAD3 protein was
crosslinked with mtDNA in isolated formaldehyde crosslinked HeLa cell
nucleoids, indicating that they are unlikely to bind mtDNA. In addition,
protease susceptibility studies suggested that the putative N-terminal
DNA-binding regions of ATAD3A and ATAD3B reside outside the
mitochondrial inner membrane.
MAPPING
Bogenhagen et al. (2008) stated that the ATAD3 locus is tandemly
duplicated in humans, generating 2 paralogs, ATAD3A and ATAD3B. The
ATAD3 genes are located on chromosome 1p36.33 (Schaffrik et al., 2006).
C1orf233
| dbSNP name | rs28737320(C,G) |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 643988 |
| snpEff Gene Name | RP11-345P4.5 |
| EntrezGene Description | chromosome 1 open reading frame 233 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1097 |
TMEM52
| dbSNP name | rs4459050(T,C) |
| ccdsGene name | CCDS35.1 |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 339456 |
| EntrezGene Description | transmembrane protein 52 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM52:NM_178545:exon5:c.A421G:p.M141V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NDY8 |
| dbNSFP Uniprot ID | TMM52_HUMAN |
| dbNSFP KGp1 AF | 0.14880952381 |
| dbNSFP KGp1 Afr AF | 0.367886178862 |
| dbNSFP KGp1 Amr AF | 0.0994475138122 |
| dbNSFP KGp1 Asn AF | 0.131118881119 |
| dbNSFP KGp1 Eur AF | 0.0435356200528 |
| dbSNP GMAF | 0.1488 |
| ESP Afr MAF | 0.333182 |
| ESP All MAF | 0.138628 |
| ESP Eur/Amr MAF | 0.038953 |
| ExAC AF | 0.116 |
LOC100129534
| dbSNP name | rs1039063(T,G); rs10910053(G,A); rs72642166(C,T); rs76142101(C,T); rs61762095(T,G); rs2279704(C,T); rs2254874(G,C); rs2036082(C,T); rs4648831(C,T); rs2840525(A,G); rs2840526(T,C); rs2643912(G,T); rs2840528(A,G); rs2645082(T,C) |
| ccdsGene name | CCDS40.1 |
| cytoBand name | 1p36.33 |
| EntrezGene GeneID | 100129534 |
| snpEff Gene Name | MORN1 |
| EntrezGene Description | small nuclear ribonucleoprotein polypeptide N pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4591 |
LOC115110
| dbSNP name | rs2147905(T,C); rs3748825(T,C); rs2985858(C,G) |
| cytoBand name | 1p36.32 |
| EntrezGene GeneID | 115110 |
| snpEff Gene Name | TNFRSF14 |
| EntrezGene Description | uncharacterized LOC115110 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4096 |
LOC100133445
| dbSNP name | rs2227312(C,A); rs2227313(T,C); rs2234152(C,T) |
| cytoBand name | 1p36.32 |
| EntrezGene GeneID | 100133445 |
| snpEff Gene Name | TNFRSF14 |
| EntrezGene Description | uncharacterized LOC100133445 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.466 |
| ExAC AF | 0.398 |
ACTRT2
| dbSNP name | rs4576609(C,T); rs3795262(T,G) |
| ccdsGene name | CCDS45.1 |
| cytoBand name | 1p36.32 |
| EntrezGene GeneID | 140625 |
| EntrezGene Description | actin-related protein T2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTRT2:NM_080431:exon1:c.C15T:p.H5H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2461 |
| ESP Afr MAF | 0.141625 |
| ESP All MAF | 0.166154 |
| ESP Eur/Amr MAF | 0.178721 |
| ExAC AF | 0.191 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608535 ACTIN-RELATED PROTEIN T2; ACTRT2
;;ARPT2;;
ACTIN-RELATED PROTEIN M2; ARPM2
OMIM Description
CLONING
By searching an EST database for actin-related proteins, Harata et al.
(2001) identified ARPM2. The deduced 377-amino acid protein contains an
actin-like ATP/ADP-binding pocket and 2 nuclear export signals. However,
residues likely to be involved in actin-actin and actin-myosin (see
160730) contacts are not well conserved in ARPM2. ARPM2 shares 48% amino
acid identity with beta-actin (102630) and 46% identity with ARPM1
(608534). RT-PCR detected ARPM2 expression in all tissues tested; the
level of expression was lower than that of beta-actin.
Heid et al. (2002) purified bovine Arpm2, which they designated Arpt2,
from the calyx fraction of epididymal sperm heads. Using peptide
sequences to search genomic and EST databases, they identified human
ARPM2. The ARPM2 protein shares 75.5% amino acid identity with ARPT1
(300487). ARPT1 and ARPM2 contain several cysteine residues not found in
beta-actin or other ARPs. Bovine Arpm2 showed an apparent molecular mass
of about 40 kD.
MAPPING
Harata et al. (2001) mapped the ARPM1 gene in silico to chromosome
1p36.32.
NPHP4
| dbSNP name | rs11121648(T,G); rs1287635(T,C); rs1287634(G,A); rs61002800(G,C); rs489933(C,T); rs12078643(C,T); rs555164(T,C); rs12122135(A,G); rs1287630(G,A); rs12405167(G,A); rs1287629(A,G); rs1287626(G,A); rs11804710(G,C); rs522985(A,G); rs499509(A,G); rs472651(C,T); rs115555125(C,T); rs905469(A,G); rs905468(C,T); rs114139049(C,T); rs868162(C,T); rs112284157(C,T); rs868163(A,G); rs905467(T,C); rs1287638(C,T); rs1287637(A,T); rs75450202(G,A); rs1622955(T,C); rs3747992(G,A); rs114545322(C,T); rs3747989(C,T); rs3747988(A,C); rs17432121(C,A); rs114573460(C,T); rs11121915(T,G); rs145926393(G,A); rs9661673(C,T); rs1287625(A,G); rs115187086(G,A); rs115534043(C,T); rs4845828(T,C); rs11121956(C,T); rs116463761(G,A); rs79321451(C,A); rs72630607(G,A); rs115932716(G,A); rs34251435(A,T); rs12079601(A,G); rs4908559(A,G); rs116462647(T,C); rs10779788(G,A); rs114871545(T,C); rs12735231(G,A); rs10746504(T,C); rs2282281(G,A); rs487654(C,T); rs494611(A,G); rs12081133(T,C); rs7550218(C,T); rs138403111(G,A); rs115994790(G,C); rs11122104(C,T); rs11122107(G,A); rs6689443(C,T); rs72856200(A,C); rs17028870(A,G); rs12134240(T,C); rs7519953(A,G); rs10864631(T,C); rs11586334(T,C); rs11577514(C,G); rs56270325(A,T); rs76984673(C,T); rs114545811(C,T); rs2312464(A,G); rs116336807(G,C); rs72857405(T,C); rs10864632(C,T); rs182101894(A,T); rs11122117(C,G); rs2134551(G,A); rs146881978(T,C); rs4908936(A,C); rs12090534(G,A); rs12084678(T,C); rs12062053(C,T); rs57446086(G,A); rs11122125(A,G); rs571655(C,T); rs12093500(G,C); rs3747987(T,C); rs11122130(A,G); rs143436710(C,T); rs115400440(T,G); rs17028879(C,T); rs6692955(G,A); rs72857418(A,G); rs115756609(G,A); rs12069778(C,T); rs12057165(A,G); rs12072386(C,G); rs12060900(G,A); rs12057260(A,C); rs6694744(A,G); rs192130523(G,A); rs138647234(C,T); rs183551539(G,T); rs142066786(G,A); rs150680594(C,T); rs515628(C,T); rs11120772(G,A); rs145095236(C,T); rs72857438(C,A); rs143158375(G,A); rs140412661(G,A); rs1889971(A,G); rs12086103(G,A); rs147540617(T,C); rs150957294(G,A); rs11587302(G,A); rs61762117(T,C); rs140458228(C,G); rs114398063(C,T); rs7549818(A,G); rs78825568(G,A); rs55676949(G,C); rs35291001(T,C); rs962662(G,A); rs142098216(G,A); rs139258970(G,C); rs72857448(G,A); rs72857450(T,C); rs11120781(T,C); rs7549324(G,A); rs11120782(A,G); rs10864245(G,A); rs7535806(G,A); rs7549369(A,C); rs144468751(A,G); rs12745546(C,A); rs142205176(G,A); rs1011994(C,T); rs149784548(T,C); rs2174124(T,C); rs35760537(G,A); rs143371979(G,A); rs148376780(T,A); rs150729272(C,T); rs139897549(G,T); rs7519679(T,C); rs7548619(G,A); rs7520105(T,C); rs11590397(G,A); rs115875752(G,A); rs11590436(G,T); rs149015647(A,T); rs12742075(A,G); rs11120805(A,G); rs11120806(C,T); rs144633876(C,A); rs12353987(C,T); rs4908583(C,T); rs10864262(T,C); rs149529921(G,A); rs9727119(A,C); rs10864264(C,T); rs145863282(T,C); rs140798376(A,G); rs11576617(C,T); rs72857457(A,T); rs115413424(G,C); rs114297856(C,A); rs869107(G,C); rs12098207(G,A); rs521736(A,G); rs144741296(G,T); rs12058794(G,A); rs34713106(T,C); rs35078529(C,T); rs114271135(G,A); rs35685456(G,A); rs116227781(G,A); rs12060459(G,A); rs12065728(C,T); rs1466923(A,G); rs72857466(T,C); rs11120832(T,C); rs144631422(G,A); rs141419442(A,G); rs114484312(G,A); rs2062784(T,C); rs12734220(A,G); rs12070803(A,G); rs2152922(G,C); rs138797443(T,C); rs150365587(C,T); rs12033563(T,C); rs143675266(T,C); rs11804463(A,G); rs1566724(G,A); rs34921218(A,G); rs140899058(G,A); rs150173097(C,T); rs145031110(T,C); rs144803499(C,G); rs6676029(G,A); rs72857479(G,A); rs551207(C,T); rs10779677(G,A); rs12032639(A,G); rs11120871(C,T); rs115534498(T,C); rs10864284(G,C); rs139399261(G,A); rs693005(A,G); rs11120875(G,A); rs6702707(C,T); rs146754523(C,G); rs12076999(C,T); rs6659420(A,G); rs114263507(A,G); rs6662680(T,C); rs72857494(G,A); rs56127510(A,G); rs6691541(C,G); rs113924109(G,A); rs6699722(T,C); rs115748491(G,A); rs7555293(T,C); rs35206665(G,A); rs34188627(G,A); rs35716311(T,A); rs11584087(T,C); rs143356904(G,A); rs35269427(G,A); rs34444818(G,C); rs6660956(T,C); rs17028951(G,C); rs12074103(G,A); rs58392806(T,C); rs12076826(G,A); rs10864292(T,C); rs2011197(C,T); rs111987560(T,A); rs72859112(T,C); rs72859114(T,G); rs72859116(C,G); rs72859118(C,G); rs72859122(G,A); rs115772366(T,C); rs12083678(C,T); rs61762129(T,C); rs113011789(A,G); rs11587241(A,C); rs10779681(T,C); rs10779682(C,A); rs11120898(C,T); rs7522246(T,C); rs7515065(C,T); rs7515070(C,T); rs35357995(T,C); rs61762132(C,T); rs6666684(C,T); rs71629759(G,A); rs2050653(G,A); rs875574(C,A); rs875573(A,G); rs12084942(C,T); rs871780(G,A); rs4908628(A,G); rs12137358(C,G); rs140233544(T,C); rs553959(T,C); rs143087336(T,C); rs2275231(T,C); rs12729290(A,T); rs12745395(G,A); rs34768831(G,T); rs2047811(T,G); rs11588889(C,A); rs6694797(A,G); rs12091974(C,G); rs2062785(C,T); rs186055712(T,G); rs116537682(T,C); rs11585166(G,C); rs146412778(T,C); rs11586662(C,A); rs12409002(T,C); rs4908458(C,T); rs4068401(T,C); rs4068400(G,A); rs4068399(G,A); rs147223718(G,A); rs115036756(T,A); rs116777435(C,A); rs4908638(C,T); rs12084871(G,A); rs76260062(A,T); rs11586352(G,A); rs57270677(G,C); rs485942(A,T); rs34794580(C,T); rs2312050(C,A); rs72859153(G,C); rs151164872(A,C); rs882128(T,C); rs115886975(C,T); rs11120933(G,A); rs1287543(C,T); rs11120934(G,A); rs4908639(G,C); rs114368032(C,G); rs4908641(G,T); rs72859167(T,C); rs10779685(T,C); rs496739(A,C); rs34501422(G,A); rs11120951(T,C); rs116382749(T,C); rs806103(G,A); rs72630649(C,T); rs806104(G,A); rs146042177(C,T); rs7552237(T,C); rs812051(G,A); rs116717649(C,A); rs6577448(G,A); rs1295111(C,G); rs145551188(T,G); rs806105(A,G); rs138294503(A,C); rs709207(C,T); rs806106(C,T); rs138589503(G,C); rs11577700(C,T); rs806107(A,G); rs140320318(G,C); rs806108(C,G) |
| ccdsGene name | CCDS44052.1 |
| cytoBand name | 1p36.31 |
| EntrezGene GeneID | 261734 |
| EntrezGene Description | nephronophthisis 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NPHP4:NM_001291593:exon12:c.G313A:p.E105K,NPHP4:NM_015102:exon15:c.G1852A:p.E618K,NPHP4:NM_001291594:exon11:c.G316A:p.E106K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6339 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75161 |
| dbNSFP Uniprot ID | NPHP4_HUMAN |
| dbNSFP KGp1 AF | 0.00824175824176 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0184696569921 |
| dbSNP GMAF | 0.008264 |
| ESP Afr MAF | 0.003544 |
| ESP All MAF | 0.011218 |
| ESP Eur/Amr MAF | 0.014847 |
| ExAC AF | 0.01 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Acquired microcephaly (in severe cases);
[Eyes];
Visual impairment, cortical (in severe cases)
NEUROLOGIC:
[Central nervous system];
Generalized clonic or tonic-clonic seizures;
Unilateral clonic seizures;
Absence seizures;
Complex partial seizures;
Myoclonic seizures;
Delayed psychomotor development;
Psychomotor delay after second year;
Mental deterioration;
Ataxia;
Status epilepticus;
EEG may be normal at first;
EEG later shows generalized spike or polyspike waves and focal spikes;
EEG may show migrating focal or multifocal origin (in severe cases);
Cerebral atrophy (in severe cases)
MISCELLANEOUS:
Marked phenotypic variability;
Most mutations occur de novo;
Onset in first year of life;
Psychomotor delay may already be apparent at onset of seizures;
May be induced by fever or hot bath;
Often refractory to medical therapy;
May be extreme phenotype of generalized epilepsy with febrile seizures
plus (GEFS+, 604233)
MOLECULAR BASIS:
Caused by mutation in the alpha subunit of the voltage-gated sodium
channel type I gene (SCN1A, 182389.0007);
Caused by mutation in the alpha subunit of the voltage-gated sodium
channel type IX gene (SCN9A, 603415.0019);
Caused by mutation in the gamma-aminobutyric acid (GABA) A receptor,
gamma-2 gene (GABRG2, 137164.0003)
OMIM Title
*607215 NEPHROCYSTIN 4; NPHP4
;;KIAA0673;;
NEPHRORETININ
OMIM Description
CLONING
Using markers covering the nephronophthisis-4 (NPHP4; 606966) locus on
1p36, Mollet et al. (2002) carried out haplotype analysis of families
affected with nephronophthisis that were not linked to previously
identified nephronophthisis loci. They narrowed the NPHP4 critical
interval to a 1-cM region containing 6 genes, the sequences of which
were available in public databases. They detected 5 mutations in the
coding region of the KIAA0673 gene, which had been shown by Ishikawa et
al. (1998) to be expressed in the kidney and was predicted to encode a
protein containing an SH3-interacting motif. Northern blot analysis
using a partial NPHP4 cDNA detected weak expression of 2 major
transcripts of approximately 4.5 and 7.5 kb in kidney, skeletal muscle,
heart, and liver, and to a lesser extent in brain and lung. Mollet et
al. (2002) obtained a full-length NPHP4 cDNA by 5-prime and 3-prime
RACE-PCR and RT-PCR. They stated that NPHP4 gene encodes a 1,250-amino
acid protein that shares 86% identity with the mouse ortholog. In an
erratum, they indicated that an error in sequence analysis had led to
the masking of a methionine codon located 176 amino acids upstream of
the previously reported initiation codon. Correction of this error
indicated that NPHP4 contains 1,426 amino acids.
By use of high-resolution haplotype analysis and by demonstration of 9
likely loss-of-function mutations in 6 affected families with NPHP4,
Otto et al. (2002) also identified the NPHP4 gene. They found that the
deduced 1,426-amino acid protein, which they called nephroretinin, is
highly conserved in evolution, with a homolog in C. elegans. Northern
blot analysis revealed broad expression of a 5-kb transcript, with
strong expression in skeletal muscle; dot blot analysis detected strong
expression in skeletal muscle and testis.
By immunostaining mouse retina, Roepman et al. (2005) determined that
Nphp1 was expressed in branching processes emanating from inner nuclear
neurons, in the postsynaptic layer of the outer plexiform layer, and in
cell bodies of photoreceptors. It also localized diffusely in the inner
segment compartment of photoreceptors.
GENE STRUCTURE
Mollet et al. (2002) and Otto et al. (2002) determined that the NPHP4
gene contains 30 exons.
MAPPING
Mollet et al. (2002) and Otto et al. (2002) independently cloned the
NPHP4 gene from the nephronophthisis-4 critical interval on 1p36.
GENE FUNCTION
Mollet et al. (2002) demonstrated the interaction of NPHP4 with NPHP1
(607100), suggesting that these 2 proteins participate in a common
signaling pathway.
Mollet et al. (2005) demonstrated that NPHP4 localized to the primary
cilia in polarized epithelial tubular cells, particularly at the basal
bodies, and associated with alpha-tubulin (see 602529), suggesting a
common role for the nephrocystin proteins in ciliary function. However,
NPHP4 was also detected at the centrosomes of dividing cells and close
to the cortical actin cytoskeleton in polarized cells. The proteins
p130Cas (BCAR1; 602941) and PTK2B (601212) were also detected in the
NPHP4-containing complex, confirming the role of the nephrocystin
proteins in cell-cell and cell-matrix adhesion signaling events. Mollet
et al. (2005) suggested that NPHP1 and NPHP4 belong to a multifunctional
complex localized in actin- and microtubule-based structures involved in
cell-cell and cell-matrix adhesion signaling, as well as in cell
division.
By yeast 2-hybrid analysis, Roepman et al. (2005) determined that NPHP4
interacted with C2 domain-containing RPGRIP1 (605446) isoforms. Analysis
of the interaction in the presence of Ca(2+) chelators indicated that
the binding was Ca(2+) independent. NPHP1 colocalized with C2-containing
RPGRIP1 isoforms in bovine and mouse retina. Mutations in NPHP4
associated with Senior-Loken syndrome-4 (606996) and mutations in RPGRP1
associated with Leber congenital amaurosis-6 (605446) disrupted the
interaction between the 2 proteins.
Delous et al. (2009) showed that nephrocystin mRNA expression was
dramatically increased during cell polarization, and shRNA-mediated
knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed
tight junction (TJ) formation, abnormal cilia formation, and
disorganized multilumen structures when grown in a 3-dimensional
collagen matrix. Some of these phenotypes were similar to those reported
for cells depleted of the TJ proteins PALS1 (MPP5; 606958) or PAR3
(PARD3; 606745). A physical interaction between these nephrocystins and
PALS1 as well as their partners PATJ (INADL; 603199) and PAR6 (PARD6A;
607484) was demonstrated, and the proteins partially colocalized in
human renal tubules. The authors concluded that the nephrocystins play
an essential role in epithelial cell organization, suggesting a
mechanism by which the histopathologic features of nephronophthisis
might develop.
Williams et al. (2011) showed that the conserved proteins Mks1 (609883),
Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l (610937),
Cc2d2a (612013), Nphp1, and Nphp4 functioned at an early stage of
ciliogenesis in C. elegans. These 8 proteins localized to the ciliary
transition zone and established attachments between the basal body and
transition zone membrane. They also provided a docking site that
restricted vesicle fusion to vesicles containing ciliary proteins.
MOLECULAR GENETICS
- Nephronophthisis 4
In patients with juvenile nephronophthisis mapping to 1p36 (NPHP4;
606966), Mollet et al. (2002) found 5 mutations in the NPHP4 gene: 3
nonsense, 1 frameshift, and 1 missense (607215.0001-607215.0005). The
nonsense and frameshift mutations resulted in putative truncated
proteins, and the missense mutation affected a residue within a highly
conserved motif. Because of an error in the original sequencing of the
NPHP4 gene, Mollet et al. (2002) published a table with the revised
designations of the mutations.
Otto et al. (2002) demonstrated mutations in the NPHP4 gene in patients
with juvenile nephronophthisis.
- Senior-Loken Syndrome 4
Otto et al. (2002) identified 2 loss-of-function mutations in the NPHP4
gene (607215.0006-607215.0007) in patients with Senior-Loken syndrome-4
(SLSN4; 606996), demonstrating that NPHP4 and SLSN4 are allelic.
HES2
| dbSNP name | rs1054274(T,G); rs1054273(C,A); rs11364(C,T); rs141712069(C,T); rs4908889(A,G); rs113269467(T,C); rs78326109(C,G); rs61780700(A,G); rs142559010(T,C); rs190274993(C,T) |
| cytoBand name | 1p36.31 |
| EntrezGene GeneID | 54626 |
| EntrezGene Description | hes family bHLH transcription factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2746 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Loss of consciousness due to hypoglycemia;
Seizures, hypoglycemic
ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia
LABORATORY ABNORMALITIES:
Hypoglycemia, postprandial;
Hyperinsulinemia, fasting;
Elevated serum insulin-to-C-peptide ratio
MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)
MOLECULAR BASIS:
Caused by mutation in the insulin receptor gene (INSR, 147670.0037)
OMIM Title
*609970 HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 2; HES2
OMIM Description
CLONING
By searching databases using mouse Hes2 as query, Katoh and Katoh (2004)
identified human HES2. The deduced 173-amino acid protein contains an
N-terminal basic helix-loop-helix domain, followed by an orange domain,
a proline-rich domain, and a C-terminal WRPW motif. HES2 ESTs were found
in a placenta cDNA library and in several cancer cDNA libraries.
GENE STRUCTURE
Katoh and Katoh (2004) determined that the HES2 gene contains 4 exons.
MAPPING
By genomic sequence analysis, Katoh and Katoh (2004) mapped the HES2 and
HES3 (609971) genes to chromosome 1p36.31.
ENO1-AS1
| dbSNP name | rs1325920(G,A) |
| cytoBand name | 1p36.23 |
| EntrezGene GeneID | 100505975 |
| snpEff Gene Name | ENO1 |
| EntrezGene Description | ENO1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.191 |
H6PD
| dbSNP name | rs11121349(G,C); rs56119172(C,G); rs55858522(G,A); rs12126056(G,A); rs4908830(A,G); rs181808395(C,T); rs6685399(C,T); rs2268176(T,G); rs1294011(G,T); rs2268175(T,C); rs2268174(C,A); rs2268173(T,C); rs2268172(C,A); rs9435148(G,C); rs12405956(G,A); rs2268171(C,T); rs56108736(G,C); rs6658895(G,A); rs186416946(T,C); rs2239561(A,G); rs2239560(G,A); rs76637581(G,A); rs2310925(T,C); rs7524046(G,A); rs11121350(T,C); rs12032814(T,A); rs11804534(T,C); rs57823928(G,C); rs11804519(A,G); rs9434732(G,T); rs9435151(C,T); rs1294010(T,C); rs732950(G,T); rs763180(G,A); rs9435155(T,C); rs9434736(G,C); rs12083129(G,A); rs7526864(A,G); rs201697732(T,C); rs60659154(G,A); rs9435156(A,G); rs61785090(G,A); rs2268170(C,T); rs6662509(C,T); rs80265342(A,G); rs3753165(T,C); rs3753164(A,G); rs9435158(C,T); rs2268169(G,A); rs185590012(G,C); rs150901527(C,T); rs111798710(A,G); rs114466775(T,C); rs113705107(T,C); rs731183(G,C); rs6688832(G,A); rs17368528(C,T); rs9434742(T,C); rs9434743(A,G); rs17368633(G,T); rs9435159(C,T); rs1294014(C,T); rs72641816(A,T); rs72641817(C,T); rs45491397(G,T); rs1294015(T,G); rs11121354(T,G); rs12314(A,C); rs57355294(G,A); rs9434747(T,C); rs3207316(C,T); rs2071931(C,T); rs61740358(C,T); rs11121356(C,T); rs12144045(G,C); rs1138467(T,C); rs9435163(G,T); rs9435164(A,T) |
| ccdsGene name | CCDS101.1 |
| cytoBand name | 1p36.22 |
| EntrezGene GeneID | 9563 |
| EntrezGene Description | hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | H6PD:NM_001282587:exon4:c.C934T:p.R312W,H6PD:NM_004285:exon4:c.C901T:p.R301W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9852 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95479 |
| dbNSFP Uniprot ID | G6PE_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 2.846e-04,1.627e-05 |
OMIM Clinical Significance
Lab:
Renal glycosuria;
Hyperglycinuria
Inheritance:
Autosomal dominant
OMIM Title
*138090 HEXOSE-6-PHOSPHATE DEHYDROGENASE; H6PD
;;GLUCOSE DEHYDROGENASE; GDH;;
GDH/6PGL ENDOPLASMIC BIFUNCTIONAL PROTEIN;;
HEXOSE-6-PHOSPHATE DEHYDROGENASE PRECURSOR;;
GLUCOSE-6-PHOSPHATE DEHYDROGENASE, SALIVARY;;
G6PD, H FORM; G6PDH;;
GLUCOSE 1-DEHYDROGENASE
OMIM Description
DESCRIPTION
Glucose dehydrogenase (GDH), or hexose-6-phosphate dehydrogenase (H6PD;
EC 1.1.1.47), is a microsomal enzyme with a dimeric structure that
oxidizes glucose-6-phosphate, glucose, galactose-6-phosphate, and
2-deoxyglucose-6-phosphate using NAD or NADP as coenzymes (summary by
Krczal et al., 1993).
CLONING
Mason et al. (1999) isolated and sequenced a cDNA encoding human H6PD.
The deduced protein contains 791 amino acids and shares extensive
homology with cytosolic G6PD (305900). H6PD is present in most tissues,
predominantly in liver, but is not present in red cells (Beutler and
Morrison, 1967; Mason et al., 1999).
GENE STRUCTURE
Mason et al. (1999) determined that the H6PD gene spans 37 kb and
contains 5 exons, the fifth of which codes for more than half of the
89-kD protein.
MAPPING
Hameister et al. (1978) showed by somatic cell hybridization that GDH is
on chromosome 1. The locus is closely linked (theta less than 0.05) to
PGD (172200). King (1982) concluded that GDH is near the end of 1p. The
PGD:Rh distance is about 17 cM in the male and 27 cM in the female;
thus, GDH may be about 12 cM distal to PGD in the male and 19 cM distal
in the female. Carritt et al. (1982) presented evidence that GDH and
ENO1 (172430) are distal to PGD and that all 3 loci are distal to
1p36.13. They presented an updated map of 1p, revising that provided by
HGM6, the Oslo workshop.
By sequence similarity to a human genomic sequence that had been mapped
to chromosome 1p36, Mason et al. (1999) mapped the human H6PD gene to
that region.
GENE FUNCTION
H6PD is able to catalyze the first 2 reactions of an endolumenal pentose
phosphate pathway, thereby generating reduced nicotinamide adenine
dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is
distinct from the cytosolic enzyme G6PD (305900), using a separate pool
of NAD(P)+ and capable of oxidizing several phosphorylated hexoses
(summary by Hewitt et al., 2005).
MOLECULAR GENETICS
- Cortisone Reductase Deficiency 1
In cortisone reductase deficiency (604931), activation of cortisone to
cortisol does not occur, suggesting a defect in 11-beta-hydroxysteroid
dehydrogenase type 1 (HSD11B1; 600713), a primary regulator of
tissue-specific glucocorticoid bioavailability. In vivo,
11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) catalyzes the
reduction of cortisone to cortisol, whereas purified enzyme acts as a
dehydrogenase, converting cortisol to cortisone. Oxoreductase activity
can be regained via a NADPH-regeneration system involving the cytosolic
enzyme glucose-6-phosphate dehydrogenase (G6PD; 305900); however,
because the catalytic domain of 11-beta-HSD1 faces into the lumen of the
endoplasmic reticulum (ER), Draper et al. (2003) hypothesized that the
endolumenal hexose-6-phosphate dehydrogenase (H6PD) regenerates NADPH in
the ER, thereby influencing directionality of 11-beta-HSD1 activity. In
3 individuals with cortisone reductase deficiency, Draper et al. (2003)
identified intronic mutations in the HSD11B1 gene (see 600713.0001) in
combination with mutations in H6PD (138090.0001, 138090.0002) and
proposed a triallelic digenic model of inheritance.
Noting that large-scale population-based studies from 3 centers (Draper
et al., 2006; Smit et al., 2007; White, 2005) had shown that the
variants found by Draper et al. (2003) were polymorphisms rather than
disease-causing mutations, Lavery et al. (2008) restudied 4 patients
with cortisone reductase deficiency, including the 3 patients studied by
Draper et al. (2003). Lavery et al. (2008) found no mutations or
sequence variants in the HSD11B1 gene. Sequencing of the H6PD gene
revealed 4 novel and 1 previously reported mutation in homozygous or
compound heterozygous state (138090.0003-138090.0006 and 138090.0001,
respectively) in all 4 patients. Expression and activity assays
demonstrated loss of function for all 5 mutations, which were not found
in 120 control chromosomes. Lavery et al. (2008) concluded that
cortisone reductase deficiency can be explained solely by inactivation
of the H6PD gene and stated that in the earlier study by Draper et al.
(2003), these mutations in H6PD were either missed or presumed to be
silent and thus of no relevance.
- Polymorphism
By the zymogram technique, Tan and Ashton (1976) found 3 phenotypes of
G6PD of the H type in human saliva. Family and population studies
suggested that these phenotypes are the products of an autosomal locus
with 2 alleles, Sgd-1 and Sgd-2. In addition to oxidizing other
hexose-6-phosphates, H6PD uses NAD as well as NADP as a coenzyme. It is
present in the microsomes. The existence of a separate G6PD isozyme in
fetal brain was suggested by Toncheva et al. (1982), who thought it was
probably determined by an autosomal gene.
King and Cook (1981) found polymorphism by isoelectric focusing. The
frequency of 3 alleles was found to be 0.723, 0.194, and 0.083. Krczal
et al. (1993) calculated the frequencies of the 3 alleles in
southwestern Germany to be 0.70, 0.18, and 0.12. Data on gene
frequencies of allelic variants were tabulated by Roychoudhury and Nei
(1988).
- Multiple Sclerosis 4
For discussion of a possible association between variation in the H6PD
gene and multiple sclerosis, see MS4 (612596).
ANIMAL MODEL
H6pd-null mice are relatively insensitive to glucocorticoids, exhibiting
fasting hypoglycemia, increased insulin sensitivity despite elevated
circulating corticosterone, and increased basal and insulin-stimulated
glucose uptake in muscle normally enriched in type II (fast) fibers,
which have increased glycogen content. Lavery et al. (2008) found
H6pd-null mice developed severe skeletal myopathy characterized by
switching of type II to type I (slow) fibers. Affected muscles had
normal sarcomeric structure but contained large intrafibrillar
membranous vacuoles, abnormal sarcoplasmic reticulum (SR) structure, and
dysregulated expression of SR proteins involved in calcium metabolism.
There was also overexpression of genes involved in the unfolded protein
response pathway. Lavery et al. (2008) concluded that the absence of
H6PD induces myopathy by altering the SR redox state, thereby impairing
protein folding and activating the unfolded protein response pathway.
MASP2
| dbSNP name | rs1033638(A,G); rs138934492(C,T); rs72550845(A,G); rs1782455(G,A); rs1782454(T,C); rs148441597(C,G); rs112338214(T,G); rs1782457(T,A); rs12711521(C,A); rs17409276(G,A); rs114957056(C,T); rs7555145(T,C); rs7555662(A,G); rs7544377(C,G); rs7556039(A,G); rs12755574(G,A); rs11583653(G,A); rs12072993(A,G); rs181112690(A,C); rs11121684(G,A); rs6695096(C,T); rs75943109(G,A); rs11121685(A,T); rs112457053(G,A); rs111984753(G,A); rs113578695(C,T); rs57360396(G,A); rs142692059(C,T); rs12142107(C,T); rs12131963(A,G); rs12136468(G,A); rs6660417(T,A); rs72870056(G,A); rs61535446(A,G); rs72870059(G,A); rs58243167(C,G); rs61773665(G,A); rs61773666(G,A); rs12136082(A,G); rs7536030(G,A); rs7536396(G,A); rs910663(G,A); rs3765900(C,T); rs3765901(G,A); rs3819991(G,A); rs9430347(T,C); rs2273345(C,T); rs2273344(C,T); rs111646202(G,A); rs10779750(T,C); rs201551849(A,C); rs66761147(C,T); rs140239262(G,A); rs367877632(C,T) |
| ccdsGene name | CCDS123.1 |
| cytoBand name | 1p36.22 |
| EntrezGene GeneID | 10747 |
| EntrezGene Description | mannan-binding lectin serine peptidase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MASP2:NM_006610:exon11:c.G1903A:p.G635R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9544 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O00187 |
| dbNSFP Uniprot ID | MASP2_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 6.507e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Alzheimer disease;
Seizures;
Cerebral cortex with spongiform changes;
Neurofibrillary tangles;
Beta-amyloid-positive senile plaques;
Prion protein-positive senile plaques
MISCELLANEOUS:
Age of onset 43-64 years
OMIM Title
*605102 MANNAN-BINDING LECTIN SERINE PROTEASE 2; MASP2
MAP19, INCLUDED
OMIM Description
DESCRIPTION
The complement system is essential for the operation of the innate and
adaptive immune defense. In addition to the classic pathway initiated by
antigen-antibody complexes and the alternative pathway initiated by
structures on microbial surfaces, there is an antibody-independent
pathway that is initiated by binding of the mannan-binding lectin (MBL;
154545), which is structurally related to C1q (see 120550), to
carbohydrates. MBL, the plasma levels of which are genetically
determined, activates the complement pathway through mannan-binding
lectin serine proteases (MASPs), such as MASP2 (summary by Thiel et al.,
1997).
CLONING
Using affinity chromatography to purify carbohydrate-binding plasma
proteins, followed by microsequence analysis and by RT-PCR on a liver
cDNA library, Thiel et al. (1997) identified a cDNA encoding MASP2.
MASP2 was expressed as a 52-kD protein under reducing conditions. The
predicted 686-amino acid MASP2 protein shares 46 to 52% amino acid
similarity (taking into account residues of a similar nature as well as
identical residues) with C1r (613785), C1s (120580), and MASP1 (600521);
these proteins also share the same domain organization. MASP2 contains a
15-amino acid signal peptide, the 3 amino acids essential for the active
center of a serine protease, and calcium-binding residues in the
epidermal growth factor (EGF; 131530)-like domain. Unlike MASP1, MASP2
has no sites for N-linked glycosylation. Overall, MASP1 is most
homologous to C1r and MASP2 is most homologous to C1s, supporting the
notion that the MBL pathway may antedate the development of the specific
immune system of vertebrates.
By screening a liver cDNA library, Stover et al. (1999) identified a
cDNA encoding a shorter variant of MASP2, which they termed MAP19
(MBL-associated plasma protein of 19 kD). The deduced 185-amino acid
MAP19 protein retains the signal peptide, the N-terminal CUB (see CUBN,
602997) domain, and the EGF-like domain of full-length MASP2, but it has
a unique C-terminal sequence (EQSL) and lacks the serine protease
catalytic domain. Northern blot analysis revealed higher expression of
the 1.0-kb MAP19 transcript than of the 2.6-kb transcript encoding the
serine protease domain of MASP2. Immunoblot analysis indicated that
uncleaved MASP2 is expressed as a 76-kD protein, while the A chain has a
molecular mass of 52 kD and the B chain has a mass of 31 kD. Stover et
al. (1999) proposed that MAP19 has a role in modulating the activation
of complement via the MBL pathway.
By biochemical purification of a 22-kD protein associated with MASP1
preparations and peptide sequence analysis, Takahashi et al. (1999)
cloned the short variant of MASP2, which they termed sMAP (small
MBL-associated protein). Northern blot and RT-PCR analyses showed that
MASP2 is expressed in the liver and that the short variant is the major
transcript.
GENE STRUCTURE
By Southern blot analysis, Stover et al. (1999) showed that the MASP2
gene spans less than 22 kb and contains 4 exons. Only the first 2 exons
of MASP2 are used for the MAP19 variant, while full-length MASP2 skips
exon 2. Takahashi et al. (1999) confirmed that MAP19 (sMAP) uses only
exons 1 and 2.
MAPPING
By FISH, Stover et al. (1999) mapped the MASP2 gene to chromosome
1p36.3-p36.2. They confirmed this localization by radiation hybrid
analysis.
GENE FUNCTION
Functional analysis by Thiel et al. (1997) showed that MASP2 activated
C4 (see 120810), a requirement for the generation of a C3
(120700)-converting complex.
MOLECULAR GENETICS
In a patient with MASP2 deficiency (613791), Stengaard-Pedersen et al.
(2003) identified homozygosity for a mutation in exon 3 of the MASP2
gene, resulting in an asp105-to-gly (D105G; 605102.0001) substitution in
the CUB1 domain.
MIR4632
| dbSNP name | rs653667(T,G) |
| ccdsGene name | CCDS145.1 |
| cytoBand name | 1p36.22 |
| EntrezGene GeneID | 100616438 |
| snpEff Gene Name | TNFRSF1B |
| EntrezGene Description | microRNA 4632 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3136 |
| ESP Afr MAF | 0.248071 |
| ESP All MAF | 0.326849 |
| ESP Eur/Amr MAF | 0.367209 |
| ExAC AF | 0.337,3.177e-04,1.629e-05 |
MIR6730
| dbSNP name | rs2275874(C,T) |
| ccdsGene name | CCDS146.1 |
| cytoBand name | 1p36.22 |
| EntrezGene GeneID | 9249 |
| EntrezGene Symbol | DHRS3 |
| snpEff Gene Name | DHRS3 |
| EntrezGene Description | dehydrogenase/reductase (SDR family) member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3797 |
| ESP Afr MAF | 0.174762 |
| ESP All MAF | 0.418192 |
| ESP Eur/Amr MAF | 0.457093 |
| ExAC AF | 0.491 |
PRAMEF12
| dbSNP name | rs1812242(T,C); rs372043644(G,A); rs848578(T,A); rs848577(G,C) |
| ccdsGene name | CCDS41254.1 |
| cytoBand name | 1p36.21 |
| EntrezGene GeneID | 390999 |
| EntrezGene Description | PRAME family member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRAMEF12:NM_001080830:exon2:c.T470C:p.M157T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95522 |
| dbNSFP Uniprot ID | PRA12_HUMAN |
| dbNSFP KGp1 AF | 0.737637362637 |
| dbNSFP KGp1 Afr AF | 0.575203252033 |
| dbNSFP KGp1 Amr AF | 0.812154696133 |
| dbNSFP KGp1 Asn AF | 0.730769230769 |
| dbNSFP KGp1 Eur AF | 0.812664907652 |
| dbSNP GMAF | 0.2622 |
| ESP Afr MAF | 0.393327 |
| ESP All MAF | 0.263186 |
| ESP Eur/Amr MAF | 0.196512 |
| ExAC AF | 0.774 |
HNRNPCL1
| dbSNP name | rs74055698(T,C) |
| ccdsGene name | CCDS30591.1 |
| cytoBand name | 1p36.21 |
| EntrezGene GeneID | 343069 |
| EntrezGene Description | heterogeneous nuclear ribonucleoprotein C-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HNRNPCL1:NM_001013631:exon2:c.A764G:p.D255G,LOC649330:NM_001146181:exon1:c.A764G:p.D255G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O60812 |
| dbNSFP Uniprot ID | HNRCL_HUMAN |
| dbNSFP KGp1 AF | 0.311355311355 |
| dbNSFP KGp1 Afr AF | 0.400406504065 |
| dbNSFP KGp1 Amr AF | 0.290055248619 |
| dbNSFP KGp1 Asn AF | 0.344405594406 |
| dbNSFP KGp1 Eur AF | 0.238786279683 |
| dbSNP GMAF | 0.3118 |
| ExAC AF | 0.211 |
RSC1A1
| dbSNP name | rs35040685(T,C); rs3766163(T,C); rs371024607(C,T) |
| ccdsGene name | CCDS161.1 |
| cytoBand name | 1p36.21 |
| EntrezGene GeneID | 84301 |
| EntrezGene Symbol | DDI2 |
| EntrezGene Description | DNA-damage inducible 1 homolog 2 (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RSC1A1:NM_006511:exon1:c.T2C:p.M1T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.033 |
| snpEff Effect | start_lost |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP Uniprot Acc | Q92681 |
| dbNSFP Uniprot ID | RSCA1_HUMAN |
| dbNSFP KGp1 AF | 0.00686813186813 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.021788 |
| ESP All MAF | 0.007381 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002246 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Prognathism;
[Mouth];
Thick, coarse lips;
[Teeth];
Natal teeth;
Malocclusion
SKELETAL:
[Hands];
Prominent interdigital folds;
Single transverse palmar creases;
First metacarpal hypoplasia;
Brachydactyly;
Single thumb creases;
[Feet];
First metatarsal hypoplasia;
Hypoplastic distal phalanges;
Brachydactyly
SKIN, NAILS, HAIR:
[Nails];
Nail dystrophy;
[Hair];
Trichodystrophy;
Straw-like fragile hair;
Irregular diameter of hair shaft with hypopigmentation and tendency
to fracture (light microscopy)
OMIM Title
*601966 REGULATORY SOLUTE CARRIER PROTEIN, FAMILY 1, MEMBER 1; RSC1A1
;;RS1
OMIM Description
DESCRIPTION
RSC1A1 is a negative regulator of Na(+)-dependent D-glucose transport
(Lambotte et al., 1996).
CLONING
Using primers based on the pig Rs1 sequence to amplify a probe from
human small intestine RNA, followed by screening a genomic library,
Lambotte et al. (1996) cloned human RSC1A1, which they called RS1. The
deduced 617-amino acid protein has a putative C-terminal transmembrane
domain. Pig and human RS1 share 74% overall identity, with 100% identity
in the C-terminal 42 amino acids that include the transmembrane domain.
Two of the 5 potential glycosylation sites in pig Rs1 are conserved in
human RS1. Lambotte et al. (1996) stated that human RS1 is expressed in
small intestine, kidney, and brain, and that pig Rs1 is expressed at the
extracellular side of brush border membranes of renal and intestinal
epithelial cells, where it colocalizes with the glucose transporter
SGLT1 (SLC5A1; 182380). In vitro-translated human RS1 had an apparent
molecular mass of 80 kD by SDS-PAGE.
GENE FUNCTION
By coexpression in Xenopus oocytes, Lambotte et al. (1996) found that
RS1 inhibited Na(+)-dependent D-glucose transport by SGLT1. Kinetic
analysis suggested that SGLT1 and RS1 interacted directly.
GENE STRUCTURE
Lambotte et al. (1996) determined that RSC1A1 is an intronless gene. The
5-prime UTR contains 2 Alu repeats, and the 3-prime UTR contains 1. The
5-prime UTR also contains a TATA box, at least 2 potential CAAT boxes,
binding sites for several transcription factors, including SP1 (189906),
AP1 (see 165160), and AP2 (TFAP2A; 107580), and 5 glucocorticoid
response elements.
MAPPING
Using FISH, Lambotte et al. (1996) mapped the RSC1A1 gene to chromosome
1p36.1.
UQCRHL
| dbSNP name | rs66673012(A,T); rs7417535(T,C); rs61744357(C,T); rs61738972(C,T) |
| cytoBand name | 1p36.21 |
| EntrezGene GeneID | 440567 |
| snpEff Gene Name | RP11-169K16.7 |
| EntrezGene Description | ubiquinol-cytochrome c reductase hinge protein-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.141 |
| ESP Afr MAF | 0.337948 |
| ESP All MAF | 0.194141 |
| ESP Eur/Amr MAF | 0.120465 |
| ExAC AF | 0.123 |
KLHDC7A
| dbSNP name | rs34109355(G,C); rs34976233(G,A); rs35013594(C,T); rs72944731(C,T); rs2992754(C,A); rs11261022(C,A); rs2992753(C,A); rs3007718(T,A); rs2992752(A,C); rs2992745(A,T); rs12061708(G,A); rs2992740(G,T); rs6667069(G,C); rs111688839(G,C); rs1889861(G,A); rs1889862(A,C); rs35259167(G,A); rs183779288(G,A); rs3007719(T,C); rs872355(G,A); rs708088(C,T) |
| ccdsGene name | CCDS185.2 |
| CosmicCodingMuts gene | KLHDC7A |
| cytoBand name | 1p36.13 |
| EntrezGene GeneID | 127707 |
| EntrezGene Description | kelch domain containing 7A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KLHDC7A:NM_152375:exon1:c.G145C:p.G49R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0113 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5VTJ3 |
| dbNSFP Uniprot ID | KLD7A_HUMAN |
| dbNSFP KGp1 AF | 0.0975274725275 |
| dbNSFP KGp1 Afr AF | 0.0914634146341 |
| dbNSFP KGp1 Amr AF | 0.138121546961 |
| dbNSFP KGp1 Asn AF | 0.0506993006993 |
| dbNSFP KGp1 Eur AF | 0.117414248021 |
| dbSNP GMAF | 0.0978 |
| ESP Afr MAF | 0.096718 |
| ESP All MAF | 0.114029 |
| ESP Eur/Amr MAF | 0.122366 |
| ExAC AF | 0.108 |
LOC100506730
| dbSNP name | rs6691134(T,G); rs3207843(G,A); rs55920101(C,T); rs67650707(T,C) |
| cytoBand name | 1p36.13 |
| EntrezGene GeneID | 100506730 |
| snpEff Gene Name | AKR7A3 |
| EntrezGene Description | uncharacterized LOC100506730 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1368 |
RNF186
| dbSNP name | rs3820317(C,T); rs1541184(C,T); rs1541185(C,T) |
| cytoBand name | 1p36.13 |
| EntrezGene GeneID | 54546 |
| EntrezGene Description | ring finger protein 186 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.101 |
OMIM Clinical Significance
Growth:
Failure to thrive
Neuro:
Mental and motor retardation
Facies:
Facial dysmorphism
Hair:
Abnormal hair
Teeth:
Abnormal teeth
Cardiac:
Myocardiopathy
Lab:
Placental S-adenosylhomocysteine hydrolase deficiency;
Hypermethioninemia
Inheritance:
Autosomal recessive
OMIM Title
*613754 RING FINGER PROTEIN 187; RNF187
;;RING DOMAIN AP1 COACTIVATOR 1; RACO1
OMIM Description
CLONING
Using a yeast 2-hybrid screen, Davies et al. (2010) identified RNF187,
which they called RACO1, as a JUN (165160)-interacting protein. The
deduced 235-amino acid protein, which is translated from a
nonconventional CTG initiation codon, has a calculated molecular mass of
26 kD. It contains an N-terminal C4HC3 RING domain. Western blot
analysis detected RACO1 expression in human HeLa and HCT116 cells and in
rat PC12 cells. In transfected HEK293 cells, RACO1 localized
predominantly to cytoplasm, with some RACO1 localized to nuclei.
GENE FUNCTION
Using a protein pull-down assay, Davies et al. (2010) confirmed that
endogenous rat Raco1 interacted with endogenous Jun. Mutation analysis
revealed that the short C-terminal region of human RACO1 bound to JUN,
and binding did not depend on JUN phosphorylation. Coexpression of RACO1
elevated JUN-dependent activation of a reporter gene. A constitutively
active form of MEKK1 (MAP3K1; 600982) enhanced JUN coactivation by
RACO1, whereas inhibition of MEK1 (MAP2K1; 176872) and MEK2 (MAP2K2;
601263) reduced JUN coactivation by RACO1. Davies et al. (2010) found
that RACO1 was polyubiquitinated on lys195 (K195), K223, or K224 near
its C terminus via autoubiquitination or via MEK1-dependent growth
factor signaling. Autoubiquitination tended to destabilize RACO1 and
involved the addition of ubiquitins linked together by their K48
residues. In contrast, ubiquitination via MEK1 signaling stabilized
RACO1 and involved ubiquitins linked by their K63 residues.
Overexpression of RACO1 increased proliferation of mouse fibroblasts,
promoted intestinal tumorigenesis in a mouse model, and cooperated with
oncogenic Ras (HRAS; 190020) in colonic hyperproliferation.
GENE STRUCTURE
Davies et al. (2010) determined that the RNF187 gene contains 4 coding
exons.
MAPPING
Hartz (2011) mapped the RNF187 gene to chromosome 1q42.13 based on an
alignment of the RNF187 sequence (GenBank GENBANK BC012758) with the
genomic sequence (GRCh37).
CAMK2N1
| dbSNP name | rs11539080(T,G) |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 55450 |
| EntrezGene Description | calcium/calmodulin-dependent protein kinase II inhibitor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01974 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Increased birth weight;
Obesity
HEAD AND NECK:
[Head];
Acrocephaly (rare);
Trigonocephaly (rare);
Brachycephaly (rare);
[Face];
Frontal bossing (rare);
Midface retrusion;
Retrognathia (rare);
[Ears];
Low-set ears;
Increased posterior angulation;
Protruding ears (rare);
Sensorineural hearing loss, mild (rare);
[Eyes];
Hypertelorism;
Epicanthal folds;
Upslanted palpebral fissures;
Nasolacrimal duct obstruction due to ectropion of lower eyelids (rare);
High-arched eyebrows;
Sparse eyebrows (rare);
[Nose];
Depressed nasal bridge;
Wide nasal bridge;
Anteverted nares;
Narrow nares (rare);
[Mouth];
Narrow palate;
High-arched palate;
[Teeth];
Multiple dental caries;
[Neck];
Short neck;
Webbed neck (rare)
CARDIOVASCULAR:
[Heart];
Dextrocardia;
Atrial septal defect (rare);
Tricuspid valve insufficiency (rare);
[Vascular];
Transposition of great vessels (rare);
Patent ductus arteriosus
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum;
Pectus excavatum;
[Breasts];
Widely spaced nipples;
Hypoplastic nipples;
Accessory nipples;
[Diaphragm];
Eventration of diaphragm;
Elevated right hemidiaphragm
ABDOMEN:
Situs inversus totalis (rare);
[External features];
Umbilical hernia (rare);
[Liver];
Left-sided liver (rare);
Central position of liver;
[Spleen];
Right-sided spleen (rare)
GENITOURINARY:
[External genitalia, male];
Small penis (rare);
Shawl scrotum (rare);
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
[Skull];
Craniosynostosis (primarily metopic, but may also involve coronal
or sagittal sutures);
[Pelvis];
Coxa vara (rare);
[Hands];
Brachydactyly;
Syndactyly, cutaneous;
Camptodactyly;
Broad thumbs;
Radially deviated thumbs;
Absent middle phalanges;
Postaxial polydactyly (rare);
Preaxial polydactyly, partial (rare);
Clinodactyly, 5th finger (rare);
[Feet];
Brachydactyly;
Syndactyly, cutaneous;
Preaxial polydactyly;
Absent middle phalanges;
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Loose skin;
[Hair];
Sparse eyebrows
NEUROLOGIC:
[Central nervous system];
Developmental delay, variable severity
MISCELLANEOUS:
Variable features present
MOLECULAR BASIS:
Caused by mutation in the multiple epidermal growth factor-like domains-8
gene (MEGF8, 604267.0001)
OMIM Title
*614986 CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II INHIBITOR 1; CAMK2N1
;;CAMKII INHIBITORY PROTEIN, ALPHA;;
CAMKIIN-ALPHA
OMIM Description
DESCRIPTION
CAMK2N1 is an endogenous inhibitor of CAMKII (see 114078), a ubiquitous
serine/threonine protein kinase that phosphorylates nearly 40 different
proteins in response to intracellular calcium oscillations (Wang et al.,
2008).
CLONING
By searching a database for sequences similar to CAMKIIN-beta (CAMK2N2;
608721), followed by RT-PCR of bone marrow stromal cells, Wang et al.
(2008) cloned human CAMK2N1, which they called CAMKIIN-alpha. The
deduced 78-amino acid protein has a calculated molecular mass of 8.6 kD.
It has a 27-amino acid conserved inhibitory region in its C-terminal
half. PCR analysis detected variable CAMKII-alpha expression in all
human tissues examined except skeletal muscle. Highest expression was
detected in colon, small intestine, and ovary.
GENE FUNCTION
Wang et al. (2008) showed that endogenous human CAMKIIN-alpha interacted
directly with calcium-activated CAMKII and inhibited CAMKII activity.
CAMKIIN-alpha did not interact with inactive CAMKII. Wang et al. (2008)
observed an inverse correlation between expression of CAMKIIN-alpha and
severity of human colon adenocarcinomas. Overexpression of CAMKIIN-alpha
in human colon carcinoma cell lines inhibited cell growth by arresting
the cell cycle at the S phase, which correlated with phosphorylation and
accumulation of the cell cycle regulator p27 (CDKN1B; 600778).
CAMKIIN-alpha did not directly phosphorylate p27, but its inhibition of
CAMKII deactivated a MEK (see 176872)/ERK (see 176948) signaling pathway
required to inhibit p27 phosphorylation and induce proteasome-dependent
degradation of nonphosphorylated p27. Deletion analysis revealed that
the C-terminal inhibitory domain of CAMKIIN-alpha was required for all
of its cellular effects.
MAPPING
Hartz (2012) mapped the CAMK2N1 gene to chromosome 1p36.12 based on an
alignment of the CAMK2N1 sequence (GenBank GENBANK DB475389) with the
genomic sequence (GRCh37).
FAM43B
| dbSNP name | rs74058407(A,G); rs3795509(T,A) |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 163933 |
| EntrezGene Description | family with sequence similarity 43, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.225 |
EPHA8
| dbSNP name | rs209736(T,C); rs209735(C,T); rs139657800(G,A); rs209751(C,G); rs209750(C,A); rs115366026(G,A); rs209749(A,C); rs209748(A,G); rs60615053(C,T); rs56796524(C,T); rs61767285(A,G); rs137874706(C,T); rs209746(T,C); rs185704683(C,T); rs145910820(G,A); rs138469609(G,A); rs209741(T,C); rs59478017(G,A); rs115131664(C,G); rs148361941(C,T); rs150436231(C,T); rs187291359(G,A); rs761398(T,A); rs116708974(T,C); rs11580191(C,T); rs150553424(G,A); rs72875426(C,T); rs114947354(G,C); rs649754(A,C); rs72651336(C,T); rs146469008(A,G); rs74611858(A,G); rs492053(A,G); rs115328469(A,G); rs189979612(A,G); rs115487004(G,A); rs56403640(C,T); rs570220(G,A); rs116335188(G,T); rs586823(A,G); rs11581616(C,T); rs682187(T,C); rs682118(C,A); rs11582171(C,A); rs667566(A,G); rs482156(G,A); rs665395(C,G); rs567711(A,G); rs10917259(A,G); rs10917260(C,T); rs651637(A,G); rs639519(T,C); rs537426(A,G); rs147744273(A,G); rs12066127(G,A); rs10917261(G,T); rs10917262(G,A); rs624005(A,G); rs3767556(G,T); rs609125(T,C); rs606002(T,C); rs11584845(C,G); rs521570(A,T); rs10917263(G,A); rs189166920(C,T); rs10917264(C,T); rs671485(T,C); rs140375453(C,T); rs145472393(G,C); rs67275312(T,A); rs61767310(A,T); rs147513349(C,T); rs72651342(C,A); rs61767311(G,A); rs209696(C,T); rs11802802(G,A); rs61767313(C,T); rs61767314(G,A); rs11801773(A,C); rs11802120(T,C); rs209693(T,G); rs116492046(T,G); rs12071465(G,A); rs209692(G,A); rs209691(G,A); rs209690(G,A); rs1005675(C,T); rs209689(A,G); rs11585855(C,A); rs11582356(G,A); rs61767315(G,A); rs72651347(G,A); rs141239679(G,T); rs12030727(T,C); rs12404556(T,C); rs664340(C,G); rs663002(C,A); rs11805067(G,A); rs11808747(C,A); rs72651352(G,A); rs209700(A,G); rs209699(A,G); rs209698(A,G); rs209697(A,G); rs114594938(C,T) |
| ccdsGene name | CCDS225.1 |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 2046 |
| EntrezGene Description | EPH receptor A8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EPHA8:NM_020526:exon14:c.G2476A:p.V826M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7182 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000923 |
| ESP Eur/Amr MAF | 0.001279 |
| ExAC AF | 0.0006831 |
OMIM Clinical Significance
INHERITANCE:
Somatic mutation
GROWTH:
[Other];
Hemihypertrophy;
Generalized, unilateral or localized disproportionate overgrowth of
any tissue
HEAD AND NECK:
[Head];
Macrocephaly;
Hyperostoses of calvaria, facial bones, and mandible;
Dolichocephaly;
[Face];
Long face;
[Eyes];
Epibulbar dermoids;
Downslanting palpebral fissures;
Ptosis;
[Nose];
Low nasal bridge;
Wide or anteverted nostrils;
[Mouth];
Open mouth
CARDIOVASCULAR:
[Vascular];
Capillary malformations;
Venous malformations;
Lymphatic malformations;
Deep vein thrombosis
RESPIRATORY:
[Lung];
Lung cysts
ABDOMEN:
[Spleen];
Splenomegaly
SKELETAL:
[Spine];
Megaspondylodysplasia;
Kyphoscoliosis;
Spinal stenosis from angular kyphoscoliosis;
[Limbs];
Overgrown long bones;
Thin cortices
SKIN, NAILS, HAIR:
[Skin];
Cerebriform connective tissue nevus;
Lymphangioma;
Lipoma;
Lipohypoplasia;
Epidermal nevi;
Hypertrophy of skin of soles;
Depigmentation/hyperpigmentation;
Hemangiomata, especially thorax and upper abdomen;
HISTOLOGY:;
Highly collagenized connective tissue;
Acanthosis;
Hyperkeratosis;
Dermal hypoplasia
NEUROLOGIC:
[Central nervous system];
Brain malformations;
Spinal cord compression by tumor infiltration;
Mental retardation, moderate (in some patients)
NEOPLASIA:
Ovarian cystadenoma;
Parotid monomorphic adenoma
MISCELLANEOUS:
Onset in infancy;
Sporadic occurrence;
Mosaic distribution of lesions;
Progressive disorder
MOLECULAR BASIS:
Caused by somatic mutation in the V-AKT murine thymoma viral oncogene
homolog 1 gene (AKT1, 164730.0001)
OMIM Title
*176945 EPHRIN RECEPTOR EphA8; EPHA8
;;EPH- AND ELK-RELATED KINASE; EEK;;
PROTEIN TYROSINE KINASE EEK;;
HEK3
OMIM Description
CLONING
Chan and Watt (1991) identified human and rat DNAs encoding 2 novel
members of the EPH subclass of putative receptor protein-tyrosine
kinases. Rat cDNA clones encoding EEK (EPH- and ELK-related kinase) were
isolated from a brain cDNA library probed with DNA encoding the kinase
region of the insulin receptor-related receptor (INSRR; 147671). The EEK
protein was predicted to contain all the amino acid residues conserved
in the catalytic domains of protein-tyrosine kinases and was most
similar to 2 putative receptor protein-tyrosine kinases of the EPH
subclass, ELK (EPHB1; 600600) and EPH, showing 69 and 57% identity,
respectively. Human genomic DNAs, encoding part of EEK as well as
another putative protein tyrosine kinase most similar to ELK (90%) and
symbolized ERK (EPHB2; 600997) for ELK-related kinase, were isolated and
partially characterized. In Northern blot analysis of rat RNA, DNAs
encoding rat EEK and human ERK hybridized to transcripts most abundant
in brain and lung, respectively. These 2 new members of the EPH subclass
of receptor protein-tyrosine kinases, EEK and ERK, may therefore have
tissue-specific functions distinct from those of the other EPH family
members.
MAPPING
Chan and Watt (1991) mapped the EPHA8 AND EPHB1 genes to chromosome 1.
GENE FAMILY
The EPH and EPH-related receptors comprise the largest subfamily of
receptor protein-tyrosine kinases. They have been implicated in
mediating developmental events, particularly in the nervous system.
Receptors in the Eph subfamily typically have a single kinase domain and
an extracellular region containing a Cys-rich domain and 2 fibronectin
type III repeats. The ligands for Eph receptors have been named ephrins
by the Eph Nomenclature Committee (1997). Based on their structures and
sequence relationships, ephrins are divided into the ephrin-A (EFNA)
class, which are anchored to the membrane by a
glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class,
which are transmembrane proteins. The Eph family of receptors are
divided into 2 groups based on the similarity of their extracellular
domain sequences and their affinities for binding ephrin-A and ephrin-B
ligands. The Eph Nomenclature Committee (1997) proposed that Eph
receptors interacting preferentially with ephrin-A proteins be called
EphA and Eph receptors interacting preferentially with ephrin-B proteins
be called EphB.
ANIMAL MODEL
Park et al. (1997) generated mice homozygous for a mutation that
disrupts the gene encoding EPHA8, a member of the Eph family of tyrosine
proteinase receptors. EphA8 -/- mice developed to term, were fertile,
and did not display obvious anatomical or physiologic defects. The mouse
EphA8 gene is expressed primarily in a rostral to caudal gradient in the
developing tectum. Axonal tracing experiments revealed that in these
mutant mice, axons from a subpopulation of tectal neurons located in the
superficial layers of the superior colliculus did not reach targets
located in the contralateral inferior colliculus. Moreover, EphA8-null
animals displayed an aberrant ipsilateral axonal tract that projected to
the ventral region of the cervical spinal cord. Retrograde labeling
revealed that these abnormal projections originated from a small
subpopulation of superior colliculus neurons that normally express the
EPHA8 gene. Park et al. (1997) suggested that EPHA8 receptors play a
role in axonal pathfinding during development of the mammalian nervous
system.
HTR1D
| dbSNP name | rs623988(C,T); rs137884002(G,T) |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 3352 |
| EntrezGene Description | 5-hydroxytryptamine (serotonin) receptor 1D, G protein-coupled |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3485 |
OMIM Clinical Significance
Skin:
Seborrheic keratoses;
Congenital seborrheic verrucae
Inheritance:
Autosomal dominant form
OMIM Title
*182133 5-@HYDROXYTRYPTAMINE RECEPTOR 1D; HTR1D
;;SEROTONIN 5-HT-1D RECEPTOR;;
5-@HYDROXYTRYPTAMINE RECEPTOR 1D-ALPHA; HTR1DA;;
RDC4
OMIM Description
The serotonin 1D receptor was initially characterized by radioligand
binding procedures using membranes derived from bovine caudate nucleus.
The 5-HT-1D receptor is known to be a G protein-coupled receptor.
Sumatriptan, an agent effective in the treatment of acute migraine, is
the only ligand yet identified that is selective for the 5-HT-1D
receptor. Weinshank et al. (1992) reported the cloning, deduced amino
acid sequences, pharmacologic properties, and second-messenger coupling
of a pair of human 5-HT-1D receptor genes, which they designated alpha
and beta due to their strong similarities. Both genes have no introns in
their coding regions, are expressed in the human cerebral cortex, and
can couple to inhibition of adenylate cyclase activity. Their
pharmacologic binding properties match closely those of human, bovine,
and guinea pig 5-HT-1D sites. Libert et al. (1991) obtained cDNA clones
encoding 4 receptors of the G protein-coupled receptor family by
selective amplification and cloning from thyroid cDNA. One of these
clones, termed RDC4 by them, showed close structural similarity with the
serotonin 5HT1A receptor (109760). By in situ hybridization, they
demonstrated that the gene (HTR1D) is located on chromosome 1 at
1p36.3-p34.3. By Southern blot analysis of a hybrid cell panel, Jin et
al. (1992) showed that the HTR1D gene is located on chromosome 1. Wilkie
et al. (1993) showed that the homologous gene in the mouse is located on
chromosome 4.
LOC100996511
| dbSNP name | rs658636(A,G); rs12096254(C,T); rs148647119(A,G); rs181424467(G,A); rs672904(C,T); rs594228(T,A); rs143637197(T,A) |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 100996511 |
| EntrezGene Description | uncharacterized LOC100996511 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06657 |
C1orf213
| dbSNP name | rs638722(T,C); rs754984(C,G) |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 148898 |
| EntrezGene Description | chromosome 1 open reading frame 213 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2553 |
| ESP Afr MAF | 0.295809 |
| ESP All MAF | 0.215836 |
| ESP Eur/Amr MAF | 0.179368 |
| ExAC AF | 0.205 |
E2F2
| dbSNP name | rs12026768(G,T); rs111903743(T,A); rs12027599(G,A); rs3820028(G,A); rs147131506(C,T); rs3218211(A,G); rs2075993(A,G); rs3218205(T,C); rs3218203(C,G); rs147537360(G,A); rs2282720(A,G); rs2811972(T,C); rs3218192(G,T); rs3218186(G,T); rs114788023(C,T); rs2075994(C,T); rs3218181(C,T); rs2811974(C,G); rs3218177(G,A); rs3218175(C,T); rs3218173(A,C); rs12041537(C,T); rs144666986(C,T); rs3218172(G,T); rs2075995(C,A); rs116694174(G,A); rs2075996(C,G); rs2038026(T,C); rs2038027(A,G); rs2282724(C,T); rs2236853(C,A) |
| ccdsGene name | CCDS236.1 |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 1870 |
| EntrezGene Description | E2F transcription factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | E2F2:NM_004091:exon4:c.C605T:p.T202I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6601 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14209 |
| dbNSFP Uniprot ID | E2F2_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.00346 |
| ESP Eur/Amr MAF | 0.004535 |
| ExAC AF | 0.002919 |
OMIM Clinical Significance
Skin:
Angiokeratoma corporis diffusum
Vascular:
Arteriovenous fistulas
Limbs:
Asymmetric hypertrophy and hyperhidrosis of a leg
Misc:
Onset in infancy and early adulthood;
No systemic symptoms
Radiology:
Arteriographic demonstration of multiple arteriovenous fistulas
Inheritance:
Autosomal dominant
OMIM Title
*600426 E2F TRANSCRIPTION FACTOR 2; E2F2
OMIM Description
See E2F1 (189971).
CLONING
Ivey-Hoyle et al. (1993) cloned a cDNA from a HeLa cell library using a
probe containing the DNA-binding domain of E2F1. The cDNA, designated
E2F2, has overall amino acid sequence similarity to E2F1 of 46%. The
same cDNA and corresponding genomic region was cloned by Lees et al.
(1993). Lees et al. (1993) also showed that expressed E2F2 bound to both
the E2F DNA recognition sites and to the RB1 protein (614041).
GENE FUNCTION
MYC (190080) induces transcription of the E2F1, E2F2, and E2F3 (600427)
genes. Using primary mouse embryo fibroblasts deleted for individual E2f
genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis
requires distinct E2F activities. The ability of Myc to induce S phase
was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4
(600659). In contrast, the ability of Myc to induce apoptosis was
markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The
authors proposed that the induction of specific E2F activities is an
essential component in the MYC pathways that control cell proliferation
and cell fate decisions.
The retinoblastoma tumor suppressor (Rb) pathway is believed to have a
critical role in the control of cellular proliferation by regulating E2F
activities. E2F1, E2F2, and E2F3 belong to a subclass of E2F factors
thought to act as transcriptional activators important for progression
through the G1/S transition. Wu et al. (2001) used a conditional gene
targeting approach to demonstrate that combined loss of these 3 E2F
factors severely affects E2F target expression and completely abolishes
the ability of mouse embryonic fibroblasts to enter S phase, progress
through mitosis, and proliferate. Loss of E2F function results in
elevation of CIP1 (116899) protein, leading to a decrease in
cyclin-dependent kinase activity and Rb phosphorylation. Wu et al.
(2001) concluded that these findings suggested a function for this
subclass of E2F transcriptional activators in a positive feedback loop,
through downmodulation of CIP1, that leads to the inactivation of
Rb-dependent repression and S phase entry. By targeting the entire
subclass of E2F transcriptional activators, Wu et al. (2001) provided
direct genetic evidence for their essential role in cell cycle
progression, proliferation, and development. Wu et al. (2001) initially
generated and interbred E2f1, E2f2, and E2f3 mutant mice, and found that
although mice null for E2f1 and E2f2 were viable and developed to
adulthood, mice null for E2f1 and E2f3 or E2f2 and E2f3 died early
during embryonic development, at or just before embryonic day 9.5,
pointing to a central role for E2F3 in mouse development.
Funke-Kaiser et al. (2003) identified 5 polymorphisms in the ECE1 gene
(600423), a candidate for human blood pressure regulation, among a
cohort of 704 European hypertensive patients. Electrophoretic mobility
shift assays revealed the specific binding of E2F2 to ECE1b promoter
sequences containing either allele of the C-338A polymorphism
(600423.0002), with the -338A allele being associated with an increased
affinity to E2F2 compared with -338C. The authors proposed a link
between the cell cycle-associated E2F family and blood pressure
regulation via a component of the endothelin system.
To address the function of E2F1, E2F2, and E2F3 in normal mammalian
cells in vivo, Chen et al. (2009) focused on the mouse retina, which is
a relatively simple central nervous system component that can be
manipulated genetically without compromising viability and has provided
considerable insight into development and cancer. The authors showed
that unlike fibroblasts, E2f1-, E2f2-, and E2f3-null retinal progenitor
cells or activated Muller glia can divide. Chen et al. (2009) attributed
this effect to functional interchangeability with Mycn (164840).
However, loss of activating E2fs caused downregulation of the p53
(191170) deacetylase Sirt1 (604479), p53 hyperacetylation, and elevated
apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo.
Chen et al. (2009) concluded that activating E2fs are not universally
required for normal mammalian cell division, but have an unexpected
prosurvival role in development.
Using a panel of tissue-specific cre-transgenic mice and conditional E2f
alleles, Chong et al. (2009) examined the effects of E2f1, E2f2, and
E2f3 triple deficiency in murine embryonic stem cells, embryos, and
small intestines. They showed that in normal dividing progenitor cells,
E2f1-3 function as transcriptional activators, but are dispensable for
cell division and instead are necessary for cell survival. In
differentiating cells E2f1-3 function in a complex with Rb (614041) as
repressors to silence E2f targets and facilitate exit from the cell
cycle. The inactivation of Rb in differentiating cells resulted in a
switch of E2f1-3 from repressors to activators, leading to the
superactivation of E2f-responsive targets and ectopic cell divisions.
Loss of E2f1-3 completely suppressed these phenotypes caused by Rb
deficiency. Chong et al. (2009) concluded that their work contextualizes
the activator versus repressor functions of E2f1-3 in vivo, revealing
distinct roles in dividing versus differentiating cells and in normal
versus cancer-like cell cycles.
MAPPING
Lees et al. (1993) mapped the E2F2 gene to 1p36 by fluorescence in situ
hybridization.
ANIMAL MODEL
Iglesias et al. (2004) generated mice deficient in both E2f1 (189971)
and E2f2. The mice developed nonautoimmune insulin-deficient diabetes
and exocrine pancreatic dysfunction characterized by endocrine and
exocrine cell dysplasia and a reduction in the number and size of acini
and islets, which were replaced by ductal structures and adipose tissue.
Mutant pancreatic cells exhibited increased rates of DNA replication but
also of apoptosis, resulting in severe pancreatic atrophy. The
expression of genes involved in DNA replication and cell cycle control
was upregulated in the E2f1/E2f2 compound mutant pancreas. Iglesias et
al. (2004) suggested that E2F1/E2F2 activity negatively controls growth
of mature pancreatic cells and is necessary for the maintenance of
differentiated pancreatic phenotypes in the adult.
ID3
| dbSNP name | rs1050096(G,A); rs2920(T,C); rs2067054(C,G); rs11574(T,C); rs2067053(T,C); rs61749352(C,G); rs142720912(C,G) |
| ccdsGene name | CCDS237.1 |
| cytoBand name | 1p36.12 |
| EntrezGene GeneID | 3399 |
| EntrezGene Description | inhibitor of DNA binding 3, dominant negative helix-loop-helix protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ID3:NM_002167:exon1:c.G256C:p.E86Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8474 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q02535 |
| dbNSFP Uniprot ID | ID3_HUMAN |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.023604 |
| ESP All MAF | 0.00815 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 2.740e-03,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Frontal lobe dementia;
Language impairment;
Word-finding difficulties;
Decrease in abstract thinking;
Motor symptoms may be present;
Parkinsonism;
Amyotrophic lateral sclerosis;
Cortical and subcortical neuronal loss in the frontal and temporal
regions;
Tau-positive inclusions may be found;
Ubiquitin-positive inclusions;
Primitive reflexes (palmomental, snout, glabellar);
[Behavioral/psychiatric manifestations];
Personality changes;
Lack of motivation;
Inappropriate laughter;
Apathy;
Irritability;
Disinhibition;
Kluver-Bucy syndrome;
Inappropriate sexual behavior;
Hyperphagia;
Hyperoralia
MISCELLANEOUS:
Mean age at onset 45 years;
Highly variable phenotype that includes several subtypes (see, e.g.,
607485, 601104);
Genetic heterogeneity (see, e.g., 600795, 105550);
Most cases do not have mutations in the MAPT gene, but map to chromosome
17q
MOLECULAR BASIS:
Caused by mutation in the microtubule-associated tau protein gene
(MAPT, 157140.0001);
Caused by mutation in the presenilin-1 gene (PSEN1, 104311.0023)
OMIM Title
*600277 INHIBITOR OF DNA BINDING 3; ID3
;;HEIR1
OMIM Description
DESCRIPTION
Members of the ID family of helix-loop-helix (HLH) proteins lack a basic
DNA-binding domain and inhibit transcription through formation of
nonfunctional dimers that are incapable of binding to DNA.
CLONING
Ellmeier et al. (1992) isolated a novel human gene encoding a
helix-loop-helix protein by molecular cloning of chromosome
1p36-specific CpG islands. Initially termed HEIR1, the ID3 gene was
localized to the neuroblastoma consensus deletion region, 1p36.2-p36.12.
Its predicted protein was 95.8% identical to the mouse HLH462 protein
and had clear homology to the mouse Id and Drosophila emc proteins. The
gene was expressed at high abundance in adult lung, kidney, and adrenal
medulla, but not in adult brain. Despite prominent HEIR1 expression in
adrenal medulla, which is a prime target for neuroblastomas, 10 of 12
neuroblastoma-derived cell lines showed very low levels of HEIR1 mRNA.
Low HEIR1 expression was generally found in tumor cell lines with NMYC
(164840) overexpression, whereas the 2 cell lines displaying high HEIR1
levels did not overexpress NMYC. Mutually exclusive expression of the 2
genes was also found by in situ hybridization in developing mouse
tissues, particularly in the forebrain neuroectoderm. Ellmeier et al.
(1992) concluded that HEIR1 expression is reduced specifically in the
majority of neuroblastomas and suggested an inverse correlation between
HEIR1 and NMYC expression in these tumors and in embryonic development.
GENE FUNCTION
ID3 is an inhibitor of E proteins, such as E2A (147141). By Northern and
Western blot analysis, Kee et al. (2001) showed that transforming growth
factor-beta (190180) in mouse rapidly induced transient Id3 expression
in B-lymphocyte precursors. This induction involved activation of the
SMAD (see 602932) transcription factor pathway.
Kaplan et al. (2005) demonstrated that bone marrow-derived hematopoietic
progenitor cells that express VEGFR1 (605070) home to tumor-specific
premetastatic sites and form cellular clusters before the arrival of
tumor cells. Preventing VEGFR1 function using antibodies or by the
removal of VEGFR1-positive cells from the bone marrow of wildtype mice
abrogated the formation of these premetastatic clusters and prevented
tumor metastasis, whereas reconstitution with selected Id3-competent
VEGFR1-positive cells established cluster formation and tumor metastasis
in Id3 knockout mice. Kaplan et al. (2005) also showed that
VEGFR1-positive cells express VLA4, also known as integrin
alpha-4-beta-1 (see 192975), and that tumor-specific growth factors
upregulate fibronectin (135600), a VLA4 ligand, in resident fibroblasts,
providing a permissive niche for incoming tumor cells. Conditioned media
obtained from distinct tumor types with unique patterns of metastatic
spread redirected fibronectin expression and cluster formation, thereby
transforming the metastatic profile. Kaplan et al. (2005) concluded that
their findings demonstrated a requirement for VEGFR1-positive
hematopoietic progenitors in the regulation of metastasis, and suggest
that expression patterns of fibronectin and
VEGFR1-positive-VLA4-positive clusters dictate organ-specific tumor
spread.
GENE STRUCTURE
Deed et al. (1994) reported a comparison of the ID3 gene with ID1
(600349) and ID2 (600386) that showed a highly conserved protein-coding
gene organization consistent with evolution from a common ancestral
gene.
Yeh and Lim (2000) determined that both the human and mouse genes
contain 3 exons spanning about 1.5 kb.
MAPPING
By using a YAC clone of ID3 for fluorescence in situ hybridization, Deed
et al. (1994) mapped the ID3 gene to 1p36.1.
White et al. (1995) excluded ID3 as a candidate for the neuroblastoma
suppressor gene because it lies outside the loss of heterozygosity
region revealed by neuroblastoma studies (see 256700).
MOLECULAR GENETICS
Using whole-genome, whole-exome, and transcriptome sequencing of 4
prototypical Burkitt lymphomas (113970) with immunoglobulin gene (IG;
see 147220)-MYC translocation (190080), Richter et al. (2012) identified
7 recurrently mutated genes. One of these genes, ID3, mapped to a region
of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36
of 53 molecularly defined Burkitt lymphomas (68%) carried potentially
damaging mutations of ID3. These were strongly enriched at somatic
hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the
IG-MYC translocation (13%) carried ID3 mutations. Richter et al. (2012)
concluded that their findings suggested that cooperation between ID3
inactivation and IG-MYC translocation is a hallmark of Burkitt
lymphomagenesis.
Love et al. (2012) described the first completely sequenced genome from
a Burkitt lymphoma tumor and germline DNA from the same affected
individual, and further sequenced the exomes of 59 Burkitt lymphoma
tumors and compared them to sequenced exomes from 94 diffuse large
B-cell lymphoma tumors. Love et al. (2012) identified 70 genes that were
recurrently mutated in Burkitt lymphomas, including ID3, GNA13 (604406),
RET (164761), PIK3R1 (171833), and the SWI/SNF genes ARID1A (603024) and
SMARCA4 (603254). Love et al. (2012) stated that their data implicate a
number of genes in cancer for the first time, including CCT6B (610730),
SALL3 (605079), FTCD (606806), and PC (608786). ID3 mutations occurred
in 34% of Burkitt lymphomas and not in diffuse large B-cell lymphomas
(DLBCLs). Love et al. (2012) showed experimentally that ID3 mutations
promote cell cycle progression and proliferation.
ANIMAL MODEL
Id proteins may control cell differentiation by interfering with DNA
binding of transcription factors. Lyden et al. (1999) demonstrated that
the targeted disruption of Id1 (600349) and Id3 in mice results in
premature withdrawal of neuroblasts in the cell cycle and expression of
neural-specific differentiation markers. Lyden et al. (1999) crossed Id1
+/- and Id3 +/- mice. Offspring lacking 1 to 3 Id alleles in any
combination were indistinguishable from wildtype, but no animals lacking
all 4 Id alleles were born. The Id1-Id3 double knockout mice displayed
vascular malformations in forebrain and absence of branching and
sprouting of blood vessels in the neuroectoderm. As angiogenesis both in
the brain and in tumors requires invasion of avascular tissue by
endothelial cells, Lyden et al. (1999) examined Id knockout mice for
their ability to support the growth of tumor xenografts. Three different
tumors failed to grow and/or metastasize in Id1 +/- Id3 -/- mice, and
any tumor growth present showed poor vascularization and extensive
necrosis. Lyden et al. (1999) concluded that Id genes are required to
maintain the timing of neuronal differentiation in the embryo and
invasiveness of the vasculature. Because the Id genes are expressed at
very low levels in adults, they make attractive targets for
antiangiogenic drug design. Lyden et al. (1999) also concluded that the
premature neuronal differentiation in Id1-Id3 double knockout mice
indicates that ID1 or ID3 is required to block the precisely timed
expression and activation of positively acting bHLH proteins during
murine development.
Pan et al. (1999) found that Id3-deficient mice had no overt
abnormalities but had compromised humoral immunity. After immunization
with T cell-dependent or T cell-independent antigens, the responses of
Id3-deficient mice were attenuated and severely impaired, respectively.
T-cell proliferative responses appeared to be intact, but IFNG
expression may have been impaired. The defect in B-cell proliferation
could be rescued by ectopic expression of Id1.
In the developing heart, Id1, Id2 (600386), and Id3 are detected in the
endocardial cushion mesenchyme from embryonic days 10.5 through 16.5,
but Id4 (600581) is absent. Fraidenraich et al. (2004) showed that Id1
to Id3 are also expressed in the epicardium and endocardium but are
absent in the myocardium. Id1 to Id3 expression becomes confined in the
leaflets of the cardiac valves as the atrioventricular endocardial
cushion tissue myocardializes. Id1 and Id3 expression persists in the
cardiac valves, endocardium, endothelium, and epicardium at postnatal
day 7. Fraidenraich et al. (2004) found that double and triple Id
knockout embryos displayed severe cardiac defects and died at
midgestation. Embryo size was reduced by 10 to 30%. Knockout embryos
displayed ventricular septal defects associated with impaired
ventricular trabeculation and thinning of the compact myocardium.
Trabeculae had disorganized sheets of myocytes surrounded by
discontinuous endocardial cell lining. Cell proliferation in the
myocardial wall was defective. Fraidenraich et al. (2004) showed that
midgestation lethality of embryos was rescued by the injection of 15
wildtype embryonic stem (ES) cells into mutant blastocysts. Myocardial
markers altered in Id mutant cells were restored to normal throughout
the chimeric myocardium. Intraperitoneal injection of ES cells into
female mice before conception also partially rescued the cardiac
phenotype with no incorporation of ES cells. Insulin-like growth
factor-1 (IGF1; 147440), a long-range secreted factor, in combination
with Wnt5a (164975), a locally secreted factor, were thought likely to
account for complete reversion of the cardiac phenotype. Fraidenraich et
al. (2004) concluded that ES cells have the potential to reverse
congenital defects through Id-dependent local and long-range effects in
a mammalian embryo.
Li et al. (2004) observed that Id3 -/- mice had difficulty maintaining
fully opened eyelids beginning at 6 months and progressing with age.
Histologic and electron microscopic analysis of mutant mice revealed
lymphocytic infiltration in the lachrymal and salivary glands in the
absence of infection, and the CD4 (186940) and CD8 (see 186910) T cells
and B cells in the infiltrates expressed both Ifng (147570) and Il4
(147780). Id3 -/- mice showed reduced tear and saliva secretion,
suggesting a disease similar to Sjogren syndrome (270150). ELISA
analysis detected both anti-SSA (SSA1; 109092) and anti-SSB (109090)
autoantibodies in Id3 -/- mice after 1 year of age. Bone marrow
transplant experiments showed that the phenotype was mediated by
hemopoietic cells, and adoptive transfer analysis attributed a dominant
role to Id3 -/- T lymphocytes. Elimination of T cells and neonatal
thymectomy demonstrated that the tear and saliva secretion defect
required sustained production of thymic T cells. Li et al. (2004)
concluded that ID3-mediated T-cell development is connected to
autoimmune disease, and they proposed that the Id3 -/- mouse is a model
for primary Sjogren syndrome.
By selective deletion of both Id2 and Id3 at the pre-T-cell receptor
(TCR) and gamma/delta TCR checkpoints in mice, Li et al. (2013) observed
a partial block at the pre-TCR checkpoint as well as increased
production of innate gamma/delta T cells. In addition, the double
deletion resulted in a dramatic increase in invariant NKT (iNKT) cells.
Li et al. (2013) proposed that there are opposing roles for ID genes in
regulating the alpha/beta and innate gamma/delta lineages. They
concluded that there is a dosage-dependent mechanism for ID genes in
repressing the fate of innate-like gamma/delta T cells versus iNKT cells
during T-cell development.
LOC644961
| dbSNP name | rs57922300(A,G); rs80088173(A,G); rs79070316(A,G); rs55663650(G,A) |
| ccdsGene name | CCDS297.2 |
| cytoBand name | 1p36.11 |
| EntrezGene GeneID | 644961 |
| snpEff Gene Name | TMEM222 |
| EntrezGene Description | actin, gamma 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1166 |
ATPIF1
| dbSNP name | rs2232720(G,T); rs6686978(G,A); rs8559(A,G); rs9508(A,G); rs115245379(G,T) |
| ccdsGene name | CCDS319.1 |
| cytoBand name | 1p35.3 |
| EntrezGene GeneID | 93974 |
| EntrezGene Description | ATPase inhibitory factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| dbNSFP LR score | 0.0713 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0178571428571 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0422163588391 |
| dbSNP GMAF | 0.01791 |
| ESP Afr MAF | 0.006358 |
| ESP All MAF | 0.021766 |
| ESP Eur/Amr MAF | 0.029658 |
| ExAC AF | 0.023 |
COL16A1
| dbSNP name | rs1061392(C,A); rs114540619(G,A); rs3817398(T,C); rs16834643(T,C); rs142404474(G,A); rs945215(T,C); rs7545321(A,G); rs16834646(G,C); rs56074668(T,C); rs60364385(C,T); rs16834652(A,G); rs60694879(G,A); rs16834658(A,C); rs10914462(A,G); rs11807560(C,T); rs41263967(C,T); rs72887309(G,C); rs2271928(G,A); rs1568396(C,G); rs12032291(A,G); rs185012160(C,T); rs76756188(G,T); rs1356803(C,G); rs10914463(C,T); rs10914464(G,A); rs57844188(G,A); rs16834664(G,A); rs2292988(C,T); rs2271929(C,G); rs72887317(T,C); rs7512805(C,T); rs147635174(C,G); rs6425778(T,A); rs7525091(A,G); rs7537646(G,A); rs2292989(A,G); rs1474182(G,A); rs78958534(G,A); rs72887321(A,G); rs35986497(G,A); rs909002(C,T); rs4949456(G,A); rs4949457(C,T); rs10798883(C,T); rs2292993(C,T); rs1123948(C,T); rs6425779(T,C); rs7540151(G,C); rs4949458(T,G); rs4949459(G,T); rs4949460(G,A); rs1568397(A,G); rs4949461(C,T); rs11590964(C,T); rs2297684(C,T); rs4949462(A,G); rs10737358(A,G); rs78189411(C,G); rs375798080(A,C); rs72887330(A,G); rs4568876(C,T); rs182398334(A,G); rs113905439(C,T); rs376511262(G,A); rs2297682(T,C); rs75020493(G,A); rs11589051(G,A); rs11589456(G,A); rs6425780(G,T); rs2297681(G,A); rs10914467(G,A); rs10798884(A,T); rs2297676(T,C); rs116200113(G,A); rs3818788(T,C); rs117922701(C,T); rs74063964(C,T); rs2275097(A,C); rs6656079(A,G); rs372561142(A,C); rs2297674(G,C); rs2228550(T,G); rs112748338(A,G); rs79699360(A,G); rs6657383(C,T); rs6681149(G,A); rs76019639(C,T); rs2228552(G,T); rs113045963(T,A); rs1815465(G,C); rs112942121(G,A); rs7536928(T,C); rs56232102(T,C); rs909000(C,T); rs10493049(A,G); rs16834691(C,T); rs72887344(C,T) |
| ccdsGene name | CCDS41297.1 |
| cytoBand name | 1p35.2 |
| EntrezGene GeneID | 1307 |
| EntrezGene Description | collagen, type XVI, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL16A1:NM_001856:exon46:c.C3016T:p.R1006W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6748 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q07092 |
| dbNSFP Uniprot ID | COGA1_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.007466 |
| ESP All MAF | 0.002511 |
| ESP Eur/Amr MAF | 0.00012 |
| ExAC AF | 0.0008328 |
OMIM Clinical Significance
Eyes:
Agenesis of macula;
Coloboma of macula
Inheritance:
Autosomal dominant
OMIM Title
*120326 COLLAGEN, TYPE XVI, ALPHA-1; COL16A1
OMIM Description
CLONING
Pan et al. (1992) cloned the gene for a new form of collagen with
features resembling those of members of the FACIT (fibril-associated
collagens with interrupted triple helices) group. Northern blot analyses
showed hybridization of the cDNA to a 5.5-kb mRNA in human fibroblasts
and keratinocytes.
By microarray analysis, Jun et al. (2001) demonstrated expression of the
COL16A1 gene in human donor corneas.
MAPPING
By in situ hybridization, Pan et al. (1992) localized the gene to
1p35-p34. They designated the collagen chain encoded by the cDNA the
alpha-1 chain of type XVI collagen. Yamaguchi et al. (1992) also cloned
and partially characterized the COL16A1 gene. Furthermore, they also
assigned the gene to chromosome 1 and regionalized it to 1p34-p13 by
examination of somatic cell hybrids containing spontaneous breaks or
translocations. Combined with the in situ hybridization data, the
findings suggested that the COL16A1 gene lies in the 1p34 band.
GENE FAMILY
The collagens fall into 2 major classes: the fibril-forming collagens
and the nonfibril-forming collagens. A long central triple-helical
domain, without gly-Xaa-Xaa interruptions, is the hallmark of the former
class; collagens type I, II, III, V, and XI, which form highly organized
fibrils in a quarter-staggered fashion, are members of this class. The
remaining collagens belong to the latter class with a common feature
being the presence of imperfections in the gly-Xaa-Xaa repeating
pattern. Within the latter class, collagens type IX, XII, and XIV form a
subgroup called the FACIT collagens (for 'fibril-associated collagens
with interrupted triple helices'). These collagens are associated with
type I or II collagen fibrils and play a role in interaction of these
fibrils with other matrix components (summary by Pan et al., 1992).
IQCC
| dbSNP name | rs3903683(T,G); rs41302746(G,C) |
| ccdsGene name | CCDS355.1 |
| cytoBand name | 1p35.1 |
| EntrezGene GeneID | 55721 |
| EntrezGene Description | IQ motif containing C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IQCC:NM_018134:exon5:c.T626G:p.F209C,IQCC:NM_001160042:exon5:c.T866G:p.F289C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F5H7T8 |
| dbNSFP KGp1 AF | 0.173534798535 |
| dbNSFP KGp1 Afr AF | 0.308943089431 |
| dbNSFP KGp1 Amr AF | 0.151933701657 |
| dbNSFP KGp1 Asn AF | 0.222027972028 |
| dbNSFP KGp1 Eur AF | 0.0593667546174 |
| dbSNP GMAF | 0.1736 |
| ESP Afr MAF | 0.291648 |
| ESP All MAF | 0.141858 |
| ESP Eur/Amr MAF | 0.065116 |
| ExAC AF | 0.126 |
TSSK3
| dbSNP name | rs61746387(C,T); rs35508255(A,G) |
| ccdsGene name | CCDS362.1 |
| CosmicCodingMuts gene | TSSK3 |
| cytoBand name | 1p35.1 |
| EntrezGene GeneID | 81629 |
| EntrezGene Description | testis-specific serine kinase 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TSSK3:NM_052841:exon2:c.C183T:p.I61I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01423 |
| ESP Afr MAF | 0.044258 |
| ESP All MAF | 0.014993 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.003871 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
CARDIOVASCULAR:
[Heart];
Normal
SKIN, NAILS, HAIR:
[Skin];
Fragility with blistering (neonatal onset);
Palmoplantar keratosis with erythema and scale;
Hyperkeratotic plaques on trunk and limbs;
HISTOLOGY:;
Peripheral and cytoplasmic desmoplakin staining (immunohistochemistry)
ELECTRON MICROSCOPY:;
Acantholysis throughout all layers of the skin;
Focal detachment of desmosomes into the intercellular spaces;
Perinuclear condensation of the suprabasal keratin intermediate filament
network;
[Nails];
Nail dystrophy;
[Hair];
Alopecia;
Woolly hair;
Sparse eyelashes;
Sparse eyebrows
MOLECULAR BASIS:
Caused by mutations in the desmoplakin gene (DSP, 125647.0004)
OMIM Title
*607660 TESTIS-SPECIFIC SERINE/THREONINE KINASE 3; TSSK3
;;SERINE/THREONINE PROTEIN KINASE 22C; STK22C;;
STK22D, MOUSE, HOMOLOG OF; STK22D
OMIM Description
CLONING
Using degenerate primers corresponding to 2 highly conserved protein
kinase motifs, Visconti et al. (2001) cloned mouse Stk22d by PCR. Using
this sequence as query, they identified an EST containing the human
homolog of Stk22d, STK22C, and they obtained the full-length cDNA by
3-prime and 5-prime RACE of a testis cDNA library. The mouse and human
proteins contain 268 amino acids and share 100% amino acid homology.
Northern blot analysis of 8 human tissues detected transcripts of 1.0
and 1.35 kb only in testis. Transcription of Stk22d in mouse testis
began 20 to 24 days after birth. In adult mouse testis, expression was
detected in round and condensing spermatids, but not in meiotic
pachytene spermatocytes.
MAPPING
By FISH, Visconti et al. (2001) mapped the STK22C gene to chromosome
1p35-p34. They mapped its mouse homolog, Stk22d, to chromosome 4E1 in a
region showing homology of synteny to human 1p35-p34.
MACF1
| dbSNP name | rs260972(C,T); rs72922966(A,G); rs260971(A,G); rs7546735(T,C); rs148019323(C,G); rs260970(G,A); rs59102092(A,C); rs260969(C,T); rs72922968(A,G); rs260968(A,G); rs72634502(C,T); rs77826036(T,C); rs260967(G,A); rs61780338(A,G); rs260966(T,C); rs147860177(T,G); rs260965(C,T); rs11205632(G,A); rs71642673(C,T); rs74714233(T,C); rs142004212(C,T); rs61066920(C,T); rs116057917(C,T); rs4660401(G,A); rs260964(T,C); rs59732233(G,A); rs12118033(G,A); rs139618353(C,T); rs56047998(A,G); rs260963(C,G); rs183910453(C,T); rs185470(G,A); rs687241(T,C); rs433065(G,A); rs72637903(G,A); rs112566467(C,T); rs11578150(T,C); rs11578277(T,A); rs56370363(G,A); rs113550032(G,A); rs80228263(T,C); rs260975(C,T); rs113603865(C,T); rs11581796(C,T); rs59244280(G,T); rs12117367(A,G); rs169010(T,C); rs141752713(C,T); rs365731(G,A); rs391138(G,A); rs434997(G,T); rs6667815(A,G); rs2282232(T,C); rs2282231(C,T); rs7535185(A,G); rs72660086(T,G); rs4660412(T,C); rs74069434(A,G); rs2036465(A,C); rs11580911(G,A); rs67637163(T,G); rs10788919(G,C); rs12126829(G,C); rs11205649(T,C); rs6691610(G,A); rs77756090(T,A); rs12124345(A,T); rs12407679(C,T); rs4660165(A,G); rs55693866(C,T); rs4660416(A,G); rs12137496(C,G); rs143527886(A,G); rs59274447(C,T); rs12128581(A,G); rs7550056(T,C); rs11205653(T,G); rs74069438(C,A); rs11580989(T,C); rs11205656(G,A); rs61386843(A,G); rs6684217(C,T); rs112205225(A,C); rs7555609(T,C); rs7543939(C,T); rs7520721(G,A); rs1967206(T,C); rs7544405(C,G); rs74069442(A,T); rs1472662(G,T); rs1021829(G,A); rs7550725(C,T); rs4660443(C,T); rs74393525(C,G); rs74702524(G,A); rs77927186(G,A); rs10788925(C,T); rs6600287(T,C); rs12075280(G,A); rs6600288(C,G); rs967529(A,G); rs967530(T,A); rs4660444(A,G); rs190170724(C,T); rs12354320(C,T); rs12354321(C,T); rs472310(C,T); rs472998(C,T); rs6661080(A,G); rs622988(C,G); rs79568645(A,G); rs67916282(T,A); rs2134472(T,G); rs111520806(T,A); rs77789426(G,A); rs12081736(A,G); rs533247(T,A); rs59983493(G,A); rs681019(C,G); rs11205684(A,G); rs4660475(A,G); rs590214(A,G); rs66848709(T,C); rs794636(C,T); rs12063189(C,G); rs6600289(C,T); rs646546(T,C); rs67452844(A,G); rs67062906(C,G); rs80343439(G,A); rs6679564(A,G); rs55734934(T,A); rs67408364(A,G); rs626520(C,A); rs11205695(A,C); rs624657(T,A); rs75778681(A,G); rs11205696(C,T); rs4660495(T,C); rs80297879(A,T); rs67758468(A,G); rs6600290(G,A); rs611412(C,G); rs10888682(A,T); rs10888683(A,T); rs660882(C,T); rs11205698(C,T); rs141612714(G,A); rs628523(A,G); rs74069446(T,C); rs60902398(A,G); rs526212(A,G); rs530768(G,A); rs143263635(C,G); rs12145367(G,C); rs656619(G,A); rs6703800(G,A); rs76718314(G,A); rs794642(G,A); rs140322812(G,A); rs12117785(G,T); rs66531516(G,A); rs114048950(G,A); rs16825863(T,G); rs661316(G,A); rs652370(T,C); rs71642677(C,T); rs12070815(C,T); rs583829(C,T); rs684581(C,T); rs502496(T,G); rs648697(G,A); rs651694(A,G); rs529887(C,T); rs17502518(C,T); rs6660622(A,G); rs10888688(A,G); rs604536(T,C); rs1537817(C,T); rs1126313(C,A); rs74069449(A,G); rs115229554(C,T); rs114260798(C,T); rs143090447(C,T); rs16825887(G,A); rs7554301(C,T); rs2455648(C,T); rs560372(G,A); rs561272(C,T); rs148849137(G,T); rs111533970(C,G); rs536193(C,T); rs595710(C,T); rs112672438(C,T); rs1537818(G,A); rs583572(C,T); rs112824904(C,T); rs688811(C,T); rs78373507(A,T); rs16825921(A,T); rs794641(C,G); rs636191(A,T); rs183731771(T,A); rs12087703(C,G); rs622621(G,A); rs145981577(A,C); rs530755(T,C); rs7538300(C,A); rs112765601(G,A); rs57214150(G,C); rs2992674(G,A); rs1290494(T,C); rs7542506(A,G); rs509301(G,C); rs12076577(G,T); rs509436(T,C); rs11205739(G,A); rs659286(T,C); rs2484762(G,T); rs520080(G,A); rs604993(A,G); rs3931300(A,G); rs74066703(G,A); rs16825939(G,A); rs16825942(G,A); rs142786949(C,T); rs6663999(G,C); rs12737392(G,A); rs148834186(C,T); rs1698831(A,C); rs496744(C,T); rs2484135(A,G); rs794638(A,T); rs72637904(C,T); rs72661925(T,A); rs115224511(A,C); rs74066704(G,C); rs78649283(A,T); rs12023553(C,A); rs112460686(G,A); rs16825953(A,G); rs591994(C,A); rs17491275(T,G); rs794637(C,T); rs59527424(G,T); rs113623989(G,A); rs16866216(A,G); rs6680962(G,C); rs74066706(C,T); rs6683629(G,A); rs72661927(A,G); rs669353(C,G); rs553560(A,G); rs4660543(A,G); rs651456(C,T); rs4660546(T,C); rs663978(A,G); rs975773(A,G); rs145142843(A,C); rs74066708(T,C); rs140615219(C,A); rs6692769(G,C); rs190455723(C,A); rs72637905(C,T); rs10493086(G,C); rs683583(C,T); rs138237429(C,T); rs142740781(T,C); rs112139327(A,C); rs582194(G,A); rs12057271(G,A); rs12069517(C,A); rs2036463(G,A); rs2036464(A,G); rs4660550(T,A); rs905381(T,G); rs12096683(A,T); rs626635(A,G); rs549393(T,C); rs12059756(T,G); rs667238(T,G); rs591199(C,T); rs495879(T,C); rs74066712(C,G); rs12089235(A,G); rs111701080(G,T); rs10788933(A,G); rs1112365(G,A); rs2490951(G,A); rs1932507(C,A); rs111496957(T,C); rs116735467(C,T); rs144021282(A,C); rs181424141(G,A); rs58716714(G,A); rs10888715(C,T); rs2254552(T,G); rs2254542(C,A); rs148780261(G,A); rs2254449(G,A); rs16837533(G,A); rs113056239(G,A); rs74066718(C,A); rs950805(A,C); rs1537819(G,A); rs12120111(G,A); rs3120279(C,T); rs3121892(G,A); rs148234053(G,A); rs2484759(A,G); rs72637906(G,A); rs71518423(A,G); rs67886352(G,A); rs2805584(G,A); rs2490947(T,C); rs60323161(T,C); rs151286488(A,G); rs66727439(C,T); rs7553009(C,T); rs1970232(C,T); rs111254532(T,C); rs16826000(G,T); rs2484758(G,C); rs11205823(T,A); rs1118139(A,G); rs2484756(A,G); rs16826009(A,G); rs58999516(G,A); rs10493087(C,G); rs2490948(T,C); rs12082877(C,T); rs2490949(A,T); rs12084111(C,T); rs12073705(G,A); rs11205828(C,T); rs16826012(T,C); rs66880209(G,A); rs55984302(G,A); rs74066722(C,G); rs4660208(A,G); rs79010504(G,C); rs2265408(C,T); rs7541085(T,C); rs7551353(G,A); rs2246257(G,A); rs2246160(A,G); rs77059509(A,C); rs74066723(A,G); rs140576655(G,A); rs1974240(G,T); rs74066724(T,G); rs1889830(A,G); rs77103344(G,A); rs79413694(T,C); rs2490950(G,A); rs4660214(T,C); rs6699928(T,G); rs11205839(G,A); rs148853384(A,G); rs16826022(G,C); rs74066725(T,G); rs74066726(T,C); rs115915034(G,A); rs4660603(C,G); rs145639560(C,T); rs74066727(G,A); rs945465(A,G); rs1537816(G,A); rs143620123(C,T); rs2252890(G,A); rs928680(A,G); rs12089264(T,C); rs3116387(T,G); rs2252549(A,T); rs2252538(G,A); rs2252410(T,G); rs1537815(A,G); rs1984142(G,C); rs150229974(A,G); rs2252049(A,G); rs12089090(T,C); rs74066729(C,T); rs3818806(G,A); rs2484751(C,A); rs74066730(A,G); rs41270799(G,A); rs74066731(A,G); rs2275188(G,A); rs74066732(A,G); rs3121896(C,T); rs146852195(G,T); rs59554900(T,C); rs373188019(G,A); rs2484750(C,T); rs1984143(G,A); rs143876874(G,A); rs2248212(T,C); rs16826036(G,C); rs146206218(C,T); rs16826038(G,A); rs2484749(A,G); rs6688708(C,G); rs16826046(A,G); rs116026083(G,C); rs1335747(T,G); rs111797516(A,G); rs61782157(C,T); rs7514695(G,T); rs2275187(G,A); rs41270803(A,G); rs2275186(C,T); rs74066735(C,T); rs9439001(A,G); rs12025847(G,A); rs57857317(G,A); rs112503435(G,A); rs80022002(T,G); rs115328404(A,T); rs61783376(T,C); rs945466(G,A); rs4660637(C,T); rs28643453(C,A); rs3121897(A,C); rs11205884(G,T); rs3120282(T,C); rs11205885(C,T); rs2484746(A,G); rs2490942(G,A); rs75505690(T,G); rs74718295(C,T); rs61783378(G,A); rs79963528(G,A); rs3116398(C,T); rs3121901(A,G); rs77086991(C,G); rs2377648(C,T); rs6692656(A,G); rs11205900(T,A); rs74066738(G,A); rs74066739(C,T); rs16826064(A,C); rs57633065(G,A); rs112943833(G,A); rs3116389(G,A); rs74066741(A,G); rs3116390(A,C); rs2889696(G,A); rs74066742(T,C); rs74066744(C,T); rs57016290(C,T); rs78389073(A,T); rs74066747(A,G); rs16826068(G,C); rs111745074(A,T); rs56221645(C,A); rs75120007(T,C); rs114768934(T,G); rs58746636(T,C); rs16826069(A,G); rs7547016(A,G); rs16826075(A,G); rs16826077(T,C); rs75770915(C,T); rs74066749(C,T); rs144022503(C,A); rs41270807(A,C); rs3121888(G,T); rs113149147(T,G); rs3121889(G,A); rs3116395(A,G); rs190681266(C,G); rs3121891(T,C); rs74066751(T,G); rs3116396(C,T); rs61783383(T,C); rs4660669(A,C); rs139416640(C,T); rs57037831(G,A); rs57657654(T,G); rs6704246(C,T); rs7528276(T,C); rs11807898(T,G); rs111623477(C,T); rs148552995(C,T); rs2490943(G,A); rs16826087(C,T); rs2490944(G,T); rs2761764(C,A); rs75075907(C,T); rs74066753(G,C); rs3754346(C,T); rs16826093(T,A); rs41270811(G,A); rs2805585(T,A); rs181803782(G,C); rs41270815(G,A); rs61779274(C,G); rs78707186(G,A); rs3118016(G,T); rs17264671(A,C); rs74066754(C,G); rs4660690(G,A); rs581422(C,T); rs593667(A,G); rs75510910(C,A); rs61779275(C,T); rs74066755(C,A); rs597311(T,G); rs597708(G,C); rs636083(T,C); rs16826103(C,T); rs636156(A,G); rs636158(T,A); rs1180373(G,A); rs146492646(G,C); rs613851(A,T); rs2256614(C,G); rs630519(T,C); rs74066763(G,T); rs143383087(T,C); rs112320204(T,A); rs583050(T,G); rs190801256(G,A); rs72661961(A,G); rs79105037(C,T); rs598415(T,C); rs613511(C,T); rs629093(A,G); rs61779277(G,A); rs61779278(A,G); rs596991(A,T); rs74066765(A,G); rs582883(T,C); rs2296172(A,G); rs12127668(C,A); rs59559317(G,A); rs61779279(C,T); rs74066767(C,T); rs2490945(T,C); rs2490946(G,A); rs80197726(T,C); rs61779282(C,G); rs7536582(G,C); rs621807(G,A); rs76111861(G,T); rs112334595(G,A); rs76256401(C,T); rs111905743(G,C); rs663834(A,G); rs663449(G,A); rs660293(T,C); rs79522721(T,G); rs592264(A,T); rs374973824(C,T); rs1180383(G,A); rs1184716(C,T); rs72661965(A,C); rs6668369(C,G); rs150902307(C,T); rs678672(A,T); rs74066769(G,A); rs666885(C,T); rs112451431(C,T); rs635943(T,C); rs149721483(A,G); rs112421123(T,G); rs61779284(G,A); rs6600291(G,A); rs74066771(C,T); rs3768299(G,A); rs12072631(A,G); rs12072715(A,G); rs6681763(C,T); rs584763(A,T); rs75731568(C,T); rs74066773(C,T); rs12096223(C,G); rs4660732(C,T); rs72928313(A,C); rs658255(T,G); rs60180523(C,A); rs12076554(A,G); rs7520599(G,A); rs61779285(C,T); rs2451672(T,G); rs74066776(C,T); rs3768300(C,T); rs3768301(C,T); rs80343368(C,G); rs74066778(T,C); rs616630(G,A); rs186663091(C,G); rs74066780(C,G); rs61073427(C,T); rs74066781(C,G); rs56278340(G,A); rs783823(A,G); rs3768302(T,G); rs653064(C,G); rs783826(T,C); rs115399293(A,G); rs72928327(T,A); rs1180376(A,G); rs61779300(G,A); rs2171979(T,A); rs74066796(C,T); rs1617212(A,G); rs1746844(T,C); rs1618798(A,G); rs1624820(C,A); rs663892(G,A); rs116243885(A,G); rs12063951(G,A); rs1180384(T,C); rs625384(C,T); rs60639051(T,C); rs116281812(A,G); rs2995513(T,C); rs645061(A,G); rs682571(G,A); rs683135(G,A); rs74066797(A,G); rs783817(C,A); rs6680153(C,T); rs599823(T,C); rs11206073(A,G); rs645234(G,T); rs783818(G,A); rs74066798(T,C); rs55975501(T,C); rs6663884(T,A); rs12061335(T,C); rs12075503(C,T); rs596705(T,C); rs12061378(T,C); rs1180372(A,G); rs2018212(T,C); rs653501(A,T); rs4660751(C,T); rs114364340(G,A); rs10489935(A,G); rs682351(A,G); rs11206102(A,C); rs587404(G,A); rs588326(A,G); rs116756012(T,C); rs78256423(A,T); rs617577(T,C); rs1775656(C,T); rs12069020(G,A); rs74972679(G,A); rs77637975(A,G); rs2296173(A,G); rs783837(C,G); rs3118014(G,A); rs16826152(G,A); rs668556(G,C); rs1180379(G,A); rs111998299(T,C); rs113356700(T,A); rs112898040(C,T); rs1180377(C,G); rs112635003(C,T); rs1746838(C,A); rs72930209(C,T); rs116060943(G,T); rs687848(A,G); rs688320(T,G); rs6671001(C,T); rs7540171(A,G); rs41270819(C,T); rs138078206(G,A); rs783841(A,T); rs61779306(G,A); rs599892(C,G); rs77563903(C,A); rs783840(G,T); rs41270821(T,C); rs658191(C,G); rs2296175(G,A); rs4660762(G,A); rs112836713(C,T); rs783820(G,A); rs112579533(A,G); rs188134768(A,C); rs1084760(T,C); rs7540050(C,A); rs7554206(T,C); rs6687066(C,T); rs813652(G,A); rs17511836(T,C); rs79420643(A,G); rs6698781(A,G); rs6698791(A,T); rs74910738(C,T); rs76030961(G,A); rs10888788(G,A); rs61779308(C,T); rs76803104(C,T); rs1623310(C,G); rs1775647(G,A); rs2995514(A,G); rs12057191(C,T); rs4617393(C,T); rs61779309(T,C); rs60295854(G,A); rs78035527(C,T); rs61779310(C,G); rs783827(A,C); rs783828(C,T); rs6665948(A,G); rs61779313(T,C); rs783829(G,A); rs722357(C,T); rs116784299(T,G); rs783830(C,T); rs2275767(C,T); rs796729(A,T); rs1626267(G,A); rs72930227(T,G); rs12138051(A,G); rs2995515(C,A); rs6691194(G,A); rs182511478(T,C); rs1775654(C,T); rs72930231(C,T); rs710915(G,A) |
| ccdsGene name | CCDS435.1 |
| cytoBand name | 1p34.3 |
| EntrezGene GeneID | 23499 |
| EntrezGene Description | microtubule-actin crosslinking factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MACF1:NM_012090:exon14:c.G1532A:p.R511H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8625 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F8W8Q1 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 2.440e-05,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Deafness, sensorineural, prelingual, profound;
Nonprogressive deafness
MOLECULAR BASIS:
Caused by mutation in the hepatic growth factor gene (HGF, 142409.0001)
OMIM Title
*608271 MICROTUBULE-ACTIN CROSS-LINKING FACTOR 1; MACF1
;;MACROPHIN 1;;
TRABECULIN-ALPHA;;
ACTIN CROSS-LINKING FACTOR 7; ACF7;;
KIAA1251
OMIM Description
DESCRIPTION
ACF7 is a member of the spectraplakin family of cytoskeletal
cross-linking proteins that possess actin- and microtubule-binding
domains (Kodama et al., 2003).
CLONING
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (1999) cloned MACF1, which they designated
KIAA1251. The 3-prime UTR of the transcript contains Alu repeat
sequences, and the deduced protein contains 1,483 amino acids. RT-PCR
ELISA detected low expression of MACF1 in lung, ovary, and liver.
Sun et al. (1999) cloned several contiguous partial MACF1 cDNAs from a
prostate cDNA library and assembled the full-length sequence. The
deduced 5,373-amino acid MACF1 protein, which they designated
trabeculin-alpha, has a calculated molecular mass of 614 kD. MACF1 has
an N-terminal actin-binding domain, followed by a plectin (601282)-like
domain, 29 central spectrin (see 182860)-like repeats, and a C-terminal
region that contain 2 tandem Ca(2+)-binding EF-hand motifs, a GAR22
(GAS2L1; 602128)-like domain, and a serine-rich region. The C terminus
also has several putative tyrosine kinase motifs. MACF1 shares 88% amino
acid with its mouse homolog. Northern blot analysis detected MACF1
expression in all tissues examined, with highest expression in heart,
skeletal muscle, prostate, intestine, colon, and gonads. Lowest
expression was in brain, spleen, thymus, liver, placenta, and lung.
Immunofluorescence analysis of several cell lines detected MACF1
distributed in a filamentous network throughout the cytoplasm, with
exclusion from the nucleus.
By PCR of the HepG2 hepatoma cell line with degenerate primers based on
conserved C-terminal domains of FAK (600758) and CAKB (601212), followed
by screening a HepG2 cell line cDNA library, Okuda et al. (1999) cloned
MACF1, which they designated macrophin. The deduced 5,430-amino acid
protein has a calculated molecular mass of 620 kD. RT-PCR detected high
expression in heart, placenta, liver, kidney, and pancreas, moderate
expression in brain and lung, and weak expression in skeletal muscle. In
situ hybridization of pancreas showed mRNA mainly in acinar tissue.
By searching sequence databases using a chicken partial cDNA that was
differentially expressed during regeneration of the auditory epithelium
after noise trauma, followed by screening pituitary gland and heart cDNA
libraries, Gong et al. (2001) cloned a splice variant of MACF1. The
deduced protein, which they called MACF1-4, has a calculated molecular
mass of 670 kD, contains 8 N-terminal plectin repeats, and has no
actin-binding domain. The authors noted that 3 other splice variants
with different N termini had been identified for mouse Macf1. mRNA dot
blot analysis showed that MACF1 was expressed ubiquitously, with highest
expression in pituitary, adrenal, thyroid, salivary gland, mammary
gland, pancreas, heart, and skeletal muscle. mRNA dot blot analysis
using a riboprobe specific for the MACF1-4 variant showed highest
expression in heart, lung, pituitary gland, and placenta. PCR analysis
using MACF1-4-specific primers detected MACF1-4 in lung, heart,
pituitary, and placenta, but not in brain, kidney, liver, pancreas,
skeletal muscle, or HepG2 hepatoma cells.
GENE FUNCTION
By sedimentation binding assay, Sun et al. (1999) confirmed that the
N-terminal actin-binding domain of MACF1 coprecipitated with F-actin.
Cytochalasin D disruption of actin filaments also resulted in a marked
but incomplete disruption of MACF1 fine filament structures and the
appearance of punctate aggregates of MACF1. Mouse Macf1 mRNA levels
increased steadily during formation of fused myotubes during
differentiation in a mouse myoblasts cell line. Kodama et al. (2003)
showed that mouse Acf7 is an essential integrator of microtubule-actin
dynamics. In mouse endodermal cells, Acf7 bound along microtubules, but
concentrated at their distal ends and at cell borders when polarized. In
the absence of Acf7, microtubules still bound Eb1 (603108) and Clip170
(179838), but they no longer grew along polarized actin bundles, nor did
they pause and tether to actin-rich cortical sites. The consequences
were long, less stable microtubules with skewed cytoplasmic trajectories
and altered dynamic instability. In response to wounding, Acf7 null
cultures activated polarizing signals, but they failed to maintain them
and coordinate migration. Rescue of these defects required the actin-
and microtubule-binding domains of Acf7. Kodama et al. (2003) concluded
that spectraplakins are important for controlling microtubule dynamics
and reinforcing links between microtubules and polarized F-actin, so
that cellular polarization and coordinated cell movements can be
sustained.
Chen et al. (2006) found that siRNA knockdown of Macf1 inhibited Wnt
signaling (see WNT1; 164820) in a mouse embryonic carcinoma cell line.
Reporter gene assays indicated that Macf1 acted upstream of Gsk3b
(605004) in the Wnt signaling pathway. Macf1 interacted directly with
Axin (see AXIN1, 603816) and translocated with the Axin complex to the
cell membrane upon Wnt stimulation.
A resident population of adult stem cells (SCs) in hair follicles is
involved in hair growth and in epidermal reepithelialization during
wound healing. Wu et al. (2011) found that adult mouse hair follicle SCs
expressed high levels of Acf7 and that phosphorylation of Acf7 by
Gsk3-beta reduced the affinity of Acf7 for microtubules. Expression of a
constitutively active Gsk3-beta mutant in hair follicle SCs resulted in
elevated phosphorylation of Acf7 and altered microtubule structure
similar to that in Acf7-knockout cells. Conversely, inhibition of
Gsk3-beta increased microtubule binding by endogenous Acf7 in hair
follicle SCs. SC migration in a wound-healing assay was inhibited by
Acf7 knockout and by both over- and underactivation of Gsk3-beta. Wu et
al. (2011) concluded that cyclic phosphorylation of Acf7 by Gsk3-beta is
required for Acf7- and microtubule-based cell migration in hair follicle
SCs.
GENE STRUCTURE
Gong et al. (2001) determined that the MACF1 gene contains at least 102
exons and spans more than 270 kb.
MAPPING
By radiation hybrid analysis, Nagase et al. (1999) mapped the MACF1 gene
to chromosome 1. Okuda et al. (1999) mapped the MACF1 gene to chromosome
1p32-p31 by radiation hybrid analysis and genomic sequence analysis. By
FISH, Sun et al. (1999) mapped the MACF1 gene to chromosome 1p34.2-p33.
Gong et al. (2001) mapped the mouse Macf1 gene to a region of mouse
chromosome 4 that shows homology of synteny to human chromosome 1p32.
ANIMAL MODEL
Chen et al. (2006) found that Macf1 -/- mice died at the gastrulation
stage and displayed developmental retardation at embryonic day 7.5 with
defects in the formation of the primitive streak, node, and mesoderm.
The phenotype was similar to that of Wnt3 (165330)-null mice and Lrp5
(604506)/Lrp6 (603507) double-knockout mice.
NFYC-AS1
| dbSNP name | rs552147(C,G); rs10789187(T,C); rs2780952(G,A); rs74718813(T,C); rs2744801(C,T); rs2744800(C,T); rs10789191(C,G) |
| cytoBand name | 1p34.2 |
| EntrezGene GeneID | 100130557 |
| EntrezGene Symbol | LOC100130557 |
| snpEff Gene Name | NFYC |
| EntrezGene Description | uncharacterized LOC100130557 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2599 |
SLFNL1
| dbSNP name | rs41308248(A,G); rs372756325(C,T); rs61734928(C,T); rs145193833(C,T); rs147059742(C,T); rs6685430(G,T) |
| cytoBand name | 1p34.2 |
| EntrezGene GeneID | 100507178 |
| EntrezGene Symbol | SLFNL1-AS1 |
| snpEff Gene Name | CTPS |
| EntrezGene Description | SLFNL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1143 |
HYI
| dbSNP name | rs2251804(T,C); rs74069990(C,T); rs2251802(G,A); rs74069991(G,A) |
| ccdsGene name | CCDS488.2 |
| cytoBand name | 1p34.2 |
| EntrezGene GeneID | 81888 |
| EntrezGene Description | hydroxypyruvate isomerase (putative) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2668 |
| ESP Afr MAF | 0.184521 |
| ESP All MAF | 0.339228 |
| ESP Eur/Amr MAF | 0.418488 |
| ExAC AF | 0.322 |
LINC01144
| dbSNP name | rs4451587(G,C) |
| cytoBand name | 1p34.1 |
| EntrezGene GeneID | 400752 |
| EntrezGene Symbol | LOC400752 |
| snpEff Gene Name | ZSWIM5 |
| EntrezGene Description | uncharacterized LOC400752 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3168 |
LINC00853
| dbSNP name | rs2245122(T,C) |
| cytoBand name | 1p33 |
| EntrezGene GeneID | 100874253 |
| snpEff Gene Name | PDZK1IP1 |
| EntrezGene Description | long intergenic non-protein coding RNA 853 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3829 |
FOXD2-AS1
| dbSNP name | rs77749789(C,T); rs3814005(T,C) |
| cytoBand name | 1p33 |
| EntrezGene GeneID | 84793 |
| snpEff Gene Name | FOXD2 |
| EntrezGene Description | FOXD2 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009642 |
FOXD2
| dbSNP name | rs2622917(G,A); rs2820966(G,A) |
| cytoBand name | 1p33 |
| EntrezGene GeneID | 2306 |
| EntrezGene Description | forkhead box D2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4587 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Horseshoe kidney;
Ectopic kidney;
Absent kidney;
Dilated Bowman capsules;
Cystic tubular dilatation in the cortex and medulla;
[Ureters];
Double ureter
SKELETAL:
[Limbs];
Short, curved forearms;
Absence of the radii;
[Hands];
Medial flexion of the hands;
Absence of the thumbs
NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Ventriculomegaly;
Dilated ventricles
MISCELLANEOUS:
One family with 2 affected fetuses has been reported (as of August
2011)
OMIM Title
*602211 FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 17; FKHL17
;;FORKHEAD-RELATED ACTIVATOR 9; FREAC9
OMIM Description
CLONING
Ernstsson et al. (1997) described the cloning of a nearly full-length
4,258-bp cDNA encoding the human forkhead gene FREAC9 (FKHL17). The
5-prime untranslated region is unusual since it is very long (2,127 bp)
and contains 15 upstream AUG codons. Hybridization to a panel consisting
of RNA derived from 50 different tissues showed that the FKHL17 gene is
transcribed exclusively in the kidney. The conceptual translation
product predicts a protein of 372 amino acids within an N-terminal
domain rich in acidic amino acids and with a high likelihood of forming
an amphipathic helix, a DNA binding forkhead domain, and a C-terminal
region that has a high probability of forming an amphipathic beta-sheet.
The amino acid sequence of the DNA binding forkhead motif of this
protein is identical to that of another forkhead protein, FREAC4
(601091), whereas 12 substitutions are present at the nucleotide level.
There are no similarities in regions outside of the DNA binding domains
of FREAC9 and FREAC4, and since the gene encoding the latter protein
maps to 5q12-q13, it is likely that evolutionary selection has acted to
maintain identical DNA binding domains between these 2 kidney-expressed
transcription factors.
MAPPING
By a combination of fluorescence in situ hybridization and somatic cell
hybrid analyses, Ernstsson et al. (1997) localized the FKHL17 gene to
chromosome 1p34-p32. Ernstsson et al. (1997) tabulated the chromosomal
localization of 15 human forkhead genes in their Table 1.
KTI12
| dbSNP name | rs2809918(C,A); rs2809917(C,T); rs2783175(A,T); rs114190370(C,A) |
| ccdsGene name | CCDS561.1 |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 112970 |
| snpEff Gene Name | TXNDC12 |
| EntrezGene Description | KTI12 homolog, chromatin associated (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02847 |
CPT2
| dbSNP name | rs3766760(G,T); rs2062015(C,G); rs2046138(G,A); rs12754957(T,C); rs78117157(C,T); rs3766759(T,G); rs139929212(A,T); rs150278375(C,G); rs59327204(G,A); rs148984426(G,A); rs187203767(T,G); rs142503511(T,C); rs141137174(T,G); rs11206125(A,C); rs11581518(A,G); rs192071234(G,A); rs7539949(G,A); rs78717670(C,T); rs1072706(T,C); rs187187529(T,C); rs140577958(G,A); rs191317017(T,C); rs184420650(T,C); rs11578832(G,A); rs143421390(C,T); rs370493(G,A); rs12737375(T,C); rs145237292(A,G); rs141553491(G,T); rs1799821(G,A); rs142600166(G,A); rs6692897(A,G); rs188460484(C,T); rs737464(A,G); rs181453495(C,A); rs141146189(G,A); rs1799822(A,G) |
| ccdsGene name | CCDS575.1 |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 1376 |
| EntrezGene Description | carnitine palmitoyltransferase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CPT2:NM_000098:exon4:c.A877G:p.S293G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6506 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P23786 |
| dbNSFP Uniprot ID | CPT2_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 8.945e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Cardiomegaly;
Dilated cardiomyopathy
RESPIRATORY:
Respiratory arrest
ABDOMEN:
[Liver];
Hepatomegaly;
Macrovesicular steatosis;
[Gastrointestinal];
Vomiting
NEUROLOGIC:
[Central nervous system];
Lethargy;
Seizures
METABOLIC FEATURES:
Hypoketotic hypoglycemia
LABORATORY ABNORMALITIES:
Decreased carnitine palmitoyltransferase II (CPT2) activity;
Decreased levels of CPT2 protein;
Decreased palmitate oxidation;
Increased liver function tests;
Hyperammonemia;
Increased creatine kinase;
Reduced total and free carnitine in plasma and tissue;
Increased long-chain acylcarnitine
MISCELLANEOUS:
Onset in infancy (3 months on);
Precipitated by febrile illness and fasting;
See also lethal neonatal (608836) and adult forms (255110)
MOLECULAR BASIS:
Caused by mutations in the carnitine palmitoyltransferase II gene
(CPT2, 600650.0001)
OMIM Title
*600650 CARNITINE PALMITOYLTRANSFERASE II; CPT2
;;CPT II
OMIM Description
DESCRIPTION
The CPT2 gene encodes carnitine palmitoyltransferase II, an enzyme that
participates in fatty acid oxidation. The carnitine palmitoyltransferase
(CPT; EC 2.3.1.21) enzyme system, in conjunction with acyl-CoA
synthetase and carnitine/acylcarnitine translocase (613698), provides
the mechanism whereby long-chain fatty acids are transferred from the
cytosol to the mitochondrial matrix to undergo beta-oxidation. The CPT I
isozymes (see CPT1A; 600528 and CPT1B; 601987) are located in the
mitochondrial outer membrane and are detergent-labile, whereas CPT II is
located in the inner mitochondrial membrane and is detergent-stable
(Bieber, 1988).
CLONING
By screening a human liver cDNA library, Finocchiaro et al. (1991)
cloned and sequenced a cDNA encoding human carnitine
palmitoyltransferase II. The deduced 658-amino acid protein contains a
25-residue NH2-terminal leader peptide. The amino acid sequence shows
82.2% homology with the rat CTP II protein.
Montermini et al. (1994) identified regulatory elements in the promoter
of the CPT2 gene.
GENE STRUCTURE
Verderio et al. (1995) determined that the CPT2 gene contains 5 exons
spanning approximately 20 kb of DNA.
MAPPING
By human-hamster somatic cell hybridization, Finocchiaro et al. (1991)
assigned the CPT2 gene (which they referred to as CPT1) to chromosome
1pter-q12. By fluorescence in situ hybridization, Minoletti et al.
(1992) refined the assignment of the CPT2 gene to 1p13-p11. However,
also using fluorescence in situ hybridization, Gellera et al. (1994)
concluded that the CPT2 gene is located in band 1p32 and that the
previously used probe that mapped the gene to 1p13-p11 'must be
considered an as yet anonymous probe.' It is now clear that the gene
mapped to chromosome 1p32 was CPT2.
GENE FUNCTION
Britton et al. (1995) distinguished CPT I and CPT II, and reported that
major control over the fatty acid oxidation process is exerted at the
level of CPT I by the unique inhibition of this enzyme by malonyl-CoA.
Slama et al. (1996) carried out complementation experiments between cell
lines derived from patients with CPT I deficiency (255120) or infantile
CPT II deficiency (600649) by measuring restoration of tritium release
from palmitate. As expected, no complementation was observed in
heteropolykaryons resulting from fusion of CPT I-deficient cells or of
CPT II-deficient cells. Conversely, complementation was observed in
fusions of CPT I- and CPT II-deficient cells. These data suggested that
the defects in CPT I deficiency and infantile CPT II deficiency are
determined by mutations in distinct genes. Palmitate oxidation by
control or CPT I-deficient cell lines decreased when these cell lines
were cocultured with infantile CPT II-deficient cell lines. This effect,
not observed in a coculture with an adult CPT II-deficient cell line,
was suppressed by a high carnitine concentration.
NOMENCLATURE
Finocchiaro et al. (1991), Minoletti et al. (1992), and Gellera et al.
(1994) all referred to the CPT gene on chromosome 1 as CPT1; it is
referred to here as CPT2 following the elucidation by Britton et al.
(1995). CPT1 (600528) maps to chromosome 11.
MOLECULAR GENETICS
- Carnitine Palmitoyltransferase II Deficiency
In a patient with infantile carnitine palmitoyltransferase II deficiency
(600649) with hypoketotic hypoglycemia and cardiomyopathy, Taroni et al.
(1992) identified a homozygous mutation in the CPT2 gene (600650.0001).
The patient was also homozygous for a mutant CPT2 allele (termed the
'ICV' allele) that carried 2 other rare polymorphisms. In a patient with
infantile CPT II deficiency reported by Demaugre et al. (1991),
Bonnefont et al. (1996) identified a homozygous mutation in the CPT2
gene (600650.0005).
In a Dutch patient with adult-onset CPT II deficiency (255110), Taroni
et al. (1993) identified compound heterozygosity for 2 mutations in the
CPT2 gene (600650.0001; 600650.0002).
Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the
antenatal, or lethal neonatal, form of CPT II deficiency (608836) who
were homozygous for an allele carrying 2 mutations in exon 4 of the CPT2
gene (600650.0009).
Isackson et al. (2008) identified compound heterozygous or homozygous
mutations in the CPT2 gene in 3 patients with lethal neonatal CPT II
deficiency (see, e.g., 600650.0013) and in 2 patients with infantile CPT
II deficiency. Three of the mutations were novel (see, e.g.,
600650.0017).
- Infection-Induced Acute Encephalopathy-4
Chen et al. (2005) found that a Japanese girl with fatal
infection-induced acute encephalopathy-4 (IIAE4; 614212) was
heterozygous for a thermolabile allele in the CPT2 gene (600650.0018).
She had significantly increased serum acylcarnitine levels during
febrile convulsions. Her 2 unaffected brothers, who were heterozygous
for the allele, and their father, who was homozygous for the allele, had
slightly increased serum acylcarnitine compared to normal values in the
nonfebrile state. The mother, who was heterozygous only for the 368I,
had normal acylcarnitine levels in the nonfebrile state.
GENOTYPE/PHENOTYPE CORRELATIONS
In a study of 19 patients with CPT II deficiency, 13 with adult onset
and 6 with infantile onset, Thuillier et al. (2003) found that all
patients with the infantile form had mutations in exon 4 or 5 of the
CPT2 gene. Twelve of the adult patients carried the S113L (600650.0002)
mutation. Although there was an overlap in residual CPT II activity
between the 2 groups (ranging from 4 to 12%), there was a significant
decrease in palmitate oxidation in the infantile group (less than 10%)
compared to the adult group (45 to 70%). Thuillier et al. (2003)
concluded that both the type and location of CPT2 mutations and at least
1 additional, unidentified genetic factor modulate the long-chain fatty
acid flux and therefore the severity of the disease.
Orngreen et al. (2005) identified 2 unrelated patients with mild
features of late-onset CPT II deficiency who each carried a single
mutation in the CPT2 gene (600650.0015 and 600650.0016). The findings
indicated that some heterozygous CPT2 mutation carriers may be
symptomatic.
SLC25A3P1
| dbSNP name | rs1299818(G,C); rs1288598(T,G) |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 163742 |
| snpEff Gene Name | RP4-796B4.1 |
| EntrezGene Description | solute carrier family 25 (mitochondrial carrier |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.326 |
MIR4781
| dbSNP name | rs74085143(G,A) |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 100616315 |
| snpEff Gene Name | TCEANC2 |
| EntrezGene Description | microRNA 4781 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09963 |
| ExAC AF | 0.019 |
LOC100507634
| dbSNP name | rs10788995(A,T) |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 100507634 |
| snpEff Gene Name | USP24 |
| EntrezGene Description | uncharacterized LOC100507634 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.281 |
MIR4422
| dbSNP name | rs17111728(T,C) |
| cytoBand name | 1p32.3 |
| EntrezGene GeneID | 100616272 |
| snpEff Gene Name | GYG1P3 |
| EntrezGene Description | microRNA 4422 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07713 |
| ExAC AF | 0.03 |
C8A
| dbSNP name | rs72670316(G,A); rs1342434(T,C); rs1342433(G,A); rs857029(A,G); rs182518760(G,A); rs145666509(C,A); rs148823214(A,G); rs622300(G,A); rs857028(T,G); rs634144(C,T); rs636879(C,T); rs662377(A,G); rs77725725(A,G); rs663352(T,A); rs664142(A,G); rs17114468(G,A); rs11802385(G,A); rs113719307(T,A); rs77187136(T,C); rs621819(C,T); rs622299(C,T); rs150491061(G,T); rs635922(T,C); rs77696206(G,A); rs72670317(C,A); rs6669054(T,G); rs668822(G,T); rs1891420(A,G); rs34047108(A,G); rs601662(A,G); rs603154(A,G); rs12406202(G,T); rs146392023(T,C); rs2269121(T,C); rs618238(G,C); rs1581942(C,T); rs618707(G,A); rs12401558(C,T); rs72670319(G,A); rs57210737(G,T); rs694090(G,T); rs2269119(G,C); rs1887977(G,A); rs706473(A,G); rs114890786(A,G); rs75068333(A,G); rs927214(G,T); rs1885002(A,G); rs652785(C,A); rs2269118(G,A); rs607221(C,T); rs594105(T,G); rs645846(A,G); rs706474(T,C); rs706475(T,A); rs2269115(C,T); rs17114506(T,C); rs2300955(G,A); rs17114511(A,G); rs2300954(T,C); rs6681119(A,T); rs1754519(A,G); rs11804514(G,T); rs77604905(A,C); rs856842(A,T); rs706476(A,C); rs6588656(C,T); rs6694643(A,T); rs6697228(T,C); rs10489624(T,C); rs80226443(T,G); rs58983677(C,T); rs181653329(A,C); rs35562962(A,C); rs72670327(C,T); rs114404344(T,G); rs658461(A,G); rs629799(A,G); rs28472455(A,G); rs2269114(T,C); rs6668097(C,T); rs6683663(A,G); rs6686359(T,C); rs6696110(T,G); rs6696924(T,G); rs6699859(T,C); rs6670243(C,T); rs1411012(A,T); rs11206932(T,A); rs3768215(C,T); rs6700128(G,C); rs2145404(G,T); rs1360151(C,T); rs679350(G,A); rs1999133(G,A); rs1329450(T,C); rs78083553(G,A); rs6661831(G,A); rs6662705(G,A); rs585061(T,C); rs11206933(A,G); rs620709(G,A); rs608567(A,G); rs1360149(C,G); rs2284952(G,T); rs2284951(T,A); rs592451(A,G); rs12116668(T,C); rs619545(C,T); rs7520004(G,A); rs7520006(G,A); rs1411009(T,C); rs607422(C,T); rs17114555(G,A); rs624298(A,G); rs61350393(G,T); rs682479(C,A); rs74893427(A,C); rs638919(T,C); rs116296609(T,C); rs635833(C,T); rs1620075(G,A); rs623077(T,C); rs11206934(T,C); rs145849377(G,A); rs607268(T,C); rs56143927(C,T); rs2284950(G,A); rs186013951(G,A); rs139810278(C,A); rs115806842(C,T); rs72670338(C,T) |
| ccdsGene name | CCDS606.1 |
| cytoBand name | 1p32.2 |
| EntrezGene GeneID | 731 |
| EntrezGene Description | complement component 8, alpha polypeptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C8A:NM_000562:exon10:c.G1454A:p.R485H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5732 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P07357 |
| dbNSFP Uniprot ID | CO8A_HUMAN |
| dbSNP GMAF | 0.08815 |
| ExAC AF | 0.077,1.830e-03,8.132e-06 |
OMIM Clinical Significance
Immunology:
Partial C4 deficiency;
Systemic lupus erythematosus
Inheritance:
Autosomal dominant
OMIM Title
*120950 COMPLEMENT COMPONENT 8, ALPHA SUBUNIT; C8A
;;C8 ALPHA
OMIM Description
DESCRIPTION
The eighth component of complement (C8) belongs to the late-acting
complement proteins (C5-C9) forming the membrane attack complex. C8 is a
serum protein that consists of 3 nonidentical subunits arranged
asymmetrically as a disulfide-linked alpha (C8A)-gamma (C8G; 120930)
dimer and a noncovalently associated beta chain (C8B; 120960). Each
component is encoded by a different gene (Kolb and Muller-Eberhard,
1976; Ng et al., 1987).
BIOCHEMICAL FEATURES
By separating the alpha-gamma dimer of C8 from the beta chain and then
subjecting the alpha-beta dimer to further treatment, Brickner and
Sodetz (1985) purified the alpha and gamma chains. When mixed, purified
alpha and gamma exhibited high affinity for each other, and purified
gamma also had affinity for C8-prime, which is composed of the alpha and
beta chains only. Brickner and Sodetz (1985) concluded that alpha
possesses a specific site for interaction with gamma and that the site
remains accessible in the isolated alpha subunit and when alpha is
associated with beta. They found that gamma associated specifically with
membrane-bound C5b-8-prime and C5b-(8-prime)9 complexes. Brickner and
Sodetz (1985) concluded that the gamma interaction site on alpha remains
accessible in C5b-8-prime and is not shielded by C9 within
C5b-(8-prime)9, and that the gamma subunit of C8 is located on the
surface of membrane-bound C5b-8 and C5b-9.
Hadders et al. (2007) determined the crystal structure of the MACPF
(membrane attack complex perforin) domain of the complement component
C8-alpha at 2.5-angstrom resolution and showed that it is structurally
homologous to the bacterial, pore-forming, cholesterol-dependent
cytolysins. The structure displayed 2 regions that in the bacterial
cytolysins refold into transmembrane beta hairpins, forming the lining
of a barrel pore. Local hydrophobicity explained why C8-alpha is the
first complement protein to insert into the membrane. The size of the
MACPF domain is consistent with known C9 pore sizes. Hadders et al.
(2007) concluded that their data implied that these mammalian and
bacterial cytolytic proteins share a common mechanism of membrane
insertion.
Rosado et al. (2007) determined the crystal structure of a bacterial
MACPF protein, Plu-MACPF from Photorhabdus luminescens, to 2.0-angstrom
resolution. The MACPF domain revealed structural similarity with
pore-forming cholesterol-dependent cytolysins from gram-positive
bacteria. Rosado et al. (2007) suggested that lytic MACPF proteins may
use a cholesterol-dependent cytolysin-like mechanism to form pores and
disrupt cell membranes.
GENE STRUCTURE
Michelotti et al. (1995) isolated overlapping genomic clones and used
them to decipher the organization of the human C8A gene. The gene
contains at least 11 exons and spans approximately 70 kb of DNA. C8A
genomic organization was found to be remarkably similar to that of C6,
C8B, and C9.
MAPPING
Rogde et al. (1984) found that the polymorphism detected by anti-C8 was
determined by a locus linked to PGM1 on 1p (maximal lod score, sexes
combined, of 8.0 at theta = 0.10). They interpreted their evidence as
suggesting that this polymorphism is in the alpha-gamma subunit. By
2-dimensional electrophoresis, Rogde et al. (1985) showed that the C8
polymorphism resides in the structural gene for the alpha chain.
Using separation by isoelectric focusing followed by immunoblotting,
Rogde et al. (1985, 1986) concluded that C8A and C8B are closely linked
to each other (lod = 3.01, theta 0.0) and to PGM1 (171900): C8A, lod =
16.5 at theta 0.09; C8B, lod = 3.54 at theta 0.11, sexes combined. Both
C8 loci are linked to Rh (maximum lod = 3.56 at theta 0.23 in males and
0.36 at theta 0.37 in females).
Rittner et al. (1986) showed that the C8A gene and PGM1 were linked with
male theta of 0.18 and female theta of 0.26. The sum of the lods for 9
families was 1.822. The genetic distances between the two C8 loci and
PGM1 appeared to be identical in males and females (Rogde et al., 1986).
As noted, a female/male ratio of 1.6 was observed between the two C8
loci and Rh. No evidence of linkage of the C8 loci to Fy was found.
Using cDNA clones for the C8-alpha and C8-beta genes for nonradioactive
in situ hybridization, Theriault et al. (1991, 1992) mapped the 2 genes
to 1p32. For both subunits the results were confirmed by hybridization
to metaphase chromosomes derived from a person with the balanced
reciprocal translocation t(1;5)(p32;q35), the hybridization signal being
observed on the derivative chromosome 5. Using BamHI RFLPs of the C8A
and C8B genes, Rogde et al. (1992) obtained a peak lod score of 4.52 at
recombination fraction of 0.0 between C8A and C8B. Combined with data
from a previous study, a maximum lod score of 22.02 at recombination
fraction 0.11, with no sex difference, was compiled for the C8-PGM1
linkage. No evidence of allelic association between the C8A and C8B
BamHI RFLPs was found.
Although the C8A and C8B loci were previously reported to be less than
2.5-kb apart, Michelotti et al. (1995) obtained results using
exon-specific probes, indicating that the loci are not as closely linked
as initially believed.
MOLECULAR GENETICS
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
In 2 unrelated Japanese patients with C8 alpha/gamma deficiency
(613790), Kojima et al. (1998) screened all 11 exons of the C8A gene and
all 7 exons of the C8G gene and their boundaries and identified
homozygous or compound heterozygous mutations in the C8A gene
(120950.0002-120950.0003). No mutation was found in the C8G gene.
ANIMAL MODEL
Komatsu et al. (1985) and Komatsu et al. (1990) described hereditary
C8-alpha-gamma deficiency in the rabbit where it was associated with
dwarfism, small thymus, small litter size, and low survival rate.
Komatsu et al. (1990) showed that the C8 deficiency was not linked to
the dw-2 locus which causes dwarfism in rabbits. Whether the dwarfism
was due to a separate locus closely linked to the C8 locus or was a
pleiotropic effect of the C8 locus was unclear.
HISTORY
Merritt et al. (1976) concluded, through family linkage studies, that a
gene for C8 is in the HLA region. Other studies failed to confirm
linkage with HLA (e.g., Giraldo et al., 1977).
Alper et al. (1983) demonstrated a second C8 polymorphism by isoelectric
focusing of serum in polyacrylamide gel and development of specific
patterns of hemolysis in an overlay gel containing C8 beta-chain
deficiency.
Nakamura et al. (1986) reported on C81 polymorphism in the Japanese.
C8B
| dbSNP name | rs605648(T,C); rs653804(C,G); rs2281598(C,G); rs642535(G,C); rs642120(T,G); rs603804(G,A); rs641714(G,C); rs591730(A,G); rs2025006(C,T); rs638423(C,T); rs684844(A,G); rs684782(C,T); rs684304(T,C); rs683824(G,A); rs612563(G,C); rs668451(C,T); rs652962(G,T); rs652553(T,C); rs581992(T,A); rs676480(A,C); rs17301153(C,T); rs594661(T,C); rs139787516(C,T); rs684216(C,G); rs116064367(A,C); rs669358(C,T); rs142113157(G,T); rs622904(A,T); rs725330(C,T); rs6669836(T,C); rs628745(T,C); rs72670358(A,G); rs626457(C,T); rs114102078(C,T); rs111927445(T,A); rs150601390(G,A); rs3768214(G,C); rs189023811(C,T); rs598772(C,T); rs11807035(T,C); rs856840(T,C); rs656598(A,C); rs72670362(C,A); rs141136423(G,A); rs2269113(C,T); rs78766017(T,C); rs597181(G,T); rs72670363(T,C); rs145392333(A,G); rs149212188(A,T); rs582317(G,A); rs12085435(G,A); rs661449(A,G); rs12136853(G,T); rs659710(A,G); rs658285(G,A); rs116022276(C,T); rs78165833(G,A); rs646606(A,G); rs706482(C,A); rs679477(T,C); rs74867817(G,A); rs1960384(C,A); rs114930135(C,T); rs7553563(G,A); rs78415143(G,A); rs649069(C,A); rs614020(G,A); rs115511830(G,A); rs647571(T,C); rs145514947(G,T); rs75015103(A,G); rs138138954(C,T); rs706483(T,C); rs142321498(C,A); rs41452950(A,G); rs585762(A,G); rs620092(C,T); rs664979(A,G); rs114173524(A,G); rs617283(A,G); rs7525070(C,T); rs56023405(A,C); rs7541538(T,C); rs1013579(C,T); rs12067507(C,T); rs114982349(G,C); rs7542230(T,C); rs605632(C,T); rs604842(C,G); rs146494180(T,G); rs586902(T,C); rs683916(A,T); rs112036408(G,A); rs668555(T,C); rs12092641(T,C); rs72670376(G,A); rs7512725(T,C); rs637253(A,G); rs599857(T,C); rs706484(T,C); rs737097(G,A); rs927212(T,C); rs927211(G,A); rs927210(A,G); rs150683548(A,T); rs2236217(C,A); rs2236216(C,T); rs146092968(T,C); rs61767007(G,A); rs78501968(G,A); rs75000477(A,G) |
| ccdsGene name | CCDS30730.1 |
| cytoBand name | 1p32.2 |
| EntrezGene GeneID | 732 |
| EntrezGene Description | complement component 8, beta polypeptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C8B:NM_001278543:exon8:c.C856T:p.R286C,C8B:NM_001278544:exon8:c.C826T:p.R276C,C8B:NM_000066:exon7:c.C1012T:p.R338C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6249 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F5H7G1 |
| dbNSFP KGp1 AF | 0.00228937728938 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.002296 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0001626 |
OMIM Clinical Significance
Immunology:
Partial C4 deficiency;
Systemic lupus erythematosus
Inheritance:
Autosomal dominant
OMIM Title
*120960 COMPLEMENT COMPONENT 8, BETA SUBUNIT; C8B
;;COMPLEMENT COMPONENT C8B;;
C8 BETA
OMIM Description
DESCRIPTION
The eighth component of complement (C8) belongs to the late-acting
complement proteins (C5-C9) forming the membrane attack complex. C8 is a
serum protein that consists of 3 nonidentical subunits arranged
asymmetrically as a disulfide-linked alpha-gamma dimer (C8A, 120950;
C8G, 120930) and a noncovalently associated beta chain (C8B). Each
component is encoded by a different gene (Ng et al., 1987; Kaufmann et
al., 1993).
GENE STRUCTURE
Herrmann et al. (1989) estimated the size of the C8B gene to be 32 to 36
kb.
By using PCR primers located in the adjacent intron sequences of C8B,
Kaufmann et al. (1993) could amplify all 12 exons of the C8B gene from
genomic DNA. These analyses and the insert sizes of the genomic lambda
clones indicated that the C8B gene has a total size of approximately 40
kb.
MAPPING
The C8A and C8B genes are closely linked on chromosome 1p (Rogde et al.,
1986).
Bahary et al. (1991) mapped the murine homolog of C8B to chromosome 4.
MOLECULAR GENETICS
By direct sequence analysis of all exon-specific PCR products from
normal and C8B-deficient persons, Kaufmann et al. (1993) found a single
C-T change in exon 9 leading to a stop codon (R428X; 120960.0001). An
allele-specific PCR system was designed to detect the normal and the
deficiency allele simultaneously. Using this approach as well as PCR
typing of the TaqI polymorphism located in intron 11, 5 families with 7
C8B-deficient members were investigated. The mutant allele was observed
in all families investigated and could therefore be regarded as a major
cause of C8B deficiency in Caucasians. In 2 C8B-deficient patients, only
1 chromosome carried the C-T change; the molecular nature of the other
allele had not been determined.
In a study of 34 unrelated families with C8B deficiency from the U.S.
and the former U.S.S.R., Saucedo et al. (1995) found that 59 (86%) of 69
null alleles were due to the C-to-T transition in exon 9. An additional
6 null alleles were caused by C-to-T transitions in exons 3 (120960.0003
and 120960.0004) and 6 (120960.0002). Two null alleles were caused by
cytosine deletions in exons 3 (120960.0005) and 5 (120960.0006). Of the
null alleles, 97% were C-to-T transitions in which an arg (64 alleles)
or gln (1 allele) was replaced by a stop codon.
- C8B Mutation Nomenclature
Using current recommendations for mutation nomenclature, Arnold et al.
(2009) numbered nucleotides of the C8B gene starting at the A of the ATG
translational start site of the coding reference sequence GENBANK
NM_000066. They noted that, traditionally, C8B nucleotides had been
numbered starting at the 5-prime end of cDNA clone GENBANK M16973. In
their Table 2, Arnold et al. (2009) provided a comparison of the
recommended mutation nomenclature used by them with the traditional
mutation nomenclature used by others, including Kaufmann et al. (1993),
Saucedo et al. (1995), and Rao et al. (2004), along with the
corresponding protein changes.
TACSTD2
| dbSNP name | rs7333(C,T); rs9583(T,C); rs3551(A,G); rs41311174(C,T) |
| cytoBand name | 1p32.1 |
| EntrezGene GeneID | 4070 |
| EntrezGene Description | tumor-associated calcium signal transducer 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2241 |
OMIM Clinical Significance
GI:
Giant hypertrophic gastritis;
Enlarged gastric mucosal folds
Lab:
Gastric glandular proliferation with nuclear polarity preservation
and cystic dilatation of gland base;
Hypochlorhydria;
Hypoproteinemia;
recessive
OMIM Title
*137290 TUMOR-ASSOCIATED CALCIUM SIGNAL TRANSDUCER 2; TACSTD2
;;MEMBRANE COMPONENT, CHROMOSOME 1, SURFACE MARKER 1; M1S1;;
GASTROINTESTINAL TUMOR-ASSOCIATED ANTIGEN 1, 40-KD GLYCOPROTEIN; GA733-1;;
GA733
OMIM Description
DESCRIPTION
The monoclonal antibody GA733 was derived from the immunization of mice
with a human stomach adenocarcinoma cell line. It has specificity to
carcinomas of other origins, such as the cervix, bladder, and lung.
CLONING
Linnenbach et al. (1989) purified the antigen from a human colorectal
carcinoma cell line and determined its partial amino acid sequence. By
using a synthetic oligonucleotide probe, they isolated 2 recombinants
from a total human genomic library. They demonstrated the existence of a
family of GA733 genes. One of the isolates had no introns; it was
transcribed in pancreatic carcinoma cell lines and in placenta. The
GA733 proteins were found to contain sequences homologous to a repeat
unit occurring 10 times in thyroglobulin (188450) and once in the
HLA-DR-associated invariant chain (142790).
Fornaro et al. (1995) cloned a cDNA encoding the GA733-1 from an ovarian
carcinoma cDNA expression library. The cDNA encodes a predicted
323-amino acid polypeptide of 35,709 Da that is 48% similar to the
GA733-2 polypeptide (EPCAM; 185535). The regions of homology cluster in
2 extracytoplasmic domains and in the putative transmembrane/cytoplasmic
region. A potential cytoplasmic phosphorylation site is also conserved.
The gene is also designated M1S1 for membrane component, chromosome 1,
surface marker 1.
GENE STRUCTURE
Linnenbach et al. (1993) stated that the single-exon gene encoding
GA733-1 contains a long ORF of 323 amino acids encoding a predicted
35.7-kD protein with 4 potential N-linked glycosylation sites. The
authors found that the amino acid sequences of GA733-1 and of the
314-residue GA733-2 predicted protein are 49% identical. From additional
sequence studies of the 9-exon GA733-1 gene and comparisons of the
promoter regions of both GA733-1 and GA733-2 genes, Linnenbach et al.
(1993) concluded that the GA33-1 gene was formed by the retroposition of
the GA733-2 gene via an mRNA intermediate.
MAPPING
Linnenbach et al. (1993) mapped the GA733-1 gene to either 1p32-p31 or
to 1p13-q12 using of human/rodent somatic cell hybrid analysis. By FISH,
Calabrese et al. (2001) mapped the TACSTD2 gene to 1p32.
MOLECULAR GENETICS
Using linkage analysis, Tsujikawa et al. (1999) mapped gelatinous
drop-like corneal dystrophy (GDLD; 204870) to a 400-kb critical region
that included M1S1. Expression analysis indicated that M1S1 is expressed
in the cornea as well as in kidney, lung, placenta, pancreas, and
prostate. All 26 affected members of 20 Japanese families were found to
be homozygotes or compound heterozygotes for 4 mutations: gln118 to ter
(Q118X; 137290.0001), gln207 to ter (Q207X; 137290.0002), ser170 to ter
(S170X; 137290.0003), and 632delA (137290.0004). The Q118X mutation
accounted for 33 of 40 (82.5%) of disease alleles. Protein expression
analysis revealed aggregation of the mutated, truncated protein in the
perinuclear region, whereas the normal protein was distributed diffusely
in the cytoplasm with a homogeneous or fine granular pattern.
Ren et al. (2002) extended molecular studies of GDLD to patients with
diverse ethnic backgrounds. They performed linkage analyses in 8
unrelated GDLD families from India, the U.S., Europe, and Tunisia. In 7
of these families, the disease locus mapped to a 16-cM interval on the
short arm of chromosome 1 that included the region of the M1S1 gene. In
addition, a 1.2-kb fragment containing the entire coding region of the
M1S1 gene was sequenced in affected individuals. Seven novel mutations
were identified in 6 families and 2 unrelated individuals. No sequence
abnormalities were detected in a single family in which the GDLD locus
was also excluded from the M1S1 region by linkage analysis. These
findings demonstrated allelic and locus heterogeneity for GDLD.
JUN
| dbSNP name | rs2760499(G,C); rs4647011(C,A); rs2811894(T,G); rs1407816(G,C) |
| cytoBand name | 1p32.1 |
| EntrezGene GeneID | 3725 |
| EntrezGene Description | jun proto-oncogene |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0404 |
OMIM Clinical Significance
Eyes:
Progressive ophthalmoplegia
Mouth:
Scrotal tongue
Neuro:
Mental retardation
Inheritance:
Autosomal dominant
OMIM Title
*165160 V-JUN AVIAN SARCOMA VIRUS 17 ONCOGENE HOMOLOG; JUN
;;ONCOGENE JUN
ACTIVATOR PROTEIN 1, INCLUDED; AP1, INCLUDED;;
ENHANCER-BINDING PROTEIN AP1, INCLUDED
OMIM Description
DESCRIPTION
The oncogene JUN is the putative transforming gene of avian sarcoma
virus 17; it appears to be derived from a gene of the chicken genome and
has homologs in several other vertebrate species. (The name JUN comes
from the Japanese 'ju-nana,' meaning the number 17.) JUN was originally
thought to be identical to the transcription factor AP1. However, it is
now known that AP1 is not a single protein, but constitutes a group of
related dimeric basic region-leucine zipper proteins that belong to the
JUN, FOS (164810), MAF (177075), and ATF (see 603148) subfamilies. The
various dimers recognize either 12-O-tetradecanoylphorbol-13-acetate
(TPA) response elements or cAMP response elements. JUN is the most
potent transcriptional activator in its group, and its transcriptional
activity is attenuated and sometimes antagonized by JUNB (165161). For a
review of the structure and function of the AP1 transcription complexes,
see Shaulian and Karin (2002).
CLONING
Bohmann et al. (1987) isolated the human protooncogene JUN and found
that the deduced amino acid sequence is more than 80% identical to that
of the viral protein. Expression of cloned cDNA in bacteria produced a
protein with sequence-specific DNA-binding properties identical to the
phorbol ester-inducible enhancer-binding protein AP1. Antibodies raised
against 2 distinct peptides derived from JUN reacted specifically with
human AP1. In addition, partial amino acid sequence of purified AP1
revealed tryptic peptides in common with the JUN protein. Nucleotide
sequence analysis indicated that the COOH-terminus of JUN is similar to
the corresponding part of a yeast transcriptional activator.
Hattori et al. (1988) isolated a genomic clone of human JUN and
determined its primary structure and transcription pattern. Transfection
experiments showed that the cloned gene is functional, as it encodes a
trans-acting factor that stimulates transcription of an AP1-dependent
reporter gene.
GENE FUNCTION
Lamph et al. (1988) investigated regulation of murine c-jun gene
transcription and found that both serum and phorbol-ester TPA induced
c-jun gene expression.
Marx (1988) reviewed information indicating that the protein encoded by
the JUN gene acts directly to activate gene transcription in response to
cell stimulation; that the product of the FOS oncogene cooperates with
the JUN product in fostering gene transcription; that there is a
structural and functional similarity between JUN and GCN4, which induces
the activity of a large set of genes needed for amino acid synthesis in
yeast; that specifically both have a DNA-binding domain on the carboxyl
end essential for the activation of genes; that the JUN and FOS proteins
are held together in a complex by a leucine zipper; and that there are
other JUN genes in addition to the original one.
Shaulian et al. (2000) found that in mouse fibroblasts, Jun was
necessary for cell cycle reentry of ultraviolet (UV)-irradiated cells
but did not participate in the response to ionizing radiation. Cells
lacking Jun underwent prolonged cell cycle arrest but resisted
apoptosis, whereas cells that expressed Jun constitutively did not
arrest and undergo apoptosis. This function of Jun was exerted through
negative regulation of p53 (191170) association with the p21 (116899)
promoter. Cells lacking Jun exhibited prolonged p21 induction, whereas
constitutive Jun inhibited UV-mediated p21 induction.
Whitfield et al. (2001) noted that apoptosis induced in rat sympathetic
neurons by nerve growth factor (NGF; see 162030) withdrawal can be
blocked by inhibitors of RNA and protein synthesis. They presented
experimental evidence that activation of the JNK (see 601158)/JUN
pathway and increased expression of BIM (603827) are key events required
for cytochrome c release and apoptosis following NGF withdrawal.
Sphingosylphosphocholine (SPC) is a deacylated derivative of
sphingomyelin known to accumulate in Niemann-Pick disease type A
(257200). SPC is a potent mitogen that increases intracellular free
Ca(2+) and free arachidonate through pathways that are only partly
protein kinase C-dependent. Berger et al. (1995) showed that SPC
increases specific DNA-binding activity of transcription activator AP1
in electrophoretic mobility-shift assays.
Using a Drosophila model synapse, Sanyal et al. (2002) analyzed cellular
functions and regulation of the immediate-early transcription factor
AP1, a heterodimer of the basic leucine zipper proteins FOS and JUN.
They observed that AP1 positively regulates synaptic strength and
synapse number, thus showing a greater range of influence than CREB
(123810). Observations from genetic epistasis and RNA quantification
experiments indicate that AP1 acts upstream of CREB, regulates levels of
CREB mRNA, and functions at the top of the hierarchy of transcription
factors known to regulate long-term plasticity. A JUN-kinase signaling
module provided a CREB-independent route for neuronal AP1 activation;
thus, CREB regulation of AP1 expression may, in some neurons, constitute
a positive feedback loop rather than the primary step in AP1 activation.
Mathas et al. (2002) found AP1 constitutively activated, with robust JUN
and JUNB overexpression, in all cell lines derived from patients with
classical Hodgkin lymphoma (236000) and anaplastic large cell lymphoma
(ALCL), but not in other lymphoma types. AP1 supported proliferation of
Hodgkin cells, but suppressed apoptosis of ALCL cells. Mathas et al.
(2002) noted that, whereas JUN is upregulated by an autoregulatory
process, JUNB is under the control of nuclear factor kappa-B (NFKB;
164011). They found that AP1 and NFKB cooperate and stimulate expression
of the cell cycle regulator cyclin D2 (123833), the protooncogene MET
(164860), and the lymphocyte homing receptor CCR7 (600242), which are
all strongly expressed in primary Hodgkin/Reed-Sternberg (HRS) cells.
Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun by assembling a multisubunit ubiquitin ligase containing
DNA damage-binding protein-1 (DDB1; 600045), cullin 4A (CUL4A; 603137),
regulator of cullins-1 (ROC1; 603814), and constitutively
photomorphogenic-1 (COP1; 608067). Ablation of any subunit by RNA
interference stabilized c-Jun and increased c-Jun-activated
transcription. Wertz et al. (2004) concluded that their findings
characterized a c-Jun ubiquitin ligase and define a specific function
for DET1 in mammalian cells.
JUN and N-terminal kinases (JNK) are essential for neuronal microtubule
assembly and apoptosis. Phosphorylation of the activating protein 1
(AP1) transcription factor c-Jun, at multiple sites within its
transactivation domain, is required for JNK-induced neurotoxicity.
Nateri et al. (2004) reported that in neurons the stability of c-Jun is
regulated by the E3 ligase SCF(Fbw7) (FBXW7; 606278), which
ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.
Fbxw7 depletion resulted in accumulation of phosphorylated c-Jun,
stimulation of AP1 activity, and neuronal apoptosis. SCF-7 therefore
antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling,
allowing neurons to tolerate potentially neurotoxic JNK activity.
Fang and Kerppola (2004) found evidence that JUN proteins ubiquitinated
by ITCH (606409) are targeted to lysosomes for degradation. Mutation of
the ITCH recognition motif in the N terminus of JUN eliminated its
ubiquitination and increased its stability.
Ikeda et al. (2004) generated transgenic mice expressing
dominant-negative c-Jun specifically in the osteoclast lineage and found
that they developed severe osteopetrosis due to impaired
osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited
soluble RANKL (602642)-induced osteoclast differentiation in vitro.
Overexpression of nuclear factor of activated T cells 1 (NFATC2; 600490)
or NFATC1 (600489) promoted differentiation of osteoclast precursor
cells into tartrate-resistant acid phosphatase-positive (TRAP-positive)
multinucleated osteoclast-like cells even in the absence of RANKL. These
osteoclastogenic activities of NFAT were abrogated by overexpression of
dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun
signaling in cooperation with NFAT is crucial for RANKL-regulated
osteoclast differentiation.
Gao et al. (2004) found in the case of c-JUN and JUNB that extracellular
stimuli modulate protein turnover by regulating the activity of an E3
ligase by means of its phosphorylation. Activation of the Jun
amino-terminal kinase (JNK; see 601158) mitogen-activated protein kinase
(MAPK) cascade after T cell stimulation accelerated degradation of c-JUN
and JUNB through phosphorylation-dependent activation of the E3 ligase
ITCH. Gao et al. (2004) found that this pathway modulates cytokine
production by effector T cells.
Nateri et al. (2005) showed that phosphorylated c-JUN interacts with the
HMG-box transcription factor TCF4 (TCF7L2; 602228) to form a ternary
complex containing c-JUN, TCF4, and beta-catenin (see 116806). Chromatin
immunoprecipitation assays revealed JNK-dependent c-JUN-TCF4 interaction
on the c-JUN promoter, and c-JUN and TCF4 cooperatively activated the
c-JUN promoter in reporter assays in a beta-catenin-dependent manner. In
the Apc(Min) mouse model of intestinal cancer (see 611731), genetic
abrogation of c-JUN N-terminal phosphorylation or gut-specific
conditional c-JUN inactivation reduced tumor number and size and
prolonged life span. Therefore, Nateri et al. (2005) concluded that the
phosphorylation-dependent interaction between c-JUN and TCF4 regulates
intestinal tumorigenesis by integrating JNK and APC/beta-catenin, 2
distinct pathways activating WNT signaling.
Koyama-Nasu et al. (2007) showed that FBL10 (FBXL10; 609078) interacted
with JUN and repressed JUN-mediated transcription in human cell lines.
Chromatin immunoprecipitation assays demonstrated that FBL10 was present
at the JUN promoter and that JUN was required for recruitment of FBL10.
FBL10 bound unmethylated CpG sequences in the JUN promoter through its
CxxC zinc finger and tethered transcriptional repressor complexes.
Suppression of FBL10 expression by RNA interference induced
transcription of JUN and JUN target genes and caused aberrant cell cycle
progression and increased UV-induced cell death. Furthermore, FBL10
protein and mRNA were downregulated in response to UV in an inverse
correlation with JUN. Koyama-Nasu et al. (2007) concluded that FBL10 is
a key regulator of JUN function.
Aguilera et al. (2011) demonstrated that unphosphorylated, but not
N-terminally phosphorylated, c-Jun interacts with MBD3 (603573) and
thereby recruits the nucleosome remodeling and histone acetylation
(NuRD) repressor complex. MBD3 depletion in colon cancer cells increased
histone acetylation at AP1-dependent promoters, which resulted in
increased target gene expression. The intestinal stem cell marker LGR5
(606667) was identified as a novel target gene controlled by c-Jun/MBD3.
Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun
activity and increased progenitor cell proliferation. In response to
inflammation, Mbd3 deficiency resulted in colonic hyperproliferation,
and Mbd3 gut-null mice showed markedly increased susceptibility to
colitis-induced tumorigenesis. Aguilera et al. (2011) noted that
concomitant inactivation of a single allele of c-Jun reverted
physiologic and pathologic hyperproliferation, as well as the increased
tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of
c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression,
and this repression is relieved by JNK (601158)-mediated c-Jun
N-terminal phosphorylation.
Using chromatin immunoprecipitation sequencing in T-helper-17 (TH17)
cells, Glasmacher et al. (2012) found that IRF4 (601900) targets
sequences enriched for AP1-IRF composite elements (AICEs) that are
cobound by BATF (612476), an AP1 factor required for TH17, B, and
dendritic cell differentiation. IRF4 and BATF bind cooperatively to
structurally divergent AICEs to promote gene activation and TH17
differentiation. The AICE motif directs assembly of IRF4 or IRF8
(601565) with BATF heterodimers and is also used in TH2, B, and
dendritic cells. Glasmacher et al. (2012) concluded that this genomic
regulatory element and cognate factors appear to have evolved to
integrate diverse immunomodulatory signals.
GENE STRUCTURE
Hattori et al. (1988) determined that the JUN gene has no introns.
MAPPING
Haluska et al. (1988) isolated a genomic DNA clone encompassing the JUN
gene and used it to determine the chromosomal location. Southern blot
analysis of a rodent-human somatic cell hybrid panel indicated that JUN
is situated on 1p. In situ hybridization narrowed the assignment to
1p32-p31, a chromosomal region involved in both translocations and
deletions in human malignancies. By in situ hybridization, Hattori et
al. (1988) mapped JUN to 1p32-p31.
Mattei et al. (1990) mapped the mouse homolog to chromosome 4. Bahary et
al. (1991) presented molecular genetic linkage maps of mouse chromosome
4 which established the breakpoints in the mouse 4/human 1p region of
homology to a 2-cM interval between Ifa and Jun in mouse and to the
interval between JUN and ACADM (607008) in the human.
ANIMAL MODEL
Hilberg et al. (1993) developed Jun-null mice by gene targeting.
Heterozygous mutant mice appeared normal, but embryos lacking Jun died
between midgestation and late gestation and exhibited impaired
hepatogenesis, altered fetal liver erythropoiesis, and generalized
edema. Jun-defective embryonic stem cells were able to participate in
the development of all somatic cells in chimeric mice except liver
cells, indicating an essential function of Jun in hepatogenesis.
By alanine substitution of ser63 and ser73 of mouse Jun, Behrens et al.
(1999) demonstrated that phosphorylation on these residues was required
for several apoptotic functions. Mouse fibroblasts carrying mutated Jun
had proliferation- and stress-induced apoptotic defects accompanied by
reduced AP1 activity. Mutant mice were smaller than controls, and they
were resistant to epileptic seizures and neuronal apoptosis induced by
the excitotoxic amino acid kainate. Primary mutant neurons were also
protected from apoptosis.
Eferl et al. (2003) used liver-specific inactivation of Jun at different
stages of tumor development to study its role in chemically induced
hepatocellular carcinomas (HCCs) in mice. The requirement for Jun was
restricted to early stages of tumor development, and the number and size
of hepatic tumors was dramatically reduced when Jun was inactivated
after the tumor had initiated. The impaired tumor development correlated
with increased levels of p53 and its target gene Noxa (PMAIP1; 604959),
resulting in the induction of apoptosis without affecting cell
proliferation. Primary hepatocytes lacking Jun showed increased
sensitivity to tumor necrosis factor-alpha (TNF; 191160)-induced
apoptosis, which was abrogated in the absence of p53. These data
indicated that JUN prevents apoptosis by antagonizing p53 activity,
illustrating a mechanism that might contribute to the early stages of
human HCC development.
MGC34796
| dbSNP name | rs7554821(G,A); rs7532243(A,C); rs74076108(G,A); rs7532358(A,G); rs1061882(A,C); rs138477680(G,C); rs6587940(T,C); rs6700526(T,C); rs111412799(C,T); rs6587941(G,A) |
| cytoBand name | 1p31.3 |
| EntrezGene GeneID | 414927 |
| snpEff Gene Name | RP11-430G17.1 |
| EntrezGene Description | sepiapterin reductase (7,8-dihydrobiopterin:NADP+ oxidoreductase) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3095 |
FOXD3
| dbSNP name | rs6588025(T,C) |
| cytoBand name | 1p31.3 |
| EntrezGene GeneID | 27022 |
| EntrezGene Description | forkhead box D3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2213 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, right ventricular;
Fibrofatty replacement of right ventricular myocardium;
Ventricular arrhythmia (sustained VT);
Syncope
SKIN, NAILS, HAIR:
[Skin];
Normal skin (no palmoplantar keratoderma);
[Hair];
Normal hair (no woolly hair)
MISCELLANEOUS:
Genetic heterogeneity;
Allelic to Naxos disease (601214)
MOLECULAR BASIS:
Caused by mutation in the junction plakoglobin gene (JUP, 173325.0002).
OMIM Title
*611539 FORKHEAD BOX D3; FOXD3
;;HFH2;;
GENESIS, MOUSE, HOMOLOG OF
OMIM Description
CLONING
Sutton et al. (1996) cloned mouse Foxd3, which they called Genesis due
to its exclusive expression in primitive cells, from an embryonal
carcinoma cDNA library. The deduced 465-amino acid protein contains a
100-amino acid central winged helix domain and several domains and
motifs found in transcriptional regulators. Northern blot analysis
detected Genesis expression in mouse embryonic stem cells and embryonal
carcinoma cells, but not in other embryonic, neonatal, or adult tissues
or cells examined. Differentiation of mouse embryonal carcinoma cells
and mouse embryonic stem cells in culture led to downregulation of
Genesis expression.
Hanna et al. (2002) noted that FOXD3 is expressed during early
embryogenesis in the epiblast and later in neural crest cells, and that
FOXD3 expression is a diagnostic marker of human embryonic stem cell
lines. Using RT-PCR, they found that mouse Foxd3 was not expressed in
unfertilized oocytes or fertilized 1-cell embryos, but it was expressed
in blastocyst-stage embryos. In situ hybridization detected Foxd3
throughout the epiblast of 6.5-day postcoitum embryo, with faint
expression in the extraembryonic region.
MAPPING
By interspecific backcross analysis, Sutton et al. (1996) mapped the
mouse Foxd3 gene to a region of chromosome 4 that shares homology of
synteny with human chromosome 1p31.
GENE FUNCTION
Sutton et al. (1996) found that mouse Genesis bound to AT-rich sequences
and showed highly specific binding to the E2 stem cell enhancer.
Cotransfection assays revealed that Genesis repressed reporter gene
expression in a dose-dependent manner in embryonic kidney cells and HeLa
cells.
Guo et al. (2002) showed that mammalian Foxd3 and Oct4 (POU5F1; 164177)
bound identical regulatory DNA sequences in the osteopontin (SPP1;
166490) promoter. Oct4 interacted directly with Foxd3, and both proteins
activated the osteopontin promoter, either alone or in combination.
Foxd3 also activated the Foxa1 (602294) and Foxa2 (600288) promoters,
and coexpression of Oct4 inhibited Foxd3-mediated activation of these
promoters.
MOLECULAR GENETICS
In affected members of a large family with autosomal dominant vitiligo
(see AIS1; 607836), Alkhateeb et al. (2005) identified a heterozygous
mutation in the promoter region of the FOXD3 gene (611539.0001). The
authors noted that FOXD3 is a regulator of melanoblast differentiation
and suggested that increased transcriptional activity conferred by the
promoter variant may suppress or alter the differentiation of
melanoblasts in these patients.
ANIMAL MODEL
Hanna et al. (2002) found that Foxd3 -/- mouse embryos died after
implantation at approximately 6.5 days postcoitum with loss of epiblast
cells, expansion of proximal extraembryonic tissues, and a distal,
mislocalized anterior organizing center. Chimera analysis revealed that
Foxd3 function was required in the epiblast and that Foxd3 -/- embryos
could be rescued by a small number of wildtype cells. Foxd3 -/-
blastocysts appeared morphologically normal and expressed Oct4, Sox2
(184429), and Fgf4 (164980), but when placed in vitro, the inner cell
mass proliferated initially and then failed to expand. Hanna et al.
(2002) concluded that FOXD3 is required for maintenance of progenitor
cells in the embryo.
MIR4794
| dbSNP name | rs17126710(C,T) |
| ccdsGene name | CCDS628.2 |
| cytoBand name | 1p31.3 |
| EntrezGene GeneID | 100616338 |
| snpEff Gene Name | CACHD1 |
| EntrezGene Description | microRNA 4794 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0225 |
| ExAC AF | 0.006524 |
MIR3671
| dbSNP name | rs147004258(C,T); rs521188(A,G) |
| cytoBand name | 1p31.3 |
| EntrezGene GeneID | 101927106 |
| EntrezGene Symbol | LOC101927106 |
| snpEff Gene Name | MIR101-1 |
| EntrezGene Description | uncharacterized LOC101927106 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
SNORD45B
| dbSNP name | rs11161620(G,A) |
| ccdsGene name | CCDS669.1 |
| cytoBand name | 1p31.1 |
| EntrezGene GeneID | 26804 |
| snpEff Gene Name | ACADM |
| EntrezGene Description | small nucleolar RNA, C/D box 45B |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1671 |
| ESP Afr MAF | 0.13984 |
| ESP All MAF | 0.224451 |
| ESP Eur/Amr MAF | 0.261678 |
| ExAC AF | 0.202,8.339e-06 |
COL24A1
| dbSNP name | rs1047895(C,T); rs1047893(T,C); rs1047892(A,C); rs17128149(T,C); rs12564080(A,C); rs12067749(T,C); rs2389973(T,C); rs145625932(C,T); rs76710587(C,T); rs1481200(C,T); rs12037785(C,A); rs61783080(G,A); rs7528385(A,G); rs79033646(A,G); rs114069383(T,C); rs4379699(T,A); rs6686719(T,C); rs2389974(C,T); rs2389975(C,G); rs12756365(A,G); rs12756841(G,A); rs6576788(T,C); rs6576789(G,A); rs143474342(A,G); rs7529942(C,A); rs7532758(C,T); rs7554621(G,A); rs7544908(A,G); rs7535884(C,T); rs6682235(C,T); rs2014750(A,T); rs2014733(A,T); rs10873718(C,G); rs10873719(G,A); rs12128916(A,T); rs7547023(G,A); rs10747324(G,A); rs6673975(C,T); rs77796844(C,T); rs399547(C,T); rs432254(C,T); rs450953(G,C); rs420515(C,T); rs2785081(G,A); rs414618(G,A); rs369999(G,A); rs381453(C,G); rs1813656(A,G); rs434853(A,T); rs373787(A,G); rs401657(C,A); rs438401(A,G); rs444875(A,G); rs383558(T,C); rs425357(A,T); rs430956(G,C); rs114431428(G,A); rs419409(C,G); rs424205(C,T); rs142806826(G,C); rs447446(C,T); rs429040(A,G); rs417887(G,A); rs418979(A,G); rs7521240(C,T); rs2785083(C,G); rs138939351(A,T); rs2764470(T,C); rs550329(G,A); rs77329135(T,C); rs369318(T,C); rs369314(T,C); rs17128257(A,G); rs10493775(C,T); rs392038(G,A); rs426831(T,C); rs366516(G,A); rs6698578(G,A); rs116725229(T,G); rs399514(T,C); rs12046489(T,A); rs6697548(T,C); rs450145(T,C); rs402885(G,T); rs142770795(A,G); rs61783134(G,T); rs184340(A,T); rs75371830(G,A); rs720619(A,G); rs313726(C,G); rs313727(C,T); rs17396994(A,G); rs313728(C,T); rs313729(A,T); rs77139550(C,T); rs313722(A,C); rs12562146(T,A); rs12563027(A,G); rs12075929(C,A); rs313723(C,A); rs12754358(C,T); rs313724(C,T); rs17128307(C,T); rs41331746(G,A); rs41371348(A,C); rs41289767(T,C); rs313725(A,G); rs366214(T,C); rs185076467(G,C); rs486417(C,T); rs188851164(T,C); rs313710(T,C); rs12128605(C,T); rs313711(G,A); rs12753056(G,A); rs313712(G,A); rs313713(G,A); rs11579570(A,T); rs313714(C,G); rs313715(G,T); rs313716(T,C); rs313717(T,C); rs313719(A,G); rs74097092(A,G); rs313720(G,C); rs313721(T,C); rs7539262(G,A); rs313731(T,A); rs313732(A,G); rs313733(A,G); rs193398(T,C); rs313734(T,C); rs313735(T,A); rs313736(C,T); rs191199838(G,A); rs313737(G,C); rs191470812(T,A); rs673506(A,G); rs61783136(G,A); rs432168(G,A); rs380654(C,G); rs414143(G,C); rs366187(G,A); rs76408018(C,T); rs1977331(T,C); rs598104(A,T); rs72950669(C,T); rs412328(G,T); rs12727784(A,G); rs190084664(T,C); rs449901(T,C); rs151255686(C,T); rs6677315(G,C); rs313738(C,A); rs187287483(G,A); rs313739(T,C); rs167518(T,C); rs313740(G,A); rs10159046(T,C); rs313741(A,T); rs12239978(C,T); rs313742(C,T); rs10158651(G,T); rs6576790(C,T); rs313744(G,A); rs172694(G,A); rs313745(G,T); rs11161677(C,T); rs78726658(G,A); rs313746(A,G); rs313747(G,A); rs313756(C,T); rs10873722(T,C); rs11161678(T,C); rs313757(C,A); rs313758(A,G); rs313759(T,G); rs78426121(G,A); rs6698633(T,C); rs12091583(C,A); rs313760(G,A); rs6576791(T,A); rs6576792(C,T); rs186376(G,T); rs6693669(C,T); rs186980825(G,A); rs1481199(G,A); rs1842579(C,T); rs6697619(T,C); rs313748(A,T); rs313762(C,G); rs313761(G,C); rs7535390(G,A); rs6661124(C,T); rs34635832(T,A); rs6676346(T,A); rs10873723(C,A); rs12727916(T,C); rs6665363(T,A); rs12760458(A,C); rs12077825(G,A); rs12098168(C,T); rs12088004(A,C); rs172693(T,C); rs11161686(C,T); rs1325260(A,G); rs72952531(G,A); rs11161687(T,C); rs313705(G,A); rs4912446(G,A); rs313706(T,C); rs10873725(T,A); rs980054(T,C); rs313698(G,T); rs313699(G,T); rs112710367(T,C); rs184339(G,T); rs4912437(C,A); rs313700(G,A); rs2297744(A,G); rs1010058(C,A); rs313701(A,T); rs115578936(T,C); rs313702(C,T); rs313703(T,C); rs313704(T,A); rs6576793(C,T); rs7530839(C,T); rs1962482(G,T); rs80059966(C,T); rs72952543(G,A); rs6695874(A,G); rs2170331(G,A); rs313707(A,G); rs11161689(C,T); rs12033218(C,T); rs313708(A,G); rs11161691(A,G); rs313709(T,C); rs556247(G,A); rs12091504(G,A); rs75241249(G,A); rs435007(T,A); rs428475(T,A); rs12124109(A,G); rs1904947(C,T); rs61785081(G,A); rs113318459(C,G); rs629140(G,C); rs383588(G,A); rs445782(G,A); rs6657706(C,T); rs437257(G,A); rs188559024(C,T); rs1871763(G,A); rs183188257(C,T); rs313763(C,T); rs12759687(T,C); rs186063872(T,C); rs313764(A,G); rs190756234(A,T); rs7523196(T,C); rs79843903(G,A); rs7520948(A,C); rs7554796(C,T); rs79683227(G,A); rs313765(A,C); rs313766(C,T); rs313767(A,G); rs11161692(C,T); rs188763(A,G); rs2256515(T,G); rs2795038(C,T); rs313768(C,G); rs313769(T,C); rs12119433(G,C); rs313770(A,G); rs313771(T,C); rs313772(T,C); rs313773(A,G); rs313774(A,G); rs313775(T,A); rs17411495(T,C); rs11161693(T,C); rs12029238(T,C); rs7544141(G,A); rs115406208(A,G); rs114937096(C,A); rs115646722(G,A); rs7549218(T,C); rs11161695(G,T); rs10873731(G,A); rs11161696(G,T); rs72952569(T,C); rs12136023(C,A); rs1564518(T,C); rs1564517(G,A); rs7524286(C,T); rs2086495(G,T); rs1564516(T,C); rs1564515(A,G); rs7536101(A,G); rs12122234(G,A); rs11161697(A,G); rs12735496(T,A); rs12739425(T,C); rs12739620(T,G); rs12725203(A,G); rs12725350(A,G); rs2892901(T,G); rs11161698(G,A); rs1072508(A,G); rs1072509(C,A); rs12740827(A,G); rs12740836(A,T); rs35841238(T,G); rs12144570(C,T); rs2170333(T,C); rs12757388(C,T); rs181016821(A,C); rs12755267(T,C); rs6701281(T,G); rs7542433(C,A); rs7556366(T,C); rs112826747(A,G); rs12727503(T,G); rs11589722(C,A); rs10732722(A,G); rs12732365(T,C); rs6671033(G,A); rs183828669(T,C); rs151195339(C,T); rs187387365(A,G); rs1965928(G,A); rs113094868(G,A); rs112245942(C,T); rs74679611(A,T); rs4912448(G,A); rs35545564(G,A); rs72712703(A,G); rs12726975(T,C); rs72712704(C,T); rs7512136(G,A); rs12746617(T,C); rs74378859(C,T); rs4912449(C,T); rs7541806(C,G); rs184802021(G,A); rs192265505(C,T); rs12133355(G,A); rs59056351(A,C); rs729102(A,G); rs12088838(T,C); rs2047788(A,G); rs142230937(A,G); rs1604568(A,G); rs1604567(T,C); rs72952597(G,T); rs11812027(A,G); rs143821366(C,T); rs10873732(A,G); rs75739884(C,T); rs146865780(A,T); rs181677382(G,A); rs10493776(T,G); rs138147770(T,C); rs1858556(T,C); rs12753255(A,C); rs1481202(G,A); rs17128475(A,C); rs10873734(A,G); rs997439(A,C); rs146900574(C,T); rs12568820(T,C); rs4146294(C,T); rs1481201(T,C); rs1502657(C,G); rs41306625(G,A); rs10493777(C,T); rs12747420(G,A); rs61785115(T,C); rs11161709(C,T); rs6703317(G,A); rs12752474(C,A); rs12734458(T,C); rs6703454(G,A); rs4486475(T,C); rs12043396(T,A); rs12568614(A,G); rs12120918(C,T); rs116258726(C,T); rs149173721(C,A); rs12136742(G,A); rs12567016(G,T); rs11161710(T,A); rs6702912(G,A); rs10782561(G,A); rs184361430(A,T); rs140606362(G,A); rs6695598(A,T); rs12755099(T,C); rs10873736(A,T); rs7516144(G,A); rs4912450(A,G); rs72712740(T,G); rs148912389(C,T); rs12564780(C,T); rs12564781(C,G); rs4272649(C,T); rs186778152(T,C); rs148454576(T,C); rs2174051(G,A); rs188537000(C,G); rs147078635(A,G); rs74511078(C,A); rs7556117(T,G); rs67487620(G,C); rs28571037(G,A); rs12407664(C,A); rs12740695(T,A); rs12759079(C,T); rs61785119(T,C); rs7526013(T,C); rs7512039(C,T); rs12751687(T,A); rs34589269(G,T); rs12742187(C,G); rs56301284(C,G); rs6673508(C,T); rs6699709(G,A); rs79159470(T,C); rs12032751(T,C); rs12745489(T,C); rs1112328(T,C); rs1112327(G,C); rs115430248(T,C); rs1112326(T,C); rs1587675(A,G); rs148387130(G,A); rs11161711(C,T); rs180840846(G,A); rs185785251(C,T); rs12723176(C,T); rs7554463(G,T); rs7512890(G,A); rs7536689(C,A); rs603297(A,C); rs1359415(C,T); rs605060(G,A); rs1354245(G,A); rs12240129(C,T); rs76633767(G,A); rs606432(A,C); rs1698733(C,A); rs75650273(A,T); rs72712775(T,C); rs861933(G,A); rs4303095(T,C); rs79263818(A,T); rs4912438(C,G); rs524192(G,A); rs597330(T,C); rs499518(T,C); rs145683647(C,T); rs186531231(A,G); rs578615(A,G); rs6666627(G,A); rs77615990(T,C); rs72712786(A,T); rs658934(A,T); rs483498(C,T); rs188399367(G,T); rs6665006(T,C); rs12411184(C,T); rs560876(C,T); rs631632(A,G); rs72712794(A,G); rs189840789(A,G); rs35826410(C,T); rs72712798(T,C); rs180852183(T,C); rs12740060(T,C); rs486726(A,G); rs72712801(G,A); rs116045312(G,A); rs606678(G,C); rs12401802(C,G); rs12751341(T,C); rs12736249(C,T); rs686272(C,T); rs10493778(G,T); rs17404261(T,C); rs559247(C,T); rs182556280(C,T); rs12747217(C,T); rs187476242(T,C); rs7538391(T,C); rs115569806(G,T); rs4584420(A,G); rs111235134(C,T); rs625872(C,T); rs115154373(A,G); rs491358(A,G); rs573444(T,G); rs608460(C,T); rs693436(C,T); rs11803202(C,A); rs593146(G,A); rs146357607(C,T); rs1324898(G,T); rs4912440(T,G); rs533090(C,A); rs647977(C,G); rs474832(C,T); rs481277(G,T); rs681639(T,C); rs570288(G,T); rs141892706(G,A); rs489141(A,G); rs607336(T,C); rs522075(C,T); rs1853735(C,T); rs72714031(A,G); rs591634(C,A); rs556848(G,A); rs12405568(C,T); rs77480927(C,T); rs472286(T,G); rs682964(C,T); rs668874(G,T); rs188613663(G,C); rs10493780(C,T); rs633028(C,G); rs537408(T,C); rs35556419(G,T); rs537550(C,T); rs1359421(G,A); rs10493782(A,G); rs482789(C,T); rs482981(T,C); rs11799965(T,G); rs589698(C,T); rs144221275(G,A); rs518829(A,C); rs17413395(G,C); rs652321(C,T); rs472154(G,C); rs115866531(A,G); rs6656538(C,T); rs6672098(T,C); rs4912453(T,C); rs9988431(G,A); rs4912454(A,G); rs4306156(A,T); rs4272648(C,T); rs4350224(G,A); rs80133350(T,A); rs2390005(T,G); rs12134342(C,T); rs2390006(T,G); rs2390007(G,A); rs2390008(T,C); rs6576794(T,A); rs6576795(C,T); rs6676497(A,C); rs12127813(A,G); rs12120406(G,A); rs61617423(G,A); rs12025292(G,A); rs75952756(T,C); rs12039529(C,T); rs6704536(G,A); rs77024527(A,T); rs7537787(C,T); rs7551636(T,A); rs687776(T,C); rs7514604(G,A); rs12025755(T,C); rs12029153(A,G); rs11161713(A,G); rs11161714(T,C); rs11161715(A,G); rs12118004(G,A); rs12403155(T,G); rs6703296(A,G); rs12031047(A,G); rs12027751(T,G); rs12023979(G,A); rs12031105(A,G); rs12031129(A,C); rs7516083(T,C); rs7547149(C,T); rs10873740(T,C); rs142746940(C,T); rs79947224(C,T); rs11161717(A,G); rs12125053(T,C); rs12135956(C,T); rs55904692(A,C); rs55892290(T,C); rs55958413(C,A); rs56278817(T,C); rs17405077(A,G); rs17405097(T,C); rs17405131(T,C); rs12040977(C,T); rs12040981(C,T); rs663463(G,A); rs663901(T,C); rs664412(T,C); rs511363(A,T); rs17128656(A,T); rs676973(G,T); rs17413771(C,T); rs582517(A,G); rs139666759(T,G); rs567617(A,C); rs584883(T,C); rs584895(T,C); rs585708(A,G); rs586240(G,T); rs535637(A,G); rs599761(G,A); rs9701002(C,A); rs12079919(A,G); rs79832745(C,T); rs532684(A,C); rs612256(C,T); rs77225202(G,T); rs613060(T,C); rs11161719(T,C); rs77218022(A,G); rs615805(T,C); rs616281(T,C); rs500756(T,A); rs617652(G,T); rs617653(T,G); rs477562(C,T); rs368915304(G,A); rs6576798(T,C); rs471070(C,T); rs631512(C,A); rs580540(G,A); rs74793007(T,G); rs368622332(G,C); rs1324899(C,T); rs521253(G,A); rs519361(C,A); rs518538(A,C); rs635397(C,T); rs516799(G,A); rs648833(C,T); rs489385(A,G); rs61783511(A,G); rs489267(A,G); rs650216(G,A); rs662369(T,C); rs570172(A,G); rs664099(T,C); rs569409(C,T); rs567565(T,G); rs4912455(A,G); rs632295(C,T); rs632697(A,G); rs538256(G,T); rs634946(T,C); rs635391(C,T); rs635713(T,G); rs636210(T,C); rs511732(G,T); rs647380(T,C); rs648866(T,A); rs574780(C,T); rs551670(G,C); rs80160804(A,G); rs6687775(T,C); rs679256(C,A); rs547023(G,A); rs680179(T,C); rs521314(T,C); rs1629358(C,T); rs1698734(T,C); rs78716972(A,G); rs1698735(C,T); rs116144332(T,G); rs1359419(T,A); rs514185(A,G); rs589343(T,C); rs489325(A,G); rs600184(G,A); rs486680(C,T); rs601167(G,C); rs6679444(T,C); rs80261525(C,T); rs565639(C,T); rs616715(T,A); rs618555(T,C); rs191765683(C,T); rs505589(G,A); rs629683(C,T); rs629719(A,G); rs17405393(C,T); rs1698736(C,T); rs2390050(T,C); rs201609975(T,C); rs631054(C,T); rs501058(G,A); rs7525617(C,T); rs631935(C,A); rs477862(G,A); rs633604(C,T); rs7547855(G,T); rs7526060(C,T); rs474106(C,T); rs473232(T,C); rs557928(A,T); rs10493787(G,C); rs648355(G,A); rs648366(A,G); rs115186110(T,C); rs10518362(T,C); rs673928(C,G); rs12564959(T,A); rs78447538(G,A); rs494796(A,G); rs1698737(T,C); rs61800686(A,G); rs373880518(G,A); rs113035681(A,G); rs78713898(C,T); rs72716124(T,A); rs569419(T,A); rs61800687(C,T); rs56353901(T,C); rs143101162(T,C); rs541936(T,C); rs6691400(C,T); rs540159(T,C); rs11161721(C,A); rs516213(G,A); rs641712(G,A); rs367693606(G,A); rs485816(A,G); rs74611176(A,G); rs657026(A,G); rs657540(G,T); rs658313(C,T); rs12090143(C,G); rs565860(T,C); rs564224(T,C); rs17405880(G,A); rs112043150(C,T); rs17405900(A,G); rs74415151(T,C); rs17414470(C,A); rs17414498(G,C); rs17414519(G,A); rs1408668(A,G); rs7411998(G,A); rs587650(A,G); rs138631692(C,T); rs74586485(G,T); rs77366239(G,A); rs113773847(T,A); rs113386773(C,T); rs112240590(T,C); rs116737369(G,C); rs115312089(C,T); rs114331847(C,A); rs116250534(A,G); rs112351822(C,T); rs113578298(G,T); rs111401973(T,G); rs77091281(C,T); rs546269(G,C); rs4912442(A,C); rs4912459(C,T); rs4912443(A,G); rs614895(A,G); rs113739725(C,T); rs112496575(C,T); rs517786(C,T); rs17414568(G,A); rs17128758(A,G); rs56392000(A,G); rs77928364(G,A); rs78460661(A,G); rs76052536(A,G); rs17131759(A,C); rs17414617(G,A); rs17406104(A,G); rs80225189(C,T); rs79403884(A,C); rs112850770(C,G); rs17406138(G,A); rs1998684(G,A); rs569541(A,G); rs645271(C,T); rs17406173(C,T); rs56229462(T,G); rs55766419(T,C); rs12746006(T,G); rs74455415(A,T); rs113601896(T,C); rs72716130(C,T); rs582141(C,G); rs7414042(T,C); rs582622(C,T); rs1393554(T,A); rs1408667(C,T); rs12567495(T,C); rs598471(C,T); rs61800722(A,T); rs17414884(G,A); rs555289(G,C); rs7552516(C,G); rs72716134(C,T); rs71506583(C,T); rs17406450(T,C); rs695051(A,G); rs61800724(C,T); rs1408666(C,T); rs35982302(A,G); rs12079760(G,A); rs61800725(A,G); rs72716135(A,C); rs640303(T,C); rs79824627(T,C); rs61800726(T,C); rs652837(C,T); rs75113288(C,G); rs12740195(A,T); rs61800727(T,C); rs12740502(A,G); rs17406471(T,C); rs12402809(C,T); rs12143304(A,G); rs566108(A,C); rs12408108(G,C); rs72958291(G,T); rs182802083(T,A); rs72958294(C,A); rs610639(C,T); rs17128768(A,C); rs7552025(G,A); rs17406644(T,C); rs12567549(G,T); rs476149(A,C); rs12729383(G,A); rs12729890(G,T); rs12743320(C,T); rs12743750(G,A); rs12743345(A,G); rs141231558(C,T); rs12744993(G,T); rs12748565(A,G); rs12748730(C,A); rs182750736(T,C); rs138395177(C,T); rs142870790(C,T); rs17406755(G,A); rs60891279(C,T); rs541395(G,A); rs61800728(T,A); rs6674872(C,T); rs11487918(G,A); rs4912460(T,C); rs4912445(A,G); rs61800729(C,T); rs597669(G,A); rs79718851(A,G); rs17415366(C,T); rs182144208(C,T); rs680613(C,T); rs679734(C,T); rs72960324(G,A); rs498554(A,T); rs75782849(G,T); rs6658643(A,G); rs12754643(A,G); rs551219(T,C); rs12750946(T,C); rs12730639(A,G); rs485204(G,C); rs148484669(C,T); rs12354099(C,T); rs72716141(G,A); rs56040491(T,A); rs12077017(C,G); rs116562486(A,C); rs10518360(C,T); rs555578(A,T); rs34848727(T,C); rs12057842(G,A); rs61800732(T,G); rs583315(C,T); rs689040(T,C); rs72960354(C,T); rs6682503(G,A); rs12353970(G,A); rs12736258(G,C); rs11161727(A,T); rs4522024(T,C); rs12723246(T,G); rs12742014(G,A); rs12354100(A,C); rs41313268(T,G); rs12756057(C,A); rs12097262(G,A); rs6703328(C,T); rs11806244(C,T); rs11801529(T,C); rs112891904(A,C); rs12733714(A,G); rs72716145(T,C); rs17415692(C,T); rs12755069(T,C); rs10443173(A,G); rs12071046(A,T); rs146243778(G,A); rs137990270(G,A); rs11802445(T,C); rs12744971(G,A); rs6665582(C,T); rs369118329(C,T); rs12566718(C,T); rs12566940(C,T); rs10443169(G,A); rs10873742(C,T); rs7548696(G,C); rs111943767(G,A); rs140426173(C,T); rs12564004(G,A); rs112458166(A,C); rs72716149(T,C); rs12744064(G,C); rs146550870(T,G); rs143136298(C,G); rs148239291(G,A); rs6686088(T,C); rs141037075(T,C); rs2202675(T,C); rs2221588(T,C); rs139361292(G,T); rs116434207(A,C); rs76680465(C,A); rs186083897(A,G); rs7545716(T,C); rs112583392(A,C); rs72960374(C,A); rs12752769(T,C); rs72716150(G,A); rs80240281(A,G); rs72716152(G,A); rs6699364(T,C); rs11585276(A,C); rs11588997(C,G); rs11583563(T,C); rs11583566(T,C); rs59767206(G,T); rs12725994(T,G); rs12744313(G,A); rs4912461(T,G); rs7514100(A,C); rs12754154(C,T); rs12736520(T,C); rs10873744(G,A); rs190465624(A,G); rs140389337(A,G); rs17415754(C,T); rs142086023(G,A); rs6687118(C,A); rs11161729(G,A); rs1507281(C,T); rs10782563(T,C); rs12723978(T,C); rs6665375(G,C); rs141977422(C,A); rs34168319(G,A); rs77867367(G,A); rs10493786(A,C); rs10493785(C,T); rs113978659(C,T); rs77771545(C,T); rs12405791(G,A); rs12758598(G,C); rs1507288(T,C); rs17415844(A,G); rs6682482(G,A); rs61802173(A,G); rs17407336(C,T); rs11161732(G,A); rs10782564(A,G); rs12082787(G,A); rs61802174(T,C); rs10873745(C,A); rs75393931(C,T); rs139672524(G,C); rs115077383(C,A); rs142980640(T,C); rs6691885(A,G); rs77934242(C,T); rs55729234(C,T); rs10873746(C,A); rs36035589(T,G); rs12728287(A,C); rs1336054(A,G); rs12043664(A,T); rs997110(A,C); rs112778051(G,A); rs1605417(C,G); rs1605416(C,A); rs883201(A,C); rs56237094(C,T); rs6672107(G,T); rs1828018(A,T); rs1911545(A,T); rs117558703(G,A); rs12044349(T,C); rs6670074(T,C); rs10047143(C,T); rs2390017(G,A); rs2390016(C,T); rs2390015(A,C); rs112059396(A,G); rs114128692(C,T); rs9988602(T,C); rs12029694(C,G); rs11161734(G,C); rs12742966(C,T); rs12093594(A,G); rs141605057(T,C); rs78783089(C,A); rs6665315(T,A); rs2221589(C,A); rs1395717(G,A); rs11161735(C,T); rs1360903(G,T); rs12755633(G,T); rs12142577(T,C); rs12047136(T,A); rs57251624(A,G); rs55912038(C,T); rs55713534(G,A); rs12048065(T,C); rs4912463(A,C); rs12023254(A,G); rs11161736(T,C); rs6690902(G,T); rs11161737(G,T); rs11581522(C,T); rs6576800(T,C); rs115268857(T,C); rs143962298(C,T); rs12057993(T,C); rs75653506(T,C); rs79954139(G,A); rs7550464(G,A); rs7550559(G,A); rs7550571(G,A); rs2039602(A,C); rs11161738(C,T); rs2039603(C,T); rs2039604(G,A); rs11161739(G,A); rs11161740(T,C); rs12075854(C,T); rs11161741(A,G); rs12565251(C,G); rs6686446(G,A); rs6675364(A,G); rs6678131(T,G); rs6663055(C,T); rs6675562(A,G); rs12024025(T,C); rs12048574(G,A); rs12024952(C,A); rs12742000(G,A); rs12024954(C,T); rs61802236(G,A); rs1414600(A,G); rs61802237(A,T); rs2892909(G,A); rs2390014(T,G); rs6666638(C,G); rs12402985(C,G); rs1108309(G,C); rs1507292(T,C); rs6686533(A,G); rs6697461(G,A); rs6691959(T,C); rs10873747(C,T); rs10873748(T,C); rs10873749(T,C); rs2221587(C,T); rs1336052(A,C); rs6680321(C,T); rs11161742(T,C); rs11161743(G,A); rs11161744(T,A); rs1995687(C,G); rs11161745(C,T); rs12567887(G,A); rs4556388(T,C); rs150713883(T,C); rs12049014(T,A); rs113167851(G,T); rs61802244(C,T); rs2390013(G,A); rs2390012(C,T); rs4631724(T,G); rs6690591(C,T); rs6690880(C,G); rs6703567(A,C); rs4144876(C,T); rs4144875(T,G); rs72716178(A,T); rs1948962(C,A); rs192989476(A,G); rs12118936(T,C); rs1507266(C,T); rs1507265(C,T); rs2174767(G,A); rs11161746(A,G); rs17128866(A,G); rs11161747(G,A); rs1507264(A,G); rs2202674(C,T); rs1876403(C,T); rs1507263(C,T); rs1507262(T,C); rs72716183(A,G); rs12569126(G,A); rs1999748(T,C); rs11578172(T,C); rs7521933(T,C); rs76713460(G,A); rs4379700(T,C); rs7531153(G,A); rs7531177(G,T); rs7554369(C,G); rs17408110(T,C); rs1507286(G,A); rs1507285(A,T); rs12117437(G,A); rs6669512(A,G); rs72716185(G,T); rs11161750(G,A); rs1507284(C,T); rs1319648(G,C); rs79295259(C,A); rs6576804(C,T); rs7516054(C,T); rs151320187(C,T); rs80180180(C,G); rs10493783(G,T); rs55740735(G,A); rs78353926(A,G); rs10873756(T,C); rs4912465(C,T); rs1507282(C,T); rs1507283(T,C); rs1414602(C,T); rs1414601(A,C); rs72716190(G,T); rs12727039(G,C); rs12407500(C,T); rs7518215(C,T); rs72716194(A,C); rs12120396(G,A); rs11161752(T,C); rs2892908(T,C); rs114960733(A,G); rs75563006(A,G); rs2135808(C,T); rs12758526(G,C); rs114898859(C,A); rs12130833(A,G); rs12072489(T,C); rs1889851(A,G); rs1889852(T,C); rs9433426(A,G); rs1507277(C,T); rs78989970(G,A); rs6576805(A,C); rs11161754(A,G); rs11161755(A,G); rs11161756(T,C); rs6576806(C,A); rs12072806(G,T); rs11161757(T,G); rs11161758(A,C); rs12074275(G,A); rs11161759(T,C); rs61803679(C,A); rs6660694(T,C); rs4656122(G,C); rs1507276(C,T); rs138592424(T,C); rs72716202(T,G); rs115538928(G,A); rs6697498(T,C); rs4656131(A,T); rs4656132(G,T); rs1999747(C,A) |
| ccdsGene name | CCDS41353.1 |
| cytoBand name | 1p22.3 |
| EntrezGene GeneID | 255631 |
| EntrezGene Description | collagen, type XXIV, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL24A1:NM_152890:exon22:c.C2441A:p.A814D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5396 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q17RW2 |
| dbNSFP Uniprot ID | COOA1_HUMAN |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0528455284553 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.015616 |
| ESP All MAF | 0.00538 |
| ESP Eur/Amr MAF | 0.000862 |
| ExAC AF | 0.002109 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Progressive cone degeneration (in some patients);
Photophobia;
Nyctalopia;
Decreased central vision;
Dyschromatopsia;
Macular granularity (in some patients);
Central macular atrophy (in some patients);
Central scotoma on Goldmann visual field (in some patients);
Supernormal and delayed scotopic rod electroretinogram (in some patients);
Cone degeneration, stationary (in some patients);
Nystagmus (in some patients);
Normal scotopic responses on rod electroretinogram (in some patients);
Severely reduced cone and absent 30Hz flicker responses on cone electroretinogram
(in some patients)
MISCELLANEOUS:
Onset in first to second decade
MOLECULAR BASIS:
Caused by mutation in the phosphodiesterase 6H, cGMP-specific, cone,
gamma gene (PDE6H, 601190.0001)
OMIM Title
*610025 COLLAGEN, TYPE XXIV, ALPHA-1; COL24A1
OMIM Description
CLONING
By EST database searching, Koch et al. (2003) identified sequences
showing homology to the C-terminal third of alpha-1 type V collagen
(COL5A1; 120215). Using a PCR-based strategy, they cloned a novel human
collagen, designated COL24A1, from a placenta cDNA library. The deduced
protein contains a 38-amino acid signal peptide, followed by a 544-amino
acid N-peptide domain, a 931-amino acid triple helix region with one
imperfect 4-amino acid insertion characteristic of invertebrate
collagens, and a 235-amino acid C-propeptide. The deduced N-peptide
domain contains a thrombospondin N-terminal-like (TSPN) motif that
shares 27.3% sequence identity with the TSPN motifs of COL5A1 and
COL11A1 (120280). Its C-propeptide domain contains 8 cysteines and
shares 28.4% identity with that of COL5A1. The COL24A1 N-peptide
sequence contains a homolog of a conserved sequence characteristic of
fibril diameter-regulating fibrillar collagen chains. COL24A1 is
predicted to have a retained N-peptide after processing. Using RT-PCR of
adult tissues, Koch et al. (2003) demonstrated that mouse Col24a1 is a
nonabundant collagen expressed in bone and retina and to a lesser degree
in cornea, skin, and tendon.
GENE FUNCTION
Using in situ hybridization, Koch et al. (2003) determined that mouse
Col24a1 is first detected in the emerging skeletal elements of the head
and appendicular skeleton at embryonic day 15. Expression at later
embryonic stages was detected in the cornea, the otic capsule, and
skeleton, where expression coincided with the formation of primary
ossification centers and sites of high type I collagen expression. Koch
et al. (2003) concluded that Col24a1 is a marker for embryonic bone
formation and may play a role in regulation of type I collagen
fibrillogenesis.
GENE STRUCTURE
Koch et al. (2003) determined that the COL24A1 gene contains 49 exons.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the COL24A1
gene to chromosome 1 (TMAP SHGC-75097).
GBP3
| dbSNP name | rs10922537(A,G); rs12058562(C,A); rs2077694(C,T); rs1409150(T,C); rs11808228(A,G); rs61766155(G,A); rs7550155(C,T); rs7527086(G,A); rs7550252(C,T); rs17433780(A,G); rs10493821(C,T); rs4142706(T,G); rs2390677(A,G); rs113626873(A,G); rs147245917(C,T); rs60788429(C,T); rs72965328(G,A); rs5015501(C,T); rs6659829(T,C); rs141433057(G,A); rs72965332(G,A); rs146670670(G,A); rs77820095(G,T); rs59316955(C,T); rs4656076(C,G); rs113490655(G,A); rs4656077(G,A); rs4656078(C,T); rs12091541(G,A); rs3795543(T,C); rs17130690(G,A); rs45456793(A,G); rs72967452(A,T); rs12089648(A,G); rs12121223(C,T); rs12089694(A,C); rs57846667(T,C); rs10922538(A,G); rs10801702(C,T); rs10922539(G,A); rs141407508(C,T); rs113611878(G,A); rs4655891(C,A); rs10922542(C,T); rs7555039(C,T); rs10922543(T,C); rs7530373(T,G) |
| ccdsGene name | CCDS717.2 |
| cytoBand name | 1p22.2 |
| EntrezGene GeneID | 2635 |
| EntrezGene Description | guanylate binding protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GBP3:NM_018284:exon6:c.C673T:p.R225W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6308 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.322802197802 |
| dbNSFP KGp1 Afr AF | 0.164634146341 |
| dbNSFP KGp1 Amr AF | 0.342541436464 |
| dbNSFP KGp1 Asn AF | 0.281468531469 |
| dbNSFP KGp1 Eur AF | 0.447229551451 |
| dbSNP GMAF | 0.3228 |
| ESP Afr MAF | 0.261008 |
| ESP All MAF | 0.388436 |
| ESP Eur/Amr MAF | 0.453721 |
| ExAC AF | 0.417,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Face];
Midface hypoplasia;
Prominent forehead;
Prominent supraorbital ridges;
[Nose];
Depressed nasal bridge (in childhood);
Small, upturned nose (in childhood);
[Teeth];
No abnormalities of teeth
CHEST:
[External features];
Pectus excavatum
SKIN, NAILS, HAIR:
[Skin];
No abnormalities of sweating;
[Nails];
Dysplastic nails (1st and 2nd toes) [Hair];
No abnormalities of hair
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Hypotonia;
Developmental delay, primarily motor, resolves in childhood
MISCELLANEOUS:
One family reported (as of May 2012)
OMIM Title
*600413 GUANYLATE-BINDING PROTEIN 3; GBP3
OMIM Description
DESCRIPTION
Guanylate-binding proteins, such as GBP3, are induced by interferon and
hydrolyze GTP to both GDP and GMP (Olszewski et al., 2006).
CLONING
Strehlow et al. (1994) identified and partially characterized a third
member of the GBP family, GBP3, which shows significant sequence
similarity to both GBP1 (600411) and GBP2 (600412).
Olszewski et al. (2006) reported that the 595-amino acid GBP3 protein
shares 88% and 76% identity with GBP1 and GBP2, respectively. All GBPs,
including GBP3, have a conserved N-terminal globular GTP-binding domain
containing 2 consensus sequences and a third T(L/V)RD sequence not found
in other GTPases. GBP3 lacks the C-terminal CaaX isoprenylation motif
found in GBP1, GBP2, and GBP5 (611467). EST database analysis indicated
wide expression of GBP3 in human tissues.
GENE FUNCTION
Using RT-PCR, Tripal et al. (2007) detected high expression of GBP1,
GBP2, and GBP3 in endothelial cells after stimulation with IFNG
(147570), TNF (191160), or IL1B (147720). Immunofluorescence analysis
demonstrated cytoplasmic expression of GBP3.
GENE STRUCTURE
Olszewski et al. (2006) determined that, like other GBPs, the GBP3 gene
contains 11 exons and begins translation in exon 2.
MAPPING
By genomic sequence analysis, Olszewski et al. (2006) mapped the GBP3
gene to the GBP gene cluster on chromosome 1p22.2. It is the most
telomeric GBP gene and is adjacent to GBP1.
LOC729930
| dbSNP name | rs623771(T,A) |
| cytoBand name | 1p22.2 |
| EntrezGene GeneID | 100421401 |
| EntrezGene Symbol | LOC100421401 |
| snpEff Gene Name | RP4-620F22.3 |
| EntrezGene Description | guanylate binding protein family, member 6 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3411 |
GEMIN8P4
| dbSNP name | rs2259685(T,C); rs2703984(A,G); rs74548088(A,T); rs7556257(G,A) |
| cytoBand name | 1p22.2 |
| EntrezGene GeneID | 492303 |
| snpEff Gene Name | ZNF326 |
| EntrezGene Description | gem (nuclear organelle) associated protein 8 pseudogene 4 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06107 |
SNORA66
| dbSNP name | rs115931438(A,G); rs10874744(G,A) |
| ccdsGene name | CCDS741.1 |
| cytoBand name | 1p22.1 |
| EntrezGene GeneID | 388650 |
| EntrezGene Symbol | FAM69A |
| snpEff Gene Name | FAM69A |
| EntrezGene Description | family with sequence similarity 69, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.006849 |
| ESP All MAF | 0.016393 |
| ESP Eur/Amr MAF | 0.020593 |
| ExAC AF | 0.017 |
ABCA4
| dbSNP name | rs3747961(T,C); rs76201551(C,T); rs17110718(A,T); rs72956525(C,T); rs12239339(A,G); rs17110724(C,A); rs1932016(G,T); rs72956538(C,T); rs72956540(G,A); rs72956543(A,G); rs115105609(T,C); rs80333611(T,A); rs4147872(G,A); rs6666559(C,G); rs6666652(C,A); rs1800717(A,G); rs12070195(G,C); rs60653897(G,A); rs11806635(C,T); rs17110736(G,A); rs78801978(G,A); rs17110743(G,A); rs10874825(C,T); rs10874826(T,C); rs10874827(C,G); rs6666176(T,G); rs141949394(C,T); rs12083802(C,T); rs78081171(A,G); rs3789374(T,C); rs3789375(T,G); rs11165060(C,T); rs4147871(A,G); rs4147870(G,A); rs4147869(C,T); rs4147868(G,C); rs12070273(A,G); rs12070274(A,T); rs12070278(A,G); rs4147866(T,C); rs1801555(A,G); rs12086793(C,T); rs4147865(G,A); rs4147864(G,A); rs17110761(C,T); rs74102054(T,A); rs17110768(C,T); rs11805625(G,C); rs11805627(G,A); rs115876130(T,C); rs11804211(A,G); rs11804569(A,G); rs74102057(C,T); rs74102058(T,C); rs74102059(A,G); rs74102060(G,A); rs59396776(T,G); rs28422025(T,C); rs4847195(C,T); rs28437464(G,A); rs58541150(A,T); rs12034084(T,A); rs12034085(T,C); rs6541408(T,C); rs35270729(C,A); rs149753560(C,T); rs55691342(C,T); rs7412750(G,A); rs61782235(C,G); rs72956569(G,T); rs11165061(A,G); rs10874829(T,A); rs112487800(C,A); rs113965124(G,A); rs111849559(G,T); rs72956573(A,T); rs7533425(C,G); rs144540817(C,T); rs1762114(A,G); rs4147863(C,T); rs2275028(C,T); rs4147862(C,T); rs145345131(T,G); rs4147861(C,A); rs3789377(G,A); rs557026(T,C); rs3789379(A,G); rs3789380(C,T); rs3789381(C,A); rs3789382(G,A); rs3789383(T,C); rs4147859(G,C); rs4147858(T,C); rs7531001(G,A); rs138873205(T,C); rs3789384(C,T); rs3789385(C,T); rs3789386(A,G); rs145297440(G,T); rs2275029(T,C); rs1800739(C,T); rs2275031(G,T); rs1191234(G,A); rs2275032(A,C); rs4147857(T,C); rs4147856(T,G); rs56166161(G,C); rs55694362(A,G); rs17110808(G,A); rs3789387(T,C); rs76368546(C,G); rs145477946(G,A); rs17110814(C,T); rs2065712(C,T); rs1801574(C,G); rs537831(G,A); rs7519657(C,T); rs2065711(C,T); rs4147855(G,A); rs565155(T,G); rs2893264(C,T); rs61782236(C,T); rs61782237(G,A); rs11165062(G,A); rs11165063(C,G); rs945067(T,C); rs17391542(G,A); rs58088273(T,C); rs12085639(G,A); rs486879(C,T); rs4147853(G,T); rs487906(G,C); rs567370(C,T); rs12082181(T,C); rs114831594(G,T); rs4147851(C,A); rs17391612(G,A); rs3789391(C,T); rs12049183(C,T); rs61782239(C,T); rs12083701(T,A); rs2275033(C,T); rs147187030(A,G); rs56307710(T,C); rs2275034(T,C); rs4147849(T,C); rs914957(T,C); rs914958(A,G); rs72958426(A,G); rs915201(A,G); rs915200(C,T); rs915199(C,T); rs11809593(G,A); rs112385574(A,G); rs11806129(A,G); rs17389488(T,C); rs6664100(G,C); rs6664390(G,A); rs6681968(T,C); rs56031604(T,C); rs17110858(A,G); rs10493867(T,C); rs4147848(G,T); rs933073(T,G); rs472908(G,A); rs12087777(T,C); rs2282229(T,A); rs1932014(G,A); rs55984244(C,T); rs1889407(G,T); rs2151847(A,C); rs115859773(G,A); rs41292681(T,C); rs11165065(G,A); rs111746122(G,A); rs3945204(T,C); rs112707138(C,T); rs17110885(G,T); rs1960277(A,T); rs17110889(C,G); rs17110891(C,G); rs945066(T,G); rs7547334(A,G); rs114846403(G,T); rs4147846(C,T); rs4147845(C,T); rs4147844(G,A); rs547806(T,C); rs2297671(G,A); rs56253197(T,C); rs7543524(G,A); rs4147841(G,A); rs113596322(T,C); rs113011227(C,T); rs11165067(G,A); rs11165068(G,A); rs17389899(A,G); rs375715233(G,A); rs17110905(G,T); rs3789393(T,C); rs12070573(C,T); rs35561994(C,G); rs34541136(T,C); rs11803885(C,A); rs17110916(G,A); rs3789395(A,C); rs1320502(C,T); rs184612341(T,C); rs12087003(A,G); rs1889548(A,C); rs182792816(A,G); rs9661266(T,G); rs11165069(C,T); rs139543506(G,A); rs111809377(A,G); rs140876019(G,A); rs17110922(A,T); rs61749454(A,G); rs17110929(A,T); rs3789398(G,A); rs3789399(G,C); rs4529714(A,G); rs17392369(G,A); rs544830(C,T); rs12123388(C,T); rs4147837(G,A); rs539435(C,G); rs74968378(A,G); rs12095320(A,G); rs12069723(C,G); rs484110(G,A); rs72725167(A,G); rs4147836(C,T); rs77969737(T,C); rs1191231(A,C); rs566927(G,A); rs17110958(A,G); rs497511(G,A); rs1191229(A,G); rs550060(A,G); rs4147835(A,G); rs521538(A,G); rs56197337(A,G); rs4147833(C,T); rs28715983(T,C); rs4847273(A,G); rs6661519(C,A); rs1007348(A,G); rs1007347(T,C); rs72960406(T,C); rs553608(T,C); rs1191232(A,G); rs3789405(T,C); rs149961899(A,G); rs3789406(G,A); rs10493868(A,G); rs3789407(G,C); rs4140392(C,T); rs7366102(T,C); rs1191228(T,C); rs1931575(T,C); rs74102102(G,C); rs2893265(A,G); rs581244(A,T); rs2151849(A,G); rs3789412(C,T); rs149802210(G,C); rs1931574(T,A); rs1334895(T,A); rs12739987(T,C); rs60298190(G,A); rs17110991(C,T); rs182019503(A,G); rs2151848(G,C); rs12759306(C,A); rs1932015(T,C); rs1761375(G,A); rs74104504(A,T); rs556353(A,G); rs4847274(G,C); rs35298667(C,T); rs112095544(G,A); rs524322(A,G); rs17111003(A,G); rs492220(T,C); rs3120133(G,T); rs116450316(C,T); rs4147830(G,A); rs114393289(T,C); rs200943894(C,T); rs2275035(C,T); rs76189878(T,C); rs4147828(A,G); rs4147827(C,G); rs526016(A,G); rs574741(T,C); rs572960(A,G); rs550142(A,G); rs546550(A,G); rs545542(G,C); rs5776202(G,A); rs17461953(A,C); rs515263(A,G); rs479110(T,C); rs481290(T,C); rs560426(C,T); rs563429(A,G); rs1209169(A,G); rs189332620(G,A); rs4847196(G,A); rs10874831(C,T); rs1191238(A,G); rs1191237(A,G); rs554931(T,C); rs483904(T,C); rs66515264(G,T); rs952499(T,C); rs181723030(G,A); rs538880(C,G); rs2068334(G,A); rs76324366(G,C); rs148650711(A,G); rs116079572(G,C); rs4147825(G,A); rs4147823(A,C); rs4147822(A,G); rs4147820(C,T); rs115177659(G,A); rs4847277(T,G); rs184229754(C,T); rs375469791(G,A); rs17100412(C,T); rs77933221(T,C); rs12088309(T,C); rs17111045(G,A); rs140972064(C,T); rs6657239(C,T); rs548122(C,G); rs3789421(G,A); rs3789422(C,T); rs3789423(T,G); rs3789424(G,A); rs577059(T,C); rs72725196(G,A); rs950283(T,C); rs7513438(G,A); rs525749(G,A); rs72960478(T,C); rs2297636(T,C); rs58269697(G,C); rs4147819(G,A); rs481931(G,T); rs571095(G,A); rs3789427(C,G); rs570878(G,T); rs34481412(C,A); rs2184451(G,A); rs1209515(T,C); rs1191236(C,G); rs77597214(C,A); rs11579526(C,T); rs56194707(C,T); rs143259811(C,T); rs75117387(G,A); rs1889406(C,A); rs3789431(C,T); rs79513058(C,A); rs61245991(G,A); rs12057375(G,T); rs4847279(T,C); rs12093963(A,G); rs11165073(C,A); rs4147816(C,T); rs4147815(G,A); rs4147814(C,T); rs4147813(C,A); rs4147812(A,C); rs4147811(C,T); rs3827712(T,C); rs3789432(T,C); rs3789433(A,G); rs115090950(A,C); rs3789434(T,C); rs58902615(T,C); rs3789435(A,G); rs3827713(G,C); rs4147810(A,G); rs2297635(G,A); rs2297634(T,C); rs1889405(C,T); rs1889404(C,T); rs3789438(G,T); rs11165074(G,A); rs12745358(G,A); rs7531875(T,A); rs7524782(C,T); rs7524869(C,A); rs4847281(T,C); rs116306224(G,A); rs4147808(G,A); rs4147807(A,G); rs3789439(T,C); rs3789440(G,A); rs12025221(T,C); rs11805421(C,T); rs10493870(C,T); rs72962308(C,A); rs56127428(T,C); rs10782976(G,A); rs55658984(T,A); rs10747458(C,T); rs3789441(C,T); rs74104526(G,A); rs3789442(G,C); rs3789443(A,G); rs3789444(C,T); rs144564277(C,T); rs7535005(C,T); rs4147805(G,A); rs4147804(G,A); rs3789445(T,G); rs4147803(G,C); rs145618578(A,T); rs11165075(T,C); rs71652552(C,G); rs3789448(G,T); rs57958442(C,T); rs4847282(T,C); rs3827714(G,A); rs11165076(G,T); rs4147802(C,T); rs77357856(C,T); rs4147801(T,C); rs4147800(C,G); rs4147799(A,G); rs11800866(T,C); rs4147798(C,T); rs2184339(T,C); rs114639377(C,T); rs57594899(C,T); rs10782977(T,C); rs113422740(G,A) |
| ccdsGene name | CCDS747.1 |
| cytoBand name | 1p22.1 |
| EntrezGene GeneID | 24 |
| EntrezGene Description | ATP-binding cassette, sub-family A (ABC1), member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCA4:NM_000350:exon31:c.C4556T:p.T1519M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5125 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P78363 |
| dbNSFP Uniprot ID | ABCA4_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 7.319e-05 |
OMIM Clinical Significance
Eyes:
Adult-onset primary open-angle glaucoma (POAG);
Increased intraocular pressure
Inheritance:
Autosomal dominant
OMIM Title
*601691 ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 4; ABCA4
;;ATP-BINDING CASSETTE TRANSPORTER, RETINA-SPECIFIC; ABCR;;
ABC TRANSPORTER, RETINA-SPECIFIC;;
PHOTORECEPTOR RIM PROTEIN; RMP
OMIM Description
DESCRIPTION
The ABCA4 gene produces an ATP-binding cassette (ABC) superfamily
transmembrane protein expressed exclusively in retinal photoreceptors
that is involved in clearance from photoreceptor cells of
all-trans-retinal aldehyde (atRAL), a byproduct of the retinoid cycle of
vision (Sun et al., 1999; Cideciyan et al., 2009).
CLONING
Allikmets et al. (1997) identified the ABCR gene among expressed
sequence tags obtained from human retina. ABCR was found to be closely
related to the mouse and human ABC1 (600046) and ABC2 (600047) genes.
The ABCR gene was not expressed detectably in any of 50 nonretinal fetal
and adult tissues examined. Other studies indicated that the gene is
uniquely retina-specific. The transcript size was estimated to be 8 kb.
Allikmets et al. (1997) reported the complete sequence of the 6,705-bp
ABCR coding region and the predicted 2,235-amino acid polypeptide
encoded by it.
Allikmets et al. (1998) revised the estimate of the size of the ABCR
gene to 6,819 bp encoding a 2,273-amino acid protein.
GENE STRUCTURE
By genomic sequence analysis, Gerber et al. (1998) and Allikmets et al.
(1998) determined that the ABCA4 gene contains at least 50 exons and
spans an estimated 150 kb. Exon sizes range from 33 bp to 266 bp.
MAPPING
Using a whole genome radiation hybrid panel, Allikmets et al. (1997)
mapped the ABCR gene to 1p21-p13, close to microsatellite markers D1S236
and D1S188. They further refined the localization by screening YACs from
the described contig between these anonymous markers. These YACs
delineated a region containing the Stargardt disease gene.
Azarian and Travis (1997) mapped the human photoreceptor rim protein
gene (RMP) to chromosome 1 by radiation hybrid analysis. By homology,
they mapped the mouse Rmp gene to chromosome 3 between the Ly37 and Tshb
loci. Nasonkin et al. (1998) refined the map position of the human ABCR
gene to 1p22.1-p21 by fluorescence in situ hybridization. By contig
mapping, Allikmets et al. (1998) localized the ABCR gene to chromosome
1p22.3-p22.2 between markers D1S3361 and D1S236.
Gross (2014) mapped the ABCA4 gene to chromosome 1p22.1 based on an
alignment of the ABCA4 sequence (GenBank GENBANK AF001945) with the
genomic sequence (GRCh37).
GENE FAMILY
The ATP-binding cassette (ABC) superfamily includes genes whose products
are transmembrane proteins involved in energy-dependent transport of a
wide spectrum of substrates across membranes. Allikmets et al. (1997)
noted that many disease-causing members of this superfamily result in
defects in the transport of specific substrates, e.g., CFTR (602421),
ALD (300100), SUR (600509), PMP70 (170995), and TAP2 (170261). In
eukaryotes, ABC genes typically encode 4 domains that include 2
conserved ATP-binding domains and 2 domains with multiple transmembrane
segments. The ATP-binding domains of the ABC genes contain motifs of
characteristic conserved residues (Walker A and B motifs) spaced by 90
to 120 amino acids. Both this conserved spacing and the 'signature' or
'C' motif just upstream of the Walker B site distinguish members of the
ABC superfamily from other ATP-binding proteins. These features allowed
the isolation of new ABC genes by hybridization, degenerate PCR, and
inspection of DNA sequence databases. Allikmets et al. (1996)
characterized 21 members of the ABC superfamily by determining their map
locations and patterns of expression.
GENE FUNCTION
Allikmets et al. (1997) localized ABCR transcripts exclusively within
photoreceptor cells, indicating that ABCR mediates the transport of an
essential molecule (or ion) either into or out of photoreceptor cells.
The ABCR gene is expressed exclusively in the retina, and in situ
hybridization localized ABCR transcripts to rod photoreceptor cells. Sun
and Nathans (1997) further localized ABCR to the disc membrane of
retinal rod outer segments. The observations narrowed the range of
plausible functions for ABCR and the corresponding range of pathogenic
mechanisms underlying Stargardt disease (STGD; 248200). The authors
commented that the accumulation of lipofuscin in the retinal pigment
epithelium in Stargardt disease might reflect a defective ABCR-mediated
transport of retinoids within the rod outer segment.
Allikmets et al. (1997) commented that the accumulation in the retinal
pigment epithelium (RPE) of a lipofuscin-like substance in STGD suggests
that the site of ABCR-mediated transport may be on the apical face of
the photoreceptor cell and that this transport may affect exchange
between the RPE and the photoreceptors.
To search for natural and artificial substrates and/or allosteric
regulators of ABCR, Sun et al. (1999) solubilized and functionally
reconstituted the purified protein into lipid membranes and surveyed a
group of structurally diverse compounds for their ability to stimulate
or inhibit ABCR ATPase activity. They observed that all-trans-retinal
stimulated the ATPase activity of ABCR 3- to 4-fold. 11-cis- and
13-cis-retinal showed similar activity. All-trans-retinal stimulated the
ATPase activity of ABCR with Michaelis-Menten behavior indicative of
simple noncooperative binding associated with a rate-limiting
enzyme-substrate intermediate in the pathway of ATP hydrolysis. Sun et
al. (1999) concluded that these and other findings supported the
hypothesis that various geometric isomers of retinal and/or other
retinoids are transported by ABCR in a reaction that is coupled to ATP
hydrolysis. The kinetic behavior implied that all-trans-retinal binds to
an intermediate in the ATPase reaction pathway and that this binding
accelerates a rate-limiting step in ATP hydrolysis and/or release of the
hydrolysis products.
Korschen et al. (1999) identified glutamic acid-rich proteins (GARPs;
see 600724) as multivalent proteins that interact with the key players
of cGMP signaling, phosphodiesterase (see 602676) and guanylate cyclase
(see 600179), and with ABCR, through 4 short repetitive sequences. In
electron micrographs, GARPs are restricted to the rim region and
incisures of discs in close proximity to the guanylate cyclase and ABCR,
whereas the phosphodiesterase is randomly distributed. Korschen et al.
(1999) concluded that the GARPs organize a dynamic protein complex near
the disc rim that may control cGMP turnover and possibly other
light-dependent processes.
Molday et al. (2000) showed by immunofluorescence microscopy and Western
blot analysis that ABCR is present in foveal and peripheral cone, as
well as rod, photoreceptors. The results suggested that the loss in
central vision experienced by patients with Stargardt macular dystrophy
arises directly from ABCR-mediated foveal cone degeneration.
The aldehyde group of all-trans-retinal reacts with the primary amine of
phosphatidylethanolamine (PE) to form an equilibrium mixture of
N-retinylidene-PE and all-trans-retinal. Beharry et al. (2004) isolated
Abca4 from bovine rod outer segment disc membranes, and using HPLC and
radiolabeled substrates, they found that Abca4 bound N-retinylidene-PE
and all-trans-retinal. ATP and GTP released these retinoids from Abca4,
but ADP, GDP, and nonhydrolyzable derivatives did not. N-retinyl-PE, the
reduced form of N-retinylidene-PE, also bound Abca4, and
all-trans-retinal bound Abca4 in the absence of PE. All-trans-retinol
did not bind Abca4. Beharry et al. (2004) concluded that ABCA4 functions
as a flippase to translocate N-retinylidene-PE from the lumen to the
cytoplasmic side of retinal disc membranes.
MOLECULAR GENETICS
- Summaries of Mutations
Allikmets (2000) gave a tally of all ABCR alleles as 350 to 400, making
the heterogeneity of ABCR comparable to that of another member of the
ABC superfamily, the cystic fibrosis transmembrane conductance regulator
(CFTR). Allelic variations in ABCR are the most prominent cause of
retinal dystrophies with mendelian inheritance patterns.
Sun et al. (2000) listed 37 reported naturally occurring ABCA4
mutations. By studying expression of ABCR variants in transiently
transfected 293 cells, they observed a wide spectrum of biochemical
defects in these variants and provided insight into the transport
mechanism of ABCR.
- Stargardt Macular Dystrophy
Allikmets et al. (1997) performed mutation analysis of the ABCR gene in
48 families with Stargardt macular dystrophy (STGD1; 248200) previously
ascertained by strict definitional criteria and shown to be linked to
1p. Using a total of 21 exons, they identified 19 different mutations
(see, e.g., 601691.0001-601691.0005), the majority representing missense
mutations in conserved amino acid positions. However, they also found
several 1- to 2-bp insertions and deletions representing frameshifts.
Two missense alterations (D847H; R943Q, 601691.0035) were found in at
least 1 control individual, suggesting that they are neutral
polymorphisms. The remaining mutations were found only in STGD patients
and not in at least 40 unrelated normal controls (80 chromosomes). The
mutations were scattered throughout the coding sequence of the ABCR
gene. Most of the patients were found to be compound heterozygotes but 2
consanguineous families (1 Saudi Arabian (601691.0002) and 1 North
American) were homozygous. In an erratum, Allikmets et al. (1997)
provided a correction of the numbering system for mutations in the ABCR
gene in Stargardt macular dystrophy. Sequencing of ABCR cDNA clones
revealed an additional 114-bp exon after position 4352. This exon adds
38 in-frame amino acids to the polypeptide and represents the major
transcript. See 601691.0004 and 601691.0005.
Nasonkin et al. (1998) reported 4 mutations in the ABCR gene in patients
with Stargardt disease: 3106G-A (601691.0011), 3211insGT (601691.0012),
2565G-A (601691.0013), and 6079C-T (601691.0004).
Lewis et al. (1999) reported results of mutation scanning and direct DNA
sequencing of all 50 exons of ABCR in 150 families segregating autosomal
recessive Stargardt disease (STGD1). ABCR variations were identified in
173 (57%) disease chromosomes, most of which represented missense amino
acid substitutions. These ABCR variants were not found in 220 unaffected
control individuals (440 chromosomes) but did cosegregate with the
disease in these families with STGD1, and many occurred in conserved
functional domains. Missense amino acid substitutions located in the
amino terminal one-third of the protein appeared to be associated with
earlier onset of the disease and may represent misfolding alleles. The 2
most common mutant alleles, gly1961 to glu (601691.0007) and ala1038 to
val (601691.0016), each identified in 16 of 173 disease chromosomes,
represented 18.5% of mutations identified. G1961E in heterozygous state
had previously been associated, at a statistically significant level,
with age-related macular degeneration (ARMD). Clinical evaluation of
these 150 families with STGD1 revealed a high frequency of ARMD in
first- and second-degree relatives. These findings supported the
hypothesis that compound heterozygous ABCR mutations are responsible for
STGD1 and that some ABCR mutations in heterozygous state may enhance
susceptibility to ARMD.
Rivera et al. (2000) studied 144 patients with Stargardt disease and 220
unaffected individuals ascertained from the German population, to
complete a comprehensive, population-specific survey of the sequence
variation in the ABCA4 gene. In addition, they studied 200 individuals
with ARMD to assess the possible role of ABCA4 in that disorder. Using a
screening strategy based primarily on denaturing gradient gel
electrophoresis, they identified a total of 127 unique alterations, of
which 90 had not previously been reported, and classified 72 as probable
pathogenic mutations. Of the 288 Stargardt disease chromosomes studied,
mutations were identified in 166, representing a detection rate of
approximately 58%. Eight different alleles accounted for 61% of the
identified disease alleles, and at least 1 of these, the L541P/A1038V
complex allele (601691.0023), appeared to be a founder mutation in the
German population. When the group with ARMD and the control group were
analyzed with the same methodology, 18 patients with ARMD and 12
controls were found to harbor possible disease-associated alterations.
This represented no significant difference between the 2 groups;
however, for detection of modest effects of rare alleles in complex
diseases, the analysis of larger cohorts of patients may be required.
Yatsenko et al. (2001) tested the hypothesis that patients with
late-onset Stargardt disease, i.e., onset at 35 years or later, retained
partial ABCR activity attributable to mild missense alleles. They
approached this study by in vivo functional analysis of various
combinations of mutant alleles. They directly sequenced the entire
coding region of ABCR and detected mutations in 33 of 50 (66%) disease
chromosomes, but surprisingly, 11 of 33 (33%) were truncating alleles.
Importantly, all 22 missense mutations were located outside the known
functional domains of ABCR (ATP-binding or transmembrane), whereas in
the general cohort of STGD1 subjects studied by Lewis et al. (1999),
alterations occurred with equal frequency across the entire protein.
Yatsenko et al. (2001) suggested that these missense mutations in
regions of unknown function are milder alleles and are more susceptible
to modifier effects. Thus, they corroborated a prediction from the model
of ABCR pathogenicity that (1) one mutant ABCR allele is always missense
in late-onset STGD1 patients, and (2) the age of onset is correlated
with the amount of ABCR activity of this allele. In addition, they
reported 3 new pseudodominant families, bringing the total to 8 of 178
outbred STGD1 families, and suggested a carrier frequency of
STGD1-associated ABCR mutations of about 4.5% (approximately 1 in 22).
Using double gradient-denaturing gradient gel electrophoresis (DG-DGGE),
Fumagalli et al. (2001) performed a mutation screen in 44 Italian
autosomal recessive Stargardt disease patients corresponding to 36
independent genomes. In 34 of the 36 patients (94.4%), 37 sequence
changes were identified, including 26 missense, 6 frameshift, 3
splicing, and 2 nonsense variations. Twenty of the 37 mutations had not
previously been described. There appeared to exist a subset of molecular
defects specific to the Italian population. The identification of at
least 2 disease-associated mutations in 4 healthy control individuals
indicated a higher than expected carrier frequency of variant ABCR
alleles in the general population. Genotype-phenotype analysis showed a
possible correlation between the nature and location of some mutations
and specific ophthalmoscopic features of STGD disease.
Fingert et al. (2006) reported a case of Stargardt disease in a patient
homozygous for a mutation in the ABCA4 gene (601691.0026) as a result of
uniparental isodisomy of chromosome 1. The patient's father was
heterozygous for the mutation.
Pal Singh et al. (2006) identified homozygous null mutations in the
ABCA4 gene (601691.0028-601691.0029) in affected members of 2 Indian
families with early-onset severe retinal dystrophy.
- Age-Related Macular Degeneration
Age-related macular degeneration (ARMD; see 153800) is the leading cause
of severe central visual impairment among the elderly and is associated
both with environmental factors such as smoking and with genetic
factors. Allikmets et al. (1997) screened 167 unrelated ARMD patients
for alterations in the ABCR gene. Thirteen different ARMD-associated
alterations, both deletions and amino acid substitutions (e.g.,
601691.0006), were found in 1 allele of ABCR in 26 patients (16%). The
authors suggested that identification of ABCR alterations will permit
presymptomatic testing for high-risk individuals and may lead to earlier
diagnosis of ARMD and to new strategies for prevention and therapy.
De La Paz et al. (1999) screened their patients with ARMD (159 familial
cases from 112 multiple families and 53 sporadic cases) and 56 racially
matched individuals with no known history of ARMD for evidence of
mutation in the ABCR gene. The authors identified only 2 of the
previously reported variants in their study population. Both variants
occurred in sporadic cases, and none was found in familial cases or in
the randomly selected population. In addition, the authors identified
several previously undescribed polymorphisms and variants in both the
ARMD and control populations. The authors concluded that mutation in the
ABCR gene is not a major genetic risk factor for ARMD in their study
population.
Shroyer et al. (1999) analyzed the ABCA4 gene in a 3-generation family
manifesting both Stargardt disease and ARMD, and identified
heterozygosity for a missense mutation (P1380L; 601691.0026) in the
paternal grandmother with ARMD, whereas the proband and his 2 paternal
cousins with Stargardt disease were compound heterozygous for the P1380L
mutation and another missense mutation (601691.0036 and 601691.0037,
respectively) in the ABCA4 gene. Shroyer et al. (1999) suggested that
carrier relatives of STGD patients may have an increased risk of
developing ARMD.
Allikmets and the International ABCR Screening Consortium (2000) tested
the original hypothesis that ABCR is a dominant susceptibility locus for
ARMD by screening 1,218 unrelated ARMD patients of North American and
western European origin and 1,258 comparison individuals from 15 centers
in North America and Europe for the 2 most frequent ARMD-associated
variants found in ABCR: G1961E (601691.0007) and D2177N (601691.0006).
One or the other of these sequence changes was found in 1 allele of ABCR
in 40 patients (3.4%) and in 13 control subjects (0.95%). These
differences were considered statistically significant. The risk of ARMD
was elevated approximately 3-fold in D2177N carriers and approximately
5-fold in G1961E carriers.
By mutation analysis in a cohort of families that manifested both STGD
and ARMD, Shroyer et al. (2001) found that ARMD-affected relatives of
STGD patients are more likely to be carriers of pathogenic STGD alleles
than predicted based on chance alone. Shroyer et al. (2001) used an in
vitro biochemical assay to test for protein expression and ATP-binding
defects, and found that mutations associated with ARMD have a range of
assayable defects ranging from no detectable defect to apparent null
alleles. Of the 21 missense ABCR mutations reported in patients with
ARMD, 16 (76%) showed abnormalities in protein expression, ATP binding,
or ATPase activity. They inferred that carrier relatives of STGD
patients are predisposed to develop ARMD.
Guymer et al. (2001) investigated the role of the G1961E (601691.0007)
and D2177N (601691.0006) alleles of the ABCA4 gene in the pathogenesis
of ARMD. They concluded that although the ABCA4 gene is definitively
involved in the pathogenesis of Stargardt disease and some cases of
photoreceptor degeneration, the alleles did not appear to be involved in
a statistically significant fraction of ARMD cases.
Single-copy variants of the ABCR gene have been shown to confer enhanced
susceptibility to ARMD. Bernstein et al. (2002) examined 19 of 33 sibs
from 15 Stargardt families who carried their respective proband's
variant ABCR allele. Some families exhibited concordance of ABCR alleles
with the macular degeneration phenotype, but others did not. Exudative
ARMD was uncommon among both probands and sibs.
- Retinitis Pigmentosa 19
Martinez-Mir et al. (1998) demonstrated that the causative mutation in a
family with retinitis pigmentosa-19 (601718) was a frameshift
(601691.0008) in the ABCR gene, which was present in homozygous state.
The authors observed that the heterozygous parents, aged 72 and 82, in
their family showed no signs of age-related macular dystrophy (ARMD).
They thought, however, that this finding did not argue against
haploinsufficiency of ABCR as the cause of ARMD; because this is a
multifactorial disorder, ABCR haploinsufficiency may be only a
predisposing factor, and not all parents of patients have ARMD. ABCR
expression is confined to rods, and the fact that these photoreceptors
are the cell type primarily affected in RP support ABCR as the gene
responsible for RP19. They pointed out that the highest concentration of
rods is 5 mm out from the fovea, within the zone that is affected in
macular degeneration. If the rods in Stargardt disease and age-related
macular degeneration produce an aberrant product, it would be expected
to reach its highest concentration in this region. Persons with 1
wildtype and 1 mutant ABCR allele would be predisposed to a late-onset
accumulation of cellular debris (drusen) and the development of ARMD.
- Cone-Rod Dystrophy 3
To evaluate the importance of the ABCA4 gene as a cause of autosomal
recessive cone-rod dystrophy (CORD3; 604116), Maugeri et al. (2000)
studied 5 patients with autosomal recessive CORD and 15 patients with
isolated CORD, all from Germany and the Netherlands. They found 19 ABCA4
mutations in 13 (65%) of 20 patients. In 6 patients, mutations were
identified in both ABCA4 alleles; in 7 patients, mutations were detected
in 1 allele. The complex ABCA4 allele L541P/A1038V (601691.0023) was
found exclusively in German patients with CORD; 1 patient carried this
complex allele in homozygous state, and 5 others were compound
heterozygous.
Following the studies of Maugeri et al. (2000), Ducroq et al. (2002)
evaluated the prevalence of ABCA4 mutations in a cohort of 55 patients
with autosomal recessive or sporadic cone-rod dystrophy. They screened
the 50 exons of the ABCA4 gene as well as the flanking intronic
sequences using DHPLC and identified 16 different mutant alleles in 13
(23.6%) of 55 patients. Among these 13 patients, 2 were homozygotes
(from 2 consanguineous families; see, e.g., 601691.0024), 4 were
compound heterozygotes, and 7 were simple heterozygotes. There was no
significant difference in the frequency of ABCA4 mutations between
autosomal recessive and sporadic cases of CORD (6 of 29 versus 7 of 26
cases, respectively). Ducroq et al. (2002) estimated that this screen
detected approximately 80% of mutations present in these families, with
unidentified mutations potentially located in promoter or intron
sequences or in undiscovered exons, and stated that the corrected
mutation frequency would then be 29.5% of all CORD cases. For a sporadic
case of cone-rod dystrophy with no ABCA4 mutation, they estimated that
the risk of the disease being inherited as an autosomal recessive
condition can be estimated to be 15.6% using the Bayesian calculation.
Fishman et al. (2003) examined 30 patients with autosomal recessive
CORD, 16 of whom harbored plausible disease-causing variations in the
ABCA4 gene. Among the mutation-positive patients, 2 distinctly different
fundus phenotypes were observed: 12 showed diffuse pigmentary
degenerative changes (type 1), whereas 4 showed either no pigmentary
changes or only a mild degree of peripheral pigment degeneration (type
2). All 16 patients showed either a central scotoma (6 patients) or both
a central scotoma and some degree of peripheral field loss (10
patients). Both cone and rod a- and b-wave electroretinogram (ERG)
amplitudes were reduced in all patients, which is diagnostic for CORD.
Of the 12 patients classified as type 1, 4 harbored an A1038V change
(601691.0016): in 2 this was the only sequence variation identified; in
1 case, it was observed in compound heterozygosity with a nonsense
mutation; and in 1 case it was found as a complex allele with an L541P
mutation (see 601691.0023). In the additional 8 patients classified as
type 1, 2 showed 2 different heterozygous missense mutations, 3 had a
single heterozygous missense mutation, and 3 had a heterozygous splice
site mutation within intron 40 (601691.0010). In the 4 patients with
considerably less funduscopically apparent pigmentary change (type 2), a
heterozygous missense mutation was observed: in 2 instances L1201R
(601691.0025), and in another 2 L2027F (601691.0004).
Ducroq et al. (2006) analyzed a large multiplex Christian Arab family
with presumed autosomal recessive CORD and 6 consanguineous loops and
found segregation of 3 distinct haplotypes at the CORD3 locus.
Sequencing of the ABCA4 gene revealed 3 different mutations segregating
with the disease in this family: 4 patients were homozygous for a splice
site mutation; 4 were compound heterozygous for the splice site mutation
and 1 of 2 missense mutations, respectively; and 1 patient was compound
heterozygous for the 2 missense mutations. Ducroq et al. (2006)
emphasized the pitfalls of homozygosity mapping in highly inbred
families when the heterozygote carrier frequency is high in the general
population.
Kitiratschky et al. (2008) screened the ABCA4 gene in 64 patients with
cone or cone-rod dystrophy and a family history consistent with
autosomal recessive inheritance. They identified mutations in 20 (31%)
of 64 patients, including 16 with CORD and 3 with cone dystrophy (see,
e.g., 601690.0007, 601690.0010, and 601691.0030-601691.0033).
- Susceptibility to Cleft Lip/Palate
For a discussion of a possible association between variation in the
ABCA4 gene and susceptibility to nonsyndromic cleft lip/palate, see
119530.
GENOTYPE/PHENOTYPE CORRELATIONS
Stargardt disease and late-onset fundus flavimaculatus (FFM) are
autosomal recessive disorders leading to macular degeneration in
childhood and adulthood, respectively. Rozet et al. (1998) screened the
entire coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM
families and showed that mutations truncating the ABCR protein
consistently led to STGD. On the other hand, all mutations identified in
FFM were missense mutations affecting uncharged amino acids. They stated
that this was the first genotype/phenotype correlation in ABCR gene
mutations.
Shroyer et al. (1999) reviewed ABCR mutations and the associated retinal
diseases and proposed a model in which ABCR activity inversely
correlates with severity of disease. In this model, truncating and
severely misfolding mutations are associated with early-onset disease
characterized by a primary photoreceptor loss and secondary retinal
pigment epithelium (RPE) defects (retinitis pigmentosa and cone-rod
dystrophy). In patients with milder mutations, photoreceptors are spared
initially, but byproducts of faulty ABCR transport lead to accumulated
material in the RPE and sequential photoreceptor loss (Stargardt disease
and fundus flavimaculatus). Similarly, ABCR-associated ARMD might be due
to the gradual accumulation of these same byproducts with eventual
photoreceptor loss.
Klevering et al. (2004) described 3 Dutch families in which different
combinations of retinal disorders occurred: ARMD, RP, and STGD in the
first family, RP and STGD in the second family, and ARMD, CORD, and STGD
in the third family. Three different mutations in the ABCA4 gene were
identified in these families. In view of the relatively high carrier
frequency of ABCA4 mutations (approximately 5%) in the general
population, Klevering et al. (2004) concluded that the occurrence of
various combinations of relatively rare retinal disorders in one family
might not be as uncommon as once believed.
Wiszniewski et al. (2005) analyzed missense mutations (see, e.g.,
601691.0023) in the photoreceptors of transgenic Xenopus laevis tadpoles
and found mislocalization of ABCA4 protein. These mutations caused
retention of ABCA4 in the photoreceptor inner segment, likely by
impairing correct folding, resulting in the total absence of physiologic
protein function. Patients with different retinal dystrophies harboring
2 misfolding alleles exhibit early age of onset (5 to 12 years) of
retinal disease. Wiszniewski et al. (2005) suggested that a class of
ABCA4 mutants may be an important determinant of the age of onset of
retinal disease.
Valverde et al. (2007) screened for mutations in the ABCA4 gene in 60
patients in 50 Spanish families with different retinal dystrophies: 16
with autosomal recessive CORD, 27 with autosomal recessive retinitis
pigmentosa, and 7 with autosomal dominant macular degeneration. Sixteen
distinct variants were identified in 25 of the families. Thirteen of the
CORD families had mutations in the ABCA4 gene; the most prevalent
mutation in these families was a 2888delG mutation (601691.0027),
accounting for 30% of the alleles detected. Putative disease-associated
alleles were identified in 9 of the RP families and in 3 of the macular
degeneration families.
In 66 individuals with known disease-causing ABCA4 alleles, Cideciyan et
al. (2009) defined retina-wide disease expression by measuring rod and
cone photoreceptor-mediated vision. Serial measurements over a mean
period of 8.7 years were consistent with a model wherein a normal
plateau phase of variable length was followed by initiation of
retina-wide disease that progressed exponentially. Estimates of the age
of disease initiation were used as a severity metric and contributions
made by each ABCA4 allele were predicted. One-third of the nontruncating
alleles were found to cause more severe disease than premature
terminations, supporting the existence of a pathogenic component beyond
simple loss of function.
ANIMAL MODEL
By SDS-PAGE and immunoblot analysis of purified bovine and frog rod
outer segments, Azarian and Travis (1997) identified 210- and 240-kD
proteins, respectively, as RMP. By peptide microsequence analysis and
degenerate primers for nested PCR on bovine and mouse retinal libraries,
Azarian and Travis (1997) isolated a mouse Rmp cDNA encoding a putative
2,310-amino acid protein. Sequence analysis predicted 86% identity and
92% similarity of mouse RMP to human ABCR protein, 3 potential
N-glycosylation sites, 12 membrane-spanning segments, 2 ABC transporter
signature motifs with potential phosphorylation sites, and 2 consensus
ATP/GTP nucleotide-binding sites. Northern blot analysis revealed
expression exclusively in retina. Immunoblot analysis showed that RMP is
expressed predominantly in the outer segments of retinal photoreceptors.
Weng et al. (1999) characterized the ocular phenotype in Abcr knockout
mice. Mice lacking the Abcr gene showed delayed dark adaptation,
increased all-trans-retinaldehyde (all-trans-RAL) following light
exposure, elevated phosphatidylethanolamine (PE) in outer segments,
accumulation of the protonated Schiff base complex of all-trans-RAL and
PE (N-retinylidene-PE), and striking deposition of a major lipofuscin
fluorophore (A2E) in retinal pigment epithelium (RPE). These data
suggested that ABCR functions as an outwardly directed flippase for
N-retinylidene-PE. Delayed dark adaptation is likely due to accumulation
in discs of the noncovalent complex between opsin and all-trans-RAL.
ABCR-mediated retinal degeneration in patients may result from
'poisoning' of the RPE due to A2E accumulation, with secondary
photoreceptor degeneration due to loss of the ABCR support role.
The primary pathologic defect in Stargardt disease is accumulation of
toxic lipofuscin pigments, such A2E, in cells of the RPE. This
accumulation was thought to be responsible for the photoreceptor death
and severe visual loss in patients with Stargardt disease. Sieving et
al. (2001) found that treatment of rodents with isotretinoin (Accutane),
an agent used in the treatment of acne, delayed rhodopsin regeneration
and slowed recovery of rod sensitivity after light exposure.
Importantly, isotretinoin did not cause photoreceptor degeneration and
actually protected photoreceptors from light-induced damage. Light
activation of rhodopsin results in its release of
all-trans-retinaldehyde, which constitutes the first reactant in A2E
biosynthesis. A side effect of treatment with isotretinoin is reduced
night vision because of its inhibitory effect on 11-cis-retinol
dehydrogenase (601617) in RPE cells. Radu et al. (2003) tested the
effects of isotretinoin on lipofuscin accumulation in Abcr knockout
mice, a model of recessive Stargardt disease. They observed by electron
microscopy that isotretinoin blocked the formation of A2E biochemically
and the accumulation of lipofuscin pigments. No significant visual loss
was observed in Abcr-null mice by electroretinography. Isotretinoin also
blocked the slower, age-dependent accumulation of lipofuscin in wildtype
mice. The results suggested that treatment with isotretinoin may inhibit
lipofuscin accumulation and delay the onset of visual loss in patients
with Stargardt disease and may be an effective treatment for other forms
of retinal or macular degeneration associated with lipofuscin
accumulation.
GPR88
| dbSNP name | rs2809823(C,A); rs2809822(C,T); rs41309189(C,T); rs2030048(A,G); rs2809817(T,C); rs2030049(C,T); rs4615860(C,T) |
| cytoBand name | 1p21.2 |
| EntrezGene GeneID | 54112 |
| EntrezGene Description | G protein-coupled receptor 88 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4853 |
COL11A1
| dbSNP name | rs9659030(T,C); rs1031820(G,A); rs1676491(T,C); rs193241275(A,G); rs11164627(G,A); rs12722976(C,G); rs184036004(T,C); rs2615999(C,A); rs12079176(G,A); rs2616000(A,T); rs12086094(T,C); rs79648533(T,C); rs1241181(G,A); rs1241182(A,C); rs1241183(G,T); rs116801205(C,T); rs12025494(C,G); rs2169608(G,C); rs1241184(G,A); rs1241185(G,A); rs2169609(T,C); rs2077569(G,A); rs1320506(A,C); rs945326(T,G); rs79348447(C,T); rs1932331(C,T); rs2783567(C,A); rs1841841(T,C); rs1463048(C,T); rs2229783(A,G); rs11164628(C,T); rs11164629(G,A); rs11164630(C,T); rs12023984(C,A); rs79940764(C,T); rs2783569(C,T); rs11164632(A,T); rs11164633(G,T); rs2615980(C,T); rs2783570(T,A); rs116183789(T,G); rs1676486(A,G); rs1763347(A,G); rs1241162(G,C); rs1241163(A,C); rs11164634(A,G); rs1085(A,C); rs1241164(C,T); rs1241165(C,A); rs1241166(G,A); rs10874662(A,C); rs962453(T,C); rs1932333(G,A); rs9988414(A,G); rs67016898(T,C); rs67621984(G,A); rs66531224(A,G); rs35486863(G,C); rs6701464(A,T); rs12731622(C,T); rs66626223(C,T); rs12736509(A,C); rs1676492(G,A); rs114031268(A,C); rs1763346(C,T); rs1463037(A,G); rs1463038(T,A); rs1463039(C,T); rs1676493(A,G); rs1676494(C,T); rs1676495(T,G); rs12142096(T,C); rs6663647(A,T); rs1676496(A,G); rs6677574(G,A); rs1622838(A,C); rs1676498(A,T); rs1676500(A,T); rs1676501(G,A); rs1676502(A,G); rs1932350(C,T); rs75157651(A,G); rs1620866(A,G); rs116452160(G,A); rs1625969(C,T); rs6702061(C,T); rs61120351(T,C); rs141440447(G,A); rs11576308(G,A); rs2622835(T,C); rs2622836(C,T); rs6664067(C,T); rs78171893(T,C); rs1676504(C,A); rs17446095(C,A); rs1463040(T,C); rs1763351(T,G); rs11164635(T,A); rs1676503(G,A); rs1026660(T,C); rs1015747(C,A); rs1676509(C,T); rs2622837(G,T); rs142192946(A,G); rs11164636(A,C); rs115079196(T,C); rs113678405(T,C); rs1463043(A,T); rs992098(C,T); rs992099(T,C); rs4908272(A,G); rs3753841(G,A); rs4908273(C,T); rs9434362(T,A); rs1241167(C,T); rs1261689(A,G); rs11164637(A,G); rs1271797(T,A); rs1241168(C,T); rs188653617(G,C); rs1841837(G,A); rs1241169(T,C); rs2376261(C,A); rs993471(G,A); rs11801437(G,A); rs1241170(A,C); rs10127873(T,C); rs10127706(C,T); rs1618201(T,C); rs4453063(T,G); rs6577340(G,T); rs1676490(C,T); rs1676489(A,C); rs4908274(A,T); rs1676488(G,C); rs1763360(G,A); rs1676487(A,G); rs1993822(C,A); rs76084218(G,A); rs2622834(G,C); rs12138977(C,T); rs2045819(T,C); rs75382656(A,G); rs2045818(C,T); rs11164641(G,A); rs11164642(A,T); rs974076(T,G); rs3767273(G,C); rs114872505(G,A); rs981961(C,T); rs1120519(C,T); rs186488777(G,A); rs6682134(T,C); rs6679803(A,G); rs4908277(C,G); rs2616013(T,C); rs2616012(A,T); rs74862204(T,A); rs2622883(T,C); rs1841840(C,T); rs1841839(T,A); rs1975919(A,G); rs1975917(G,A); rs2376262(T,C); rs1564141(A,G); rs1564140(A,G); rs2126643(T,C); rs1463047(A,T); rs984023(C,G); rs984022(G,C); rs2126642(G,A); rs2616011(C,G); rs181302919(A,G); rs2622866(T,C); rs78495213(A,G); rs1841838(T,G); rs2622865(T,C); rs12045404(A,G); rs1463045(C,A); rs12046389(A,C); rs1463044(C,T); rs2616010(C,T); rs2616009(T,C); rs12143740(A,G); rs2616008(G,C); rs146732785(C,A); rs2622864(G,A); rs3126210(T,C); rs3126211(G,A); rs3102057(C,T); rs3126212(G,A); rs2615994(T,C); rs2615991(G,C); rs76926820(A,C); rs111784238(A,G); rs112522521(A,G); rs137999321(T,C); rs2622862(A,T); rs2615988(G,A); rs10047217(G,T); rs2615986(G,T); rs2622861(C,T); rs12144670(C,T); rs2199553(T,C); rs2622860(G,T); rs7543705(C,T); rs12134969(T,G); rs80231982(A,T); rs4908279(T,A); rs74596090(A,C); rs2061709(G,C); rs11799623(C,T); rs11809227(A,C); rs141164569(G,A); rs6691075(A,G); rs115229340(C,A); rs61812695(A,G); rs2061708(G,C); rs115514007(G,A); rs3102051(A,G); rs3102052(T,C); rs10747433(A,C); rs17506286(T,C); rs1966958(A,G); rs12142523(A,C); rs12142524(A,G); rs1966959(A,G); rs12743365(C,T); rs2615996(A,G); rs11811018(A,T); rs2615997(G,T); rs4908280(G,T); rs2622848(T,C); rs115892936(G,A); rs2622849(T,C); rs181053814(G,A); rs79197219(A,G); rs12140064(A,T); rs6663034(A,C); rs10874665(T,C); rs6699118(C,A); rs3102053(T,C); rs12136748(T,C); rs2615984(A,G); rs76492845(A,T); rs114003434(C,T); rs185126539(A,G); rs75596108(C,T); rs188367623(C,A); rs142053205(T,C); rs6672647(T,C); rs2615985(G,A); rs6670486(A,T); rs74410477(T,C); rs1381927(T,G); rs371928755(T,A); rs373254810(G,T); rs149149774(A,C); rs1564143(G,T); rs1564144(A,G); rs1012283(C,T); rs143069533(C,T); rs1012282(A,G); rs4353117(A,T); rs184000455(G,A); rs201141572(A,G); rs1841834(G,A); rs78602581(G,C); rs114946420(C,G); rs78723570(A,T); rs1824691(G,T); rs7552614(A,G); rs2615987(G,T); rs151129679(G,A); rs4908281(T,C); rs184755355(T,G); rs185092171(G,T); rs191723118(A,G); rs115741620(T,C); rs76425600(G,T); rs34277983(T,G); rs115789538(G,A); rs150722815(G,C); rs12755987(A,G); rs11164647(T,C); rs189279991(C,A); rs75139950(C,G); rs12143676(T,A); rs115818502(C,G); rs2615990(G,A); rs10874668(G,A); rs181078943(C,A); rs144318271(G,A); rs11164648(A,G); rs188974050(G,A); rs190923979(A,G); rs142381815(G,C); rs2254082(G,C); rs2622854(C,T); rs12118365(T,C); rs138113043(C,T); rs142393735(T,C); rs145924969(A,C); rs184482241(T,G); rs17447925(A,G); rs2061704(C,T); rs2622843(G,A); rs2622844(T,A); rs150346970(T,C); rs189830849(G,A); rs182452464(A,G); rs10782914(G,T); rs185654452(G,A); rs190109637(C,T); rs1903787(A,G); rs187839956(C,G); rs11164649(T,G); rs143516804(C,T); rs114094014(C,T); rs2622846(G,A); rs12119971(T,C); rs12025848(T,A); rs12124588(A,G); rs116129457(T,A); rs11164650(T,G); rs186275262(C,T); rs986944(C,T); rs12119459(G,A); rs10047106(C,A); rs2615978(G,C); rs1463035(T,C); rs115962455(A,G); rs7544130(A,C); rs7532572(C,A); rs7532757(C,A); rs12121661(T,C); rs2615977(A,C); rs2615976(A,C); rs12121824(T,C); rs2622858(G,C); rs114056305(C,T); rs2615975(C,T); rs35498106(T,C); rs2622857(T,C); rs1463034(C,T); rs71664951(T,C); rs114652354(T,C); rs114866563(C,A); rs34413966(C,T); rs10874671(G,C); rs189265243(T,C); rs1870958(G,T); rs34253876(T,C); rs12139120(C,A); rs3126215(C,T); rs11809524(C,T); rs78308033(T,C); rs10782915(T,C); rs78089634(T,C); rs76617635(C,T); rs3102058(T,C); rs78504529(C,T); rs2622867(T,A); rs186633961(A,G); rs2622868(T,C); rs2786125(A,G); rs2622870(G,T); rs10874672(T,A); rs11164653(T,C); rs149912767(T,C); rs2786124(G,A); rs17507469(A,C); rs12753781(T,G); rs76683643(C,T); rs2622873(T,C); rs181942311(G,C); rs2622874(A,C); rs2376279(C,T); rs12131957(T,C); rs12135531(A,G); rs2929162(C,T); rs114121248(G,T); rs2251895(A,G); rs12136577(A,T); rs116296541(C,A); rs2622876(G,A); rs2929163(A,G); rs2622877(T,A); rs186583987(T,C); rs4098282(G,A); rs2252146(T,A); rs113491456(T,G); rs7521389(C,T); rs1572515(G,C); rs12047268(C,G); rs2929161(T,C); rs12138447(A,G); rs12043105(A,T); rs10458505(G,T); rs9645399(C,T); rs2622841(G,A); rs12042830(T,A); rs181735029(T,C); rs112951540(A,G); rs11164656(A,G); rs139193069(T,A); rs945748(C,T); rs186832415(T,C); rs10747435(T,A); rs57843906(T,A); rs58181035(A,G); rs79473144(A,T); rs116688150(G,A); rs114388214(A,C); rs7523020(T,C); rs11164657(A,C); rs4908283(T,C); rs2065922(T,G); rs59050890(C,T); rs78306841(G,A); rs7523441(G,T); rs71664966(A,G); rs75957832(G,A); rs12725698(T,C); rs12744290(G,A); rs12726009(T,A); rs1415350(T,C); rs35071880(G,A); rs12744488(C,T); rs12128196(C,A); rs12726958(T,C); rs2050601(G,A); rs75059956(C,T); rs76596933(G,A); rs79509104(G,A); rs35671668(T,C); rs6577342(G,C); rs6667609(T,G); rs34243101(G,A); rs10782916(A,G); rs10782917(T,C); rs115724290(A,G); rs34762213(A,G); rs11164658(G,T); rs12131097(C,T); rs34408616(T,A); rs116721555(G,A); rs36005955(T,A); rs6674148(T,A); rs35979991(C,T); rs139340166(G,A); rs71664968(A,G); rs10493991(T,C); rs34138324(C,A); rs951414(T,A); rs75826721(C,A); rs1337174(C,T); rs1337175(A,G); rs35648695(A,G); rs35884314(G,A); rs35872185(G,A); rs12754606(G,C); rs71664969(G,A); rs112138834(T,C); rs141799416(T,C); rs78342625(A,G); rs6700031(G,A); rs77834876(G,T); rs12036215(C,G); rs80174154(A,G); rs115634769(C,T); rs10782918(T,C); rs1337177(C,T); rs1337178(C,T); rs138545921(C,T); rs7541571(G,A); rs12731591(C,T); rs6665095(C,T); rs12125729(A,T); rs12123031(T,C); rs12126622(A,T); rs12081652(C,T); rs144245175(T,G); rs12717796(A,G); rs78728772(A,G); rs12127590(A,C); rs36011373(A,G); rs2184879(C,T); rs80140099(T,C); rs1337179(G,T); rs74647258(A,G); rs79658382(T,C); rs17507967(G,C); rs79181493(T,C); rs61816501(T,C); rs146344488(A,G); rs61816502(G,T); rs61816503(C,G); rs61816504(C,T); rs3908854(T,C); rs3908855(C,T); rs79105340(C,T); rs184193143(C,T); rs4013869(A,G); rs4400632(A,T); rs12121641(T,C); rs3861743(T,C); rs3850459(T,C); rs12121762(T,C); rs116123528(C,A); rs1538041(G,A); rs60534143(G,A); rs57183243(A,G); rs7517682(G,A); rs13374856(A,C); rs58882054(A,C); rs2376284(G,A); rs57548736(C,T); rs9701540(A,G); rs7544444(C,T); rs13374615(T,A); rs12131383(C,T); rs13375231(C,T); rs10782920(G,A); rs1591636(A,G); rs4489579(G,A); rs76837428(T,C); rs4478834(T,C); rs77094262(T,C); rs76583397(G,A); rs12118796(G,A); rs12122632(T,G); rs58982976(T,C); rs79660279(C,T); rs77365395(C,T); rs74391599(A,G); rs71664978(T,C); rs190155207(C,A); rs34137810(T,C); rs111943741(A,T); rs1415349(G,A); rs140191308(T,C); rs35573953(T,C); rs61816515(A,G); rs7542495(A,C); rs7542602(A,T); rs7552698(G,A); rs7552870(G,A); rs79216307(A,G); rs116260851(G,A); rs114419904(A,T); rs112889013(G,A); rs61816516(T,C); rs77300930(C,G); rs6695665(T,C); rs34637912(C,A); rs59640131(G,C); rs76751471(C,T); rs114818575(A,G); rs4357546(C,T); rs12733029(A,T); rs115231708(A,G); rs112282311(C,A); rs78844542(G,A); rs71664979(A,T); rs116743449(A,C); rs12129078(A,G); rs114240834(T,G); rs13375833(C,T); rs13375103(A,T); rs7519039(T,C); rs10782921(C,T); rs13374456(G,A); rs10735777(C,T); rs77260579(C,A); rs71655803(A,T); rs113012043(A,T); rs12124555(G,A); rs1591637(C,T); rs12132053(A,G); rs61817081(G,A); rs112455069(T,A); rs116507278(G,A); rs140756469(C,A); rs147484813(C,T); rs12140473(C,T); rs1337180(A,G); rs10874675(A,G); rs61817082(T,A); rs12742552(G,C); rs115126926(T,C); rs116195762(A,G); rs115218197(A,T); rs78395916(T,C); rs114069792(G,A); rs78846384(C,T); rs12136338(A,C); rs150816220(G,C); rs114450408(C,T); rs7522293(A,G); rs77713323(T,C); rs116303092(T,C); rs116786201(G,A); rs34822172(A,G); rs79300645(G,A); rs61817084(T,C); rs35351574(A,G); rs11164661(G,A); rs4497231(T,G); rs115585645(T,C); rs115144937(T,C); rs77635978(C,G); rs12740738(A,G); rs12722908(T,C); rs12131399(T,A); rs1538048(C,G); rs1538047(T,G); rs115501987(C,A); rs12142411(C,T); rs1337189(T,A); rs1337188(C,T); rs139367449(C,T); rs1337187(T,C); rs1337186(C,A); rs6577346(G,A); rs6577347(C,T); rs2889351(C,T); rs6577348(A,C); rs6577349(G,T); rs6668897(C,T); rs12136865(A,G); rs115282447(T,C); rs1337185(C,G); rs1932986(T,C); rs116264652(C,T); rs115450391(T,A); rs10874676(A,G); rs10874677(G,A); rs146232701(A,G); rs61817085(T,C); rs11811864(C,A); rs1415354(A,G); rs114024263(C,G); rs1415353(C,T); rs115369409(T,A); rs12116763(C,G); rs12116792(C,A); rs10747437(C,T); rs12131769(G,T); rs114390033(C,T); rs115264484(G,C); rs4480381(C,T); rs1953674(G,A); rs1953673(C,T); rs1953672(T,A); rs1337184(A,T); rs114110904(G,A); rs114453998(T,C); rs11164662(C,G); rs116458923(C,A); rs61817086(A,G); rs4908285(T,C); rs4907986(C,T); rs4391683(G,A); rs188589424(C,A); rs12121105(C,T); rs112547358(A,T); rs4908286(G,T); rs4908287(A,C); rs4908288(G,C); rs4908289(T,C); rs4908290(A,G); rs12057386(C,A); rs11164665(G,A); rs11164666(C,A); rs145170697(A,G); rs11164667(C,T); rs10874679(T,A); rs7556513(G,A); rs72987856(A,G); rs1415364(C,T); rs6577351(A,G); rs113251100(C,G); rs1415363(A,G); rs2889339(G,A); rs111252443(G,A); rs6577352(G,A); rs11586849(T,A); rs11164668(G,A); rs11164669(T,C); rs1337195(C,T); rs143936387(C,T); rs7531081(C,G); rs6577353(T,C); rs78717067(T,C); rs12092111(T,G); rs12142575(T,A); rs113099967(A,G); rs9970114(A,G); rs1337194(A,G); rs77830731(G,A); rs1415362(G,T); rs76727689(G,T); rs1415361(C,T); rs1415360(A,G); rs1572521(T,G); rs116697245(C,T); rs7550118(C,T); rs17127465(T,C); rs1415359(C,T); rs10493988(A,G); rs1337193(T,A); rs10493987(C,T); rs113897206(C,T); rs17101127(G,C); rs1415358(A,C); rs114823243(C,T); rs1415356(G,A); rs17462015(T,C); rs1337192(T,C); rs2376280(G,A); rs2376281(A,T); rs1337191(C,T); rs1890044(T,C); rs10493986(T,C); rs182635797(G,A); rs10493985(C,T); rs17127490(A,G); rs1337190(G,T); rs11164672(C,T); rs185072168(G,A); rs78195975(C,T); rs1415355(T,G); rs147548505(G,A); rs4908291(A,T); rs6691654(G,A) |
| ccdsGene name | CCDS778.1 |
| cytoBand name | 1p21.1 |
| EntrezGene GeneID | 1301 |
| EntrezGene Description | collagen, type XI, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/pubmed?term=22922875 |
| Annovar Function | COL11A1:NM_001190709:exon51:c.C3851T:p.P1284L,COL11A1:NM_080629:exon52:c.C4004T:p.P1335L,COL11A1:NM_001854:exon52:c.C3968T:p.P1323L,COL11A1:NM_080630:exon50:c.C3620T:p.P1207L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9155 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/pubmed?term=22922875 |
| dbNSFP KGp1 AF | 0.532509157509 |
| dbNSFP KGp1 Afr AF | 0.0589430894309 |
| dbNSFP KGp1 Amr AF | 0.734806629834 |
| dbNSFP KGp1 Asn AF | 0.70979020979 |
| dbNSFP KGp1 Eur AF | 0.609498680739 |
| dbSNP GMAF | 0.4674 |
| ESP Afr MAF | 0.139582 |
| ESP All MAF | 0.451715 |
| ESP Eur/Amr MAF | 0.388372 |
| ExAC AF | 0.589 |
OMIM Clinical Significance
Eyes:
Coloboma of iris, choroid and retina
Inheritance:
Autosomal dominant
OMIM Title
*120280 COLLAGEN, TYPE XI, ALPHA-1; COL11A1
OMIM Description
CLONING
Yoshioka et al. (1995) reported 93% sequence identity between the
predicted amino acid sequence of mouse and human type XI collagen.
Cloning experiments also revealed alternative splicing of the sequence
coding for 85 residues located within the acidic region of the
amino-globular domain of alpha-1 (XI). Analysis of RNA samples from
different embryonic tissues suggested that alternative splicing may be
confined to tissue destined to become bone.
Bernard et al. (1988) showed that the cDNA-derived amino acid sequence
of type XI collagen shows a variety of structural features
characteristic of fibril-forming collagens. In addition, nucleotide
sequence analysis of a selected portion of the human gene showed the
characteristic 54-bp exon motif. They concluded, therefore, that type XI
collagen belongs to the group of fibrillar collagens. They also
suggested that expression of this gene is not restricted to cartilage,
as previously thought, since the cDNA libraries from which the clones
were isolated originated from both cartilaginous and noncartilaginous
tissues.
GENE FUNCTION
Jacenko et al. (1994) pointed out the usefulness of studies of the more
than 40 well-characterized murine skeletal dysplasias as contributions
to the understanding of human osteochondrodysplasias. As one example,
they pointed to the work of Li et al. (1993), which demonstrated that
the mutation in the mouse autosomal recessive disease chondrodysplasia
(cho) maps to mouse chromosome 3 in the same region as the COL11A1 gene.
Li et al. (1995) demonstrated deletion of a cytidine residue about 570
nucleotides downstream of the translation initiation codon in COL11A1
mRNA from cho homozygotes. The deletion caused a reading frame shift and
introduced a premature stop codon. Limb bones of newborn cho/cho mice
are wider at the metaphyses than normal bones and only about half the
normal length. The findings demonstrate that collagen XI is essential
for normal formation of cartilage collagen fibrils and the cohesive
properties of cartilage. The results also suggest that the normal
differentiation and spatial organization of growth plate chondrocytes
are critically dependent on the presence of type XI collagen in
cartilage extracellular matrix.
By microarray analysis, Jun et al. (2001) demonstrated expression of the
COL11A1 gene in human donor corneas.
Fichard et al. (1994) reviewed collagens V (120215) and XI and commented
on their fundamental role in the control of fibrillogenesis, probably by
forming a core within the fibrils. Another characteristic of these
collagens is the partial retention of their N-propeptide extensions in
tissue forms, which is unusual for known fibrillar collagens. The tissue
locations of collagen V and XI are different, but their structural and
biologic properties seem to be closely related. Their primary structures
are highly conserved at both the gene and the protein level, and this
conservation is the basis of their similar biologic properties. In
particular, they are both resistant to mammalian collagenases, and
surprisingly sensitive to trypsin. Although they have both cell adhesion
and heparin binding sites that could be crucial in physiologic processes
such as development and wound healing, the 2 collagens are usually
buried within the major collagen fibrils. It had become evident that
several collagen-type molecules are, in fact, heterotypic associations
of chains from both collagens V and XI, demonstrating that these 2
collagens are not distinct types but a single type that can be called
collagen V/XI.
GENE STRUCTURE
Annunen et al. (1999) characterized the genomic structure of the COL11A1
gene. The gene spans over 150 kb and consists of 68 exons. The exons
were numbered 1 to 67, with numbers 6A and 6B used for the sixth and
seventh exons (previously called IIA and IIB) because they are
alternatively spliced and do not exist in the same mRNA (Zhidkova et
al., 1995). Exons numbered 9-15 by Bernard et al. (1988) corresponded to
exon 16-22 in the numbering of Annunen et al. (1999). No cysteinyl
residue was found in the triple-helical region. The amino acid at
position 690 was methionine instead of tryptophan, an amino acid rarely
found in collagen triple helices.
MAPPING
The gene for at least one subunit of type XI collagen was assigned to
chromosome 1 by probing of DNA isolated from flow-sorted chromosomes
(Henry et al., 1988); by in situ hybridization, the gene was
regionalized to 1p21.
Sirko-Osadsa et al. (1996) presented evidence that a form of Stickler
syndrome (Stickler syndrome type II, 604841) is caused by a mutation in
the COL11A1 gene. They identified and used intragenic and highly linked
markers of COL11A1 to show that this locus was linked to Stickler
syndrome in families in which linkage to COL11A2 and COL2A1 had been
excluded.
MOLECULAR GENETICS
Richards et al. (1996) studied a 4-generation family in which 7
individuals were affected with Stickler syndrome type II with vitreous
and retinal abnormalities and 9 individuals were normal. The authors
demonstrated linkage to the COL11A1 gene region. Mutation analysis of
COL11A1 was performed on RT-PCR products using RNA extracted from
cultured dermal fibroblasts. Sequence analysis revealed that affected
individuals were heterozygous for a gly97-to-val substitution
(120280.0001) that disrupts the Gly-X-Y collagen sequence. SSCP analysis
of 100 chromosomes from 50 unrelated controls revealed only the pattern
of bands seen in normal family members. Richards et al. (1996) concluded
that collagen XI is an important structural component of human vitreous.
Annunen et al. (1999) identified 15 novel mutations in the COL11A1 gene
and 8 in the COL2A1 gene in patients with Marshall syndrome (MRSHS;
154780), Stickler syndrome, or Stickler-like syndrome. Most of the
mutations in the COL11A1 gene altered the splicing consensus sequences,
but all of them affected the splicing-consensus sequences of 54-bp
exons, as reported by Griffith et al. (1998). In addition, one patient
had a genomic deletion resulting in the loss of a 54-bp exon
(120280.0002). Nine out of 10 of these mutations affected the splicing
of 54-bp exons in the region spanning exons 38 to 54 of the gene.
Although more than one-third of the exons in this region are 90 or 108
bp in size, no splicing mutations were found in them.
Martin et al. (1999) pointed out that Stickler syndrome patients with
mutations in COL11A1 show a 'beaded' or type 2 vitreous phenotype. In 5
families with the type 2 vitreous phenotype, Martin et al. (1999)
identified 2 families that were linked to COL11A1; sequencing identified
mutations resulting in shortened collagen chains, one through exon
skipping and the other through a multiexon deletion.
Majava et al. (2007) analyzed 44 patients with a phenotype suggestive of
Stickler syndrome or Marshall syndrome who were negative for mutations
in the COL2A1 gene, and they identified mutations in COL11A1 in 10
patients (see, e.g., 120280.0002 and 120280.0006). Four of the 10
mutation-positive patients were diagnosed with Marshall syndrome, but
the remaining 6 showed an overlapping Marshall/Stickler phenotype.
Majava et al. (2007) concluded that heterozygous COL11A1 mutations can
result in either Marshall syndrome or Stickler syndrome, and also in
phenotypes that are difficult to classify with respect to the 2
disorders. A type I vitreous anomaly was diagnosed in a patient with a
mutation in COL11A1 (120280.0006), suggesting that the vitreous
phenotype does not always allow prediction of the defective gene in
Stickler and Marshall syndromes.
Lumbar disc herniation (see 603932), degeneration and herniation of the
nucleus pulposus of the intervertebral disc of the lumbar spine, is one
of the most common musculoskeletal disorders. Type XI collagen is
important for cartilage collagen formation and for organization of the
extracellular matrix. Mio et al. (2007) identified an association
between polymorphism of the COL11A1 gene and lumbar disc herniation in
Japanese populations. A single-nucleotide polymorphism (4603C-T;
120280.0007) had the most significant association with lumbar disc
herniation, P = 3.3 x 10(-6). Normally, the COL11A1 gene is highly
expressed in the intervertebral disc; its expression was decreased in
the intervertebral disc in patients with lumbar disc herniation. The
expression level was inversely correlated with the severity of disc
degeneration. The transcript containing the disease-associated allele
was decreased because of its decreased stability. These observations
indicated that type XI collagen is critical for intervertebral disc
metabolism and that its decrease is related to lumbar disc herniation.
Tompson et al. (2010) sequenced the COL11A1 gene in 2 unrelated patients
with fibrochondrogenesis and demonstrated that each was a compound
heterozygote for a loss-of-function mutation on one allele and a
mutation predicting substitution for a conserved triple-helical glycine
residue on the other (120280.0008-120280.0011). The parents who were
carriers of a missense mutation had myopia. Early-onset hearing loss was
noted in both parents who carried a loss-of-function allele. Tompson et
al. (2010) suggested that COL11A1 is a locus for mild, dominantly
inherited hearing loss and that there might be phenotypic manifestations
among carriers.
In a mother and son with Marshall syndrome, Ala-Kokko and Shanske (2009)
identified heterozygosity for a splice site mutation in the COL11A1 gene
(120280.0012). The mother, who was more mildly affected, was mosaic for
the mutation; the authors stated that this was the first report of
mosaicism in Marshall syndrome.
ANIMAL MODEL
Implication of type XI collagen in human osteochondrodysplasias was
supported by the fact that mice with chondrodysplasia (cho), an
autosomal recessive disorder in which there is neonatal lethality, small
mandible, cleft palate, small thorax, disproportionate limbs, and
fragile cartilage (Seegmiller et al., 1971), were shown to have
abnormality in the alpha-1 chain of type XI collagen.
HISTORY
Morris and Bachinger (1987) concluded that type XI collagen is a trimer
consisting of 3 different polypeptides--alpha-1, alpha-2, and alpha-3.
All 3 chains retain non-triple-helical domains. Wu and Eyre (1995),
however, provided evidence that what was formerly termed the alpha-3
chain of type XI collagen is actually transcribed from the COL2A1 gene
(120140).
AMY2B
| dbSNP name | rs143638758(C,T); rs77004565(G,A); rs12127290(A,G); rs17014907(A,T); rs2050592(T,C); rs11184461(G,A); rs6690291(C,T); rs17014910(C,G); rs17014913(A,G); rs17014917(T,C); rs4847096(C,T); rs7515452(A,G); rs77729677(A,G); rs9435607(G,A); rs12075225(C,A); rs75966519(A,T); rs12132040(A,G); rs17851840(T,C); rs79005152(A,T); rs184979235(G,A); rs75811309(C,G); rs77808139(C,T) |
| ccdsGene name | CCDS782.1 |
| cytoBand name | 1p21.1 |
| EntrezGene GeneID | 280 |
| EntrezGene Description | amylase, alpha 2B (pancreatic) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AMY2B:NM_020978:exon7:c.G856A:p.G286R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8871 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P19961 |
| dbNSFP Uniprot ID | AMY2B_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 1.626e-05 |
OMIM Clinical Significance
GU:
Secondary amenorrhea
Thorax:
Galactorrhea
Oncology:
Pituitary adenoma
Radiology:
Enlarged sella turcica
Inheritance:
Autosomal dominant
OMIM Title
*104660 AMYLASE, PANCREATIC, B; AMY2B
OMIM Description
See 104650.
ACTG1P4
| dbSNP name | rs12132911(C,T) |
| cytoBand name | 1p21.1 |
| EntrezGene GeneID | 648740 |
| snpEff Gene Name | AMY2B |
| EntrezGene Description | actin, gamma 1 pseudogene 4 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1437 |
PRMT6
| dbSNP name | rs11555268(C,T); rs3791185(G,A) |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 55170 |
| EntrezGene Description | protein arginine methyltransferase 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| dbNSFP LR score | 0.048 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ExAC AF | 0.006485 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Deafness, sensorineural, prelingual, profound;
Nonprogressive deafness
MOLECULAR BASIS:
Caused by mutation in the hepatic growth factor gene (HGF, 142409.0001)
OMIM Title
*608274 PROTEIN ARGININE N-METHYLTRANSFERASE 6; PRMT6
OMIM Description
DESCRIPTION
Protein arginine N-methyltransferases, such as PRMT6, catalyze the
sequential transfer of a methyl group from S-adenosyl-L-methionine to
the side chain nitrogens of arginine residues within proteins to form
methylated arginine derivatives and S-adenosyl-L-homocysteine.
CLONING
By searching the genome for PRMT family members, followed by 5-prime
RACE of a kidney cDNA library, Frankel et al. (2002) cloned PRMT6. The
deduced 375-amino acid protein has a calculated molecular mass of 41.9
kD. PRMT6 contains a catalytic core sequence and no additional domains.
The catalytic cores of PRMT6 and PRMT2 (601961) shares 38% amino acid
identity. Northern blot analysis detected broad expression of 2.4- and
2.6-kb transcripts. Confocal microscopy of fluorescence-labeled PRMT6
showed strong nuclear localization in transfected HeLa cells.
GENE FUNCTION
Frankel et al. (2002) assayed the PRMT activity of recombinant PRMT6
overexpressed in E. coli. PRMT6 demonstrated type I PRMT activity,
forming both omega-N(G)-monomethylarginine and asymmetric
omega-N(G),N(G)-dimethylarginine derivatives on a recombinant glycine-
and arginine-rich substrate. There was an initial accumulation of the
monomethyl species followed by accumulation of the final
dimethylarginine product. A comparison of substrate specificities
revealed that PRMT6 is functionally distinct from PRMT1 (602950) and
PRMT4, which are also type I PRMTs. In addition, PRMT6 displayed
automethylation activity.
El-Andaloussi et al. (2006) determined that human POLB (174760) formed a
complex with and was methylated by PRMT6. In vitro, methylated POLB
possessed significantly higher DNA polymerase activity when compared to
that of unmodified enzyme. The increase in DNA polymerase activity upon
methylation was due to the enhanced DNA binding and processivity of
POLB.
Following up on the observation that asymmetric dimethylation of histone
H3 (see 602810) arginine-2 (H3R2me2a) countercorrelates with di- and
trimethylation of H3 lysine-4 (H3K4me2, H3K4me3) on human promoters,
Guccione et al. (2007) demonstrated that the arginine methyltransferase
PRMT6 catalyzes H3R2 dimethylation in vitro and controls global levels
of H3R2me2a in vivo. H3R2 methylation by PRMT6 was prevented by the
presence of H3K4me3 on the H3 tail. Conversely, the H3R2me2a mark
prevented methylation of H3K4 as well as binding to the H3 tail by an
ASH2 (604782)/WDR5 (609012)/MLL (159555) family methyltransferase
complex. Chromatin immunoprecipitation showed that H3R2me2a was
distributed within the body and at the 3-prime end of human genes,
regardless of their transcriptional state, whereas it was selectively
and locally depleted from active promoters, coincident with the presence
of H3K4me3. Guccione et al. (2007) concluded that hence, the mutual
antagonism between H3R2 and H3K4 methylation, together with the
association of MLL family complexes with the basal transcription
machinery, may contribute to the localized patterns of H3K4
trimethylation characteristic of transcriptionally poised or active
promoters in mammalian genomes.
MAPPING
By genomic sequence analysis, Frankel et al. (2002) mapped the PRMT6
gene to chromosome 1.
FNDC7
| dbSNP name | rs2990871(A,T); rs3006865(G,A); rs34261442(C,T); rs3006866(G,A); rs10494094(T,C); rs1333124(C,T); rs11102287(T,G); rs11102288(C,A); rs79643501(A,G); rs914807(T,C); rs914806(A,G); rs4970804(G,A); rs12070845(G,A); rs72980755(T,G); rs2184083(A,G); rs4970805(A,G); rs145406401(C,T); rs4970806(C,T); rs4970807(T,C); rs4423040(G,T); rs4970743(G,C); rs4970808(C,T); rs4970744(C,T); rs369113222(A,G); rs3006869(G,T); rs10494095(A,G); rs2026485(A,G); rs968632(A,G); rs2990878(A,G); rs74647482(G,A); rs11582005(G,A); rs4494160(T,C); rs3006870(A,G); rs1981051(C,T); rs147512638(G,A); rs11102312(G,A); rs10857900(T,G); rs114307220(C,A); rs2065515(C,A); rs10494096(G,A); rs4484951(T,C); rs150364624(G,A); rs17026815(T,C); rs7529771(T,C); rs55891684(T,A); rs3006871(G,A); rs76462144(C,A); rs4970809(A,G); rs4970810(G,A); rs115438468(G,A); rs2990874(A,T); rs7523408(G,A); rs28684574(A,C); rs2151327(T,C); rs2151328(C,T); rs1277017(C,T); rs377522474(G,C); rs1277018(A,G); rs11102324(G,C); rs116354388(A,G); rs1277019(T,C); rs2275343(G,T); rs189832987(A,G); rs7522448(G,T); rs928477(G,A); rs928478(G,A); rs1277031(G,C); rs77349163(T,A); rs6687345(C,T); rs78335134(G,A); rs191320700(T,C) |
| ccdsGene name | CCDS44185.1 |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 163479 |
| EntrezGene Description | fibronectin type III domain containing 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FNDC7:NM_001144937:exon10:c.C2054T:p.P685L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7346 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0206043956044 |
| dbNSFP KGp1 Afr AF | 0.0914634146341 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02066 |
| ESP Afr MAF | 0.078529 |
| ESP All MAF | 0.02668 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.007628 |
GPSM2
| dbSNP name | rs12047639(A,C); rs74113521(G,A); rs2131903(G,A); rs12752045(C,T); rs374510103(G,C); rs79451450(T,C); rs67312582(A,G); rs59076670(A,G); rs58519661(A,G); rs7542414(G,A); rs149859988(C,T); rs12048340(A,T); rs10857987(G,A); rs6692517(A,T); rs12046219(G,A); rs72984607(C,T); rs72984609(G,A); rs74113532(C,G); rs7547386(C,G); rs12736847(A,C); rs183755098(C,G); rs12729728(C,A); rs10776765(T,C); rs77113761(C,T); rs35100394(C,G); rs116369874(C,A); rs72984612(T,C); rs72984614(T,C); rs12120692(T,C); rs338468(C,T); rs41279678(G,A); rs12028832(A,G); rs12734623(A,G); rs12126300(A,G); rs67648221(C,T); rs338488(A,T); rs2270536(A,T); rs338489(A,G); rs338490(A,G); rs11102616(G,T); rs9662782(T,G); rs338491(C,G); rs180806606(A,G); rs10776766(A,G); rs338492(C,G); rs10857995(T,A); rs338493(G,A); rs7521011(T,C); rs112922738(G,A); rs338494(A,G); rs11102626(T,C); rs11102632(T,C); rs6699472(T,C); rs12033197(G,A); rs114208558(G,C); rs1690722(G,A); rs1664423(G,T); rs12034332(G,A); rs1690721(C,T); rs1664421(T,C); rs74113536(C,G); rs1664420(C,T); rs1664419(G,A); rs11102642(C,T); rs1690720(C,T); rs2591001(G,A); rs11102643(G,A); rs74113539(T,C); rs9662017(A,T); rs142214319(G,A); rs11804980(T,A); rs11804981(T,A); rs338469(A,C); rs338470(C,T); rs3754456(A,G); rs35089879(C,T); rs338471(C,T); rs58037560(C,G); rs12130952(T,C); rs168106(C,T); rs76844349(G,A); rs338472(G,C); rs150089340(C,T); rs12077339(A,G); rs35229560(G,T); rs74636173(T,A); rs12405026(G,A); rs338473(A,T); rs338474(C,T); rs338475(T,C); rs11102650(C,G); rs338476(A,C); rs74113452(T,G); rs338477(A,G); rs338478(T,G); rs58151869(A,G); rs139683351(A,G); rs4970816(T,C); rs17030869(A,C); rs12034820(T,C); rs705268(G,A); rs12404265(G,A); rs11102655(G,A); rs9661361(G,T); rs1664417(A,G); rs10858009(C,G); rs9729098(G,A); rs12755454(C,G); rs12079547(A,C); rs369527701(A,G); rs60505357(T,C); rs839860(A,G); rs839859(T,C); rs1769731(G,A); rs1769730(C,T); rs839858(A,T); rs839857(G,A); rs74113459(T,C); rs839856(A,G); rs839855(A,G); rs59443808(C,T); rs839854(T,G); rs72699240(G,A); rs12565372(G,C); rs1051868(G,A); rs12030(T,C); rs14209(T,G); rs10607(C,T) |
| ccdsGene name | CCDS792.2 |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 29899 |
| EntrezGene Description | G-protein signaling modulator 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPSM2:NM_013296:exon4:c.G380A:p.R127Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5861 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P81274 |
| dbNSFP Uniprot ID | GPSM2_HUMAN |
| dbNSFP KGp1 AF | 0.0769230769231 |
| dbNSFP KGp1 Afr AF | 0.144308943089 |
| dbNSFP KGp1 Amr AF | 0.0552486187845 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.100263852243 |
| dbSNP GMAF | 0.07576 |
| ESP Afr MAF | 0.097821 |
| ESP All MAF | 0.098032 |
| ESP Eur/Amr MAF | 0.09814 |
| ExAC AF | 0.086 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Coarse facies;
[Ears];
Sensorineural hearing loss;
Meniere syndrome;
[Eyes];
Conjunctiva shows dilated blood vessels;
Fundi show dilated blood vessels with corkscrew-like tortuosity;
[Nose];
Enlarged nasal tip;
Depressed nasal bridge;
[Mouth];
Thick lips
SKIN, NAILS, HAIR:
[Skin];
Angiokeratoma corporis diffusum;
Hyperkeratosis;
Dry skin;
Maculopapular eruption, diffuse;
Telangiectasia on lips and oral mucosa
MUSCLE, SOFT TISSUE:
Lymphedema
NEUROLOGIC:
[Central nervous system];
Intellectual impairment, mild;
Vertigo;
MRI may show atrophy of the cerebrum;
White mater abnormalities in the posterior periventricular region;
[Peripheral nervous system];
Peripheral axonal neuropathy;
Distal limb muscle weakness;
Distal sensory impairment of all modalities;
Sural nerve biopsy shows decreased density of myelinated fibers and
axonal degeneration
LABORATORY ABNORMALITIES:
Decreased or absent alpha-N-acetylgalactosaminidase protein;
Decreased or absent alpha-N-acetylgalactosaminidase activity;
Diverse tissue cell types (vascular endothelial cells, adipocytes,
Schwann cells, leukocytes) have membrane-lined cytoplasmic vacuoles
with amorphous and filamentous material;
Glycoamino aciduria;
Increased urinary O-linked sialopeptides
MISCELLANEOUS:
Adult onset;
Allelic disorder to Schindler disease (609241)
MOLECULAR BASIS:
Caused by mutation in the alpha-N-acetylgalactosaminidase gene (NAGA,
104170.0002)
OMIM Title
*609245 G PROTEIN SIGNALING MODULATOR 2; GPSM2
;;LEU-GLY-ASN REPEAT-ENRICHED PROTEIN; LGN;;
TRANSDUCIN-BINDING PARTNER, ROD-SPECIFIC;;
PINS, DROSOPHILA, HOMOLOG OF
OMIM Description
DESCRIPTION
Heterotrimeric G proteins transduce extracellular signals received by
cell surface receptors into integrated cellular responses. GPSM2 belongs
to a group of proteins that modulate activation of G proteins (Blumer et
al., 2002).
CLONING
Using GNAI2 (139360) as bait in a yeast 2-hybrid screen of a B-cell cDNA
library, followed by screening a HeLa cell cDNA library, Mochizuki et
al. (1996) cloned full-length GPSM2, which they designated LGN due to
the presence of 10 leu-gly-asn repeats in the protein. The deduced
677-amino acid protein has a calculated molecular mass of 76 kD. The
N-terminal half of LGN contains the leu-gly-asn repeats, which are
located within 7 repeats of about 40 amino acids that form alpha helices
interrupted by turns. The C-terminal half of LGN contains 4 GoLoco
motifs (G-alpha-i/o-Loco), which are involved in guanine nucleotide
exchange. LGN also has several potential protein kinase phosphorylation
sites. RT-PCR detected LGN expression in all tissues examined.
Blumer et al. (2002) determined that human LGN shares 59% amino acid
identity with rat activator of G protein signaling-3 (AGS3, or GPSM1;
609491), with most similarity in the 7 N-terminal tetratricopeptide
repeat (TPR) motifs and the 4 C-terminal G protein regulatory motifs.
Western blot analysis detected Lgn in all rat tissues and specific brain
regions examined. Lgn was expressed in all cell lines tested and in
primary cultures of rat cortical neurons, astroglia, and microglia. In
primary neuronal cultures, Lgn was nonhomogeneously distributed in the
cell body, neuronal processes, and nucleus.
MAPPING
By genomic sequence analysis, Blumer et al. (2002) mapped the GPSM2 gene
to chromosome 1p13.1.
GENE STRUCTURE
Blumer et al. (2002) determined that the GPSM2 gene contains 14 exons
and spans about 44.7 kb.
GENE FUNCTION
Blumer et al. (2002) found that activation of NMDA receptors (see
138252) and elevated intracellular calcium in primary rat neuronal
cultures caused redistribution of Lgn into punctate structures in the
cell body and neuronal processes. Distribution of Lgn was dynamic in
actively dividing rat pheochromocytoma cells and COS-7 cells. During the
cell cycle, Lgn relocalized from the nucleus to the midbody, where it
colocalized with F-actin at the site of daughter cell separation during
cytokinesis.
Nair et al. (2005) investigated the presence of a guanosine diphosphate
(GDP) dissociation inhibitor (GDI) for transducin (139330) in rod
photoreceptor cells. Western blot analysis showed Lgn (but not Ags3 or
Ags1) in mouse and bovine retina. By immunofluorescence microscopy of
mouse retinal sections, Lgn was localized mostly in the inner segments
and outer plexiform layer of photoreceptor cells in both light and dark
conditions. Lgn was present in the cytosol, membrane, and the
detergent-resistant cytoskeletal fraction. The ratio of Lgn to
transducin was at least 1:15. The alpha subunit of transducin in its
GDP-bound state interacted with endogenous and recombinant Lgn, and the
recombinant G protein regulatory motif of Lgn reduced the rate of
guanosine triphosphate (GTP) exchange. Nair et al. (2005) concluded that
photoreceptor inner segments contain Lgn, which can bind to the alpha
subunit of transducin and potentially regulate its function.
Walsh et al. (2010) evaluated inner ear expression of Gpsm2 in mice
using immunohistochemistry. There was embryonic and perinatal expression
of Gpsm2 at the apical surfaces of the hair and supporting cells in the
cochlea, utricle, saccule, and cristae. In the cochlea, Gpsm2
localization extended throughout the greater epithelial ridge. At
postnatal day (P) 0, cochlear hair cells showed asymmetric localization
of Gpsm2 at the lateral edge, a pattern that was not present in hair
cells at embryonic day (E) 16.5. Gpsm2 also localized in pillar cells in
P0 inner ears. By P15, Gpsm2 had disappeared at the apical surface of
the cells but persisted in pillar cells. In adult mice, Gpsm2 was
concentrated specifically in the head region of the inner pillar cells.
RT-PCR studies showed that Gpsm2 expression decreased rapidly between
E16.5 and P30, dropping to a level in adult mice that was approximately
20% of that at E16.5, indicating developmental regulation.
Using in vivo skin-specific lentiviral RNA interference, Williams et al.
(2011) investigated spindle orientation regulation and provided direct
evidence that LGN, NuMA (164009), and dynactin (DCTN1; 601143) are
involved. In compromising asymmetric cell divisions, Williams et al.
(2011) uncovered profound defects in stratification, differentiation,
and barrier formation, and implicate Notch (190198) signaling as an
important effector. Williams et al. (2011) concluded that asymmetric
cell division components act by reorienting mitotic spindles to achieve
perpendicular divisions, which in turn promote stratification and
differentiation. Furthermore, the resemblance between their knockdown
phenotypes and Rbpj (147183) loss-of-function mutants provided important
clues that suprabasal Notch signaling is impaired when asymmetric cell
divisions do not occur.
MOLECULAR GENETICS
In affected members of a Palestinian kindred with Chudley-McCullough
syndrome (CMCS; 604213), Walsh et al. (2010) identified a homozygous
mutation in the GPSM2 gene (R127X; 609245.0001). All unaffected parents
were heterozygous for the mutation. The findings indicated that GPSM2 is
essential to the development of normal hearing, and Walsh et al. (2010)
postulated that the R127X mutation caused a defect in the maintenance of
cell polarity and spindle orientation in hair and supporting cells of
the developing inner ear. By homozygosity mapping followed by candidate
gene analysis, Yariz et al. (2012) identified a homozygous truncating
mutation in the GPSM2 gene (Q562X; 609245.0002) in affected members of a
consanguineous Turkish family with CMCS. Although the families reported
by Walsh et al. (2010) and Yariz et al. (2012) were originally reported
to have autosomal recessive nonsyndromic deafness 82 (DFNB82),
neuroimaging studies by Doherty et al. (2012) found abnormalities,
including short, thin corpus callosum, heterotopia, frontal
polymicrogyria, cerebellar dysplasia, and an arachnoid cyst, consistent
with a diagnosis of Chudley-McCullough syndrome.
By homozygosity mapping and whole-exome sequencing of patients with
Chudley-McCullough syndrome, Doherty et al. (2012) identified homozygous
or compound heterozygous mutations in the GPSM2 gene
(609245.0003-609245.0006). The disorder was characterized by severe to
profound deafness and characteristic brain abnormalities on
neuroimaging, including ventriculomegaly, partial agenesis of the corpus
callosum, heterotopia, frontal polymicrogyria, cerebellar dysplasia, and
arachnoid cysts. Despite these abnormalities, neurodevelopment was
essential normal, except in 1 child who had mild to moderate
intellectual disability. Only 2 patients had seizures, which were well
controlled. There were no apparent genotype/phenotype correlations.
Doherty et al. (2012) postulated that the disorder results from
asymmetric cell divisions in the brain during development.
ANIMAL MODEL
Lee et al. (2006) tested whether cell polarity genes, known to regulate
embryonic neuroblast asymmetric cell division, also regulate neuroblast
self-renewal. Clonal analysis in Drosophila larval brains showed that
pins mutant neuroblasts rapidly fail to self-renew, whereas lgl (600966)
mutant neuroblasts generate multiple neuroblasts. Notably, lgl pins
double-mutant neuroblasts all divide symmetrically to self-renew,
filling the brain with neuroblasts at the expense of neurons. The lgl
pins neuroblasts show ectopic cortical localization of atypical protein
kinase C (aPKC; see 176960), and a decrease in aPKC expression reduces
neuroblast numbers, suggesting that aPKC promotes neuroblast
self-renewal. In support of this hypothesis, Lee et al. (2006) found
that neuroblast-specific overexpression of membrane-targeted aPKC, but
not a kinase-dead version, induced ectopic neuroblast self-renewal. Lee
et al. (2006) concluded that cortical aPKC kinase activity is a potent
inducer of neuroblast self-renewal.
AMIGO1
| dbSNP name | rs141240479(C,T) |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 57463 |
| snpEff Gene Name | CYB561D1 |
| EntrezGene Description | adhesion molecule with Ig-like domain 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial nerve palsies;
[Eyes];
Ophthalmoplegia;
Optic atrophy (1 patient)
CARDIOVASCULAR:
[Vascular];
Stroke, ischemic;
Stroke, hemorrhagic;
Small-vessel disease;
Polyarteritis nodosa;
Aneurysms;
Stenosis;
Hypertension (in some patients)
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Gastrointestinal pain
GENITOURINARY:
[Kidneys];
Renal artery aneurysms
SKELETAL:
Arthritis;
[Hands];
Ischemic digital necrosis;
[Feet];
Ischemic digital necrosis
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa;
Livedo reticularis;
Erythema nodosum;
Urticarial rash;
Purpura;
HISTOLOGY:;
Vasculitis in the reticular dermis;
Inflammatory infiltrate;
Interstitial neutrophils and macrophages;
Perivascular T lymphocytes;
Leukocytoclastic vasculitis;
Panniculitis
MUSCLE, SOFT TISSUE:
Myalgia
NEUROLOGIC:
[Central nervous system];
Neurologic sequelae of stroke;
Altered mental status;
Hemiplegia;
Headache;
Ataxia;
Agitation;
Cranial nerve dysfunction;
Aphasia;
Lacunar infarcts in the deep-brain nuclei, brainstem, internal capsule
seen on imaging;
[Peripheral nervous system];
Raynaud phenomenon;
Neuropathy
METABOLIC FEATURES:
Fever, recurrent
HEMATOLOGY:
Lupus anticoagulant (in some patients);
Anemia (in some patients);
Thrombocytosis (in some patients)
IMMUNOLOGY:
Immunodeficiency;
Hypogammaglobulinemia (in some patients);
Leukopenia;
Leukocytosis
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Acute-phase reactants during fever
MISCELLANEOUS:
Variable age at onset, usually in first decade, but can occur later;
Variable manifestations;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0001)
OMIM Title
*615689 ADHESION MOLECULE WITH Ig-LIKE DOMAIN 1; AMIGO1
;;AMPHOTERIN-INDUCED GENE AND OPEN READING FRAME; AMIGO;;
ALIVIN 2; ALI2;;
KIAA1163
OMIM Description
DESCRIPTION
AMIGO1 belongs to a family of cell surface transmembrane proteins that
interact with one another. These proteins are predicted to function in
cell adhesion (Kuja-Panula et al., 2003).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Hirosawa et al. (1999) cloned AMIGO1, which they designated
KIAA1163. The deduced 437-amino acid protein has an immunoglobulin (Ig)
domain, 4 leucine-rich repeats (LRRs), and an LRR C-terminal domain.
RT-PCR ELISA showed variable AMIGO1 expression in all adult and fetal
tissues examined except fetal liver. Highest expression was detected in
adult heart, brain, skeletal muscle, and ovary and in fetal brain.
Within specific adult brain regions, highest expression was detected in
amygdala.
By searching databases for sequences similar to rat Ali1 (AMIGO2;
615690), Ono et al. (2003) identified human AMIGO1, which they called
ALI2. The deduced ALI2 protein contains an N-terminal signal sequence,
followed by a cysteine-rich domain, 7 LRRs, a second cysteine-rich
domain, an Ig C2-like loop, a transmembrane region, and a C-terminal
intracellular domain. Human ALI2 shares 38% and 34% amino acid identity
with human ALI1 and ALI3 (AMIGO3; 615691), respectively, and 89%
identity with its mouse ortholog.
By searching EST databases for homologs of rat Amigo, followed by
5-prime RACE of THP-1 monocytic leukemia cells, Kuja-Panula et al.
(2003) cloned human AMIGO. The deduced full-length protein contains 493
amino acids. Kuja-Panula et al. (2003) reported that the AMIGO proteins
contain 6 LRRs. The AMIGO protein family shares highest similarity with
the SLIT family of extracellular axon-guiding proteins (see 603742) and
with the NOGO66 receptor (RTN4R; 605566). RT-PCR analysis of 12 mouse
tissues detected highest Amigo expression in cerebrum, cerebellum, and
retina, with weaker expression in liver, kidney, small intestine,
spleen, lung, and heart. In situ hybridization and immunohistochemical
analysis of developing and mature rat nervous system revealed
predominant Amigo mRNA and protein expression at myelinated and
nonmyelinated fiber tracts. Database analysis revealed orthologs of the
3 AMIGO proteins in pufferfish. The authors identified the kekkon
protein family as possible orthologs in Drosophila, but they noted that
the intracellular C-terminal domains of the AMIGO and kekkon proteins
lack homology.
GENE FUNCTION
Using ordered differential display and RT-PCR analyses, Kuja-Panula et
al. (2003) found that expression of Amigo was induced in cultured
embryonic rat hippocampal neurons by amphoterin (HMGB1; 163905), a
neurite outgrowth-promoting factor. Immobilized Amigo promoted
attachment and neurite outgrowth of rat hippocampal neurons. Protein
pull-down assays with GPF- or epitope-tagged proteins revealed that
AMIGO1, AMIGO2, and AMIGO3 showed both homophilic and heterophilic
interactions following expression in HEK293T cells.
MAPPING
Hartz (2014) mapped the AMIGO1 gene to chromosome 1p13.3 based on an
alignment of the AMIGO1 sequence (GenBank GENBANK AB032989) with the
genomic sequence (GRCh37).
UBL4B
| dbSNP name | rs76478226(C,T); rs12125479(G,A); rs114022036(C,T) |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 164153 |
| EntrezGene Description | ubiquitin-like 4B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.02765 |
| ESP All MAF | 0.009507 |
| ESP Eur/Amr MAF | 0.000236 |
| ExAC AF | 0.003729 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, dilated;
Cardiomyopathy, hypertrophic;
Congestive heart failure
ABDOMEN:
[Liver];
Liver failure;
Microvesicular steatosis;
Decreased mitochondrial complex I activity
MUSCLE, SOFT TISSUE:
Muscle weakness;
Hypotonia;
Exercise intolerance;
Decreased mitochondrial complex I activity
NEUROLOGIC:
[Central nervous system];
Encephalopathy;
Cerebellar stroke;
Cerebral edema
METABOLIC FEATURES:
Reye-like episode;
Hypoglycemia;
Lactic acidosis
HEMATOLOGY:
Thrombocytopenia
LABORATORY ABNORMALITIES:
Hypoglycemia;
Elevated plasma ammonia;
Elevated liver transaminases;
Elevated serum lactate;
Elevated lactate dehydrogenase;
Elevated prothrombin time;
Hypoketotic dicarboxylic aciduria (in some patients);
Elevated long-chain acylcarnitine species (in some patients)
MISCELLANEOUS:
Onset usually in infancy;
Clinical presentation varies;
Onset may be precipitated by viral infection, Reye-like episode following
ingestion of aspirin;
Favorable response to treatment with riboflavin
MOLECULAR BASIS:
Caused by mutation in the acyl-CoA dehydrogenase-9 gene (ACAD9, 611103.0001)
OMIM Title
*611127 UBIQUITIN-LIKE 4B; UBL4B
OMIM Description
CLONING
By yeast 2-hybrid screen using Tex15 (605795) as bait, Yang et al.
(2007) cloned mouse Ubl4b. The deduced 188-amino acid protein contains a
72-amino acid ubiquitin domain. RT-PCR and Western blot analysis
detected Ubl4b mRNA and protein only in mouse testis. Immunofluorescence
analysis revealed Ubl4b in the cytoplasm of elongated spermatids, but
not in spermatocytes, round spermatids, Leydig cells, or Sertoli cells,
suggesting Ubl4b functions in late spermiogenesis. By database analysis,
Yang et al. (2007) identified human UBL4B and several mammalian
orthologs.
GENE STRUCTURE
Yang et al. (2007) determined that the mouse Ubl4b gene contains no
introns.
MAPPING
Yang et al. (2007) stated that the mouse Ubl4b gene maps to chromosome 3
and that the human UBL4B gene is in a syntenic region where it is
flanked by ALX3 (606014) and SLC6A17 (610299) on chromosome 1p13.3.
EVOLUTION
Yang et al. (2007) presented evidence that Ubl4b arose by retroposition
of the 4-exon Ubl4a gene (312070) at least 170 million years ago, prior
to the radiation of therian mammals.
KCNC4
| dbSNP name | rs72988885(A,C); rs663810(T,C); rs2784144(A,G); rs2761439(G,A); rs2603592(T,A); rs2603593(A,T); rs2603594(G,A); rs2603595(T,A); rs615204(T,C); rs11102064(T,C); rs187252090(C,T); rs12410908(G,A); rs628594(A,G); rs512079(T,C); rs514092(C,T); rs193081497(G,A); rs12736166(A,G); rs611587(C,G); rs12411176(G,A); rs183074590(C,T); rs2784146(T,A); rs114668488(A,G); rs192602492(G,A); rs2784147(G,C); rs2761440(G,A); rs2784148(G,C); rs75758195(G,A); rs57855778(T,C); rs375288185(G,T); rs897171(G,C); rs2282262(C,T); rs488016(A,G); rs2077399(C,G); rs958798(G,T); rs79154420(C,A); rs114937306(G,A); rs72990514(T,C); rs139115482(C,T); rs114238433(C,T); rs76650108(C,T); rs77581383(C,T); rs10429940(T,C); rs734695(G,A); rs67330514(G,C); rs17025562(C,T); rs12062357(G,A) |
| ccdsGene name | CCDS821.1 |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 3749 |
| EntrezGene Description | potassium voltage-gated channel, Shaw-related subfamily, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNC4:NM_004978:exon3:c.T1729C:p.S577P,KCNC4:NM_001039574:exon3:c.T1729C:p.S577P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8519 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.005901 |
| ESP All MAF | 0.002691 |
| ESP Eur/Amr MAF | 0.001047 |
| ExAC AF | 0.0008782 |
OMIM Clinical Significance
Neuro:
Ataxia due to posterior column degeneration;
Progressive vibratory and postural sensibility loss;
Muscle stretch reflex losses;
Flexor plantar responses;
Pain and temperature sensations preserved;
No cerebellar or pyramidal tract involvement
Skel:
Scoliosis
Misc:
Age of onset between 19 and 30 years
Inheritance:
Autosomal dominant
OMIM Title
*176265 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 4;
KCNC4
OMIM Description
Potassium channels are a family of membrane proteins present in all
eukaryotic cells. Their diverse functions include maintaining membrane
potential, regulating cell volume, and modulating electrical
excitability in neurons. Four sequence-related potassium channel genes,
Shaker, Shaw, Shab, and Shal, have been identified in Drosophila. Each
member of this Drosophila gene family has been shown to have a human
homolog. McPherson et al. (1991) used a panel of human/rodent somatic
cell hybrids to assign member 4 of the Shaw-related subfamily to human
chromosome 1; see Ghanshani et al. (1992). Rudy et al. (1991) reported
the cloning of a human K+ channel ShIII cDNA (HKShIIIC) obtained from a
brainstem cDNA library. By in situ hybridization, they demonstrated that
the gene maps to 1p21.
PROK1
| dbSNP name | rs113657477(A,C); rs884735(A,T); rs66809949(G,A); rs34662277(G,A); rs71665092(C,T); rs74116704(C,T); rs1914955(G,A); rs3795828(G,A); rs62623571(C,T); rs146968434(G,T); rs17628304(A,C); rs75815680(T,C); rs190708957(C,G); rs139576490(C,T); rs1416815(C,T); rs142841023(A,T); rs72975135(T,C); rs7513898(G,A); rs7551116(T,A); rs7514102(G,A); rs149653585(C,T); rs1044837(C,T) |
| ccdsGene name | CCDS825.1 |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 84432 |
| EntrezGene Description | prokineticin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PROK1:NM_032414:exon2:c.C142T:p.R48W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.784 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P58294 |
| dbNSFP Uniprot ID | PROK1_HUMAN |
| dbNSFP KGp1 AF | 0.0196886446886 |
| dbNSFP KGp1 Afr AF | 0.0792682926829 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01974 |
| ESP Afr MAF | 0.06355 |
| ESP All MAF | 0.022144 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 6.172e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Tall stature;
[Other];
Normal to accelerated growth
HEAD AND NECK:
[Head];
Dolichocephaly;
Macrocephaly;
[Face];
Asymmetric face;
Prominent brow;
Maxillary prognathism, mild;
Pointed chin;
Small chin;
[Ears];
Prominent ears;
Dysplastic ears;
Simple ears;
Hearing impairment;
[Eyes];
Ptosis;
Epicanthal folds;
[Nose];
Saddle nose;
Bulbous nasal tip
ABDOMEN:
[Gastrointestinal];
Feeding difficulties, neonatal
SKELETAL:
[Hands];
Large, fleshy hands
SKIN, NAILS, HAIR:
[Skin];
Tendency to overheat;
Lack of perspiration;
[Nails];
Dysplastic toenails
MUSCLE, SOFT TISSUE:
Hypotonia, neonatal
NEUROLOGIC:
[Central nervous system];
Global developmental delay;
Delayed motor development;
Absent or delayed speech development;
Compromised expressive language development, severe;
Mental retardation, moderate to severe;
Generalized hypotonia;
Seizures;
[Peripheral nervous system];
Increased tolerance to pain;
Hyporeflexia, neonatal;
Abnormal reflexes;
[Behavioral/psychiatric manifestations];
Inappropriate chewing behavior;
Autistic features;
Poor social interaction;
Poor communication;
Aggressive behavior
MISCELLANEOUS:
Wide phenotypic variation;
Some patients do not have dysmorphic features;
Heterozygous deletion of the terminal band 22q13.3 including SHANK3
(606230)
MOLECULAR BASIS:
A contiguous gene syndrome caused by deletion (160kb to 9Mb) of 22q13.3
OMIM Title
*606233 PROKINETICIN 1; PROK1
;;PK1; PRK1;;
ENDOCRINE GLAND-DERIVED VASCULAR ENDOTHELIAL GROWTH FACTOR; EG-VEGF
OMIM Description
DESCRIPTION
Endocrine gland-derived vascular endothelial growth factor (EG-VEGF)
induces proliferation, migration, and fenestration in capillary
endothelial cells derived from endocrine glands. Its expression is
induced by hypoxia and is restricted to the steroidogenic glands (ovary,
testis, adrenal, and placenta). Its expression is often complementary to
the expression of VEGF (192240), suggesting that these molecules
function in a coordinated manner.
CLONING
LeCouter et al. (2001) screened a library of purified human secreted
proteins for the ability to induce proliferation in primary bovine
adrenal cortex-derived capillary endothelial cells. EG-VEGF was capable
of inducing a strong and reproducible mitogenic response. Mature EG-VEGF
is a protein with a relative molecular mass of 8,600 encoded by a cDNA
cloned from human ovary library. The 1.4-kb cDNA encodes a protein of
105 amino acids with a well defined signal sequence. The mature protein
is predicted to have 86 amino acids, including 10 cysteines, and an
expected isoelectric point of 8.46. These cysteines potentially form 5
disulfide bridges. EG-VEGF displays a high degree of homology to a
nontoxic protein purified from the venom of the black mamba snake, venom
protein A (VPRA). The structure of native VPRA was solved, and the
disulfide bridge partners were revealed. The number and spacing of
cysteines are completely conserved between VPRA and EG-VEGF. BV8, a
human molecule closely related to a peptide isolated from the
yellow-bellied toad, is 58% identical to the EG-VEGF mature protein.
There is also significant homology to the carboxy-terminal sequence of
Xenopus dickkopf (see 605189) and to colipase (120105).
Li et al. (2001) identified EG-VEGF as prokineticin-1.
GENE FUNCTION
EG-VEGF is mitogenic and chemoattractive and able to induce
fenestration. EG-VEGF expression is induced by hypoxia, and there is an
HIF1 (603348) binding site present on EG-VEGF. EG-VEGF is able to induce
angiogenesis and ovarian cyst formation. Northern blot analysis
demonstrated expression in testis, ovary, adrenal gland, and placenta. A
signal was detectable in prostate after prolonged exposure.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PROK1
gene to chromosome 1 (TMAP SHGC-16135).
LOC440602
| dbSNP name | rs4839425(C,T); rs1890674(G,A); rs2298252(A,G); rs925972(C,T); rs1573239(A,G); rs925971(A,T); rs74117687(G,A); rs925970(G,A); rs1857516(T,C); rs815327(T,C); rs181941241(G,A) |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 643160 |
| EntrezGene Symbol | CYMP |
| snpEff Gene Name | CYMP |
| EntrezGene Description | chymosin pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unitary_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1667 |
KCNA10
| dbSNP name | rs11806812(T,C); rs1281175(T,C); rs36028106(C,T); rs3748731(C,A); rs1281174(T,C); rs3768456(A,G) |
| ccdsGene name | CCDS826.1 |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 3744 |
| EntrezGene Description | potassium voltage-gated channel, shaker-related subfamily, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNA10:NM_005549:exon1:c.A761G:p.N254S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.3729 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q16322 |
| dbNSFP Uniprot ID | KCA10_HUMAN |
| dbNSFP KGp1 AF | 0.0334249084249 |
| dbNSFP KGp1 Afr AF | 0.134146341463 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.03306 |
| ESP Afr MAF | 0.072401 |
| ESP All MAF | 0.02568 |
| ESP Eur/Amr MAF | 0.001744 |
| ExAC AF | 0.008848 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Long, narrow face;
[Eyes];
Hypotelorism;
[Mouth];
High-arched palate;
Cleft lip;
Cleft palate;
[Teeth];
Single central upper incisor
GENITOURINARY:
[Kidneys];
Hydronephrosis
SKELETAL:
[Skull];
Hypoplastic mandible;
[Limbs];
Proximal radial head dislocation;
Mesomelia;
short radii;
Ulnar hypoplasia/aplasia;
[Hands];
Oligodactyly;
Absent thumb;
Proximally placed thumb
OMIM Title
*602420 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER
10; KCNA10
OMIM Description
DESCRIPTION
Potassium (K) channels are important components of virtually all cells
and play critical roles in many cellular functions. KCNA10 represents a
novel class of K channel specifically regulated by cGMP (summary by
Orias et al., 1997).
See 176260 for a general discussion of potassium voltage-gated ion
channels.
CLONING
Orias et al. (1997) cloned the human homolog of rabbit KCNA10, a gene
encoding a Shaker-related potassium-selective channel specifically
regulated by cGMP. Human KCNA10, a predicted 511-amino acid protein, is
85% identical to the rabbit protein.
MAPPING
Orias et al. (1997) used fluorescence in situ hybridization and PCR of
YACs to map the KCNA10 gene to 1p13.1, a region that also contains KCNA3
(176263).
KCNA3
| dbSNP name | rs2029685(T,C); rs1493381(G,A); rs189740308(A,G); rs10857831(G,A); rs2797520(T,C); rs2797521(T,G); rs78468676(A,G); rs6537675(G,A); rs2797522(C,T); rs2821548(G,A); rs2797523(T,C); rs2797524(G,C); rs17635693(T,C); rs116316792(G,A); rs2821547(G,A); rs2640488(C,T); rs2640487(C,T); rs77553558(G,A); rs2797525(C,T); rs2640486(T,C); rs2640485(A,C); rs2821546(T,A); rs78855939(T,C); rs2640484(T,C); rs1389279(G,A); rs2640483(A,G); rs2840384(A,G); rs75210252(G,C); rs2640482(C,A); rs1319782(C,T); rs76525015(T,C); rs2640481(G,A); rs2640480(C,A); rs192816784(G,A); rs1058184(A,C) |
| cytoBand name | 1p13.3 |
| EntrezGene GeneID | 3738 |
| snpEff Gene Name | AL365361.1 |
| EntrezGene Description | potassium voltage-gated channel, shaker-related subfamily, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intergenic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3926 |
OMIM Clinical Significance
Neuro:
Ataxia due to posterior column degeneration;
Progressive vibratory and postural sensibility loss;
Muscle stretch reflex losses;
Flexor plantar responses;
Pain and temperature sensations preserved;
No cerebellar or pyramidal tract involvement
Skel:
Scoliosis
Misc:
Age of onset between 19 and 30 years
Inheritance:
Autosomal dominant
OMIM Title
*176263 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER
3; KCNA3
;;MK3, MOUSE, HOMOLOG OF;;
POTASSIUM CHANNEL 3; PCN3;;
KV1.3
OMIM Description
See 176260 for a general discussion of potassium voltage-gated ion
channels.
CLONING
Lymphocytes express 3 distinct types of voltage-gated potassium ion
channels according to function, state of activation, and timing during
development (Grissmer et al., 1990). These have been termed n, n-prime,
and l. The n potassium ion channel plays an essential role in T-cell
proliferation and activation in the human. The 3 channels are encoded by
the mouse MK1, MK2, and MK3 genes; the type n potassium channel is
encoded by the MK3 gene.
Philipson et al. (1991) isolated cDNAs encoding 3 human potassium
channels (PCNs), PCN1 (176267), PCN2 (176266), and PCN3. All 3 proteins
are related to the Drosophila Shaker voltage-gated potassium channel,
and contain 6 membrane-spanning domains with a Shaker-type repeat in the
fourth segment. The predicted 519-amino acid PCN3 protein shares 67%
sequence identity with PCN1.
GENE FUNCTION
Rus et al. (2005) stated that myelin-reactive T cells from the blood of
multiple sclerosis (MS) patients have a high level of Kv1.3 expression,
suggesting they were effector memory T cells that had undergone repeated
rounds of activation in vivo. In contrast, myelin-reactive T cells from
the peripheral blood of healthy controls have low Kv1.3 levels,
consistent with naive central memory T cells. By immunohistochemical
analysis, they showed that Kv1.3 was highly expressed in postmortem MS
brain inflammatory infiltrates. The expression pattern revealed not only
Kv1.3-positive T cells in the perivenular infiltrate but also in the
parenchyma of demyelinated MS lesions and normal-appearing gray and
white matter. Rus et al. (2005) further found that a subset of T cells
from the cerebrospinal fluid exists in a primed state ready to become
effector memory T cells.
MAPPING
Grissmer et al. (1990) found by study of somatic cell hybrids that the
human MK3 gene is located on chromosome 13 and the human MK2 gene on
chromosome 12. Both Attali et al. (1992) and Folander et al. (1994)
mapped KCNA3 to chromosome 1. Attali et al. (1992) used isotopic in situ
hybridization to map it to 1p13.3; Folander et al. (1994) used analysis
of human/hamster somatic cell hybrid DNAs and fluorescence in situ
hybridization to map it to 1p21, 'approximately at the border of 1p13.'
ANIMAL MODEL
Xu et al. (2003) reported that Kv1.3 -/- mice weighed significantly less
than control littermates. Moreover, knockout mice were protected from
diet-induced obesity and gained significantly less weight than
littermate controls when placed on a high-fat diet. While food intake
did not differ significantly between Kv1.3 -/- mice and controls, basal
metabolic rate, measured at rest by indirect calorimetry, was
significantly higher in knockout animals. The authors hypothesized that
Kv1.3 channels may participate in pathways that regulate body weight,
and channel inhibition may increase basal metabolic rate.
TRIM45
| dbSNP name | rs1289662(G,A); rs1289661(T,C); rs1289660(A,G); rs10923208(A,G); rs1289659(A,G); rs12118664(G,T); rs1048635(G,A); rs1289658(A,G); rs1290530(A,G); rs76987957(C,G); rs58501866(G,A); rs1289657(C,T); rs3738413(C,T); rs755592(A,G); rs1289655(C,T); rs749902(C,T); rs2764859(T,C); rs3795655(C,T) |
| ccdsGene name | CCDS893.1 |
| cytoBand name | 1p13.1 |
| EntrezGene GeneID | 80263 |
| EntrezGene Description | tripartite motif containing 45 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TRIM45:NM_025188:exon3:c.G1238A:p.R413Q,TRIM45:NM_001145635:exon3:c.G1184A:p.R395Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5383 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0952380952381 |
| dbNSFP KGp1 Afr AF | 0.0609756097561 |
| dbNSFP KGp1 Amr AF | 0.113259668508 |
| dbNSFP KGp1 Asn AF | 0.113636363636 |
| dbNSFP KGp1 Eur AF | 0.0949868073879 |
| dbSNP GMAF | 0.09504 |
| ESP Afr MAF | 0.061961 |
| ESP All MAF | 0.091189 |
| ESP Eur/Amr MAF | 0.106163 |
| ExAC AF | 0.105 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Growth retardation
HEAD AND NECK:
[Head];
High forehead;
[Ears];
Deafness, sensorineural, congenital;
[Eyes];
Upslanting palpebral fissures;
Cataracts (uncommon)
ABDOMEN:
[Liver];
Hepatic fibrosis;
Cirrhosis;
Cholestasis;
[Gastrointestinal];
Diarrhea;
Enteropathy
SKIN, NAILS, HAIR:
[Skin];
Erythema;
Ichthyosis
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Hypotonia;
[Peripheral nervous system];
Peripheral neuropathy
LABORATORY ABNORMALITIES:
Increased very-long chain fatty acids
MISCELLANEOUS:
Onset at birth;
May result in early death from severe diarrhea;
Prevalent in Quebec
MOLECULAR BASIS:
Caused by mutation in the adaptor-related protein complex 1, sigma-1
subunit gene (AP1S1, 603531.0001)
OMIM Title
*609318 TRIPARTITE MOTIF-CONTAINING PROTEIN 45; TRIM45
OMIM Description
DESCRIPTION
TRIM45 belongs to a family of tripartite motif (TRIM) proteins that play
important roles in a variety of cellular functions, including cell
proliferation, differentiation, development, oncogenesis, and apoptosis
(Wang et al., 2004).
CLONING
Using the conserved B-box-1 domain to search an EST database, followed
by PCR and 5-prime and 3-prime RACE of an embryonic heart cDNA library,
Wang et al. (2004) cloned TRIM45. The deduced 580-amino acid protein has
a calculated molecular mass of 64 kD. TRIM45 contains an N-terminal RING
finger, followed by B-box-1 and B-box-2 domains, an alpha-helical
coiled-coil region, and a C-terminal filamin (see FLNA; 300017)-type
immunoglobulin domain. Northern blot analysis of adult tissues detected
a 3.6-kb transcript expressed at highest levels in skeletal muscle,
followed by brain, pancreas, and heart. Northern blot analysis of human
embryonic tissues showed highest expression in brain, followed by lung,
skeletal muscle, heart, and intestine. TRIM45 localized to both the
cytoplasm and nuclei of transfected COS-7 cells.
GENE FUNCTION
Using reporter plasmids to assay the effect of TRIM45 on the
transcriptional activity of COS-7 cells, Wang et al. (2004) found that
TRIM45 overexpression inhibited endogenous Elk1 (311040) transcriptional
activity and Mek1 (MAP2K1; 176872)-mediated Elk1 transcriptional
activity by about 80%. Using an AP1 (see 165160) reporter, they found
TRIM45 reduced AP1 transcriptional activity by 69%.
GENE STRUCTURE
Wang et al. (2004) determined that the TRIM45 gene contains 6 exons and
spans about 10.7 kb.
MAPPING
By genomic sequence analysis, Wang et al. (2004) mapped the TRIM45 gene
to chromosome 1p22.
HSD3BP4
| dbSNP name | rs17023979(C,T); rs61628102(A,C); rs10494226(G,A); rs12563561(T,C); rs2008921(G,A); rs12123783(A,C); rs2008694(A,G); rs4659202(A,G); rs78170381(A,T); rs4659203(T,C); rs4659204(C,A); rs4659205(C,A); rs10802113(A,G); rs12032931(G,A); rs12030462(T,C); rs6672394(T,C); rs4659206(T,C); rs4659207(A,G); rs2885796(T,C); rs1812822(G,C); rs4426020(G,A); rs415630(G,A); rs111487780(C,T); rs113690307(C,T); rs113481790(G,T); rs112703777(C,G); rs138739548(G,A); rs2092930(G,A); rs1884504(C,T); rs113471480(G,A); rs113688924(G,A); rs112794764(G,T); rs3862258(T,C) |
| cytoBand name | 1p12 |
| EntrezGene GeneID | 128102 |
| EntrezGene Description | hydroxy-delta-5-steroid dehydrogenase, 3 beta, pseudogene 4 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04867 |
ADAM30
| dbSNP name | rs35273427(T,C); rs2793823(G,A); rs2641348(A,G) |
| ccdsGene name | CCDS907.1 |
| cytoBand name | 1p12 |
| EntrezGene GeneID | 11085 |
| EntrezGene Description | ADAM metallopeptidase domain 30 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ADAM30:NM_021794:exon1:c.A2209G:p.T737A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0008 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UKF2 |
| dbNSFP Uniprot ID | ADA30_HUMAN |
| dbNSFP KGp1 AF | 0.119047619048 |
| dbNSFP KGp1 Afr AF | 0.355691056911 |
| dbNSFP KGp1 Amr AF | 0.0828729281768 |
| dbNSFP KGp1 Asn AF | 0.020979020979 |
| dbNSFP KGp1 Eur AF | 0.05672823219 |
| dbSNP GMAF | 0.1194 |
| ESP Afr MAF | 0.277349 |
| ESP All MAF | 0.132016 |
| ESP Eur/Amr MAF | 0.057558 |
| ExAC AF | 0.093 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Dilation of dermal capillaries
SKIN, NAILS, HAIR:
[Skin];
Collodion membrane at birth (in some patients);
Fine white or greyish-white scales;
Erythroderma (in some patients);
Hyperlinearity of palms (in some patients);
Palmoplantar keratoderma (in some patients);
Scales on scalp (in some patients);
HISTOLOGY:;
Hyperkeratosis;
Orthokeratosis (in some patients);
Thickening of stratum corneum, mild;
Acanthosis, moderate;
Parakeratosis, moderate;
Granular layer normal or slightly prominent;
Perivascular lymphocytic infiltrate, dermal, mild;
Dilation of dermal capillaries
MISCELLANEOUS:
Disease complicated by recurrent sepsis in some patients
MOLECULAR BASIS:
Caused by mutation in the cytochrome P450, family 4, subfamily F,
polypeptide 22 gene (CYP4F22, 611495.0001)
OMIM Title
*604779 A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 30; ADAM30
OMIM Description
Metalloproteinase-disintegrins such as ADAM30 are type 1 transmembrane
proteins that contain a unique domain structure including a zinc-binding
metalloproteinase domain and are expressed on the cell surface (summary
by Cerretti et al., 1999).
CLONING
By searching a DNA sequence database, Cerretti et al. (1999) identified
2 ESTs representing the novel ADAMs ADAM29 (604778) and ADAM30. The
ADAM30 EST encodes a polypeptide with sequence similarity to the
cysteine-rich region of ADAM21 (603713). Cerretti et al. (1999) screened
a human testis cDNA library with the ADAM30 EST and isolated cDNAs
encoding 2 forms of ADAM30 that differ in the cytoplasmic domain. The
first predicted ADAM30 protein has 790 amino acids and contains all of
the domains characteristic of ADAMs including a signal sequence, a
prodomain with a cysteine switch, a metalloproteinase-like domain, a
disintegrin-like domain, a cysteine-rich domain, a transmembrane domain,
and a C-terminal cytoplasmic domain. The metalloproteinase domain of
ADAM30 has a consensus zinc-binding motif, suggesting that ADAM30 is
proteolytically active. The second form of ADAM30, which the authors
called ADAM30-beta, has a deletion of 9 amino acids in its cytoplasmic
domain compared to the first form, resulting in a protein with 781 amino
acids. Northern blot analysis of a variety of human tissues detected an
approximately 3.0-kb ADAM30 transcript only in testis.
MAPPING
By radiation hybrid mapping, Cerretti et al. (1999) mapped the ADAM30
gene to chromosome 1p13-p11.
PDIA3P1
| dbSNP name | rs72708526(G,A); rs1816802(T,C); rs72708527(G,A); rs17159909(T,A); rs62623395(A,G); rs62623392(G,A); rs72708529(T,G); rs115428662(A,G); rs115000329(C,T) |
| cytoBand name | 1q21.1 |
| EntrezGene GeneID | 171423 |
| EntrezGene Symbol | PDIA3P |
| snpEff Gene Name | FMO5 |
| EntrezGene Description | protein disulfide isomerase family A, member 3 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02433 |
| ExAC AF | 0.035 |
NBPF23P
| dbSNP name | rs828482(C,A); rs4107887(G,C); rs828481(A,G); rs11462639(C,T); rs7513204(C,T); rs12032012(G,A); rs116087943(G,C); rs60101117(A,G); rs828515(T,C); rs828517(T,C); rs190384856(G,C); rs116156140(C,T); rs116058233(T,A); rs828518(A,G); rs116460951(G,A); rs2055964(A,G); rs140984598(G,A); rs12079190(G,C); rs12041563(A,G); rs191829741(G,A); rs7521007(G,A); rs11587304(C,A); rs17162001(T,C); rs35700699(G,A); rs4950737(T,G); rs114975913(C,T); rs7550570(A,T); rs191310517(A,G) |
| cytoBand name | 1q21.2 |
| EntrezGene GeneID | 100302292 |
| EntrezGene Symbol | NBPF23 |
| snpEff Gene Name | NBPF23 |
| EntrezGene Description | neuroblastoma breakpoint family, member 23 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | intergenic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2544 |
APH1A
| dbSNP name | rs11548267(T,C) |
| ccdsGene name | CCDS41390.1 |
| cytoBand name | 1q21.2 |
| EntrezGene GeneID | 51107 |
| EntrezGene Description | APH1A gamma secretase subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06336 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Generalized tonic-clonic seizures (GTCS) on awakening;
GTCS during 'leisure' time (evening);
Myoclonic seizures may occur;
Absence seizures may occur
MISCELLANEOUS:
Variable age of onset (6 to 35 years);
Precipitated by sleep deprivation
MOLECULAR BASIS:
Caused by mutation in the chloride channel-2 gene (CLCN2, 600570.0001)
OMIM Title
*607629 ANTERIOR PHARYNX DEFECTIVE 1, C. ELEGANS, HOMOLOG OF, A; APH1A
OMIM Description
DESCRIPTION
APH1 is a multipass transmembrane protein that interacts with presenilin
(see PSEN1; 104311) and nicastrin (APH2; 605254) as a functional
component of the gamma-secretase complex. The gamma-secretase complex is
required for the intramembrane proteolysis of a number of membrane
proteins, including the amyloid-beta precursor protein (APP; 104760) and
Notch (190198).
CLONING
By searching a sequence database for homologs of the C. elegans Aph1
gene, which carries mutations in the anterior pharynx-defective
phenotype, Goutte et al. (2002) identified human APH1A and APH1B
(607630). The predicted 251- and 257-amino acid APH1A and APH1B proteins
share 33% and 34% identity with C. elegans Aph1, respectively. APH1A had
been identified as CGI-78 by Lai et al. (2000).
Francis et al. (2002) identified 2 presenilin enhancers in C. elegans,
Aph1 and Pen2 (607632). By searching sequence databases, they identified
APH1A and APH1B as human homologs of Aph1, and they identified homologs
in mouse, zebrafish, and Drosophila. The predicted 247-amino acid APH1A
protein contains 7 transmembrane domains and shares 59% identity with
APH1B and 99% identity with mouse Aph1a. Francis et al. (2002) also
identified an APH1A alternative splice form in human and mouse that
results in a 265-amino acid protein with a different C terminus.
Lee et al. (2002) isolated APH1A and APH1B cDNAs from a glioblastoma
cDNA library. By Western blot analysis, they showed that APH1A has a
relative molecular mass of approximately 30 kD.
GENE FUNCTION
Goutte et al. (2002) showed that C. elegans embryos with mutations in
the Aph1 gene lacked the anterior pharynx but could develop a relatively
normal posterior pharynx, a phenotype similar to that associated with
mutations in Notch pathway components. After analyzing Aph1 mutant
embryos, they concluded that Aph1 and presenilins are required for cell
surface localization of the Notch component Aph2 (nicastrin).
By analyzing C. elegans mutant phenotypes, Francis et al. (2002)
determined that Aph1 and Pen2 were required for Glp1/Notch-mediated
signaling, both in embryonic patterning and in postembryonic germline
proliferation. They observed that the human APH1 and PEN2 genes
partially rescued the C. elegans mutant phenotypes, demonstrating
conserved functions. Human APH1 and PEN2 had to be provided together to
rescue the mutant phenotypes, and inclusion of PSEN1 improved rescue.
Francis et al. (2002) concluded that APH1 and PEN2 cooperate closely in
the same process to promote presenilin activity. Using RNA-mediated
interference assays to inactivate Aph1, Pen2, or nicastrin in cultured
Drosophila cells, Francis et al. (2002) observed reduction in
gamma-secretase cleavage of beta-APP and Notch substrates and reduction
in the levels of processed presenilin. They concluded that APH1 and PEN2
are required for Notch pathway signaling, gamma-secretase cleavage of
beta-APP, and presenilin protein accumulation. In a commentary, Goutte
(2002) discussed the contribution of Francis et al. (2002) to current
understanding of how presenilins mediate the gamma-secretase cleavage of
Notch transmembrane receptors and transmembrane beta-APP.
Using coimmunoprecipitation and nickel affinity pull-down approaches,
Lee et al. (2002) showed that mammalian APH1A and APH1B physically
associated with nicastrin and presenilin heterodimers in vivo.
Inactivation of endogenous APH1 using small interfering RNAs resulted in
decreased presenilin levels, accumulation of gamma-secretase substrates,
and reduction of gamma-secretase products. Lee et al. (2002)
hypothesized that APH1 is a functional component of the gamma-secretase
complex required for the intramembrane proteolysis of APP and Notch.
Gamma-secretase activity requires the formation of a stable, high
molecular mass protein complex that, in addition to the endoproteolyzed
fragmented form of presenilin, contains essential cofactors including
nicastrin, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila
APH1 increases the stability of Drosophila presenilin holoprotein in the
complex. Depletion of PEN2 by RNA interference prevented endoproteolysis
of presenilin and promoted stabilization of the holoprotein in both
Drosophila and mammalian cells, including primary neurons. Coexpression
of Drosophila Pen2 with Aph1 and nicastrin increased the formation of
presenilin fragments as well as gamma-secretase activity. Thus, Takasugi
et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein
in the complex, whereas PEN2 is required for endoproteolytic processing
of presenilin and conferring gamma-secretase activity to the complex.
GENE STRUCTURE
By genomic sequence analysis, Lee et al. (2002) determined that the
APH1A gene spans 3.6 kb. The longer APH1A isoform (APH1AL) is encoded by
7 exons, while the shorter isoform (APH1AS) is encoded by 6 exons.
BIOCHEMICAL FEATURES
- Crystal Structure
The gamma-secretase complex, comprising presenilin (PSEN1; 104311), PEN2
(PSENEN; 607632), APH1AL, and nicastrin (APH2; 605254), is a
membrane-embedded protease that controls a number of important cellular
functions through substrate cleavage. Lu et al. (2014) reported the
3-dimensional structure of an intact human gamma-secretase complex at
4.5-angstrom resolution, determined by cryoelectron microscopy
single-particle analysis. The gamma-secretase complex comprises a
horseshoe-shaped transmembrane domain, which contains 19 transmembrane
segments and a large extracellular domain from nicastrin, which sits
immediately above the hollow space formed by the transmembrane
horseshoe. The nicastrin extracellular domain is structurally similar to
a large family of peptidases exemplified by the glutamate
carboxypeptidase PSMA.
MAPPING
By radiation hybrid analysis, Francis et al. (2002) mapped the APH1A
gene to chromosome 1.
RFX5
| dbSNP name | rs7552906(A,G); rs1752387(T,C); rs2233854(G,C); rs1752386(G,A) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 5993 |
| EntrezGene Description | regulatory factor X, 5 (influences HLA class II expression) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3774 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash
HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia
IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells
NEOPLASIA:
Increased risk of malignant lymphoma
LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Increased interleukin 10;
Elevated levels of vitamin B12
MISCELLANEOUS:
Onset in early childhood;
Recessive inheritance has been reported
MOLECULAR BASIS:
Caused by mutation in the Fas antigen gene (FAS, 134637.0001);
Caused by mutation in the Fas ligand gene (FASL, 134638.0001)
OMIM Title
*601863 REGULATORY FACTOR X, 5; RFX5
OMIM Description
Major histocompatibility complex (MHC) class II molecules are
heterodimeric transmembrane glycoproteins consisting of alpha and beta
chains. In man, there are 3 MHC class II isotypes: HLA-DR, -DP, and -DQ.
MHC class II molecules play a key role in the immune system. They
present exogenous antigenic peptides to the receptor of CD4+ T-helper
lymphocytes, thereby triggering the antigen-specific T-cell activation
events required for the initiation and sustenance of immune responses.
Durand et al. (1997) noted that the crucial role in the control of the
immune response is exemplified by the finding that ectopic or aberrantly
high levels of MHC class II expression is associated with autoimmune
diseases, while a lack of MHC class II expression results in a severe
immunodeficiency syndrome called MHC class II deficiency, or the bare
lymphocyte syndrome type II (BLS; 209920). At least 4 complementation
groups have been identified in B-cell lines established from patients
with BLS. The molecular defect responsible for complementation group A
resides in the gene encoding CIITA (MHC2TA; 600005). CIITA is a
non-DNA-binding transactivator that functions as a molecular switch
controlling both cell-type-specific and inducible MHC class II gene
transcription. In contrast, the defects in complementation groups B, C,
and D all lead to a deficiency in RFX, a nuclear protein complex that
binds to the X box of MHC class II promoters (see RFX2; 142765). The
lack of RFX binding activity in complementation group C results from
mutations in the gene encoding the 75-kD subunit of RFX (Steimle et al.,
1995). This gene was called RFX5 because it is the fifth member of the
growing family of DNA-binding proteins sharing a novel and highly
characteristic DNA-binding domain called the RFX motif.
Two of the genes defective in the 5 complementation groups identified in
class II-negative bare lymphocyte syndrome or in corresponding
laboratory mutants have been cloned (Mach et al., 1996). One gene
encodes RFX5; the other, MHC2TA (CIITA), encodes a large protein with a
defined acidic transcriptional activation domain. The latter protein
does not interact with DNA. Scholl et al. (1997) demonstrated that RFX5
can activate transcription only in cooperation with CIITA. RFX5 and
CIITA associate to form a complex capable of activating transcription
from class II MHC promoters. In this complex, promoter specificity is
determined by the DNA binding domain of RFX5 and the general
transcription apparatus is recruited by the acidic activation domain of
CIITA.
Nekrep et al. (2000) demonstrated a direct interaction between the C
terminus of RFXAP (601861) and RFXANK (603200); mutant RFXAP or RFXANK
proteins failed to bind. The authors found that RFX5 binds only to the
RFXANK-RFXAP scaffold and not to either protein alone. However, neither
the scaffold nor RFX5 alone can bind DNA. Nekrep et al. (2000) concluded
that the binding of the RFXANK-RFXAP scaffold to RFX5 leads to a
conformational change in the latter that exposes the DNA-binding domain
of RFX5. The DNA-binding domain of RFX5 anchors the RFX complex to MHC
class II X and S promoter boxes. Another part of the RFX5 protein
interacts with MHC2TA. The authors pointed out that mutation of either
protein in complementation group B or group D of BLS patients prevents
its binding to the other protein, explaining why MHC class II promoters
are bare in the bare lymphocyte syndrome.
Emery et al. (1996) reviewed RFX1, RFX5, and other members of the RFX
family of DNA-binding proteins.
Villard et al. (1997) mapped the RFX5 gene to chromosome 1q21 by
fluorescence in situ hybridization.
Villard et al. (1997) characterized the mutations in 4 patients with MHC
class II deficiency known to harbor a defect in the RFX5 gene.
Hosts and pathogens evolve various responses for controlling infection
and evading destruction, respectively. Using column chromatography,
Zhong et al. (2001) identified a factor in Chlamydia trachomatis, the
causative organism of trachoma and chronic urogenital infection, that
degrades the transcription factors RFX5 and USF1 (191523). The
degradation of these host factors correlates with the suppression of MHC
class I and class II antigen expression in infected cells, thereby
suppressing the host immune response.
Nekrep et al. (2002) identified an arg149-to-gln mutation (R149Q;
601863.0005) in the DNA-binding domain of RFX5 (residues 92 to 168) in
cell lines (termed 'Ker' cell lines) derived from the histoidentical
twins lacking MHC class II transcription reported by Wolf et al. (1995)
and Douhan et al. (1996). Functional and structural modeling analyses
indicated that the mutant protein was incapable of binding the X box of
the HLA-DRA (142860) promoter, whereas expression of wildtype RFX5 in
the Ker cell lines rescued MHC class II expression.
MIR554
| dbSNP name | rs79661940(T,G) |
| ccdsGene name | CCDS1000.1 |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 693139 |
| snpEff Gene Name | TUFT1 |
| EntrezGene Description | microRNA 554 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0202 |
| ESP Afr MAF | 0.084821 |
| ESP All MAF | 0.026214 |
| ESP Eur/Amr MAF | 0.000558 |
| ExAC AF | 0.00755 |
RPTN
| dbSNP name | rs3001978(T,C); rs75957773(T,C); rs77415490(A,G) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 126638 |
| EntrezGene Description | repetin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4697 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Achromatic retinal patches;
Retinal astrocytoma;
Optic gliomas;
[Mouth];
Pitted dental enamel;
Gingival fibroma
CARDIOVASCULAR:
[Heart];
Wolf-Parkinson-White syndrome;
Cardiac rhabdomyoma
RESPIRATORY:
[Lung];
Lymphangiomyomatosis, rare
GENITOURINARY:
[Kidneys];
Renal cysts;
Tumors of the kidney (may progress to malignancy in less than 2%)
SKELETAL:
Cystic areas of bone rarefaction, esp. phalanges
SKIN, NAILS, HAIR:
[Skin];
Facial angiofibroma (adenoma sebaceum);
White ash leaf-shaped macules;
Shagreen patch;
Subcutaneous nodules;
Cafe-au-lait spots;
Subungual fibromata
NEUROLOGIC:
[Central nervous system];
Hamartomatous lesions of the brain;
Subependymal nodules;
Cortical tubers;
Infantile spasms;
Seizures;
Mental retardation (30%);
Learning difficulties;
Intracranial calcification by x-ray or CT;
[Behavioral/psychiatric manifestations];
Attention deficit disorder;
Hyperactivity;
Autism
ENDOCRINE FEATURES:
Precocious puberty;
Hypothyroidism
NEOPLASIA:
Myocardial rhabdomyoma;
Multiple bilateral renal angiomyolipoma;
Ependymoma;
Renal carcinoma;
Giant cell astrocytoma;
Chordoma;
Benign tumors of the eye, heart, and lungs
LABORATORY ABNORMALITIES:
Increased frequency of premature centromere disjunction (PCD) in cultured
fibroblasts, esp. chromosome 3;
Allelic loss on 16p13.3 in angiomyolipoma, cardiac rhabdomyoma, cortical
tuber, and giant cell astrocytoma
MISCELLANEOUS:
Genetic heterogeneity (see 191100);
Many studies have reported that the phenotype of tuberous sclerosis-2
(TSC2) is more severe than that of tuberous sclerosis-1 (e.g., lower
IQ, more seizures, more macules, cust-like cortical tubers);
Highly variable phenotype;
One-third of cases are familial;
Majority of cases are sporadic;
Prevalence of 1 in 6,000 to 1 in 10,000;
Frequent new mutations (~60%) and/or gonadal mosaicism in TSC2
MOLECULAR BASIS:
Caused by mutation in the tuberin gene (TSC2, 191092.0001)
OMIM Title
*613259 REPETIN; RPTN
OMIM Description
The RPTN gene encodes repetin, an extracellular epidermal matrix protein
that is expressed in the epidermis and at high levels in eccrine sweat
glands, the inner sheaths of hair roots, and the filiform papilli of the
tongue (summary by Green et al., 2010).
CLONING
Using mouse Rptn to probe a human chromosome 1-specific cosmid library,
followed by 5-prime RACE of human keratinocyte RNA, Huber et al. (2005)
cloned full-length RPTN. The deduced 784-amino acid protein has a
calculated molecular mass of 91 kD. RPTN contains 2 N-terminal EF hand
motifs, a central domain containing 28 repeats of the consensus sequence
QxDRQGQSSHYG, and a glutamine- and arginine-rich C-terminal domain.
Northern blot analysis detected a 4-kb RPTN transcript in human thymus,
epidermis, and foreskin and in keratinocyte suspension cultures. Very
low expression was detected in adherent keratinocyte cultures, and none
was detected in other tissues. Immunofluorescence analysis detected RPTN
in the upper granular layer of human interfollicular epidermis, in
acrosyringium, in the upper cell layers of foreskin epidermis, in a
granular pattern in filiform papillae of tongue, in upper layer cells of
lingual interpapillae, and in the inner root sheath of hair follicle.
Immunoelectron microscopy showed strongest RPTN immunoreactivity in
granular layers associated with keratohyalin granules, with more diffuse
cytoplasmic expression in the transition zone between stratum granulosum
and stratum corneum. RPTN was not expressed in upper cornified layers of
skin. RPTN had an apparent molecular mass of 100 kD by SDS-PAGE.
GENE FUNCTION
Huber et al. (2005) showed that the recombinant N-terminal domain of
RPTN bound calcium reversibly.
GENE STRUCTURE
Huber et al. (2005) determined that the RPTN gene contains 3 exons and
spans at least 5.6 kb. The first exon is noncoding.
MAPPING
By genomic sequence analysis and FISH, Huber et al. (2005) mapped the
RPTN gene to chromosome 1q21, where it lies between the trichohyalin
(TCHH; 190370) and profilaggrin (FLG; 135940) genes within the epidermal
differentiation complex. They mapped the mouse Rptn gene to a region of
chromosome 3F that shares homology of synteny with human chromosome
1q21.
EVOLUTION
Green et al. (2010) published a draft sequence of the Neandertal genome.
Comparisons of the Neandertal genome to the genomes of 5 present-day
humans from different parts of the world identified a number of genomic
regions that may have been affected by positive selection in ancestral
modern humans, including genes involved in metabolism and in cognitive
and skeletal development. Green et al. (2010) found 78 nucleotide
substitutions that change the protein coding capacity of genes where
modern humans are fixed for a derived state and where Neandertals carry
the ancestral (chimpanzee-like) state. Thus, relatively few amino acid
changes have become fixed in the last few hundred thousand years of
human evolution, an observation consistent with a complementary study
(Burbano et al., 2010). There are only 5 genes with more than 1 fixed
substitution changing the primary structure of the encoding proteins.
One of these is RPTN, which encodes repetin, an extracellular epidermal
matrix protein that is expressed in the epidermis and at high levels in
eccrine sweat glands, the inner sheaths of hair roots, and the filiform
papilli of the tongue. Green et al. (2010) also showed that Neandertals
shared more genetic variants with present-day humans in Eurasia than
with present-day humans in sub-Saharan Africa, suggesting that gene flow
from Neandertals into the ancestors of non-Africans occurred before the
divergence of Eurasian groups from each other.
FLG
| dbSNP name | rs1933061(T,A); rs144643375(A,G); rs113077448(T,C); rs77422831(C,T); rs3091276(A,G); rs6681433(T,C); rs113241501(G,C); rs71625200(T,C); rs2184953(A,G); rs7512553(A,G); rs3126079(G,T); rs12407748(C,T); rs111360507(C,T); rs12405241(G,A); rs12405278(G,A); rs12407807(C,T); rs11204978(G,T); rs112252908(T,C); rs112272688(T,C); rs115324644(A,T); rs73005481(A,G); rs112344919(C,A); rs66831674(A,G); rs3120653(A,G); rs112822174(G,T); rs74129461(C,T); rs113685999(T,G); rs113652604(G,T); rs111791016(T,C); rs137997325(G,A); rs113136594(G,A); rs11584340(G,A) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 2312 |
| EntrezGene Description | filaggrin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Intrauterine growth retardation;
Postnatal growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Coarse facies;
Facial hypertrichosis;
[Ears];
Preauricular skin tag;
Hearing loss;
[Eyes];
Bushy eyebrows;
Long eyelashes;
Ptosis;
Hypotelorism;
Strabismus;
Myopia;
Nystagmus;
Astigmatism;
[Nose];
Flat nasal bridge;
Broad nasal tip;
Choanal atresia;
[Mouth];
Wide mouth;
Full lips;
Cleft palate;
High-arched palate;
[Teeth];
Delayed dentition
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
Atrial septal defect;
Tetralogy of Fallot;
[Vascular];
Patent ductus arteriosus
RESPIRATORY:
Frequent upper and lower respiratory tract infections (early life)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Short sternum;
[Diaphragm];
Diaphragmatic hernia
ABDOMEN:
[External features];
Umbilical hernia;
[Gastrointestinal];
Gastric ulcer;
Duodenal ulcer;
Neonatal intussusception;
Intestinal malrotation;
Feeding problems
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
Hypospadias;
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
Absent uterus;
[Kidneys];
Hydronephrosis;
Ectopic kidney;
Small kidney;
[Ureters];
Microureter
SKELETAL:
Joint laxity;
Delayed bone age;
[Spine];
Scoliosis;
Kyphosis;
Spina bifida occulta;
[Pelvis];
Coxa valga;
[Limbs];
Radial head dislocation;
Small to absent patellae;
[Hands];
Hypoplastic to absent terminal phalanges (especially fifth finger);
Single transverse palmar crease;
[Feet];
Hypoplastic to absent terminal phalanges (especially fifth toe)
SKIN, NAILS, HAIR:
[Skin];
Cutis marmorata;
Hemangioma;
Single transverse palmar crease;
Sacral dimple;
[Nails];
Hypoplastic to absent fifth finger- and toenails;
[Hair];
Bushy eyebrows;
Long eyelashes;
Lumbosacral hirsutism;
Sparse scalp hair;
Facial hypertrichosis
NEUROLOGIC:
[Central nervous system];
Severe expressive language delay;
Mental retardation;
Moderate to severe hypotonia;
Dandy-Walker malformation;
Hypoplastic corpus callosum;
Partial agenesis of corpus callosum;
Agenesis of anterior commissure;
Seizures;
[Behavioral/psychiatric manifestations];
Unusual fears;
Pervasive developmental disorder;
Aggressive behavior
MISCELLANEOUS:
Majority of affected individuals are female (85%);
Majority are sporadic cases, affected sibs have been described
OMIM Title
*135940 FILAGGRIN; FLG
PROFILAGGRIN, INCLUDED
OMIM Description
DESCRIPTION
Profilaggrin is a major protein component of the keratohyalin granules
of mammalian epidermis. It is initially expressed as a large polyprotein
precursor which is subsequently proteolytically processed into
individual functional filaggrin molecules. The filaggrins show wide
species variations and their aberrant expression has been implicated in
a number of keratinizing disorders (Baden et al., 1974; Holbrook et al.,
1982; Sybert et al., 1985).
CLONING
McKinley-Grant et al. (1989) isolated a cDNA clone encoding human
filaggrin. They demonstrated that the human gene encodes a polyprotein
precursor containing numerous tandem filaggrin repeats. This structure
is similar to that of the mouse; however, the human filaggrin repeat is
much longer (972 basepairs; 324 amino acids) and shows little sequence
homology to the mouse protein. They found furthermore that the human
filaggrin repeats show considerable sequence variations; such
polymorphism is not found in the mouse. By peptide mapping, they defined
a short linker sequence within the human filaggrin repeat that is
excised by proteolysis to yield functional molecules. They showed by in
situ hybridization that the expression of the gene for the human
filaggrin precursor is tightly regulated at the transcriptional level in
terminally differentiating epidermis.
Gan et al. (1990) isolated genomic DNA and cDNA clones encoding the
5-prime and 3-prime ends of the human gene and mRNA. They found evidence
of likely CAT and TATA sequences, an intron in the 5-prime untranslated
region, and several potential regulatory sequences. The gene is made up
of repeats, all of the same length. Sequences showed considerable
variation, most attributable to single-base changes. Thus, human
filaggrin consists of a heterogeneous population of molecules of
different sizes, charges, and sequences. Amino acid sequences encoding
the amino and carboxyl termini were more conserved, as were the 5-prime
and 3-prime DNA sequences flanking the coding portions of the gene. The
presence of unique restriction enzyme sites in these conserved flanking
sequences enabled Gan et al. (1990) to calculate the size of the
full-length gene and the number of repeats in it; depending on the
source of genomic DNA, the gene contains 10, 11, or 12 filaggrin repeats
that segregate in families in a normal mendelian manner. Thus, the human
profilaggrin gene is polymorphic with respect to size due to simple
allelic differences between individuals.
GENE STRUCTURE
The FLG gene comprises 3 exons (Presland et al., 1992).
MAPPING
Using a cDNA clone as a probe in the study of a panel of mouse-human
somatic cell hybrids retaining overlapping subsets of human chromosomal
regions and for chromosomal in situ hybridization, McKinley-Grant et al.
(1989) demonstrated that the human filaggrin gene maps to 1q21.
Rothnagel et al. (1994) mapped the homologous gene to mouse chromosome 3
by PCR analyses of DNAs isolated from mouse/Chinese hamster somatic cell
hybrids.
Genes of 3 protein families that are specifically expressed in the
course of terminal differentiation of human epidermis have been mapped
to 1q21. Volz et al. (1993) showed that these genes are physically
linked within 2.05 Mb of DNA in the following order: calpactin I light
chain (CAL1L; 114085), trichohyalin (THL; 190370), profilaggrin,
involucrin (IVL; 147360), small proline-rich protein (SPRR1A; 182265),
loricrin (LOR; 152445), and calcyclin (CACY; 114110).
GENE FUNCTION
Smith et al. (2006) reviewed the function of filaggrin, also known as
filament-aggregating protein, in the formation of the stratum corneum.
Keratohyalin granules in the granular layer of interfollicular epidermis
are predominantly composed of the 400-kD protein profilaggrin. Following
a short, unique N-terminal domain, most of the profilaggrin molecule
consists of 10 to 12 repeats of the 324-residue filaggrin sequence (Gan
et al., 1990). Upon terminal differentiation of granular cells,
profilaggrin is proteolytically cleaved into filaggrin peptides of
approximately 37 kD and the N-terminal domain containing an S100-like
calcium-binding domain. Filaggrin rapidly aggregates the keratin
cytoskeleton, causing collapse of the granular cells into flattened
anuclear squames. This condensed cytoskeleton is crosslinked by
transglutaminases during formation of the cornified cell envelope (CCE).
The CCE is the outermost barrier layer of the skin which not only
prevents water loss but also impedes the entry of allergens and
infectious agents. Filaggrin is therefore a key protein in facilitating
epidermal differentiation and maintaining barrier function.
MOLECULAR GENETICS
In 15 kindreds with ichthyosis vulgaris (146700), Smith et al. (2006)
identified homozygous or compound heterozygous mutations R501X
(135940.0001) and 2282del4 (135940.0002) in the FLG gene in individuals
with a moderate or severe phenotype. They concluded that these mutations
are semidominant; heterozygotes show a very mild phenotype with
incomplete penetrance. The mutations showed a combined allele frequency
of approximately 4% in populations of European ancestry, explaining the
high incidence of ichthyosis vulgaris. Profilaggrin is the major protein
of keratohyalin granules in the epidermis. During terminal
differentiation, it is cleaved into multiple filaggrin peptides that
aggregate keratin filaments. The resultant matrix is crosslinked to form
a major component of the cornified cell envelope. Smith et al. (2006)
found that loss or reduction of this major structural protein leads to
varying degrees of impaired keratinization.
Twin and family studies have indicated a highly heritable predisposition
to atopic disease, including atopic dermatitis (see 603165), allergy,
and asthma (see 600807). Although genetic studies have focused on
immunologic mechanisms of atopic dermatitis, a primary epithelial
barrier defect has been anticipated (Cookson and Moffatt, 2002).
Filaggrin is a key protein that facilitates terminal differentiation of
the epidermis and formation of the skin barrier. Palmer et al. (2006)
showed that 2 independent loss-of-function genetic variants, R501X
(135940.0001) and 2282del4 (135940.0002), in the FLG gene are very
strong predisposing factors for atopic dermatitis (605803). These
mutations had been shown to be the cause of ichthyosis vulgaris in 15
families and isolated cases (Smith et al., 2006). The R501X and 2282del4
variants, carried by approximately 9% of people of European origin, also
showed highly significant association with asthma occurring in the
context of atopic dermatitis. This work established a key role for
impaired skin barrier function in the development of atopic disease.
Sandilands et al. (2007) showed that the 2 common filaggrin-null
mutations reported by Smith et al. (2006) and Palmer et al. (2006) are
ancestral European variants carried on conserved haplotypes. To
facilitate comprehensive analysis in other populations, they reported a
strategy for full sequencing of this large, highly repetitive gene, and
described 15 variants, including 7 that are prevalent. All the variants
were either nonsense or frameshift mutations that, in representative
cases, resulted in loss of filaggrin production in the epidermis. In an
Irish case-control study, the 5 most common European mutations showed a
strong association with moderate to severe childhood eczema. They found
3 additional rare null mutations in this case series, suggesting that
the genetic architecture of filaggrin-related atopic dermatitis consists
of both prevalent and rare risk alleles.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and confirmed a highly significant association
between the null mutations and eczema and concomitant asthma. Moreover,
the authors found that these mutations predisposed to asthma, allergic
rhinitis, and allergic sensitization only in the presence of eczema,
highlighting the importance of the epidermal barrier in the pathogenesis
of these disorders (the so-called 'atopic march').
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese
patients with ichthyosis vulgaris from 4 unrelated families who were
negative for the R501X and 2282del4 mutations, and identified
heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA
(135940.0004), respectively. The authors then screened 143 Japanese
patients with atopic dermatitis from 140 unrelated families for the
novel null mutations and identified S2554X in 6 patients and 3321delA in
2 patients; they were not found in 156 unrelated Japanese nonatopic and
nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting
that the R501X and 2282del4 mutations were absent from a total of 253
Japanese individuals, including their patients with ichthyosis vulgaris
and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations
in Japan are different from those found in European-origin populations.
Hu et al. (2012) found association between a nonsense variant in the FLG
gene (K4022X; 135940.0005) and the psoriasis/ichthyosis vulgaris
phenotype in the Chinese population. Hu et al. (2012) noted that
Nemoto-Hasebe et al. (2009) reported heterozygosity for the same
variant, which they designated K4021X, in Japanese patients with atopic
dermatitis.
ANIMAL MODEL
Netherton syndrome (256500) is an autosomal recessive multisystemic
disorder characterized by congenital ichthyosiform erythroderma, hair
shaft defects and atopy, caused by mutation in the SPINK5 gene (605010).
Hewett et al. (2005) created mice with an R820X mutation in the Spink5
gene. Newborn homozygotes developed a severe ichthyosis with a loss of
skin barrier function and dehydration, resulting in death within a few
hours. Biochemical analysis of skin revealed a substantial increase in
the proteolytic processing of profilaggrin into its constituent
filaggrin monomers. The authors suggested that in the absence of SPINK5
there is an abnormal increase in the processing of profilaggrin, and
that this may play a direct role in the observed deficit in the adhesion
of the stratum corneum and the severely compromised epidermal barrier
function.
Fallon et al. (2009) reported a 1-bp deletion mutation, 5303delA,
analogous to common human FLG mutations, within the murine Flg gene in
the spontaneous mouse mutant 'flaky tail' (ft). Fallon et al. (2009)
demonstrated that topical application of allergen to mice homozygous for
this mutation resulted in cutaneous inflammatory infiltrates and
enhanced cutaneous allergen priming with development of
allergen-specific antibody responses. These data validated flaky tail as
a useful model of filaggrin deficiency and provided experimental
evidence for the hypothesis that antigen transfer through a defective
epidermal barrier is a key mechanism underlying elevated IgE
sensitization and initiation of cutaneous inflammation in humans with
filaggrin-related atopic disease.
LCE3E
| dbSNP name | rs17659359(G,C); rs147856683(G,A) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 353145 |
| EntrezGene Description | late cornified envelope 3E |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2479 |
| ESP Afr MAF | 0.210036 |
| ESP All MAF | 0.223958 |
| ESP Eur/Amr MAF | 0.231091 |
| ExAC AF | 0.262 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Colorectal adenomas;
Colorectal polyps;
Colorectal carcinoma
GENITOURINARY:
[Internal genitalia, female];
Endometrial carcinoma
NEOPLASIA:
Colorectal carcinoma;
Endometrial carcinoma
MISCELLANEOUS:
Tumors are microsatellite stable;
Onset usually before age 40 years;
Patients develop multiple tumors
MOLECULAR BASIS:
Caused by mutation in the polymerase (DNA-directed), delta 1, catalytic
subunit gene (POLD1, 174761.0001)
OMIM Title
*612617 LATE CORNIFIED ENVELOPE PROTEIN 3E; LCE3E
;;LATE ENVELOPE PROTEIN 17; LEP17
OMIM Description
For background information on the LCE gene cluster, see 612603.
CLONING
By database analysis to identify human orthologs of mouse genes encoding
late envelope proteins (LEPs), Marshall et al. (2001) identified LCE3E,
which they called LEP17. RT-PCR detected LEP17 in human skin, esophagus,
and heart.
Using real-time PCR, Jackson et al. (2005) detected very low LCE3E
expression in adult and fetal skin. Low LCE3E expression was also
detected in internal epithelia, including vulva, tongue, and esophagus.
GENE FUNCTION
Jackson et al. (2005) showed that expression of LCE3E was upregulated in
cultured normal human keratinocytes by ultraviolet radiation. At 48
hours after irradiation, the level of LCE3E was upregulated over
350-fold compared with mock-irradiated controls. LCE3E expression was
not regulated by calcium.
GENE STRUCTURE
Jackson et al. (2005) determined that LCE3E is a single-exon gene.
MAPPING
By genomic sequence analysis, Marshall et al. (2001) mapped the LCE3E
gene within the LCE gene cluster on chromosome 1q21. Jackson et al.
(2005) determined that the LCE3E gene lies within intron 1 of the LCE3C
gene (612615) and is oriented in the opposite direction. They stated
that the mouse Lce3e gene maps to a syntenic LCE gene cluster on
chromosome 3F1.
LCE3C
| dbSNP name | rs73019253(C,T) |
| ccdsGene name | CCDS1015.1 |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 353144 |
| EntrezGene Description | late cornified envelope 3C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LCE3C:NM_178434:exon1:c.C256T:p.R86C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0012 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5T5A8 |
| dbNSFP Uniprot ID | LCE3C_HUMAN |
| dbNSFP KGp1 AF | 0.0192307692308 |
| dbNSFP KGp1 Afr AF | 0.0691056910569 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00874125874126 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.01928 |
| ESP Afr MAF | 0.052135 |
| ESP All MAF | 0.021642 |
| ESP Eur/Amr MAF | 0.000941 |
| ExAC AF | 0.006792 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Colorectal adenomas;
Colorectal polyps;
Colorectal carcinoma
GENITOURINARY:
[Internal genitalia, female];
Endometrial carcinoma
NEOPLASIA:
Colorectal carcinoma;
Endometrial carcinoma
MISCELLANEOUS:
Tumors are microsatellite stable;
Onset usually before age 40 years;
Patients develop multiple tumors
MOLECULAR BASIS:
Caused by mutation in the polymerase (DNA-directed), delta 1, catalytic
subunit gene (POLD1, 174761.0001)
OMIM Title
*612615 LATE CORNIFIED ENVELOPE PROTEIN 3C; LCE3C
;;LATE ENVELOPE PROTEIN 15; LEP15
OMIM Description
For background information on the LCE gene cluster, see 612603.
CLONING
By database analysis to identify human orthologs of mouse genes encoding
late envelope proteins (LEPs), Marshall et al. (2001) identified LCE3C,
which they called LEP15. RT-PCR detected strong LEP15 expression in
human esophagus, but not in skin or heart.
Using real-time PCR, Jackson et al. (2005) detected very low LCE3C
expression in human skin. Low expression was also detected in internal
epithelia, including esophagus and tongue, but not in vulva.
Wang et al. (2001) cloned mouse Lce3c, which they called Eig3. RT-PCR
detected Eig3 expression in mouse stomach and epidermis, and it was
overexpressed in keratinocytes expressing E2f1 (189971) and E2f4
(600659). Eig3 expression was highly increased in mouse skin papillomas,
but not in squamous carcinomas.
GENE STRUCTURE
Jackson et al. (2005) determined that the LCE3C gene has an unusual
extended 3-exon structure compared with other LCE genes. The LCE3C gene
spans about 90 kb. The single-exon LCE3E (612617) and LCE3D (612616)
genes are located within LCE3E introns 1 and 2, respectively, and are
oriented in the opposite direction relative to LCE3C.
MAPPING
By genomic sequence analysis, Marshall et al. (2001) mapped the LCE3C
gene within the LCE gene cluster on chromosome 1q21. Jackson et al.
(2005) stated that the mouse Lce3c gene maps to a syntenic LCE gene
cluster on chromosome 3F1.
MOLECULAR GENETICS
For a discussion of a possible association between variants in the LCE3C
gene and psoriasis, see PSORS4 (603935).
LCE4A
| dbSNP name | rs1332496(T,C); rs73011196(G,C) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 199834 |
| EntrezGene Description | late cornified envelope 4A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 1.0 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Colorectal adenomas;
Colorectal polyps;
Colorectal carcinoma
GENITOURINARY:
[Internal genitalia, female];
Endometrial carcinoma
NEOPLASIA:
Colorectal carcinoma;
Endometrial carcinoma
MISCELLANEOUS:
Tumors are microsatellite stable;
Onset usually before age 40 years;
Patients develop multiple tumors
MOLECULAR BASIS:
Caused by mutation in the polymerase (DNA-directed), delta 1, catalytic
subunit gene (POLD1, 174761.0001)
OMIM Title
*612618 LATE CORNIFIED ENVELOPE PROTEIN 4A; LCE4A
;;LATE ENVELOPE PROTEIN 8; LEP8
OMIM Description
For background information on the LCE gene cluster, see 612603.
CLONING
By database analysis to identify human orthologs of mouse genes encoding
late envelope proteins (LEPs), Marshall et al. (2001) identified LCE4A,
which they called LEP8.
Using real-time PCR, Jackson et al. (2005) detected very low LCE4A
expression in adult and fetal skin. Little to no expression was detected
in vulva, tongue, and esophagus.
MAPPING
By genomic sequence analysis, Marshall et al. (2001) mapped the LCE4A
gene to the LCE gene cluster on chromosome 1q21. Jackson et al. (2005)
stated that the mouse Lce4a gene maps to a syntenic LCE gene cluster on
chromosome 3F1.
C1orf68
| dbSNP name | rs1332500(G,C); rs873775(A,C); rs41268474(G,A); rs59194678(C,G); rs944682(A,G); rs3814350(G,T); rs3814351(G,C) |
| ccdsGene name | CCDS44226.1 |
| CosmicCodingMuts gene | C1orf68 |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 100129271 |
| EntrezGene Description | chromosome 1 open reading frame 68 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C1orf68:NM_001024679:exon1:c.G77C:p.S26T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0058 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5T750 |
| dbNSFP Uniprot ID | XP32_HUMAN |
| dbNSFP KGp1 AF | 0.35119047619 |
| dbNSFP KGp1 Afr AF | 0.526422764228 |
| dbNSFP KGp1 Amr AF | 0.378453038674 |
| dbNSFP KGp1 Asn AF | 0.18006993007 |
| dbNSFP KGp1 Eur AF | 0.353562005277 |
| dbSNP GMAF | 0.3512 |
| ExAC AF | 0.29 |
SPRR2D
| dbSNP name | rs1048296(A,C); rs682472(T,G); rs682473(C,T) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 6703 |
| EntrezGene Description | small proline-rich protein 2D |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4807 |
SPRR2C
| dbSNP name | rs2928(A,C); rs541364(A,G) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 6702 |
| snpEff Gene Name | SPRR2G |
| EntrezGene Description | small proline-rich protein 2C (pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4628 |
OMIM Clinical Significance
Skel:
Slipped capilal femoral epiphysis
Joints:
Coxarthrosis
Inheritance:
Autosomal dominant form
OMIM Title
182269 SMALL PROLINE-RICH PROTEIN 2C; SPRR2C
OMIM Description
See 182267. SPRR2C appears to be a pseudogene due to a C-to-T transition
in the sixth codon resulting in a TAG stop codon (Gibbs et al., 1993).
LOR
| dbSNP name | rs12043009(G,A) |
| ccdsGene name | CCDS30870.1 |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 4014 |
| EntrezGene Description | loricrin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LOR:NM_000427:exon2:c.G870A:p.G290G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0611 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.224358974359 |
| dbNSFP KGp1 Afr AF | 0.396341463415 |
| dbNSFP KGp1 Amr AF | 0.182320441989 |
| dbNSFP KGp1 Asn AF | 0.0821678321678 |
| dbNSFP KGp1 Eur AF | 0.240105540897 |
| dbSNP GMAF | 0.225 |
| ESP Afr MAF | 0.295596 |
| ESP All MAF | 0.210383 |
| ESP Eur/Amr MAF | 0.171481 |
| ExAC AF | 0.18 |
OMIM Clinical Significance
Misc:
Longevity
Inheritance:
Possible monogenic influence at a relatively small number of loci
OMIM Title
*152445 LORICRIN; LOR
EPIDERMAL DIFFERENTIATION COMPLEX, INCLUDED; EDC, INCLUDED
OMIM Description
CLONING
Loricrin, with involucrin (147360), is a major component of the
crosslinked cell envelope of the epidermis, otherwise known as cornified
cell envelope (CE), marginal, or peripheral band. Hohl et al. (1991)
isolated and characterized a full-length cDNA clone encoding human
loricrin. Like mouse loricrin, it was found to be
glycine-serine-cysteine rich, although the sequences were not conserved.
Yoneda et al. (1992) identified 2 allelic size variants of LOR,
resulting from sequence variation in the second glycine loop domain.
There were multiple sequence variants within these 2 size class alleles
due to various deletions of 12 bp (4 amino acids) in the major loop of
this glycine loop domain. By use of a specific loricrin antibody in
immunogold electron microscopy, they showed that loricrin appears
initially in the granular layer of human epidermis and forms composite
keratohyalin granules with profilaggrin, but localizes to the cell
periphery (cell envelope) of fully differentiated stratum corneum cells.
GENE STRUCTURE
Using a specific human cDNA clone, Yoneda et al. (1992) isolated and
characterized the human loricrin gene. They showed that it has a single
intron of 1,188 bp in the 5-prime untranslated region and no introns in
the coding segment.
Rothnagel et al. (1994) isolated and characterized the mouse loricrin
gene. The gene has a simple structure consisting of a single intron of
1,091 basepairs within the 5-prime noncoding sequence and an
uninterrupted open reading frame.
MAPPING
By analysis of human-rodent somatic cell hybrids, followed by in situ
hybridization with a biotin-labeled genomic DNA clone, Yoneda et al.
(1992) mapped the single-copy LOR gene to chromosome 1q21. Localization
of the LOR gene to chromosome 1q21 was confirmed by Volz et al. (1993).
Using PCR analyses of DNAs isolated from mouse/Chinese hamster somatic
cell hybrids, Rothnagel et al. (1994) mapped both the loricrin and the
profilaggrin (FLG; 135940) genes to mouse chromosome 3. Genetic linkage
analysis had shown that the 2 genes lie within 1.5 +/- 1.1 cM of each
other in the mouse. Rothnagel et al. (1994) showed, furthermore, that
both genes map in the vicinity of the 'flaky tail' (ft) and 'soft coat'
(soc) loci. They suggested that abnormalities in these genes may be
involved in these mutant phenotypes.
- Epidermal Differentiation Complex
Volz et al. (1993) demonstrated physical linkage, within 2.05 Mb of DNA
on chromosome 1q21, of several genes involved in epidermal
differentiation. These genes comprise 3 families. One family, which is
closely associated with the formation of the cornified cell envelope in
the uppermost layers of the epidermis, includes loricrin, involucrin
(147360), and small proline-rich protein (182265). The second family
includes several members of the S100 family of small calcium-binding
proteins, namely, calcyclin (114110) and calpactin I light chain
(114085). The third family includes profilaggrin (FLG; 135940) and
trichohyalin (190370).
Marenholz et al. (1996) reported genetic analysis of the epidermal
differentiation complex (EDC) and associated markers within a 6-Mb YAC
contig mapping to human chromosome 1q21. They integrated the map of
genetic markers (STSs) on 1q21 with the map of genes in the EDC and with
a map of 24 YAC clones. The EDC defined by Mischke et al. (1996)
contains 3 families of genes that are related structurally,
functionally, and evolutionarily. Genes in this complex play an
important role in terminal differentiation of the human epidermis. The
first family of the EDC consists of 13 genes, including involucrin,
loricrin, and 3 classes of small proline rich proteins: 2 SPRR1 genes
(see 182265), 8 SPRR2 genes (see 182267), and 1 SPRR3 gene (182271).
These genes encode structural proteins of the human epidermis, and
transglutaminase crosslinking of these proteins yields the cornified
cell envelope. The second family of the EDC consists of profilaggrin and
trichohyalin. These genes encode intermediate filament-associated
proteins that are synthesized in the granular layer of the epidermis and
conjoin with the keratin filaments of keratinocytes during
cornification. The third family of genes in the EDC consists of 10 genes
of the S100 family, S100A1 (176940) through S100A10 (114085). These
encode small calcium-binding proteins with 2 EF-hands. Marenholz et al.
(1996) noted that calcium levels tightly control epidermal
differentiation and expression of EDC genes.
See 612603 for information on the late cornified envelope (LCE) gene
complex, which spans over 320 kb in the EDC (Jackson et al., 2005).
EVOLUTION
Backendorf and Hohl (1992) suggested that the clustered organization of
loricrin, involucrin, and all SPR (small proline rich) genes on 1q21
indicates that the genes were created by gene duplication of a common
ancestral gene and have diverged by evolving internal domains specific
for each. They demonstrated the amino acid homologies of SPR1, SPR2, and
SPR3 with loricrin and involucrin.
GENE FUNCTION
Yoneda and Steinert (1993) produced a transgenic mouse bearing the human
loricrin transgene which they found was expressed in mouse epithelial
tissues in an appropriate developmental manner but at an overall level
about twice that of endogenous mouse loricrin. No alteration was
observed in the flexible structure or function of the epithelial
tissues, however.
Candi et al. (1995) presented evidence that both transglutaminase-1
(190195) and transglutaminase-3 (600238) play essential and
complementary roles in crosslinking of loricrin in vivo. Failure to
crosslink loricrin by transglutaminase-1 may explain the phenotype of
lamellar ichthyosis (242300), a recessive disorder caused by mutations
in the TGM1 gene.
MOLECULAR GENETICS
In an extended family in Ohio with Vohwinkel syndrome and ichthyosis
(604117), Maestrini et al. (1996) demonstrated linkage to the epidermal
differentiation complex (EDC) on 1q21; they calculated a maximum
multipoint lod score of 14.3. The loricrin gene maps to the EDC and
sequencing of the gene revealed a 1-bp insertion (152445.0001) that
shifted the translation frame of the C-terminal gly- and gln/lys-rich
domains, and was thought likely to impair cornification. The authors
stated that this was the first evidence for a defect in an EDC gene in a
human disease.
Ishida-Yamamoto et al. (1997) found that affected members of a Japanese
family with the variant form of Vohwinkel syndrome had a mutation in the
loricrin gene (152445.0002). To determine whether the mutant loricrin
molecules predicted by DNA sequencing are expressed in vivo and to
define their pathologic effects, Ishida-Yamamoto et al. (2000) raised
antibodies against synthetic peptides corresponding to C-terminal
sequences common to loricrin mutants known at that time. Immunoblotting
of horny cell extracts from loricrin keratoderma patients showed
specific bands for mutant loricrin. Immunohistochemistry of loricrin
keratoderma skin biopsies showed positive immunoreactivity to the mutant
loricrin antibodies in the nuclei of differentiated epidermal
keratinocytes. The immunostaining was localized to the nucleoli of the
lower granular cell layer. As keratinocyte differentiation progressed,
the immunoreactivity moved gradually into the nucleoplasm, leaving
nucleoli mostly nonimmunoreactive. No substantial staining was observed
along the cornified cell envelope. This study confirmed that mutant
loricrin was expressed in the loricrin keratoderma skin. Ishida-Yamamoto
et al. (2000) concluded that mutant loricrin, as a dominant-negative
disrupter, is not likely to affect cornified cell envelope crosslinking
directly, but seems to interfere with nuclear/nucleolar functions of
differentiating keratinocytes.
In genotype and haplotype analysis of 2 independent cohorts of psoriasis
(see PSORS4; 603935) and atopic dermatitis (see ATOD2; 605803) patients,
Giardina et al. (2006) detected a significant association between
haplotypes defined by MIDDLE and ENDAL16 markers and psoriasis (p =
0.0000036) and atopic dermatitis (p = 0.0276), colocalizing to a 42-kb
interval on chromosome 1q21 containing a single gene, LOR. Analysis of
SNPs from regulatory and coding regions of LOR did not show evidence of
association for either of the 2 diseases, but expression profiles of LOR
in skin biopsies showed reduced levels in psoriasis and increased levels
in atopic dermatitis, suggesting a specific misregulation of LOR mRNA
production.
S100A12
| dbSNP name | rs4772(A,G) |
| cytoBand name | 1q21.3 |
| EntrezGene GeneID | 6283 |
| EntrezGene Description | S100 calcium binding protein A12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1125 |
| ESP Afr MAF | 0.088743 |
| ESP All MAF | 0.106566 |
| ESP Eur/Amr MAF | 0.115698 |
| ExAC AF | 0.102 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Weight loss, progressive;
[Other];
Thin body habitus;
Marked cachexia
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural;
[Eyes];
External ophthalmoplegia, progressive (PEO);
Ptosis
ABDOMEN:
[Gastrointestinal];
Gastrointestinal dysmotility;
Malabsorption;
Intermittent diarrhea;
Chronic malnutrition;
Chronic intestinal pseudoobstruction;
Gastroparesis;
Abdominal pain;
Vomiting;
Constipation, chronic;
Diverticulosis;
Diverticulitis;
Intestinal perforation
MUSCLE, SOFT TISSUE:
Mitochondrial myopathy;
Distal limb muscle weakness (less common);
Distal limb muscle atrophy (less common);
Ragged red fibers seen on muscle biopsy;
mtDNA depletion see on muscle biopsy;
Multiple mitochondrial DNA (mtDNA) deletions seen on muscle biopsy;
Decreased activity of cytochrome c oxidase in most cases seen on muscle
biopsy;
Decreased activities of complexes I, III, and IV, variable;
Subsarcolemmal accumulations of abnormally shaped mitochondria seen
on electron microscopy
NEUROLOGIC:
[Central nervous system];
Leukoencephalopathy;
Hypodensity of cerebral white matter seen on MRI;
[Peripheral nervous system];
Peripheral neuropathy;
Loss of distal sensation;
Areflexia;
Sensorimotor axonal/demyelinating neuropathy
METABOLIC FEATURES:
Lactic acidosis
LABORATORY ABNORMALITIES:
Decreased activity of thymidine phosphorylase;
Increased serum thymidine;
Increased serum deoxyuridine
MISCELLANEOUS:
Onset in second to fifth decade;
Progressive disorder;
Early death in early adulthood often associated with diverticulitis
and intestinal perforation
MOLECULAR BASIS:
Caused by mutation in the thymidine phosphorylase gene (TYMP, 131222.0001)
OMIM Title
*603112 S100 CALCIUM-BINDING PROTEIN A12; S100A12
;;CALCIUM-BINDING PROTEIN IN AMNIOTIC FLUID; CAAF1;;
CALGRANULIN-RELATED PROTEIN; CGRP;;
CALGRANULIN C;;
p6;;
EXTRACELLULAR NEWLY IDENTIFIED RAGE-BINDING PROTEIN; ENRAGE
OMIM Description
CLONING
Members of the S100 protein family are low molecular mass acidic
proteins characterized by cell-type-specific expression and the presence
of 2 EF-hand calcium-binding domains. The calgranulins are S100 proteins
that are expressed in neutrophils, and are abundant in infiltrating
monocytes and granulocytes under conditions of chronic inflammation. See
calgranulin A (S100A8; 123885). Guignard et al. (1995) identified an
S100 protein, called p6, that is expressed in neutrophils and monocytes
and that crossreacts with antibodies against calgranulin A. They found
that p6 constituted 5% of the total cytosolic protein in resting
neutrophils. Ilg et al. (1996) purified p6, or S100A12, from neutrophils
and determined its protein sequence and molecular mass. Although S100A12
has a relative mass of 10.4 kD, it migrates as a 6-kD protein by
SDS-PAGE. Marti et al. (1996) isolated S100A12 from extracts of adult
Onchocerca volvulus, a human tissue-dwelling parasite that causes
onchocerciasis (river blindness). They designated the protein CGRP for
'calgranulin-related protein' because, compared to other members of the
S100 family, it had the highest homology to calgranulins. The sequence
of the 91-amino acid S100A12 shares 40%, 46%, and 70% identity with
those of calgranulin A, calgranulin B (S100A9; 123886), and pig
calgranulin C, respectively.
Using primers based on the bovine CAAF1 sequence and nested PCR,
Yamamura et al. (1996) cloned S100A12 from polymorphonuclear leukocyte
(PMN) RNA. The deduced 92-amino acid protein has a calculated molecular
mass of about 10.6 kD and contains 2 EF-hand motifs. Northern blot
analysis revealed abundant expression of a 0.7-kb transcript in PMNs,
lower expression in spleen and esophagus, and no expression in adult
human skin.
GENE FUNCTION
Hofmann et al. (1999) reported that RAGE (600214) is a central cell
surface receptor for S100A12, which they referred to as ENRAGE
(extracellular newly identified RAGE-binding protein), and related
members of the S100/calgranulin superfamily. Interaction of ENRAGE with
cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes
triggered cellular activation, with generation of key proinflammatory
mediators. In murine models, blockade of ENRAGE/RAGE quenched
delayed-type hypersensitivity and inflammatory colitis by arresting
activation of central signaling pathways and expression of inflammatory
gene mediators.
Cole et al. (2001) found that a C-terminal 15-amino acid, 1.69-kD
fragment of S100A12 has antimicrobial properties. Further sequence
analysis revealed a putative zinc-binding domain as well as an
alpha-helical conformation. Both the native and synthetic peptides
displayed antimicrobial activity under acidic conditions in the presence
of physiologic ZnCl2 concentrations.
GENE STRUCTURE
Wicki et al. (1996) sequenced and characterized the S100A12 gene. They
found that the gene contains 3 exons, as do other S100 genes, and spans
1.75 kb.
By Southern blot analysis, Yamamura et al. (1996) determined that the
S100A12 gene is present in single copy and contains a classic upstream
TATAAA box. Their analysis suggested that the gene spans 4.1 kb.
MAPPING
By direct R-banding FISH, Yamamura et al. (1996) mapped the S100A12 gene
to chromosome 1q21.2-q22. By genomic sequence analysis, Wicki et al.
(1996) mapped the S100A12 gene maps within a cluster of S100 genes on
chromosome 1q21, between between S100A8 and S100A9.
MUC1
| dbSNP name | rs4072037(C,T) |
| ccdsGene name | CCDS55642.1 |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 4582 |
| EntrezGene Description | mucin 1, cell surface associated |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/pubmed?term=20700443,20729852 |
| Annovar Function | MUC1:NM_001204293:exon2:c.G66A:p.T22T,MUC1:NM_002456:exon2:c.G66A:p.T22T,MUC1:NM_001204291:exon2:c.G93A:p.T31T,MUC1:NM_001204286:exon2:c.G93A:p.T31T,MUC1:NM_001044392:exon2:c.G93A:p.T31T,MUC1:NM_001044391:exon2:c.G66A:p.T22T,MUC1:NM_001044393:exon2:c.G66A:p.T22T,MUC1:NM_001204297:exon2:c.G93A:p.T31T,MUC1:NM_001204294:exon2:c.G66A:p.T22T,MUC1:NM_001204292:exon2:c.G93A:p.T31T,MUC1:NM_001018016:exon2:c.G93A:p.T31T,MUC1:NM_001204289:exon2:c.G93A:p.T31T,MUC1:NM_001204285:exon2:c.G66A:p.T22T,MUC1:NM_001204296:exon2:c.G93A:p.T31T,MUC1:NM_001204287:exon2:c.G93A:p.T31T,MUC1:NM_001018017:exon2:c.G66A:p.T22T,MUC1:NM_001204288:exon2:c.G93A:p.T31T,MUC1:NM_001204295:exon2:c.G93A:p.T31T,MUC1:NM_001044390:exon2:c.G66A:p.T22T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/pubmed?term=20700443,20729852 |
| dbSNP GMAF | 0.3186 |
| ESP Afr MAF | 0.355651 |
| ESP All MAF | 0.427649 |
| ESP Eur/Amr MAF | 0.464535 |
| ExAC AF | 0.578 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Hirsutism
GENITOURINARY:
[External genitalia, female];
Normal external genitalia;
[Internal genitalia, female];
Aplasia of Mullerian duct derivatives;
Dysgenesis of Mullerian duct derivatives;
Absent or rudimentary vagina;
Absent or rudimentary uterus;
Functional ovaries;
[Kidneys];
Unilateral renal aplasia (rare)
SKIN, NAILS, HAIR:
[Skin];
Acne;
[Hair];
Hirsutism
ENDOCRINE FEATURES:
Hyperandrogenism;
Amenorrhea, primary
LABORATORY ABNORMALITIES:
Elevated testosterone;
Elevated androstenedione
MISCELLANEOUS:
Normal female secondary sexual characteristics
MOLECULAR BASIS:
Caused by mutation in the wingless-type MMTV integration site family,
member 4 gene (WNT4, 603490.0001)
OMIM Title
*158340 MUCIN 1, TRANSMEMBRANE; MUC1
;;MUCIN 1, URINARY;;
PEANUT-REACTIVE URINARY MUCIN; PUM;;
MUCIN, TUMOR-ASSOCIATED EPITHELIAL;;
POLYMORPHIC EPITHELIAL MUCIN; PEM;;
EPITHELIAL MEMBRANE ANTIGEN; EMA
OMIM Description
DESCRIPTION
Mucins are heavily glycosylated proteins thought to function in the
protection of epithelial surfaces. Secreted and transmembrane mucins
form a protective mucous barrier, and transmembrane mucins may also
function in signaling the presence of adverse conditions in the
extracellular environment. MUC1 is a transmembrane mucin normally
expressed on the apical borders of secretory epithelial cells (Yin et
al., 2003).
CLONING
Gendler et al. (1990) and Lan et al. (1990) independently cloned
full-length human MUC1. The deduced protein contains an N-terminal
domain that harbors a signal peptide and degenerate repeats, followed by
a long variable number of tandem repeats (VNTR) domain, and a C-terminal
domain that has a degenerate repeat region, a transmembrane domain, and
a short cytoplasmic domain. The VNTR region consists of a variable
number of a 20-amino acid repeat and contains numerous serine and
threonine residues that represent potential O-glycosylation sites. The
C-terminal domain contains 5 possible N-glycosylation sites and several
additional potential O-glycosylation sites. The deduced MUC1 protein
reported by Lan et al. (1990) had approximately 42 tandem repeats,
resulting in a 1,255-amino acid protein with a calculated molecular mass
of 122 kD. Using Northern blot analysis, Lan et al. (1990) detected a
major 4.4-kb MUC1 transcript in several pancreatic and breast tumor cell
lines.
Levitin et al. (2005) stated that alternative splicing of MUC1 produces
isoforms that differ in their N and C termini, lack the tandem repeat
array of full-length MUC1, or may be secreted rather than tethered to
the cell membrane. They identified a splice variant encoding a MUC1
isoform, called MUC1/ZD, that lacks both the tandem repeat array and has
a unique C terminus due to a frame shift. The 73-amino acid protein is
identical to full-length MUC1 only in the N-terminal signal peptide and
subsequent 30 amino acids. Immunohistochemical analysis of skin showed
MUC1/ZD expression in epithelial cells of sebaceous glands, hair
follicles, and epidermis. Full-length MUC1 was also expressed in
epithelial cells of sebaceous glands. MUC1/ZD localized to the cell
surface and interstitial space. It had an apparent molecular mass of 7
to 8 kD by SDS-PAGE. Under nonreducing conditions, its mass was about 64
kD, suggesting that MUC1/ZD forms oligomers linked by disulfide bonds
between cysteine residues.
Wei et al. (2006) stated that MUC1 is translated as a single polypeptide
that is cleaved into 2 subunits in the endoplasmic reticulum. The
extracellular N-terminal subunit (MUC1N) contains variable numbers of
20-amino acid tandem repeats that are extensively modified by O-linked
glycans. The C-terminal subunit (MUC1C) consists of a 58-amino acid
extracellular domain, a 28-amino acid transmembrane domain, and a
72-amino acid cytoplasmic tail. MUC1N extends well beyond the glycocalyx
and is tethered to the cell membrane by MUC1C. MUC1C also accumulates in
the cytosol of transformed cells and is targeted to the nucleus and
mitochondria.
Using real-time RT-PCR, Moehle et al. (2006) found that MUC1 was highly
expressed in adult prostate, mammary gland, trachea, lung, small
intestine, and colon, and in fetal lung. Lower expression was detected
in placenta, kidney, and pancreas, followed by testis, uterus, salivary
gland and stomach. Weak expression was detected in spinal cord, thyroid,
bone marrow, and thymus.
GENE FUNCTION
Gendler et al. (1990) studied the polymorphic epithelial mucin present
on the surface of human mammary cells. It is developmentally regulated
and aberrantly expressed in breast cancer.
Li et al. (2003) stated that beta-catenin (CTNNB1; 116806) binds
directly to a serine-rich motif in the MUC1 cytoplasmic domain (CD), and
that the interaction is regulated by MUC1-CD phosphorylation. They
showed that MUC1 localized to the surface of transfected rat
fibroblasts, and that the MUC1 C-terminal subunit and beta-catenin
colocalized in the nucleus. The amount of nuclear beta-catenin increased
following MUC1 expression. MUC1-expressing fibroblasts were tumorigenic
in nude mice.
Yin et al. (2003) found that oxidative stress increased expression of
MUC1 in several human cell lines. In turn, MUC1 induced expression of
the antioxidant enzymes superoxide dismutase (SOD1; 147450), catalase
(CAT; 115500), and glutathione peroxidase (GPX1; 138320). MUC1 also
attenuated the apoptotic response to oxidative stress.
Rahn et al. (2004) stated that ICAM1 (147840) binds the MUC1
extracellular domain and that binding promotes adhesion of
MUC1-expressing tumor cells to a simulated vessel wall containing ICAM1
with sufficient strength to withstand shear stress equivalent to
physiologic blood flow. They reported that the interaction of MUC1 with
ICAM1 triggered intracellular calcium oscillations in MUC1-expressing
cells. Oscillations were reduced by inhibition of SRC family kinases
(190090), phosphoinositol-3 kinase (see PIK3CA; 171834) and
phospholipase C (see PLCG1; 172420), and by disruption of lipid rafts,
but not by inhibition of mitogen-activated protein kinases (see MAPK1;
176948).
Wei et al. (2006) found that MUC1C associated with estrogen
receptor-alpha (ESR1; 133430) and that the interaction was stimulated by
17-beta-estradiol in human breast carcinoma cell lines. MUC1 bound
directly to the ESR1 DNA-binding domain and stabilized ESR1 by blocking
its ubiquitination and degradation. Chromatin immunoprecipitation assays
demonstrated that MUC1 associated with ESR1 complexes on
estrogen-responsive promoters, enhanced ESR1 promoter occupancy, and
increased recruitment of p160 (PELP1; 609455) coactivators SRC1 (NCOA1;
602691) and GRIP1 (604597). MUC1 stimulated ESR1-mediated transcription
and contributed to estradiol-mediated growth and survival of breast
cancer cells.
The amnion membrane of placenta performs a unique physiologic role as a
physical barrier between the fetal and external environment, and appears
to have antibacterial and antiadhesive properties. Using DNA microarrays
to examine gene expression patterns in normal human placenta, Sood et
al. (2006) found that MUC1 is highly expressed in the amnion. Muc1
knockout mice have chronic uterine infection caused by overgrowth of
normal bacteria of the reproductive tract (DeSouza et al., 1999). The
structure and expression patterns of mucin proteins suggest that they
may protect the mucous membranes by sterically inhibiting bacterial
access to the cell membrane. An association between high expression of
MUC1 and aggressiveness of some cancers has prompted speculation that
this glycoprotein favors metastasis by inhibiting cell adhesion (Levi et
al., 2004). Together, these observations suggested to Sood et al. (2006)
that expression of MUC1 may confer antibacterial and antiadhesive
properties to amnion.
Lu et al. (2006) noted that MUC1 interacts with Pseudomonas aeruginosa
(PA) through flagellin. They found that, compared with wildtype mice,
mice deficient in Muc1 cleared PA more efficiently, recruited more
neutrophils, and expressed higher levels of Tnf (191160) and Kc (CXCL1;
155730) in bronchoalveolar lavage fluid. ELISA showed that
Muc1-deficient alveolar macrophages stimulated with PA flagellin in
vitro secreted more Tnf, while Muc1-deficient tracheal epithelial cells
produced more Kc. Small interfering RNA-mediated knockdown of MUC1 in
human bronchial epithelial cells induced IL8 (146930) expression.
Expression of MUC1 in human embryonic kidney cells attenuated TLR5
(603031)-dependent IL8 release in response to flagellin. Expression of
MUC1 lacking the cytoplasmic tail in these cells abolished
flagellin-induced production of IL8. Lu et al. (2006) concluded that
MUC1 suppresses pulmonary innate immunity and proposed that its
antiinflammatory activity may play an important modulatory role during
microbial infection.
Both MUC1 and galectin-3 (LGALS3; 153619) are widely expressed in human
carcinomas. Ramasamy et al. (2007) showed that, following glycosylation
on asn36, MUC1C induced galectin-3 expression by suppressing expression
of miRNA322 (MIRN322; 300682), a microRNA that destabilizes galectin-3
transcripts. In turn, galectin-3 bound MUC1C at the glycosylated asn36
site and formed a bridge between MUC1 and epidermal growth factor
receptor (EGFR; 131550), integrating MUC1 with EGF (131530) signaling.
By microarray analysis, Moehle et al. (2006) found coordinated
downregulation of mucins, including MUC1, in ileum and colon of Crohn
disease and ulcerative colitis (see 266600) patients compared with
controls. They identified an NF-kappa-B (see 164011)-binding site in the
MUC1 promoter and showed that activation of the NF-kappa-B signaling
pathway by inflammatory cytokines TNF-alpha (TNF; 191160) and TGF-beta
(TGFB1; 190180) upregulated MUC1 mRNA expression nearly 8-fold and
2-fold, respectively.
GENE STRUCTURE
Levitin et al. (2005) reported that the MUC1 gene contains 7 coding
exons.
Gendler et al. (1990) identified a TATAA box and multiple GC boxes in
the upstream region of the MUC1 gene.
MAPPING
Swallow et al. (1987,1987) mapped the PUM locus to 1q21-q24 by somatic
cell hybrid studies and in situ hybridization.
Swallow et al. (1988) found close linkage of Duffy blood group (110700)
and PUM (maximum lod score = 4 at theta = 0). Middleton-Price et al.
(1988) found linkage of alpha-spectrin (182860) and PUM (maximum lod
score = 5.98 at theta = 0.05); both loci may lie within 1q21. Anderson
et al. (1989) presented results of linkage studies of PUM and chromosome
1 markers in the CEPH families.
By analysis of interspecific backcross mice, Kingsmore et al. (1995)
mapped the homologous gene to mouse chromosome 3.
MOLECULAR GENETICS
Karlsson et al. (1983) demonstrated a genetically determined
polymorphism of a human urinary mucin by the separation technique of SDS
polyacrylamide gel electrophoresis followed by detection with
radioiodinated lectins. Peanut agglutinin was the most effective lectin;
hence, the proposed designation peanut-reactive urinary mucin (PUM).
Karlsson et al. (1983) identified 4 common alleles with codominant
inheritance. The same polymorphic protein is expressed in other normal
and malignant tissues of epithelial origin including the mammary gland.
Variation in white cell DNA detected with a cDNA probe for mammary mucin
exactly matches the variation of the protein as demonstrated after
electrophoresis using a series of monoclonal antibodies; studies in 2
large families demonstrated the precise correspondence. It appears that
a series of tandem repeats constitutes much of the coding region of the
PUM gene and that the allelic variation is due to variation in the
number of repeats, as occurs in the hypervariable minisatellite regions
of DNA.
Swallow et al. (1987) presented evidence obtained using a cDNA that the
PUM locus is a hypervariable 'minisatellite' region similar to those
described by several groups, but novel in that it is transcribed and
translated, and that the same polymorphism is demonstrable in the
expressed gene product.
Gendler et al. (1990) found that the number of repeats in the VNTR
domain of the MUC1 gene in 69 northern Europeans varied from 21 to 125,
with the dominant numbers being 41 and 85. The most common genotype
observed (5 of 69 individuals) was the heterozygote consisting of the 2
most common alleles.
A polymorphism due to a G/A substitution in exon 2, responsible for a
genetically determined variation in splicing of the MUC1 transcript, was
reported by Ligtenberg et al. (1990, 1991). Pratt et al. (1996) reported
a CA repeat polymorphism within intron 6 of the gene. The various
results supported the notion that the VNTR polymorphism in the coding
sequence of MUC1 was not caused by unequal reciprocal recombination at
meiosis.
Silva et al. (2001) evaluated the MUC1 VNTR polymorphism in a series of
174 patients with chronic gastritis in a population from northern
Portugal with a high incidence of gastric carcinoma (137215). The data
were compared with those from blood donors and patients with gastric
cancer from the same population. Significant differences were observed
between patients with chronic gastritis and blood donors and also
between patients with chronic gastritis and patients with gastric
cancer. Homozygotes for small MUC1 VNTR alleles were significantly
associated with gastric carcinoma as well as with chronic atrophic
gastritis and incomplete intestinal metaplasia, the 2 well established
precursor lesions of gastric carcinoma, suggesting that MUC1 genotypes
may define different susceptibility backgrounds in the gastric
carcinogenesis pathway.
Fowler et al. (2003) investigated hypervariability in MUC1 and concluded
that it may have functional consequences.
- Medullary Cystic Kidney Disease 1
In affected members of 6 unrelated families with autosomal dominant
medullary cystic kidney disease-1 (MCKD1; 174000), Kirby et al. (2013)
identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an
extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat
(VNTR) sequence in the MUC1 gene (158340.0001). The insertion was
predicted to cause a frameshift, resulting in a mutant protein with many
copies of a novel repeat sequence, but lacking a downstream
self-cleavage module and both the transmembrane and intracellular
domains characteristic of the wildtype MUC1 precursor protein. A similar
cytosine insertion was found in 13 of 21 additional families with the
disorder who were studied, consistent with its being a fully penetrant
cause of disease. The disorder was characterized by adult onset of
slowly progressive renal failure, minimal proteinuria, decreased
glomerular filtration rate (GFR), and occasional findings of renal cysts
on ultrasound. Renal biopsy showed tubulointerstitial fibrosis and
tubular atrophy. End-stage renal disease occurred in the third to
seventh decades of life. Antibodies against a peptide synthesized to
correspond to the predicted mutant VNTR sequence showed specific
intracellular staining in epithelial cells from the loop of Henle,
distal tubule, and collecting duct of patients that was not seen in
controls. The mutant MUC1 showed partial colocalization with wildtype
MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized
that the mutation was missed by massively parallel sequencing and was
found only by diligent analysis of the linked region using cloning,
Southern blot analysis, long-range PCR, and reconstruction of the VNTR
allele in patients and controls.
ANIMAL MODEL
McAuley et al. (2007) observed a rapid progressive increase in
gastrointestinal expression of Muc1 after oral infection of mice with
Campylobacter jejuni. Systemic spread occurred in Muc1 -/- mice, but not
in wildtype mice, and Muc1 -/- mice showed more small intestinal damage,
as manifested by increased apoptosis with enucleated and shed villous
epithelium, after C. jejuni infection. Muc1 -/- mice were not more
susceptible to S. typhimurium than wildtype mice. Testing of chimeric
mice showed that prevention of systemic infection was due exclusively to
Muc1 expression on mucosal rather than hematopoietic cells. Muc1
enhanced resistance to the C. jejuni cytolethal distending toxin (Cdt),
and bacteria lacking Cdt were deficient in colonizing the
gastrointestinal tracts of Muc1 -/- mice. McAuley et al. (2007)
concluded that MUC1 is critical in limiting mucosal infection and that
MUC1 expression enhances resistance to C. jejuni Cdt.
GBA
| dbSNP name | rs9628662(T,G); rs2009578(G,A); rs114452199(G,A); rs2075569(C,T); rs151028758(G,A); rs150466109(T,C); rs190033289(A,G); rs1800442(A,G); rs3754485(A,G); rs1800438(C,T); rs11264345(T,A); rs10908459(C,T); rs12034326(A,G) |
| ccdsGene name | CCDS1102.1 |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 2629 |
| EntrezGene Description | glucosidase, beta, acid |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GBA:NM_001005741:exon3:c.A38G:p.K13R,GBA:NM_000157:exon2:c.A38G:p.K13R,GBA:NM_001005742:exon3:c.A38G:p.K13R,GBA:NM_001171812:exon2:c.A38G:p.K13R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7108 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B7Z5G2 |
| dbNSFP KGp1 AF | 0.0201465201465 |
| dbNSFP KGp1 Afr AF | 0.0873983739837 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0202 |
| ESP Afr MAF | 0.070813 |
| ESP All MAF | 0.02422 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 7.099e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
IMMUNOLOGY:
Enlarged lymph nodes;
Lymphocytosis, polyclonal B-cell;
Bone marrow shows lymphoid hyperplasia;
Defective antibody production against polysaccharide-based vaccines;
Normal titers to T cell-dependent vaccines;
Relative T-cell anergy;
Decreased IgM;
Recurrent infections
NEOPLASIA:
Chronic lymphocytic leukemia, B-cell, susceptibility to
MISCELLANEOUS:
One family and 1 unrelated patient have been reported (last curated
April 2013)
MOLECULAR BASIS:
Caused by mutation in the caspase recruitment domain-containing protein
11 gene (CARD11, 607210.0001)
OMIM Title
*606463 GLUCOSIDASE, BETA, ACID; GBA
;;ACID BETA-GLUCOSIDASE;;
BETA-GLUCOSIDASE, ACID;;
BETA-GC;;
GLUCOCEREBROSIDASE;;
GLUCOSYLCERAMIDASE
GLUCOCEREBROSIDASE PSEUDOGENE, INCLUDED; GBAP, INCLUDED
OMIM Description
DESCRIPTION
Acid beta-glucocerebrosidase, also known as beta-glucosidase (GBA; EC
3.2.1.45), is a lysosomal enzyme that catalyzes the breakdown of the
glycolipid glucosylceramide (GlcCer) to ceramide and glucose (Beutler,
1992).
CLONING
Sorge et al. (1985) isolated and characterized a cDNA clone
corresponding to the human beta-glucosidase gene from a human cDNA
library. Using the ATG at positions 154-156 as the correct initiator
codon, the deduced protein is 515 amino acids long and contains a
19-amino acid signal sequence. The mature 496-residue protein has a
calculated molecular mass of 55.4 kD. The cDNA directed the synthesis of
functional glucocerebrosidase when expressed in mammalian cells.
Tsuji et al. (1986) isolated GBA cDNA clones from a human hepatoma cDNA
library. The deduced 516-residue protein has a calculated molecular mass
of 57 kD.
Sorge et al. (1987) demonstrated that human GBA cDNA contains 2
potential ATG start codons, with the upstream ATG resulting in a protein
with a 39-amino acid signal peptide and the downstream ATG resulting in
a protein with a 19-amino acid signal peptide. The corresponding signal
peptides differed in their hydrophobicity. Either ATG could function to
produce active enzyme in cultured fibroblasts. Functional enzyme
activity from either translation products was found predominantly in
lysosomes.
Reiner et al. (1988) isolated 2 different genomic clones encoding human
GBA from a fetal liver library. These clones represented 2
glucocerebrosidase genes, which the authors designated 6-1 and 10-2. The
second gene is a putative pseudogene (see below). Both genes had
identifiable promoter regions, but the promoter of gene 6-1 was much
more efficient than that for gene 10-2 in a chloramphenicol
acetyltransferase assay. Reiner et al. (1988) stated that both genes
appear to be mapped at the same locus (Choudary et al., 1986).
Horowitz et al. (1989) identified 2 GBA mRNA species: a major 2.6-kb
transcript and a minor 2.2-kb transcript.
O'Neill et al. (1989) found that the human and mouse GBA amino acid
sequences share 86% identity. All 5 amino acids known to be essential
for normal enzymatic activity are conserved between mouse and man. Only
1 ATG translation initiation signal was present in the mouse sequence,
whereas 2 have been reported in the human sequence.
- Pseudogene
Horowitz et al. (1989) sequenced a GBA pseudogene, which is 96%
homologous to the functional gene. Compared to the functional gene, the
pseudogene has large deletions within several introns, representing Alu
sequences flanked by direct repeats, as well as base pair changes
scattered throughout the gene. Reiner and Horowitz (1988) found that the
promoter of the glucocerebrosidase pseudogene has demonstrable activity
when attached to a reporter gene. They commented that mutations in the
rest of the gene must render the mRNA vulnerable to breakdown or other
functional abnormality such that no enzyme is synthesized.
By studies of RNA from lymphoblasts and fibroblasts from patients with
Gaucher disease (see 230800) and normal subjects, Sorge et al. (1990)
found that the pseudogene was consistently transcribed and that in some
cases the level of transcription seemed to be approximately equal to
that of the functional gene. The mouse genome did not appear to contain
the pseudogene.
Tayebi et al. (1996) reported a method to distinguish the
glucocerebrosidase gene from the pseudogene, which is 2 kb shorter than
the expressed gene. The technique involved the use of long-template PCR
and PCR primers to simultaneously generate a 5.6-kb fragment from the
functional glucocerebrosidase gene and a 3.9-kb fragment from the
pseudogene. The PCR products were then individually purified and used in
subsequent experiments for mutation detection.
GENE STRUCTURE
Horowitz et al. (1989) determined that the GBA gene contains 11 exons.
MAPPING
Shafit-Zagardo et al. (1981) assigned the GBA gene to chromosome
1p11-qter. Devine et al. (1982) narrowed the assignment to 1q42-qter. By
study of hamster-human somatic cell hybrids, Barneveld et al. (1983)
assigned GBA to 1q21-q31, which was consistent with the studies of
Shafit-Zagardo et al. (1981) but not with those of Devine et al. (1982).
Three studies suggested localization of the GBA gene in distal 1q31 or
proximal subband 1q32.1 (Philip et al., 1985). By somatic cell
hybridization and in situ hybridization, Ginns et al. (1985) placed GBA
at 1q21.
Cormand et al. (1997) used an intragenic polymorphism of the GBA gene
(6144A-G) to localize GBA in relation to markers in the Genethon human
linkage map and to a 3.2-cM interval at chromosome 1q21. No
recombination was found between 6 markers and the GBA gene. Three of the
markers, D1S2777, D1S303, and D1S2140, are present in YAC clone 887h8
which also contains the GBA gene and the PKLR gene (609712). Mateu et
al. (2002) found complete linkage disequilibrium in the PKLR-GBA region
over 70 kb in a set of worldwide populations. Variation at PKLR-GBA was
also tightly linked to that at the GBA pseudogene. Thus, a 90-kb linkage
disequilibrium block was observed, which points to a low recombination
rate in this region.
By linkage studies of interspecific backcrosses of Mus spretus and Mus
musculus domesticus, Seldin (1989) demonstrated that the Gba gene is
located on mouse chromosome 3. O'Neill et al. (1989) pointed out that
although the NGFB (162030) and GBA loci are syntenic in both mouse and
the human (they are about 7.6 cM apart on mouse chromosome 3), they
represent a conserved segment that spans the centromere in man.
- Pseudogene
The GBA pseudogene is located approximately 16 kb downstream from GBA
(Sorge et al., 1990).
Zimran et al. (1989) identified a new mutation which represented
crossing-over between the GBA gene and the pseudogene, resulting in a
fusion gene designated 'XOVR.' Zimran et al. (1990) reported that this
'Lepore-like' glucocerebrosidase fusion gene consisted of the 5-prime
end of the functional gene and the 3-prime end of the pseudogene. The
location of a pseudogene near the functional gene for GBA on chromosome
1q may be the basis of disease-producing changes in the functional gene
through gene conversion, similar to what occurs with the CYP21 gene
(613815) on 6p (Horowitz, 1990).
GENE FUNCTION
Reczek et al. (2007) found that LIMP2 (SCARB2; 602257) bound beta-GC,
but not alpha-galactosidase (GLA; 300644) or alpha-glucosidase (GAA;
606800). Beta-GC and LIMP2 interacted in the endoplasmic reticulum, and
both proteins traversed the Golgi and endocytic compartments together en
route to lysosomes. In vitro, low pH attenuated binding between the 2
proteins, suggesting that acidic lysosomal pH facilitates dissociation
of beta-GC from LIMP2. Cross-linking experiments with transfected COS
cells suggested that the beta-GC-LIMP2 complex is about 250 kD in size,
consistent with a 2:2 beta-GC:LIMP2 stoichiometry. Mutation analysis
revealed that a coiled-coil motif within the luminal domain of LIMP2 was
required for beta-GC binding. Knockdown of LIMP2 in HeLa cells via small
interfering RNA significantly reduced lysosomal beta-GC content and
resulted in mistargeting of beta-GC for secretion. Limp2 knockout in
mice significantly reduced beta-GC content in liver and kidney, but had
no effect on beta-GC mRNA. Limp2 -/- mice, but not wildtype mice, showed
elevated serum beta-GC and increased GlcCer content in liver and lung,
but not in kidney, spleen, and brain. Limp2 -/- mice did not show a
robust Gaucher-like phenotype. Reczek et al. (2007) concluded that LIMP2
functions as a mannose-6-phosphate-independent receptor for lysosomal
targeting of beta-GC.
Jovic et al. (2012) found that PI4KII-alpha (PI4K2A; 609763) and
PI4KIII-beta (PI4KB; 602758), both of which synthesize
phosphatidylinositol-4-phosphate (PtdIns4P), had distinct and sequential
roles in the lysosomal delivery of beta-GC and LIMP2. Activity of
PI4KIII-beta at the Golgi was required to drive exit of LIMP2 from the
Golgi, whereas PI4KII-alpha at the trans-Golgi network regulated sorting
of LIMP2 toward the late endosome/lysosome compartment. Knockdown or
inhibition of PI3KIII-beta led to accumulation of LIMP2 at the Golgi
compartment, and knockdown of either LIMP2 or PI4KII-alpha increased
beta-GC secretion. Mutations in PI4KII-alpha that disrupted its
association with AP3 (see AP3B1; 603401) disrupted lysosomal LIMP2
targeting.
MOLECULAR GENETICS
The numbering system used for mutations in the MOLECULAR GENETICS
ALLELIC VARIANTS sections in this entry is based on the mature GBA
protein and not including the 39-residue signal peptide.
- Gaucher Disease, Types I, II, and III
Nearly 200 mutations in the GBA gene have been described in patients
with Gaucher disease types I (230800), II (230900), and III (231000)
(Jmoudiak and Futerman, 2005).
Tsuji et al. (1987) identified a mutation in the GBA gene (L444P;
606463.0001) in patients with Gaucher disease types I, II, and III. Two
of the 5 patients with type II and 7 of the 11 with type III were
homozygous for this mutation, whereas 4 of 20 patients with type I
Gaucher disease had this mutant allele in heterozygous state. The L444P
substitution occurs naturally in the GBA pseudogene.
Latham et al. (1990) presented a useful diagram of 9 mutations in the
GBA gene identified in patients with Gaucher disease. Four of the
mutations (L444P; D409H; 606463.0006, A456P and V460V; 606463.0009) were
known to be present also in the pseudogene.
Beutler (1993), Mistry and Cox (1993), Horowitz and Zimran (1994),
Beutler et al. (1994), Beutler and Gelbart (1996), and Stone et al.
(2000) provided updates on mutations in the GBA gene causing Gaucher
disease.
In an analysis of 60 type I and type III Gaucher patients, Sidransky et
al. (1994) found that the 5 most common Gaucher mutations, N370S
(606463.0003), L444P, R463C (606463.0008), 84insG, (606463.0014) and
IVS2+1G-A (606463.0015), were identified in patients with or without
neurologic manifestations. The findings indicated that Gaucher patients
sharing identical genotypes can exhibit considerable clinical
heterogeneity.
Grace et al. (1997) identified 6 new pathogenic mutations in the GBA
gene in 5 severely affected type I and type II Gaucher disease patients
of non-Jewish descent.
Sidransky et al. (1996) described homozygosity for a triply mutant GBA
allele (606463.0009) in 2 conceptuses from an Afghan family with
perinatal lethal Gaucher disease (608013). The findings were comparable
to those in the 'knockout' Gaucher mouse in which absence of enzyme was
incompatible with long survival (Tybulewicz et al., 1992). In an infant
with perinatal lethal Gaucher disease, Tayebi et al. (1997) identified
homozygosity for a null mutation in the GBA gene (606463.0034). This
case confirmed the essential role of GBA in human development.
Germain et al. (1998) described an exhaustive screening strategy,
involving fluorescence-assisted mismatch analysis using universal
primers, and succeeded in identifying both Gaucher disease mutant
alleles in all 25 patients studied. A total of 18 different mutations
and a new Gaucher disease haplotype were detected.
In a patient with perinatal lethal Gaucher disease, Grace et al. (1999)
identified 2 pathogenic alleles in the GBA gene. Stone et al. (2000)
reported 6 children who presented at birth with collodion-type skin
changes and hepatosplenomegaly and were found to be
beta-glucocerebrosidase-deficient. All died shortly after birth or in
the first year of life from respiratory insufficiency or progressive
neurologic disease. Three of the cases were homozygous for GBA mutations
(see 606463.0009 and 606463.0042) and the others were compound
heterozygotes.
Park et al. (2002) noted that an E326K substitution had been identified
in patients with all 3 types of Gaucher disease, but in each instance it
was found on the same allele with another GBA mutation (see, e.g.,
606463.0011). The authors identified the E326K allele in 1.3% of
patients with Gaucher disease and in 0.9% of controls, indicating that
it is a polymorphism. Montfort et al. (2004) performed functional
analyses of 13 GBA mutant alleles identified in Gaucher disease
patients. The mutations were expressed in Sf9 cells using a baculovirus
expression system. The authors obtained results suggesting that the
E326K mutation should be considered a 'modifier variant' rather than a
neutral polymorphism, as previously suggested (Grace et al., 1999; Park
et al., 2002).
Tayebi et al. (2003) studied DNA samples from 240 patients with Gaucher
disease, using several complementary approaches to identify and
characterize recombinant alleles. Among 480 alleles studied, 59
recombinant alleles were identified, including 34 gene conversions, 18
fusions, and 7 downstream duplications. At least 1 recombinant allele
was present in 22% of the patients. In patients with Gaucher disease
types I, II, and III, the authors found recombinant alleles with the
following frequencies among alleles: 26 of 310, 18 of 74, and 15 of 96,
respectively. Several patients carried 2 recombinations or mutations on
the same allele. Generally, alleles resulting from nonreciprocal
recombination (gene conversion) could be distinguished from those
arising by reciprocal recombination (crossover and exchange), and the
length of the converted sequence was determined. Homozygosity for a
recombinant allele was associated with early lethality. Ten different
sites of crossover and a shared pentamer motif sequence (CACCA) that
could be a hotspot for recombination were identified.
Emre et al. (2008) analyzed the GBA gene in 57 unrelated Turkish
patients with Gaucher disease and identified 103 mutant alleles (90.3%)
carrying 11 different mutations, 3 of which were novel. The most
frequent mutations included L444P (42%), N370S (30%), D409H (4.3%), and
R463C (3.5%).
- Late-Onset Parkinson Disease and Lewy Body Dementia
Goker-Alpan et al. (2004) reported 10 unrelated families with Gaucher
disease in which obligate or confirmed carriers of GBA mutations
developed Parkinson disease (see PD; 168600). In the family of a proband
with Gaucher disease type III, the proband's father, paternal
grandfather, and paternal great-aunt developed parkinsonism, and all
were found to carry the mutant GBA allele that was found in the proband;
2 asymptomatic family members did not have the allele. Nine of 40
additional families with Gaucher disease had similar findings, but there
was no correlation with specific GBA mutations. Most of the patients
with parkinsonism developed neurocognitive changes. Goker-Alpan et al.
(2004) suggested that heterozygosity for mutations in the GBA gene may
be a risk factor for the development of parkinsonism.
Aharon-Peretz et al. (2004) reported an association between Parkinson
disease and mutations in the GBA gene in Ashkenazi Jews by screening for
6 GBA mutations most common among this population. One or 2 mutant GBA
alleles were identified in 31 (31.3%) of 99 Ashkenazi patients with
idiopathic PD: 28 were heterozygous and 3 were homozygous for one of
these mutations. Among 74 Ashkenazi patients with Alzheimer disease (AD;
104300), 3 (4.1%) were carriers of Gaucher disease and among 1,543
controls, 95 (6.2%) were carriers of Gaucher disease. Patients with PD
had significantly greater odds of being carriers of Gaucher disease than
did patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0).
Among PD patients, those who were carriers of Gaucher disease were
younger than those who were not carriers (mean age at onset, 60.0 years
vs 64.2 years, respectively). Aharon-Peretz et al. (2004) suggested that
some GBA mutations are susceptibility factors for Parkinson disease.
Aharon-Peretz et al. (2005) observed no difference in overall clinical
manifestations and age at disease onset between 40 Ashkenazi Jewish PD
patients who carried GBA mutations and 108 Ashkenazi Jewish PD patients
without GBA mutations.
Toft et al. (2006) did not find an association between PD and 2 common
GBA mutations, L444P and N370S, among 311 Norwegian patients with
Parkinson disease. Mutant GBA alleles were identified in 7 (2.3%)
patients and 8 (1.7%) controls.
Goker-Alpan et al. (2006) identified heterozygous mutations in the GBA
gene in 8 (23%) of 35 patients with dementia with Lewy bodies (DLB;
127750). Four of these individuals carried the N370S mutation. One of 28
patients with Parkinson disease also carried a heterozygous N370S
mutation. The authors postulated that a mutant GBA enzyme may take on a
different and unexpected role that may contribute to the development of
synucleinopathies.
Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%)
of 331 Chinese patients with typical Parkinson disease and none of 347
controls. The age at onset was lower and the percentage of women higher
in patients with the L444P mutation compared to those without the
mutation. Tan et al. (2007) noted that the findings were significant
because Gaucher disease is extremely rare among the Chinese.
Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish
patients with PD carried a GBA mutation, compared to 4.2% of elderly and
6.35% of young controls. The proportion of severe GBA mutation carriers
among patients was 29% compared to 7% among young controls. Severe and
mild GBA mutations increased the risk of developing PD by 13.6- and
2.2-fold, and were associated with decreased age at PD onset. Gan-Or et
al. (2008) concluded that genetic variance in the GBA gene is a risk
factor for PD.
Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184
Taiwanese patients with PD. Six other GBA variants were identified in 1
patient each, yielding a total of 7 different mutations in 10 patients
(5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA
gene would reveal additional variant that may contribute to PD.
Mata et al. (2008) identified heterozygosity for either the L444P or
N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 DLB
patients, and 2 (0.4%) of 554 control individuals, all of European
origin. Mata et al. (2008) estimated that the population-attributable
risk for GBA mutations in Lewy body disorders was only about 3% in
patients of European ancestry.
Nichols et al. (2009) identified 9 different mutations in the GBA gene,
including 5 previously reported variants, in 161 (12.2%) of 1,325
patients with Parkinson disease from 99 (17.5%) of 566 PD families,
respectively. Statistical analysis indicated that presence of 1 of the 5
previously reported GBA mutation was associated with increased risk of
PD as well as earlier age at disease onset compared to controls without
a GBA mutation.
In a 16-center worldwide study comprising 5,691 PD patients (including
780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis),
Sidransky et al. (2009) demonstrated a strong association between GBA
mutations and Parkinson disease. Direct sequencing for only the L444P or
N370S mutations identified either mutation in 15% of Ashkenazi patients
and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either
mutation was found in 3% of patients and less than 1% of controls.
However, full gene sequencing identified GBA mutations in 7% of
non-Ashkenazi patients. The odds ratio for any GBA mutation in patients
compared to controls was 5.43 across all centers. Compared to PD
patients without GBA mutations, patients with GBA mutations presented
earlier with the disease, were more likely to have affected relatives,
and were more more likely to have atypical manifestations, including
cognitive defects. Sidransky et al. (2009) concluded that while GBA
mutations are not likely a mendelian cause of PD, they do represent a
susceptibility factor for development of the disorder.
Neumann et al. (2009) identified 14 different heterozygous mutations in
the GBA gene in 33 (4.18%) of 790 British patients with Parkinson
disease and in 3 (1.17%) of 257 controls. Three novel mutations (see,
e.g., D443N; 606463.0048) were identified, and the most common mutations
were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3
patients). Four (12%) patients had a family history of the disorder,
whereas 29 (88%) had sporadic disease. The mean age at onset was 52.7
years, and 12 (39%) patients had onset before age 50. Fifteen (48.39%)
of the patients with GBA mutations developed cognitive decline,
including visual hallucinations. The male-to-female ratio of GBA
carriers within the PD group was 5:2, which was significantly higher
than that of the whole study group. Most patients responded initially to
L-DOPA treatment. Neuropathologic examination of 17 GBA mutation
carriers showed typical PD changes, with widespread and abundant
alpha-synuclein pathology, and most also had neocortical Lewy body
pathology. The prevalence of GBA mutations in British patients with
sporadic PD was 3.7%, indicating that mutations in the GBA gene may be
the most common risk factor for development of PD in this population. In
an accompanying letter, Gan-Or et al. (2009) found that the data
presented by Neumann et al. (2009) indicated that patients with mild GBA
mutations had later age at onset (62.9 years vs 49.8 years) and lower
frequency of cognitive symptoms (25% vs 55.6%) compared to patients with
severe GBA mutations.
PD brains are characterized by accumulation of aggregated
alpha-synuclein (SNCA; 163890), in addition to neurodegeneration.
Mazzulli et al. (2011) found that postmortem brains of patients with GD
and features of PD, as well as mouse models of GD, showed neuronal
accumulation of SNCA. Functional loss of GCase and resultant GlcCer
accumulation in cultured mouse cortical neurons and human neurons
reprogrammed from induced pluripotent stem cells resulted in compromised
lysosomal degradation of long-lived proteins, including SNCA. Elevated
cellular GlcCer also promoted SNCA aggregation. SNCA accumulation in
turn inhibited normal lysosomal GCase activity in neurons and PD brain.
In apparently normal human cortical samples, SNCA protein content,
particularly high molecular mass species, correlated inversely with
GCase activity. Mazzulli et al. (2011) hypothesized that a
positive-feedback loop between defective SNCA and/or GCase could lead to
self-propagating neurodegeneration over time.
Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P
mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD
(before 45 years of age) and in none (0%) of 252 ethnically matched
controls. Six (85.7%) of the 7 patients had psychiatric symptoms,
including major depressive disorder, generalized anxiety disorder, and
obsessive compulsive disorder, which was significantly higher than the
prevalence of these disorders in controls (24.7%). In addition, 57% of
mutation carriers presented with cognitive decline compared to 5.7% of
controls. The N370S mutation was not found in any of the Mexican
individuals, suggesting a similarity to Asian populations in which the
N370S mutation is almost nonexistent. Gonzalez-del Rincon et al. (2013)
concluded that the risk for PD conferred by GBA mutations may be higher
than previously thought, and that GBA-associated PD may predispose to
psychiatric symptoms.
GENOTYPE/PHENOTYPE CORRELATIONS
Theophilus et al. (1989) confirmed the high frequency of the N370S
mutation in Ashkenazi Jewish patients with type I Gaucher disease.
Homozygotes were mildly affected older persons, and the mutant allele
was not found in any patient with neuronopathic disease. Furthermore,
they confirmed that the L444P mutation was the predominant allele in
Gaucher disease type II and type III.
Koprivica et al. (2000) used several approaches, including direct
sequencing, Southern blotting, long-template PCR, restriction
digestions, and the amplification refraction mutation system, to
genotype 128 patients with type I Gaucher disease (64 of Ashkenazi
Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with
type III Gaucher disease. More than 97% of the mutant alleles were
identified. Fourteen novel mutations and many rare mutations were
detected. Recombinant alleles were found in 19% of the patients. Four
mutations (N370S, 84insG, IVS2+1G-A, and L444P) accounted for 93% of the
mutant alleles in the Ashkenazi Jewish type I patients, but for only 49%
of mutant alleles in the non-Jewish type I patients. Heterozygosity for
N370S resulted in type I Gaucher disease, whereas homozygosity for L444P
was associated with type III. Genotype L444P/recombinant allele resulted
in type II Gaucher disease, and homozygosity for a recombinant allele
was associated with perinatal lethal disease.
Homozygosity for the D409H mutation (606464.0006) has been reported in
Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995)
patients with neuronopathic Gaucher disease and cardiovascular
calcifications, a specific subtype known as 'Gaucher disease type IIIC'
(231005) (Bohlega et al., 2000). These reports demonstrate a
particularly tight pan-ethnic association between phenotype and genotype
in this variant form of Gaucher disease.
Ron and Horowitz (2005) tested glucocerebrosidase protein levels,
N-glycans processing, and intracellular localization in skin fibroblasts
derived from patients with Gaucher disease. Their results strongly
suggested that mutant glucocerebrosidase variants presented variable
levels of ER retention and underwent ER-associated degradation in the
proteasomes. The degree of ER retention and proteasomal degradation was
1 of the factors that determined Gaucher disease severity.
In a review of the molecular genetics of Gaucher disease, Hruska et al.
(2008) noted that most GBA mutations can be found in patients with
various forms of the disorder. The phenotype is mainly determined by the
combination of mutations on both alleles; thus the prediction of
phenotype from genotypic data has limited utility. In addition, it has
become increasingly difficult to categorize patients into 1 of the 3
classic types of Gaucher disease, indicating that the phenotypes fall
into a continuum, with the major distinction being the presence and
degree of neurologic function.
POPULATION GENETICS
Beutler (1993) stated that the 2 most common mutations in the Ashkenazi
Jewish population were N370S and 84insG, representing approximately 77%
and 13% of mutant alleles, respectively. These 2 mutations, together
with L444P, IVS2+1G-A, and V394L (606463.0005), account for 98% of the
disease-causing alleles in this population. Each of these mutations was
found in the context of a single haplotype, consistent with a founder
effect.
Diaz et al. (2000) used short tandem repeat (STR) markers to map a
9.3-cM region containing the GBA locus and to genotype 261 Ashkenazi
Jewish N370S chromosomes, 60 European non-Jewish N370S chromosomes, and
62 Ashkenazi Jewish 84insG chromosomes. A highly conserved haplotype at
4 markers flanking GBA was observed on both the Ashkenazi chromosomes
and the non-Jewish N370S chromosomes, suggesting the occurrence of a
founder common to the 2 populations. The presence of different divergent
haplotypes suggested the occurrence of de novo, recurrent N370S
mutations. In contrast, a different conserved haplotype at these markers
was identified on the 84insG chromosomes, which was unique to the
Ashkenazi population. On the basis of linkage disequilibrium values, the
non-Jewish European N370S chromosomes had greater haplotype diversity
and less linkage disequilibrium at the markers flanking the conserved
haplotype than did the Ashkenazi N370S chromosomes. This finding was
considered consistent with the presence of the N370S mutation in the
non-Jewish European population before the founding of the Ashkenazi
population. Coalescence analyses for the N370S and 84GG mutations
estimated similar coalescence times, of 48 and 55.5 generations ago,
respectively. (Coalescence time refers to the number of generations to
the most recent common ancestor, MRCA.) The results of these studies
were consistent with a significant bottleneck occurring in the Ashkenazi
population during the first millennium, when the population became
established.
ANIMAL MODEL
A naturally occurring canine model of Gaucher disease was reported by
van de Water et al. (1979) but was not propagated. Tybulewicz et al.
(1992) produced a murine model by targeted disruption of the mouse Gba
gene. A null allele was created in embryonic stem cells, and the
genetically modified cells were used to establish a mouse strain
carrying the mutation. Mice homozygous for the mutation had less than 4%
of normal glucocerebrosidase activity, died within 24 hours of birth,
and stored glucocerebroside in lysosomes of cells of the
reticuloendothelial system.
To produce mice with point mutations that correspond to the clinical
types of Gaucher disease, Liu et al. (1998) devised a highly efficient
1-step mutagenesis method, called the single insertion mutagenesis
procedure (SIMP), to introduce human disease mutations into the mouse
Gba gene. By use of SIMP, they generated mice carrying either the very
severe triply mutant allele (606463.0009) that can cause type II disease
or the less severe L444P mutation associated with type III disease. Mice
homozygous for the triple mutation had little GBA enzyme activity and
accumulated glucosylceramide in brain and liver. In contrast, the mice
homozygous for the L444P mutation had higher levels of GBA activity and
no detectable accumulation of glucosylceramide in brain and liver.
Surprisingly, both point mutation mice died within 48 hours of birth,
apparently of a compromised epidermal permeability barrier caused by
defective glucosylceramide metabolism in the epidermis.
Enquist et al. (2007) generated transgenic mice with targeted disruption
of the Gba gene, but low expression of the gene in skin to prevent early
lethality. The mice showed a phenotype similar to the severe
neuronopathic form of Gaucher disease, including rapid motor
dysfunction, seizures, and hyperextension of the neck associated with
severe neurodegeneration and apoptotic neuronal cell death. Some neurons
had large vacuoles indicating neuronal lipid accumulation. A second
mouse model with Gba deficiency restricted to neural and glial cell
progenitors demonstrated a similar neuropathology as the first mouse
model, but with a delayed onset and slower disease progression. These
findings indicated that Gba deficiency within microglial cells of
hematopoietic origin is not the primary determinant of the CNS
pathology, but may influence disease progression. The findings also
showed that normal hematopoietic-derived microglial cells could not
rescue the neurodegenerative phenotype.
HCN3
| dbSNP name | rs7549276(G,A); rs7551854(G,T); rs12044063(A,T); rs7367998(T,C); rs7520184(G,A); rs61749584(G,A); rs367783028(G,C); rs34218829(G,T); rs11264352(T,C); rs11264353(G,C); rs12724449(A,C); rs77762657(T,C); rs11264355(C,G); rs3814319(G,A); rs3814318(C,T) |
| ccdsGene name | CCDS1108.1 |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 57657 |
| EntrezGene Description | hyperpolarization activated cyclic nucleotide-gated potassium channel 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HCN3:NM_020897:exon4:c.G1000A:p.V334I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7649 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9P1Z3 |
| dbNSFP Uniprot ID | HCN3_HUMAN |
| dbNSFP KGp1 AF | 0.00228937728938 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002296 |
| ESP Afr MAF | 0.022015 |
| ESP All MAF | 0.007535 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.002057 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Loss of consciousness due to hypoglycemia;
Seizures, hypoglycemic
ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia
LABORATORY ABNORMALITIES:
Hypoglycemia, postprandial;
Hyperinsulinemia, fasting;
Elevated serum insulin-to-C-peptide ratio
MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)
MOLECULAR BASIS:
Caused by mutation in the insulin receptor gene (INSR, 147670.0037)
OMIM Title
*609973 HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL
3; HCN3
;;KIAA1535
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned HCN3, which they designated
KIAA1535. The cDNA contains a repetitive element in its 3-prime proximal
region, and the deduced protein contains 703 amino acids. RT-PCR ELISA
detected high HCN3 expression in adult liver and kidney and fetal liver
and brain, intermediate expression in adult whole brain, lung, pancreas,
spleen, testis, ovary, and all specific brain regions examined, and
little to no expression in heart and skeletal muscle.
By PCR of human brain cDNA, Stieber et al. (2005) cloned HCN3. The
deduced protein shares more than 80% homology in the transmembrane
segment, pore region, and cyclic nucleotide-binding domain with other
HCN proteins. RNA dot blot analysis detected HCN3 expression in neuronal
tissues only. Expression was high in fetal brain and adult cerebellum
and intermediate in nucleus accumbens, thalamus, and pituitary gland,
with little to no expression in other brain regions examined.
GENE FUNCTION
Stieber et al. (2005) found that overexpression of HCN3 in human
embryonic kidney cells induced a voltage-gated inward cation current.
Like other HCNs, HCN3 conducted both potassium and sodium ions with a
3:1 preference for potassium ions. HCN3 bound cAMP, but unlike other
HCNs, its activity was not modulated by intracellular cAMP.
Using yeast 2-hybrid and immunoprecipitation analyses, Cao-Ehlker et al.
(2013) found that Kctd3 (613272) interacted specifically with Hcn3 in
mouse brain and not with other Hcn channels examined. When expressed
alone, Hcn3 localized predominantly to intracellular structures in
transfected HEK293 cells; however, coexpression of Hcn3 with Kctd3
resulted in membrane targeting of Hcn3 and profoundly increased Hcn3
current density. The C-terminal half of Kctd3 interacted with Hcn3, but
the N-terminal half of Kctd3 was required to stimulate Hcn3 currents.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the HCN3 gene
to chromosome 1.
RUSC1-AS1
| dbSNP name | rs16836822(T,G); rs12741581(C,T) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 284618 |
| snpEff Gene Name | FDPS |
| EntrezGene Description | RUSC1 antisense RNA 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RUSC1-AS1:NM_001039517:exon2:c.A693C:p.R231S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
| ESP Afr MAF | 0.057809 |
| ESP All MAF | 0.018779 |
| ESP Eur/Amr MAF | 0.000241 |
| ExAC AF | 0.005058 |
ASH1L-AS1
| dbSNP name | rs60424986(T,C) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 645676 |
| snpEff Gene Name | ASH1L |
| EntrezGene Description | ASH1L antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03076 |
MSTO1
| dbSNP name | rs116250724(G,A) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 55154 |
| EntrezGene Description | misato 1, mitochondrial distribution and morphology regulator |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01423 |
RXFP4
| dbSNP name | rs142076460(C,T) |
| ccdsGene name | CCDS1124.1 |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 339403 |
| EntrezGene Description | relaxin/insulin-like family peptide receptor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RXFP4:NM_181885:exon1:c.C89T:p.P30L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0118 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8TDU9 |
| dbNSFP Uniprot ID | RL3R2_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.001768 |
| ESP Eur/Amr MAF | 0.002442 |
| ExAC AF | 0.001277 |
MIR7851
| dbSNP name | rs116119559(G,A); rs12080245(G,A); rs7513082(G,A); rs34444588(C,T); rs75852693(T,A); rs11582305(A,T); rs12128541(A,G); rs71630611(G,T); rs76830943(T,C); rs182600204(G,A); rs12735992(C,T); rs2297792(T,C); rs34224286(C,T); rs73004941(C,T); rs34673835(C,T); rs79918764(T,C); rs12138913(G,C); rs74543372(C,T); rs12136348(T,C); rs10158536(G,A); rs114310455(A,G); rs112048360(C,T); rs61813293(G,T); rs10796957(C,T); rs3754293(A,G); rs7541(C,T); rs111593253(G,A); rs6427299(C,T); rs192774800(T,A); rs149995244(T,C); rs145200618(C,T); rs2275073(C,A); rs12049195(G,A); rs72708251(G,C); rs149208921(T,C); rs116445755(T,G); rs2275075(A,G); rs7517412(A,G); rs11264432(G,A); rs11583438(C,G); rs3814314(T,A); rs10047112(A,G); rs3738593(C,T); rs114684670(T,C); rs74610158(G,T); rs6691151(C,T); rs61813324(C,T); rs200642479(G,C); rs11313903(T,G); rs12076700(C,G); rs12063564(T,C); rs12035615(C,T); rs12035654(C,T); rs11264434(C,T); rs145152366(C,T); rs4661146(G,C); rs143216166(G,C); rs28653480(A,G); rs7531942(A,G); rs9919256(G,A); rs10737170(C,A); rs1962065(C,T); rs6691659(A,G); rs190456452(C,T); rs74116481(G,T); rs6700693(T,C); rs74116482(G,C); rs150227100(C,T); rs12565130(G,A); rs11264438(C,G); rs6661281(T,C); rs79029071(C,T); rs76462222(T,C); rs915179(A,G); rs56106339(T,C); rs72708262(C,T); rs915180(C,T); rs58799304(T,A); rs12131777(T,C); rs955383(G,A); rs11584621(T,A); rs2485662(T,C); rs2485661(T,C); rs547915(T,C); rs481995(A,C); rs675661(A,G); rs582690(C,G); rs584025(C,T); rs28637701(G,A); rs517606(G,T); rs503815(T,C); rs609625(C,G); rs501791(C,T); rs610918(C,T); rs653969(C,T); rs521354(G,A); rs6686943(T,C); rs693671(T,C); rs9427236(C,T); rs2993269(G,C); rs502488(C,T); rs500940(C,T); rs11264440(C,T); rs671728(T,C); rs672200(T,G); rs2993268(A,G); rs2993267(A,G); rs4661147(G,A); rs2485676(A,G); rs471679(C,G); rs2485674(T,C); rs2485672(C,A); rs6657367(G,A); rs593987(G,A); rs594028(T,G); rs622834(T,C); rs623189(G,A); rs2430417(A,G); rs113448831(G,A); rs573739(T,A); rs573735(G,C); rs59351839(A,T); rs16837187(A,G); rs528636(A,G); rs543235(G,A); rs79200804(G,A); rs11264441(G,A); rs75820612(T,C); rs16837193(C,T); rs665979(C,G); rs513043(T,G); rs666869(A,G); rs509551(C,A); rs508641(T,C); rs577492(T,C); rs480886(C,G); rs682267(A,G); rs113369887(G,T); rs2485668(T,C); rs2485667(C,T); rs2430416(A,G); rs2430415(A,G); rs10158206(C,T); rs2485665(G,A); rs2430414(G,A); rs56702163(G,C); rs569025(A,C); rs78499673(C,T); rs11264442(G,T); rs11264443(C,T); rs11264444(G,T); rs11264445(C,T); rs538089(T,C); rs2485664(C,T); rs646840(G,T); rs534807(G,A); rs16837198(A,G); rs505058(T,C); rs476000(G,A); rs553016(C,T); rs520973(C,T); rs520910(T,C); rs80264244(A,G); rs7339(G,C); rs568036(A,G); rs568035(C,T); rs6669212(G,A); rs114280323(C,T); rs536857(A,G); rs545731(G,A); rs11803917(C,T); rs11264447(G,T); rs12073543(C,G); rs374747703(G,A); rs73006722(C,T); rs72708271(G,T); rs79749077(A,G); rs73006728(G,A); rs59714961(G,T); rs79488990(T,C); rs377210156(C,T); rs4661033(C,T); rs185959776(G,C); rs56276404(A,G); rs56396025(G,C); rs55669209(T,C); rs74116499(A,C); rs112049226(G,A); rs3738582(C,G); rs142870369(A,G); rs147122599(C,T); rs143873773(C,T); rs12239871(C,T); rs146044698(G,C); rs12128066(T,C); rs11588323(C,T); rs11264448(A,C); rs73006732(T,C); rs1984508(A,G); rs1985510(G,C); rs6659312(G,A); rs75404435(C,G); rs28483156(A,G); rs55877556(A,G); rs35505957(G,A); rs4843971(G,T); rs4843972(A,G); rs146484844(C,G); rs750461(G,C); rs8061153(T,C); rs13336767(G,A); rs35954296(C,T); rs56920362(G,T); rs7499587(T,C); rs12918736(C,G); rs145960692(C,T); rs58771995(C,T); rs79926295(T,C); rs8045380(C,T); rs1974866(G,A); rs1974867(T,C); rs8063442(T,G); rs142549101(G,A); rs4240779(T,C); rs6539958(A,G); rs36017235(C,T); rs35978246(G,T); rs12922725(A,G); rs78895525(C,T); rs79395476(C,T); rs35358082(A,G); rs62051379(C,T); rs16975769(G,T); rs6539966(G,C); rs4843410(T,C); rs7204836(A,G); rs62051380(C,G); rs9925740(G,A); rs9938179(A,G); rs12934363(A,G); rs35045648(C,A); rs116409803(G,A); rs35385995(G,T); rs12917784(G,C); rs59817555(C,T); rs58808946(C,T); rs732461(C,T); rs74831340(C,T); rs7184409(T,C); rs732460(G,T); rs4531756(C,T); rs4384624(G,C); rs75264091(C,G); rs182217027(T,C); rs111923062(G,A); rs76678921(C,A); rs76925161(C,T); rs73253204(T,G); rs13333163(C,T); rs12598891(T,C); rs12598362(A,G); rs35297506(C,A); rs12921685(C,T); rs67659612(C,T); rs11861015(G,A); rs754709(G,A); rs754710(C,T); rs754711(C,T); rs754712(C,T); rs744257(G,T); rs744255(G,T); rs744258(T,G); rs12448744(G,T); rs76426882(C,G); rs73253212(C,T); rs34341288(G,A); rs191235041(G,A); rs118057119(G,A); rs11640338(A,G); rs4843185(G,A); rs3815794(C,T); rs111367262(G,C); rs12444392(C,T); rs7404958(A,G); rs7404699(C,T); rs8049049(T,C); rs117279475(C,G); rs146498039(C,T); rs7192888(T,C); rs115291271(C,G); rs3812967(T,G); rs7195186(A,G); rs12149202(G,A); rs12149210(G,A); rs74034023(C,A); rs184174610(A,T); rs4843481(C,T); rs736845(T,C); rs929865(T,G); rs5016328(G,C); rs2303202(A,G); rs139704692(C,G); rs111235592(G,C); rs12149168(G,T); rs59013010(C,T); rs61212986(G,A); rs9940601(A,C); rs709805(G,A); rs1049868(T,C); rs76785102(C,G); rs871290(G,C); rs2029(C,A); rs11865(A,G); rs11865681(G,C); rs8571(G,A); rs35953313(T,A); rs1974868(C,T); rs1974869(G,A); rs4565(C,G); rs9534(T,C); rs3751716(G,A); rs1053328(C,T); rs3815795(C,T); rs10514608(C,G); rs16975817(G,A); rs11640540(A,C); rs73253274(G,T); rs4843506(T,A); rs4143866(A,G); rs11646052(A,G); rs4143865(T,A); rs889502(A,G); rs74034032(T,C); rs28639715(C,T); rs114451921(C,T); rs60676374(C,G); rs2363293(T,C); rs112279733(G,A); rs147472921(C,T); rs11864891(C,A); rs11861678(G,A); rs11649034(A,G); rs11117254(A,G); rs111996022(A,T); rs35444818(C,A); rs146672859(T,G); rs73253286(T,C); rs72803017(C,A); rs71389142(C,T); rs186520897(T,C); rs11117258(A,G); rs149329820(G,A); rs35003522(C,T); rs6540014(T,C); rs9930110(T,C); rs8048967(C,T); rs9930592(T,A); rs13338404(G,A); rs13332432(C,G); rs3794665(C,G); rs4325564(A,G); rs3764269(C,T); rs192124915(G,A); rs400479(T,C); rs117138064(C,G); rs73255103(G,T); rs374029(G,A); rs557035(A,C); rs113440551(C,T); rs79510961(G,T); rs73255111(C,T); rs1868871(T,C); rs381624(G,A); rs380996(G,A); rs421043(A,G); rs386282(C,T); rs411437(C,A); rs6540028(A,G); rs402939(C,T); rs2489(A,G); rs1044338(C,T); rs441239(G,A); rs78289833(G,A); rs75271412(G,C); rs392863(C,T); rs16975838(G,A); rs896262(C,A); rs8063094(C,T); rs889503(C,T); rs394692(T,G); rs9806851(A,T); rs896261(C,T); rs403665(A,G); rs382148(C,G); rs385807(G,C); rs381181(C,T); rs896260(G,C); rs385270(T,C); rs449943(G,A); rs4843225(T,C); rs370198(G,T); rs76409379(A,T); rs8061069(A,G); rs4843561(C,T); rs8046219(T,A); rs381366(G,T); rs77455942(A,C); rs570227(A,G); rs74565774(C,T); rs378187(A,C); rs115469228(C,T); rs28539315(G,C); rs28742166(A,T); rs4843575(G,A); rs377457(A,G); rs442090(G,A); rs146010144(G,T); rs537273(C,T); rs141872625(G,A); rs451871(C,T); rs115730643(G,C); rs7188724(T,A); rs114652010(A,G); rs12921380(T,C); rs452141(C,T); rs506043(C,T); rs11866436(C,T); rs142491040(G,A); rs2077339(C,T); rs2004453(C,T); rs417363(A,G); rs102822(G,C); rs11117268(T,A); rs73255136(C,T); rs396867(T,G); rs755464(T,A); rs112401531(T,C); rs138017776(C,T); rs72803037(C,T); rs7185608(A,G); rs114053520(C,A); rs11644122(C,T); rs56252890(T,C); rs143212296(C,G); rs7773(C,G); rs517710(A,G); rs400694(A,G); rs4843587(C,G); rs4843588(G,A); rs2305357(C,G); rs4843234(C,T); rs377473(A,G); rs403815(C,T); rs142251795(C,T); rs411927(C,T); rs407302(G,A); rs115881109(C,T); rs419811(C,T); rs420497(C,T); rs373935(A,G); rs4843596(T,C); rs141285264(T,C); rs555302(A,G); rs416877(G,A); rs77530920(G,A); rs2167345(G,A); rs1551150(A,G); rs111899722(C,A); rs622780(A,G); rs113673867(G,A); rs76096233(C,T); rs140593225(G,A); rs9930090(T,C); rs9923765(C,T); rs396180(A,G); rs55785961(C,T); rs112426523(T,A); rs372010(A,G); rs446292(C,A); rs74034061(C,T); rs373835(A,G); rs74034063(C,G); rs410369(G,A); rs115130777(A,G); rs79897775(C,T); rs74552677(C,G); rs373328(C,T); rs144537683(G,A); rs416287(C,T); rs400882(G,A); rs146794058(T,A); rs399447(T,G); rs371218(C,T); rs392072(A,G); rs381170(A,T); rs381964(G,C); rs433010(G,C); rs9308354(G,A); rs55982975(C,A); rs449740(G,C); rs364489(T,C); rs2362465(C,T); rs368375(G,A); rs74425562(C,A); rs11117284(G,A); rs441931(C,G); rs442069(C,G); rs377062(T,C); rs112429591(A,C); rs111308616(C,T); rs386041(T,G); rs386061(T,C); rs682834(G,C); rs567265(A,C); rs7190685(T,C); rs11648021(C,T); rs7199402(C,A); rs7204284(G,C); rs16975876(T,C); rs76706469(C,G); rs451754(C,T); rs76014391(C,T); rs17804860(C,G); rs439406(A,C); rs79318029(C,T); rs66512666(C,A); rs391458(G,C); rs80300008(A,G); rs403764(A,T); rs116518324(C,T); rs419504(T,G); rs112767628(A,T); rs371980(C,A); rs371014(G,A); rs403472(G,A); rs10863186(T,C); rs57395437(A,G); rs28402278(T,C); rs440642(C,A); rs114756567(G,A); rs441236(C,A); rs16975880(T,G); rs391278(G,C); rs445514(C,T); rs113316939(A,T); rs112006792(G,A); rs150871907(C,A); rs72803073(C,T); rs377970(G,A); rs8051534(G,C); rs390924(A,G); rs401577(G,A); rs190167224(A,G); rs59969227(C,G); rs74391206(G,A); rs415418(A,G); rs380869(G,C); rs372507(G,A); rs394094(T,C); rs409342(A,G); rs1862733(C,T); rs410639(A,C); rs410687(A,C); rs369694(G,T); rs55711551(G,A); rs77505759(G,T); rs889501(C,T); rs408988(G,A); rs76586042(G,A); rs2122782(G,C); rs8049350(C,T); rs10863188(T,G); rs367496(C,G); rs10863189(G,C); rs10863190(G,C); rs369071(C,A); rs388140(C,T); rs388438(C,T); rs554790(C,G); rs391990(G,A); rs74034067(T,G); rs144443485(C,T); rs72803087(C,T); rs11117293(G,A); rs394623(G,C); rs471950(C,T); rs79829983(G,A); rs399955(C,T); rs58088197(C,T); rs400272(C,T); rs9934627(G,C); rs656241(T,C); rs60087206(G,A); rs383764(T,C); rs419006(A,T); rs388576(G,A); rs397492(G,A); rs419468(T,C); rs408253(A,G); rs111270017(C,G); rs372395(T,C); rs388855(A,G); rs72803098(G,C); rs446444(G,A); rs416326(A,G); rs78934189(T,C); rs55891350(C,T); rs55884883(C,T); rs75020858(C,T); rs78856189(G,A); rs79357913(T,A); rs111390352(G,A); rs12935298(G,C); rs2443332(C,T); rs9922856(A,T); rs55883333(G,C); rs141673503(G,A); rs366362(A,G); rs396480(C,T); rs190448163(G,A); rs6540076(A,G); rs11117297(T,C); rs368765(A,G); rs114038266(C,A); rs408126(C,T); rs4338826(T,C); rs60236762(T,C); rs4843670(T,C); rs443344(A,G); rs301148(C,G); rs2362464(A,T); rs117894346(G,C); rs301145(G,T); rs4843678(T,A); rs301144(A,G); rs78722158(A,G); rs115832016(G,T); rs301141(C,G); rs2432409(G,C); rs301140(C,G); rs150033679(G,A); rs374752749(T,A); rs12448566(T,G) |
| ccdsGene name | CCDS58038.1 |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 4000 |
| EntrezGene Symbol | LMNA |
| snpEff Gene Name | LMNA |
| EntrezGene Description | lamin A/C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_intronic |
| dbNSFP LR score | 0.5857 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | D6RAQ3 |
| dbNSFP KGp1 AF | 0.173534798535 |
| dbNSFP KGp1 Afr AF | 0.530487804878 |
| dbNSFP KGp1 Amr AF | 0.10773480663 |
| dbNSFP KGp1 Asn AF | 0.0174825174825 |
| dbNSFP KGp1 Eur AF | 0.0910290237467 |
| dbSNP GMAF | 0.1736 |
| ESP Afr MAF | 0.450286 |
| ESP All MAF | 0.187544 |
| ESP Eur/Amr MAF | 0.072074 |
| ExAC AF | 0.101 |
PAQR6
| dbSNP name | rs759330(G,A); rs7513351(C,T); rs2075165(G,A); rs12401854(C,T) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 79957 |
| snpEff Gene Name | BGLAP |
| EntrezGene Description | progestin and adipoQ receptor family member VI |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2484 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly (1 patient);
[Face];
Retrognathia (1 patient);
[Eyes];
Broad palpebral fissures (1 patient)
ABDOMEN:
[Liver];
Hepatomegaly (1 patient);
Micronodular cirrhosis (1 patient);
Macrovesicular steatosis (1 patient);
[Gastrointestinal];
Anal anteposition (1 patient);
Diarrhea, recurrent (1 patient);
Inflammatory bowel disease (1 patient)
GENITOURINARY:
[Kidneys];
Proximal tubulopathy (1 patient)
SKELETAL:
[Hands];
Postaxial polydactyly (1 patient)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, mild;
Axial hypotonia (1 patient);
Seizures;
Loss of consciousness (1 patient);
Intracranial bleeding (1 patient)
IMMUNOLOGY:
Primary combined immunodeficiency (1 patient);
Recurrent infections (1 patient);
Hypogammaglobulinemia (1 patient);
T-cell dysfunction (1 patient);
Granulocyte dysfunction (1 patient)
HEMATOLOGY:
Bleeding due to vitamin K deficiency (1 patient)
LABORATORY ABNORMALITIES:
Abnormal isoelectric focusing of serum transferrin (type 2 pattern);
Abnormal liver enzymes (1 patient)
MISCELLANEOUS:
Onset at birth;
Death in infancy (1 patient);
Two unrelated patients with slightly different phenotypes have been
reported (last curated August 2013)
MOLECULAR BASIS:
Caused by mutation in the component of oligomeric Golgi complex 6
gene (COG6, 606977.0001)
OMIM Title
*614579 PROGESTIN AND ADIPOQ RECEPTOR FAMILY, MEMBER 6; PAQR6
OMIM Description
CLONING
By searching databases for sequences encoding a 7-transmembrane domain
similar to those of ADIPOR1 (607945) and ADIPOR2 (607946), Tang et al.
(2005) identified PAQR6. The deduced 344-amino acid protein shares
significant similarity with ADIPOR1 and ADIPOR2 only in the central
7-transmembrane domain region. Database analysis revealed a mouse
ortholog, which shares 87% amino acid identity with human PAQR6. RT-PCR
analysis of 20 human tissues detected weak PAQR6 expression in brain
only.
GENE STRUCTURE
Tang et al. (2005) determined that the PAQR6 gene contains 7 coding
exons.
MAPPING
By genomic sequence analysis, Tang et al. (2005) mapped the PAQR6 gene
to chromosome 1q22.
VHLL
| dbSNP name | rs12128785(A,G) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 391104 |
| snpEff Gene Name | C1orf85 |
| EntrezGene Description | von Hippel-Lindau tumor suppressor-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.214 |
RHBG
| dbSNP name | rs144731218(A,G); rs4661039(A,G); rs145536681(C,T); rs189906493(G,T); rs2985714(A,G); rs2985713(G,C); rs55745020(G,C); rs11585523(G,A); rs4641304(A,G); rs2842855(A,G); rs2842854(C,T); rs12039851(G,C); rs116417628(T,C); rs147289415(A,G); rs11585330(A,T); rs2842853(T,A); rs11587027(G,C); rs115546054(T,C); rs2842852(C,T); rs113598440(G,A); rs2245623(G,A); rs115064565(G,A); rs11586833(T,A); rs2842851(C,T); rs2764405(G,T); rs57409696(T,G); rs2842849(C,T); rs3001787(A,G); rs6690897(C,T); rs3001788(A,G); rs942679(C,A); rs139396821(C,G); rs3748569(G,A); rs3748568(G,A); rs752640(G,A); rs752641(T,C); rs1408828(G,A); rs872120(C,T); rs954916(G,T); rs4618959(G,A); rs867921(T,C); rs3790462(G,A); rs6668419(A,G); rs6668731(A,G); rs74116830(C,T); rs6668857(A,G) |
| cytoBand name | 1q22 |
| EntrezGene GeneID | 57127 |
| EntrezGene Description | Rh family, B glycoprotein (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RHBG:NM_001256396:exon3:c.G137A:p.G46D,RHBG:NM_020407:exon2:c.G227A:p.G76D,RHBG:NM_001256395:exon3:c.G20A:p.G7D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7389 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H310 |
| dbNSFP Uniprot ID | RHBG_HUMAN |
| dbNSFP KGp1 AF | 0.278388278388 |
| dbNSFP KGp1 Afr AF | 0.193089430894 |
| dbNSFP KGp1 Amr AF | 0.301104972376 |
| dbNSFP KGp1 Asn AF | 0.101398601399 |
| dbNSFP KGp1 Eur AF | 0.456464379947 |
| dbSNP GMAF | 0.2782 |
| ESP Afr MAF | 0.225374 |
| ESP All MAF | 0.372136 |
| ESP Eur/Amr MAF | 0.447326 |
| ExAC AF | 0.374 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Normal stature
SKELETAL:
Early onset osteoarthritis;
Multiple epiphyseal dysplasia;
[Pelvis];
Arthralgia (hip);
Small proximal femoral epiphyses;
Broad, short femoral neck;
Coxa vara;
High greater trochanter;
[Limbs];
Small, irregular epiphyses (distal femoral, proximal tibiae, distal
radii, distal ulnae);
Mild metaphyseal irregularities (distal femoral, proximal tibiae,
proximal humeri, distal radii, distal ulnae);
Genua valga;
Arthralgias (knees);
Submetaphyseal vertical striations;
[Hands];
Small, irregular epiphyses (first metacarpal);
Delayed carpal ossification;
[Feet];
Delayed tarsal ossification
MISCELLANEOUS:
Genetic heterogeneity (see EDM1 132400, EDM2 600204, EDM3 600969,
EDM4 226900);
Allelic to spondyloepimetaphyseal dysplasia, MATN-3 related (608728);
Allelic to hand osteoarthritis (607850)
MOLECULAR BASIS:
Caused by mutation in the matrilin 3 gene (MATN3, 602109.0001)
OMIM Title
*607079 RHESUS BLOOD GROUP, B GLYCOPROTEIN; RHBG
OMIM Description
CLONING
Using degenerate primers based on the mouse Rhbg sequence, Liu et al.
(2001) cloned a partial human RHBG sequence by PCR of a liver cDNA
library. They obtained a full-length clone by 5-prime and 3-prime RACE.
The deduced 458-amino acid protein has a calculated molecular mass of
about 50 kD and contains a single glycosylation site and 12
transmembrane domains. The human and mouse proteins share 85% sequence
identity, and RHBG is 56% identical to RHCG (605381), a nonerythroid
Rhesus protein. Northern blot analysis revealed 1 major and several
minor transcripts expressed in kidney and multiple transcripts expressed
at moderate levels in liver and ovary. Analysis of fetal tissues
revealed robust expression of several forms in kidney and weak
expression in liver. In mouse, a single band was detected in kidney and
liver. In situ hybridization of mouse tissues revealed Rhbg expression
in dermal hair follicles and papillae. In kidney, it was expressed in
the epithelial linings of convoluted tubules and loops of Henle, and in
liver, it was confined to hepatocytes. Transfected fluorescence-tagged
RHBG localized to the plasma membrane and to some intracellular
granules. Deglycosylation experiments confirmed N-glycosylation of RHBG
expressed in a liver cell line.
BIOCHEMICAL FEATURES
- Crystal Structure
Khademi et al. (2004) determined the crystal structure of the ammonia
channel from the Amt/MEP/Rh protein superfamily at 1.35-angstrom
resolution. The channel spans the membrane 11 times. Two structurally
similar halves span the membrane with opposite polarity. Structures with
and without ammonia or methyl ammonia show a vestibule that recruits
NH4+/NH3, a binding site for NH4+, and a 20 angstrom-long hydrophobic
channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable
interactions for NH3 were seen within the channel and used conserved
histidines. Khademi et al. (2004) concluded that reconstitution of AmtB
into vesicles shows that AmtB conducts uncharged ammonia.
MAPPING
Liu et al. (2001) mapped the RHBG gene to chromosome 1q21.3 by FISH. By
linkage analysis, they mapped the mouse gene to an area of chromosome 3
that shows homology of synteny to human chromosome 1q21.
OR10T2
| dbSNP name | rs60530245(G,A); rs34465440(A,G); rs12062580(A,G); rs6662382(T,C) |
| ccdsGene name | CCDS30895.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128360 |
| EntrezGene Description | olfactory receptor, family 10, subfamily T, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10T2:NM_001004475:exon1:c.C942T:p.S314S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09871 |
| ESP Afr MAF | 0.098502 |
| ESP All MAF | 0.079898 |
| ESP Eur/Amr MAF | 0.070365 |
| ExAC AF | 0.103 |
OR10K2
| dbSNP name | rs137874220(C,T); rs12239443(T,G); rs150834362(A,G); rs34616883(G,A); rs142299510(G,C) |
| ccdsGene name | CCDS30896.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 391107 |
| EntrezGene Description | olfactory receptor, family 10, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10K2:NM_001004476:exon1:c.G864A:p.M288I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0056 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IF99 |
| dbNSFP Uniprot ID | O10K2_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.007717 |
| ESP All MAF | 0.002768 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0007889 |
OR10K1
| dbSNP name | rs78779179(C,T); rs76205582(C,G); rs188612034(C,T); rs76117330(T,C) |
| ccdsGene name | CCDS30897.1 |
| CosmicCodingMuts gene | OR10K1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 391109 |
| EntrezGene Description | olfactory receptor, family 10, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10K1:NM_001004473:exon1:c.C364T:p.R122C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5703 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGX5 |
| dbNSFP Uniprot ID | O10K1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 8.132e-05,8.132e-06 |
OR10R2
| dbSNP name | rs62621279(G,A); rs62642483(A,C); rs61741711(C,T); rs3820678(G,A); rs6679056(A,G); rs1418843(C,T); rs62621280(T,A) |
| ccdsGene name | CCDS30898.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 343406 |
| EntrezGene Description | olfactory receptor, family 10, subfamily R, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10R2:NM_001004472:exon1:c.G91A:p.E31K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0036 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGX6 |
| dbNSFP Uniprot ID | O10R2_HUMAN |
| dbNSFP KGp1 AF | 0.00915750915751 |
| dbNSFP KGp1 Afr AF | 0.0365853658537 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.009183 |
| ESP Afr MAF | 0.022469 |
| ESP All MAF | 0.007766 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0027 |
OR6Y1
| dbSNP name | rs41273491(C,T) |
| ccdsGene name | CCDS30899.1 |
| CosmicCodingMuts gene | OR6Y1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 391112 |
| EntrezGene Description | olfactory receptor, family 6, subfamily Y, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6Y1:NM_001005189:exon1:c.G754A:p.V252I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0004 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGX8 |
| dbNSFP Uniprot ID | OR6Y1_HUMAN |
| dbNSFP KGp1 AF | 0.233516483516 |
| dbNSFP KGp1 Afr AF | 0.0589430894309 |
| dbNSFP KGp1 Amr AF | 0.204419889503 |
| dbNSFP KGp1 Asn AF | 0.386363636364 |
| dbNSFP KGp1 Eur AF | 0.245382585752 |
| dbSNP GMAF | 0.2337 |
| ESP Afr MAF | 0.089877 |
| ESP All MAF | 0.183069 |
| ESP Eur/Amr MAF | 0.230814 |
| ExAC AF | 0.232 |
OR6P1
| dbSNP name | rs116531378(G,A); rs12080815(A,G); rs12081915(A,G) |
| ccdsGene name | CCDS53391.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128366 |
| EntrezGene Description | olfactory receptor, family 6, subfamily P, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6P1:NM_001160325:exon1:c.C553T:p.L185F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0008 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGX9 |
| dbNSFP Uniprot ID | OR6P1_HUMAN |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.0223577235772 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.019509 |
| ESP All MAF | 0.005913 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001582 |
OR10X1
| dbSNP name | rs140204457(A,C); rs16840360(A,G); rs863360(G,A); rs863361(C,T); rs863362(C,T); rs863363(A,G) |
| ccdsGene name | CCDS30900.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128367 |
| EntrezGene Description | olfactory receptor, family 10, subfamily X, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10X1:NM_001004477:exon1:c.T661G:p.S221A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0321 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGY0 |
| dbNSFP Uniprot ID | O10X1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 4.879e-05 |
OR10Z1
| dbSNP name | rs76424590(C,T); rs2427808(A,T) |
| ccdsGene name | CCDS30901.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128368 |
| EntrezGene Description | olfactory receptor, family 10, subfamily Z, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10Z1:NM_001004478:exon1:c.C244T:p.L82F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.004 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGY1 |
| dbNSFP Uniprot ID | O10Z1_HUMAN |
| dbNSFP KGp1 AF | 0.0311355311355 |
| dbNSFP KGp1 Afr AF | 0.134146341463 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03122 |
| ESP Afr MAF | 0.119156 |
| ESP All MAF | 0.041289 |
| ESP Eur/Amr MAF | 0.001395 |
| ExAC AF | 0.012 |
OR6K2
| dbSNP name | rs61322025(A,G); rs111363268(G,A); rs413029(C,T) |
| ccdsGene name | CCDS30902.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 81448 |
| EntrezGene Description | olfactory receptor, family 6, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6K2:NM_001005279:exon1:c.T759C:p.F253F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03627 |
| ESP Afr MAF | 0.137313 |
| ESP All MAF | 0.046901 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 0.013 |
OR6K3
| dbSNP name | rs28568406(G,A); rs857703(G,A); rs73030055(C,T); rs145868292(A,G); rs857705(C,T) |
| ccdsGene name | CCDS30903.2 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 391114 |
| EntrezGene Description | olfactory receptor, family 6, subfamily K, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6K3:NM_001005327:exon1:c.C743T:p.P248L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0036 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGY3 |
| dbNSFP Uniprot ID | OR6K3_HUMAN |
| dbNSFP KGp1 AF | 0.41804029304 |
| dbNSFP KGp1 Afr AF | 0.457317073171 |
| dbNSFP KGp1 Amr AF | 0.419889502762 |
| dbNSFP KGp1 Asn AF | 0.416083916084 |
| dbNSFP KGp1 Eur AF | 0.393139841689 |
| dbSNP GMAF | 0.4187 |
| ESP Afr MAF | 0.475715 |
| ESP All MAF | 0.411502 |
| ESP Eur/Amr MAF | 0.378605 |
| ExAC AF | 0.388 |
OR6K6
| dbSNP name | rs16840974(G,C); rs16840976(C,T); rs16840980(G,A); rs16840986(T,C); rs74122455(A,G); rs16840991(C,T); rs16841009(T,C); rs16841017(C,T); rs74122456(C,T); rs16841025(G,A); rs16841033(A,T); rs16841038(G,A); rs78251441(G,A); rs16841045(A,G) |
| ccdsGene name | CCDS30904.1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128371 |
| EntrezGene Description | olfactory receptor, family 6, subfamily K, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6K6:NM_001005184:exon1:c.G117C:p.E39D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0251 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGW6 |
| dbNSFP Uniprot ID | OR6K6_HUMAN |
| dbNSFP KGp1 AF | 0.032967032967 |
| dbNSFP KGp1 Afr AF | 0.136178861789 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03306 |
| ESP Afr MAF | 0.111212 |
| ESP All MAF | 0.037829 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.01 |
OR6N1
| dbSNP name | rs857824(C,T); rs857825(T,C); rs857826(A,G); rs857827(A,G); rs6666753(G,A); rs1864346(C,T) |
| ccdsGene name | CCDS30905.1 |
| CosmicCodingMuts gene | OR6N1 |
| cytoBand name | 1q23.1 |
| EntrezGene GeneID | 128372 |
| EntrezGene Description | olfactory receptor, family 6, subfamily N, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6N1:NM_001005185:exon1:c.G878A:p.R293H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.085 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGY5 |
| dbNSFP Uniprot ID | OR6N1_HUMAN |
| dbNSFP KGp1 AF | 0.714743589744 |
| dbNSFP KGp1 Afr AF | 0.764227642276 |
| dbNSFP KGp1 Amr AF | 0.790055248619 |
| dbNSFP KGp1 Asn AF | 0.601398601399 |
| dbNSFP KGp1 Eur AF | 0.732189973615 |
| dbSNP GMAF | 0.286 |
| ESP Afr MAF | 0.220381 |
| ESP All MAF | 0.262033 |
| ESP Eur/Amr MAF | 0.283372 |
| ExAC AF | 0.679,8.132e-06 |
OR10J3
| dbSNP name | rs11265165(T,C) |
| ccdsGene name | CCDS30909.1 |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 441911 |
| EntrezGene Description | olfactory receptor, family 10, subfamily J, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10J3:NM_001004467:exon1:c.A704G:p.Q235R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5JRS4 |
| dbNSFP Uniprot ID | O10J3_HUMAN |
| dbNSFP KGp1 AF | 0.211080586081 |
| dbNSFP KGp1 Afr AF | 0.219512195122 |
| dbNSFP KGp1 Amr AF | 0.113259668508 |
| dbNSFP KGp1 Asn AF | 0.428321678322 |
| dbNSFP KGp1 Eur AF | 0.0883905013193 |
| dbSNP GMAF | 0.2112 |
| ESP Afr MAF | 0.152065 |
| ESP All MAF | 0.103414 |
| ESP Eur/Amr MAF | 0.078488 |
| ExAC AF | 0.131 |
OR10J1
| dbSNP name | rs10908721(G,A); rs10908722(G,T); rs12048482(A,G); rs76241483(C,T); rs12409540(T,A) |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 26476 |
| EntrezGene Description | olfactory receptor, family 10, subfamily J, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08724 |
| ESP Afr MAF | 0.221289 |
| ESP All MAF | 0.089728 |
| ESP Eur/Amr MAF | 0.022326 |
| ExAC AF | 0.962 |
OR10J5
| dbSNP name | rs35393723(G,A); rs56786307(T,A); rs4656837(C,T) |
| ccdsGene name | CCDS30910.1 |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 127385 |
| EntrezGene Description | olfactory receptor, family 10, subfamily J, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10J5:NM_001004469:exon1:c.C697T:p.R233W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHC4 |
| dbNSFP Uniprot ID | O10J5_HUMAN |
| dbNSFP KGp1 AF | 0.100732600733 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.14364640884 |
| dbNSFP KGp1 Asn AF | 0.013986013986 |
| dbNSFP KGp1 Eur AF | 0.201846965699 |
| dbSNP GMAF | 0.101 |
| ESP Afr MAF | 0.050613 |
| ESP All MAF | 0.139859 |
| ESP Eur/Amr MAF | 0.185581 |
| ExAC AF | 0.162 |
APCS
| dbSNP name | rs2808661(A,G) |
| ccdsGene name | CCDS1186.1 |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 325 |
| EntrezGene Description | amyloid P component, serum |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | APCS:NM_001639:exon2:c.A432G:p.V144V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.07989 |
| ESP Afr MAF | 0.036314 |
| ESP All MAF | 0.133323 |
| ESP Eur/Amr MAF | 0.183023 |
| ExAC AF | 0.846 |
OMIM Clinical Significance
GU:
Secondary amenorrhea
Thorax:
Galactorrhea
Oncology:
Pituitary adenoma
Radiology:
Enlarged sella turcica
Inheritance:
Autosomal dominant
OMIM Title
*104770 AMYLOID P COMPONENT, SERUM; APCS
;;SERUM AMYLOID P; SAP;;
PENTRAXIN 2, SHORT; PTX2
OMIM Description
CLONING
Mantzouranis et al. (1985) isolated cDNA for the P component of human
serum amyloid and determined the complete sequence of the precursor.
MAPPING
Mantzouranis et al. (1985) assigned the APCS gene to chromosome 1 by
studies of somatic cell hybrids. The gene is probably closely situated
to that for C-reactive protein (CRP; 123260) with which it shows
homology. By in situ hybridization, the assignment was made to segment
1q12-q23 (Floyd-Smith et al., 1985, 1986).
Ionasescu et al. (1987) found a maximum lod score of 3.26 at theta =
0.05 for linkage of APCS with the Duffy blood group locus (110700). A
RFLP marker of APCS was used. The linkage is consistent with the
physical assignment of the 2 loci.
GENETIC VARIABILITY
Woo et al. (1987) found a genetic marker for susceptibility to
amyloidosis in juvenile arthritis: an 8.8-kb RFLP band determined by a
polymorphic DNA site 5-prime to the SAP gene. Homozygosity for the
alternative 5.6-kb band was found in none of 28 amyloid patients. Among
19 juvenile arthritic patients without amyloidosis, the distribution of
the polymorphism was the same as that in the normal group. With a RFLP
of the cloned mouse Sap gene, Whitehead et al. (1988) demonstrated that
the gene maps to chromosome 1 in the same region specified by
quantitative variation in Sap levels. They thought it might be
significant that the same region includes CRP, SAP, and histone genes,
all of which have products that interact with DNA.
BIOCHEMICAL FEATURES
- Crystal Structure
Lu et al. (2008) described the structural mechanism for pentraxin's
binding to Fc-gamma-R and its functional activation of
Fc-gamma-R-mediated phagocytosis and cytokine secretion. The complex
structure between human SAP and Fc-gamma-RIIa (146790) showed a
diagonally bound receptor on each SAP pentamer with both D1 and D2
domains of the receptor contacting the ridge helices from 2 SAP
subunits. The 1:1 stoichiometry between SAP and Fc-gamma-RIIa implied
the requirement for multivalent pathogen binding for receptor
aggregation. Mutational and binding studies showed that pentraxins are
diverse in their binding specificity for Fc-gamma-R isoforms but
conserved in their recognition structure. The shared binding site for
SAP and IgG caused competition for Fc-gamma-R binding and the inhibition
of immune complex-mediated phagocytosis by soluble pentraxins. Lu et al.
(2008) concluded that their results established antibody-like functions
for pentraxins in the Fc-gamma-R pathway, suggested an evolutionary
overlap between the innate and adaptive immune systems, and had
therapeutic implications for autoimmune diseases.
ANIMAL MODEL
Botto et al. (1997) generated mice with a targeted deletion of the SAP
gene. Induction of reactive amyloidosis was retarded in these mice,
demonstrating the participation of SAP in pathogenesis of amyloidosis in
vivo and confirming that inhibition of SAP binding to amyloid fibrils is
an attractive therapeutic target. Pepys et al. (2002) developed a drug
that is a competitive inhibitor of SAP binding to amyloid fibrils. This
palindromic compound also crosslinks and dimerizes SAP molecules,
leading to their very rapid clearance by the liver and thus producing a
marked depletion of circulating human SAP. Pepys et al. (2002) suggested
that this mechanism of drug action potently removes SAP from human
amyloid deposits in tissues and may provide a new therapeutic approach
to both systemic amyloidosis and diseases associated with local amyloid,
including Alzheimer disease (104300) and type 2 diabetes (125853).
Bodin et al. (2010) demonstrated that administration of anti-human SAP
antibodies to mice with amyloid deposits containing human SAP triggers a
potent, complement-dependent, macrophage-derived giant cell reaction
that swiftly removes massive visceral amyloid deposits (see 105200)
without adverse effects. Anti-SAP antibody treatment is clinically
feasible because circulating human SAP can be depleted in patients by
the bis-D-proline compound CPHPC, thereby enabling injected anti-SAP
antibodies to reach residual SAP in the amyloid deposits.
SLAMF9
| dbSNP name | rs146934418(T,G); rs35438196(C,G); rs2840583(C,T); rs1317520(A,G); rs2789418(G,A); rs2249707(C,T); rs148625770(G,A); rs2789417(T,G); rs146654789(T,A); rs2789416(A,C) |
| ccdsGene name | CCDS1191.1 |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 89886 |
| EntrezGene Description | SLAM family member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLAMF9:NM_001146172:exon2:c.A289T:p.I97F,SLAMF9:NM_033438:exon2:c.A289T:p.I97F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5244 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96A28 |
| dbNSFP Uniprot ID | SLAF9_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.011348 |
| ESP All MAF | 0.003844 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0008864 |
PIGM
| dbSNP name | rs2275404(G,A); rs4322226(A,G) |
| cytoBand name | 1q23.2 |
| EntrezGene GeneID | 93183 |
| EntrezGene Description | phosphatidylinositol glycan anchor biosynthesis, class M |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1322 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Congenital primary aphakia;
Microphthalmia;
Anterior segment of eye aplasia;
Absent iris;
Sclerocornea
MISCELLANEOUS:
Allelic to anterior segment mesenchymal dysgenesis (107250)
MOLECULAR BASIS:
Caused by mutation in the forkhead box E3 gene (FOXE3, 601094.0002)
OMIM Title
*610273 PHOSPHATIDYLINOSITOL GLYCAN, CLASS M; PIGM
;;PIGM MANNOSYLTRANSFERASE
OMIM Description
DESCRIPTION
Glycosylphosphatidylinositol (GPI) is a membrane anchor for many cell
surface proteins. It is a complex glycolipid that is attached to
proteins containing a GPI attachment site. The biosynthesis of GPI
involves the sequential addition of sugars to phosphatidylinositol. PIGM
transfers the first mannose from dolichol-phosphate-mannose to
phosphatidylinositol, initiating synthesis of the 3-mannose GPI core
(Maeda et al., 2001).
CLONING
By expression cloning, Maeda et al. (2001) isolated a rat cDNA that
restored the surface expression of GPI-anchored proteins in a
GPI-deficient human B-cell line. By database searching for sequences
similar to the rat cDNA, followed by RT-PCR, Maeda et al. (2001) cloned
human PIGM. The deduced 423-amino acid protein has 10 transmembrane
domains and a conserved DXD motif in a hydrophilic region following the
first transmembrane domain. The DXD motif binds manganese and has a role
in binding nucleotide sugar substrates. Transfection experiments in CHO
cells localized PIGM to the endoplasmic reticulum. Maeda et al. (2001)
showed that the N and C termini of PIGM are cytoplasmic, and that the
DXD motif is on the luminal side.
GENE FUNCTION
Maeda et al. (2001) demonstrated that PIGM is a mannosyltransferase
involved in the synthesis of the GPI core, and that the DXD motif is
essential for enzymatic activity.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PIGM
gene to chromosome 1 (TMAP RH68788).
MOLECULAR GENETICS
Almeida et al. (2006) identified a homozygous mutation in the promoter
region of the PIGM gene (610273.0001) in 3 patients from 2 unrelated
consanguineous families with glycosylphosphatidylinositol deficiency
(610293).
KLHDC9
| dbSNP name | rs11576830(A,C); rs1128750(G,A); rs1128752(C,T) |
| ccdsGene name | CCDS30919.1 |
| CosmicCodingMuts gene | KLHDC9 |
| cytoBand name | 1q23.3 |
| EntrezGene GeneID | 126823 |
| EntrezGene Description | kelch domain containing 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KLHDC9:NM_001007255:exon1:c.A511C:p.S171R,KLHDC9:NM_152366:exon1:c.A511C:p.S171R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0635 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NEP7-2 |
| dbNSFP KGp1 AF | 0.290293040293 |
| dbNSFP KGp1 Afr AF | 0.0873983739837 |
| dbNSFP KGp1 Amr AF | 0.292817679558 |
| dbNSFP KGp1 Asn AF | 0.396853146853 |
| dbNSFP KGp1 Eur AF | 0.34036939314 |
| dbSNP GMAF | 0.2902 |
| ESP Afr MAF | 0.092711 |
| ESP All MAF | 0.218026 |
| ESP Eur/Amr MAF | 0.282309 |
| ExAC AF | 0.262 |
SDHC
| dbSNP name | rs11265589(T,C); rs16832809(A,G); rs78370127(T,C); rs12745115(G,A); rs74956457(G,A); rs16832811(A,C); rs57120973(A,G); rs16832813(C,T); rs75504721(C,T); rs34589411(T,C); rs79322864(T,A); rs78733287(C,A); rs139576530(C,T); rs144308699(T,C); rs75781067(T,C); rs111751106(T,C); rs75630286(G,C); rs56280055(C,T); rs55706531(A,G); rs6679543(A,T); rs75694778(G,C); rs66535289(C,T); rs16832817(A,G); rs16832820(A,G); rs60261157(G,A); rs4256831(T,C); rs16832823(C,T); rs12069801(T,C); rs79861094(T,G); rs60958200(G,T); rs56355322(A,T); rs55981028(A,G); rs58758353(G,A); rs16832824(A,C); rs4255402(C,T); rs4622080(A,G); rs4255403(C,T); rs112946310(C,T); rs55747162(T,C); rs16832826(T,G); rs55961103(A,G); rs56411570(T,C); rs61618989(G,A); rs77341632(A,G); rs10159083(T,C); rs55955603(G,A); rs75003425(C,G); rs74127622(T,G); rs74884887(A,T); rs79290777(T,A); rs76022526(G,A); rs60345130(T,C); rs57884260(C,T); rs60792683(G,T); rs57931640(C,T); rs146670432(G,A); rs4308999(G,A); rs72714971(A,G); rs60078979(G,A); rs77237059(T,G); rs13376158(C,G); rs112762992(C,T); rs13375385(G,A); rs36059328(G,A); rs35949692(G,C); rs55754455(C,G); rs11588994(C,T); rs80041327(T,C); rs74794560(G,A); rs76603937(C,G); rs74127624(A,G); rs4291521(C,T); rs115751802(G,C); rs4233369(G,C); rs4309000(A,G); rs75938678(G,A); rs74127629(G,A); rs74127630(C,T); rs74127632(A,G); rs7530775(T,C); rs115930665(G,A); rs149865440(G,A); rs55864322(A,G); rs74127635(G,T); rs74127636(G,C); rs12741391(A,T); rs34006306(T,G); rs57306652(A,T); rs55809622(T,G); rs11265590(A,G); rs4463689(A,T); rs7412460(T,C); rs4656297(T,G); rs61174143(A,G); rs74127638(T,C); rs74127639(A,G); rs59559479(T,C); rs74127640(A,G); rs74127641(C,T); rs11265591(T,G); rs59747425(C,T); rs58842513(T,C); rs56868836(A,G); rs59774375(C,T); rs79823281(C,T); rs73024045(A,T); rs4282845(G,C); rs75135629(C,T); rs149375851(G,A); rs9970904(C,T); rs11265592(C,T); rs75220658(T,A); rs16832835(G,A); rs76730031(G,C); rs9330294(C,T); rs16832842(T,C); rs17394957(C,T); rs16832846(T,A); rs60982690(C,A); rs35046931(A,G); rs4077290(G,A); rs112714776(G,A); rs74349299(T,A); rs112828491(C,G); rs61326870(G,A); rs56007456(A,G); rs57421557(G,A); rs77671418(A,G); rs35130144(A,G); rs79028594(T,G); rs76555727(G,T); rs151086489(G,A); rs35215727(T,C); rs67307769(C,T); rs35006684(A,T); rs55694670(C,T); rs4481873(A,G); rs61461118(C,T); rs12745476(C,T); rs7547940(T,C); rs57473118(C,T); rs76055913(T,C); rs59191996(T,C); rs58418155(C,T); rs74127656(T,A); rs74127657(C,T); rs60405593(T,G); rs55698724(T,C); rs56028608(C,A); rs61653684(C,T); rs57841279(G,A); rs56290916(A,T); rs114919002(T,C); rs80246038(A,G); rs12757174(T,C); rs112737166(A,G); rs61308286(C,G); rs61447446(C,T); rs58874147(C,T); rs60435895(C,T); rs60799370(A,G); rs74127658(C,T); rs76703105(A,G); rs4631719(C,T); rs4477296(A,T); rs4634926(C,G); rs4469725(G,A); rs113563654(C,A); rs61304797(C,A); rs16832850(G,T); rs60882053(T,G); rs16832851(T,C); rs12730813(A,G); rs4634927(T,C); rs4474277(G,A); rs4319356(G,A); rs34779243(T,C); rs55839314(G,A); rs200843971(T,G); rs55898518(G,C); rs59037769(T,C); rs55783815(T,C); rs60179510(A,T); rs58055613(T,C); rs74653919(T,C); rs8266(G,A); rs4600063(A,G); rs3935401(A,G); rs12239492(C,G) |
| ccdsGene name | CCDS1230.1 |
| cytoBand name | 1q23.3 |
| EntrezGene GeneID | 6391 |
| EntrezGene Description | succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SDHC:NM_003001:exon4:c.G238A:p.A80T,SDHC:NM_001035513:exon2:c.G79A:p.A27T,SDHC:NM_001035512:exon3:c.G136A:p.A46T,SDHC:NM_001278172:exon3:c.G136A:p.A46T,SDHC:NM_001035511:exon4:c.G238A:p.A80T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8555 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q99643-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Teeth];
Misshapen teeth;
Large teeth;
Irregular teeth;
Missing teeth
SKIN, NAILS, HAIR:
[Skin];
Normal sweating;
[Nails];
Dystrophic fingernails;
Dystrophic toenails;
Thin, flat fingernail plates;
[Hair];
Thin body hair;
Fine scalp hair;
Thin scalp hair;
Sparse scalp hair (in some patients);
Hairs can be painlessly plucked with little force;
Sparse or absent eyebrows;
Sparse or absent eyelashes
MISCELLANEOUS:
One Pakistani family reported (last curated November 2012)
OMIM Title
*602413 SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT C, INTEGRAL MEMBRANE PROTEIN,
15-KD; SDHC
;;SUCCINATE DEHYDROGENASE 3, INTEGRAL MEMBRANE SUBUNIT; SDH3;;
SUCCINATE DEHYDROGENASE CYTOCHROME b
OMIM Description
Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme
complex in both the tricarboxylic acid cycle and the aerobic respiratory
chains of mitochondria in eukaryotic cells and prokaryotic organisms.
Complex II in mitochondria has 4 subunits. In order of decreasing
molecular weight, they are the flavoprotein (SDHA; 600857), the
iron-sulfur protein (SDHB; 185470), and 2 integral membrane proteins:
the large cytochrome b, cybL or C, subunit (SDHC) and the small cybS or
D subunit (SDHD; 602690). Of the 5 mitochondrial complexes, I to V,
complex II is the only one with no subunits encoded by the mitochondrial
genome.
CLONING
Hirawake et al. (1997) deduced the amino acid sequences of the large
(cybL, encoded by the SDHC gene) and small (cybS, encoded by the SDHD
gene) subunits of cytochrome b in human liver complex II from cDNAs
isolated by homology probing with mixed primers for the polymerase chain
reaction. The mature cybL and cybS proteins contain 140 and 103 amino
acids, respectively, and show little similarity to the amino acid
sequences of the subunits from other species, in contrast to the highly
conserved features of the flavoprotein (Fp) subunit (encoded by the SDHA
gene) and the iron-sulfur protein (Ip) subunit (encoded by the SDHB
gene).
GENE FUNCTION
Oxidative damage has a role in cellular and organismal aging. Especially
toxic are the reactive oxygen byproducts of respiration and other
biologic processes. A mutant of the mev1 gene of Caenorhabditis elegans
had been found to be hypersensitive to raised oxygen concentrations.
Unlike the wildtype, its life span decreased dramatically as oxygen
concentrations were increased from 1 to 60%. Strains bearing this
mutation accumulated markers of aging (such as fluorescent materials and
protein carbonyls) faster than the wildtype. Ishii et al. (1998) showed
that mev1 encodes a subunit of the enzyme succinate dehydrogenase
cytochrome b, which is a component of complex II of the mitochondrial
electron transport chain. They found that the ability of complex II to
catalyze electron transport from succinate to ubiquinone was compromised
in the mev1 animals. This was thought to cause an indirect increase in
superoxide levels, which in turn leads to oxygen hypersensitivity and
premature aging. The results indicated that mev1 governs the rate of
aging by modulating the cellular response to oxidative stress. This
particular mutation in the mev1 mutant was shown to be a missense change
resulting in a glycine to glutamic acid substitution in cyt1. The
identity of the mev1 gene was established through its sequence homology
to bovine succinate dehydrogenase cytochrome b(560) (Cochran et al.,
1994). The wildtype gene introduced into the mev1 strain resulted in
rescue from the hypersensitivity to raised oxygen concentrations. This
was thought to be the first mutation in the SDH cytochrome b subunit to
be identified in animals.
GENE STRUCTURE
Elbehti-Green et al. (1998) found that the SDHC gene contains 6 exons.
MAPPING
By study of Chinese hamster-human somatic cell hybrids in which the
hamster parental cell was deficient in succinate dehydrogenase,
Mascarello et al. (1980) showed that the presence of human chromosome 1
correlated with restoration of SDH activity. SDH consists of 2
dissimilar peptides of 70,000 and 30,000 Da. These may be determined by
separate genes or derived from a single proenzyme. It was presumed that,
because it mapped to chromosome 1, the iron sulfur protein subunit gene
complemented the deficiency in the mutant. Oostveen et al. (1995) found
that in fact it was protein from the bovine SDH3 gene (encoding 1 of the
2 integral membrane proteins) that complemented the hamster mutation.
The authors localized the human SDH3 gene to the short arm of chromosome
one, within 1 to 2 Mb from the centromere. There are therefore 2 genes
for complex II on human chromosome 1. Additionally, Oostveen et al.
(1995) stated that Southern analyses of human genomic DNA suggested that
there are multiple SDH3 genes or pseudogenes.
By fluorescence in situ hybridization (FISH), Hirawake et al. (1997)
mapped the genes for cybL and cybS to 1q21 and 11q23, respectively.
Elbehti-Green et al. (1998) confirmed the assignment of the SDHC gene to
1q21 by FISH.
MOLECULAR GENETICS
Defective mitochondrial respiratory enzymes cause myopathy and
neurologic diseases in humans, with pathologies that include precocious
aging. Compared with defects in the other 4 complexes, abnormalities in
complex II are rare and clinical presentation varies among individuals
(Riggs et al., 1984; Martin et al., 1988; Bourgeron et al., 1995; Taylor
et al., 1996).
Since mutations in the SDHD gene, encoding the small subunit of
cytochrome b in mitochondrial complex II, had been shown to be the site
of mutation causing paraganglioma type 1 (PGL1; 168000), Niemann and
Muller (2000) sought mutations in SDHC, SDHA, and SDHB in a family with
the non-maternally imprinted paraganglioma type 3 (PGL3; 605373). They
found a G-to-A transition in exon 1 of SDHC in all affected individuals
(602413.0001).
Baysal et al. (2004) described a family with PGL3 in which an 8,372-bp
deletion in the SDHC gene (602413.0003) was transmitted both maternally
and paternally, without evidence of genomic imprinting. They also
identified the deletion in an unrelated sporadic case. They concluded
that hereditary paraganglioma with imprinted transmission is restricted
to SDHD among complex II genes.
In 2 families with paraganglioma and gastric stromal sarcoma (606864),
McWhinney et al. (2007) identified 2 different germline mutations in the
SDHC gene, respectively (see, e.g., 602413.0004). In 4 other families
with the dyad, the authors also found germline mutations in the SDHB
(see, e.g., 185470.0012 and 185470.0013) and SDHD (602690.0027) genes,
respectively. None of the patients had mutations in the KIT (164920) or
PDGFRA (173490) genes, which have been associated with gastrointestinal
tumors.
Janeway et al. (2011) identified a germline mutation in the SDHC gene
(602413.0004) in a 16-year-old girl with sporadic occurrence of
gastrointestinal stromal tumor (GIST; 606764).
HSPA6
| dbSNP name | rs35740080(G,C); rs72633678(A,T); rs404508(T,C); rs753856(C,G) |
| cytoBand name | 1q23.3 |
| EntrezGene GeneID | 3310 |
| snpEff Gene Name | FCGR2A |
| EntrezGene Description | heat shock 70kDa protein 6 (HSP70B') |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1341 |
OMIM Clinical Significance
Cardiac:
Congenital heart malformation;
Hypoplastic left heart syndrome
Inheritance:
Autosomal dominant vs. multifactorial
OMIM Title
*140555 HEAT-SHOCK 70-KD PROTEIN 6; HSPA6
;;HSP70B-PRIME
OMIM Description
CLONING
HSPA6 (HPS70B-prime) is a stress-induced heat-shock gene encoding a
basic 70-kD protein. It is a close homolog of HSPA7 (140556), formerly
designated HSP70B (Leung et al., 1990).
Leung et al. (1992) stated that both HSPA6 and HSPA7 represent
functional genes, as determined by analyses of mRNA from heat-shocked
human cells using sequence-specific oligonucleotides. After heat shock
at 45 degrees C, HSPA6 mRNA was detected in fibroblast, HeLa, and Daudi
cells, whereas HSPA7 mRNA was detected only in fibroblasts.
Parsian et al. (2000) found that HSPA6 and HSPA7 share 98% nucleotide
identity through their putative coding regions. However, HSPA7 was
predicted to lack protein-coding potential. Orthologs of HSPA6 and HSPA7
were not detected in mouse by Southern blot analysis.
GENE FUNCTION
Using RT-PCR, Parsian et al. (2000) detected the expression of HSPA6 and
HSPA7 only after heat shock in human W138 and HeLa cells. HSPA6 was more
strongly expressed following heat shock.
MAPPING
By hybridization analyses of a somatic cell hybrid DNA panel, Leung et
al. (1992) found that HSPA6 and HSPA7 localize to 1q. A BamHI
polymorphism in the HSPA7 gene was present in a predominantly Asian
population.
Grosz et al. (1992) concluded that bovine HSP70-4 is homologous to HSPA6
or HSPA7 because it is syntenic with amylase-1 (104700) and PGM1
(171900), both of which are on human chromosome 1.
Using FISH, Parsian et al. (2000) mapped the HSPA6 and HSPA7 genes to
within 5 to 10 Mb of each other on chromosome 1q23.1.
Brzustowicz et al. (2002) stated that the HSPA6 and HSPA7 genes are
located on chromosome 1q22, according to sequence data provided by the
Human Genome Project, and are in close proximity to a susceptibility
locus for schizophrenia (604906).
RPL31P11
| dbSNP name | rs114384494(C,T); rs61804205(T,C); rs1256287(A,G); rs1256288(C,G); rs6686673(T,C) |
| cytoBand name | 1q23.3 |
| EntrezGene GeneID | 641311 |
| EntrezGene Description | ribosomal protein L31 pseudogene 11 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01791 |
SH2D1B
| dbSNP name | rs164126(G,A); rs16861748(C,A); rs164125(G,A); rs16861751(G,A); rs17852003(C,T); rs34001279(G,T); rs164124(G,A); rs164123(A,G); rs61809468(G,T); rs164122(C,T); rs348625(G,C); rs12139643(G,C); rs72702031(A,G); rs61809469(G,A); rs61809470(G,C); rs57962498(T,C); rs189436(T,A); rs2655730(A,T); rs2655729(A,G); rs139953958(G,A); rs10753802(T,C); rs2632549(C,A); rs185913243(T,G); rs3122549(C,T); rs3121196(G,A); rs11589974(G,A); rs2265613(G,A); rs7522371(G,C); rs73031063(C,T); rs66877709(C,T); rs351449(G,A); rs351450(C,T); rs12746024(C,A); rs59214620(T,C); rs55740620(C,A); rs369301298(G,C); rs351451(G,A); rs351452(A,T); rs73031072(G,A); rs351453(T,C); rs351454(C,G); rs351455(G,A); rs11576975(T,C); rs351456(C,T); rs351457(T,C); rs367887649(C,T); rs415883(G,T); rs453579(G,A); rs72703856(G,A); rs2250489(C,T); rs348629(G,A); rs238773(G,T); rs164137(C,T); rs348628(T,A); rs164406(C,T); rs164136(C,T); rs164135(G,T); rs164134(C,T); rs115177220(A,C); rs164133(G,C); rs35688243(A,G); rs12745630(C,G) |
| ccdsGene name | CCDS30928.1 |
| cytoBand name | 1q23.3 |
| EntrezGene GeneID | 117157 |
| EntrezGene Description | SH2 domain containing 1B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SH2D1B:NM_053282:exon4:c.C366A:p.N122K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6035 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O14796-2 |
| dbNSFP KGp1 AF | 0.10347985348 |
| dbNSFP KGp1 Afr AF | 0.0325203252033 |
| dbNSFP KGp1 Amr AF | 0.121546961326 |
| dbNSFP KGp1 Asn AF | 0.138111888112 |
| dbNSFP KGp1 Eur AF | 0.114775725594 |
| dbSNP GMAF | 0.1028 |
| ESP Afr MAF | 0.039265 |
| ESP All MAF | 0.088421 |
| ESP Eur/Amr MAF | 0.113605 |
| ExAC AF | 0.107,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608510 SH2 DOMAIN-CONTAINING 1B; SH2D1B
;;EWS/FLI1-ACTIVATED TRANSCRIPT 2; EAT2
OMIM Description
DESCRIPTION
By binding phosphotyrosines through its free SRC (190090) homology-2
(SH2) domain, EAT2 regulates signal transduction through receptors
expressed on the surface of antigen-presenting cells (Morra et al.,
2001).
CLONING
By representational difference analysis of NIH 3T3 mouse fibroblasts
expressing the EWS (133450)/FLI1 (193067) fusion protein, an aberrant
transcription factor, Thompson et al. (1996) cloned mouse Eat2. The
deduced 132-amino acid Eat2 protein consists principally of an SH2
domain flanked by short N and C termini. Northern blot analysis detected
a major transcript of about 1.5 kb in mouse spleen and lung, and these
tissues also expressed larger transcripts at weaker levels. A band of
about 1.2 kb was expressed at low levels in liver, skeletal muscle, and
kidney. No expression was detected in heart, brain, and testis. RT-PCR
detected EAT2 transcripts in normal human peripheral blood lymphocytes
and thymus. Expression was also detected in Ewing sarcoma (612219) cell
lines containing either EWS/FLI1 or EWS/ERG (165080) fusion genes, as
well as in some tumor cell lines without the EWS/FLI1 fusion gene.
Morra et al. (2001) cloned human EAT2 by PCR of a splenocyte cDNA
library. The deduced protein contains 132 amino acids. RT-PCR detected
Eat2 in 2 mouse B-leukemia cell lines, purified B lymphocytes and
macrophages, and peritoneal exudate macrophages from mice lacking T and
B cells. Expression was not detected in thymus or a mouse T-leukemia
cell line. Human EAT2 was amplified in 5 of 6 B-lymphoma or
lymphoblastoid cell lines tested.
Tangye et al. (2002) cloned EAT2 from a spleen cDNA library. The EAT2
protein shares 64% and 45% identity with mouse Eat2 and human SAP
(300490), respectively, and it has a calculated molecular mass of 15.3
kD.
GENE FUNCTION
Thompson et al. (1996) created NIH 3T3 cells containing a
transformation-competent, inducible EWS/FLI1 transgene. Abundant
EWS/FLI1 transcripts were detected within 2 hours of induction, and
endogenous Eat2 expression was detected 4 hours after induction.
Expression of Eat2 also correlated with transformation of NIH 3T3 cells
by chimeric proteins related to EWS/FLI1, but not by unrelated genes. By
in vitro binding assays, Thompson et al. (1996) demonstrated that mouse
Eat2 bound phosphotyrosine in a manner dependent on the invariant
arginine in the FLVRES motif of the SH2 domain.
Using a variation of the yeast 2-hybrid assay, Morra et al. (2001)
determined that mouse Eat2 bound to the cytoplasmic tail of the
lymphocyte antigen CD150 (603492). Immunoprecipitation of cotransfected
COS-7 cells confirmed this interaction and indicated that Eat2 also
bound the related receptors CD84 (604513), CD229 (600684), and CD244
(605554). Eat2 binding blocked SHP2 (176876) recruitment to these
receptors. Eat2 did not bind CD150 and CD229 when the critical tyrosine
was mutated to phenylalanine. Overexpression of Eat2 induced tyrosine
phosphorylation of the CD150-related receptors.
Most CD2 family proteins interact with SAP via specific tyrosine-based
motifs, but B cells that express CD84 do not express SAP. Therefore,
Tangye et al. (2002) predicted that a functional SAP homolog exists in B
lymphocytes and suggested EAT2 as a candidate. Immunoprecipitation
analysis of CD84/SAP- and CD84/EAT2-transfected cells showed that
tyrosine-phosphorylated CD84 can associate with both SAP and EAT2.
BIOCHEMICAL FEATURES
Morra et al. (2001) analyzed crystals of mouse Eat2 grown with a
14-amino acid segment identical to the cytoplasmic tail of human CD150
with phosphorylated tyr281. The phosphotyrosine was coordinated in an
unusual 3-pronged fashion in which the conventional 2-pronged
interaction observed in other SH2 domain complexes was present with a
third interaction with amino acids N-terminal to tyr281.
GENE STRUCTURE
Morra et al. (2001) determined that the EAT2 gene contains 4 exons and
spans about 14.7 kb. It also has an alternative exon 3a. The 5-prime UTR
contains a canonical TATA box, and the 3-prime UTR contains 3 ARE
recognition sites.
MAPPING
By FISH, Thompson et al. (1996) mapped the EAT2 gene to chromosome 1q22.
LOC100422212
| dbSNP name | rs6693661(T,C); rs7546952(A,G); rs12404157(G,A); rs35083841(C,T); rs11584957(C,T) |
| cytoBand name | 1q23.3 |
| snpEff Gene Name | RP11-408E1.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2782 |
ANKRD36BP1
| dbSNP name | rs2205699(C,A); rs2205698(A,G); rs3795609(T,G); rs2205697(G,A) |
| cytoBand name | 1q24.2 |
| EntrezGene GeneID | 84832 |
| snpEff Gene Name | SFT2D2 |
| EntrezGene Description | ankyrin repeat domain 36B pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.421 |
F5
| dbSNP name | rs6427196(C,G); rs372473794(G,T); rs2187952(G,A); rs75764442(A,G); rs9332678(A,T); rs2040444(G,A); rs76510731(T,A); rs4656685(C,T); rs9332672(G,A); rs3820060(T,G); rs371357967(C,G); rs6670407(G,T); rs2420369(T,A); rs9332667(G,C); rs9332666(G,C); rs9332665(T,G); rs3766103(C,T); rs368184352(T,C); rs2227244(T,C); rs2213866(A,G); rs2213867(T,C); rs80030498(G,A); rs9332658(A,G); rs77136555(T,G); rs2420370(G,C); rs6682179(T,C); rs9332655(A,G); rs9332653(G,A); rs12749055(T,G); rs370366327(G,A); rs9332651(G,A); rs2420371(G,A); rs114542453(G,A); rs9332643(C,T); rs9332640(G,C); rs142282880(A,T); rs12131397(A,C); rs2301515(C,T); rs115191744(C,A); rs2301517(T,C); rs9332635(T,C); rs9332634(G,C); rs114407237(A,G); rs116720755(A,G); rs76904241(G,C); rs9332628(T,G); rs9332627(G,A); rs9332624(T,G); rs2420372(A,G); rs2420373(C,T); rs372987550(A,G); rs9332623(A,G); rs140267827(T,G); rs6009(T,C); rs6008(G,A); rs6030(T,C); rs2157581(A,G); rs2187953(A,C); rs916438(T,A); rs9332620(C,T); rs9332619(G,A); rs6427197(C,A); rs6701330(T,C); rs12040141(A,G); rs369673052(A,G); rs140678900(C,T); rs6670393(A,C); rs147838710(C,T); rs375021245(C,T); rs1121789(A,C); rs12042044(A,C); rs4656187(C,T); rs4656687(T,C); rs7535409(A,G); rs10800453(T,A); rs1557570(G,T); rs75548771(C,T); rs1557572(A,C); rs3766109(A,T); rs114462822(T,C); rs10800454(A,G); rs9332607(G,A); rs9287090(G,A); rs1800594(A,G); rs368369078(C,T); rs6032(T,C); rs4525(T,C); rs4524(T,C); rs6021(T,C); rs6017(A,G); rs2239851(C,A); rs2239852(C,T); rs6675244(T,C); rs6662593(G,A); rs6686805(A,C); rs6662696(G,A); rs9332600(C,T); rs138230297(C,T); rs9332599(G,A); rs9287092(C,A); rs1018827(A,G); rs9332596(A,G); rs9332595(G,C); rs9332593(C,T); rs9332592(G,A); rs929130(G,A); rs9332591(G,A); rs9332590(A,G); rs370759289(C,A); rs3766110(A,C); rs114485509(A,T); rs3766111(T,C); rs367850262(G,A); rs3766112(C,G); rs3766113(A,G); rs369059896(G,T); rs1894694(T,C); rs6672595(C,T); rs13306345(T,A); rs13306344(G,A); rs79186925(T,C); rs370208599(G,A); rs12143223(G,C); rs67790508(T,G); rs12121164(C,T); rs12046953(G,A); rs10919186(G,C); rs12026997(C,T); rs12044669(A,G); rs1894695(C,G); rs2420374(G,A); rs1894696(C,T); rs7534224(G,A); rs200479468(C,A); rs58875232(T,C); rs10800455(A,G); rs6025(T,C); rs10800456(A,G); rs10158595(C,T); rs2420375(G,C); rs2420376(G,A); rs2420377(G,A); rs9332586(G,A); rs2298909(A,T); rs721161(C,G); rs2213868(G,A); rs9332582(C,T); rs368800527(G,C); rs10919191(T,A); rs113807710(T,C); rs6679295(G,C); rs7533223(G,C); rs6427198(A,T); rs181325466(C,T); rs6427199(G,A); rs6657551(A,G); rs6427200(G,A); rs111393903(T,A); rs2239853(T,C); rs2239854(G,A); rs9332578(G,A); rs4656688(C,T); rs4656689(A,G); rs4656188(G,T); rs1894698(A,G); rs1894699(C,G); rs1981491(A,G); rs3766117(T,C); rs7548857(C,T); rs9332570(C,G); rs9332569(C,A); rs6023(G,A); rs6012(C,T); rs6427201(C,T); rs6427202(C,T); rs6427203(A,C); rs7529700(A,G); rs141800405(G,A); rs6022(C,A); rs6029(C,T); rs7545236(A,C); rs7534848(T,C); rs7522982(C,G); rs9332562(T,C); rs1894700(G,C); rs1894701(T,C); rs9332559(G,A); rs1894702(G,T); rs3766119(C,A); rs3766120(G,A); rs3766121(C,A); rs3820061(T,C); rs7540556(T,C); rs4656690(T,C); rs10919192(C,T); rs10919193(C,T); rs4268401(T,C); rs74443587(A,G); rs7554566(A,G); rs7544132(T,A); rs61805771(A,G); rs6678795(G,A); rs61805772(A,T); rs35852972(A,C); rs724509(T,A); rs724508(G,T); rs724507(T,C); rs2236871(T,C); rs2236870(G,A); rs77450480(A,G); rs76130893(A,C); rs2040442(A,G); rs2040443(T,A); rs2236869(T,G); rs6685578(C,G); rs17521545(G,T); rs12402407(A,C); rs12402701(T,G); rs12403625(G,A); rs16862361(A,G); rs7553699(T,G); rs2213869(T,C); rs7542088(C,A); rs7542345(G,A); rs7542281(C,T); rs2187954(G,C); rs9332556(G,T); rs2187955(G,A); rs9332554(G,A); rs9332553(C,A); rs6670678(A,G); rs9332546(C,T); rs9287095(G,A); rs2298908(C,T); rs2298907(C,G); rs2298906(T,G); rs2298905(C,T); rs7528914(A,C); rs9332542(G,A); rs111768355(C,T); rs2227245(C,T); rs2213870(C,A); rs2213871(A,G); rs9332533(T,C); rs9332531(A,C); rs9332529(G,A); rs6691048(C,T); rs9332517(G,A); rs9332516(G,T); rs115715160(T,C); rs9332513(C,T); rs112306566(G,A); rs12406092(G,A); rs10800457(C,A); rs2213873(G,A); rs6662176(T,A); rs12567645(C,A); rs35902866(C,T); rs11587922(C,T); rs4656692(A,G); rs4656693(C,T); rs4656694(C,T); rs114646797(G,A); rs4656695(G,T); rs116443202(C,T); rs34580812(C,G); rs9332511(G,A); rs9332510(G,A); rs16862374(T,A); rs16862375(A,C); rs16862377(A,C); rs12755775(G,A); rs16862380(A,T); rs77417616(A,G); rs17587779(G,C); rs75539640(C,T); rs10489184(T,C); rs113843429(T,C); rs10753787(T,C); rs10800458(G,T); rs9332504(C,G); rs6703462(G,T); rs6703487(C,T); rs6703865(G,A); rs6028(T,C); rs6664922(C,G); rs3753305(C,G); rs10919197(T,G) |
| ccdsGene name | CCDS1281.1 |
| cytoBand name | 1q24.2 |
| EntrezGene GeneID | 2153 |
| EntrezGene Description | coagulation factor V (proaccelerin, labile factor) |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=2153&%3Brs=6025|http://www.ncbi.nlm.nih.gov/omim/227400,600880|http://omim.org/entry/612309#0001|http://omim.org/entry/227400#0001|http://www.ncbi.nlm.nih.gov/pubmed?term=22672568 |
| Annovar Function | F5:NM_000130:exon10:c.A1601G:p.Q534R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6605 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=2153&%3Brs=6025|http://www.ncbi.nlm.nih.gov/omim/227400,600880|http://omim.org/entry/612309#0001|http://omim.org/entry/227400#0001|http://www.ncbi.nlm.nih.gov/pubmed?term=22672568 |
| dbNSFP KGp1 AF | 0.994047619048 |
| dbNSFP KGp1 Afr AF | 1.0 |
| dbNSFP KGp1 Amr AF | 0.991712707182 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.986807387863 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.004312 |
| ESP All MAF | 0.021375 |
| ESP Eur/Amr MAF | 0.030116 |
| ExAC AF | 0.979 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Neonatal vitreous hemorrhages
CARDIOVASCULAR:
[Vascular];
Superficial thrombophlebitis;
Deep venous thrombosis;
Intraabdominal venous thrombosis
RESPIRATORY:
[Lung];
Pulmonary embolism
SKIN, NAILS, HAIR:
[Skin];
Neonatal purpura fulminans
NEUROLOGIC:
[Central nervous system];
Spastic cerebral palsy;
Developmental delay;
Seizures;
Periventricular hemorrhagic infarction
LABORATORY ABNORMALITIES:
Plasma protein C deficiency
MISCELLANEOUS:
May be lethal in infancy if untreated;
Variable severity;
Occasional late-onset of symptoms with homozygosity (e.g. 612283.0005
protein C deficiency, homozygous);
See also autosomal dominant form (176860)
MOLECULAR BASIS:
Caused by mutation in the protein C gene (PROC, 612283.0003)
OMIM Title
*612309 COAGULATION FACTOR V; F5
;;PROTEIN C COFACTOR; PCCF;;
ACTIVATED PROTEIN C COFACTOR;;
APC COFACTOR;;
LABILE FACTOR
FACTOR V LEIDEN, INCLUDED
OMIM Description
DESCRIPTION
The F5 gene encodes coagulation factor V, a large 330-kD plasma
glycoprotein that circulates with little or no activity. Factor V is
converted to the active form, factor Va, by thrombin (F2; 176930), which
generates a heavy chain and a light chain held together by calcium ions.
Activated factor V serves as an essential protein in the coagulation
pathway and acts as a cofactor for the conversion of prothrombin to
thrombin by factor Xa (F10; 613872). Factor Va is inactivated by
activated protein C (PROC; 612283) (Kane and Davie, 1986; Cripe et al.,
1992).
CLONING
Kane et al. (1987) isolated clones corresponding to a portion of the F5
gene from a human hepatocellular carcinoma (Hep G2) cDNA library. The
deduced 938-residue partial protein was composed of a 651-residue light
chain and a 287-residue connecting region. The amino acid sequence of
the light chain region was about 40% identical to the corresponding
region of factor VIII (F8; 300841).
Jenny et al. (1987) isolated a complete cDNA for factor V from a human
fetal liver cDNA library and determined that the deduced amino acid
sequence consists of 2,224 residues including a 28-residue leader
peptide. The triplicated A domain and duplicated C domain showed
approximately 40% identity with the corresponding domains in factor
VIII. Factor V contains 37 potential N-linked glycosylation sites, 25 of
which are in the B domain, and a total of 19 cysteine residues.
GENE STRUCTURE
Cripe et al. (1992) determined that the F5 gene contains 25 exons.
MAPPING
Riddell et al. (1987) and Wang et al. (1988) mapped the F5 gene to
chromosome 1 by Southern hybridization to somatic cell hybrid DNAs. By
in situ hybridization, F5 was regionalized to 1q21-q25. Dahlback et al.
(1988) confirmed the assignment of F5 to human chromosome 1 by
hybridization studies of a panel of human-rodent somatic cell hybrids,
and mapped the rat gene to chromosome 13. Combining linkage data with
the physical assignment of the F5 locus, McAlpine et al. (1989)
concluded that F5 lies in the 1q23 band. They found that F5 and AT3
(107300) are closely linked, with F5 located distal to AT3.
GENE FUNCTION
Bauer (1994) reviewed the significance of the APC cofactor in the
protein C anticoagulant pathway and illustrated it with a useful
diagram.
BIOCHEMICAL FEATURES
- Crystal Structure
Macedo-Ribeiro et al. (1999) determined 2 crystal structures of the C2
domain of human factor Va. The conserved beta-barrel framework provides
a scaffold for 3 protruding loops, one of which adopts markedly
different conformations in the 2 crystal forms. Macedo-Ribeiro et al.
(1999) proposed a mechanism of calcium-independent, stereospecific
binding of factors Va and VIIIa to phospholipid membranes on the basis
of (1) immersion of hydrophobic residues at the apices of these loops in
the apolar membrane core; (2) specific interactions with
phosphatidylserine head groups in the groove enclosed by these loops;
and (3) favorable electrostatic contacts of basic side chains with
negatively charged membrane phosphate groups.
MOLECULAR GENETICS
In discussing the good and bad aspects of factor V functionality and
durability, Mann and Kalafatis (2003) referred to factor V as a
combination of Dr. Jekyll and Mr. Hyde. Mutations resulting in the
absence or dysfunction of activated factor V lead to hemorrhagic
disease, whereas mutations resulting in excessive longevity of the
active species are associated with thrombosis. Factor V is thus required
for a good outcome (Dr. Jekyll) but also is a potential source of
disaster (Mr. Hyde).
- Factor V Deficiency
In a patient with mild bleeding due to factor V deficiency (227400),
Guasch et al. (1998) identified a homozygous mutation in the F5 gene
(612309.0004).
In a Korean woman with bleeding due to factor V deficiency, van Wijk et
al. (2001) identified compound heterozygosity for 2 mutations in the F5
gene (612309.0006; 612309.0007).
- Thrombophilia Due to Activated Protein C Resistance
In affected members of a family with thrombophilia due to APC resistance
(THPH2; 188055), Bertina et al. (1994) identified a heterozygous R506Q
mutation (612309.0001) in the F5 gene. This variant was referred to as
factor V Leiden, named after the town in the Netherlands where Bertina
et al. (1994) discovered the defect. Bertina et al. (1994) identified
the same R506Q mutation in 56 of 64 patients with APC-resistant
thrombosis from a larger cohort of 301 consecutive patients with a first
episode of deep vein thrombosis. The mutation was homozygous in 6
patients.
Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive
patients with recurrent thromboembolism.
Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and
7% of the Swedish population carried the mutant R506Q allele. The high
frequency of a single factor V mutation in diverse groups of people
raised the question of whether positive selection pressure was involved
in maintaining it in the population. Majerus (1994) suggested that a
slight thrombotic tendency may confer some advantage in fetal
implantation.
In a patient with thrombophilia due to APC resistance, Williamson et al.
(1998) identified a heterozygous R306T mutation in the F5 gene
(612309.0003). The mutation was also present in a first-degree relative
with APC resistance.
In 2 Caucasian brothers with thrombophilia due to APC resistance,
Mumford et al. (2003) identified compound heterozygosity for 2 mutations
in the F5 gene: a missense mutation (I359T; 612309.0013) and a nonsense
mutation (E119X; 612309.0014). Both brothers developed spontaneous
venous thromboses in the second decade of life. One presented at the age
of 14 years with thrombosis of the right femoral vein and inferior vena
cava; an older brother had recurrent episodes of femoral vein thrombosis
from the age of 18 years and was managed with long-term warfarin
therapy. Heterozygous family members were asymptomatic.
- Pseudohomozygosity for Factor V Leiden
Castaman et al. (1997) and Castoldi et al. (1998) described patients
with thrombosis who were compound heterozygous for factor V Leiden and a
factor V deficiency allele. The patients were referred to as having
'pseudohomozygosity' for factor V Leiden, since they presented with
venous thromboembolic events. Although the resistance to APC is in the
range of factor V Leiden homozygotes, genotyping demonstrated
heterozygosity for the factor V Leiden mutation. Those with F5 null
mutations showed only factor V Leiden molecules, and those with
deficient mutations show decreased levels of F5 that were insufficient
to protect against thrombosis.
Zehnder et al. (1999) identified a man with thrombophilia who was
compound heterozygous for factor V Leiden and a null allele of the F5
gene (612309.0005). The patient had 50% of normal levels of F5, all of
which was of the Leiden type; hence he was pseudohomozygous for factor V
Leiden.
Among 7 families with 11 pseudohomozygotes and 45 relatives, Castaman et
al. (1999) found that 16 relatives were heterozygous factor V Leiden
carriers, 9 showed partial factor V deficiency, and 20 had no
abnormalities. Deep vein thrombosis occurred in 4 of 11 (36.3%)
pseudohomozygous patients, in 6 of 16 (37.4%) factor V Leiden carriers,
and in 1 of 20 (5%) normal relatives. Castaman et al. (1999) concluded
that pseudohomozygosity for APC resistance carries a significantly
higher risk for venous thromboembolism in comparison to normal subjects,
but probably not in comparison to heterozygous FV Leiden carriers.
- Other Disease Associations
Faisel et al. (2004) analyzed the allele and genotype frequencies of 2
F5 polymorphisms, M385T, R485K, and the R506Q Leiden mutation in 133
Finnish women with preeclampsia (189800) and 112 controls. There were
statistically significant differences in R485K allele (p = 0.003) and
genotype (p = 0.03) frequencies between patients and controls. The A
allele of R485K was overrepresented among the patients (12%) compared to
the controls (4%), with an odds ratio (OR) of 2.8 (95% CI, 1.2-6.2) for
combined A genotypes. Faisel et al. (2004) concluded that genetic
variations in the factor V gene other than the Leiden mutation may play
a role in disease susceptibility.
Hao et al. (2004) conducted a large-scale case-control study exploring
the associations of 426 single-nucleotide polymorphisms (SNPs) with
preterm delivery in 300 mothers with preterm delivery and 458 mothers
with term deliveries. Twenty-five candidate genes were included in the
final haplotype analysis, and there was a significant association
between a F5 gene haplotype and preterm delivery.
HISTORY
Hayward et al. (1996) described an autosomal dominant bleeding disorder
in a Quebec family that was associated with reduced to normal platelet
counts, defective epinephrine aggregation, and multiple glycoprotein
abnormalities. This disorder had been previously designated 'factor V
(Quebec)' by Tracy et al. (1984) because of abnormalities in platelet
factor V. However, Hayward et al. (1996, 1997) and Janeway et al. (1996)
determined that, although platelet factor V was indeed deficient in this
disorder, several other platelet alpha-granular proteins were also
deficient. The findings indicated that this was not a primary defect of
factor V, but rather a distinct entity, now referred to as the Quebec
platelet disorder (601709).
ANIMAL MODEL
Cui et al. (1996) found that approximately half of homozygous factor
V-null mouse embryos died at embryonic days 9 to 10, possibly as a
result of an abnormality in the yolk-sac vasculature. The remaining
homozygous deficient mice progressed normally to term, but died from
massive hemorrhage within 2 hours of birth. Considered together with the
milder phenotypes generally associated with deficiencies of other
clotting factors, the findings demonstrated the primary role of the
common coagulation pathway and the absolute requirement for functional
factor V for prothrombinase activity. The results also provided direct
evidence for the existence of other critical hemostatic functions for
thrombin in addition to fibrin clot formation, and identified a
previously unrecognized role for the coagulation system in early
mammalian development.
Cui et al. (2000) found that mice carrying the R504Q mutation,
homologous to human factor V Leiden (R506Q), were viable and fertile and
exhibited normal survival. Compared with wildtype mice, adult homozygous
mice demonstrated a marked increase in spontaneous tissue fibrin
deposition. On a mixed genetic background, homozygous mice developed
disseminated intravascular thrombosis in the perinatal period, resulting
in significant mortality shortly after birth. Cui et al. (2000)
suggested that these results may explain the high degree of conservation
of the R504/R506 activated protein C cleavage site within factor V among
mammalian species.
SELE
| dbSNP name | rs4786(T,C); rs5359(T,C); rs5357(A,G); rs3917437(G,A); rs3917436(A,G); rs3917435(A,T); rs3917434(C,T); rs5356(A,G); rs3917432(T,A); rs3917430(G,C); rs5355(G,A); rs3917428(G,A); rs3917427(A,G); rs3917425(A,T); rs5368(G,A); rs5367(A,G); rs3917458(A,T); rs3917424(T,C); rs1076637(C,T); rs1076638(T,C); rs3917423(T,C); rs5363(A,G); rs1534904(T,G); rs2076059(C,T); rs3917421(G,C); rs3917419(G,A); rs3917417(C,T); rs3917413(A,G); rs3917412(T,C); rs3917411(A,T); rs5362(A,G); rs5361(T,G); rs3917410(A,G); rs56386914(T,C); rs4656708(A,C); rs56034882(C,T); rs56362866(C,T); rs1800016(T,C); rs1800015(T,C); rs3917406(A,G); rs76471717(T,C); rs77114906(T,G); rs3917403(A,G); rs78121884(T,C); rs3917402(C,T); rs3917453(G,T); rs932307(G,A); rs1805193(C,A); rs3917400(G,A); rs5353(T,C); rs3917397(T,C) |
| ccdsGene name | CCDS1283.1 |
| cytoBand name | 1q24.2 |
| EntrezGene GeneID | 6401 |
| EntrezGene Description | selectin E |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SELE:NM_000450:exon4:c.A445C:p.S149R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7722 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P16581 |
| dbNSFP Uniprot ID | LYAM2_HUMAN |
| dbNSFP KGp1 AF | 0.0549450549451 |
| dbNSFP KGp1 Afr AF | 0.0325203252033 |
| dbNSFP KGp1 Amr AF | 0.0773480662983 |
| dbNSFP KGp1 Asn AF | 0.013986013986 |
| dbNSFP KGp1 Eur AF | 0.089709762533 |
| dbSNP GMAF | 0.0551 |
| ESP Afr MAF | 0.041307 |
| ESP All MAF | 0.083884 |
| ESP Eur/Amr MAF | 0.105698 |
| ExAC AF | 0.084,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Multifactorial
GENITOURINARY:
[Internal genitalia, female];
Endometriosis;
Ectopic placement of endometrial tissue;
Ovarian endometriotic cysts;
'Chocolate' cysts of ovary;
Dysmenorrhea, severe;
Pelvic pain, severe;
Decreased fertility;
Peritoneal inflammation;
Peritoneal fibrosis;
Peritoneal adhesions
MISCELLANEOUS:
Affects up to 10% of women in their reproductive years;
Autosomal recessive inheritance with decreased penetrance (50%) is
associated with a susceptibility locus on chromosome 10q26
OMIM Title
*131210 SELECTIN E; SELE
;;E-SELECTIN;;
ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; ELAM1;;
ELAM
OMIM Description
DESCRIPTION
Endothelial leukocyte adhesion molecule-1 is expressed by
cytokine-stimulated endothelial cells. It is thought to be responsible
for the accumulation of blood leukocytes at sites of inflammation by
mediating the adhesion of cells to the vascular lining. It exhibits
structural features homologous to those of LYAM1 (153240), including the
presence of lectin- and EGF-like domains followed by short consensus
repeat (SCR) domains that contain 6 conserved cysteine residues. These
proteins are part of the selectin family of cell adhesion molecules
(Watson et al., 1990; Collins et al., 1991).
GENE STRUCTURE
Collins et al. (1991) established that the ELAM gene is present in
single copy in the human genome and contains 14 exons spanning about 13
kb of DNA. The positions of exon-intron boundaries correlated with the
putative functional subdivisions of the protein.
MAPPING
Watson et al. (1990) found that the ELAM1 gene is in the same 300-kb
segment as the GRMP (173610) and LYAM1 genes on chromosome 1.
By analysis of human-mouse hybrid cell lines, Collins et al. (1991)
assigned the ELAM gene to the 1q12-qter region. LYAM1 and GRMP have been
localized to 1q, as have also the structurally related complement
binding proteins, e.g., C4BPA (120830), suggesting that these genes may
share a common evolutionary history.
GENE FUNCTION
The glaucomas are a group of optic neuropathies comprising the leading
cause of irreversible blindness worldwide. Elevated intraocular pressure
due to a reduction in normal aqueous outflow is a major causal risk
factor. Wang et al. (2001) found that ELAM1, the earliest marker for the
atherosclerotic plaque in the vasculature, was consistently present on
trabecular meshwork cells in the outflow pathways of eyes with glaucomas
of diverse etiology. They determined expression of ELAM1 to be
controlled by activation of an interleukin-1 (see 147760) autocrine
feedback loop through transcription factor NK-kappa-B (see 164011), and
activity of this signaling pathway was shown to protect trabecular
meshwork cells against oxidative stress. Wang et al. (2001) concluded
that their findings characterized a protective stress response specific
to the eye's aqueous outflow pathways and provided the first known
diagnostic indicator of glaucomatous trabecular meshwork cells. They
further indicated that common mechanisms contribute to the
pathophysiology of the glaucomas and vascular diseases.
Using affinity chromatography, pull-down assays, and mass spectrometric
analysis on adenocarcinoma cell lines, Gout et al. (2006) showed that
SELE bound death receptor-3 (DR3, or TNFRSF25; 603366) on the cancer
cells. Western blot analysis revealed that the SELE-binding protein was
recognized by anti-DR3 antibodies. Anti-DR3 or knockdown of DR3 by small
interfering RNA decreased adhesion of colon cancer cells to SELE and to
SELE-expressing endothelial cells. Moreover, DR3 inhibition and
knockdown impaired transendothelial migration of adenocarcinoma cells
and blocked p38 (MAPK14; 600289) and ERK (see MAPK1; 176948) activation
by SELE. DR3 was expressed as high molecular mass isoforms in primary
human colon carcinomas, but not in normal colon tissue. SELE activation
of DR3 failed to induce apoptosis in colon cancer cells, except when ERK
was inhibited. Gout et al. (2006) concluded that SELE activation of DR3
on colon cancer cells triggers activation of p38 and ERK and confers
migration and survival advantages. They proposed that activation of DR3
by SELE acts as a switch that regulates metastasis by allowing colon
cancer cells to escape apoptosis.
MOLECULAR GENETICS
Iida and Nakamura (2003) constructed a high-resolution SNP map in the
55-kb region of chromosome 1q24-q25 corresponding to the SELE and SELL
genes.
Blood soluble E-selectin (sE-selectin) levels have been related to
various conditions such as type 2 diabetes (125853). Qi et al. (2010)
performed a genomewide association study among women of European
ancestry from the Nurses' Health Study, and identified
genomewide-significant associations between a cluster of markers at the
ABO locus (110300) on chromosome 9q34 and plasma sE-selectin
concentration. The strongest association was with dbSNP rs651007, which
explained approximately 9.71% of the variation in sE-selectin
concentrations. dbSNP rs651007 was also nominally associated with
soluble intracellular cell adhesion molecule-1 (sICAM1; 147840) and
TNFR2 (TNFRSF1B; 191191) levels, independent of sE-selectin. The
genetic-inferred ABO blood group genotypes were also associated with
sE-selectin concentrations. The genetic-inferred blood group B was
associated with a decreased risk of type 2 diabetes compared with blood
group O, adjusting for sE-selectin, sICAM1, TNFR2, and other covariates.
The authors concluded that the genetic variants at the ABO locus affect
plasma sE-selectin levels and diabetes risk, and that the genetic
associations with diabetes risk were independent of sE-selectin levels.
- Role in Leukocyte Recruitment
Neutrophil accumulation at sites of inflammation is mediated by specific
groups of cell adhesion molecules including the CD18 integrins (600065)
on leukocytes and the selectins (P-selectin (173610) and E-selectin on
the endothelium and L-selectin (153240) on the leukocytes). This is
supported by studies of patients with leukocyte adhesion deficiency
syndromes whose leukocytes are genetically deficient in the expression
of CD18 or selectin carbohydrate ligands (e.g., leukocyte adhesion
deficiency type II; 266265). However, inherited deficiency or
dysfunction of endothelial cell adhesion molecules involved in leukocyte
recruitment had not been described. DeLisser et al. (1999) described a
child with recurrent infections and clinical evidence of impaired pus
formation reminiscent of a leukocyte adhesion deficiency syndrome, but
whose neutrophils were functionally normal and expressed normal levels
of CD18, L-selectin, and sialyl-Lewis x. In contrast,
immunohistochemical staining of inflamed tissue from the patient showed
the absence of E-selectin from the endothelium, although E-selectin mRNA
was present. However, E-selectin protein was expressed, as significantly
elevated levels of circulating soluble E-selectin were detected, the
molecular size of which was consistent with a proteolytically cleaved
form of E-selectin. Gene sequencing failed to show evidence of a
secreted mutant variant. These findings were thought to represent the
first description of a potentially inherited dysfunction of an
endothelial cell adhesion molecule involved in leukocyte recruitment and
provided additional evidence in the human of the importance of
endothelial selectins in the inflammatory response.
- S128R Polymorphism
Since adhesion molecules such as members of the selectin family
participate in the interaction between leukocytes and the endothelium
and appear to be involved in the pathogenesis of atherosclerosis, Wenzel
et al. (1994) sought DNA polymorphisms in the ELAM1 gene, which appears
to be expressed only in activated endothelium. They identified an A-to-C
transversion at cDNA nucleotide 561, resulting in an amino acid exchange
from serine to arginine at codon 128 (S128R) in the epidermal growth
factor-like domain. They found a significantly higher frequency of the
mutation in 97 patients aged 50 years or less with angiographically
proven severe atherosclerosis (arginine allele frequency, 0.155)
compared with an unselected population (arginine allele frequency,
0.088), as well as in 40 patients aged 40 years or less (arginine allele
frequency, 0.21).
Zheng et al. (2001) examined whether a polymorphism in the SELE gene,
due to a G-to-T mutation (98G-T) in the untranslated region of exon 2,
was related to premature coronary artery disease (CAD). Both lipid and
nonlipid risk factors, including the S128R substitution studied by
Wenzel et al. (1994), were also assessed. The frequency of the 98G-T
mutation was found to be significantly increased among male patients
under 45 years of age and female patients under 55 years of age. After
controlling for other CAD risk factors by multiple logistic analysis,
the 98G-T mutation was still a significant predictor of premature CAD.
Rao et al. (2002) found that CHO cell monolayers expressing SELE with
the S128R polymorphism recruited significantly greater numbers of Th2
and Th0, but not Th1, memory T cells than monolayers expressing wildtype
SELE. They proposed that the S128R polymorphism extends the range of
lymphocytes recruited by SELE, possibly providing a mechanism for the
increased susceptibility to vascular inflammatory disease associated
with S128R.
- Associations Pending Confirmation
Accumulation of leukocytes within the glomerulus and interstitium of the
kidney is considered to be a key pathogenetic mechanism in various types
of glomerulonephritis. The selectins represent one group of adhesion
molecules involved in these interactions. Evidence from various sources
suggests an involvement of E-selectin, L-selectin, and perhaps
P-selectin, as reviewed by Takei et al. (2002). The genes for these 3
forms of selectin are clustered on 1q24-q25. Takei et al. (2002) found
that 2 SNPs in the E-selectin gene and 6 SNPs in the L-selectin gene are
significantly associated with IgA nephropathy (IGAN; 161950) in Japanese
patients. All 8 SNPs were in almost complete linkage disequilibrium.
By genomewide linkage and candidate gene-based association studies,
Chang et al. (2007) demonstrated that a replicated linkage peak for
blood pressure regulation on human chromosome 1q23-q32, homologous to
mouse and rat quantitative trait loci (QTLs) for blood pressure,
contains at least 3 genes associated with blood pressures level in
multiple samples: ATP1B1 (182330), RGS5 (603276), and SELE. Individual
variants in these 3 genes accounted for 2- to 5-mm Hg differences in
mean systolic blood pressure, and the cumulative effect reached 8 to 10
mm Hg. Because the associated alleles in these genes are relatively
common (frequency more than 5%), these 3 genes are important
contributors to elevated blood pressure in the population at large.
Chang et al. (2007) viewed the probable relationship between each of
these genes and blood pressure regulation.
ANIMAL MODEL
Forlow et al. (2002) stated that mice lacking both Selp (173610) and
Sele kept under specific pathogen-free barrier conditions have high
circulating neutrophil counts and develop hypercellular cervical lymph
nodes containing numerous plasma cells, severe ulcerative dermatitis,
conjunctivitis, and lung pathology, eventually leading to premature
death. They hypothesized that the pathology in Selp and Sele
double-knockout mice might be due to dysfunctional lymphocyte activity
and, to test this hypothesis, they crossed Selp and Sele double-knockout
mice with mice deficient in Rag1 (179615), which lack mature T and B
lymphocytes. The triple-knockout mice had high circulating neutrophil
counts and plasma Gcsf (CSF3; 138970), but none developed the
conjunctivitis or dermatitis observed in Selp and Sele double-knockout
mice. Histopathologic analysis revealed fewer lung anomalies and smaller
cervical lymph nodes, which contained few mononuclear cells and no
plasma cells, in triple-knockout mice compared with Selp and Sele
double-knockout mice. Forlow et al. (2002) concluded that the severe
disease phenotype, but not the elevated neutrophil counts, in Selp and
Sele double-knockout mice depends on lymphocyte function.
Using fluorescence intravital microscopy (IVM) with homing assays,
Hidalgo et al. (2002) examined the repopulation of bone marrow of
sublethally irradiated nonobese diabetic (NOD)/severe combined
immunodeficiency (SCID) mice, which have multiple defects in innate and
adaptive immunologic functions, with human CD34 (142230)-positive
hematopoietic progenitor cells obtained either from cord blood or from
adult bone marrow or peripheral blood. Human hematopoietic progenitor
cells rolled and arrested in NOD/SCID bone marrow microvessels, and the
rolling capacity of neonatal cord blood cells was much lower than that
of adult cells. Rolling and retention were nearly abolished in NOD/SCID
Selp -/- Sele -/- mice and in NOD/SCID Sele -/- mice. Flow cytometric
and IVM analyses suggested that the neonatal defect resulted from
expression of a nonfunctional form of SELPLG (600738) on cord blood
CD34-positive cells that were unable to bind Selp. This subset of cells
was enriched in CD34-positive/CD38 (107270)-low/negative progenitors.
Hidalgo et al. (2002) proposed that manipulation of expression of
selectins and their ligands may improve homing of cord blood
CD34-positive cells to bone marrow.
NOMENCLATURE
Bevilacqua et al. (1991) suggested that the homologous proteins involved
in cell-cell adhesion be referred to as selectins to reflect the
involvement of carbohydrate recognition in their functions. Individual
members of the family would be designated by a prefix capital letter, as
is done for the cadherins (e.g., 114020). Letters would be chosen based
on the tissue of original discovery and would not imply cell-type
specificity. ELAM1 was termed E-selectin.
TOP1P1
| dbSNP name | rs16828330(A,C); rs113642819(G,A); rs45542731(T,C); rs2223477(A,G); rs12057885(C,G); rs111790068(C,T); rs12737633(A,G) |
| ccdsGene name | CCDS1295.1 |
| cytoBand name | 1q24.3 |
| EntrezGene GeneID | 7151 |
| snpEff Gene Name | FMO4 |
| EntrezGene Description | topoisomerase (DNA) I pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0427 |
GAS5-AS1
| dbSNP name | rs16846478(A,T); rs1322771(A,G) |
| cytoBand name | 1q25.1 |
| EntrezGene GeneID | 100506046 |
| snpEff Gene Name | DARS2 |
| EntrezGene Description | GAS5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.124 |
RASAL2-AS1
| dbSNP name | rs964993(G,A) |
| cytoBand name | 1q25.2 |
| EntrezGene GeneID | 100302401 |
| snpEff Gene Name | RASAL2 |
| EntrezGene Description | RASAL2 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2241 |
| ExAC AF | 0.129,9.313e-04 |
MIR4424
| dbSNP name | rs56088671(C,T) |
| cytoBand name | 1q25.2 |
| EntrezGene GeneID | 100616328 |
| EntrezGene Description | microRNA 4424 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1244 |
| ExAC AF | 0.024 |
FLJ23867
| dbSNP name | rs74132573(C,T); rs3843273(A,G); rs6425612(A,C); rs56203087(G,A); rs56211231(G,A); rs11126(C,T); rs12145255(C,T); rs7513063(G,A); rs61809095(T,C) |
| cytoBand name | 1q25.2 |
| EntrezGene GeneID | 200058 |
| snpEff Gene Name | QSOX1 |
| EntrezGene Description | uncharacterized protein FLJ23867 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01653 |
| ExAC AF | 0.002654 |
IER5
| dbSNP name | rs41268464(G,A) |
| cytoBand name | 1q25.3 |
| EntrezGene GeneID | 51278 |
| EntrezGene Description | immediate early response 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05142 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEOPLASIA:
Meningioma
MISCELLANEOUS:
Adult onset;
More common in women;
Frequency increases with advancing age;
High recurrence rate;
Incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the homolog of the Drosophila suppressor of
fused gene (SUFU, 607035.0007);
Caused by mutation in the SWI/SNF-related, matrix-associated, actin-dependent
regulator of chromatin, subfamily 1, member 1 gene (SMARCE1, 603111.0002).
OMIM Title
*607177 IMMEDIATE-EARLY RESPONSE GENE 5; IER5
OMIM Description
CLONING
Williams et al. (1999) cloned a novel member of the slow-kinetics
immediate-early response gene family, designated Ier5, from a mouse
brain cDNA library. Mouse Ier5 encodes a deduced 308-amino acid protein
with a predicted molecular mass of 31.9 kD. The N-terminal 49 amino
acids show 57% sequence identity with those of the Ier2 protein. Ier5
contains 3 potential nuclear targeting signals, a possible PEST
sequence, which suggests rapid protein degradation, and several
potential phosphorylation sites. Northern blot analysis of total
cellular RNA from serum-starved NIH 3T3 cells showed no detectable
transcription in quiescent cells, but detected a single transcript
within 30 minutes after exposure to serum. Transcription was also
stimulated by the growth factors TPA (173370), FGF (see 131220), and
PDGF (see 173430), and did not appear to be dependent on protein kinase
C (see 176960) activity.
GENE STRUCTURE
Williams et al. (1999) identified 2 possible Ets-1 sites, a number of
potential Sp1 sites, and 3 potential AP1-binding sites in the promoter
region of the mouse Ier5 gene. The IER5 genes in humans and mice are
highly homologous to their counterpart in zebrafish. In all of these
organisms, IER5 is an intronless gene (Gottgens et al., 2002).
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the IER5
gene to chromosome 1 (TMAP stSG23644).
TEDDM1
| dbSNP name | rs2038891(G,A); rs6667958(A,G); rs12733426(C,G); rs6424853(A,G); rs6698722(G,A); rs6674281(A,G); rs143555913(A,G); rs7551829(G,A) |
| cytoBand name | 1q25.3 |
| EntrezGene GeneID | 127670 |
| EntrezGene Description | transmembrane epididymal protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3411 |
LOC284648
| dbSNP name | rs580096(A,G) |
| cytoBand name | 1q25.3 |
| EntrezGene GeneID | 284648 |
| EntrezGene Description | uncharacterized LOC284648 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01882 |
ZNF281
| dbSNP name | rs1128817(G,A) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 23528 |
| EntrezGene Description | zinc finger protein 281 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2309 |
GPR25
| dbSNP name | rs3738250(G,T) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 2848 |
| EntrezGene Description | G protein-coupled receptor 25 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2342 |
OMIM Clinical Significance
Eyes:
Retinitis pigmentosa;
Eyelid ptosis;
Enophthalmos
Endocrine:
Hypopituitarism;
Growth hormone deficiency;
Thyroid stimulating hormone deficiency
GU:
Nephronophthisis;
Renal failure
Skel:
Skeletal dysplasia
GI:
Liver fibrosis
Ears:
Conduction deafness
Inheritance:
? Autosomal recessive
OMIM Title
*602174 G PROTEIN-COUPLED RECEPTOR 25; GPR25
OMIM Description
Using degenerate PCR of genomic DNA with primers based on the sequence
of SLC1 (601751), Jung et al. (1997) identified a novel G
protein-coupled receptor, GPR25. The GPR25 gene has no introns and
encodes a polypeptide of 360 amino acids. The predicted protein contains
7 putative transmembrane domains. Its closest homolog is GPR15 (601166).
Jung et al. (1997) used fluorescence in situ hybridization to map the
GPR25 gene to human chromosome 1q32.1, in close proximity to several
other G protein-coupled receptors.
CACNA1S
| dbSNP name | rs12139527(A,G); rs1546416(A,G); rs6427875(T,C); rs6675915(T,C); rs371715155(G,A); rs12566395(G,T); rs1507147(G,A); rs1876386(C,T); rs5010839(A,T); rs2279944(C,T); rs13374149(C,T); rs67602696(C,T); rs2297906(T,C); rs55861132(G,A); rs10494827(G,C); rs374751793(T,C); rs60112590(A,G); rs56927717(C,T); rs12122809(C,T); rs3913893(C,G); rs12407188(G,C); rs3850625(G,A); rs2297905(C,T); rs7535428(T,G); rs7538449(T,G); rs55734382(C,T); rs12065493(C,T); rs75777080(G,A); rs6702590(A,G); rs3861928(T,G); rs3767498(A,G); rs3767499(T,C); rs12029212(C,G); rs3767500(C,G); rs3767501(C,T); rs56855516(C,T); rs3818873(C,T); rs10800755(G,C); rs10800756(G,A); rs12032370(C,T); rs146329303(G,A); rs16847603(A,G); rs3767503(C,A); rs3767504(C,A); rs376386660(C,T); rs4915473(T,C); rs4915474(C,T); rs58124792(G,A); rs73075033(G,A); rs7556265(T,C); rs4915475(T,C); rs12046840(G,A); rs2297904(G,A); rs16847607(G,A); rs61614423(C,T); rs2297903(A,C); rs12048771(G,C); rs55922503(A,T); rs12403523(A,T); rs12406017(C,T); rs147501976(A,G); rs10920103(G,T); rs139460517(A,G); rs75990530(C,T); rs16847613(G,A); rs12565866(C,G); rs12565884(C,T); rs7411594(G,A); rs3767505(T,C); rs3820421(A,T); rs2297901(G,T); rs77394706(G,A); rs7519715(T,C); rs16847636(A,G); rs66839237(G,C); rs7415038(A,G); rs147061115(T,G); rs10920104(G,T); rs9427711(A,G); rs376826434(T,G); rs60807321(A,G); rs78165102(G,A); rs9427712(G,A); rs9427467(T,C); rs9427713(G,A); rs2886329(A,G); rs16847659(T,C); rs9427468(T,C); rs9333652(G,A); rs74765910(G,A); rs10800757(C,T); rs10920106(C,T); rs374902603(G,T); rs79984703(C,A); rs3767508(T,C); rs3767510(C,T); rs113175669(C,T); rs200091030(G,A); rs1998721(A,G); rs191566268(G,C); rs3820422(A,G); rs906316(C,T); rs10920107(G,A); rs373131077(G,A); rs925060(T,G); rs6672094(A,G); rs376287234(C,T); rs116379218(A,G); rs4915476(G,A); rs4915477(A,G); rs9427714(A,G); rs4915213(C,T); rs11811602(G,A); rs11579279(A,C); rs6427877(A,G); rs12119957(T,G); rs6667959(T,C); rs6413914(T,C); rs942707(T,C); rs12026017(T,G); rs10920109(T,G); rs942705(C,T); rs942704(A,C); rs7516825(C,T); rs11577079(G,T); rs6664806(C,T); rs10920111(C,G); rs10920112(C,T); rs11585193(C,G); rs6689533(A,T); rs12737797(C,A); rs12737822(C,T); rs77685812(T,C); rs116258903(C,T); rs3767511(T,C); rs12724643(T,C); rs12743065(G,T); rs4915478(G,A); rs12743376(G,A); rs57511066(T,C); rs41267505(G,T); rs16847694(G,T); rs150954040(G,A); rs59722106(C,T); rs58264851(T,C); rs191507817(C,A); rs16847699(C,T); rs61734621(G,A); rs2296384(T,C); rs3753960(A,G); rs3767513(G,C); rs10159219(A,G); rs78298142(G,A); rs10159326(A,G); rs146993217(A,G); rs2296383(G,A); rs3820423(G,A); rs2147798(C,G); rs6684689(G,A); rs57397293(C,A); rs139589977(C,T); rs60533026(C,A); rs78884365(C,A); rs140375211(G,A); rs4915483(T,C); rs6427878(C,T); rs6677721(G,C); rs6704355(A,G); rs7534906(G,A); rs16847724(T,C); rs17454870(G,A); rs2038845(A,C); rs12409138(C,T); rs7538060(G,A); rs16847726(C,T); rs877444(C,G); rs61353098(C,G); rs12409449(C,T); rs6699862(T,C); rs12404542(G,A); rs376295128(C,T); rs1574408(A,G); rs74136319(C,A); rs1536129(C,A); rs1536128(C,T); rs111604126(G,A); rs16847736(G,C); rs116817858(G,A); rs17454947(C,A); rs12131939(T,C); rs78121438(A,C); rs35372141(A,T); rs141640827(A,G); rs16847737(G,C); rs12405259(G,A); rs80092188(G,A); rs144073562(G,C); rs10449267(A,G); rs10920115(T,G); rs10920117(T,C); rs112721192(C,T); rs79829191(T,A); rs79360307(C,T); rs12408707(A,T); rs12146106(C,T); rs12135240(T,C); rs12561765(C,T); rs12022389(C,T); rs12409114(A,T); rs10920118(G,A); rs10920119(T,C); rs115862074(G,A); rs12239772(A,G); rs2365293(T,C); rs150268206(A,T); rs998135(T,C); rs372211116(G,A); rs77735972(G,C); rs1325313(C,T); rs10920120(C,G); rs4915214(T,A); rs16847743(A,G); rs12132807(T,C); rs112656009(G,A); rs79271474(A,C); rs112372655(G,T); rs4915484(G,C); rs112614882(C,T); rs113323488(C,G); rs4915215(T,C); rs4915216(T,G); rs4915217(T,A); rs113116887(C,A); rs57226052(C,T); rs58364051(A,G); rs113791888(T,C); rs111428237(C,T); rs113144001(C,T); rs113487025(C,T); rs75268997(T,C); rs111324866(G,A); rs74711827(A,G); rs78509201(T,C); rs187964335(A,T); rs1325312(A,G); rs1325311(G,A); rs1325310(C,T); rs112868209(G,A); rs150520884(C,T); rs1325309(T,A); rs7513829(C,A); rs10920121(C,T); rs79018219(A,C); rs4498834(T,C); rs7516898(G,A); rs112912299(C,T) |
| ccdsGene name | CCDS1407.1 |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 779 |
| EntrezGene Description | calcium channel, voltage-dependent, L type, alpha 1S subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CACNA1S:NM_000069:exon8:c.C1112T:p.T371M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9138 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q13698 |
| dbNSFP Uniprot ID | CAC1S_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0004147 |
OMIM Clinical Significance
Limbs:
Camptodactyly;
Proximal interphalangeal finger joint contractures
Joints:
Knee-joint subluxation
Misc:
Fifth finger most frequently affected
Lab:
Associated taurinuria
Inheritance:
Autosomal dominant
OMIM Title
*114208 CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1S SUBUNIT; CACNA1S
;;CALCIUM CHANNEL, L TYPE, ALPHA-1 POLYPEPTIDE, ISOFORM 3, SKELETAL
MUSCLE; CACNL1A3;;
CCHL1A3;;
CALCIUM CHANNEL, SKELETAL MUSCLE DIHYDROPYRIDINE-SENSITIVE, ALPHA-1
SUBUNIT;;
CaV.1
OMIM Description
DESCRIPTION
The major type of voltage-sensitive Ca(2+) channels in skeletal muscle
is the slowly inactivating L-type that is sensitive to calcium channel
blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines, and
benzothiazepines. These skeletal muscle Ca(2+) channels play a key role
in excitation-contraction coupling, a process whereby electrical signals
generated by action potentials at the muscle cell surface are transduced
into intracellular release of calcium and ultimately muscle fiber
contraction. The DHP-sensitive L-type Ca(2+) channel from skeletal
muscle is an oligomeric protein composed of 2 high molecular weight
polypeptide subunits (alpha-1 and alpha-2) and 3 smaller units (beta,
gamma, and delta) (Campbell et al., 1988; Catterall, 1991).
CLONING
Hogan et al. (1994) cloned a CACNL1A3 cDNA from a human skeletal muscle
cDNA library. The deduced 1,873-amino acid protein has a calculated
molecular mass of 212.3 kD. It contains 4 homologous transmembrane
repeats, each of which consists of 5 hydrophobic alpha helices and 1
positively charged segment, a potential calcium-binding E-F hand motif,
and several phosphorylation and N-linked glycosylation sites.
GENE STRUCTURE
By isolation of overlapping genomic DNA clones from human cosmid, phage,
and P1 libraries, Hogan et al. (1996) defined the sequences of the exons
and flanking introns of the CACNL1A3 gene. The gene spans 90 kb and
contains 44 exons.
MAPPING
Using a rat brain cDNA probe for Cchl1a3 for hybridization to Southern
blots of DNAs from a panel of Chinese hamster/mouse somatic cell
hybrids, Chin et al. (1992) showed that the gene maps to mouse
chromosome 1. Analysis of interspecific crosses positioned the Cchl1a3
gene 1.3 cM proximal to the Pep-3 locus. Thus the corresponding gene in
humans is probably located on distal 1q, since Pep-3 corresponds to PEPC
(170000), which is located on human 1q42.
Gregg et al. (1993) used all of the nucleotides based on a partial
sequence of the CACNL1A3 gene to PCR amplify specifically the human gene
in human/rodent somatic cell hybrids, thus allowing the assignment of
the gene to chromosome 1. A polymorphic dinucleotide repeat was
identified in the human clone and by PCR was typed on CEPH families to
position the CACNL1A3 gene between D1S52 and D1S70 on 1q31-q32.
Drouet et al. (1993) mapped this gene to mouse chromosome 1 and human
1q32 by in situ hybridization. They confirmed the localization in the
mouse by linkage studies in a C57BL/6 x Mus spretus interspecific
backcross. Drouet et al. (1993) localized the mdg mutation to mouse
chromosome 1 by analyzing the offspring of an interspecific backcross
segregating the mutant allele and showed that it is very closely linked
to the myogenin (Myog) locus. Iles et al. (1994) also used in situ
hybridization to map the CACNL1A3 gene to 1q32.
GENE FUNCTION
Tang et al. (2012) observed altered splicing of CAV1.1 in muscle of
patients with myotonic dystrophy-1 (DM1; 160900) and DM2 (602668)
compared with normal adult muscle and muscle of patients with
facioscapulohumeral muscular dystrophy (FSHD; see 158900). A significant
fraction of CAV1.1 transcripts in DM1 and DM2 muscle showed skipping of
exon 29, which represents a fetal splicing pattern resulting in deletion
of 19 amino acids in the extracellular loop between transmembrane
segment 21 and the positively charged transmembrane segment 22. Forced
exclusion of exon 29 in normal mouse skeletal muscle altered channel
gating properties and increased current density and peak electrically
evoked calcium transient magnitude. Downregulation of Mbnl1 (606516) in
mouse cardiac muscle or overexpression of Cugbp1 (601074) in mouse
tibialis anterior muscle enhanced skipping of exon 29, suggesting that
these splicing factors may be involved in the CAV1.1 splicing defect in
myotonic dystrophy.
MOLECULAR GENETICS
- Hypokalemic Periodic Paralysis Type 1
Using an intragenic microsatellite as a marker, Fontaine et al. (1994)
demonstrated that the CACNL1A3 gene maps to chromosome 1q31-q32 and
shares a 5-cM interval with the gene for hypokalemic periodic paralysis
(HOKPP1; 170400). In 2 informative families, they showed that CACNL1A3
cosegregated with hypokalemic periodic paralysis without recombinants,
making it a strong candidate for the HOKPP gene. Ptacek et al. (1994)
proved that CACNL1A3 indeed was the site of mutations in hypokalemic
periodic paralysis. Among 11 unrelated probands, they found mutations in
1 of 2 adjacent nucleotides within the same codon that predicted
substitution of a highly conserved arginine in the S4 segment of domain
4 by either histidine (R1239H; 114208.0001) or glycine (R1239G;
114208.0002). In 1 kindred, the mutation arose de novo.
In a Dutch hypokalemic periodic paralysis kindred with 55 affected
members in the last 5 generations, Boerman et al. (1995) used
microsatellite markers to demonstrate linkage to 1q31-q32. A G-to-A
transition causing the arg528-to-his substitution (R528H; 114208.0003)
was demonstrated as the causative mutation.
Elbaz et al. (1995) found the R1239H mutation in 8 of 16 families with
hypokalemic periodic paralysis of Caucasian origin; the R528H mutation
was found in the other 8 families. Using dinucleotide repeats contained
within or close to the CACNL1A3 gene, in conjunction with demonstration
of a de novo arg1239-to-his mutation, Elbaz et al. (1995) showed that a
founder effect is unlikely to account for the 2 predominant mutations.
Sillen et al. (1997) identified 2 different mutations in the CACNL1A3
gene in 13 Scandinavian families, 10 of whom had the R528H mutation and
3 of whom had the R1239H mutation. Furthermore, there was evidence of a
founder effect in 8 of the 9 Danish families with hypokalemic periodic
paralysis consisting of haplotypes of microsatellite markers close to
and within the CACNL1A3 gene, as well as information of the geographic
origin of the families. Reduced penetrance in males with the
arg528-to-his mutation was found in several cases.
Matthews et al. (2009) identified mutations in the CACNA1S or SCN4A gene
in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations,
including 3 novel mutations, affected arginine residues in the S4
voltage sensing region in 1 of the transmembrane domains of each gene.
The most common mutations affected residues arg528 (R528H; 25 cases) and
arg1239 (R1239H and R1239G; 39 cases) in the CACNA1S gene. The most
common mutations in SCN4A affected residues arg672 (see, e.g.,
603967.0016) and arg1132. The findings supported the hypothesis that
loss of positive charge in S4 voltage sensors is important to the
pathogenesis of this disorder. (Sokolov et al., 2007).
- Malignant Hyperthermia
Malignant hyperthermia susceptibility (see 145600) is characterized by
genetic heterogeneity. However, except for the MHS1 locus, which
corresponds to the skeletal muscle ryanodine receptor (RYR1; 180901) and
for which several mutations had been described, no direct molecular
evidence for a mutation in another gene had been reported until the
discovery by Monnier et al. (1997) of a mutation in the CACNL1A3 gene
segregating with the disorder in a large French family (see MHS5;
601887). Linkage analysis performed with an intragenic polymorphic
microsatellite marker of the CACNL1A3 gene generated a 2-point lod score
of 4.38 at a recombination fraction of 0.0. Sequence analysis showed a
3333G-A transition, resulting in an arg1086-to-his amino acid
substitution in the gene product (114208.0004), which segregated
perfectly with the MHS phenotype in this family. The mutation was
localized to a very different part of the alpha-1 subunit of the human
skeletal muscle L-type voltage-dependent calcium channel (VDCC),
compared with the mutations previously reported in patients with
hypokalemic periodic paralysis. The findings suggested a direct
interaction between the skeletal muscle VDCC and the ryanodine receptor
in the skeletal muscle sarcoplasmic reticulum. In an accompanying
editorial, Hogan (1997) emphasized that normothermia does not rule out
the diagnosis of malignant hyperthermia. Hyperthermia was a late sign in
the proband described by Monnier et al. (1997).
- Susceptibility to Thyrotoxic Periodic Paralysis
Thyrotoxic periodic paralysis (TTPP; see 188580) is a frequent
complication of thyrotoxicosis among Chinese men. To determine the
genetic basis of TTPP, Kung et al. (2004) studied 97 male TTPP patients,
77 Graves disease (275000) patients without TTPP, and 100 normal male
subjects. They detected 12 single-nucleotide polymorphisms (SNPs) in
Cav1.1 (CACNA1S), 3 of which were novel. Significant differences in the
SNP genotype distribution between TTPP compared with Graves disease
controls and normal controls were seen at a 5-prime flanking region SNP
and 2 intronic SNPs. The authors concluded that because these SNPs lie
at or near a thyroid hormone-responsive element (TRE), it is possible
that they may affect the binding affinity of the TRE and modulate the
stimulation of thyroid hormone on the Cav1.1 gene.
ANIMAL MODEL
In the mouse, the gene for the alpha-1 subunit, symbolized Cchl1a3, is
mutant in 'muscular dysgenesis' (mdg), a lethal autosomal recessive
disorder in which there is total lack of excitation-contraction coupling
in homozygotes (Gluecksohn-Waelsch, 1963; Pai, 1965). In the affected
muscle, the reduction of the level of slow Ca(2+)
channel/dihydropyridine receptor and the lack of L type Ca(2+) current
indicate that this channel may be implicated in the mutation. The
alpha-1 subunit of the channel, which contains the DHP binding site and
the voltage sensor element, is missing in mdg/mdg animals. In mice,
Tanabe et al. (1988) found that microinjection of alpha-1 cDNA into
mdg/mdg myotubes can restore a normal excitation-contraction coupling.
Chaudhari (1992) reported that the mdg mutation is characterized by
deletion of nucleotide 4010 in the cDNA transcribed from the gene
encoding the alpha-1 subunit, resulting in a shift of the translational
reading frame.
ASCL5
| dbSNP name | rs113606337(C,T); rs115077718(A,G); rs3738262(A,G); rs3738263(A,G) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 647219 |
| snpEff Gene Name | CACNA1S |
| EntrezGene Description | achaete-scute family bHLH transcription factor 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04545 |
RPS10P7
| dbSNP name | rs4310467(C,G); rs4345829(C,T); rs645251(G,A) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 376693 |
| snpEff Gene Name | RP11-134G8.5 |
| EntrezGene Description | ribosomal protein S10 pseudogene 7 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1974 |
MIR6740
| dbSNP name | rs139998616(G,A) |
| ccdsGene name | CCDS1418.1 |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 6051 |
| EntrezGene Symbol | RNPEP |
| snpEff Gene Name | RNPEP |
| EntrezGene Description | arginyl aminopeptidase (aminopeptidase B) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 0.0001947 |
TMEM183A
| dbSNP name | rs1046529(T,C); rs372799828(A,G) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 92703 |
| EntrezGene Description | transmembrane protein 183A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09045 |
LINC00628
| dbSNP name | rs2942138(T,C); rs6691171(T,C); rs77780518(T,C); rs6691293(T,C); rs192884141(C,T) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 127841 |
| snpEff Gene Name | RP11-739N20.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 628 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | ambiguous_orf |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3131 |
TMEM81
| dbSNP name | rs10494858(C,T); rs4950979(G,A); rs16855059(A,G); rs4951168(C,T) |
| ccdsGene name | CCDS1450.1 |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 388730 |
| EntrezGene Description | transmembrane protein 81 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM81:NM_203376:exon1:c.G726A:p.V242V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.07805 |
| ESP Afr MAF | 0.234226 |
| ESP All MAF | 0.101415 |
| ESP Eur/Amr MAF | 0.033372 |
| ExAC AF | 0.071 |
LOC284578
| dbSNP name | rs77516432(C,T); rs10900512(A,G); rs12755324(A,G); rs11240517(G,A); rs11809978(G,A); rs10082150(A,G) |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 284578 |
| EntrezGene Description | uncharacterized LOC284578 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02663 |
SLC26A9
| dbSNP name | rs2282430(C,T); rs78944112(G,A); rs12733647(G,T); rs115873961(A,T); rs77367497(G,C); rs35843105(C,T); rs16856447(A,G); rs76988577(C,G); rs9438438(T,C); rs6669481(T,C); rs57455787(C,T); rs61224910(C,T); rs72752923(A,C); rs16830364(A,G); rs6593973(A,G); rs6593974(A,C); rs60255052(T,C); rs60716530(T,C); rs60644810(A,G); rs35694044(T,A); rs16830370(C,T); rs6421774(C,A); rs11240592(G,A); rs9438401(A,T); rs12757540(C,A); rs11804268(A,G); rs16856462(T,C); rs3811428(C,T); rs7366689(T,C); rs16856468(A,G); rs60001177(C,T); rs12723666(G,A); rs201612612(C,T); rs16856470(C,T); rs74146718(C,T); rs16856473(G,A); rs6689422(T,C); rs6697817(G,A); rs6674850(C,T); rs6674855(C,T); rs6674874(C,T); rs112406552(A,C); rs12759719(T,C); rs68189466(A,G); rs12131280(A,G); rs9438439(T,C); rs35648260(T,G); rs12132920(T,C); rs35360452(T,G); rs12135510(G,T); rs9793153(G,A); rs12083912(G,A); rs143102364(C,A); rs74941717(G,A); rs6690395(G,T); rs190835731(A,C); rs148369348(G,A); rs138924415(G,A); rs74146721(C,T); rs7538856(T,G); rs7366893(T,C); rs375732406(G,A); rs12727528(G,A); rs7367849(G,C); rs372739139(T,C); rs12133152(G,A); rs79688078(C,T); rs9438404(C,T); rs140636537(G,A); rs11240594(G,A); rs76093999(G,A); rs141197165(A,T); rs7366204(C,T); rs34803033(A,G); rs76506634(A,G); rs80313886(C,T); rs3811424(A,G); rs143557818(C,T); rs376495942(T,A); rs61639400(C,G); rs61198391(G,A); rs16856494(C,T); rs11240595(G,T); rs9438405(T,A); rs7512462(T,C); rs7555185(A,G); rs12042328(G,C); rs116090311(T,G); rs35427314(G,A); rs11240596(T,A); rs76277466(G,T); rs28661171(T,G); rs3811423(G,T); rs375080186(T,A); rs1995006(T,C); rs74655045(A,T); rs1891309(A,G); rs1891310(G,T); rs115556659(A,G); rs1473537(C,T); rs12082872(A,T); rs60733130(C,T); rs16856520(G,T); rs56029782(G,A); rs60401692(A,T); rs147655754(G,A); rs34190121(C,T); rs7549173(C,G); rs6696811(C,G); rs72752927(A,G); rs7521316(T,C); rs117201576(C,T); rs2036100(C,G); rs1874361(A,C); rs11240598(C,G); rs7555534(C,T); rs6593975(C,T); rs6593976(A,C); rs61814953(T,C); rs111581209(C,T); rs6673820(A,G); rs6661355(C,T); rs7415921(G,T); rs72752928(C,T); rs1342061(T,A); rs61707153(G,A); rs58234800(A,G); rs79698238(C,G); rs373924194(C,T); rs116115387(C,T) |
| ccdsGene name | CCDS30990.1 |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 115019 |
| EntrezGene Description | solute carrier family 26 (anion exchanger), member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC26A9:NM_052934:exon19:c.G2230A:p.V744M,SLC26A9:NM_134325:exon19:c.G2230A:p.V744M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.631 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7LBE3 |
| dbNSFP Uniprot ID | S26A9_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.00123 |
| ESP Eur/Amr MAF | 0.001628 |
| ExAC AF | 0.003293 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Severe myopia (> -6.00 diopters);
Detached retina
MISCELLANEOUS:
Genetic heterogeneity
OMIM Title
*608481 SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 9; SLC26A9
OMIM Description
DESCRIPTION
The members of the SLC26 family of transporters, such as SLC26A9, are
well conserved across species and mediate the electroneutral exchange of
chloride for bicarbonate or sulfate across the plasma membrane (Lohi et
al., 2002).
CLONING
By database analysis followed by PCR of a lung cDNA library, Lohi et al.
(2002) cloned SLC26A9. The deduced 791-amino acid protein contains an
N-terminal transporter family domain, an anti-sigma factor domain, and a
C-terminal PDZ-protein interacting motif. SLC26A9 is predicted to have a
9-transmembrane structure with an intracellular N-terminal domain and an
extracellular C-terminal domain. Lohi et al. (2002) also identified
splice variants that encode proteins with an N-terminal truncation of
the first 89 amino acids, or the deletion of amino acids 90 to 126.
Northern blot analysis of several tissues detected expression
predominantly in lung. PCR analysis detected expression in lung and some
expression in pancreas and prostate. Immunohistochemical staining showed
SLC26A9 within the cytoplasm of bronchiolar and alveolar epithelium.
There was some membrane-associated SLC26A9 in alveoli.
GENE FUNCTION
By functional expression in Xenopus oocytes, Lohi et al. (2002)
demonstrated SLC26A9-mediated induction of chloride, sulfate, and
oxalate transport. Transport was inhibited by an anion exchange
inhibitor and by thiosulfate, but not by oxalate or glucose.
GENE STRUCTURE
Lohi et al. (2002) determined that the SLC26A9 gene contains 21 exons
and spans about 25 kb.
MAPPING
By genomic sequence analysis, Lohi et al. (2002) mapped the SLC36A9 gene
to chromosome 1. The upstream sequence contains a putative TATA box.
MIR6769B
| dbSNP name | rs1953090(T,G) |
| ccdsGene name | CCDS30996.1 |
| cytoBand name | 1q32.1 |
| EntrezGene GeneID | 9641 |
| EntrezGene Symbol | IKBKE |
| snpEff Gene Name | IKBKE |
| EntrezGene Description | inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2098 |
| ExAC AF | 0.236,2.441e-05 |
LOC148696
| dbSNP name | rs12123251(G,A); rs761277(A,G); rs190447347(C,T); rs7512286(A,G); rs2235768(G,C); rs34385765(A,G); rs2724398(A,G); rs72729038(T,C) |
| cytoBand name | 1q32.2 |
| EntrezGene GeneID | 101929385 |
| EntrezGene Symbol | LOC101929385 |
| snpEff Gene Name | C1orf132 |
| EntrezGene Description | uncharacterized LOC101929385 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2585 |
G0S2
| dbSNP name | rs932375(G,C); rs3817870(T,C); rs142125926(C,A); rs1473683(T,G) |
| cytoBand name | 1q32.2 |
| EntrezGene GeneID | 50486 |
| EntrezGene Description | G0/G1switch 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1446 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Progressive thickening and furrowing of facial skin
SKELETAL:
Periostosis;
Arthralgia;
[Limbs];
Swelling of knees;
Periosteal hyperostosis of knee;
Patellar sclerosis;
Sclerosis of distal femur;
Sclerosis of distal tibiofibular joint;
[Hands];
Loss of normal tabulation of metacarpals and phalanges;
Cortical thickening of metacarpals and proximal and middle phalanges;
Digital clubbing;
[Feet];
Cortical thickening and acroosteolysis;
Digital clubbing
SKIN, NAILS, HAIR:
[Skin];
Thick facial skin;
Furrowed facial skin
LABORATORY ABNORMALITIES:
Elevated urinary PGE(2) levels;
Relatively low urinary PGE-M levels
MISCELLANEOUS:
Manifestations present in second decade of life;
Mild features such as digital clubbing may be apparent in older heterozygotes
MOLECULAR BASIS:
Caused by mutation in the solute carrier organic anion transporter
family, member 2A1 gene (SLCO2A1, 601460.0001)
OMIM Title
*614447 G0/G1 SWITCH GENE 2; G0S2
OMIM Description
CLONING
By differential display to identify genes expressed during
lectin-induced switch from G0 to G1 in human blood mononuclear cells,
Russell and Forsdyke (1991) identified G0S2. The deduced 103-amino acid
protein has a calculated molecular mass of 11.3 kD. It has 2 potential
alpha-helical domains separated by a hydrophobic beta sheet, which is
flanked by basic amino acids. G0S2 also has potential phosphorylation
sites near its N and C termini.
Using Northern blot analysis, Welch et al. (2009) found that G0S2 was
widely expressed in human tissues, with highest expression in peripheral
blood, followed by skeletal muscle and heart. Epitope-tagged G0S2
localized to mitochondria in H1299 nonsmall lung cancer cells.
GENE FUNCTION
Using expression profiling, Welch et al. (2009) found that expression of
G0S2 was significantly upregulated in primary human fibroblasts treated
with the proapoptotic factor TNF-alpha (TNF; 191160). Inhibition of
NF-kappa-B (see 164011) abrogated G0S2 induction by TNF-alpha.
Overexpression of G0S2 alone induced apoptosis in H1299 and HCT116 human
cancer cell lines, but not in normal human fibroblasts. However, G0S2
primed normal fibroblasts to undergo apoptosis in response to DNA
damage. Knockdown of G0S2 abrogated the proapoptotic effect of
TNF-alpha. G0S2 interacted with the antiapoptotic protein BCL2 (151430)
in vitro and in HeLa cell mitochondrial fractions. Interaction of G0S2
with BCL2 antagonized the protective effect of BCL2 by preventing the
interaction of BCL2 with BAX (600040). Welch et al. (2009) found that
G0S2 expression was epigenetically silenced in several human cancer cell
lines and was downregulated with high frequency in nonsmall cell lung
cancers. They concluded that G0S2 is a proapoptotic protein that is
induced by TNF-alpha and activated via NF-kappa-B signaling.
GENE STRUCTURE
Russell and Forsdyke (1991) determined that the G0S2 gene contains 2
exons and spans about 1 kb. The first exon is noncoding. The promoter
region contains several TATAA and CCAAT elements and several CpG
dinucleotides. A CpG island begins in the immediate 5-prime flank and
extends to the proximal two-thirds of the last exon of G0S2. Russell and
Forsdyke (1991) also identified several potential transcription
factor-binding sites in the promoter region, including sites for AP1
(see 165160), AP2 (TFAP2A; 107580), AP3, and NF-kappa-B.
MAPPING
By genomic sequence analysis, Schutte et al. (2000) mapped the G0S2 gene
to chromosome 1q32-q41.
C1orf74
| dbSNP name | rs651141(A,C); rs7550857(C,A) |
| cytoBand name | 1q32.2 |
| EntrezGene GeneID | 148304 |
| snpEff Gene Name | IRF6 |
| EntrezGene Description | chromosome 1 open reading frame 74 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3122 |
LPGAT1
| dbSNP name | rs2298095(C,T); rs4480424(C,T); rs11119805(T,A); rs192611665(A,G); rs3795834(T,C); rs1803468(G,A); rs72747044(T,C); rs12566620(T,C); rs10465691(G,A); rs11119806(C,A); rs11119807(C,T); rs61828259(C,T); rs28368551(G,A); rs11585946(G,A); rs75245874(G,A); rs114290319(C,T); rs12145346(C,A); rs7518285(G,A); rs7518833(G,A); rs6704043(T,C); rs76231407(C,A); rs12039450(A,G); rs72747049(C,T); rs72747051(G,A); rs55738027(A,G); rs4951424(A,G); rs143951999(G,A); rs12023717(C,T); rs79141138(T,C); rs6699292(C,T); rs117288513(C,T); rs60200148(G,A); rs4951425(T,C); rs6669803(A,G); rs6672393(T,C); rs142957610(G,A); rs17018028(C,T); rs17018032(C,T); rs4951547(C,T); rs6703711(A,G); rs17018038(A,G); rs7524009(G,A); rs12084756(A,G); rs12022627(C,T); rs6664082(T,C); rs6664386(T,C); rs139676782(G,A); rs6673226(G,A); rs12024375(C,T); rs56295475(T,G); rs12088743(T,C); rs80252318(T,G); rs6680326(G,A); rs12121773(C,T); rs12122562(C,A); rs12144745(G,A); rs2050953(G,A); rs12123889(C,T); rs11119809(T,C); rs150656425(A,C); rs55768405(G,T); rs80286344(T,C); rs114830146(T,A); rs114501975(G,A); rs72746513(A,T); rs17018048(G,A); rs6540705(T,C); rs76691585(G,A); rs6693275(C,G); rs12040681(T,C); rs145545514(A,G); rs75904546(T,A); rs116792112(G,A); rs12023263(C,T); rs116054723(C,T); rs4951548(C,A); rs10863922(A,C); rs12046116(G,C); rs56225609(C,T); rs56794231(G,A); rs72746521(T,C); rs72746522(C,T); rs115992060(C,T); rs4951426(G,A); rs4951549(C,T); rs4951550(C,T); rs12095938(G,A); rs4951551(G,A); rs143202482(C,T); rs6677888(A,T); rs12046648(T,C); rs17653254(G,A); rs114073650(A,C); rs6684049(T,G); rs12144072(T,C); rs12117000(G,T); rs72746524(A,G); rs142017735(C,T); rs190595299(G,A); rs12562933(C,T); rs1539195(C,T); rs12046293(T,C); rs12410970(G,A); rs1539196(A,C); rs4951427(C,G); rs72746525(C,T); rs12116638(G,A); rs11119810(G,A); rs11119811(G,A); rs10158561(C,G); rs74758659(C,T); rs75591012(G,A); rs150552771(T,C); rs12126561(C,G); rs12119787(G,C); rs76368499(C,T); rs6540707(C,T); rs72746529(A,C); rs72746531(T,C); rs114526316(C,G); rs6656780(G,A); rs72746535(T,C); rs114500893(A,C); rs12129627(C,T); rs76515383(T,C); rs373065729(C,G); rs377059746(A,G); rs12122929(G,A); rs11119812(T,C); rs143807997(A,G); rs138241450(G,A); rs115819907(T,C); rs1418047(T,C); rs12128221(C,T); rs6698841(T,G); rs77554650(A,C); rs55648545(G,A); rs80178087(T,G); rs12122086(T,C); rs113211502(G,T); rs56074728(T,C); rs3738197(C,T); rs12077561(C,T); rs1065607(T,C); rs7515713(T,A); rs138490008(A,C); rs7526682(G,C); rs7518896(T,C); rs12123135(A,C); rs12134302(C,A); rs12126667(G,A); rs55843903(G,C); rs78804235(G,A); rs9651110(C,T); rs7517565(C,T); rs146212276(A,T); rs12138283(C,A); rs4951552(A,C); rs11119813(T,G); rs12131727(G,A); rs147900776(C,T); rs2105322(T,C); rs11487823(A,G); rs11119814(A,T); rs12125042(A,C); rs191554357(C,G); rs12126742(T,C); rs12129362(G,A); rs111704251(G,A); rs7533951(T,A); rs78910290(C,T); rs145017537(G,C); rs189321213(G,A); rs12128147(A,G); rs61828491(T,C); rs140371203(G,T); rs2000168(T,C); rs4951553(G,A); rs12129315(A,T); rs12565318(A,C); rs12565546(T,A); rs4951429(G,A); rs55687837(G,A); rs55836176(T,C); rs6540709(A,G); rs7553567(A,G); rs115861007(C,T); rs12076991(T,C); rs79469025(A,T); rs72746563(C,A); rs7545377(T,C); rs79776336(T,C); rs12142878(C,T); rs10863924(G,A); rs10863925(C,T); rs77406998(A,G); rs12038038(T,C); rs10863926(T,C); rs6703304(A,T); rs12136792(T,G); rs4951430(C,T); rs12059988(C,A); rs148696348(G,A); rs76932297(G,T); rs61598472(C,T); rs12568179(G,A); rs11119816(A,G); rs12138188(A,G); rs74652891(T,A); rs12120603(C,A); rs12139319(A,C); rs12145721(C,T); rs6702617(A,G); rs4320838(C,T); rs78187247(G,C) |
| ccdsGene name | CCDS31018.1 |
| cytoBand name | 1q32.3 |
| EntrezGene GeneID | 9926 |
| EntrezGene Description | lysophosphatidylglycerol acyltransferase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LPGAT1:NM_014873:exon5:c.A598G:p.K200E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7353 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q92604 |
| dbNSFP Uniprot ID | LGAT1_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0002358 |
SNORA16B
| dbSNP name | rs792442(C,T) |
| ccdsGene name | CCDS55686.1 |
| cytoBand name | 1q32.3 |
| EntrezGene GeneID | 692157 |
| snpEff Gene Name | PPP2R5A |
| EntrezGene Description | small nucleolar RNA, H/ACA box 16B |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1915 |
| ESP Afr MAF | 0.071918 |
| ESP All MAF | 0.173178 |
| ESP Eur/Amr MAF | 0.21773 |
| ExAC AF | 0.778 |
FAM71A
| dbSNP name | rs7533306(A,G); rs79381401(G,A); rs111491824(C,T); rs3122712(A,G); rs3122713(A,G); rs3795842(C,T) |
| cytoBand name | 1q32.3 |
| EntrezGene GeneID | 149647 |
| snpEff Gene Name | ATF3 |
| EntrezGene Description | family with sequence similarity 71, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3563 |
LINC00538
| dbSNP name | rs17021621(G,A); rs7550337(T,C) |
| cytoBand name | 1q32.3 |
| EntrezGene GeneID | 100861504 |
| snpEff Gene Name | RP11-478J18.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 538 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05739 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Keratoconus;
Conical protrusion of cornea with curvature greater than 47 D on topography;
Prominent corneal nerves;
Corneal thinning;
Stromal scar tissue (in some patients);
Acentric or irregular corneal video keratography shapes
OMIM Title
*614635 LONG INTERGENIC NONCODING RNA 538; LINC00538
;;YIYA
OMIM Description
DESCRIPTION
LINC00538 is a noncoding RNA found in placental mammals that appears to
have a role in cell cycle progression (Yang et al., 2012).
CLONING
By sequentially depleting HEK293 cell total RNA of ribosomal, messenger,
and small RNAs, followed by random primer RT-PCR and 5-prime RACE, Yang
et al. (2012) obtained a full-length LINC00538 clone, which they called
YIYA. YIYA is an unspliced 1,906-nucleotide RNA that lacks a consensus
Kozak sequence or significant ORF. Northern blot analysis detected a
1.9-kb YIYA transcript in all rhesus monkey tissues and human cell lines
examined. Highest expression was detected in heart, smooth, and skeletal
muscle tissues. In synchronized HeLa cells, YIYA expression was highest
at S phase. Orthologs of YIYA were detected in placental mammals only.
GENE FUNCTION
Using quantitative real-time PCR, Yang et al. (2012) found that
expression of YIYA was upregulated in several cancers compared with
normal tissues, apparently due to genomic amplification. Overexpression
of YIYA in HEK293 cells led to an accumulation of cells in S phase.
GENE STRUCTURE
Yang et al. (2012) determined that LINC00538 is a single-exon gene.
MAPPING
By genomic sequence analysis, Yang et al. (2012) mapped the LINC00538
gene to chromosome 1q41.
LOC728463
| dbSNP name | rs6604604(C,A); rs7550232(A,C); rs10482718(A,G) |
| cytoBand name | 1q41 |
| EntrezGene GeneID | 728463 |
| snpEff Gene Name | TGFB2 |
| EntrezGene Description | uncharacterized LOC728463 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1208 |
AURKAPS1
| dbSNP name | rs2808017(T,G) |
| ccdsGene name | CCDS31028.1 |
| cytoBand name | 1q41 |
| EntrezGene GeneID | 25782 |
| EntrezGene Symbol | RAB3GAP2 |
| snpEff Gene Name | RAB3GAP2 |
| EntrezGene Description | RAB3 GTPase activating protein subunit 2 (non-catalytic) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03489 |
CCDC185
| dbSNP name | rs10907376(G,A) |
| ccdsGene name | CCDS1537.1 |
| CosmicCodingMuts gene | C1orf65 |
| cytoBand name | 1q41 |
| EntrezGene GeneID | 164127 |
| EntrezGene Symbol | C1orf65 |
| snpEff Gene Name | C1orf65 |
| EntrezGene Description | chromosome 1 open reading frame 65 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC185:NM_152610:exon1:c.G986A:p.G329D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N715 |
| dbNSFP Uniprot ID | CA065_HUMAN |
| dbNSFP KGp1 AF | 0.205128205128 |
| dbNSFP KGp1 Afr AF | 0.178861788618 |
| dbNSFP KGp1 Amr AF | 0.237569060773 |
| dbNSFP KGp1 Asn AF | 0.125874125874 |
| dbNSFP KGp1 Eur AF | 0.266490765172 |
| dbSNP GMAF | 0.2048 |
| ESP Afr MAF | 0.195867 |
| ESP All MAF | 0.238302 |
| ESP Eur/Amr MAF | 0.25972 |
| ExAC AF | 0.177 |
MIR6741
| dbSNP name | rs74150559(G,T) |
| ccdsGene name | CCDS31043.1 |
| cytoBand name | 1q42.12 |
| EntrezGene GeneID | 29920 |
| EntrezGene Symbol | PYCR2 |
| snpEff Gene Name | PYCR2 |
| EntrezGene Description | pyrroline-5-carboxylate reductase family, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03719 |
| ESP Afr MAF | 0.135724 |
| ESP All MAF | 0.046056 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.012 |
ZNF847P
| dbSNP name | rs138557162(G,C) |
| cytoBand name | 1q42.13 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01148 |
C1orf35
| dbSNP name | rs144791518(G,A) |
| ccdsGene name | CCDS1566.1 |
| cytoBand name | 1q42.13 |
| EntrezGene GeneID | 79169 |
| EntrezGene Description | chromosome 1 open reading frame 35 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C1orf35:NM_024319:exon8:c.C727T:p.R243W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0352 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BU76 |
| dbNSFP Uniprot ID | MMTA2_HUMAN |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 7.319e-05 |
IBA57-AS1
| dbSNP name | rs4348717(T,C) |
| cytoBand name | 1q42.13 |
| EntrezGene GeneID | 574432 |
| snpEff Gene Name | GJC2 |
| EntrezGene Description | IBA57 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02893 |
| ExAC AF | 0.988 |
HIST3H3
| dbSNP name | rs2230656(G,T) |
| ccdsGene name | CCDS1572.1 |
| cytoBand name | 1q42.13 |
| EntrezGene GeneID | 8290 |
| EntrezGene Description | histone cluster 3, H3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST3H3:NM_003493:exon1:c.C189A:p.I63I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3003 |
| ESP Afr MAF | 0.417158 |
| ESP All MAF | 0.273335 |
| ESP Eur/Amr MAF | 0.114767 |
| ExAC AF | 0.82 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602820 HISTONE GENE CLUSTER 3, H3 HISTONE; HIST3H3
;;HISTONE GENE CLUSTER 3, H3;;
HIST3 CLUSTER, H3;;
H3 HISTONE FAMILY, MEMBER T; H3FT; H3T;;
H3.4
OMIM Description
For background information on histones, histone gene clusters, and the
H3 histone family, see HIST1H3A (602810).
CLONING
Albig et al. (1996) identified a gene, which they called H3.4, encoding
a member of the H3 class of histones. Albig and Doenecke (1997)
designated this gene H3T. By sequence analysis, Albig et al. (1996)
found that H3T differs by 4 amino acid residues from the consensus
mammalian H3 structure (H3.1; see 602810) and shows the consensus
promoter and 3-prime flanking portions typical of replication-dependent
histones. Preliminary data indicated that H3T is expressed in testicular
cells.
Tachiwana et al. (2008) noted that H3T is expressed at low levels in
HeLa cells and in some somatic tissues in mouse.
MAPPING
By analysis of a somatic cell hybrid panel and by fluorescence in situ
hybridization, Albig et al. (1996) mapped the H3T gene to chromosome
1q42, outside the gene clusters that contain the other
replication-dependent H3 genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 1q42, which they called histone gene
cluster-3 (HIST3), contains 3 histone genes, including HIST3H3.
GENE FUNCTION
See HIST1H3A (602810) for functional information on the H3 histone
family.
- H3T Histone
The histone chaperones NAP1 (NAP1L1; 164060) and NAP2 (NAP1L4; 601651)
facilitate nucleosome assembly by first depositing preformed tetramers
made up of 2 molecules each of histones H3 and H4 (see 602822) onto DNA
prior to the addition of tetramers made up of 2 molecules each of
histones H2A (see 142720) and H2B (see 609904). Using recombinant human
proteins in an in vitro nucleosome formation assay, Tachiwana et al.
(2008) showed that NAP2, but not NAP1, could load H3T/H4 tetramers onto
DNA. Mutation analysis revealed that ala111 of H3.1, but not val111 of
H3T, promoted binding to NAP1.
BTNL10
| dbSNP name | rs6665115(T,C) |
| cytoBand name | 1q42.13 |
| EntrezGene GeneID | 100129094 |
| snpEff Gene Name | RP5-915N17.9 |
| EntrezGene Description | butyrophilin-like 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | BTNL10:NM_001287262:exon2:c.A182G:p.H61R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.491758241758 |
| dbNSFP KGp1 Afr AF | 0.310975609756 |
| dbNSFP KGp1 Amr AF | 0.588397790055 |
| dbNSFP KGp1 Asn AF | 0.454545454545 |
| dbNSFP KGp1 Eur AF | 0.591029023747 |
| dbSNP GMAF | 0.4927 |
| ExAC AF | 0.542 |
EXOC8
| dbSNP name | rs953(A,G); rs2064766(G,A); rs140970776(C,T); rs10489609(T,C); rs75696360(C,T); rs11122272(A,G) |
| cytoBand name | 1q42.2 |
| EntrezGene GeneID | 149371 |
| snpEff Gene Name | C1orf124 |
| EntrezGene Description | exocyst complex component 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4885 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Intrauterine growth retardation (IUGR)
HEAD AND NECK:
[Head];
Microcephaly (-4 SD)
SKELETAL:
Arthrogryposis
MUSCLE, SOFT TISSUE:
Fetal akinesia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, severe;
Lack of speech;
Lack of psychomotor development;
Fetal akinesia;
Spastic tetraplegia;
Seizures;
Malformations of cortical development;
Thin cortex;
Polymicrogyria;
Thin corpus callosum;
Gyral simplification;
Delayed cerebellar development (in some patients);
Delayed brainstem development (in some patients);
[Behavioral/psychiatric manifestations];
Automutilation;
Stereotypic hand movements
PRENATAL MANIFESTATIONS:
[Movement];
Fetal akinesia
MISCELLANEOUS:
Onset in utero or at birth;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the kinesin family member 5C gene (KIF5C, 604593.0001)
OMIM Title
*615283 EXOCYST COMPLEX COMPONENT 8; EXOC8
;;EXOCYST COMPLEX, 84-KD SUBUNIT; EXO84;;
SEC84, S. CEREVISIAE, HOMOLOG OF; SEC84
OMIM Description
DESCRIPTION
EXOC8 is a subunit of the exocyst, an evolutionarily conserved octameric
complex involved in post-Golgi targeting of secretory vesicles to
discreet membrane sites. The small GTPase RAL (see RALA; 179550) appears
to regulate exocyst assembly, in part, through its interaction with
EXOC8 (Moskalenko et al., 2003).
CLONING
Moskalenko et al. (2003) cloned human EXOC8, which they called EXO84.
The deduced 725-amino acid protein contains a putative pleckstrin (PLEK;
173570) homology (PH) domain near its N terminus and a central domain
conserved in Dor1 (COG8; 606979)-like proteins. The PH domain was
predicted to mediate lipid binding, and the Dor1 domain was predicted to
be involved in vesicle targeting.
GENE FUNCTION
Using yeast 2-hybrid analysis of HEK293T cells, Moskalenko et al. (2003)
showed that human EXO84 interacted with RALA and RALB (179551), but not
with any other small GTPase examined. RALA and RALB interacted with
EXO84 and with SEC5 (EXOC2; 615329), but not with any other exocyst
component examined. In vitro binding assays revealed that EXO84
interacted with GTP-bound RALA, and truncation analysis revealed that
the PH domain of EXO84 was required for the interaction. Membrane
depolarization resulted in recruitment of the isolated RAL-binding
domain of EXO84 to membranes, and this recruitment required
lipid-binding prenylated RALB. The PH domain of EXO84 also interacted
with liposomes containing radiolabeled phosphatidylinositol
3,4,5-trisphosphate, or PI(3,4,5)P3, and, more weakly, with PI(4,5)P2.
RAL-GTP competed with PI(3,4,5)P3 for EXO84 binding. In rat PC12 cells,
Exo84 appeared to fractionate with a subcomplex of vesicles that
included Sec10 (EXOC5; 604469), but not Sec5.
Using short hairpin RNAs, Issaq et al. (2010) found that knockdown of
EXO85 or SEC5, but not RAL-binding protein-1 (RALBP1; 605801), reduced
the tumorigenic potential of oncogenic RAS (HRAS; 190020)-transformed
human cells, as measured by cell proliferation in culture, colony growth
in soft agar, and tumor growth following injection in nude mice.
MAPPING
Hartz (2013) mapped the EXOC8 gene to chromosome 1q42.2 based on an
alignment of the EXOC8 sequence (GenBank GENBANK AK096460) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
For discussion of mutation in the EXOC8 as a possible cause of Joubert
syndrome (see 213300), see 615283.0001.
SNRPD2P2
| dbSNP name | rs112422735(G,A); rs112527476(T,C) |
| cytoBand name | 1q42.2 |
| EntrezGene GeneID | 645339 |
| EntrezGene Description | small nuclear ribonucleoprotein D2 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01745 |
DISC2
| dbSNP name | rs115785539(C,T); rs11122342(A,T); rs7548597(G,T); rs147869284(G,A); rs2759341(G,A); rs6672782(C,G) |
| ccdsGene name | CCDS31055.1 |
| cytoBand name | 1q42.2 |
| EntrezGene GeneID | 100303453 |
| EntrezGene Symbol | TSNAX-DISC1 |
| snpEff Gene Name | DISC1 |
| EntrezGene Description | TSNAX-DISC1 readthrough (NMD candidate) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007805 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Prenatal-onset growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Eyes];
Ptosis;
[Nose];
Pear-shaped nose;
Narrow alae nasi;
Long philtrum;
[Mouth];
Thin upper lip
SKELETAL:
[Limbs];
Knee contracture;
[Hands];
Polydactyly, preaxial;
Interphalangeal joint contractures
SKIN, NAILS, HAIR:
[Skin];
Atopic dermatitis;
[Hair];
Sparse hair;
Widow's peak;
Thick eyebrows
NEUROLOGIC:
[Central nervous system];
Mental retardation
OMIM Title
*606271 DISRUPTED IN SCHIZOPHRENIA 2; DISC2
OMIM Description
DESCRIPTION
DISC2 is thought to specify a noncoding RNA molecule antisense to DISC1
(605210). Both genes were found to be disrupted by a translocation in a
large schizophrenia (181500) kindred.
CLONING
Millar et al. (2000) isolated and sequenced the breakpoints on
chromosomes 1 and 11 in a Scottish family (St. Clair et al., 1990)
carrying a translocation (1;11)(q42.1;q14.3). No genes were found in the
region surrounding the chromosome 11 breakpoint. By contrast, the
corresponding region on chromosome 1 was gene-dense, and not 1 but 2
novel genes were directly disrupted by the translocation. Because of the
association with the mental illness in this family, these genes were
named 'disrupted in schizophrenia' 1 and 2 (DISC1, 605210 and DISC2).
DISC2 appears to be a single-exon noncoding structural RNA gene that is
antisense to DISC1, an arrangement observed at other loci where the
antisense RNA may regulate expression of the sense gene. Millar et al.
(2000) concluded that DISC1 and DISC2 should be considered formal
candidate genes for susceptibility to psychiatric illness.
GENE FUNCTION
Millar et al. (2000) suggested that by analogy to other examples of
mammalian genes with endogenous antisense RNA transcripts, DISC2
presents an attractive mechanism by which DISC1 expression may be
regulated.
MAPPING
That the DISC2 gene resides on chromosome 1q42.1 is demonstrated by its
disruption in a translocation t(1;11)(q42.1;q14.3) (Millar et al.,
2000).
MAP10
| dbSNP name | rs12092514(C,G); rs10797593(T,C); rs201625156(G,A); rs12409898(C,T); rs61746497(G,A); rs3766497(G,T); rs61739198(A,G); rs12048236(A,G); rs61735495(G,A); rs1845789(C,T); rs145939521(G,A); rs2795462(A,T); rs16858236(G,A); rs10910626(A,G); rs10489578(C,G) |
| cytoBand name | 1q42.2 |
| EntrezGene GeneID | 54627 |
| snpEff Gene Name | KIAA1383 |
| EntrezGene Description | microtubule-associated protein 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
MIR4427
| dbSNP name | rs701213(T,C); rs701214(C,T) |
| ccdsGene name | CCDS1599.1 |
| cytoBand name | 1q42.2 |
| EntrezGene GeneID | 100616390 |
| snpEff Gene Name | KCNK1 |
| EntrezGene Description | microRNA 4427 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2994 |
| ExAC AF | 0.102 |
LGALS8-AS1
| dbSNP name | rs2799419(T,C); rs16833769(C,G); rs3754245(C,T); rs3820564(A,G) |
| cytoBand name | 1q43 |
| EntrezGene GeneID | 100287902 |
| snpEff Gene Name | LGALS8 |
| EntrezGene Description | LGALS8 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07346 |
RYR2
| dbSNP name | rs1881548(A,G); rs74146691(T,C); rs12123449(A,G); rs1406413(A,G); rs12123625(A,T); rs12124723(A,G); rs2463865(G,T); rs2490347(A,G); rs74146692(G,C); rs10925298(T,G); rs142030349(C,T); rs12081905(C,T); rs10925299(C,T); rs11582448(G,A); rs115156041(G,A); rs4659488(T,C); rs1569188(G,A); rs1124814(A,G); rs10925300(C,T); rs61831870(C,T); rs183260257(G,T); rs72764017(T,C); rs73120075(G,A); rs12742508(C,G); rs370554221(A,T); rs4233467(T,C); rs4233468(C,T); rs68115334(A,T); rs57636512(C,T); rs9428651(T,G); rs9428652(G,A); rs34647600(A,G); rs34249406(C,A); rs10925303(G,A); rs10458438(T,C); rs12034700(A,G); rs9428653(G,A); rs60946806(C,G); rs57148162(G,A); rs10802584(T,A); rs10802585(A,G); rs16834780(A,G); rs17668834(G,A); rs16834782(G,T); rs9428368(C,A); rs9428369(C,T); rs9428654(A,G); rs9428655(C,G); rs6671060(T,G); rs6671079(T,C); rs6658508(C,T); rs6673755(T,C); rs6673763(T,C); rs12756907(G,A); rs6673872(T,C); rs10802586(T,C); rs9428370(A,G); rs9428371(G,C); rs9428372(G,T); rs10754591(G,C); rs4006358(C,T); rs4006359(G,T); rs2385610(C,T); rs2385611(G,A); rs6428985(C,T); rs6681409(A,G); rs6684299(T,G); rs4623687(G,A); rs4284252(A,C); rs4253907(G,A); rs6672173(C,T); rs2891826(T,C); rs4609414(T,C); rs4659767(G,A); rs4659768(C,T); rs78783961(T,C); rs6697811(T,C); rs10925304(C,T); rs2385612(C,T); rs75606339(T,C); rs76090957(G,A); rs59202334(C,T); rs9428373(C,T); rs12023598(C,G); rs2997486(C,G); rs78117705(C,T); rs61425842(T,C); rs6684412(C,A); rs59173404(A,G); rs58773141(G,A); rs9428374(C,A); rs9428658(C,T); rs10802587(G,A); rs10925307(A,G); rs10925308(T,G); rs6428989(A,G); rs4074496(A,T); rs4076465(A,C); rs4076466(A,G); rs12118388(T,C); rs12059960(T,G); rs12058831(A,G); rs180674326(T,A); rs4256803(G,A); rs11805513(C,G); rs6686489(G,T); rs6686490(G,T); rs116580341(C,A); rs10802588(T,C); rs186062909(G,A); rs6428990(A,G); rs10157718(T,A); rs6428991(C,T); rs77004232(G,A); rs6428992(G,A); rs6428993(T,A); rs6428994(G,C); rs6428995(G,C); rs12131634(C,T); rs6676748(T,A); rs150849879(G,A); rs146810500(C,T); rs10754592(A,C); rs9428375(T,A); rs7529190(A,T); rs16834810(G,A); rs2385608(C,G); rs78774164(C,T); rs7551249(G,A); rs7551672(G,A); rs7551978(G,C); rs12131303(C,A); rs12070071(G,A); rs9428660(A,C); rs7511682(T,C); rs6701985(A,G); rs7554607(A,G); rs73115908(C,T); rs4297281(T,C); rs16834822(G,T); rs12071372(A,C); rs6696837(T,G); rs2039689(G,A); rs2490346(T,C); rs12043330(C,T); rs2485576(G,A); rs2490345(A,G); rs6703352(T,C); rs115327170(G,A); rs16834839(T,C); rs139849341(C,G); rs2485579(A,G); rs6691537(C,T); rs1415714(T,C); rs1980798(T,G); rs17612827(T,C); rs10925315(G,T); rs182861933(T,G); rs12128519(G,A); rs12125175(A,G); rs17669728(C,T); rs10925316(A,G); rs2485596(A,G); rs2485597(A,G); rs12033905(G,A); rs9428662(C,T); rs191238386(T,A); rs2485598(C,T); rs2485600(T,C); rs11587273(C,T); rs17669838(G,A); rs151122463(C,T); rs11583937(G,A); rs4659769(C,T); rs11587813(C,T); rs12139283(C,A); rs2490390(T,C); rs12140458(C,A); rs9287218(A,C); rs1933127(A,G); rs12130378(A,G); rs115348987(C,T); rs1933128(A,G); rs1933129(T,A); rs138138970(G,T); rs11810113(C,T); rs7524016(G,A); rs2485557(T,G); rs2485558(G,C); rs2485559(C,A); rs7524399(G,A); rs10925318(C,T); rs137967972(T,C); rs12132380(T,C); rs2490389(A,C); rs2490388(C,A); rs2485560(G,A); rs116709636(A,G); rs2490387(T,C); rs73117615(G,A); rs2485562(A,G); rs77125434(G,A); rs2485563(G,A); rs2485564(G,A); rs114195894(C,T); rs10925319(G,A); rs11808576(G,A); rs2490386(G,T); rs2485565(C,A); rs41454545(C,G); rs2490385(T,C); rs73117619(C,T); rs73117620(A,C); rs12092816(C,T); rs56666032(G,A); rs2485567(T,G); rs78050752(C,T); rs116167964(A,C); rs2485568(G,A); rs145879616(G,C); rs1415711(T,C); rs2485569(G,A); rs117407907(G,A); rs2485570(G,T); rs6693720(G,T); rs2490384(T,C); rs2490383(G,A); rs12095795(C,T); rs1981177(C,A); rs1981178(A,G); rs113343467(G,T); rs116222596(A,G); rs2485571(G,A); rs2039690(C,T); rs76112761(G,T); rs80274683(G,A); rs2485572(A,G); rs34815086(A,G); rs115060574(G,A); rs4659771(T,G); rs9943191(T,C); rs145143883(C,T); rs2485573(G,A); rs2490381(C,T); rs2490380(G,A); rs141423341(C,T); rs2490379(T,C); rs2490378(G,T); rs113486481(C,T); rs2490377(G,A); rs60571504(C,A); rs115189372(G,C); rs10737813(G,A); rs12139096(A,G); rs12142661(G,A); rs2490376(G,A); rs2485574(C,T); rs10495389(T,G); rs2490375(T,G); rs2490374(C,T); rs56823734(T,C); rs1337797(T,C); rs1337798(G,A); rs2490373(T,C); rs1415712(A,G); rs73117632(T,C); rs73117634(C,T); rs73117635(T,G); rs113999926(T,C); rs2485575(A,G); rs74587768(A,G); rs73117640(A,C); rs80276960(G,A); rs73117641(T,C); rs73117643(C,G); rs6670388(G,A); rs16834884(T,C); rs78801070(A,G); rs16834885(T,G); rs57865888(T,G); rs61292828(A,T); rs2490372(G,A); rs75972682(A,G); rs16834891(C,T); rs73119307(A,G); rs74644555(A,G); rs73119310(T,C); rs6657602(T,C); rs2485577(T,C); rs73119311(T,C); rs12562895(G,C); rs2485578(A,T); rs2490371(G,A); rs2490370(C,A); rs145737556(A,T); rs75642694(T,C); rs75324253(C,A); rs73119313(G,A); rs114232489(C,G); rs2485580(T,C); rs2490369(T,G); rs10495390(G,A); rs77056592(C,T); rs1409052(A,G); rs1890153(C,A); rs73119318(T,C); rs2485584(A,G); rs56853715(C,T); rs12403050(G,A); rs2485585(A,G); rs10925333(A,G); rs150166236(G,T); rs59119367(G,A); rs1415715(T,C); rs2485586(A,G); rs145586684(T,C); rs2485587(C,T); rs2490368(T,C); rs2485588(A,G); rs2038889(A,G); rs111435669(T,G); rs1337799(A,G); rs1024272(C,A); rs2485590(G,A); rs114153818(G,A); rs2485591(G,A); rs2485592(A,C); rs2490367(A,G); rs2485593(A,G); rs2490366(A,T); rs114383061(G,A); rs2490365(C,T); rs1361115(G,A); rs1361116(G,T); rs150341559(C,T); rs2490364(A,G); rs78430017(C,T); rs116035709(A,G); rs1415716(G,A); rs2490363(T,C); rs114709370(G,A); rs1337800(G,T); rs114115862(T,C); rs2485594(G,A); rs2490362(C,T); rs10925334(T,A); rs111658123(A,T); rs148491426(C,G); rs73119336(T,A); rs2490359(T,C); rs115109796(C,T); rs2027253(T,A); rs57868848(C,T); rs12089014(C,T); rs80125085(C,T); rs73119340(C,T); rs41356946(G,A); rs114261803(C,G); rs73119343(A,G); rs1555834(C,G); rs145519882(T,C); rs78779075(T,C); rs10925336(C,T); rs10925337(A,G); rs1110246(G,A); rs2490358(A,G); rs10449289(A,G); rs884641(G,A); rs57674757(C,T); rs114411755(A,T); rs12072243(A,G); rs1008958(C,T); rs1008957(A,T); rs114407386(C,G); rs75727259(T,C); rs1008956(T,G); rs116389412(A,G); rs115639431(T,G); rs2490357(G,T); rs145834328(A,C); rs115686532(A,G); rs1415718(A,T); rs2485599(T,G); rs150778838(G,A); rs2490356(A,G); rs7547032(C,T); rs2485601(T,G); rs115323039(T,C); rs114369704(T,C); rs111365118(T,C); rs6667246(T,C); rs6667669(T,G); rs148456645(A,G); rs114913717(A,G); rs2490354(A,G); rs6668274(A,T); rs114615422(G,C); rs12082388(A,G); rs115700140(C,T); rs115652697(C,T); rs56967315(C,A); rs2490353(C,T); rs12746235(C,T); rs115638108(C,T); rs116170281(C,G); rs2490352(A,G); rs2490351(G,A); rs1337801(G,A); rs9730301(G,A); rs78500509(C,T); rs150696708(T,C); rs115296835(A,G); rs116034579(A,G); rs2485603(C,T); rs112941616(C,T); rs114871833(A,G); rs12074532(A,G); rs2485604(C,G); rs77318967(C,T); rs1806641(G,T); rs146219879(A,G); rs115673349(A,G); rs792553(C,G); rs115659724(C,T); rs75486960(T,G); rs57938337(G,A); rs142478989(T,C); rs145519990(A,G); rs622149(G,A); rs6661423(C,T); rs1317125(T,C); rs1415720(C,T); rs1106158(G,A); rs1106159(A,G); rs75238248(A,G); rs1106160(C,T); rs628040(A,G); rs584832(T,C); rs637169(A,G); rs584790(T,C); rs115024123(A,G); rs6668069(C,T); rs113480359(C,A); rs6683225(T,C); rs6680857(A,C); rs78961582(A,G); rs611878(G,A); rs12749494(G,C); rs694708(G,A); rs115670791(G,A); rs11811696(C,T); rs679760(T,A); rs113089148(C,A); rs7543800(T,G); rs75231857(A,T); rs6694250(T,C); rs78560056(C,A); rs4659774(G,A); rs75284506(T,G); rs115639475(C,T); rs1421211(C,T); rs268788(T,G); rs268787(A,C); rs268786(C,A); rs268785(T,C); rs149728465(G,A); rs2211009(T,C); rs1765887(A,G); rs676100(G,A); rs651028(C,T); rs7527812(A,G); rs583557(G,A); rs6673714(A,T); rs6676288(A,G); rs588920(G,A); rs634758(G,A); rs6688338(G,A); rs77055391(A,C); rs187909(G,A); rs187910(A,G); rs268789(C,T); rs12088313(T,G); rs7544666(G,A); rs7526053(C,T); rs12729522(T,C); rs169165(C,A); rs169166(G,A); rs12097733(C,G); rs268790(T,C); rs6693781(A,G); rs670828(G,A); rs12401834(C,A); rs10925341(A,G); rs688983(A,G); rs77879584(A,T); rs116308951(A,G); rs12724105(A,G); rs79278878(A,T); rs57771459(G,C); rs111434904(T,C); rs621689(C,A); rs12065427(C,T); rs12065439(C,T); rs648681(C,T); rs6692782(A,G); rs12752563(G,A); rs637520(C,T); rs75178305(G,A); rs683787(A,G); rs12048873(G,A); rs7556438(G,A); rs638910(T,C); rs60763927(G,A); rs639409(G,A); rs60607268(A,G); rs6658907(G,T); rs68135125(G,C); rs55778283(C,T); rs114888997(T,C); rs617676(C,G); rs619459(A,G); rs12046714(G,A); rs12043412(A,G); rs678298(A,G); rs628414(A,G); rs667363(G,A); rs7516180(T,A); rs7524125(G,A); rs7513886(A,T); rs640915(C,T); rs10158020(C,T); rs602897(A,G); rs75136878(C,T); rs139790821(G,A); rs79360905(C,T); rs604735(A,T); rs2111736(C,A); rs113145746(C,A); rs618083(G,T); rs636517(C,T); rs671216(T,C); rs672145(A,G); rs144573136(G,A); rs694200(A,T); rs685324(G,C); rs2152884(G,A); rs6663087(T,G); rs6696598(C,T); rs597924(T,C); rs7521414(T,G); rs61832415(T,G); rs140414567(C,A); rs6703530(C,T); rs114378732(C,T); rs74897838(G,A); rs6661229(C,T); rs12564189(C,T); rs116557946(A,C); rs17626494(A,G); rs10802591(A,G); rs77353320(C,T); rs870872(C,T); rs7541818(G,A); rs143613595(A,G); rs7541924(G,A); rs12353981(G,A); rs74147203(G,A); rs16835011(C,G); rs6428998(A,G); rs28396811(T,C); rs144399727(G,T); rs140040948(A,G); rs73121650(G,A); rs74424196(G,A); rs7541015(T,A); rs617383(T,C); rs74147204(A,G); rs376501627(G,T); rs73121653(T,A); rs77530750(A,G); rs74802762(A,G); rs67501358(G,A); rs115118437(A,G); rs371714779(G,T); rs116691192(T,C); rs73121655(A,G); rs6683160(A,C); rs373170952(C,T); rs200106801(T,A); rs4545325(G,A); rs674446(C,A); rs12407646(C,T); rs114173853(C,T); rs10495391(G,A); rs1362841(T,C); rs12078693(C,G); rs11801278(A,G); rs116192881(T,C); rs192404970(T,C); rs114555331(A,G); rs74147205(G,A); rs7552374(T,C); rs115800629(T,G); rs10925345(C,T); rs10802592(A,G); rs116118735(G,A); rs10802593(A,G); rs115427210(C,T); rs55702285(C,G); rs116833437(C,T); rs10925346(C,T); rs73121662(C,T); rs114335212(C,G); rs76312231(A,G); rs1832340(G,C); rs115831905(G,A); rs1243110(A,G); rs10925347(A,T); rs12408892(C,T); rs11587851(C,T); rs72764083(T,C); rs72764084(A,T); rs628304(C,T); rs11584450(G,A); rs61832418(G,C); rs55924146(T,A); rs635214(T,C); rs75369658(G,A); rs636167(G,A); rs1362844(C,T); rs652792(T,C); rs653351(T,A); rs6663668(T,G); rs78516773(G,A); rs664779(T,A); rs79873879(A,G); rs12127545(T,C); rs78786832(C,A); rs16835024(G,A); rs581645(G,A); rs581693(A,G); rs12137834(C,T); rs10925348(T,A); rs75959277(G,A); rs12126976(A,G); rs679735(T,C); rs680160(T,C); rs596655(G,T); rs138839026(G,A); rs75804850(G,A); rs666787(A,G); rs80069255(C,A); rs611392(C,A); rs78771356(C,T); rs114197095(A,T); rs141718974(A,T); rs11806248(G,A); rs77988258(C,T); rs632275(C,G); rs268784(C,A); rs268783(G,A); rs268782(T,C); rs268781(A,G); rs1345498(T,C); rs1540375(C,G); rs6675194(G,T); rs268779(A,G); rs78522423(A,C); rs6669874(T,C); rs6667286(A,T); rs792561(T,C); rs16835036(T,C); rs111570004(T,G); rs73123341(C,T); rs76308577(G,A); rs585717(C,T); rs74952539(T,C); rs73123343(C,T); rs888438(G,T); rs17627064(C,T); rs11810170(C,G); rs17627087(T,A); rs1362842(G,A); rs6428999(G,A); rs6429000(G,C); rs73123346(T,C); rs888439(T,C); rs73123348(A,G); rs76650090(T,C); rs11811065(C,A); rs11806340(A,T); rs78430722(G,A); rs116277607(G,C); rs12133002(A,G); rs10925351(T,C); rs138141093(G,T); rs111679859(G,C); rs10802594(C,T); rs73123353(T,A); rs76445055(C,T); rs10925352(C,T); rs16835048(C,T); rs7527600(A,T); rs16835052(T,C); rs6663810(C,G); rs77278513(G,A); rs35272209(G,A); rs1813697(C,T); rs116392890(G,A); rs10925353(A,G); rs115124358(G,A); rs10925354(T,C); rs2111735(C,T); rs114451930(C,T); rs918241(C,A); rs10802595(A,G); rs138393308(A,C); rs950964(T,C); rs16835058(T,C); rs1421207(C,G); rs6689924(A,G); rs10495392(C,T); rs961121(G,T); rs10495393(T,C); rs961120(T,G); rs55955432(G,A); rs114616300(C,G); rs115616968(C,T); rs59491546(A,G); rs147313342(G,A); rs34208676(A,G); rs76271703(G,A); rs17678801(C,T); rs12025027(C,T); rs10158497(A,G); rs2065985(G,A); rs111950100(T,A); rs6429001(G,A); rs12045453(T,A); rs2058931(G,A); rs2058932(G,A); rs10925355(A,G); rs56938085(G,A); rs17678954(A,T); rs7551647(T,C); rs7551532(A,G); rs139122391(C,T); rs10495394(A,G); rs1933232(A,G); rs12043216(A,G); rs4233470(C,T); rs4659491(T,C); rs2275288(C,T); rs2275287(C,T); rs7526874(G,A); rs12091915(A,T); rs1004466(T,G); rs112449104(G,A); rs142635102(G,T); rs7519473(A,C); rs75088605(G,A); rs181994521(A,C); rs2098504(A,G); rs56360482(A,G); rs6429002(T,A); rs6429003(C,T); rs76324217(G,T); rs74147221(C,T); rs7548636(C,A); rs61832458(C,T); rs79112027(T,C); rs147368812(T,C); rs61832459(T,G); rs75477931(A,C); rs7513160(C,T); rs7513357(C,T); rs6661133(C,G); rs7520389(C,T); rs61834060(T,C); rs7536817(T,C); rs6429004(G,A); rs12046077(T,C); rs181705216(G,A); rs7537963(A,G); rs7526639(C,T); rs7526759(C,T); rs79386322(G,A); rs58114547(G,A); rs7526245(T,G); rs10802596(A,T); rs116779943(G,A); rs7534580(G,A); rs4659780(G,A); rs7530547(A,T); rs7533036(T,G); rs1856287(G,T); rs1833420(A,G); rs73125455(T,C); rs10754595(G,T); rs12729955(T,C); rs190110925(T,C); rs10925358(C,T); rs6682911(T,C); rs142019218(C,T); rs2860125(C,T); rs12565306(C,T); rs6686679(A,C); rs73125457(T,C); rs12024073(A,G); rs10802597(C,T); rs4659781(C,T); rs4659782(T,C); rs12095763(A,G); rs4659783(A,T); rs1421210(A,G); rs1345497(G,A); rs6694083(A,C); rs2891873(A,G); rs79437802(C,G); rs7538075(C,A); rs1421209(A,T); rs10925359(A,G); rs10802598(A,G); rs112323241(G,A); rs112643141(C,T); rs2111737(T,C); rs2385809(G,A); rs2891874(C,T); rs10754596(A,G); rs1345496(C,T); rs58185430(A,G); rs12024815(A,G); rs992148(G,A); rs992147(C,G); rs184628010(T,C); rs7532774(A,G); rs146765853(G,A); rs76109607(C,T); rs79264835(G,C); rs11802494(T,C); rs12072541(G,A); rs2058934(A,C); rs12069189(T,C); rs12066348(G,A); rs10754597(T,G); rs10754598(T,A); rs16835116(C,T); rs1421208(C,T); rs2058933(G,A); rs16835122(T,G); rs141207830(A,G); rs16835126(A,C); rs16835128(C,A); rs6687722(C,T); rs9651079(G,A); rs12134865(C,T); rs12067632(A,G); rs12029451(A,G); rs7530279(C,G); rs1030116(T,C); rs143785160(C,G); rs2385810(C,T); rs138380492(G,A); rs1030115(A,G); rs10737814(A,C); rs7547502(T,G); rs10737815(T,C); rs10925363(A,G); rs10925364(C,T); rs6694999(A,G); rs12127036(A,G); rs10925365(G,T); rs6682878(C,T); rs59608377(A,G); rs59008456(G,A); rs16835134(C,G); rs10802599(G,C); rs16835136(G,A); rs962915(C,G); rs10802600(T,C); rs60874299(T,C); rs10802601(A,G); rs10925366(G,A); rs10802602(C,G); rs61834133(C,G); rs61834134(C,T); rs10925367(T,C); rs34345736(C,T); rs10925368(A,G); rs34548782(C,T); rs192217866(T,G); rs12727992(G,A); rs12728123(G,A); rs12164567(A,G); rs12728161(G,A); rs12729454(C,T); rs12164577(T,C); rs12749456(A,G); rs12753804(T,C); rs12729784(C,T); rs12129966(T,G); rs10925369(T,A); rs10925370(T,C); rs12124563(A,G); rs12124564(A,G); rs34841839(T,C); rs12743962(G,C); rs12749212(C,A); rs12734757(T,C); rs1362843(G,A); rs954579(G,A); rs12071287(A,G); rs59069459(C,A); rs57362400(A,C); rs58409558(G,C); rs184867032(A,G); rs58913393(A,G); rs59198429(G,A); rs58740045(A,T); rs58713790(G,A); rs58778960(G,A); rs57244918(A,C); rs59008834(C,T); rs1832391(A,G); rs7545410(C,G); rs7514372(A,G); rs7516798(T,C); rs7516891(T,C); rs7516997(T,A); rs55989929(G,A); rs61134816(A,T); rs2543036(A,G); rs2787106(T,C); rs918240(A,G); rs918239(A,C); rs918238(T,C); rs35524456(A,C); rs74147238(T,G); rs12755424(C,T); rs116123803(C,T); rs35588486(C,T); rs192373924(C,G); rs73127272(G,A); rs60937147(G,C); rs35201933(T,A); rs28690813(A,T); rs974893(C,A); rs73127280(T,A); rs2787105(G,C); rs147492107(G,A); rs1362840(A,C); rs78465436(T,G); rs73127289(A,G); rs2808221(T,A); rs59285584(C,T); rs140288715(A,G); rs2543039(A,T); rs115532552(A,C); rs16835142(T,C); rs2808224(T,C); rs2808225(C,A); rs116441166(T,C); rs375938347(T,C); rs2160857(C,T); rs114007521(T,C); rs188844843(G,A); rs114500010(T,C); rs6429005(A,G); rs2543038(A,G); rs10802604(A,T); rs147777313(G,A); rs61406707(C,G); rs58201575(T,G); rs2543037(T,G); rs10925372(C,G); rs2491323(T,G); rs12048201(T,G); rs2808226(T,C); rs16835155(G,C); rs2185016(C,T); rs116227452(C,T); rs10925373(A,T); rs2787102(A,G); rs10925374(T,C); rs7552427(C,T); rs2787110(T,G); rs116128470(T,G); rs2787109(T,C); rs76959365(A,G); rs57205543(T,C); rs2787108(T,C); rs9428376(C,A); rs9428666(G,T); rs2808227(T,C); rs2050657(C,A); rs58775990(A,T); rs57907893(G,C); rs2042052(C,T); rs74147242(T,G); rs2050656(C,T); rs888441(A,G); rs116344486(C,T); rs12023820(A,G); rs12022790(G,C); rs2787103(T,C); rs10925380(T,G); rs11577314(G,A); rs2787107(A,G); rs147657466(T,A); rs10802607(T,C); rs147003424(G,C); rs12024357(T,C); rs112509226(C,T); rs12023636(A,G); rs10802608(T,A); rs12026757(A,G); rs4336842(A,G); rs4634897(G,T); rs10925384(G,C); rs6429006(C,A); rs4399145(G,A); rs4475735(A,G); rs4478798(A,G); rs184148788(A,C); rs7545575(A,G); rs7534225(C,T); rs7545768(A,G); rs4638118(G,A); rs7514255(G,T); rs16835165(G,C); rs16835167(G,A); rs16835168(C,T); rs16835170(T,C); rs143059857(C,A); rs66539875(G,T); rs12074134(T,C); rs12073120(A,T); rs10925385(T,C); rs10925386(C,A); rs12405398(T,C); rs7550611(A,G); rs28420757(C,T); rs28535193(T,C); rs16835174(T,G); rs143134805(C,T); rs7551196(A,G); rs373940313(A,G); rs76389372(A,G); rs4290053(T,A); rs145529645(G,C); rs16835184(G,A); rs12032009(T,C); rs6674456(G,A); rs150453467(G,A); rs12073854(T,G); rs6678397(G,T); rs6670163(T,G); rs6703660(C,T); rs16835185(C,G); rs10925387(C,T); rs78317370(C,A); rs144186480(A,G); rs74147246(G,A); rs57242802(C,G); rs79510842(A,G); rs10925388(A,G); rs10925389(T,C); rs74147247(A,G); rs10925390(A,G); rs139414435(C,T); rs10925391(A,C); rs4615830(A,C); rs76415279(G,C); rs74147248(A,T); rs77258527(G,A); rs6672004(T,G); rs78095833(C,T); rs138079482(C,T); rs74147249(C,T); rs74147250(C,T); rs61832494(C,G); rs9661385(A,G); rs139973605(C,T); rs73102457(C,T); rs10802609(G,C); rs10925394(A,G); rs190912093(G,T); rs145236784(G,A); rs10925395(A,G); rs187812838(T,C); rs7511662(C,T); rs17682073(A,G); rs11583145(T,C); rs16835188(C,T); rs4659786(A,G); rs12079827(G,T); rs10925396(T,C); rs12131332(T,A); rs16835191(T,C); rs4376724(A,C); rs10754601(A,G); rs10925398(A,C); rs10754602(T,A); rs10925399(T,C); rs10925400(T,C); rs4233471(G,A); rs141575081(C,T); rs74147258(A,G); rs145391912(C,T); rs184101828(G,A); rs10925401(T,C); rs77459544(G,A); rs4393145(G,T); rs7522832(A,G); rs12407312(A,G); rs4659787(C,T); rs56369530(T,C); rs11799387(C,T); rs77582588(G,A); rs147509036(A,G); rs188354239(C,A); rs16835213(A,C); rs10925402(G,A); rs6677656(T,C); rs6677658(T,C); rs10925403(A,T); rs12734448(C,T); rs12041443(A,G); rs10925404(G,T); rs10925405(C,T); rs4255374(G,T); rs75807432(A,C); rs10925407(G,A); rs148994141(C,T); rs147282057(C,T); rs10925408(G,A); rs56363825(G,A); rs12569314(C,A); rs139333804(G,A); rs12039295(A,C); rs4492606(T,G); rs141871872(G,T); rs4484913(C,A); rs147122040(C,T); rs12058770(C,A); rs4130683(T,C); rs112515982(A,G); rs12138976(T,C); rs12061692(C,G); rs139494044(C,T); rs7547960(G,C); rs6429009(C,T); rs143347329(C,T); rs12064384(C,T); rs12047277(G,T); rs7543586(T,G); rs4233472(A,G); rs150756464(A,G); rs139559191(G,A); rs12091802(A,G); rs144994027(A,G); rs55966904(G,C); rs4659495(C,A); rs4659788(A,T); rs7555780(T,C); rs12240094(G,A); rs7556153(T,A); rs12239122(C,G); rs10802611(T,C); rs10737816(A,C); rs6666845(G,A); rs185910947(C,T); rs4291489(C,T); rs10802612(T,C); rs143655347(A,G); rs148274474(G,A); rs4659496(C,T); rs4659497(A,G); rs6673700(G,A); rs4465196(T,C); rs4659791(T,A); rs4659792(C,A); rs12744635(T,C); rs146128763(A,G); rs13376665(G,A); rs12691536(C,T); rs73104423(A,G); rs138192404(G,A); rs12750546(T,C); rs16835216(A,G); rs148220794(G,A); rs10925411(T,C); rs10754603(T,C); rs17631862(C,T); rs16835219(G,A); rs12404673(C,A); rs12145251(A,G); rs59976682(A,G); rs11581397(C,T); rs11577402(G,A); rs151057545(C,T); rs144611443(C,T); rs7547449(C,A); rs12724256(A,T); rs180711819(A,G); rs6673182(G,T); rs6673187(G,C); rs10925412(A,G); rs6429010(T,A); rs4633277(C,T); rs4579745(T,A); rs192997414(G,A); rs140331513(A,G); rs4593814(C,A); rs186577871(A,G); rs16835232(T,A); rs111251225(G,A); rs143837721(C,T); rs148164673(A,G); rs72765972(G,A); rs139150070(A,G); rs16835235(C,T); rs16835238(G,A); rs185055467(C,T); rs139899014(C,T); rs149978719(C,T); rs113850354(G,A); rs74147260(C,A); rs186610757(A,G); rs7528353(T,A); rs7525969(A,C); rs140929958(C,T); rs6674675(A,G); rs10458440(T,C); rs4388696(C,T); rs10458441(A,G); rs7532079(A,G); rs189527773(G,A); rs146024374(C,T); rs143369196(G,A); rs185811364(G,A); rs142514599(A,C); rs4498793(T,G); rs4590661(T,C); rs6429013(C,A); rs12123446(G,A); rs75184339(A,T); rs77680952(T,A); rs79892271(T,C); rs4233474(C,T); rs16835242(A,C); rs191986669(G,A); rs12132285(C,A); rs12121168(A,T); rs3924864(T,C); rs4376723(T,G); rs201361069(A,T); rs4418585(C,A); rs113790162(C,T); rs7552945(T,C); rs4528105(C,G); rs4272613(T,A); rs73104473(C,T); rs4330910(T,C); rs113221427(T,A); rs115179236(A,G); rs10429914(T,C); rs60811417(C,T); rs115762102(T,C); rs7537614(A,G); rs74147263(T,C); rs114719843(G,C); rs73104482(G,A); rs76901078(T,A); rs73104485(G,C); rs4537543(C,T); rs7540869(A,G); rs7529251(C,T); rs7543367(T,C); rs75484013(G,A); rs10925414(T,C); rs17633019(G,A); rs10925415(A,G); rs12754712(C,G); rs11808468(C,A); rs7535793(C,T); rs7549654(T,C); rs7552202(T,C); rs2997967(A,G); rs2998400(G,T); rs12139603(C,T); rs2997971(A,G); rs2998401(T,C); rs10925416(C,T); rs12028845(A,G); rs2927926(A,C); rs10925417(A,G); rs77653511(T,A); rs74328949(G,T); rs2927927(A,G); rs2927928(G,A); rs6661949(T,C); rs2998402(T,C); rs12087410(C,G); rs6666203(A,G); rs6702161(C,T); rs73106464(A,T); rs146572084(T,C); rs1842078(T,C); rs60284110(T,C); rs74147271(C,T); rs7547289(C,A); rs2927929(T,C); rs2927930(A,G); rs2805419(T,C); rs2805420(G,A); rs10925418(T,C); rs2927931(C,T); rs9428377(A,G); rs11807644(G,T); rs11806224(A,T); rs12239686(T,C); rs12240168(C,G); rs12240206(C,T); rs11584859(A,G); rs113291480(G,A); rs73106477(C,T); rs2927932(G,A); rs75986783(C,A); rs2998404(A,G); rs2927933(G,A); rs10925420(T,C); rs2100969(A,G); rs2086209(C,T); rs2893584(T,C); rs4659796(G,A); rs10925421(G,C); rs114468854(T,C); rs189420808(A,G); rs6429014(C,A); rs6429015(C,T); rs872817(A,G); rs872816(C,T); rs6429016(C,T); rs6429017(C,T); rs191877191(G,C); rs7521183(C,A); rs2392692(G,A); rs2392691(C,G); rs2392690(C,T); rs2893583(C,G); rs34889106(T,G); rs6429018(G,A); rs4351630(G,T); rs2927934(T,C); rs4512635(T,A); rs374313309(C,T); rs371878264(G,A); rs3765097(C,T); rs6682119(G,A); rs56850445(A,G); rs56084906(T,C); rs61380594(A,G); rs61182572(A,G); rs78281932(G,A); rs2045955(T,C); rs11588591(G,A); rs1478912(T,C); rs74147276(G,A); rs1382583(G,T); rs1382584(G,A); rs1351201(T,A); rs16835272(T,C); rs189344553(T,C); rs2045956(A,C); rs2127153(G,A); rs2808222(G,A); rs3753617(A,C); rs74147280(G,A); rs1842079(A,G); rs1842080(A,G); rs1842081(A,C); rs1842082(G,C); rs1478913(C,G); rs74147282(C,T); rs74147283(A,G); rs3766834(A,G); rs2618679(A,G); rs12063070(C,T); rs1382586(C,T); rs75735124(G,A); rs7532096(C,T); rs186035715(T,G); rs10925424(T,C); rs12094480(A,G); rs10925426(C,T); rs16835279(A,T); rs7524451(G,A); rs2805440(A,G); rs12048032(G,A); rs2618681(A,G); rs4436381(A,C); rs151136401(C,A); rs4329502(C,A); rs4397648(T,C); rs4436382(A,G); rs4625270(T,C); rs4367778(G,C); rs4329503(C,T); rs12123335(C,T); rs12142057(A,G); rs10802613(A,G); rs10754604(A,G); rs10754606(A,T); rs12046814(A,T); rs12021902(G,A); rs9428379(G,A); rs10159268(T,A); rs10925429(T,C); rs10925430(A,G); rs10925431(G,A); rs10754607(G,A); rs10754608(T,C); rs1871303(G,A); rs922489(T,C); rs922490(A,T); rs1871304(A,T); rs6669057(G,A); rs6657818(A,G); rs6657946(A,C); rs6429019(T,C); rs6663913(T,C); rs6429020(A,T); rs6663929(T,C); rs6661372(A,G); rs185308498(A,C); rs10802614(A,G); rs115395056(C,T); rs2998405(T,C); rs150758308(G,A); rs2927938(G,A); rs11577191(A,G); rs16835294(A,G); rs9428380(G,A); rs6655991(C,G); rs74147286(C,T); rs6429021(T,G); rs6429022(G,C); rs6429023(A,G); rs73110414(C,T); rs117628294(G,A); rs138758887(G,C); rs8179365(A,G); rs2618683(G,A); rs76477645(T,C); rs147548201(A,G); rs139389635(C,T); rs80127105(C,T); rs78020632(C,T); rs12093514(T,C); rs113677520(A,G); rs2927935(G,T); rs116074106(G,A); rs113640003(T,C); rs2998406(C,T); rs78248272(C,A); rs73110419(A,C); rs12142897(A,G); rs1982645(T,C); rs12117452(G,A); rs16835307(C,T); rs12060093(G,A); rs6673954(A,G); rs138720561(A,G); rs9428668(G,T); rs2927936(G,C); rs2927937(G,A); rs2998407(C,G); rs75134454(T,C); rs7534841(A,G); rs12058655(A,G); rs7535046(A,G); rs2026287(T,G); rs2927941(A,T); rs2997973(C,G); rs2998408(A,G); rs2927942(T,G); rs10925432(G,A); rs2127154(C,T); rs12069211(C,T); rs2997974(G,A); rs112782987(C,T); rs2997975(G,A); rs2127155(G,T); rs112290804(G,A); rs12022208(A,C); rs12022241(A,G); rs147831574(C,T); rs150077761(G,A); rs61833801(C,T); rs112562917(C,T); rs2086210(C,A); rs113692544(C,T); rs2255277(G,T); rs2010045(C,T); rs2255271(C,G); rs2010033(G,A); rs2010032(T,C); rs2010030(A,G); rs10495397(A,G); rs16835325(C,T); rs13374561(G,A); rs1382588(A,G); rs78053841(G,A); rs2805422(G,A); rs2618698(G,A); rs2805423(G,A); rs2618699(T,C); rs2618700(C,G); rs10802615(G,A); rs2618701(C,T); rs3766839(G,A); rs2997976(T,C); rs2997977(A,G); rs3101797(A,G); rs12075439(G,A); rs147074840(C,T); rs2618702(A,G); rs2805425(G,A); rs75784461(T,C); rs144124181(T,C); rs11580260(T,C); rs10802616(G,A); rs2618669(T,C); rs3766840(A,G); rs3766841(A,G); rs3766842(G,A); rs6672388(G,A); rs2618651(T,C); rs2618721(C,T); rs2805428(C,T); rs2618716(C,G); rs77733360(G,C); rs12035214(T,C); rs111927044(T,C); rs139493499(C,T); rs10925438(G,A); rs114065667(G,A); rs12143355(C,G); rs182094946(A,T); rs151277144(C,T); rs80328839(T,A); rs9633356(A,G); rs10925439(T,C); rs8179362(A,G); rs12130761(A,T); rs2805429(C,G); rs75753138(A,G); rs35077109(G,A); rs2618690(G,A); rs2805430(A,C); rs2618691(G,A); rs2618692(G,A); rs2805431(A,C); rs2990542(T,C); rs2805432(A,G); rs2618693(G,A); rs1824855(T,C); rs1812409(A,G); rs1382587(G,A); rs2805434(A,G); rs2779357(T,A); rs2618694(A,C); rs2779356(G,A); rs2618695(T,C); rs2990541(G,A); rs2805435(G,T); rs2779355(T,C); rs2805436(A,G); rs2779354(T,C); rs2779353(T,C); rs2779352(T,C); rs2779351(G,A); rs184410053(G,C); rs2618696(G,T); rs2805437(C,T); rs2779350(G,A); rs2805438(G,A); rs71642897(G,T); rs3121872(G,A); rs3121873(G,A); rs2997978(G,C); rs115508235(G,A); rs2990540(T,A); rs61832560(T,A); rs12084251(A,T); rs2997979(G,C); rs2805439(A,G); rs1600256(C,T); rs2805441(T,G); rs2805442(A,G); rs76347764(A,C); rs2779359(T,C); rs2805443(G,A); rs10737817(G,A); rs2779360(T,C); rs12061334(C,T); rs2618703(C,T); rs2247192(T,C); rs77619056(A,G); rs149242656(G,A); rs2805445(G,C); rs12141713(G,A); rs12134408(T,A); rs2618709(G,A); rs10925444(T,C); rs10925445(C,T); rs2779361(T,G); rs10925446(G,A); rs10925447(G,C); rs12137163(G,T); rs2779362(T,G); rs12137167(G,T); rs2805446(T,C); rs12145623(C,T); rs12137978(G,A); rs114356013(C,T); rs2779365(A,G); rs1930308(G,A); rs12085148(T,C); rs2779366(T,G); rs10925449(C,G); rs2061841(G,A); rs16835364(C,T); rs2779367(T,G); rs147989798(G,A); rs2490928(T,C); rs10925450(A,G); rs111629676(C,T); rs117225144(G,A); rs187487938(G,C); rs2805449(G,T); rs2779369(C,T); rs12047583(T,C); rs2779370(G,A); rs2618718(T,C); rs2618674(T,C); rs3766844(T,C); rs3766845(T,A); rs2618678(T,C); rs115264366(G,A); rs2618680(A,G); rs10925451(A,G); rs2779371(T,C); rs10925452(C,T); rs12409861(G,A); rs2805450(T,C); rs2490929(G,C); rs2483038(T,C); rs2257106(T,C); rs2257101(T,G); rs2257096(A,G); rs4347205(C,A); rs2257095(A,G); rs149915000(G,A); rs56885757(G,T); rs1975961(A,G); rs1975960(A,C); rs2618673(T,C); rs2618672(C,T); rs1963523(A,G); rs146883800(C,T); rs2779372(A,G); rs2779373(T,A); rs2618671(C,G); rs2779374(T,C); rs7517131(A,G); rs2618670(C,G); rs1547279(T,C); rs10754610(G,A); rs2805452(C,G); rs2779376(T,A); rs2618668(T,C); rs2618667(A,G); rs2779377(T,A); rs183704095(C,A); rs2618666(A,G); rs116825502(G,A); rs74915980(G,A); rs10754611(A,G); rs2779378(A,G); rs2779379(T,G); rs189506898(G,A); rs2779380(T,C); rs2618665(T,C); rs2618663(A,G); rs2618662(A,G); rs2618661(T,C); rs2253273(A,G); rs2805453(T,C); rs61832577(T,C); rs2618660(A,G); rs139144691(G,A); rs2779383(A,G); rs111903308(A,G); rs75117670(C,T); rs2306238(G,A); rs61832578(T,G); rs2805454(T,C); rs146026459(A,G); rs10802618(G,T); rs2779384(C,T); rs79868233(C,A); rs58274684(A,C); rs183075515(A,C); rs61832580(T,C); rs2805456(G,A); rs57646193(A,G); rs2618656(A,G); rs10925456(G,A); rs2805457(C,T); rs2805458(C,T); rs77300928(G,A); rs2618654(T,G); rs2779385(G,C); rs2618653(A,G); rs2805459(G,A); rs2805460(A,T); rs2779386(T,C); rs75759545(G,A); rs7521789(A,G); rs2779387(A,C); rs2805461(A,G); rs2779389(A,C); rs2805463(A,G); rs10754612(C,A); rs2805464(G,A); rs186203927(C,T); rs16835391(G,T); rs2805465(G,T); rs16835398(G,A); rs2805466(A,G); rs2779390(A,C); rs2805467(A,G); rs115108564(A,G); rs2805468(A,G); rs2779391(T,C); rs12067971(T,A); rs78410736(A,G); rs76178515(A,C); rs59123049(G,C); rs2805471(T,C); rs61832596(C,G); rs2127148(T,G); rs138056299(G,C); rs2061836(T,C); rs2805473(C,G); rs2779392(A,G); rs2805474(G,A); rs2779393(A,G); rs2779394(T,C); rs1382582(A,G); rs722581(T,C); rs74147445(G,A); rs2805475(A,G); rs2805476(G,C); rs2805477(A,C); rs2779395(C,T); rs2805388(G,A); rs2779396(T,C); rs149812793(G,A); rs2779397(C,T); rs1930310(A,G); rs2169902(T,C); rs1930311(G,T); rs1930313(G,A); rs2127147(C,T); rs2010430(G,A); rs1031862(T,C); rs199852415(C,T); rs201207200(T,C); rs75733509(T,A); rs77071137(C,A); rs2100972(C,T); rs2100971(C,T); rs2100970(C,T); rs2779400(A,T); rs2805389(A,G); rs3766865(A,G); rs3766866(C,T); rs2618720(A,T); rs41476050(C,T); rs2248295(G,A); rs2805390(A,G); rs2779401(C,T); rs1824860(C,T); rs1824859(G,A); rs141530209(T,A); rs2779403(T,G); rs115967772(G,A); rs139672578(T,G); rs2805391(T,C); rs2618719(A,C); rs2805392(T,C); rs2805393(G,A); rs12129119(T,C); rs2805394(T,C); rs2779404(C,T); rs2805395(G,A); rs2618717(C,T); rs2805396(G,A); rs78159899(G,A); rs2990544(A,G); rs2779405(G,T); rs2990545(T,A); rs2805397(C,A); rs10218600(C,A); rs2779406(C,T); rs191397911(G,A); rs2805398(A,C); rs142907829(C,G); rs2805399(T,C); rs2805400(G,A); rs34729156(G,A); rs2779407(C,T); rs79843107(A,G); rs2779408(C,T); rs12742423(T,A); rs2618686(A,G); rs2779409(G,A); rs149756745(G,A); rs2927940(G,T); rs147592982(C,G); rs2805401(G,A); rs2779410(T,G); rs61832624(C,G); rs2805402(G,A); rs2779411(G,T); rs2779412(G,A); rs12139829(C,T); rs2618677(G,A); rs2618676(C,T); rs2779413(C,G); rs6689392(C,A); rs2779414(A,G); rs2618675(C,T); rs78583737(G,A); rs74877090(G,A); rs2779415(C,A); rs10925459(C,T); rs2779416(G,A); rs12141182(C,T); rs10157412(G,A); rs10159419(T,C); rs6693543(C,T); rs10157579(G,A); rs59644507(C,A); rs12131136(A,C); rs10157121(T,C); rs12134560(G,T); rs12131976(T,G); rs2779417(A,G); rs2805403(G,T); rs2779418(C,T); rs2779419(A,G); rs2990546(T,G); rs4528106(G,A); rs2805404(T,C); rs10925460(G,A); rs12135525(G,T); rs12132980(T,G); rs12133009(T,A); rs12135600(G,A); rs12133069(T,G); rs145257138(A,G); rs12132315(A,G); rs2805405(C,T); rs12133120(A,C); rs2618704(G,A); rs10925461(A,G); rs61832625(C,T); rs76047569(A,G); rs7524496(T,C); rs74929626(G,C); rs7532497(G,T); rs2779421(G,C); rs7555843(C,T); rs12691537(C,T); rs7556030(C,T); rs2990547(C,T); rs7527508(T,C); rs7513677(C,T); rs10925462(A,G); rs10754613(G,A); rs2779422(A,G); rs10925463(C,T); rs35280595(T,C); rs10925464(A,G); rs2255179(T,A); rs28604544(T,C); rs28457838(G,A); rs28441340(G,A); rs28614786(A,G); rs28758333(C,T); rs28588355(A,G); rs10802622(G,A); rs12125549(A,G); rs79901985(A,G); rs1842083(A,G); rs1842084(A,G); rs1842085(G,A); rs7534483(T,A); rs34542976(T,C); rs2618705(T,C); rs56181727(T,C); rs4415553(C,T); rs2392628(T,C); rs2893573(T,G); rs142464452(A,G); rs12042518(C,T); rs7554280(C,T); rs7520927(A,G); rs7554494(C,G); rs2618707(A,G); rs2127157(C,T); rs117948798(A,G); rs10925465(G,C); rs10925466(C,G); rs2997969(T,C); rs12140714(C,A); rs71642899(G,A); rs145968528(A,C); rs1842086(T,G); rs1412708(G,A); rs1842087(C,T); rs1478914(G,A); rs2779423(C,T); rs2779424(G,T); rs2805408(A,G); rs60893259(G,C); rs146657526(G,A); rs2618708(T,C); rs2618710(G,C); rs12131801(A,G); rs2251514(A,G); rs13375271(A,G); rs13375361(T,C); rs2779425(C,T); rs2618711(T,C); rs2779426(G,A); rs6429026(G,C); rs7522458(C,T); rs1564272(A,G); rs75798536(G,A); rs6683323(A,G); rs149251523(C,T); rs1987939(G,A); rs1987938(G,A); rs117513061(T,A); rs981302(C,G); rs9970866(T,C); rs981301(G,A); rs2779427(T,C); rs12725303(G,A); rs74147484(A,G); rs12043270(C,T); rs12033746(T,C); rs2805409(A,C); rs2805410(A,G); rs6689871(T,C); rs2618712(C,T); rs2805411(G,A); rs1332777(A,G); rs79721844(G,A); rs2779428(G,A); rs2779429(T,A); rs59574575(A,G); rs2618713(C,T); rs2779430(T,C); rs2779431(T,C); rs2618714(T,G); rs1382589(A,G); rs1824857(A,T); rs2618715(G,A); rs2997970(G,A); rs2927943(T,C); rs2805412(A,G); rs2779432(C,T); rs2805413(A,G); rs1478915(G,A); rs113802000(G,A); rs12136895(G,A); rs1478916(C,G); rs3766869(G,A); rs1842088(A,G); rs1842090(C,T); rs2990548(A,C); rs1824858(C,A); rs1817410(A,G); rs12239847(A,G); rs1855129(G,A); rs1074189(A,G); rs60876482(C,T); rs78693701(A,C); rs1086690(G,A); rs1086691(G,A); rs2127159(C,T); rs34350977(T,C); rs34658370(C,G); rs148736520(C,T); rs791540(C,T); rs35851096(C,T); rs58615439(G,C); rs77159536(G,A); rs2805418(G,A); rs791541(A,T); rs955882(G,C); rs1412707(C,T); rs707193(C,T); rs68176363(A,T); rs66837875(C,A); rs791543(G,A); rs141958298(G,A); rs79373028(C,A); rs142166122(G,A); rs143389392(G,A); rs112672011(T,A); rs141392860(T,G); rs2779347(A,C); rs144924490(C,T); rs12409807(A,G); rs12410114(T,A); rs16835465(C,A); rs2151183(A,C); rs2779348(T,G); rs2779349(T,C); rs113940538(G,A); rs78423676(A,G); rs35601523(A,G); rs615619(A,G); rs13374055(C,T); rs74147118(G,C); rs74147119(T,C); rs13376031(A,G); rs77347263(C,T); rs1717783(A,G); rs10925473(C,T); rs7546045(C,T); rs12121663(C,T); rs6429029(T,C); rs6666311(T,C); rs7518640(A,G); rs146677105(T,C); rs146623914(T,C); rs75198469(G,A); rs143326382(C,T); rs10733119(A,G); rs16832058(A,G); rs114534505(G,A); rs3820216(A,G); rs3766871(G,A); rs77042224(T,G); rs12097234(T,C); rs596502(C,T); rs10925474(A,G); rs949697(C,G); rs489872(T,C); rs76380019(C,T); rs507797(A,C); rs142352244(G,A); rs6672539(T,C); rs6670041(A,T); rs7529695(T,C); rs6429030(G,C); rs489088(T,C); rs616734(T,G); rs1775833(A,C); rs7541221(G,A); rs578741(A,G); rs553267(T,C); rs1775836(T,C); rs6429031(C,G); rs61834867(T,C); rs6671652(T,A); rs74147124(T,A); rs6683048(G,A); rs6659362(C,G); rs571092(T,C); rs571026(T,C); rs512336(A,G); rs7531957(T,G); rs615869(G,A); rs939698(G,A); rs663152(A,T); rs678541(C,T); rs10159353(C,A); rs12123043(G,A); rs1759123(A,G); rs12725099(C,T); rs1759121(G,C); rs137892095(A,G); rs1759119(G,A); rs147312790(A,G); rs1717782(G,A); rs1967581(A,G); rs1967582(G,A); rs148541127(C,T); rs142862036(C,T); rs476078(T,C); rs1891557(T,C); rs10925477(T,C); rs10925478(G,C); rs10802626(G,A); rs12563366(A,G); rs1967579(T,G); rs1967580(C,A); rs11585501(C,A); rs10925479(A,T); rs10925480(A,G); rs7526807(C,T); rs7538471(A,G); rs75658478(G,A); rs3736543(G,A); rs6698949(G,A); rs56728595(A,G); rs2139981(C,A); rs2139982(T,A); rs74147180(T,C); rs115823392(C,T); rs671348(C,T); rs143552839(A,G); rs35399041(T,C); rs146523976(T,C); rs578152(C,A); rs3753629(A,T); rs188895284(C,T); rs142213295(C,A); rs147578863(C,T); rs707189(T,C); rs1023214(A,G); rs505489(A,C); rs530109(T,C); rs78229019(G,A); rs3766875(T,A); rs117521315(C,T); rs626383(C,G); rs627201(A,G); rs1029088(C,A); rs483864(A,C); rs145204385(C,T); rs1475678(G,A); rs78712240(G,T); rs3766876(T,G); rs6429032(C,T); rs1342836(G,A); rs515088(A,G); rs7529291(G,A); rs6429033(G,A); rs112345899(C,T); rs76678214(A,G); rs11583646(G,A); rs11583669(G,A); rs4542202(A,G); rs11587550(C,T); rs34222875(G,A); rs112339788(C,T); rs10802628(A,G); rs111947371(A,G); rs1342835(C,T); rs3766877(C,T); rs113178331(T,C); rs11583033(A,G); rs112581211(T,C); rs12076934(A,G); rs1775835(C,T); rs7511898(A,G); rs1630261(T,C); rs138989087(G,C); rs7514424(T,G); rs138192174(C,T); rs149582354(A,C); rs3766878(A,G); rs16835566(C,A); rs114741035(A,T); rs548426(A,G); rs150751025(C,T); rs116577407(G,A); rs10495399(T,G); rs12725455(C,T); rs3766879(A,G); rs490987(A,G); rs490057(C,A); rs489969(G,A); rs74615107(A,G); rs112136690(T,C); rs487056(C,T); rs625006(A,G); rs115141379(C,A); rs139037532(C,A); rs112581119(T,A); rs10925483(A,G); rs11805641(T,A); rs138899382(A,G); rs684923(C,T); rs2184014(C,A); rs141708048(C,T); rs180914538(C,T); rs513189(A,G); rs611219(A,G); rs622625(T,C); rs78923354(T,C); rs939701(T,C); rs145377657(T,C); rs182692925(G,A); rs149178863(G,A); rs143294628(C,G); rs112185877(G,A); rs550231(C,A); rs138281633(T,A); rs115894581(T,C); rs669375(A,G); rs16835603(A,G); rs150375980(C,G); rs3766881(C,T); rs78292472(G,A); rs145975139(A,G); rs515474(C,G); rs589806(C,T); rs115178041(A,G); rs489001(G,T); rs74902329(A,G); rs590705(T,C); rs3766882(G,A); rs79450580(C,T); rs111951883(G,A); rs1949666(A,C); rs78223160(T,C); rs139088766(T,C); rs607785(T,A); rs959012(A,C); rs10925484(T,G); rs75183055(A,T); rs1342834(A,G); rs619137(G,A); rs475234(C,T); rs471647(G,A); rs559344(T,C); rs651250(G,C); rs77377851(C,T); rs114656105(A,G); rs10925487(C,T); rs77687614(C,T); rs112364106(A,T); rs1521746(C,G); rs677620(G,A); rs521707(G,A); rs677730(T,C); rs1953076(T,C); rs144812384(G,T); rs10925488(G,A); rs498869(G,A); rs10925489(C,T); rs12060573(C,T); rs74580364(A,G); rs144402582(G,A); rs375217959(C,T); rs114841529(A,G); rs1759126(A,G); rs115647177(T,C); rs6657332(G,T); rs477245(C,A); rs79022356(C,T); rs2012813(T,C); rs12141209(T,C); rs79660759(A,G); rs6429034(A,G); rs147118731(G,A); rs4659803(C,G); rs12217140(T,C); rs13374681(C,T); rs12097238(T,G); rs12097314(T,C); rs2069160(A,T); rs12562500(G,C); rs13374921(C,T); rs6665145(T,G); rs6662515(A,G); rs12059169(T,C); rs12121446(G,A); rs77377000(T,G); rs12408511(A,T); rs75585385(G,A); rs1533772(A,G); rs16835626(C,G); rs6676781(A,G); rs76553469(T,A); rs147575439(A,G); rs10925493(G,A); rs10802629(G,A); rs74373300(G,A); rs191855668(C,G); rs12124472(C,T); rs79611403(T,C); rs116706284(C,T); rs77224381(T,C); rs12074235(C,G); rs1879672(C,A); rs78119942(T,C); rs111236663(G,A); rs10925494(G,T); rs4659804(A,C); rs12404257(C,T); rs78531876(T,C); rs116164267(C,T); rs80025851(C,T); rs12119754(G,A); rs10802630(T,C); rs61832682(T,A); rs12032093(C,A); rs78286286(C,T); rs12032174(C,T); rs76723403(C,A); rs115888615(A,G); rs151290888(T,C); rs140502095(G,A); rs10925495(G,A); rs7532996(G,A); rs12062682(T,C); rs1521743(T,G); rs12028693(G,A); rs4659805(G,T); rs61832683(C,T); rs55885307(T,C); rs2461315(A,G); rs2797435(G,A); rs2256949(T,G); rs1521745(G,C); rs1521744(T,C); rs10925497(A,G); rs3736539(A,G); rs12121414(G,T); rs4427395(G,A); rs114666746(C,T); rs148979312(G,A); rs77961583(A,C); rs10925498(G,T); rs12754190(G,A); rs2797436(T,G); rs114619329(C,T); rs78352952(G,A); rs149293500(G,A); rs939699(C,T); rs57887440(A,G); rs182536296(G,A); rs2797437(T,A); rs11803385(G,A); rs2797439(G,A); rs12040571(C,A); rs73099995(G,T); rs12125625(A,C); rs142457162(G,T); rs1851290(A,G); rs2392695(A,G); rs12127746(A,T); rs12239308(T,A); rs12068043(A,C); rs140995784(A,G); rs2685299(C,T); rs2685300(A,G); rs115635360(G,A); rs2819758(A,C); rs9662438(T,G); rs149967238(C,T); rs2819757(A,G); rs189318216(C,T); rs12081586(G,A); rs78665423(C,T); rs2797441(C,T); rs76721410(A,G); rs2797442(A,G); rs114565811(T,A); rs2819775(T,G); rs142627781(A,G); rs75160509(A,C); rs144256966(G,A); rs2797444(C,T); rs7555850(C,T); rs6670697(A,G); rs2819774(T,A); rs74149914(G,T); rs2685301(C,T); rs12060532(C,G); rs12140998(G,T); rs74149915(C,G); rs10925500(C,A); rs2797445(C,T); rs143241713(T,G); rs2685302(T,C); rs1879673(G,A); rs12086956(T,G); rs4465197(C,A); rs1915781(G,A); rs2797446(A,C); rs2685297(T,C); rs114847736(C,T); rs139663730(T,C); rs2685296(A,G); rs2685295(A,G); rs2819772(T,C); rs73101974(A,G); rs61830281(A,G); rs960472(C,T); rs10925501(C,T); rs12145884(G,T); rs149188937(A,T); rs3905206(C,T); rs10925502(G,A); rs12567537(A,G); rs1521747(A,T); rs112512941(A,G); rs16835682(A,G); rs10925504(T,C); rs2797447(G,A); rs12141832(T,G); rs2797448(T,C); rs2819771(A,G); rs373729065(A,G); rs2685298(A,C); rs12143088(A,G); rs12057693(G,A); rs16835702(A,G); rs16835705(G,A); rs2797449(A,G); rs115649793(C,A); rs116772770(C,G); rs12146052(T,G); rs2685289(C,T); rs2819770(C,T); rs7527324(G,A); rs2819769(G,A); rs2685290(C,G); rs2685291(A,G); rs2819768(A,T); rs2819767(A,G); rs187400655(G,T); rs2685292(T,A); rs10925507(G,A); rs1474259(G,A); rs2177065(A,G); rs10495401(G,A); rs140116422(G,A); rs147290118(G,A); rs73101985(A,G); rs2819766(C,G); rs113726515(T,C); rs72753209(G,A); rs116233306(G,A); rs2685294(A,G); rs2222384(T,C); rs139241998(T,C); rs1464460(A,T); rs1464461(T,C); rs1464462(C,T); rs12081123(C,T); rs150605366(A,G); rs9645346(A,C); rs2819765(G,A); rs2253831(C,T); rs3817436(A,G); rs2819764(G,T); rs6690602(T,G); rs2819763(G,C); rs6699085(G,A); rs2819762(T,C); rs143451004(A,G); rs12120206(A,G); rs1521742(C,G); rs1464458(A,G); rs12123249(A,G); rs1949665(C,T); rs6668208(C,T); rs12134478(C,T); rs2819761(G,A); rs12126928(G,C); rs10802632(C,A); rs2253244(G,A); rs12125297(T,C); rs2253083(T,G); rs2253074(G,T); rs55977546(T,C); rs2250079(C,T); rs16835759(G,A); rs2250049(G,A); rs2250042(T,C); rs2250036(G,A); rs12742059(A,C); rs2249847(C,A); rs16835777(G,A); rs2249287(C,T); rs12565261(T,C); rs2249179(T,C); rs11584594(G,A); rs79387075(G,A); rs57827447(G,A); rs3766887(T,A); rs3766888(A,G); rs60147694(G,C); rs3766889(T,G); rs12755289(A,G); rs16835789(G,C); rs143900387(C,T); rs146860455(G,A); rs111441159(A,G); rs77426162(T,C); rs16835792(C,T); rs111616867(G,C); rs12135982(C,T); rs58025317(C,T); rs12737847(T,C); rs12733934(A,G); rs16835804(A,T); rs16835809(A,G); rs114895406(G,A); rs790889(T,C); rs201829896(C,T); rs79476275(C,G); rs2275690(T,C); rs1773471(A,G); rs2256242(A,G); rs16835818(G,A); rs6681352(A,C); rs76214638(A,G); rs1341870(A,G); rs145356180(A,G); rs113675540(G,T); rs5026204(G,A); rs16835821(T,C); rs113403176(C,G); rs138601215(G,C); rs114111854(C,T); rs790904(G,C); rs114289907(A,G); rs117645754(G,A); rs790903(A,G); rs790902(G,A); rs790901(A,G); rs790900(A,C); rs790899(G,A); rs117058809(G,A); rs11806850(T,C); rs2790345(T,C); rs12760444(C,T); rs1796909(A,G); rs114837762(G,T); rs10925509(A,G); rs1796910(T,G); rs10925510(T,C); rs61830311(A,G); rs12751842(T,A); rs1339642(G,T); rs12043362(G,A); rs2794817(T,C); rs138816044(G,A); rs2794818(T,C); rs35751717(C,T); rs1773455(A,G); rs1629280(C,G); rs2794819(A,G); rs111336328(C,T); rs182571531(C,T); rs1856580(G,T); rs7543732(A,G); rs2790347(A,G); rs2794820(G,T); rs34463991(G,A); rs1773457(C,T); rs2794821(T,C); rs1629566(T,C); rs1773458(T,C); rs2790348(T,G); rs77628775(G,A); rs113129182(G,C); rs7533051(A,G); rs7533057(A,G); rs2794822(A,G); rs2794823(A,G); rs2790349(A,G); rs2794824(A,T); rs141488432(C,T); rs16835838(G,A); rs1538606(G,A); rs9428385(G,C); rs1773459(G,A); rs2794829(C,T); rs2794831(T,A); rs148660379(G,A); rs10802633(A,C); rs790879(A,G); rs790880(A,T); rs13376113(A,T); rs114267651(G,A); rs790881(A,T); rs790882(T,A); rs790883(T,C); rs790884(C,T); rs790885(C,T); rs1086493(G,A); rs2819776(A,C); rs813173(T,C); rs790886(A,G); rs147394907(T,C); rs7550039(C,T); rs115743899(G,A); rs16835868(T,C); rs790887(A,G); rs16835869(G,C); rs74965250(A,T); rs790888(G,C); rs2794832(G,A); rs2794833(G,A); rs2794834(C,T); rs10925517(T,C); rs10925518(T,C); rs1773464(G,A); rs12057995(T,C); rs116057374(C,T); rs186532820(G,A); rs1112440(A,T); rs76868356(C,A); rs2794835(A,G); rs1891246(T,G); rs75716856(G,A); rs2275691(C,T); rs114303476(C,T); rs74376530(G,A); rs6703409(C,T); rs6678561(G,A); rs4659808(C,T); rs4659809(G,A); rs6703841(C,T); rs4659810(G,A); rs2486554(C,G); rs2486555(G,A); rs1773465(C,T); rs1796914(G,A); rs1613445(A,G); rs2486556(A,G); rs2794837(C,T); rs2790350(T,A); rs2819733(A,G); rs2819734(T,C); rs182154643(G,A); rs2790351(A,G); rs7517343(C,T); rs2819735(A,G); rs2794838(C,G); rs1773467(A,T); rs2794839(C,G); rs2819737(T,G); rs145927859(C,T); rs1773468(C,G); rs2794840(A,G); rs2790352(G,A); rs2096128(A,G); rs7551347(C,T); rs2487792(C,T); rs2790355(A,C); rs9428695(G,A); rs2493903(G,A); rs9428699(C,T); rs12024181(A,T); rs2819741(T,C); rs2794841(C,A); rs2819742(A,G); rs12067535(G,C); rs2819743(G,T); rs790894(G,C); rs790893(C,T); rs73106016(G,A); rs12025891(G,A); rs1891247(A,G); rs1891248(C,T); rs1935266(G,A); rs6695129(G,A); rs2275692(C,T); rs6429040(C,T); rs6429041(G,T); rs4659502(C,A); rs4659819(T,C); rs4659503(C,T); rs74595361(A,G); rs4659504(C,T); rs12036292(C,T); rs12026501(T,A); rs12025731(A,G); rs74703306(C,A); rs16835891(C,G); rs12594(A,G); rs16835904(C,T) |
| ccdsGene name | CCDS55691.1 |
| cytoBand name | 1q43 |
| EntrezGene GeneID | 6262 |
| EntrezGene Description | ryanodine receptor 2 (cardiac) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RYR2:NM_001035:exon90:c.C12842T:p.T4281M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6743 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DGV4 |
| ESP Afr MAF | 0.00106 |
| ESP All MAF | 0.000333 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 8.986e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal dystrophy;
Corneal opacities;
[Teeth];
Delayed primary teeth eruption;
Failure of secondary teeth eruption
OMIM Title
*180902 RYANODINE RECEPTOR 2; RYR2
;;RYANODINE RECEPTOR, CARDIAC
OMIM Description
CLONING
Otsu et al. (1990) cloned a cDNA encoding the calcium-release channel
(ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum.
Zorzato et al. (1990) cloned human RYR2 that encodes a 5,032-amino acid
protein with a calculated molecular mass of 563.5 kD, which is made
without an N-terminal signal sequence. Analysis of RYR2 sequence
indicates that 10 potential transmembrane sequences in the C-terminal
fifth of the molecule and 2 additional potential transmembrane sequences
nearer to the center of the molecule could contribute to the formation
of the Ca(2+) conducting pore. The remainder of the molecule is
hydrophilic and presumably constitutes the cytoplasmic domain of the
protein.
GENE STRUCTURE
Tiso et al. (2001) determined that the RYR2 gene encompasses 105 exons.
MAPPING
Otsu et al. (1990) located the human cardiac ryanodine receptor on
chromosome 1 by analysis of rodent/human somatic cell hybrids. By
fluorescence in situ hybridization, Otsu et al. (1993) demonstrated that
the RYR2 gene is located in the interval between 1q42.1 and 1q43. Mattei
et al. (1994) used in situ hybridization to map the murine Ryr2 gene to
13A1-13A2.
BIOCHEMICAL FEATURES
- Crystal Structure
Tung et al. (2010) showed the 2.5-angstrom resolution crystal structure
of a region spanning 3 domains of ryanodine receptor type 1 (RyR1;
180901), encompassing amino acid residues 1-559. The domains interact
with each other through a predominantly hydrophilic interface. Docking
in RyR1 electron microscopy maps unambiguously places the domains in the
cytoplasmic portion of the channel, forming a 240-kD cytoplasmic
vestibule around the 4-fold symmetry axis. Tung et al. (2010) pinpointed
the exact locations of more than 50 disease-associated mutations in
full-length RyR1 and RyR2. The mutations can be classified into 3
groups: those that destabilize the interfaces between the 3
amino-terminal domains, disturb the folding of individual domains, or
affect 1 of the 6 interfaces with other parts of the receptor. Tung et
al. (2010) proposed a model whereby the opening of RyR coincides with
allosterically couples motions within the N-terminal domains. This
process can be affected by mutations that target various interfaces
within and across subunits. Tung et al. (2010) proposed that the crystal
structure provides a framework to understand the many disease-associated
mutations in RyRs that have been studied using functional methods, and
would be useful for developing new strategies to modulate RyR function
in disease states.
GENE FUNCTION
The ryanodine receptor on the sarcoplasmic reticulum is the major source
of calcium required for cardiac muscle excitation-contraction coupling.
The channel is a tetramer comprised of 4 RYR2 polypeptides and 4
FK506-binding proteins (see FKBP12.6, or FKBP1B; 600620). Marx et al.
(2000) showed that protein kinase A (PKA; see 176911) phosphorylation of
RYR2 dissociates FKBP12.6 and regulates the channel open probability.
Using cosedimentation and coimmunoprecipitation, the authors defined a
macromolecular complex comprised of RYR2, FKBP12.6, PKA, the protein
phosphatases PP1 (see 603771) and PP2A (see 603113), and an anchoring
protein, AKAP6 (604691). In failing human hearts, Marx et al. (2000)
showed that RYR2 is PKA hyperphosphorylated, resulting in defective
channel function due to increased sensitivity to calcium-induced
activation.
Using a quantitative yeast 2-hybrid system, Tiso et al. (2002) analyzed
and compared the interaction between FKBP12.6 and 3 mutated FKBP12.6
binding regions. An RYR2 mutation (R2474S, 180902.0002) causing
catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772)
markedly increased the binding of RYR2 to FKBP12.6, whereas RYR2
mutations (N2386I, 180902.0005; Y2392C) causing familial right
ventricular dysplasia-2 (ARMD2; 600996) significantly decreased this
binding. Tiso et al. (2002) suggested that ARVD2-associated mutations
increase RYR2-mediated calcium release to the cytoplasm, whereas
CPVT-associated mutations do not significantly affect cytosolic calcium
levels, and that this might explain the clinical differences between the
2 diseases.
In animals with heart failure and in patients with inherited forms of
exercise-induced sudden cardiac death, depletion of the
channel-stabilizing protein calstabin-2 (FKBP1B) from the ryanodine
receptor-calcium release channel complex causes an intracellular calcium
leak that can trigger fatal cardiac arrhythmias. Wehrens et al. (2004)
found that a derivative of 1,4-benzothiazepine increased the affinity of
calstabin-2 for RYR2, which stabilized the closed state of RYR2 and
prevented the calcium leak that triggers arrhythmias. Wehrens et al.
(2004) postulated that enhancing the binding of calstabin-2 to RYR2 may
be a therapeutic strategy for common ventricular arrhythmias.
Wehrens et al. (2003) found that during exercise, RYR2 phosphorylation
by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing
intracellular Ca(2+) release and cardiac contractility. Fkbp12.6 -/-
mice consistently exhibited exercise-induced cardiac ventricular
arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked
to exercise-induced arrhythmias in patients with CPVT, also known as
stress-induced polymorphic ventricular tachycardia, reduced the affinity
of FKBP12.6 for RYR2 and increased single-channel activity under
conditions that simulated exercise. These data suggested that 'leaky'
RYR2 channels can trigger fatal cardiac arrhythmias, providing a
possible explanation for CPVT.
Jiang et al. (2003) characterized several rabbit Ryr3 (180903) splice
variants. One variant lacking a predicted transmembrane helix formed a
heteromeric channel with Ryr2 when coexpressed in HEK293 cells and had a
dominant-negative effect on Ryr2 channel activity.
Lehnart et al. (2004) reviewed the RYR2-FKBP1B interaction and its role
in heart failure and genetic forms of arrhythmias.
In experimentally induced failing hearts of beagle dogs, Yamamoto et al.
(2008) previously demonstrated that defective interdomain interaction
between the N-terminal domain (residues 1 to 600) and the central domain
(residues 2000 to 2500) resulted in domain unzipping, Ca(2+) leak
through the Ryr2 channel, and both cAMP-dependent hyperphosphorylation
and Fkbp12.6 dissociation of Ryr2. Further studies showed that K201, a
1,4-benzothiazepine derivative, bound to residues 2114 to 2149, and that
K201 interrupted interaction of domain(2114-2149) with residues 2234 to
2750, which appeared to mediate stabilization of Ryr2 and inhibit Ca(2+)
leak.
MOLECULAR GENETICS
Stress-induced polymorphic ventricular tachycardia occurs in the
structurally intact heart with onset of manifestations in childhood and
adolescence. Affected individuals present with syncopal events and with
a distinctive pattern of highly reproducible, stress-related,
bidirectional ventricular tachycardia in the absence of either
structural heart disease or a prolonged QT interval. Because this
disorder had been shown to map to 1q42-q43, the same region as RYR2, and
because of the likelihood that delayed afterdepolarizations underlie
arrhythmia in this disorder, Priori et al. (2001) hypothesized that
mutations in the RYR2 gene may be responsible. They studied 12 probands
presenting with bidirectional ventricular tachycardia that was
reproducibly induced by exercise stress testing and/or isoproterenol
infusion and identified missense mutations in 4 (see
180902.0001-180902.0004).
Arrhythmogenic right ventricular dysplasia type 2 (ARVD2; 600996) is an
autosomal dominant cardiomyopathy, characterized by partial degeneration
of the myocardium of the right ventricle, electrical instability, and
sudden death. Tiso et al. (2001) identified RYR2 mutations in 4
independent ARVD2 families (see, e.g., 180902.0005 and 180902.0006). In
myocardial cells the RYR2 protein, activated by Ca(2+), induces the
release of calcium from the sarcoplasmic reticulum into the cytosol.
RYR2 is the cardiac counterpart of RYR1 (180901), the skeletal muscle
ryanodine receptor, which is involved in malignant hyperthermia
susceptibility (MHS1; 145600) and in central core disease (CCD; 117000).
The identified RYR2 mutations occurred in 2 highly conserved regions,
strictly corresponding to those where mutations causing MHS1 or CCD are
clustered in the RYR1 gene.
Priori et al. (2002) analyzed the RYR2 gene in 26 probands with CPVT in
whom mutations had been excluded in the KCNQ1 (607542), KCNH2 (152427),
SCN5A (600163), KCNE1 (176261), and KCNE2 (603796) genes and identified
9 different mutations in 10 probands, respectively (see, e.g.,
180902.0001 and 180902.0010). With the inclusion of 4 previously
reported mutation-positive families (Priori et al., 2001) in this study,
Priori et al. (2002) found 9 family members who were RYR2 mutation
carriers, 5 of whom had exercise-induced arrhythmias at clinical
evaluation and 4 of whom were phenotypically silent (incomplete
penetrance).
George et al. (2003) expressed 3 CPVT1-linked RYR2 mutations in a
cardiomyocyte cell line. They found that phenotypic characteristics in
resting cells expressing mutant RYR2 were indistinguishable from those
expressing the wildtype. However, Ca(2+) release was augmented in cells
expressing mutant RYR2 after RYR activation (caffeine or
4-chloro-m-cresol) or beta-adrenergic stimulation (isoproterenol).
Interaction between RYR2 and FKBP1A remained intact after caffeine or
4-chloro-m-cresol activation, but was dramatically disrupted by
isoproterenol or forskolin, both of which elevated cAMP to similar
magnitudes in all cells and were associated with equivalent
hyperphosphorylation of mutant and wildtype RYR2.
Similar mortality rates of approximately 33% by age 35 years and a
threshold heart rate of 130 bpm, above which exercise induces
ventricular arrhythmias, are observed in Finnish families with
stress-induced polymorphic ventricular tachycardia caused by a
pro2328-to-ser (P2328S; 180902.0007), val4653-to-phe (V4653F;
180902.0008), or gln4201-to-arg (Q4201R; 180902.0009) mutation in the
RYR2 gene. Exercise activates the sympathetic nervous system, increasing
cardiac performance as part of the 'fight or flight' stress response.
Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2
channels using PKA phosphorylation. All 3 RYR2 mutations exhibited
decreased binding of calstabin-2, a subunit that stabilizes the closed
state of the channel. After PKA phosphorylation, these mutants showed a
significant gain-of-function defect consistent with leaky calcium
release channels and a significant rightward shift in the half-maximal
inhibitory magnesium concentration. Treatment with an experimental drug
enhanced the binding of calstabin-2 to RYR2 and normalized channel
function. Lehnart et al. (2004) suggested that stabilization of the RYR2
channel complex may represent a molecular target for the treatment and
prevention of exercise-induced arrhythmias and sudden death in these
patients.
Benkusky et al. (2004) reviewed RYR1 and RYR2 mutations and their role
in muscle and heart disease, respectively.
Jiang et al. (2004) studied 3 mutations in the RYR2 gene linked to
ventricular tachycardia and sudden death, including N4104K (180902.0003)
and characterized their effects on store-overload-induced Ca(2+) release
(SOICR) in human embryonic kidney cells. SOICR refers to the spontaneous
Ca(2+) release that occurs when the sarcoplasmic reticulum store Ca(2+)
content reaches a critical level. They demonstrated that the 3 mutations
markedly increased the occurrence of SOICR. At the molecular level, they
showed that these mutations increased the sensitivity of single RyR2
channels to activation by luminal Ca(2+). Jiang et al. (2004) concluded
that the increased sensitivity reduced the threshold for SOICR, thereby
increasing the propensity for triggered arrhythmia.
In studies in HEK293 cells, Jiang et al. (2007) found that, in contrast
to all other disease-linked RYR2 mutations characterized previously, the
catecholaminergic idiopathic ventricular fibrillation-associated A4860G
mutation (180902.0010) diminished the response of RYR2 to activation by
luminal Ca(2+) but had little effect on the sensitivity of the channel
to activation by cytosolic Ca(2+), and the transfected cells exhibited
no SOICR. Jiang et al. (2007) concluded that loss of luminal Ca(2+)
activation and SOICR activity can cause ventricular fibrillation and
sudden death.
In affected individuals from 2 families with CPVT associated with
sinoatrial and atrioventricular node dysfunction, atrial arrhythmias,
and dilated cardiomyopathy, Bhuiyan et al. (2007) identified a
heterozygous deletion of exon 3 of the RYR2 gene (180902.0011). The
authors noted that these families expanded the phenotypic spectrum of
human RYR2-related diseases.
Medeiros-Domingo et al. (2009) analyzed all 105 RYR2 exons using PCR,
HPLC, and sequencing in 110 unrelated patients with a clinical diagnosis
of CPVT and in 45 additional unrelated patients with an initial
diagnosis of exercise-induced long QT syndrome (LQTS; see 192500) but
who had a QTc of less than 480 ms and who were negative for mutation in
12 genes known to cause LQTS. The authors identified 63 possible
CPVT1-associated mutations that were not found in 400 reference alleles
in 73 (47%) of the 155 patients; 13 new mutation-containing exons were
identified, with two-thirds of the patients having mutations in 1 of 16
exons. Three large genomic rearrangements involving exon 3 were detected
in 3 unrelated cases. Medeiros-Domingo et al. (2009) stated that 45 of
the 105 translated exons of the RYR2 gene were now known to host
possible mutations, but that a tiered targeting strategy for CPVT should
be considered, since approximately 65% of CPVT1-positive cases would be
discovered by selective analysis of just 16 exons.
ANIMAL MODEL
Takeshima et al. (1998) generated Ryr2 -/- mice, which died at
approximately embryonic day 10 with morphologic abnormalities in the
heart tube. Prior to embryonic death, large vacuolate sarcoplasmic
reticula and structurally abnormal mitochondria began to develop in the
mutant cardiac myocytes, and the vacuolate sarcoplasmic reticula
appeared to contain high concentrations of Ca(2+). A Ca(2+) transient
evoked by caffeine was abolished in mutant cardiac myocytes. Treatment
with ryanodine did not exert a major effect on spontaneous Ca(2+)
transients in control cardiac myocytes at embryonic days 9.5-11.5.
Takeshima et al. (1998) proposed that RYR2 does not participate
principally in Ca(2+) signaling during excitation-contraction coupling
in the embryonic heart but functions as a major Ca(2+) leak channel to
maintain the normal range of luminal Ca(2+) levels in the developing
sarcoplasmic reticulum.
Jiang et al. (2002) characterized the properties of an R4496C mutation
in mouse Ryr2, which is equivalent to the disease-causing human RYR2
mutation R4497C (180902.0004). Binding studies in HEK293 cells using
tritium-labeled ryanodine revealed that the R4496C mutation resulted in
an increase in RYR2 channel activity, particularly at low
concentrations, and enhanced the sensitivity of RYR2 to activation by
Ca(2+) and by caffeine. HEK293 cells transfected with R4496C Ryr2
displayed spontaneous Ca(2+) oscillations more frequently than cells
transfected with wildtype Ryr2. Substitution of a negatively charged
glutamate for the positively charged R4496 further enhanced basal
channel activity, whereas replacement of R4496 by a positively charged
lysine had no significant effect on basal activity. Jiang et al. (2002)
concluded that charge and polarity at residue 4496 play an essential
role in RYR2 channel gating, and that enhanced basal activity of RYR2
may underlie an arrhythmogenic mechanism for effort-induced ventricular
tachycardia.
Wehrens et al. (2006) generated transgenic mice with a ser2808-to-ala
substitution (S2808A) of the Ryr2 gene. In vitro and in vivo studies
showed that the Ryr2 alanine-2808 channels could not be phosphorylated
by protein kinase A, indicating that serine-2808 is the dominant
functional phosphorylation site on Ryr2 channels. Transgenic mice with
heart failure induced by ligation of the left anterior descending artery
showed a higher ejection fraction and improved cardiac function compared
to wildtype mice with induced heart failure. Wehrens et al. (2006)
concluded that PKA-mediated hyperphosphorylation of serine-2808 on the
Ryr2 channel is a critical mediator of progressive cardiac dysfunction
after myocardial infarction.
Kannankeril et al. (2006) generated mice heterozygous for the human
disease-associated arg176-to-gln (R176Q) mutation in the Ryr2 gene and
observed no fibrofatty infiltration or structural abnormalities
characteristic of arrhythmogenic right ventricular dysplasia, but right
ventricular end-diastolic volume was decreased in the mutant mice
compared to controls. Ventricular tachycardia was observed after
caffeine and epinephrine injection in Ryr2 R176Q heterozygotes but not
in wildtype mice. Isoproterenol administration during intracardiac
programmed stimulation increased the number and duration of ventricular
tachycardia episodes in mutants but not controls. Isolated
cardiomyocytes from Ryr2 R176Q heterozygous mice exhibited a higher
incidence of spontaneous Ca(2+) oscillations in the absence and presence
of isoproterenol compared with controls. Kannankeril et al. (2006)
suggested that the R176Q mutation in RYR2 predisposes the heart to
catecholamine-induced oscillatory calcium-release events that trigger a
calcium-dependent ventricular arrhythmia.
Lehnart et al. (2008) found that mice heterozygous for the human
CPVT-associated mutation R2474S in Ryr2 exhibited spontaneous
generalized tonic-clonic seizures (which occurred in the absence of
cardiac arrhythmias), exercise-induced ventricular arrhythmias, and
sudden cardiac death. Treatment with an Ryr2-specific compound that
enhanced binding of calstabin-2 to the mutant receptor inhibited channel
leak, prevented cardiac arrhythmias, and raised the seizure threshold.
Lehnart et al. (2008) concluded that CPVT is a combined neurocardiac
disorder in which leaky RYR2 channels in brain cause epilepsy and in
heart cause exercise-induced sudden death.
BECN1P1
| dbSNP name | rs56335758(G,A); rs3851304(G,T) |
| cytoBand name | 1q43 |
| EntrezGene GeneID | 441925 |
| EntrezGene Description | beclin 1, autophagy related, pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Function | BECN1P1:NM_001290693:exon1:c.G472A:p.E158K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2971 |
LOC101928068
| dbSNP name | rs78990436(G,A); rs111820695(A,T); rs75052541(T,G); rs112475785(G,C); rs10927358(A,C); rs145277813(A,G); rs113222968(T,C); rs6700087(T,G); rs112610445(T,C); rs10927360(A,T); rs140522774(G,A); rs79588899(C,G); rs111540558(G,A); rs56335655(G,A); rs55761375(A,T); rs149188247(G,A); rs111272034(T,C) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 101928068 |
| snpEff Gene Name | EFCAB2 |
| EntrezGene Description | uncharacterized LOC101928068 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01745 |
MIR3916
| dbSNP name | rs146777343(C,A) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 100500849 |
| snpEff Gene Name | 5S_rRNA |
| EntrezGene Description | microRNA 3916 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | rRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003673 |
| ExAC AF | 0.0004944 |
VN1R5
| dbSNP name | rs1778540(T,C); rs1778541(C,T); rs41308154(C,T) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 317705 |
| EntrezGene Description | vomeronasal 1 receptor 5 (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2112 |
| ESP Afr MAF | 0.388194 |
| ESP All MAF | 0.187204 |
| ESP Eur/Amr MAF | 0.096616 |
| ExAC AF | 0.86 |
OR2B11
| dbSNP name | rs12065526(G,A); rs4925663(C,T); rs73140586(A,G); rs6695302(C,T); rs11583410(A,C) |
| ccdsGene name | CCDS31090.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127623 |
| EntrezGene Description | olfactory receptor, family 2, subfamily B, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2B11:NM_001004492:exon1:c.C878T:p.T293I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5JQS5 |
| dbNSFP Uniprot ID | OR2BB_HUMAN |
| dbNSFP KGp1 AF | 0.122710622711 |
| dbNSFP KGp1 Afr AF | 0.215447154472 |
| dbNSFP KGp1 Amr AF | 0.182320441989 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.125329815303 |
| dbSNP GMAF | 0.1226 |
| ESP Afr MAF | 0.199728 |
| ESP All MAF | 0.163694 |
| ESP Eur/Amr MAF | 0.145233 |
| ExAC AF | 0.123 |
OR2W5
| dbSNP name | rs10925061(T,C); rs12141850(T,C); rs74152607(G,A); rs12123109(C,T) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 441932 |
| EntrezGene Description | olfactory receptor, family 2, subfamily W, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2W5:NM_001004698:exon1:c.T564C:p.S188S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3338 |
| ESP Afr MAF | 0.437812 |
| ESP All MAF | 0.348839 |
| ESP Eur/Amr MAF | 0.303256 |
| ExAC AF | 0.294 |
OR2G2
| dbSNP name | rs12737801(C,G); rs1151687(G,C); rs61732336(A,G); rs869111(A,G); rs74152638(G,A) |
| ccdsGene name | CCDS31092.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 81470 |
| EntrezGene Description | olfactory receptor, family 2, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2G2:NM_001001915:exon1:c.C70G:p.P24A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGZ5 |
| dbNSFP Uniprot ID | OR2G2_HUMAN |
| dbNSFP KGp1 AF | 0.0778388278388 |
| dbNSFP KGp1 Afr AF | 0.0650406504065 |
| dbNSFP KGp1 Amr AF | 0.104972375691 |
| dbNSFP KGp1 Asn AF | 0.0034965034965 |
| dbNSFP KGp1 Eur AF | 0.129287598945 |
| dbSNP GMAF | 0.07759 |
| ESP Afr MAF | 0.078756 |
| ESP All MAF | 0.120022 |
| ESP Eur/Amr MAF | 0.141163 |
| ExAC AF | 0.118 |
OR2G3
| dbSNP name | rs61748963(A,G); rs12072304(G,A); rs61730407(A,G); rs61737569(C,A) |
| ccdsGene name | CCDS31093.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 81469 |
| EntrezGene Description | olfactory receptor, family 2, subfamily G, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2G3:NM_001001914:exon1:c.A175G:p.M59V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0008 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGZ4 |
| dbNSFP Uniprot ID | OR2G3_HUMAN |
| dbNSFP KGp1 AF | 0.0613553113553 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.127071823204 |
| dbNSFP KGp1 Asn AF | 0.0034965034965 |
| dbNSFP KGp1 Eur AF | 0.109498680739 |
| dbSNP GMAF | 0.06152 |
| ESP Afr MAF | 0.024739 |
| ESP All MAF | 0.088959 |
| ESP Eur/Amr MAF | 0.12186 |
| ExAC AF | 0.099 |
OR13G1
| dbSNP name | rs138028749(G,A); rs28446289(G,A); rs56096718(C,G); rs28556931(T,A); rs28555391(G,A); rs28402945(T,A); rs28711149(T,A) |
| ccdsGene name | CCDS31094.1 |
| CosmicCodingMuts gene | OR13G1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 441933 |
| EntrezGene Description | olfactory receptor, family 13, subfamily G, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13G1:NM_001005487:exon1:c.C676T:p.R226C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.1304 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGZ3 |
| dbNSFP Uniprot ID | O13G1_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Microphthalmia, bilateral;
Coloboma of iris;
Coloboma, choreoretinal;
Coloboma, uveoretinal
MISCELLANEOUS:
Reduced penetrance
MOLECULAR BASIS:
Caused by mutation in the sonic hedgehog gene (SHH, 600725.0016)
OMIM Title
*611677 OLFACTORY RECEPTOR, FAMILY 13, SUBFAMILY G, MEMBER 1; OR13G1
;;OR1-37
OMIM Description
CLONING
OR1-37 (OR13G1) is a member of a large multigene family encoding
transmembrane signaling proteins required for odorant discrimination
(Mainic et al., 2004).
MAPPING
By sequence analysis, Mainic et al. (2004) mapped the OR1-37 gene to
chromosome 1q44.
MOLECULAR GENETICS
Family history is a major risk factor for myocardial infarction (MI).
Shiffman et al. (2005) hypothesized that a gene-centric association
study that was not limited to candidate genes could identify novel
genetic associations with MI. They analyzed more than 11,000 SNPs in
almost 7,000 genes in 3 sequential studies involving a total of 1,332
Caucasian MI patients and 1,772 controls. They found 4 gene variants
associated with MI (p less than 0.05; false-discovery rate less than
10%): palladin (608092) (odds ratio = 1.40); a tyrosine kinase, ROS1
(165020) (OR = 1.75); and 2 G protein-coupled receptors, TAS2R50
(609627) (OR = 1.58), and OR13G1 (OR = 1.40). The odds ratios cited were
for carriers of 2 versus 0 risk alleles.
OR6F1
| dbSNP name | rs41268353(C,A); rs2282316(A,G); rs6665599(G,C); rs6587382(C,G); rs7512807(A,G); rs61730470(A,G) |
| ccdsGene name | CCDS31095.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 343169 |
| EntrezGene Description | olfactory receptor, family 6, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6F1:NM_001005286:exon1:c.G744T:p.V248V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04132 |
| ESP Afr MAF | 0.012937 |
| ESP All MAF | 0.051899 |
| ESP Eur/Amr MAF | 0.07186 |
| ExAC AF | 0.055 |
OR1C1
| dbSNP name | rs1552812(T,G); rs1552813(C,T); rs41304163(G,C) |
| ccdsGene name | CCDS41481.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 26188 |
| EntrezGene Description | olfactory receptor, family 1, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1C1:NM_012353:exon1:c.A609C:p.G203G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2369 |
| ESP Afr MAF | 0.481916 |
| ESP All MAF | 0.230818 |
| ESP Eur/Amr MAF | 0.108789 |
| ExAC AF | 0.845,1.796e-04 |
OR14A16
| dbSNP name | rs6695283(A,G); rs6681046(G,A); rs74152818(A,G); rs61740923(G,A); rs56958172(G,A); rs10888249(A,G) |
| ccdsGene name | CCDS31097.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 284532 |
| EntrezGene Description | olfactory receptor, family 14, subfamily A, member 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR14A16:NM_001001966:exon1:c.T713C:p.I238T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHC5 |
| dbNSFP Uniprot ID | O14AG_HUMAN |
| dbNSFP KGp1 AF | 0.998168498168 |
| dbNSFP KGp1 Afr AF | 0.991869918699 |
| dbNSFP KGp1 Amr AF | 1.0 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.00123 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 1.0 |
OR11L1
| dbSNP name | rs6681483(A,G); rs6667389(G,A); rs10888255(C,G); rs10888256(C,T); rs4607924(G,C); rs10888257(C,T); rs1339845(T,C); rs78126803(C,T) |
| ccdsGene name | CCDS31098.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391189 |
| EntrezGene Description | olfactory receptor, family 11, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR11L1:NM_001001959:exon1:c.T903C:p.V301V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.129 |
| ESP Afr MAF | 0.336586 |
| ESP All MAF | 0.19268 |
| ESP Eur/Amr MAF | 0.118953 |
| ExAC AF | 0.109 |
OR2W3
| dbSNP name | rs61750779(C,T); rs189993261(C,T); rs10888267(C,T); rs12135078(G,A); rs12139390(A,C); rs61756679(G,A); rs11204545(T,A); rs11204546(T,C) |
| ccdsGene name | CCDS31099.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 343171 |
| EntrezGene Description | olfactory receptor, family 2, subfamily W, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2W3:NM_001001957:exon1:c.C364T:p.R122W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7Z3T1 |
| dbNSFP Uniprot ID | OR2W3_HUMAN |
| dbNSFP KGp1 AF | 0.0961538461538 |
| dbNSFP KGp1 Afr AF | 0.260162601626 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.125874125874 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.09642 |
| ESP Afr MAF | 0.22946 |
| ESP All MAF | 0.081501 |
| ESP Eur/Amr MAF | 0.005698 |
| ExAC AF | 0.035 |
OR2L8
| dbSNP name | rs4925787(T,C); rs4925583(A,G); rs4925792(A,G); rs10888280(A,G) |
| ccdsGene name | CCDS31101.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391190 |
| EntrezGene Description | olfactory receptor, family 2, subfamily L, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2L8:NM_001001963:exon1:c.T468C:p.C156C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4564 |
| ESP Afr MAF | 0.187472 |
| ESP All MAF | 0.461633 |
| ESP Eur/Amr MAF | 0.397907 |
| ExAC AF | 0.529 |
OR2AK2
| dbSNP name | rs41304159(T,C); rs6664332(G,A); rs4478844(G,A); rs74153220(C,T) |
| ccdsGene name | CCDS31102.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391191 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AK, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AK2:NM_001004491:exon1:c.T89C:p.V30A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NG84 |
| dbNSFP Uniprot ID | O2AK2_HUMAN |
| dbNSFP KGp1 AF | 0.0283882783883 |
| dbNSFP KGp1 Afr AF | 0.0223577235772 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0367132867133 |
| dbNSFP KGp1 Eur AF | 0.0382585751979 |
| dbSNP GMAF | 0.02847 |
| ESP Afr MAF | 0.01566 |
| ESP All MAF | 0.026603 |
| ESP Eur/Amr MAF | 0.032209 |
| ExAC AF | 0.024,8.132e-06 |
OR2L5
| dbSNP name | rs150668862(G,A); rs116811538(G,A); rs12753585(A,G) |
| ccdsGene name | CCDS58068.1 |
| CosmicCodingMuts gene | OR2L1P |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 284521 |
| EntrezGene Symbol | OR2L13 |
| EntrezGene Description | olfactory receptor, family 2, subfamily L, member 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2L5:NM_001258284:exon1:c.G333A:p.A111A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 0.0005123 |
OR2L2
| dbSNP name | rs73141396(T,C); rs73141398(A,G); rs6658141(G,C); rs6658161(G,A); rs112747916(G,C) |
| ccdsGene name | CCDS31103.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 284521 |
| EntrezGene Symbol | OR2L13 |
| EntrezGene Description | olfactory receptor, family 2, subfamily L, member 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2L2:NM_001004686:exon1:c.T310C:p.L104L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01745 |
| ESP Afr MAF | 0.075125 |
| ESP All MAF | 0.02568 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.007758 |
OR2L3
| dbSNP name | rs55893924(T,C) |
| ccdsGene name | CCDS31104.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391192 |
| EntrezGene Description | olfactory receptor, family 2, subfamily L, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2L3:NM_001004687:exon1:c.T771C:p.T257T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.309 |
| ESP Afr MAF | 0.385837 |
| ESP All MAF | 0.296231 |
| ESP Eur/Amr MAF | 0.133232 |
| ExAC AF | 0.182 |
OR2M1P
| dbSNP name | rs6587422(G,T); rs6587423(A,G); rs41295946(G,A) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 388762 |
| EntrezGene Description | olfactory receptor, family 2, subfamily M, member 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1635 |
| ExAC AF | 0.087 |
OR2M5
| dbSNP name | rs147834003(A,G); rs79657684(T,C); rs77923536(C,A); rs148081072(G,C); rs145157861(G,A); rs73141283(A,G) |
| ccdsGene name | CCDS31105.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127059 |
| EntrezGene Description | olfactory receptor, family 2, subfamily M, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2M5:NM_001004690:exon1:c.A67G:p.T23A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0039 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A3KFT3 |
| dbNSFP Uniprot ID | OR2M5_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.012029 |
| ESP All MAF | 0.004075 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001139 |
OR2M3
| dbSNP name | rs4916112(G,A); rs12562957(T,C); rs150518305(T,C) |
| ccdsGene name | CCDS31107.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127062 |
| EntrezGene Description | olfactory receptor, family 2, subfamily M, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2M3:NM_001004689:exon1:c.G333A:p.E111E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4844 |
| ESP Afr MAF | 0.382206 |
| ESP All MAF | 0.462171 |
| ESP Eur/Amr MAF | 0.382442 |
| ExAC AF | 0.565 |
OR2M4
| dbSNP name | rs6666148(C,T); rs41303133(C,A) |
| ccdsGene name | CCDS31108.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 26245 |
| EntrezGene Description | olfactory receptor, family 2, subfamily M, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2M4:NM_017504:exon1:c.C528T:p.H176H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3209 |
| ESP Afr MAF | 0.499092 |
| ESP All MAF | 0.336076 |
| ESP Eur/Amr MAF | 0.252558 |
| ExAC AF | 0.748 |
OR2T12
| dbSNP name | rs6667171(C,A) |
| ccdsGene name | CCDS31110.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127064 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T12:NM_001004692:exon1:c.G902T:p.R301L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NG77 |
| dbNSFP Uniprot ID | O2T12_HUMAN |
| dbNSFP KGp1 AF | 0.766483516484 |
| dbNSFP KGp1 Afr AF | 0.739837398374 |
| dbNSFP KGp1 Amr AF | 0.707182320442 |
| dbNSFP KGp1 Asn AF | 0.856643356643 |
| dbNSFP KGp1 Eur AF | 0.744063324538 |
| dbSNP GMAF | 0.2328 |
| ESP Afr MAF | 0.23241 |
| ESP All MAF | 0.245271 |
| ESP Eur/Amr MAF | 0.25186 |
| ExAC AF | 0.775,1.626e-05,1.626e-05 |
OR2M7
| dbSNP name | rs4916129(C,T); rs7555310(A,G); rs7555424(A,G) |
| ccdsGene name | CCDS31111.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391196 |
| EntrezGene Description | olfactory receptor, family 2, subfamily M, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2M7:NM_001004691:exon1:c.G571A:p.D191N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NG81 |
| dbNSFP Uniprot ID | OR2M7_HUMAN |
| dbNSFP KGp1 AF | 0.403846153846 |
| dbNSFP KGp1 Afr AF | 0.142276422764 |
| dbNSFP KGp1 Amr AF | 0.430939226519 |
| dbNSFP KGp1 Asn AF | 0.491258741259 |
| dbNSFP KGp1 Eur AF | 0.494722955145 |
| dbSNP GMAF | 0.404 |
| ESP Afr MAF | 0.221289 |
| ESP All MAF | 0.438779 |
| ESP Eur/Amr MAF | 0.449744 |
| ExAC AF | 0.502 |
OR14C36
| dbSNP name | rs28728105(C,T); rs28448343(A,G); rs2039824(C,T); rs28377739(G,A); rs28545014(G,T); rs74467694(G,T) |
| ccdsGene name | CCDS31112.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127066 |
| EntrezGene Description | olfactory receptor, family 14, subfamily C, member 36 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR14C36:NM_001001918:exon1:c.C18T:p.T6T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4656 |
| ESP Afr MAF | 0.416931 |
| ESP All MAF | 0.482162 |
| ESP Eur/Amr MAF | 0.430465 |
| ExAC AF | 0.525 |
OR2T4
| dbSNP name | rs57795102(A,G); rs28698997(C,T) |
| ccdsGene name | CCDS31113.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127074 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T4:NM_001004696:exon1:c.A92G:p.N31S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH00 |
| dbNSFP Uniprot ID | OR2T4_HUMAN |
| dbNSFP KGp1 AF | 0.0682234432234 |
| dbNSFP KGp1 Afr AF | 0.264227642276 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.06841 |
| ESP Afr MAF | 0.213409 |
| ESP All MAF | 0.080763 |
| ESP Eur/Amr MAF | 0.011611 |
| ExAC AF | 0.026 |
OR2T6
| dbSNP name | rs7417616(A,G); rs6587467(T,G); rs6693032(C,A); rs6701129(T,C); rs954474(C,T); rs954475(T,G) |
| ccdsGene name | CCDS31114.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 254879 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T6:NM_001005471:exon1:c.A61G:p.N21D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHC8 |
| dbNSFP Uniprot ID | OR2T6_HUMAN |
| dbNSFP KGp1 AF | 0.340659340659 |
| dbNSFP KGp1 Afr AF | 0.532520325203 |
| dbNSFP KGp1 Amr AF | 0.265193370166 |
| dbNSFP KGp1 Asn AF | 0.424825174825 |
| dbNSFP KGp1 Eur AF | 0.188654353562 |
| dbSNP GMAF | 0.3411 |
| ESP Afr MAF | 0.454607 |
| ESP All MAF | 0.253883 |
| ESP Eur/Amr MAF | 0.151047 |
| ExAC AF | 0.244,1.626e-05 |
OR2T1
| dbSNP name | rs28599722(A,G); rs41269351(A,G) |
| ccdsGene name | CCDS31115.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 26696 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T1:NM_030904:exon1:c.A74G:p.H25R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O43869 |
| dbNSFP Uniprot ID | OR2T1_HUMAN |
| dbNSFP KGp1 AF | 0.334249084249 |
| dbNSFP KGp1 Afr AF | 0.0467479674797 |
| dbNSFP KGp1 Amr AF | 0.411602209945 |
| dbNSFP KGp1 Asn AF | 0.305944055944 |
| dbNSFP KGp1 Eur AF | 0.505277044855 |
| dbSNP GMAF | 0.3343 |
| ESP Afr MAF | 0.137994 |
| ESP All MAF | 0.418268 |
| ESP Eur/Amr MAF | 0.43814 |
| ExAC AF | 0.464 |
OR2G6
| dbSNP name | rs58955396(A,G); rs9727474(T,C); rs149255742(G,A); rs9330305(A,T) |
| ccdsGene name | CCDS31119.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 391211 |
| EntrezGene Description | olfactory receptor, family 2, subfamily G, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2G6:NM_001013355:exon1:c.A175G:p.M59V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0012 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5TZ20 |
| dbNSFP Uniprot ID | OR2G6_HUMAN |
| dbNSFP KGp1 AF | 0.025641025641 |
| dbNSFP KGp1 Afr AF | 0.109756097561 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02571 |
| ESP Afr MAF | 0.092147 |
| ESP All MAF | 0.031601 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 0.008856 |
OR2T10
| dbSNP name | rs61732484(C,G); rs28733753(T,A); rs61997185(C,A); rs28664620(A,G); rs28405936(G,A) |
| ccdsGene name | CCDS31121.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127069 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T10:NM_001004693:exon1:c.G903C:p.L301F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGZ9 |
| dbNSFP Uniprot ID | O2T10_HUMAN |
| dbNSFP KGp1 AF | 0.0627289377289 |
| dbNSFP KGp1 Afr AF | 0.252032520325 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0065963060686 |
| dbSNP GMAF | 0.0629 |
| ESP Afr MAF | 0.225735 |
| ESP All MAF | 0.078058 |
| ESP Eur/Amr MAF | 0.006854 |
| ExAC AF | 0.025 |
OR2T11
| dbSNP name | rs1892442(T,C); rs28555577(G,C); rs1892443(A,G); rs34397542(A,G); rs34674180(T,C) |
| ccdsGene name | CCDS31122.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 127077 |
| EntrezGene Description | olfactory receptor, family 2, subfamily T, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2T11:NM_001001964:exon1:c.A926G:p.Q309R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH01 |
| dbNSFP Uniprot ID | O2T11_HUMAN |
| dbNSFP KGp1 AF | 0.959706959707 |
| dbNSFP KGp1 Afr AF | 0.855691056911 |
| dbNSFP KGp1 Amr AF | 0.980662983425 |
| dbNSFP KGp1 Asn AF | 0.998251748252 |
| dbNSFP KGp1 Eur AF | 0.988126649077 |
| dbSNP GMAF | 0.03949 |
| ESP Afr MAF | 0.143762 |
| ESP All MAF | 0.053029 |
| ESP Eur/Amr MAF | 0.009087 |
| ExAC AF | 0.98 |
OR14I1
| dbSNP name | rs114135727(A,T); rs148884002(T,C); rs55871516(T,C); rs141569215(T,C); rs2000390(C,T); rs41311583(G,T); rs11485825(G,A); rs4509608(C,T); rs4575113(T,C); rs4462184(A,G) |
| ccdsGene name | CCDS31125.1 |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 401994 |
| EntrezGene Description | olfactory receptor, family 14, subfamily I, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR14I1:NM_001004734:exon1:c.T911A:p.V304E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0021 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6ND48 |
| dbNSFP Uniprot ID | O14I1_HUMAN |
| dbNSFP KGp1 AF | 0.0178571428571 |
| dbNSFP KGp1 Afr AF | 0.0792682926829 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01791 |
| ESP Afr MAF | 0.064231 |
| ESP All MAF | 0.021759 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.005913 |
LYPD8
| dbSNP name | rs181480206(C,T); rs73148521(G,A) |
| cytoBand name | 1q44 |
| EntrezGene GeneID | 646627 |
| EntrezGene Description | LY6/PLAUR domain containing 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002296 |
SOX11
| dbSNP name | rs4371338(G,A); rs12105008(G,A); rs144951011(A,G); rs13419910(A,G); rs66465560(T,C); rs142925849(A,G); rs141307258(C,T); rs6729137(A,G); rs114368150(C,T) |
| cytoBand name | 2p25.2 |
| EntrezGene GeneID | 6664 |
| EntrezGene Description | SRY (sex determining region Y)-box 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4467 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Congenital nuclear cataract (in some patients);
Pulverulent cataract (in some patients);
'Sunflower' cataract (in some patients)
LABORATORY ABNORMALITIES:
Elevated serum ferritin;
Normal serum iron;
Normal transferrin saturation;
Normal red cell counts;
Elevated ferritin L subunit;
Serum ferritin hyperglycosylation
MISCELLANEOUS:
Cataracts may be subclinical in some patients;
Age at diagnosis of cataract may range up to 40 years;
Severity of clinical phenotype varies both within and between kindreds;
Some patients born in consanguineous families may carry homozygous
mutations, but the phenotype does not appear to be more severe
MOLECULAR BASIS:
Caused by mutation in the ferritin light chain gene (FTL, 134790.0001)
OMIM Title
*600898 SRY-BOX 11; SOX11
;;SRY-RELATED HMG-BOX GENE 11
OMIM Description
CLONING
Using the partial clones of both human and mouse SOX11 genes, Jay et al.
(1995) cloned and characterized the human SOX11 gene. The SOX11 sequence
is strongly conserved with the chicken homolog and is related to SOX4.
It contains several putative transcriptional activator or repressor
domains. The authors observed that the SOX11 expression pattern is
consistent with the hypothesis that this gene is important in the
developing nervous system.
MAPPING
Jay et al. (1995) mapped the SOX11 gene to chromosome 2p25 by
fluorescence in situ hybridization.
GENE FUNCTION
Shim et al. (2012) identified a conserved nonexonic element (E4),
located 7.3 kb downstream of the Fezf2 (607414) transcription start
site, that is required for the specification of corticospinal neuron
identity and connectivity. Shim et al. (2012) found that Sox4 (184430)
and Sox11 functionally compete with the repressor Sox5 (604975) in the
transactivation of E4. Shim et al. (2012) showed that SOX4 and SOX11 are
crucial in regulating reelin (RELN; 600514) expression and the
inside-out pattern of cortical layer formation, independent of E4 or
Fezf2 and probably involving interactions with distinct regulatory
elements. Cortex-specific double deletion of Sox4 and Sox11 led to the
loss of Fezf2 expression, failed specification of corticospinal neurons
and, independent of Fezf2, a reeler-like inversion of layers. Moreover,
SOX4 and SOX11 have additional roles, since in mice lacking both genes,
the cortex and olfactory bulb are smaller and cell death is increased.
Thus, SOX4 and SOX11 have pleiotropic functions, which are probably
mediated by distinct regulatory elements and downstream target genes
that are involved in multiple developmental processes. Shim et al.
(2012) showed evidence supporting the emergence of functional
SOX-binding sites in E4 during tetrapod evolution, and their subsequent
stabilization in mammals and possibly amniotes. Shim et al. (2012)
concluded that SOX transcription factors converge onto a cis-acting
element of Fezf2 and form critical components of a regulatory network
controlling the identity and connectivity of corticospinal neurons.
GENE FAMILY
SRY (480000) is the testis-determining gene located on the Y chromosome
of mammals. It encodes a protein whose most striking feature is a motif
of 78 amino acids conserved with respect to the DNA binding domain of
the high mobility group (HMG) proteins. Jay et al. (1995) noted that
more than 100 HMG box-containing proteins had been reported at that time
and are classified in 2 distinct subgroups according to the
sequence-specificity of the binding, the number of DNA binding domains,
and phylogenetic considerations (Laudet et al., 1993). An important
subgroup of HMG box-containing proteins includes SRY and SRY box-related
(SOX) sequences. They contain only 1 DNA-binding domain, and they bind
to DNA in a sequence-specific manner. They are all potential
transcription factors implicated in the developmental control of gene
expression. Degenerate PCR-based methods enabled the cloning and
sequencing of a great number of new SRY-related box sequences in both
vertebrates and invertebrates.
MOLECULAR GENETICS
Tsurusaki et al. (2014) identified 2 de novo missense mutations in the
SOX11 gene (Y116C, 600898.0001 and S60P, 600898.0002) in 2 unrelated
female patients with mental retardation-27 (MRD27; 615866). Both
mutations occurred in the HMG domain in 2 evolutionarily conserved amino
acids. Tsurusaki et al. (2014) showed that both mutations caused
decreased transcriptional activation compared to wildtype. SOX11 is
exclusively expressed in fetal and adult brain and in adult heart.
Targeted disruption of Sox11 in mice resulted in a 23% birth weight
reduction and lethality after the first postnatal week in homozygotes,
due to hypoplastic lungs and ventricular septation defects. In addition,
skeletal malformations, including of phalanges, and abdominal defects
were observed. Physical and functional abnormalities in heterozygotes
had not been described. Sox11 knockdown experiments in zebrafish showed
microcephaly and brain abnormalities. Tsurusaki et al. (2014) commented
that SOX11 is the downstream transcriptional factor of the PAX6
(607108)-BAF (603811) complex, highlighting the importance of the BAF
complex and SOX11 transcriptional network in brain development.
MIR7515HG
| dbSNP name | rs1053830(T,C); rs10192411(A,G); rs140063979(C,T) |
| cytoBand name | 2p25.2 |
| EntrezGene GeneID | 100506216 |
| EntrezGene Symbol | LOC100506216 |
| snpEff Gene Name | AC097517.2 |
| EntrezGene Description | uncharacterized LOC100506216 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1084 |
RRM2
| dbSNP name | rs5030743(C,G); rs6432065(T,C); rs6737932(T,C); rs116696933(G,A); rs148818815(G,A); rs115966142(A,T); rs6741290(T,C); rs72542796(A,G); rs72544297(G,A); rs182467300(G,A); rs72544298(A,G); rs7577557(C,T); rs7577887(C,A); rs7603436(G,A); rs370799457(G,A); rs6759180(G,A); rs77323676(C,T); rs61754180(T,C); rs138102168(C,T); rs75249934(T,C); rs140034020(C,G); rs4668664(A,G); rs375182199(G,C); rs114571498(G,A) |
| ccdsGene name | CCDS1669.1 |
| cytoBand name | 2p25.1 |
| EntrezGene GeneID | 6241 |
| EntrezGene Description | ribonucleotide reductase M2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RRM2:NM_001165931:exon8:c.G1051C:p.E351Q,RRM2:NM_001034:exon8:c.G871C:p.E291Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8503 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P31350 |
| dbNSFP Uniprot ID | RIR2_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 5.692e-05 |
OMIM Clinical Significance
Nose:
Extremely short nose;
Upturned nose;
Small nares;
Nares directed anteriorly;
Long thin philtrum
Mouth:
Narrow lips;
Downturned outer lip margins
Abdomen:
Inguinal hernia
Inheritance:
Autosomal dominant
OMIM Title
*180390 RIBONUCLEOTIDE REDUCTASE, M2 SUBUNIT; RRM2
;;RIBONUCLEOTIDE REDUCTASE, SMALL SUBUNIT;;
RIBONUCLEOTIDE REDUCTASE, R2 SUBUNIT; R2
OMIM Description
DESCRIPTION
The RRM2 gene encodes the small subunit (R2) of ribonucleotide
reductase, the heterodimeric enzyme that catalyzes the rate-limiting
step in deoxyribonucleotide synthesis.
CLONING
Pavloff et al. (1992) cloned human RRM1 (180410) and RRM2 cDNAs from a
breast carcinoma cDNA library. The deduced 389-amino acid RRM2 protein
has a molecular mass of 45 kD and is 1 amino acid shorter than the
equivalent mouse protein. The human and mouse RRM2 proteins share 96%
homology in the C terminus, but only 69% in the first 68 residues in the
N terminus.
GENE FUNCTION
In dividing cells, ribonucleotide reductase is essential for the
production of deoxyribonucleotides before DNA synthesis in S phase.
Neither of its 2 subunits, R1 or R2, are detectable in quiescent cells.
In cycling cells, RRM2 mRNA and protein are present throughout the cell
cycle (summary by Parker et al., 1994).
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was RRM2. These 37 genes included several
splicing factors for which knockdown generates mitotic spindle defects.
In addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
MAPPING
Yang-Feng et al. (1986, 1987) carried out chromosomal mapping of RRM2 by
means of a full-length mouse cDNA. By Southern blot analysis of
interspecies somatic cell hybrid lines and by in situ hybridization,
Yang-Feng et al. (1987) found that the 4 chromosomal sites carrying
M2-related sequences are 1p33-p31, 1q21-q23, 2p25-p24, and Xp21-p11. In
the mouse, M2 sequences were found on chromosomes 4, 7, 12, and 13 by
somatic cell hybrid studies. By Southern analysis of human and mouse
hydroxyurea-resistant cells that overproduce M2 due to gene
amplification, Yang-Feng et al. (1987) identified the amplified
restriction fragments as those that map to human chromosome 2 and to
mouse chromosome 12. The sites other than 2p probably represent
pseudogenes, particularly the ones on the X chromosome since active
genes on mammalian X chromosomes are conserved and no RRM2 sequence was
found on the mouse X chromosome. Ornithine decarboxylase (ODC; 165640)
is coamplified with RRM2 in human and rodent hydroxyurea-resistant cell
lines. Using cDNA clones, Yang-Feng et al. (1987) mapped ODC to the same
region of human chromosome 2. In an RRM2 overproducing mouse cell line,
they found amplification of the chromosome 12-specific restriction
fragments. Thus, the functional loci of both RRM2 and ODC are on murine
chromosome 12.
KCNF1
| dbSNP name | rs3732104(A,G); rs3732105(C,T) |
| ccdsGene name | CCDS1676.1 |
| CosmicCodingMuts gene | KCNF1 |
| cytoBand name | 2p25.1 |
| EntrezGene GeneID | 3754 |
| EntrezGene Description | potassium voltage-gated channel, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNF1:NM_002236:exon1:c.A468G:p.A156A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09596 |
| ESP Afr MAF | 0.051818 |
| ESP All MAF | 0.124653 |
| ESP Eur/Amr MAF | 0.162039 |
| ExAC AF | 0.853 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Brachycephaly;
Cranium bifidum, anterior;
[Eyes];
Hypertelorism;
Telecanthus;
Myopia (in some patients);
Ptosis (in some patients);
Corneal dermoid cyst (rare);
Glaucoma (rare);
Optic nerve hypoplasia, segmental (rare);
Persistent primary vitreous (rare);
[Nose];
Bifid nose;
Nostril notching;
Broad nasal tip;
Separation of nostrils;
[Mouth];
Carp-shaped mouth (in some patients);
Cleft lip;
Cleft palate
RESPIRATORY:
[Airways];
Upper airway obstruction, severe (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism (in some patients)
SKELETAL:
[Skull];
Persistent craniopharyngeal canal (rare);
Vertical clivus (in some patients);
[Limbs];
Patellar hypoplasia or aplasia (in some patients);
Tibial hypoplasia;
[Hands];
Preaxial polydactyly;
Preaxial polysyndactyly;
[Feet];
Preaxial polydactyly;
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Vertical creases of plantar surface between first and second toes;
[Nails];
Clubbed, thickened nails of halluces (1 patient)
NEUROLOGIC:
[Central nervous system];
Encephalocele;
Agenesis of corpus callosum;
Hypoplasia of corpus callosum;
Ventricular dilatation;
Mental retardation;
Periventricular nodular heterotopia;
Choroid plexus cyst;
Septum pellucidum deficient or cavum;
Calcification of the falx;
Interhemispheric lipoma;
Absent olfactory bulbs;
Enlarged sella turcica;
Absence of anterior pituitary;
Fenestrated basilar artery;
Persistent falcine venous sinus;
Retrocerebellar cyst;
Seizures
ENDOCRINE FEATURES:
Hypopituitarism (in some patients)
MISCELLANEOUS:
Brain anomalies variable;
Four unrelated patients with ZSWIM6 mutations have been described
(last curated September 2014)
MOLECULAR BASIS:
Caused by mutation in the zinc finger SWIM domain-containing protein
6 (ZSWIM6, 615951.0001)
OMIM Title
*603787 POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY F, MEMBER 1; KCNF1
;;KH1
OMIM Description
CLONING
Voltage-gated potassium channels are a family of plasma membrane
proteins containing 6 putative transmembrane domains. See KCNA1
(176260). Su et al. (1997) identified ESTs encoding 2 novel putative
potassium channels, KH1 and KH2 (603788). By screening a fetal brain
library with a probe derived from the KH1 EST, they isolated cDNAs
corresponding to the entire KH1 coding region. The KH1 gene shares 88%
nucleotide homology with a rat potassium channel gene, IK8. The
predicted 495-amino acid human protein contains 6 putative transmembrane
domains. Northern blot analysis revealed that KH1 was expressed as a
5-kb mRNA in all tissues tested, with the highest levels in heart. A
2.4-kb transcript was detected only in brain.
MAPPING
By fluorescence in situ hybridization, Su et al. (1997) mapped the KCNF1
gene to 2p25.
MSGN1
| dbSNP name | rs34069439(A,T); rs35858730(C,T); rs79834893(G,A); rs13001625(T,C) |
| ccdsGene name | CCDS42657.1 |
| cytoBand name | 2p24.2 |
| EntrezGene GeneID | 343930 |
| EntrezGene Description | mesogenin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MSGN1:NM_001105569:exon1:c.A240T:p.E80D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NI15 |
| dbNSFP Uniprot ID | MSGN1_HUMAN |
| dbNSFP KGp1 AF | 0.32967032967 |
| dbNSFP KGp1 Afr AF | 0.29674796748 |
| dbNSFP KGp1 Amr AF | 0.408839779006 |
| dbNSFP KGp1 Asn AF | 0.027972027972 |
| dbNSFP KGp1 Eur AF | 0.540897097625 |
| dbSNP GMAF | 0.3297 |
| ESP Afr MAF | 0.350128 |
| ESP All MAF | 0.492028 |
| ESP Eur/Amr MAF | 0.417292 |
| ExAC AF | 0.46 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Atrial fibrillation;
Dilation of left atrial chamber;
Dilation of left ventricular chamber
MISCELLANEOUS:
Mean age of diagnosis 40 years
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide precursor A gene (NPPA,
108780.0001)
OMIM Title
*612209 MESOGENIN 1; MSGN1
OMIM Description
CLONING
Basic helix-loop-helix (bHLH) proteins are transcriptional regulatory
proteins that govern cell fate determination and tissue differentiation
in the embryo. Yoon and Wold (2000) identified a novel bHLH gene, which
they designated mesogenin-1, in mouse and Xenopus. In both organisms the
gene is specifically expressed in unsegmented paraxial mesoderm and its
immediate progenitors.
GENE FUNCTION
Yoon and Wold (2000) found that a striking feature of mesogenin-1
expression is that it terminates abruptly in presumptive somites
(somitomeres). In functional assays, mesogenin-1 from either mouse or
frog efficiently drove nonmesodermal cells to assume a phenotype with
molecular and cellular characteristics of early paraxial mesoderm.
To determine the mechanism controlling somite number, Gomez et al.
(2008) compared somitogenesis in zebrafish, chicken, mouse, and corn
snake embryos. They presented evidence that in all of these species a
similar 'clock-and-wavefront' mechanism operates to control
somitogenesis; in all of them, somitogenesis is brought to an end
through a process in which the presomitic mesoderm, having first
increased in size, gradually shrinks until it is exhausted, terminating
somite formation. Using MSGN1 expression as a readout for posterior
gradients, Gomez et al. (2008) were able to show that in snake embryos,
the segmentation clock rate is much faster relative to developmental
rate than in other amniotes, leading to a greatly increased number of
smaller-sized somites.
MAPPING
Hartz (2008) mapped the MSGN1 gene to chromosome 2p24.2 based on an
alignment of mouse Msgn1 (GenBank GENBANK AF261105) with the human
genomic sequence (build 36.1). Mouse and human MSGN1 share 90.2%
nucleotide sequence identity.
ANIMAL MODEL
Yoon and Wold (2000) found that deletion of the mouse mesogenin-1 gene
caused complete failure of somite formation and segmentation of body
trunk and tail, leading to complete absence of all trunk paraxial
mesoderm derivatives, including skeletal muscle, vertebrae, and ribs at
14.5 days postcoitus. Axial and lateral mesoderm developed normally. At
the molecular level, there was dramatic loss of expression within
presomitic mesoderm of Notch (see 190198)/Delta (see 606582) pathway
components and oscillating somitic clock genes that are thought to
control segmentation and somitogenesis.
KCNS3
| dbSNP name | rs12470669(T,C); rs35349881(C,A); rs57421222(T,A); rs56327406(G,A); rs6531064(G,T); rs56406041(A,G); rs78514918(C,T); rs56171351(G,A); rs2344695(G,A); rs13021599(C,T); rs1031769(A,G); rs7599944(A,G); rs7602920(T,G); rs1350881(A,G); rs12618825(A,G); rs12621776(G,A); rs7587293(A,G); rs62130421(C,T); rs116377605(C,T); rs143570534(G,A); rs12476484(G,A); rs10197393(T,C); rs145787922(A,G); rs143597221(G,A); rs114595227(C,T); rs35217340(G,C); rs6531065(C,T); rs7561495(G,A); rs67013411(C,G); rs56394291(A,G); rs11695812(T,C); rs11695907(T,C); rs4832510(C,T); rs4832511(C,T); rs1841654(G,A); rs1841653(G,A); rs13009092(G,A); rs6531067(T,C); rs115120666(C,T); rs1824600(T,C); rs1461952(G,C); rs2061608(G,A); rs4832512(C,T); rs2061607(A,G); rs4832513(A,G); rs4832514(T,C); rs12614783(T,C); rs4482481(T,C); rs115118666(C,A); rs17316191(T,C); rs10177831(G,A); rs10181323(G,C); rs12478311(C,A); rs10184119(G,A); rs10208653(C,T); rs1461954(T,C); rs16984043(G,C); rs13382709(C,T); rs7557530(C,T); rs7583266(G,A); rs11680994(A,G); rs146173606(C,T); rs139410743(A,T); rs138408901(G,T); rs7559784(C,T); rs7559787(C,T); rs13018733(A,G); rs145408031(C,T); rs11682481(A,G); rs73222777(C,G); rs56407709(A,G); rs4637119(C,T); rs10186418(A,G); rs11894724(T,C); rs6747325(G,A); rs13396005(C,T); rs7587588(T,G); rs7587589(T,C); rs12615672(C,G); rs7599853(G,A); rs73225038(G,C); rs971255(C,T); rs73225040(A,G); rs1461951(C,G); rs2344693(T,A); rs1381458(T,A); rs4832518(T,A); rs1870823(C,T); rs73225043(G,A); rs12991837(C,T); rs12464113(G,A); rs10169199(G,A); rs11096498(C,A); rs4240212(G,A); rs12476193(G,A); rs3810834(G,T); rs3810835(C,T); rs1564004(C,T); rs3788961(G,A); rs1461950(A,T); rs73918988(T,C); rs4553827(T,C); rs1870822(G,A); rs77233361(G,A); rs2344690(C,T); rs1564009(G,C); rs10153737(C,T); rs1564008(T,C); rs113187076(C,G); rs4832520(A,G); rs1461949(G,A); rs7602501(A,G); rs11696049(A,G); rs2880924(G,A); rs13010403(G,C); rs4832401(C,T); rs115121136(C,T); rs1461947(G,T); rs1585529(T,C); rs4832521(A,G); rs1461946(G,A); rs6725712(G,C); rs1461945(C,A); rs150341444(A,G); rs1599518(G,A); rs184724188(C,T); rs73225061(T,C); rs4832523(G,A); rs10201855(C,G); rs11675993(T,C); rs73918990(C,T); rs72770477(A,G); rs2045720(T,C); rs113984602(A,G); rs2045719(G,T); rs72770479(A,G); rs6714959(T,G); rs4832402(G,A); rs35186900(C,T); rs7569719(T,C); rs4240213(G,A); rs34658212(C,T); rs3747516(G,A); rs4832524(A,G); rs3747515(G,A); rs114049563(T,C) |
| ccdsGene name | CCDS1692.1 |
| cytoBand name | 2p24.2 |
| EntrezGene GeneID | 3790 |
| EntrezGene Description | potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNS3:NM_001282428:exon3:c.C1145T:p.A382V,KCNS3:NM_002252:exon3:c.C1145T:p.A382V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6888 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BQ31 |
| dbNSFP Uniprot ID | KCNS3_HUMAN |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0223577235772 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.022923 |
| ESP All MAF | 0.008227 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 1.870e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolonged QT interval on EKG;
Syncope;
Torsade de pointes;
Ventricular fibrillation;
Sudden cardiac death
MISCELLANEOUS:
Association of cardiac events with exercise;
Genetic heterogeneity (see LQT1 192500);
Patients with more severe phenotype have been reported with mutations
in more than 1 LQTS-related gene;
GEI (gene-environment interaction) - association of cardiac events
with drug administration
MOLECULAR BASIS:
Caused by mutation in the sodium channel, voltage-gated, type V, alpha
polypeptide gene (SCN5A, 600163.0001)
OMIM Title
*603888 POTASSIUM CHANNEL, VOLTAGE-GATED, DELAYED-RECTIFIER, SUBFAMILY S,
MEMBER 3; KCNS3
;;VOLTAGE-GATED POTASSIUM CHANNEL 9.3; KV9.3
OMIM Description
For general information on voltage-gated potassium channels, see KCNS1
(602905).
CLONING
Stocker and Kerschensteiner (1998) cloned a full-length rat cDNA
encoding the potassium channel alpha subunit Kcns3, which they named
Kv9.3. The predicted Kcns3 protein has all of the hallmarks of a
voltage-gated potassium channel. Northern blot analysis detected Kcns3
expression in a wide variety of tissues, with the most abundant
expression found in lung and brain.
GENE FUNCTION
Stocker and Kerschensteiner (1998) did not detect inward or outward
currents in Xenopus oocytes that had been injected with rat Kcns3 cRNA.
They noted that alpha subunits belonging to the Kv9 subfamily appear to
modulate the electrophysiologic properties of other voltage-gated
potassium channels.
MAPPING
The human KCNS3 coding sequence has been deposited in GenBank (GENBANK
AF043472). The KCNS3 gene has been tentatively mapped to 2p24.
MOLECULAR GENETICS
Hao et al. (2005) analyzed 3 SNPs in the KCNS3 gene in 228 individuals
with extreme airway hyperresponsiveness (see 600807) and 444 controls.
In single-SNP analysis, the dbSNP rs1031771 G allele (OR, 1.42; p =
0.006) and the dbSNP rs1031772 T allele (OR, 1.40; p = 0.018) were
associated with a significantly higher risk of airway
hyperresponsiveness; haplotype analysis also detected a significant
association (p = 0.006). Hao et al. (2005) suggested that SNPs located
in the 3-prime downstream region of KCNS3 have a significant role in the
etiology of airway hyperresponsiveness.
RHOB
| dbSNP name | rs1062292(G,T) |
| cytoBand name | 2p24.1 |
| EntrezGene GeneID | 388 |
| EntrezGene Description | ras homolog family member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4628 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Optic atrophy;
Decreased visual acuity;
Cataract
NEUROLOGIC:
[Central nervous system];
Tremor, mild;
Extrapyramidal signs, mild
MISCELLANEOUS:
Onset of optic atrophy in childhood;
Neurologic symptoms are not always present or may appear late
MOLECULAR BASIS:
Caused by mutation in the OPA3 gene (606580.0002)
OMIM Title
*165370 RAS HOMOLOG GENE FAMILY, MEMBER B; RHOB
;;APLYSIA RAS-RELATED HOMOLOG 6; ARH6;;
ARHB;;
ONCOGENE RHO H6; RHOH6
OMIM Description
CLONING
A family of RAS proteins, originally designated RHO proteins, were
identified and isolated from protein products expressed in the marine
snail, Aplysia (Madaule and Axel, 1985). In humans, the products of
these genes, called ARH (Aplysia ras-related homologs), display striking
homology to the products of the classic RAS genes. Madaule and Axel
(1985) identified 3 classes of ARH genes, designated H6, H9 (RHOC;
165380), and H12 (RHOA; 165390). Chardin et al. (1988) reported the
complete H6 coding sequence and renamed the gene RhoB. The predicted
protein is 196 amino acids long.
GENE FUNCTION
Ridley and Hall (1992) showed that Rho stimulates actin stress fiber
production and the formation of focal adhesions when it is microinjected
into serum-starved Swiss 3T3 cells. Addition of serum or growth factors
such as PDGF also induced actin reorganization and stress fibers, but
when Rho was inhibited focal adhesion and stress fiber assembly were
impaired.
The actin cytoskeleton undergoes extensive remodeling during cell
morphogenesis and motility. The small guanosine triphosphatase Rho
regulates such remodeling. In their Figure 3C, Maekawa et al. (1999)
diagrammed proposed signaling pathways for Rho-induced remodeling of the
actin cytoskeleton. They demonstrated that LIM kinase (see 601329) is
phosphorylated and activated by ROCK (601702), a downstream effector of
Rho, and that LIM kinase, in turn, phosphorylates cofilin (601442).
Sandilands et al. (2004) found that RhoB colocalized with active Src
(190090) in the cytoplasm of mouse embryonic fibroblasts, and they
presented evidence that RhoB is a component of 'outside-in' signaling
pathways that coordinate Src activation with translocation to
transmembrane receptors.
MAPPING
By a combination of Southern analysis of somatic cell hybrid panels and
in situ hybridization, Cannizzaro et al. (1990) mapped the genes RHOB to
2pter-p12, ARH12 (RHOA) to 3p21, and ARH9 (RHOC) to 5q31-qter.
KLHL29
| dbSNP name | rs201205628(A,T); rs11125010(T,A); rs11125011(G,A); rs13033444(A,G); rs79382761(T,C); rs13015234(C,T); rs7600155(T,C); rs2918003(A,G); rs139049357(G,A); rs74563576(G,T); rs1030907(T,C); rs7574585(C,T); rs2577754(G,A); rs7588652(A,G); rs7588657(A,G); rs115039817(A,G); rs6742888(T,C); rs2723146(T,C); rs114648840(G,A); rs142498485(C,T); rs6756971(G,A); rs6743827(A,T); rs6746692(A,T); rs55754103(G,A); rs114217920(G,A); rs76186685(T,C); rs2723147(A,G); rs2723148(T,C); rs720247(C,A); rs721894(C,A); rs1370692(C,T); rs920271(T,C); rs2723107(T,A); rs75481601(T,C); rs2118500(T,C); rs114989789(G,A); rs2577753(T,A); rs2723108(A,C); rs7560798(T,C); rs2577752(A,G); rs2723109(T,C); rs115328571(G,A); rs2577751(A,G); rs10173248(C,T); rs1530046(C,T); rs2577750(G,A); rs2577749(C,T); rs2577748(T,C); rs2577747(A,G); rs80238555(C,G); rs2577746(A,G); rs17045288(A,G); rs1370695(A,G); rs2577744(T,A); rs114983347(A,G); rs17045299(C,G); rs7564609(A,C); rs7564616(A,G); rs720291(C,T); rs75899752(A,G); rs2577743(A,G); rs6738019(G,A); rs17045311(G,A); rs2723110(G,A); rs142763621(G,C); rs12986598(G,T); rs12621454(A,G); rs57886860(T,C); rs7606048(C,T); rs2723111(A,G); rs2339806(C,T); rs2339807(G,A); rs75642972(C,T); rs11125018(T,A); rs73921809(T,C); rs2723113(G,A); rs78782434(T,C); rs1438130(G,A); rs6544822(C,T); rs7560355(C,T); rs2577742(A,G); rs55859063(T,C); rs4665592(G,A); rs7572683(C,T); rs7586414(A,C); rs72776726(C,T); rs116405231(A,T); rs7576473(C,T); rs7576481(C,T); rs60570337(G,A); rs79231422(G,A); rs72776732(C,T); rs6761321(G,A); rs11125022(G,A); rs60976014(G,A); rs55758235(T,C); rs920274(C,A); rs140721924(T,C); rs6747467(G,A); rs62126851(T,G); rs11125023(A,G); rs35758471(T,G); rs68155475(T,A); rs55875934(C,T); rs920273(T,C); rs920272(T,C); rs12468653(G,C); rs893430(T,C); rs893429(A,G); rs893427(T,C); rs7557436(T,A); rs747345(G,A); rs737564(C,T); rs737565(C,A); rs747344(A,G); rs115422720(T,A); rs729616(C,A); rs12327992(C,A); rs6544842(A,G); rs7574031(G,A); rs2033769(A,G); rs11887598(C,A); rs11898097(G,A); rs13407828(T,C); rs6727901(G,C); rs6714827(A,G); rs10182178(G,A); rs146278633(C,T); rs7608780(T,A); rs11125025(C,A); rs11884091(C,T); rs62126853(C,T); rs7572348(G,C); rs874125(T,G); rs1078960(G,C); rs873543(C,T); rs6726802(G,A); rs55974999(C,A); rs17710394(G,A); rs59968444(T,G); rs62126855(A,G); rs12476055(G,C); rs4665211(G,A); rs6544851(G,A); rs112091346(C,T); rs12615000(C,T); rs7573494(T,G); rs7570872(A,G); rs13413299(T,G); rs1438137(A,G); rs62125373(T,C); rs10207469(G,A); rs79335098(G,T); rs17710455(A,G); rs60947230(T,C); rs12621098(A,G); rs11899857(A,G); rs17045345(C,T); rs6740439(A,G); rs56190828(A,G); rs2164867(G,A); rs17045350(G,A); rs2164866(T,C); rs11900350(C,T); rs11889528(G,A); rs11890645(G,A); rs11886900(T,C); rs11886954(T,C); rs11890726(G,A); rs11885831(A,G); rs1122546(A,G); rs1123258(T,C); rs1469976(A,G); rs11887302(T,G); rs725507(C,T); rs2015406(C,T); rs763456(A,G); rs73921821(G,A); rs73921822(C,A); rs6544857(A,C); rs6544858(T,C); rs6544859(A,G); rs6544860(A,G); rs6544861(C,A); rs6756357(G,A); rs11689283(C,T); rs13417938(C,T); rs4989093(A,T); rs1020094(G,T); rs1020093(A,G); rs7601850(T,A); rs55777935(G,A); rs17045393(G,A); rs4665212(A,G); rs62125377(A,G); rs4665213(A,G); rs4665214(T,C); rs12477825(C,T); rs4665215(G,A); rs10172684(A,G); rs6544862(C,A); rs112367506(G,A); rs72776769(G,A); rs139185949(C,T); rs7597223(C,T); rs7558233(A,T); rs57241086(T,G); rs56182113(G,A); rs59454437(A,G); rs9751374(A,G); rs7586272(T,C); rs4665594(G,T); rs11903250(A,G); rs113360886(G,C); rs11903458(A,G); rs78847868(C,T); rs76013013(C,T); rs7601551(T,C); rs73921828(A,G); rs112941388(C,A); rs1530045(G,A); rs74517174(C,T); rs111517216(T,C); rs113949342(C,G); rs62125382(C,G); rs744109(A,G); rs729790(G,T); rs78361314(G,C); rs146040132(T,C); rs17045420(A,G); rs13398858(A,G); rs17045423(T,C); rs6708065(A,C); rs114938120(C,A); rs4665596(A,T); rs147987240(C,T); rs1653748(C,G); rs116053444(G,A); rs115245357(G,A); rs78943504(T,C); rs58192135(G,A); rs10175479(C,G); rs114196472(C,T); rs10178369(C,A); rs11125053(A,G); rs140034565(T,C); rs60425099(G,A); rs112919491(G,A); rs13404371(C,T); rs58912751(G,A); rs150699464(A,G); rs13407541(C,A); rs56331748(G,A); rs1465674(C,G); rs59272901(T,A); rs58383808(A,G); rs4665597(G,C); rs4665216(G,A); rs4665598(C,A); rs4665217(A,C); rs1465675(C,T); rs13011734(G,A); rs1465676(A,G); rs1465677(G,A); rs1864807(T,C); rs1864808(G,C); rs11686915(A,G); rs115162992(G,A); rs58248995(G,A); rs6712599(C,T); rs6727500(A,G); rs13028083(C,G); rs9678885(A,G); rs375254801(C,T); rs149078026(G,A); rs747002(A,G); rs62125387(C,G); rs10169643(G,C); rs10206453(A,G); rs10206465(A,T); rs1368080(A,G); rs10490750(T,C); rs11677730(G,A); rs934363(A,G); rs66903185(G,A); rs7582844(C,T); rs115908742(G,A); rs7601971(T,C); rs4665600(A,T); rs181828293(C,T); rs13408828(C,T); rs182182782(T,C); rs11692722(A,G); rs6722920(C,T); rs1709292(C,T); rs9808369(C,G); rs9808019(G,A); rs9808020(G,A); rs143072348(T,C); rs6741991(A,G); rs6742202(A,C); rs72778307(C,A); rs9309130(A,G); rs1653749(C,G); rs1344751(C,A); rs1628100(G,T); rs1653750(C,T); rs1653751(A,G); rs1653752(G,A); rs1653753(A,T); rs7609374(A,C); rs1368081(A,T); rs1653754(T,C); rs1709331(A,G); rs960973(C,T); rs1368082(C,T); rs1653757(C,T); rs1653758(C,T); rs1653759(A,G); rs1709329(A,G); rs77462127(T,A); rs1344752(A,G); rs1653760(G,A); rs57808559(C,T); rs1347040(T,C); rs1545008(C,T); rs57637967(C,T); rs1653762(C,T); rs1653763(T,G); rs7563989(G,A); rs1623027(C,T); rs1653764(A,G); rs76832595(A,C); rs74660964(G,T); rs151300793(G,C); rs1709328(T,G); rs7566604(T,C); rs7605823(C,T); rs1653765(A,G); rs1709327(G,T); rs78289578(C,G); rs1653766(G,A); rs1709326(T,G); rs1709310(C,A); rs934364(A,G); rs13009868(T,C); rs9679511(G,T); rs1653767(G,C); rs934365(A,T); rs934366(C,T); rs74426073(G,A); rs1653768(T,C); rs1653769(G,A); rs934368(T,C); rs1653771(G,A); rs61030790(C,T); rs1653772(A,G); rs12617382(A,G); rs12614051(C,T); rs59344944(G,A); rs151073332(C,T); rs1653773(G,A); rs377059682(C,T); rs6719599(A,T); rs6722403(A,G); rs1653774(G,C); rs75422727(G,A); rs10203512(G,A); rs1653775(G,C); rs116176817(G,A); rs72849023(G,C); rs67501036(G,A); rs934369(T,C); rs1709299(C,G); rs934370(G,A); rs76194236(C,T); rs6747761(G,C); rs13022418(T,C); rs1709298(C,G); rs62125400(C,T); rs1653777(G,A); rs79104699(C,A); rs1709297(C,T); rs79701594(G,T); rs12712975(A,G); rs6732165(C,T); rs6760173(G,T); rs1613177(G,A); rs78291796(T,A); rs7602557(T,C); rs139014733(G,A); rs13433064(A,C); rs1864809(G,C); rs28445516(C,T); rs146385671(G,A); rs11682018(G,C); rs1653778(G,C); rs13012633(T,A); rs55637974(T,G); rs13015374(A,G); rs1864810(A,T); rs13411948(G,C); rs193113865(G,A); rs141865871(C,G); rs114933555(C,T); rs748858(C,T); rs748859(C,T); rs748860(C,T); rs748861(G,A); rs748857(A,G); rs78004801(T,C); rs11679334(T,C); rs145795239(C,T); rs934371(G,A); rs934372(G,A); rs1560590(G,C); rs138390787(C,T); rs4665603(G,A); rs4665604(G,A); rs76193254(A,G); rs55724212(G,A); rs77157924(G,C); rs1709316(C,T); rs11898503(G,A); rs76603446(A,T); rs139192839(G,A); rs1709317(T,G); rs1709318(C,T); rs11678782(C,G); rs11678785(C,G); rs4497835(A,T); rs4563178(T,G); rs12472268(A,G); rs7576864(T,C); rs4665606(C,T); rs77484985(C,G); rs1709337(A,G); rs1653780(T,C); rs1709335(A,G); rs1653781(T,A); rs112858787(G,C); rs6745031(G,A); rs72793544(T,G); rs1709295(G,T); rs1709296(G,A); rs80355652(G,A); rs72793548(G,A); rs72793553(T,A); rs1709324(A,G); rs72793555(G,A); rs934373(A,C); rs111528951(T,C); rs934374(A,G); rs934375(G,A); rs11686973(A,G); rs72793559(G,A); rs55785228(G,A); rs72793562(C,A); rs1709334(A,G); rs72793564(C,T); rs4665607(A,G); rs1709333(A,C); rs80343132(G,A); rs72793565(C,T); rs1709301(A,G); rs113810923(G,A); rs1709302(A,C); rs13383440(G,C); rs72793569(G,A); rs1653782(T,C); rs1653783(T,C); rs1709303(A,G); rs1709304(G,A); rs1469624(T,A); rs145589038(G,A); rs1432268(A,G); rs1709305(G,A); rs1653786(A,G); rs4665220(T,C); rs1709306(C,T); rs1709307(T,G); rs17498513(A,T); rs115940473(G,A); rs1632574(T,A); rs146570030(G,A); rs4665222(A,G); rs11676765(T,C); rs17445645(G,A); rs62125425(C,T); rs57823781(T,A); rs4665609(A,C); rs62125427(C,T); rs62125428(G,A); rs11678752(G,A); rs1653787(C,T); rs11673875(A,G); rs76206101(C,T); rs2339787(T,G); rs2339788(A,G); rs2879580(G,A); rs2137900(C,G); rs2137901(A,T); rs146060560(C,T); rs4284788(C,T); rs116471376(G,A); rs2879581(C,G); rs2879582(T,G); rs2879583(G,A); rs2339789(G,A); rs141450095(T,C); rs10165828(C,T); rs876085(T,A); rs1653718(G,A); rs2018271(G,T); rs2018457(G,A); rs1709339(A,G); rs11677517(C,T); rs59801326(G,T); rs17045560(T,C); rs1560591(A,G); rs141872058(C,T); rs4665225(A,G); rs11686638(C,A); rs4665226(C,T); rs1709311(C,A); rs4665227(G,A); rs11695396(T,C); rs1864806(G,A); rs1814367(A,G); rs6544949(A,G); rs75665814(T,C); rs873315(G,A); rs1653719(G,C); rs73919762(G,A); rs4665228(A,G); rs1653720(T,C); rs78983208(G,A); rs146645550(G,A); rs12624312(C,T); rs13035193(G,A); rs72849625(G,A); rs1653721(A,G); rs4665229(A,G); rs1709323(G,A); rs72849631(C,T); rs1653722(T,C); rs17045574(C,A); rs1709322(A,C); rs1653723(T,C); rs145941926(G,T); rs1653724(T,C); rs1709321(A,G); rs142923617(T,A); rs17505355(C,T); rs1709320(G,A); rs1709319(G,A); rs874868(G,T); rs1107536(C,T); rs2077184(A,G); rs114023956(A,T); rs2005028(A,T); rs2005337(G,A); rs4665613(C,T); rs6544966(C,T); rs140893445(G,A); rs7563031(C,T); rs4665614(T,C); rs4665615(G,A); rs181556082(C,T); rs17041545(C,T); rs4665230(C,T); rs1653725(T,C); rs6735243(G,C); rs112977034(C,T); rs1709291(C,T); rs73919771(G,A); rs10204807(A,G); rs138875254(G,A); rs79976924(A,G); rs17045626(C,T); rs4380180(A,C); rs2060165(G,T); rs1709300(A,G); rs151308303(G,A); rs138478755(C,T); rs815350(G,C); rs531963(C,T); rs73919775(T,G); rs605518(C,T); rs605953(T,G); rs555680(C,G); rs606374(A,G); rs182666694(G,A); rs11681555(G,A); rs116150927(C,T); rs57453445(T,C); rs1030281(G,A); rs1030282(G,A); rs586617(T,G); rs17045677(A,G); rs56142949(T,C); rs6544984(C,T); rs7599266(C,T); rs13405191(T,C); rs59339625(G,C); rs77947606(A,G); rs13027532(A,C); rs78439072(C,G); rs115101014(G,A); rs116155099(A,G); rs2161787(G,A); rs17045693(G,A); rs1078853(C,A); rs644744(C,T); rs1078855(A,G); rs6711873(G,A); rs647046(A,G); rs648302(C,T); rs114918499(G,A); rs732747(G,C); rs183921864(G,A); rs1974910(C,T); rs115040515(G,A); rs731806(C,T); rs563757(T,C); rs11687192(G,A); rs4665616(C,T); rs10865225(G,A); rs142335162(C,T); rs10865226(G,T); rs12470568(T,G); rs34873545(G,C); rs583168(G,A); rs17045705(C,T); rs613117(G,A); rs77246136(C,T); rs56069757(G,A); rs6707311(C,G); rs73919785(A,G); rs11125139(G,C); rs12476219(T,C); rs672643(C,G); rs6712940(A,G); rs966792(A,C); rs6720634(T,C); rs1117889(T,C); rs564548(T,C); rs564552(G,A); rs570102(T,C); rs11125140(C,T); rs12478372(G,C); rs487305(T,C); rs60643321(G,A); rs35679492(C,A); rs669531(A,G); rs522939(G,A); rs2280122(G,A); rs80351465(G,A); rs473796(A,C); rs11694227(T,C); rs499593(G,A); rs12623405(A,C); rs368411293(G,A); rs4665233(C,G); rs605750(A,G); rs139945044(G,A); rs13016077(G,C); rs562786(C,T); rs34889183(A,G); rs10445929(G,A); rs4665618(C,T); rs147796704(A,G); rs542438(G,A); rs2339848(C,T); rs667412(A,G); rs2339849(T,G); rs577293(G,A); rs11125146(A,G); rs619287(G,C); rs139018703(G,A); rs473553(C,T); rs475309(A,G); rs477284(G,A); rs6713007(G,A); rs1544822(T,C); rs635182(A,G); rs60599542(A,G); rs148045062(A,G); rs665650(A,G); rs140618260(T,C); rs144479806(G,A); rs485251(G,A); rs488971(C,T); rs1548020(G,A); rs4665619(C,T); rs518113(G,A); rs11125150(G,A); rs11903148(C,T); rs72780399(G,A); rs148412996(G,A); rs577843(C,A); rs35232886(T,C); rs72782203(G,A); rs528065(G,A); rs34782587(C,T); rs11688819(G,A); rs75133321(G,A); rs151238852(A,G); rs482525(G,A); rs482639(A,C); rs689184(C,T); rs2247662(C,T); rs543012(T,C); rs78822935(C,G); rs115047994(C,T); rs71437496(G,A); rs573517(G,A); rs574470(A,G); rs626589(T,A); rs577082(G,A); rs491421(C,T); rs113946629(A,T); rs815356(G,A); rs497973(G,A); rs642931(T,C); rs527176(G,C); rs3731616(T,C); rs72782218(C,T); rs671119(A,G); rs73919796(T,A); rs627973(T,C); rs535200(G,A); rs727291(C,T); rs956401(C,T); rs139920969(C,T); rs10207235(T,C); rs11125152(C,T); rs13386930(G,A); rs10174766(G,A); rs889864(T,G); rs889865(C,A); rs66981954(C,T); rs7581165(C,A); rs59654499(G,A); rs72792051(G,A); rs115868889(C,G); rs7594424(G,A); rs371113909(G,A); rs10167185(G,C); rs6721623(C,T); rs144133464(G,A); rs75543844(T,A); rs4665624(A,C); rs4665625(G,A); rs3795932(T,C); rs114533658(G,A); rs4665235(C,G); rs3795933(G,A); rs3795934(T,C); rs3795935(A,G); rs3795936(A,C); rs66983662(A,G); rs11681314(G,A); rs146953578(G,T); rs143989432(G,C); rs66523860(A,G); rs747622(G,C); rs749331(G,A); rs144098931(C,T); rs12713000(G,A); rs4665626(A,T); rs115800423(G,A); rs141115960(G,A); rs76157714(G,A); rs7593191(G,A); rs4665627(T,C); rs1078345(A,G); rs115310366(T,A); rs116839611(A,T); rs146799919(C,A); rs889866(T,C); rs187610997(G,C); rs143808728(C,A); rs1862901(T,C); rs1862902(A,C); rs115627483(C,T); rs12623694(A,G); rs1991083(C,T); rs6733007(C,T); rs142090285(A,G); rs7586023(C,G); rs1007194(G,C); rs1007195(A,G); rs56009471(A,C); rs12616649(G,A); rs2007088(C,G); rs141260494(G,A); rs737665(G,A); rs2098769(C,T); rs6715626(G,A); rs12617532(G,T); rs11125160(G,A); rs184243880(G,A); rs144240912(T,A); rs72794281(G,A); rs6753001(C,A); rs4665628(T,A); rs4665629(A,T); rs13019016(C,G); rs115667927(C,T); rs13024974(C,T); rs7588944(C,T); rs55836224(T,C); rs147281582(C,A); rs34668726(C,G); rs12713004(A,G); rs115328233(T,C); rs151029749(C,G); rs72794291(C,T); rs889862(C,T); rs72794293(A,G); rs4665630(C,T); rs12233033(T,G); rs11125163(T,C); rs7564319(T,G); rs7567043(T,C); rs7576404(G,A); rs145966587(G,A); rs6713865(A,G); rs6713979(A,G); rs6714016(A,G); rs72796103(G,A); rs4665236(C,T); rs4665237(G,T); rs115262962(G,A); rs56343114(C,G); rs55987381(T,C); rs113236579(G,T); rs2712105(A,G); rs72796106(A,C); rs140407760(G,A); rs142226013(G,A); rs77669541(T,C); rs7578606(T,C); rs142998026(G,A); rs116587446(G,T); rs114187477(A,C); rs116457029(G,A); rs147387079(A,G); rs141079058(G,T); rs149614836(T,C); rs138642449(C,T); rs141036535(G,T); rs144896234(G,A); rs55859418(C,A); rs140969070(G,A); rs12105433(G,A); rs72796108(C,A); rs114636670(G,A); rs139219156(T,C); rs139921028(T,A); rs149563287(G,A); rs149501929(C,T); rs72796110(T,A); rs72796112(G,T); rs72796114(C,G); rs751313(G,T); rs751314(G,C); rs115763875(C,T); rs149066168(T,C); rs114689407(C,T); rs139284588(G,C); rs143206543(G,C); rs138558164(G,A); rs141988464(G,C); rs146309370(A,G); rs115611893(G,A); rs114129185(C,T); rs4555304(G,T); rs111313762(A,C); rs12618900(C,T); rs2551345(G,C); rs113831544(T,A); rs2551347(C,T); rs55806536(A,G); rs3795938(C,T); rs2551348(T,C); rs116057535(T,C); rs2551349(A,G); rs72796116(C,T); rs2551350(T,C); rs115229198(C,G); rs2551351(C,T); rs142830713(C,T); rs17045812(C,T); rs72796119(C,T); rs55947039(G,A); rs2712078(C,G); rs2551353(T,C); rs116699585(C,T); rs72796125(C,T); rs61744252(G,A); rs3795942(C,T); rs114781169(G,A); rs3795943(C,G); rs72796130(T,C); rs112623241(G,A); rs79951345(C,A); rs3795944(A,G); rs2551354(G,C); rs3795945(C,G); rs3795946(G,C); rs6756280(A,G); rs11683876(G,A); rs113188532(G,A); rs17507628(T,C); rs2551357(A,G); rs11679039(A,C); rs1862899(G,A); rs1862900(C,A); rs55801864(C,T); rs11125168(C,T); rs80009843(G,A); rs12469552(A,G); rs143430187(T,C); rs6650796(T,C); rs6650797(G,T); rs12466745(T,C); rs72796138(C,T); rs77064076(C,T); rs3795948(T,C); rs3795949(C,A); rs147154001(C,T); rs113392291(C,T); rs56152044(A,G); rs2712096(A,G); rs4665634(A,G); rs7560892(A,G); rs4233701(G,C); rs4233702(G,T); rs17045819(T,C); rs116187684(G,A); rs2712098(A,G); rs112624693(C,T); rs9261(C,T) |
| ccdsGene name | CCDS54335.1 |
| cytoBand name | 2p24.1 |
| EntrezGene GeneID | 114818 |
| EntrezGene Description | kelch-like family member 29 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KLHL29:NM_052920:exon11:c.G1929A:p.G643G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5005 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbNSFP KGp1 AF | 0.0238095238095 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0448548812665 |
| dbSNP GMAF | 0.02388 |
| ESP Afr MAF | 0.025289 |
| ESP All MAF | 0.03548 |
| ESP Eur/Amr MAF | 0.039912 |
| ExAC AF | 0.039 |
AGBL5-AS1
| dbSNP name | rs113203688(C,A); rs11126836(C,T) |
| cytoBand name | 2p23.3 |
| snpEff Gene Name | AGBL5 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
C2orf16
| dbSNP name | rs148803487(G,A); rs1919125(C,G); rs1919126(C,A); rs1919127(T,C); rs13416968(T,C); rs1919128(A,G); rs12329054(T,C); rs3811644(A,G); rs13408423(C,T); rs13392197(C,T); rs28381983(T,C) |
| ccdsGene name | CCDS42666.1 |
| cytoBand name | 2p23.3 |
| EntrezGene GeneID | 84226 |
| EntrezGene Description | chromosome 2 open reading frame 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C2orf16:NM_032266:exon1:c.G1593A:p.R531R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.009167 |
| ESP All MAF | 0.002982 |
| ESP Eur/Amr MAF | 0.000121 |
| ExAC AF | 0.0008495 |
MYADML
| dbSNP name | rs10184060(C,T); rs10196645(T,C); rs150652031(C,T); rs935623(T,G); rs4670913(C,A); rs2290101(C,G); rs4477896(T,C); rs2367810(C,G); rs11684598(G,A); rs75672894(G,T); rs186420472(G,A); rs76421656(A,T); rs7574695(C,T) |
| cytoBand name | 2p22.3 |
| EntrezGene GeneID | 151325 |
| EntrezGene Description | myeloid-associated differentiation marker-like (pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.247 |
LOC100288911
| dbSNP name | rs149280614(A,G) |
| cytoBand name | 2p22.3 |
| EntrezGene GeneID | 100288911 |
| snpEff Gene Name | CRIM1 |
| EntrezGene Description | uncharacterized LOC100288911 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003673 |
OXER1
| dbSNP name | rs2278584(G,C); rs2278585(G,T); rs12617777(C,A); rs2278586(G,C); rs1992286(T,G); rs12712859(C,T); rs34142793(C,G) |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 165140 |
| snpEff Gene Name | HAAO |
| EntrezGene Description | oxoeicosanoid (OXE) receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2778 |
ZFP36L2
| dbSNP name | rs9170(G,A) |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 678 |
| snpEff Gene Name | THADA |
| EntrezGene Description | ZFP36 ring finger protein-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07668 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Spastic paraplegia;
Upper limbs may be affected;
Abnormal gait;
Hyperreflexia;
Extensor plantar responses;
Ataxia (in some patients);
Cerebellar atrophy (in some patients);
Spinal cord atrophy (1 family);
[Peripheral nervous system];
Axonal motor neuropathy
MISCELLANEOUS:
Onset usually in the first decade;
Later onset has been reported
MOLECULAR BASIS:
Caused by mutation in the patatin-like phospholipase domain-containing
protein 6 (PNPLA6, 603197.0001)
OMIM Title
*612053 ZINC FINGER PROTEIN 36-LIKE 2; ZFP36L2
;;ZFP36-LIKE 2;;
EGF RESPONSE FACTOR 2; ERF2;;
TIS11D, MOUSE, HOMOLOG OF; TIS11D
OMIM Description
DESCRIPTION
ZFP36L2 is a member of the tristetraprolin (TTP, or ZFP36; 190700)
family of CCCH-type tandem zinc finger proteins. These proteins can bind
to transcripts containing AU-rich elements (AREs), resulting in
deadenylation and destabilization of bound transcripts (summary by
Ramos, 2012).
CLONING
Nie et al. (1995) cloned ZFP36L2, which they called ERF2, by screening a
human cDNA library using the mouse homolog, Tis11d, as probe. The
deduced 493-amino acid protein has a calculated molecular mass of 51 kD.
It contains a zinc finger domain, polyglutamine and polyproline tracts
that may act as transcriptional activators, a polyalanine tract, and 3
putative phosphorylation sites. Clusters of serine, proline, alanine,
and glycine account for nearly half of the ERF2 sequence. Human ERF2
contains 97 additional amino acids at its C terminus relative to mouse
Tis11d, but it shares 90% amino acid identity with mouse Tis11d prior to
the C-terminal divergence. The C-terminal end of ERF2 is highly
homologous to the C-terminal end of human ERF1 (ZFP36L1; 601064).
Ino et al. (1995) independently cloned ZFP36L2, which they called
TIS11D. The deduced 492-amino acid protein contains 2 zinc-binding
cysteine-histidine motifs. Northern blot analysis detected a 3.7-kb
transcript expressed at variable levels in all tissues and leukemic
cells examined.
GENE STRUCTURE
Ino et al. (1995) determined that the ZF36L2 gene contains 2 exons.
Except for the 3-prime UTR, the entire gene is GC rich. The promoter
region contains a GC box, a CAT box, and a CRE element. The 3-prime UTR
contains 5 copies of the ATTTA sequence, a characteristic of unstable
mRNAs.
GENE FUNCTION
Zhang et al. (2013) demonstrated that the RNA-binding protein ZFP36L2 is
a transcriptional target of the glucocorticoid receptor (GR; 138040) in
burst-forming unit-erythroid (BFU-E) progenitors and is required for
BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid
differentiation from the BFU-E stage, but its expression is maintained
by all tested GR agonists that stimulate BFU-E self-renewal, and the GR
binds to several potential enhancer regions of ZFP36L2. Knockdown of
ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division
but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown
of ZFP36L2 in transplanted erythroid progenitors prevented expansion of
erythroid lineage progenitors normally seen following induction of
anemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to
mRNAs that are induced or maintained at high expression levels during
terminal erythroid differentiation and negatively regulates their
expression levels. ZFP36L2 therefore functions as part of a molecular
switch promoting BFU-E self-renewal and a subsequent increase in the
total numbers of colony-forming unit-erythroid (CFU-E) progenitors and
erythroid cells that are generated.
MAPPING
Ino et al. (1995) mapped the ZFP36L2 gene maps to chromosome 6p21.3.
However, Hartz (2008) mapped the ZFP36L2 gene to chromosome 2p21 based
on an alignment of the ZFP36L2 sequence (GenBank GENBANK U07802) with
the genomic sequence (build 36.1).
ANIMAL MODEL
Ramos (2012) stated that female mice homozygous for a truncated form of
Zfp36l2 lacking 29 N-terminal amino acids could cycle and ovulate
normally and that their ova could be fertilized. However, when crossed
with wildtype males, their embryos were able to undergo the initial
cleavage step, but they arrested at the 2-cell stage. Ramos (2012) found
that the truncation, which deletes an unconventional leucine-rich
repeat, stabilized mutant Zfp36l2 against lipopolysaccharide-induced
degradation when expressed in bone marrow-derived macrophages. Truncated
Zfp36l2 was indistinguishable from wildtype Zfp36l2 in all other
measures examined, including cellular localization, binding to RNAs
containing AREs, and deadenylation of a model ARE transcript.
LINC01126
| dbSNP name | rs17030566(C,G); rs149006688(C,T); rs138224709(C,T); rs745763(T,C) |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 100129726 |
| snpEff Gene Name | THADA |
| EntrezGene Description | long intergenic non-protein coding RNA 1126 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04178 |
| ExAC AF | 0.006772 |
LOC728819
| dbSNP name | rs755862(G,C); rs143787127(C,G); rs3828297(A,G); rs74589926(C,A); rs4952675(T,C) |
| ccdsGene name | CCDS1812.1 |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 728819 |
| snpEff Gene Name | PLEKHH2 |
| EntrezGene Description | hCG1645220 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4481 |
| ESP Afr MAF | 0.325397 |
| ESP All MAF | 0.293697 |
| ESP Eur/Amr MAF | 0.279166 |
| ExAC AF | 0.632 |
SLC3A1
| dbSNP name | rs3738985(A,C); rs74836631(A,G); rs60255301(G,C); rs58033322(C,A); rs73924294(G,A); rs713448(T,C); rs116777358(C,A); rs713447(T,G); rs112444890(T,A); rs6724939(G,A); rs6725076(G,A); rs113690640(G,A); rs58122551(T,C); rs35347977(C,T); rs35627501(G,C); rs10194161(C,T); rs12473699(G,A); rs140317484(C,T); rs10427398(T,C); rs10427326(C,T); rs6747853(T,G); rs11124986(G,A); rs72802972(C,T); rs115812520(T,C); rs9309115(A,T); rs10427177(T,C); rs10427366(G,T); rs73924295(C,T); rs60436711(C,T); rs189441718(T,A); rs6716912(A,T); rs6717066(A,G); rs2340808(T,C); rs1441048(T,C); rs113187530(C,T); rs3768919(G,A); rs72873476(T,C); rs75881878(C,T); rs13018340(C,T); rs111934021(C,T); rs113746611(T,A); rs60842937(C,T); rs6743551(C,A); rs6743552(C,A); rs6715202(A,G); rs6744505(C,A); rs4952708(A,C); rs6719144(A,G); rs6705549(T,A); rs6706053(T,C); rs6748528(G,A); rs73924297(T,C); rs6544756(G,A); rs7600730(G,A); rs142020853(C,T); rs4952709(A,G); rs13387773(C,G); rs13004485(A,G); rs4953081(A,G); rs28391744(T,C); rs75023238(G,A); rs4953082(G,A); rs4952710(T,C); rs72802976(C,T); rs12470232(T,C); rs2165421(G,A); rs17579820(T,C); rs72802978(C,T); rs369181060(A,G); rs28465110(T,A); rs112322245(C,G); rs145785246(G,A); rs6544757(C,G); rs186772218(A,C); rs17032095(G,A); rs12987415(C,T); rs28558584(A,T); rs112533309(C,T); rs3738984(C,T); rs3738983(T,C); rs6544758(G,A); rs115245600(G,C); rs140120639(C,T); rs12479407(T,C); rs6705951(A,C); rs12470084(C,A); rs6716849(C,T); rs6745281(A,C); rs141050990(C,G); rs11684679(G,C); rs6721421(G,A); rs12471381(C,T); rs141567606(G,C); rs2340809(A,G); rs74261795(C,A); rs2340810(T,C); rs74327041(C,T); rs139794622(T,C); rs113456314(G,T); rs56733642(C,T); rs7609180(A,G); rs72802986(C,A); rs115174729(C,T); rs72802988(G,A); rs10198291(C,T); rs10174537(A,G); rs17579904(T,C); rs112638904(G,C); rs1372080(C,T); rs12476997(G,C); rs28582427(C,T); rs376219902(G,T); rs145786038(T,C); rs2005202(G,C); rs10210581(C,T); rs375855698(G,C); rs72802993(G,C); rs1946932(C,G); rs1372079(C,T); rs1372078(T,A); rs146066270(G,C) |
| ccdsGene name | CCDS1819.1 |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 6519 |
| EntrezGene Description | solute carrier family 3 (amino acid transporter heavy chain), member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC3A1:NM_000341:exon2:c.C566T:p.T189M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.99 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q07837 |
| dbNSFP Uniprot ID | SLC31_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.004229 |
| ESP Eur/Amr MAF | 0.005814 |
| ExAC AF | 2.635e-03,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Rapid weight gain in late childhood (HCS);
[Other];
Failure to thrive (birth to 6-8 years) (HCS);
Failure to thrive, severe (2p21del)
HEAD AND NECK:
[Head];
Dolichocephaly (HCS);
[Face];
Frontal bossing (2p21del);
[Ears];
Large ears (2p21del);
Posteriorly rotated ears (2p21del);
[Eyes];
Almond-shaped eyes (2p21del);
Long eyelashes (2p21del);
Ptosis (HCS);
[Nose];
Depressed nasal bridge (2p21del);
[Mouth];
Tented upper lip (HCS)
ABDOMEN:
[Gastrointestinal];
Feeding problems (HCS and 2p21del)
GENITOURINARY:
[Kidneys];
Nephrolithiasis (HCS and 2p21del);
[Bladder];
Bladder cystine calculi (2p21del)
SKIN, NAILS, HAIR:
[Hair];
Long eyelashes (2p21del)
MUSCLE, SOFT TISSUE:
Red-ragged fibers (2p21del);
Normal muscle fiber (HCS)
NEUROLOGIC:
[Central nervous system];
Seizures, neonatal (2p21del);
No seizures (HCS);
Hypotonia (HCS and 2p21del);
Developmental delay, severe (2p21del);
Mental retardation, moderate-severe (2p21del);
[Behavioral/psychiatric manifestations];
Hyperphagia in late childhood (HCS)
VOICE:
Nasal speech (HCS)
METABOLIC FEATURES:
Cystinuria, type I (HCS and 2p21del)
ENDOCRINE FEATURES:
Growth hormone deficiency (HCS);
Hypergonadotropic hypogonadism (HCS)
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements (2p21del and HCS);
[Delivery];
Postdates delivery (HCS)
LABORATORY ABNORMALITIES:
Lactic acidemia (2p21del);
Normal lactate (HCS);
Transient neonatal hypocalcemia (2p21del);
Transient neonatal hypoglycemia (2p21del);
Increased urinary cystine, arginine, lysine, and ornithine (HCS and
2p21del);
Normal mitochondrial respiratory chain complex I-V (HCS);
Decreased mitochondrial respiratory chain complex (2p21del)
MISCELLANEOUS:
Both contiguous gene syndromes show similar features such as cystinuria,
growth impairment, and hypotonia;
however, neonatal seizures, severe mental retardation, distinct dysmorphic
features, and mitochondrial dysfunction are unique to 2p21 deletion
syndrome (2p21del)
MOLECULAR BASIS:
HCS is a contiguous gene syndrome caused by 23.8-75.5kb deletion containing
the SLC3A1 (104614) and PREPL (609557) genes;
2p21del syndrome is a contiguous gene syndrome caused by 179kb deletion
containing the SLC3A1 (104614), PREPL (609557), PPM1B (603770),
and C2orf34 (609559) genes
OMIM Title
#606407 HYPOTONIA-CYSTINURIA SYNDROME
;;CYSTINURIA WITH MITOCHONDRIAL DISEASE;;
HOMOZYGOUS 2p16 DELETION SYNDROME, FORMERLY
HOMOZYGOUS 2p21 DELETION SYNDROME, INCLUDED
OMIM Description
A number sign (#) is used with this entry because hypotonia-cystinuria
syndrome is a contiguous gene syndrome caused by a homozygous deletion
on chromosome 2p21 that disrupts the SLC3A1 (104614) and PREPL (609557)
genes. The deletion ranges in size from 23.8 to 75.5 kb.
Larger homozygous deletions in this region, including a 179-kb deletion,
result in a more severe phenotype termed the '2p21 deletion syndrome.'
Genes deleted in the 2p21 deletion syndrome include SLC3A1, PREPL, PPM1B
(603770), C2ORF34 (609559), and possibly other genes.
Homozygous mutations in the SLC3A1 gene result in isolated cystinuria
(220100).
CLINICAL FEATURES
Parvari et al. (2001) identified 4 male and 3 female patients from an
extended, small Bedouin family who presented with an autosomal recessive
syndrome consisting of cystinuria as well as neonatal seizures,
hypotonia, severe somatic and developmental delay, facial dysmorphism,
and lactic acidosis. The patients were born at term with normal growth
parameters, but had linear growth impairment and severe failure to
thrive. All had moderate to severe mental retardation. Brain CT scans
were normal. Dysmorphic facies included frontal bossing, almond-shaped
eyes, long eyelashes, depressed nasal bridge, and large, posteriorly
rotated ears. Renal and/or bladder cystine calculi were detected in all
patients as early as 9 months. Serum lactate level was elevated in 4 of
the 7 patients, and studies of muscle biopsies suggested mitochondrial
dysfunction.
Jaeken et al. (2006) reported 11 patients from 9 families with
hypotonia-cystinuria syndrome. Seven families were Flemish and 2 were
French. The clinical features were similar to those reported by Parvari
et al. (2001), but were milder. The phenotype was characterized by
generalized hypotonia at birth, cystine nephrolithiasis, growth hormone
deficiency, minor facial dysmorphism, and failure to thrive, followed by
hyperphagia and rapid weight gain in late childhood. Facial dysmorphism
included dolichocephaly, ptosis, and tented upper lip. Gross motor
development was mildly to moderately retarded, and 3 patients required
special education. All patients had nasal speech. Seven patients showed
late puberty, 4 with hypergonadotropic hypogonadism. All patients had
nephrolithiasis in the first decade. There was no evidence of a
mitochondrial disease.
Chabrol et al. (2008) reported a brother and sister, born of unrelated
Moroccan parents from the same village, with a phenotype that was
intermediate between hypotonia-cystinuria syndrome and the 2p21 deletion
syndrome. Both showed neonatal hypotonia with inability to suck, delayed
motor development, and later growth delay. The boy had slight
craniofacial dysmorphism including dolichocephaly, frontal bossing, mild
ptosis of the eyelids, slight epicanthal folds, arched philtrum, and
retrognathia. He was lost from follow-up until at the age of 17 years
when he showed moderate mental retardation with learning disabilities
and episodes of weakness and fatigability. A younger sister showed
arthrogryposis, muscular hypotrophy and hypotonia, and absent deep
tendon reflexes at birth. At 8 years, she still showed muscular
weakness, hypotonia, and obvious mental retardation. Brain MRI showed
localized unspecific white matter subcortical signal anomalies and
muscle biopsy showed mitochondrial complex IV deficiency. Both patients
had at least 1 episode of renal calculus. Two older brothers had died in
infancy with severe unexplained hypotonia.
MAPPING
By linkage analysis of a Bedouin family with hypotonia-cystinuria
syndrome, Parvari et al. (2001) found that the patients were homozygous
for the same deletion on chromosome 2p, including the SLC3A1 gene, which
was originally reported by the authors as '2p16.' Repeated failures to
amplify the 10 exons of the SLC3A1 gene indicated a large deletion in
this region.
Parvari et al. (2005) corrected and refined the localization of the
deletion in the hypotonia-cystinuria syndrome to chromosome 2p21.
MOLECULAR GENETICS
In all affected patients of a Bedouin family with hypotonia-cystinuria
syndrome, Parvari et al. (2001) identified a homozygous 179-kb deletion
on chromosome 2p, including the SLC3A1, PPM1B, and PREPL genes. All
parents were heterozygous for the deletion. The authors suggested that
the early age at onset of renal calculi in these patients was compatible
with complete deletion of the SLC3A1 gene. The contribution of the other
deleted genes to the phenotype could not be established. Parvari et al.
(2005) reported the transcription content of the deleted region on 2p21.
They determined that the first exon of an additional gene, C2ORF34, was
also located within the deleted region. C2ORF34 was not expressed in
patients with the 2p21 deletion.
In 11 patients from 9 families with hypotonia-cystinuria syndrome,
Jaeken et al. (2006) identified deletions on 2p21 ranging in size from
23.8 kb to 75.5 kb. All had complete deletion of the SLC3A1 gene.
Further analysis showed that all patients also had deletion of the PREPL
gene, but there was normal expression of the flanking genes C2ORF34 and
PPM1B. Jaeken et al. (2006) concluded that the cystinuria was due to
deletion of the SLC3A1 gene and that the additional phenotypic features
could be attributed to deletion of the PREPL gene.
In 2 Moroccan sibs with atypical hypotonia-cystinuria syndrome. Chabrol
et al. (2008) identified a homozygous 77.4-kb deletion of chromosome
2p21, including the SLC3A1, PREPL and C2ORF34 genes. Atypical clinical
features included mild to moderate mental retardation and respiratory
chain complex IV deficiency in 1 of the sibs.
NOMENCLATURE
Parvari et al. (2001) originally mapped the deletion in
hypotonia-cystinuria syndrome to chromosome 2p16, but later Parvari et
al. (2005) corrected and refined the location of the deletion to 2p21.
The former title 'homozygous 2p16 deletion syndrome' is retained here
for historical purposes.
SOCS5
| dbSNP name | rs41435249(T,C); rs6705737(A,G); rs6737848(C,G); rs12151534(A,G); rs11676737(T,C); rs41458449(G,C); rs41363950(A,G); rs41379148(A,G); rs6746471(G,A); rs973491(T,C); rs10168342(G,A); rs35825831(T,G); rs10168357(G,A); rs13411633(A,G); rs4522653(T,A); rs13412085(A,T); rs10172110(G,T); rs17822019(T,C); rs6741642(C,T); rs41413046(G,T); rs7594523(G,C); rs28702871(C,T); rs6748938(C,G); rs17770970(A,T); rs2061182(A,G); rs74565496(A,G); rs72802426(T,G); rs12998753(A,G); rs12998762(A,C); rs12999586(C,T); rs13025984(T,C); rs142465109(T,G); rs7570376(T,C); rs41371146(G,A); rs10189994(T,C); rs10190001(T,C); rs10190187(T,C); rs148920731(A,G); rs146201961(T,C); rs72802429(T,A); rs72802430(C,T); rs1471057(T,C); rs1471056(C,T); rs6544917(T,G); rs6544918(A,G); rs4953414(G,C); rs56224128(G,T); rs370312752(A,G); rs72802435(G,A); rs13402099(G,A); rs7566758(C,T); rs897530(C,G); rs897529(T,C); rs897528(A,G); rs990289(A,G); rs6544919(G,T); rs111795485(T,C); rs6727737(C,T); rs6745858(T,C); rs6731970(G,A); rs6735101(G,A); rs72802441(A,T); rs9807932(T,C); rs1813505(A,G); rs113371671(G,C); rs112478009(A,G); rs35158352(C,T); rs72802445(A,T); rs114233238(T,A); rs1456009(T,C); rs79790496(A,T); rs79444632(C,T); rs10192254(G,T); rs78298398(G,A); rs6741706(T,C); rs141960154(A,C); rs9677272(A,T); rs114290175(C,T); rs7580649(G,C); rs146945615(G,A); rs55817465(A,G); rs17771005(G,A); rs17771017(A,G); rs4952843(A,G); rs17771098(G,T); rs17822294(G,A); rs17771201(C,T); rs13391877(T,A); rs11903382(G,A); rs13429704(G,T); rs17771255(G,A); rs11889273(T,A); rs1867819(A,T); rs79034138(A,G); rs74931250(T,G); rs60470928(A,G); rs78050783(A,G); rs73926574(C,G); rs17039203(A,T); rs34186074(T,C); rs6760403(T,G); rs17771357(G,A); rs114493244(G,A); rs116459706(C,T); rs28715577(G,A); rs10187320(A,T); rs1867820(G,A); rs10190841(A,G); rs10167561(C,T); rs6714964(T,A); rs72802448(C,G); rs6728559(A,G); rs72802451(A,C); rs6728881(A,G); rs72802454(T,G); rs72802455(A,G); rs72802456(A,G); rs144458652(T,C); rs62134765(C,G); rs72802458(G,A); rs4953415(G,A); rs147647316(C,T); rs4953416(A,G); rs72802460(T,G); rs17035560(A,G); rs6711782(C,T); rs55928499(G,T); rs13399271(C,A); rs13399713(C,T); rs6727934(T,C); rs13402553(C,G); rs6716072(G,A); rs72802462(T,G); rs34401107(A,C); rs10196768(T,G); rs7584870(T,A); rs72802463(C,T); rs72802464(A,T); rs72802465(T,A); rs78530730(G,T); rs78331617(C,T); rs10439427(T,C); rs17035565(A,G); rs7562173(G,C); rs2045290(G,A); rs2045291(C,G); rs4575769(C,T); rs17035570(C,G); rs11125087(G,C); rs72802467(A,G); rs13025595(A,G); rs6730949(T,C); rs6718677(C,T); rs12329330(A,G); rs11695058(A,G); rs10209683(A,G); rs72802468(A,T); rs72802469(C,T); rs7573534(C,G); rs41518447(T,C); rs13426735(T,C); rs17035588(A,G); rs79642564(A,G); rs7568007(T,C); rs72802470(A,T); rs4953418(C,T); rs12474054(A,G); rs144824543(T,C); rs41483445(G,A); rs6738426(A,G); rs41489952(C,G); rs371477717(C,T); rs17771838(G,A); rs3768720(T,G); rs10221923(A,G); rs3768719(T,G); rs17823065(T,C); rs1058157(G,A); rs17771942(A,T); rs4953419(T,G) |
| ccdsGene name | CCDS1830.1 |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 9655 |
| EntrezGene Description | suppressor of cytokine signaling 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SOCS5:NM_144949:exon2:c.C1226T:p.A409V,SOCS5:NM_014011:exon2:c.C1226T:p.A409V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8195 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75159 |
| dbNSFP Uniprot ID | SOCS5_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Myopathy
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Hypotonia;
Macrocephaly (due to Dandy-Walker malformation)
HEMATOLOGY:
Coagulation abnormalities
LABORATORY ABNORMALITIES:
Elevated creatine kinase;
Prolonged activated partial prothrombin time (aPPT);
Abnormal serum transferrin pattern by isoelectric focusing (hyposialylation)
MOLECULAR BASIS:
Caused by mutation in the beta-1,4-galactosyltransferase gene (B4GALT1,
137060.0001).
OMIM Title
*607094 SUPPRESSOR OF CYTOKINE SIGNALING 5
;;SOCS5;;
CYTOKINE-INDUCIBLE SH2 PROTEIN 6; CIS6;;
KIAA0671
OMIM Description
DESCRIPTION
After cytokine receptor binding, signals are transduced by Janus kinases
(e.g., JAK1; 147795) and STAT proteins (e.g., STAT1; 600555).
Suppressors of cytokine signaling, such as SOCS5, negatively regulate
this signal transduction. A C-terminal domain called the SOCS box, or
CIS homology domain, is conserved in this family of inhibitory proteins.
CLONING
By screening for cDNAs with the potential to encode large proteins
expressed in brain, Ishikawa et al. (1998) identified a cDNA encoding
KIAA0671. The 536-amino acid protein was predicted to be homologous to
the mouse Socs5 protein. RT-PCR analysis detected wide expression that
was weak in pancreas and spleen.
By searching an EST database for sequences containing the central SH2
domain of SOCS proteins, followed by screening a placenta cDNA library,
Magrangeas et al. (2000) obtained a cDNA encoding SOCS5. The human
protein is 95% similar to the mouse protein (Hilton et al., 1998). It
contains an N-terminal region of 378 amino acids, followed by the SH2
domain, which is immediately adjacent to the C-terminal SOCS box.
Northern blot analysis revealed wide expression of a 4.2-kb transcript
in tissues and in all myeloma cell lines tested.
MAPPING
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the KIAA0671
gene to chromosome 2. Using FISH, Magrangeas et al. (2000) found signals
on both chromosomes 3p22 and 2p21.
MIR559
| dbSNP name | rs58450758(C,T) |
| ccdsGene name | CCDS1833.1 |
| cytoBand name | 2p21 |
| EntrezGene GeneID | 693144 |
| snpEff Gene Name | EPCAM |
| EntrezGene Description | microRNA 559 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2002 |
| ESP Afr MAF | 0.278136 |
| ESP All MAF | 0.129602 |
| ESP Eur/Amr MAF | 0.065312 |
| ExAC AF | 0.067 |
TSPYL6
| dbSNP name | rs843707(G,A); rs62139254(A,T); rs843706(C,A); rs73934418(T,A); rs73934419(T,C); rs150422943(G,A); rs6735998(C,G); rs843705(C,G); rs10165485(T,C); rs843704(C,T); rs201798777(G,A); rs111886241(G,A) |
| ccdsGene name | CCDS1850.1 |
| cytoBand name | 2p16.2 |
| EntrezGene GeneID | 388951 |
| snpEff Gene Name | ACYP2 |
| EntrezGene Description | TSPY-like 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2388 |
RPL23AP32
| dbSNP name | rs61739882(G,C); rs1802889(C,T) |
| ccdsGene name | CCDS33198.1 |
| cytoBand name | 2p16.2 |
| EntrezGene GeneID | 56969 |
| snpEff Gene Name | SPTBN1 |
| EntrezGene Description | ribosomal protein L23a pseudogene 32 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
| ExAC AF | 5.130e-03,8.341e-06 |
PRORSD1P
| dbSNP name | rs2589061(C,T); rs184835825(G,T); rs2589060(C,G); rs2589058(T,C); rs2576694(C,G); rs2917781(G,C); rs2920959(G,A); rs2966465(C,A); rs6545484(G,C); rs17046820(A,T); rs7577510(G,A); rs111522237(G,T) |
| cytoBand name | 2p16.1 |
| EntrezGene GeneID | 344405 |
| snpEff Gene Name | AC012358.1 |
| EntrezGene Description | prolyl-tRNA synthetase associated domain containing 1, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09183 |
MIR217
| dbSNP name | rs150436368(A,G) |
| cytoBand name | 2p16.1 |
| EntrezGene GeneID | 406999 |
| snpEff Gene Name | AC011306.2 |
| EntrezGene Description | microRNA 217 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
| ESP Afr MAF | 0.042173 |
| ESP All MAF | 0.013114 |
| ESP Eur/Amr MAF | 0.000419 |
| ExAC AF | 0.003472 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Low birth length;
[Weight];
Low birth weight;
[Other];
Intrauterine growth retardation;
Poor somatic growth
HEAD AND NECK:
[Head];
Microcephaly, severe (-9 S.D.);
Low sloping forehead;
Micrognathia;
[Ears];
Prominent helices;
[Eyes];
Cataracts;
[Nose];
Prominent nasal bridge;
Choanal atresia
SKELETAL:
Arthrogryposis;
Contractures
MUSCLE, SOFT TISSUE:
Increased muscle tone
NEUROLOGIC:
[Central nervous system];
Psychomotor retardation, profound;
Cerebral atrophy, severe;
Cerebellar atrophy;
Spasticity;
Absence of the corpus callosum;
Delayed myelination;
Loss of neurons affecting all cortical layers;
Little polarity in remaining neurons;
Abnormal cell orientation;
Poor dendritic maturation;
Cell degeneration;
Gliosis
MISCELLANEOUS:
Onset at birth;
Death usually by 1 year of age;
One consanguineous Arab Israeli family has been reported (last curated
February, 2013)
MOLECULAR BASIS:
Caused by mutation in the zinc finger protein 335 gene (ZNF335, 610827.0001)
OMIM Title
*615096 MICRO RNA 217; MIR217
;;miRNA217
OMIM Description
DESCRIPTION
Micro RNAs, such as MIR217, are small noncoding RNAs that inhibit gene
expression by binding to target mRNAs, usually in the 3-prime region,
causing mRNA degradation or suppressing translation (Yin et al., 2012).
GENE FUNCTION
Using expression profiling to identify miRNAs upregulated in senescent
human umbilical vein endothelial cells (HUVECs) in late passage (44
doublings) compared with young cultures in early passage (8 doublings),
Menghini et al. (2009) identified MIR217. Northern blot and quantitative
RT-PCR analyses confirmed MIR217 upregulation during senescence in
HUVECs. Computational analysis identified the histone deacetylase Sirt1
(604479) as a potential MIR217 target. MIR217 downregulated expression
of a SIRT1 reporter gene and downregulated expression of SIRT1 in
transfected HUVECs and human aortic endothelial cells. Overexpression of
MIR217 induced a premature senescence-like phenotype in early-passage
HUVECs and caused acetylation of the SIRT1 target genes FOXO1 (FOXO1A;
136533) and ENOS (NOS3; 163729), but not p53 (TP53; 191170). Menghini et
al. (2009) found evidence for elevated MIR217, downregulated SIRT1, and
elevated acetylation of SIRT1 target genes in human atherosclerotic
lesions. They concluded that MIR217 downregulates SIRT1 expression and
activity and contributes to the aging phenotype.
Yin et al. (2012) found that Mir217 regulated Sirt1 expression in mouse
liver and mouse AML-12 hepatocytes. Chronic ethanol exposure
specifically induced Mir217 expression and caused excessive fat
accumulation in AML-12 cells in culture and in mouse livers in vivo.
Reporter gene assays and transfection experiments revealed that Mir217
downregulated expression of Sirt1 concomitant with altered expression of
Sirt1-regulated genes encoding lipogenic or fatty acid oxidation
enzymes. Mir217 also disturbed the splicing and function of the lipid
regulator lipin-1 (LPIN1; 605518). Overexpression of Mir217 exacerbated
ethanol-dependent downregulation of Sirt1.
MAPPING
Menghini et al. (2009) stated that the MIR217 gene maps to chromosome
2p16.1.
MIR216A
| dbSNP name | rs41291179(A,T) |
| cytoBand name | 2p16.1 |
| EntrezGene GeneID | 406998 |
| snpEff Gene Name | AC011306.2 |
| EntrezGene Description | microRNA 216a |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0652 |
| ESP Afr MAF | 0.173788 |
| ESP All MAF | 0.089223 |
| ESP Eur/Amr MAF | 0.052205 |
| ExAC AF | 0.052 |
MIR4432
| dbSNP name | rs243080(G,A) |
| cytoBand name | 2p16.1 |
| EntrezGene GeneID | 100616473 |
| snpEff Gene Name | U1 |
| EntrezGene Description | microRNA 4432 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4734 |
| ExAC AF | 0.209 |
LOC100132215
| dbSNP name | rs185616288(G,T) |
| cytoBand name | 2p15 |
| EntrezGene GeneID | 100132215 |
| snpEff Gene Name | EHBP1 |
| EntrezGene Description | uncharacterized LOC100132215 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
DBIL5P2
| dbSNP name | rs2162014(C,A); rs984682(G,A); rs4671457(C,T) |
| cytoBand name | 2p15 |
| EntrezGene GeneID | 100169989 |
| snpEff Gene Name | WDPCP |
| EntrezGene Description | diazepam binding inhibitor-like 5 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4789 |
LOC102724321
| dbSNP name | rs79825906(G,A); rs61732614(C,G); rs17032757(A,G); rs140626932(T,C) |
| cytoBand name | 2p14 |
| EntrezGene GeneID | 101060019 |
| EntrezGene Symbol | LOC101060019 |
| snpEff Gene Name | AC007403.1 |
| EntrezGene Description | uncharacterized LOC101060019 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1162 |
ASPRV1
| dbSNP name | rs3087933(C,T); rs3796097(T,C) |
| cytoBand name | 2p13.3 |
| EntrezGene GeneID | 151516 |
| EntrezGene Description | aspartic peptidase, retroviral-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3049 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Sensorineural deafness (reported in 1 family);
[Mouth];
Aphthous ulcers, episodic
ABDOMEN:
Abdominal pain, episodic
SKIN, NAILS, HAIR:
[Skin];
Rash, episodic;
Urticaria, episodic
SKELETAL:
Arthralgias, episodic
MUSCLE, SOFT TISSUE:
Myalgias, episodic
NEUROLOGIC:
[Central nervous system];
Headache, episodic
METABOLIC FEATURES:
Fever, episodic
LABORATORY ABNORMALITIES:
Serum C-reactive protein may be increased
MISCELLANEOUS:
Onset in infancy;
Phenotypic variability;
Episodes are triggered by cold exposure;
Episodes last 2 days to 1 week
MOLECULAR BASIS:
Caused by mutations in the NLR family, pyrin-domain containing 12
gene (NLRP12, 609648.0001)
OMIM Title
*611765 ASPARTIC PEPTIDASE, RETROVIRAL-LIKE 1; ASPRV1
;;SKIN ASPARTIC PROTEASE; SASP;;
SASPase;;
TPA-INDUCIBLE ASPARTIC PROTEINASE; TAPS;;
MUNO
OMIM Description
CLONING
By SDS-PAGE analysis of proteins expressed in epidermal differentiation,
followed by peptide sequencing, and RT-PCR of a human keratinocyte cDNA
library, Bernard et al. (2005) cloned SASP. The deduced 343-amino acid
protein has a calculated molecular mass of 37 kD, and an alternate
isoform of 259 amino acids has a molecular mass of 28.5 kD. SASP shares
similarity with aspartyl proteases with a retroviral-type signature,
such as the equine anemia virus (EIAV) protease. SASP contains a
predicted N-myristoylation domain, a dileucine site, N-glycosylation,
sulfation, phosphorylation, myristoylation, and amidation sites, and a
putative transmembrane domain. SASP shares 87% amino acid homology with
its mouse ortholog. Northern blot analysis of human tissues detected
SASP expression primarily in skin with lower expression in brain.
Western blot analysis of human epidermis detected 14-kD and 28-kD
isoforms, and the authors suggested that the 14-kD form represents the
activated protease while the 28-kD form is an epidermal proform SASP.
Bernard et al. (2005) suggested that activation may be related to
keratinocyte differentiation, and they noted a persistence of the
inactivated form throughout the stratum corneum in psoriatic epidermis
compared to normal epidermis.
GENE FUNCTION
Using a fluorescence-based protease assay, Bernard et al. (2005)
demonstrated SASP catalytic activity. They showed that recombinant 28-kD
SASP catalyzed the hydrolysis of casein and primarily hydrolyzed 1 bond
in the oxidized B chain of insulin at glu13-ala14. Recombinant 28-kD
SASP autocatalytically generated an active 14-kD protein. Analysis of
active-site directed mutations determined that SASP is a member of the
aspartic protease family and that asp212 is the key active site amino
acid. Bernard et al. (2005) noted that the HIV protease inhibitor
indinavir inhibited SASP autoactivation activity while aspartic protease
inhibitor pepstatine did not inhibit SASP autoactivation.
GENE STRUCTURE
Bernard et al. (2005) determined that the SASP gene contains a single
exon with no introns and spans 2.35 kb.
MAPPING
By genomic sequence analysis, Bernard et al. (2005) mapped the ASPRV1
gene to chromosome 2p13.1.
EGR4
| dbSNP name | rs2229294(G,A); rs7558708(G,A) |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 1961 |
| EntrezGene Description | early growth response 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2571 |
| ESP Afr MAF | 0.368 |
| ESP All MAF | 0.15649 |
| ESP Eur/Amr MAF | 0.063536 |
OMIM Clinical Significance
Ears:
Thickened earlobes;
Congenital conductive deafness;
Curvature of long crus of incus;
Absent stapes head
Inheritance:
Autosomal dominant
OMIM Title
*128992 EARLY GROWTH RESPONSE 4; EGR4
;;NERVE GROWTH FACTOR-INDUCED CLONE C; NGFIC
OMIM Description
DESCRIPTION
NGFIC is a nerve growth factor-induced early response gene that encodes
a C2/H2 zinc finger protein (Crosby et al., 1992).
CLONING
Crosby et al. (1992) cloned the NGFIC gene, which encodes a predicted
478-amino acid protein containing 3 zinc fingers of the C2/H2 subtype
near the carboxy terminus.
MAPPING
By use of fluorescence in situ hybridization, Crosby et al. (1992)
localized the human EGR4 gene to 2p13. Barrow et al. (1994) demonstrated
that the homologous gene in the mouse (Egr4) maps to chromosome 6 in a
region of conserved homology of synteny with human chromosome 2.
ALMS1-IT1
| dbSNP name | rs6749671(G,A); rs6749680(G,A); rs79454010(T,C) |
| ccdsGene name | CCDS42697.1 |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 7840 |
| EntrezGene Symbol | ALMS1 |
| snpEff Gene Name | ALMS1 |
| EntrezGene Description | Alstrom syndrome 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02571 |
NAT8B
| dbSNP name | rs4852974(A,G); rs62619834(C,A); rs2001490(C,G); rs2012574(G,C) |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 51471 |
| snpEff Gene Name | AC092653.5 |
| EntrezGene Description | N-acetyltransferase 8B (GCN5-related, putative, gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.259 |
| ESP Afr MAF | 0.172038 |
| ESP All MAF | 0.25073 |
| ESP Eur/Amr MAF | 0.291047 |
| ExAC AF | 0.727,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
ABDOMEN:
Recurrent abdominal pain since childhood;
[Pancreas];
Chronic pancreatitis;
Pancreatic calcifications;
Intraductal calculi, especially in the caput;
Increased risk of pancreatic cancer
ENDOCRINE FEATURES:
Increased incidence of fibrocalculus pancreatic diabetes (FCPD);
Insulin-dependent but ketosis-resistant diabetes
NEOPLASIA:
Increased risk of pancreatic cancer
MISCELLANEOUS:
Median age at onset is 21 years;
Occurs most often in developing countries in tropical regions;
No phenotypic difference between patients who are homozygous or heterozygous
for mutations in the SPINK1 gene
MOLECULAR BASIS:
Caused by mutation in the serine protease inhibitor, kazal-type-1
gene (SPINK1, 167790.0001)
OMIM Title
*608190 N-ACETYLTRANSFERASE 8B; NAT8B
;;CAMELLO, XENOPUS, HOMOLOG OF, 2; CML2
OMIM Description
CLONING
By searching an EST database for sequences similar to the Xenopus
camello protein, Popsueva et al. (2001) identified CML2. The deduced
227-amino acid protein shares significant similarity with other camello
proteins, including a conserved N-terminal hydrophobic domain and
C-terminal consensus motifs of GCN5 (see 602301)-related
N-acetyltransferases.
By genomic sequence analysis, EST database analysis, and sequencing
genomic DNA from 24 individuals, Veiga-da-Cunha et al. (2010) found that
NAT8B contains a stop codon at codon 16. The only NAT8B sequence lacking
the stop codon at codon 16 was that reported by Popsueva et al. (2001),
which has a ser16 codon. Veiga-da-Cunha et al. (2010) suggested that
ser16 results from an extremely rare mutation or a sequencing error.
Translation of NAT8B was predicted to begin at the next in-frame
methionine, met25. This N-terminally truncated protein lacks a number of
conserved residues found in NAT8 (606716) and NAT8L (610647) homologs,
suggesting that NAT8B is inactive.
GENE FUNCTION
Veiga-da-Cunha et al. (2010) found that truncated NAT8B and NAT8
proteins beginning at met25 were inactive against a good NAT8 substrate.
They concluded that NAT8B is inactive in humans.
GENE STRUCTURE
Veiga-da-Cunha et al. (2010) determined that exon 2 of the NAT8B gene
contains the complete reading frame.
MAPPING
Veiga-da-Cunha et al. (2010) stated that the NAT8B gene is a tandem
duplication of the NAT8 gene on chromosome 2p13.1-p12.
DCTN1-AS1
| dbSNP name | rs12328744(C,G); rs78749719(A,G) |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 100189589 |
| snpEff Gene Name | DCTN1 |
| EntrezGene Description | DCTN1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2011 |
MRPL53
| dbSNP name | rs1047911(C,A) |
| ccdsGene name | CCDS1944.1 |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 116540 |
| EntrezGene Description | mitochondrial ribosomal protein L53 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MRPL53:NM_053050:exon1:c.G10T:p.A4S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96EL3 |
| dbNSFP Uniprot ID | RM53_HUMAN |
| dbNSFP KGp1 AF | 0.5 |
| dbNSFP KGp1 Afr AF | 0.80487804878 |
| dbNSFP KGp1 Amr AF | 0.273480662983 |
| dbNSFP KGp1 Asn AF | 0.828671328671 |
| dbNSFP KGp1 Eur AF | 0.162269129288 |
| dbSNP GMAF | 0.4995 |
| ESP Afr MAF | 0.29369 |
| ESP All MAF | 0.330591 |
| ESP Eur/Amr MAF | 0.138055 |
| ExAC AF | 0.268,4.880e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolongation of corrected QT interval (in some patients);
Long isoelectric ST segment (in some patients);
Late-onset T wave (in some patients);
Atrioventricular node block, 2:1, intermittent (in some patients);
Atrial fibrillation (in some patients)
MISCELLANEOUS:
Risk of sudden death with exertion
MOLECULAR BASIS:
Caused by mutation in the type IV voltage-gated sodium channel beta
subunit gene (SCN4B, 608256.0001)
OMIM Title
*611857 MITOCHONDRIAL RIBOSOMAL PROTEIN L53; MRPL53
OMIM Description
DESCRIPTION
Mitochondria have their own translation system for production of 13
inner membrane proteins essential for oxidative phosphorylation. MRPL53
is a component of the large subunit of the mitochondrial ribosome that
is encoded by the nuclear genome (Koc et al., 2001).
CLONING
By searching databases using bovine Mrpl53 as query, Koc et al. (2001)
identified human MRPL53. They also identified MRPL53 homologs in mouse
and C. elegans, but not in Drosophila, yeast, E. coli, or Arabidopsis.
Mouse and human MRPL53 share 85.6% amino acid identity.
MAPPING
By genomic sequence analysis, Zhang and Gerstein (2003) mapped the
MRPL53 gene to chromosome 2p12. They identified an MRPL53 pseudogene on
chromosome 1.
LBX2-AS1
| dbSNP name | rs144314244(C,G) |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 151534 |
| snpEff Gene Name | PCGF1 |
| EntrezGene Description | LBX2 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001377 |
TLX2
| dbSNP name | rs73949678(A,C) |
| cytoBand name | 2p13.1 |
| EntrezGene GeneID | 3196 |
| snpEff Gene Name | DQX1 |
| EntrezGene Description | T-cell leukemia homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Febrile seizures;
Afebrile seizures;
Generalized tonic-clonic seizures;
Absence seizures;
Myotonic seizures;
Atonic seizures
MISCELLANEOUS:
Highly variable phenotype;
Onset of febrile seizures typically between 6 months and 6 years of
age;
Persistence of febrile seizures beyond age 6 years;
Development of afebrile seizures later in childhood;
Incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the voltage-gated sodium channel, type I, beta
subunit gene (SCN1B, 600235.0001)
OMIM Title
*604240 T-CELL LEUKEMIA, HOMEOBOX 2; TLX2
;;HOMEOBOX 11-LIKE 1; HOX11L1;;
TLX2;;
NCX;;
ENX
OMIM Description
CLONING
On the basis of the mouse Tlx2 (Hox11l1) sequence, Puliti et al. (1999)
designed primers to amplify human genomic DNA. Based on the sequence of
the PCR product, 2 human specific primers were synthesized to screen the
CEPH YAC library. Two human YAC clones were identified that contain the
human homolog of the mouse Tlx2 gene.
GENE FUNCTION
The mouse Hox11l1 gene is expressed from embryonic day 9.5 through day
13.5 and is specifically detectable in the dorsal root ganglia, cranial
and enteric nerve ganglia, and adrenal glands, while in adult animals
its expression is limited to the adrenal gland and the intestine. Since
the expression of Hox11l1 is restricted to tissues derived from neural
crest cells, Hatano et al. (1997) hypothesized a role for this gene in
the proliferation and/or differentiation of enteric peripheral nervous
system.
GENE STRUCTURE
Iitsuka et al. (1999) identified a retinoic acid response element in the
human and mouse HOX11L1 promoters. They also identified an enhancer
element in the mouse promoter that was crucial for tissue-specific
expression, and this element was conserved in the human promoter. The
enhancer element bound nuclear proteins from both human and mouse
neuroblastoma cells.
MAPPING
HOX11 (186770)-related genes are scattered on different chromosomes
(Dear et al., 1993). Using a mouse EST cDNA clone showing sequence
homology with Hox11l1 cDNA to perform FISH, Puliti et al. (1999) mapped
the mouse Hox11l1 gene to chromosome 6, band C3-D1. This region of mouse
chromosome 6 shows homology of synteny with human 2p14-p13. Using FISH,
Puliti et al. (1999) localized the HOX11L1 gene to chromosome
2p13.1-p12.
ANIMAL MODEL
Hatano et al. (1997) and Shirasawa et al. (1997) generated transgenic
mice carrying Tlx2 null mutations. Homozygous mice were viable but
developed megacolon with hyperinnervated enteric neurons, similar to
human neuronal intestinal dysplasia (601223, 243180).
REG1P
| dbSNP name | rs17016388(A,G); rs6750149(A,G); rs6721752(C,T); rs3769506(G,T); rs139425770(G,A); rs183992851(C,T); rs11678299(C,G); rs3819317(G,A); rs879022(C,T); rs11684223(T,C); rs3819315(C,T); rs879021(C,A); rs111357846(C,T); rs892867(G,A); rs1963424(T,A) |
| cytoBand name | 2p12 |
| EntrezGene GeneID | 5969 |
| EntrezGene Description | regenerating islet-derived 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1276 |
LRRTM1
| dbSNP name | rs6733871(T,C) |
| ccdsGene name | CCDS1966.1 |
| cytoBand name | 2p12 |
| EntrezGene GeneID | 347730 |
| EntrezGene Description | leucine rich repeat transmembrane neuronal 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LRRTM1:NM_178839:exon2:c.A989G:p.N330S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86UE6 |
| dbNSFP Uniprot ID | LRRT1_HUMAN |
| dbNSFP KGp1 AF | 0.366758241758 |
| dbNSFP KGp1 Afr AF | 0.483739837398 |
| dbNSFP KGp1 Amr AF | 0.28453038674 |
| dbNSFP KGp1 Asn AF | 0.554195804196 |
| dbNSFP KGp1 Eur AF | 0.188654353562 |
| dbSNP GMAF | 0.3664 |
| ESP Afr MAF | 0.449841 |
| ESP All MAF | 0.270414 |
| ESP Eur/Amr MAF | 0.178488 |
| ExAC AF | 0.266 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Recurrent sinusitis;
[Ears];
Recurrent serous otitis
CARDIOVASCULAR:
[Heart];
Centrally located heart
RESPIRATORY:
Recurrent respiratory infections due to ciliary dysfunction;
Respiratory cilia have shortened or absent outer dynein arms;
[Lung];
Brochiectasis due to poor ciliary clearance
ABDOMEN:
Situs ambiguus;
[Liver];
Centrally located liver
IMMUNOLOGY:
Recurrent infections due to ciliary dysfunction
MISCELLANEOUS:
Genetic heterogeneity, see CILD1 (244400)
MOLECULAR BASIS:
Caused by mutation in the thioredoxin domain-containing 3 gene (TXNDC3,
607421.0001)
OMIM Title
*610867 LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN 1: LRRTM1
OMIM Description
CLONING
By database analysis using the leucine-rich repeats (LRRs) of the SLIT
(see SLIT1; 603742) proteins, followed by RT-PCR of brain RNA, Lauren et
al. (2003) cloned LRRTM1. The deduced 522-amino acid protein contains an
N-terminal signal sequence, followed by 10 extracellular LRRs flanked by
cysteine-rich domains, a transmembrane region, and an intracellular
tail. LRRTM1 has 3 N-glycosylation sites, several putative
phosphorylation sites, and a C terminus that ends in the sequence ECEV,
which is a characteristic of LRRTM family members. Lauren et al. (2003)
also identified mouse Lrrtm1, which shares 96% amino acid identity with
human LRRTM1. Orthologs of LRRTM1 were detected in databases derived
from several vertebrate species but not in databases derived from
Drosophila or C. elegans. RT-PCR analysis of human tissues detected
highest LRRTM1 expression in salivary gland and in brain, including
hippocampus, thalamus, caudate nucleus, corpus callosum, and amygdala.
Expression was intermediate in cerebellum, small intestine, spinal cord,
stomach, testis, and uterus. In developing mice, Lrrtm1 was expressed at
embryonic day 13 and 15. Highest levels were reached at postnatal day 1
and persisted into adulthood. In situ hybridization of adult mouse brain
detected widespread Lrrtm1 expression predominantly in neurons.
GENE STRUCTURE
Lauren et al. (2003) determined that the LRRTM1 gene contains a single
coding exon.
MAPPING
By genomic sequence analysis, Lauren et al. (2003) mapped the LRRTM1
gene to chromosome 2p12 about 3 Mb centromeric to the LRRTM4 (610870)
gene. LRRTM1 lies on the opposite strand within intron 6 of the CTNNA2
gene (114025). They mapped the mouse Lrrtm1 gene to chromosome 6C3,
which shares homology of synteny with human chromosome 2p12.
LOC1720
| dbSNP name | rs17022658(G,A); rs115805323(A,G); rs11126880(A,T) |
| cytoBand name | 2p12 |
| EntrezGene GeneID | 1720 |
| snpEff Gene Name | AC098817.5 |
| EntrezGene Description | dihydrofolate reductase pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01699 |
FUNDC2P2
| dbSNP name | rs1968722(T,C); rs1531047(C,T); rs2124178(A,G) |
| cytoBand name | 2p11.2 |
| EntrezGene GeneID | 388965 |
| EntrezGene Description | FUN14 domain containing 2 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | transcribed_processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3099 |
| ExAC AF | 0.728 |
TCF7L1
| dbSNP name | rs13003453(T,G); rs10195517(C,T); rs72838189(T,G); rs12474138(G,A); rs55984939(T,C); rs76710632(G,C); rs62162824(A,G); rs111462901(C,T); rs7584403(C,T); rs1835812(A,G); rs62162825(G,A); rs72838190(C,T); rs369042123(A,G); rs6754757(T,G); rs56168805(T,G); rs56213912(G,A); rs62162827(G,A); rs1807310(G,A); rs62162828(G,C); rs62162830(A,T); rs57097797(A,T); rs2583566(T,C); rs75632482(A,T); rs17762108(T,C); rs72932603(T,C); rs145487523(G,A); rs2568216(G,A); rs112745129(G,A); rs2583541(C,T); rs13008771(C,T); rs1808639(A,G); rs17711242(T,G); rs2248065(G,A); rs2248068(A,C); rs2248072(G,A); rs2248075(C,T); rs2248076(A,G); rs2248079(A,G); rs4832144(C,T); rs2568217(T,C); rs2568218(T,G); rs17025940(G,A); rs2568219(G,A); rs6754217(C,T); rs55886208(G,A); rs35035277(T,C); rs7570315(T,C); rs2568221(C,T); rs2568222(A,G); rs6723581(T,A); rs62162851(C,T); rs2583540(T,A); rs7560555(C,A); rs2568223(C,G); rs2583539(C,A); rs2568224(C,G); rs62162852(C,T); rs2568225(T,C); rs10520406(T,C); rs17025951(G,A); rs17762406(T,C); rs72932641(C,A); rs2568226(A,T); rs72932646(T,C); rs62162853(C,T); rs62162854(A,G); rs11679513(G,A); rs72932649(C,G); rs72932652(C,A); rs59117861(A,G); rs6547596(G,C); rs6547597(T,C); rs72932658(T,C); rs55801685(C,A); rs10186759(C,T); rs66856432(G,A); rs76117226(G,A); rs11684525(G,A); rs72932662(T,C); rs1560587(A,T); rs145606817(A,C); rs72840118(C,T); rs11691660(T,G); rs62162857(C,T); rs62162858(A,T); rs6739252(T,C); rs55948631(A,G); rs137882758(T,C); rs11686370(T,C); rs59197302(A,G); rs11691849(A,G); rs11682047(C,T); rs140789337(G,A); rs11693369(A,T); rs74457100(A,G); rs75450748(G,A); rs11126981(C,A); rs72932665(A,G); rs144738899(G,A); rs1030625(C,T); rs79222457(C,T); rs115421849(C,T); rs2583542(G,A); rs55802812(T,C); rs2568197(C,T); rs60541175(C,T); rs2583543(A,C); rs2568198(A,G); rs111859481(G,A); rs2568199(A,G); rs2568200(A,G); rs1864804(G,A); rs2568201(A,G); rs2583545(G,A); rs10167557(G,A); rs2568203(C,T); rs78445322(T,C); rs114367793(G,A); rs11126982(T,C); rs2568204(G,A); rs2583546(T,C); rs2568205(T,C); rs2568206(A,C); rs2583547(G,A); rs13432342(G,A); rs78179407(T,C); rs2568207(A,T); rs74935588(C,A); rs113505112(G,C); rs2583548(T,C); rs58064065(T,A); rs2568208(T,A); rs2583549(G,T); rs61637222(G,T); rs1432264(T,C); rs2568210(C,T); rs2568211(A,G); rs10183679(G,A); rs880092(T,C); rs880093(A,T); rs112700667(G,A); rs874838(A,G); rs753814(C,T); rs2007125(C,T); rs13423910(T,C); rs747078(A,C); rs72932681(T,C); rs2439703(C,T); rs61276534(A,G); rs77718305(C,T); rs57871178(T,C); rs6733735(T,C); rs6747032(A,G); rs6722568(G,A); rs114432482(A,G); rs56691726(A,G); rs10192927(C,T); rs11126983(G,A); rs12478357(T,C); rs59112392(G,T); rs11126984(T,C); rs11126985(G,A); rs72932687(G,A); rs59898676(A,G); rs4832148(C,T); rs4831995(A,G); rs57015835(T,G); rs17026029(T,C); rs7557425(A,G); rs12476165(C,T); rs11692829(G,T); rs11681532(A,G); rs17026034(G,A); rs6742305(C,T); rs62165582(C,T); rs10208803(G,T); rs11695920(C,T); rs2043228(T,C); rs6721730(A,G); rs11126986(A,G); rs4832149(G,A); rs115372289(G,A); rs6709118(G,A); rs6709476(G,A); rs62165583(C,T); rs112515051(A,G); rs186926560(A,G); rs191765768(G,A); rs149869645(T,C); rs72932696(A,G); rs6547598(A,G); rs6715431(T,A); rs6547599(A,T); rs6547600(C,T); rs11126987(T,C); rs4494743(A,C); rs11892343(G,A); rs6743132(T,C); rs60918184(C,G); rs11891881(C,T); rs11902445(A,G); rs11689554(T,C); rs11674371(A,G); rs723465(G,T); rs1347039(A,G); rs6749940(T,C); rs72934616(G,A); rs60593886(C,T); rs72934620(C,G); rs7588165(G,A); rs140913358(G,T); rs116066682(G,A); rs6547601(A,C); rs62165588(G,A); rs9653568(A,G); rs62165589(G,A); rs10205484(G,A); rs72934626(T,G); rs6547602(A,G); rs6753357(C,T); rs11675205(G,A); rs7602052(G,A); rs72934630(C,G); rs6725679(A,G); rs6725799(A,G); rs60161685(A,G); rs6758778(G,A); rs6758805(G,A); rs6708270(C,A); rs1012256(G,A); rs6752527(C,T); rs17026102(T,C); rs6547603(T,C); rs6719095(T,C); rs111982432(T,A); rs6547604(T,C); rs116131980(C,T); rs62165594(T,C); rs17763748(T,G); rs7580690(T,C); rs17712901(G,A); rs186934514(A,C); rs62165595(G,A); rs17763853(A,G); rs7581133(T,G); rs6547605(G,A); rs72934638(A,G); rs11684211(G,A); rs77254788(C,T); rs73943082(G,C); rs78012323(G,A); rs2043229(G,A); rs17026108(G,A); rs2043230(A,T); rs72840024(G,T); rs7592438(T,A); rs7596495(G,A); rs190885007(G,A); rs11904127(G,A); rs11904105(C,T); rs11674662(G,A); rs11681706(T,G); rs7584666(A,T); rs115550005(C,G); rs2366264(G,T); rs1991738(A,G); rs11686410(T,A); rs11126989(T,A); rs11689667(T,C); rs6547607(T,C); rs883650(T,C); rs883651(G,A); rs11683948(C,T); rs908301(C,T); rs882883(G,T); rs1554109(A,C); rs181559208(C,T); rs4408730(G,A); rs17026124(A,G); rs76433308(T,C); rs149022726(A,G); rs7340255(G,A); rs7576082(G,A); rs140040237(G,A); rs11675489(A,G); rs62162671(C,T); rs11686782(G,A); rs10195229(G,A); rs193191057(C,T); rs7340132(A,G); rs147958236(A,G); rs10201321(G,A); rs10201483(C,A); rs10201660(G,A); rs10201489(C,T); rs10201753(G,C); rs114747473(G,A); rs4441469(G,A); rs114140927(T,G); rs62162674(G,C); rs12714137(A,C); rs12714138(G,A); rs139428392(C,T); rs6745529(G,T); rs10184690(A,C); rs10184810(A,C); rs4832151(A,G); rs4832152(G,A); rs145337116(G,A); rs908300(G,A); rs882831(A,G); rs4346385(A,G); rs117159767(C,T); rs6747629(T,C); rs6732834(C,T); rs6733190(C,T); rs6748258(T,A); rs6733515(G,A); rs6736348(G,A); rs6736366(G,A); rs10165984(T,C); rs11126990(T,C); rs116547388(G,T); rs10204252(G,A); rs10180579(A,T); rs10206876(C,A); rs4832153(T,C); rs4832154(T,C); rs4831998(T,C); rs6745204(G,A); rs6547608(G,A); rs116433378(G,A); rs7598047(G,A); rs114174397(A,G); rs7600828(C,G); rs34644194(A,G); rs148275811(G,A); rs7601117(G,A); rs115942112(T,A); rs7574856(A,G); rs7574999(A,G); rs187008279(C,T); rs62162678(T,C); rs112134288(G,A); rs6547609(T,C); rs6719501(T,G); rs62162679(C,T); rs7559779(G,C); rs76277927(A,G); rs6719271(A,G); rs6748174(G,A); rs79115793(A,G); rs369465078(C,T); rs7607282(C,T); rs10185095(T,C); rs56389676(A,G); rs56409903(G,A); rs72840047(A,G); rs79282357(T,C); rs7572226(T,C); rs114220248(C,T); rs139922251(C,A); rs59353316(A,C); rs6718291(C,A); rs142238970(A,G); rs7569653(G,A); rs7583983(T,C); rs76812146(T,A); rs56191302(C,G); rs137942571(A,G); rs56329464(A,G); rs4832155(G,A); rs4832156(A,G); rs4832157(A,G); rs4832158(G,A); rs4832159(T,G); rs114648647(C,T); rs55650677(G,A); rs74619566(A,G); rs10178604(C,T); rs10178705(C,T); rs75912143(G,A); rs7564589(C,T); rs73943084(A,G); rs10184914(G,A); rs55993057(G,A); rs8179703(T,C); rs59211453(G,T); rs55943620(T,C); rs56297212(G,A); rs872470(A,G); rs13001442(A,G); rs13033165(T,C); rs72934690(G,A); rs10174520(A,G); rs73943089(T,C); rs72934693(A,G); rs11900333(C,A); rs77680559(T,C); rs12714139(C,A); rs138821408(G,A); rs115049709(C,T); rs6741339(C,G); rs151161792(G,A); rs139080475(C,T); rs56311472(C,G); rs73943090(G,T); rs114491292(G,A); rs76090477(A,G); rs59059406(T,C); rs73943091(G,A); rs59653199(T,C); rs4497880(G,A); rs72934702(A,G); rs72936604(T,C); rs113988926(T,C); rs149975109(G,A); rs150537132(C,T); rs79028776(G,A); rs9248(G,A); rs873033(G,C) |
| ccdsGene name | CCDS1971.1 |
| cytoBand name | 2p11.2 |
| EntrezGene GeneID | 83439 |
| EntrezGene Description | transcription factor 7-like 1 (T-cell specific, HMG-box) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCF7L1:NM_031283:exon4:c.T478A:p.S160T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5291 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HCS4 |
| dbNSFP Uniprot ID | TF7L1_HUMAN |
| dbNSFP KGp1 AF | 0.00961538461538 |
| dbNSFP KGp1 Afr AF | 0.0426829268293 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.009642 |
| ESP Afr MAF | 0.030413 |
| ESP All MAF | 0.01038 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.00396 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604652 TRANSCRIPTION FACTOR 7-LIKE 1; TCF7L1
;;TRANSCRIPTION FACTOR 3, FORMERLY; TCF3, FORMERLY
OMIM Description
DESCRIPTION
TCF/LEF transcription factors, such as TCF7L1, are mediators of the Wnt
(see 164820) signaling pathway and are antagonized by the TGF-beta
(TGFB1; 190180) signaling pathway (Sagara and Katoh, 2000).
CLONING
The high mobility group (HMG) box is a DNA-binding domain. TCF7
(189908), also called TCF1, and LEF1 (153245), also called TCF1-alpha,
are human lymphoid transcription factors that contain a virtually
identical HMG box. By PCR of human genomic DNA using degenerate
oligonucleotides based on the HMG boxes of TCF7 and LEF1, Castrop et al.
(1992) identified the TCF7L1 and TCF7L2 (602228) genes, which they
called TCF3 and TCF4, respectively. TCF7L1 and TCF7L2 were not expressed
in cells of lymphoid lineage. The deduced amino acid sequences of the
HMG boxes of TCF7L1, TCF7L2, and TCF7 show striking homology. The
authors suggested the existence of a subfamily of TCF7-like HMG
box-containing transcription factors.
By searching databases for homologs of mouse Tcf3, followed by PCR of a
small intestine cDNA library and screening of a fetal lung cDNA library,
Sagara and Katoh (2000) cloned human TCF7L1, which they called TCF3. The
deduced 588-amino acid protein contains a beta-catenin (CTNNB1;
116806)-binding domain at its N terminus, followed by an HMG box, a
nuclear translocation signal, and 2 putative CTBP (see 602618)-binding
sites at its C terminus. TCF7L1 shares 58% amino acid identity with
TCF7L2, its closest homolog among human TCF proteins. Northern blot
analysis detected a 3.0-kb TCF7L1 transcript in human stomach and in
some human gastric cancer cell lines.
GENE FUNCTION
Using Northern blot analysis, Sagara and Katoh (2000) found that TCF7L1
was occasionally upregulated in primary gastric cancer compared with
normal gastric mucosa. Overexpression of TCF7L1 in MKN28 human gastric
cancer cell lines resulted in 8-fold resistance to mitomycin C compared
with controls. DTD (NQO1; 125860) mRNA was downregulated in MKN28 cell
lines overexpressing TCF7L1 and in primary gastric cancer with TCF7L1
upregulation. The DTD protein, which is implicated in mitomycin C
activation, was also downregulated in MKN28 cell lines overexpressing
TCF7L1. Sagara and Katoh (2000) concluded that mitomycin C resistance
induced by TCF7L1 overexpression in gastric cancer is likely due to DTD
downregulation.
Merrill et al. (2001) showed that Lef1 and Tcf3 controlled
differentiation of multipotent stem cells in mouse skin. Lef1 required
Wnt signaling and stabilized beta-catenin to express hair-specific
keratins and control hair differentiation. In contrast, Tcf3 acted
independently of its beta-catenin-interacting domain to suppress
features of epidermal differentiation, in which Tcf3 was normally shut
off, and promote features of the follicle outer root sheath and
multipotent stem cells.
By immunofluorescence analysis, Nguyen et al. (2006) found that
embryonic mouse skin progenitors expressed Tcf3. Using an inducible Tcf3
expression system in mice, they showed that postnatal Tcf3 reactivation
caused committed epidermal cells to induce genes associated with an
undifferentiated, Wnt-inhibited state, and that Tcf3 promoted a
transcriptional program shared by embryonic and postnatal stem cells.
Genes repressed by Tcf3 included transcriptional regulators of the
epidermal, sebaceous gland, and hair follicle differentiation programs,
and all 3 terminal differentiation pathways were suppressed by postnatal
Tcf3 induction. Nguyen et al. (2006) concluded that, in the absence of
Wnt signals, Tcf3 functions in skin stem cells to maintain an
undifferentiated state, and that through Wnt signaling, Tcf3 directs
these cells along the hair lineage.
To balance self-renewal and differentiation, embryonic stem (ES) cells
must control the levels of several transcription factors, including
NANOG (607937). Pereira et al. (2006) showed that Tcf3 limited the
steady-state levels of Nanog mRNA, protein, and promoter activity in
self-renewing mouse ES cells. Chromatin immunoprecipitation and promoter
reporter assays showed that Tcf3 bound to a promoter regulatory region
of the Nanog gene and repressed its transcriptional activity. Repression
of Nanog required the groucho (see 600189) interaction domain of Tcf3.
Absence of Tcf3 delayed differentiation of ES cells in vitro by allowing
elevated Nanog levels to persist through 5 days of embryoid body
formation. Pereira et al. (2006) concluded that TCF3-mediated control of
NANOG expression allows ES cells to balance the creation of
lineage-committed and undifferentiated cells.
ANIMAL MODEL
Nguyen et al. (2009) found that knockout of Tcf3 or Tcf4 individually
had no overt effect on hair phenotype in mice, but Tcf3/Tcf4 double
knockout resulted in a severe skin and hair defects. Newborn
Tcf3/Tcf4-null skin was thinner than normal and often lacked whiskers.
Tcf3/Tcf4-null skin showed signs of apoptosis and, when grafted onto
nude mice, became shrunken, was unable to repair wounds, and was
progressively lost, showing an inability to maintain long-term
self-renewing populations of skin epithelia. Tcf3/Tcf4-null skin cells
grew poorly in culture and did not survive passaging. Microarray
analysis of mRNAs expressed by normal and Tcf3/Tcf4-null skin suggested
that Tcf3 and Tcf4 maintain skin epithelial stem cells through
Wnt-dependent and Wnt-independent signaling.
NOMENCLATURE
The TCF7L1 gene, although initially designated TCF3, should not be
confused with the TCF3 gene (147141), also known as E2A. TCF7L1 encodes
a TCF/LEF transcription factor involved in Wnt signaling, whereas TCF3
encodes the basic helix-loop-helix (bHLH) transcription factors E12 and
E47.
LOC100630918
| dbSNP name | rs6729475(C,A); rs4258795(C,T); rs1446667(T,G) |
| cytoBand name | 2p11.2 |
| EntrezGene GeneID | 100630918 |
| snpEff Gene Name | MAT2A |
| EntrezGene Description | uncharacterized LOC100630918 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1267 |
LOC90784
| dbSNP name | rs144680933(C,T); rs116397673(C,A); rs6724612(C,T); rs4832233(T,C); rs12622009(T,C); rs74998226(G,A); rs7606062(A,G); rs7582484(C,G); rs138406344(C,A); rs76873798(C,A); rs6704777(A,G) |
| cytoBand name | 2p11.2 |
| EntrezGene GeneID | 90784 |
| EntrezGene Description | uncharacterized LOC90784 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
MIR4780
| dbSNP name | rs10202149(C,T) |
| ccdsGene name | CCDS33240.1 |
| cytoBand name | 2p11.2 |
| EntrezGene GeneID | 100616447 |
| snpEff Gene Name | SMYD1 |
| EntrezGene Description | microRNA 4780 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05005 |
| ExAC AF | 0.006852 |
ADRA2B
| dbSNP name | rs3813662(A,C); rs4907299(G,T); rs2229169(T,G) |
| cytoBand name | 2q11.1 |
| EntrezGene GeneID | 151 |
| EntrezGene Description | adrenoceptor alpha 2B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07989 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, sensorineural, especially affecting high frequencies
CARDIOVASCULAR:
[Vascular];
Hypertension
GENITOURINARY:
[Kidneys];
Glomerulonephropathy;
Hematuria, gross and microscopic;
Proteinuria;
End-stage renal failure;
Thinning of the glomerular basement membrane (early in the disease);
Thickening of the glomerular basement membrane (later in the disease);
Splitting of the glomerular basement membrane;
Diffuse lamellation of the glomerular basement membrane
LABORATORY ABNORMALITIES:
Hematuria, gross and microscopic;
Proteinuria
MISCELLANEOUS:
Progressive disorder;
Hearing loss is variable
MOLECULAR BASIS:
Caused by mutation in the collagen, type IV, alpha-3 gene (COL4A3,
120070.0009)
OMIM Title
*104260 ALPHA-2B-ADRENERGIC RECEPTOR; ADRA2B
;;ALPHA-2-ADRENERGIC RECEPTOR-LIKE 1;;
ADRA2L1
OMIM Description
CLONING
Regan et al. (1988) and Lomasney et al. (1990) cloned the ADRA2B gene.
By Northern blot analysis of various rat tissues, Lomasney et al. (1990)
detected expression of ADRA2B in liver and kidney. Unique pharmacology
and tissue localization suggested that this was a previously
unidentified subtype.
MAPPING
Regan et al. (1988) indicated that in addition to the platelet
alpha-2-adrenergic receptor (ADRA2A, encoded by chromosome 10; 104210)
and the renal form of receptor (ADRA2C, encoded by chromosome 4;
104250), a related protein is coded by chromosome 2. By hybridization
with somatic cell hybrids, Lomasney et al. (1990) showed that the ADRA2B
gene is located on chromosome 2.
GENE FUNCTION
Alpha-2-adrenergic receptors have a critical role in regulating
neurotransmitter release from sympathetic nerves and from adrenergic
neurons in the central nervous system. To help elucidate the individual
roles of the 3 highly homologous alpha-2-adrenergic receptors (ADRA2A,
ADRA2B, and ADRA2C) in this process, Hein et al. (1999) studied
neurotransmitter release in mice in which the genes encoding the 3
alpha-2-adrenergic-receptor subtypes were disrupted. Hein et al. (1999)
demonstrated that both the ADRA2A and ADRA2C subtypes are required for
normal presynaptic control of transmitter release from sympathetic
nerves in the heart and from central noradrenergic neurons. ADRA2A
receptors inhibited transmitter release at high stimulation frequencies,
whereas the ADRA2C subtype modulated neurotransmission at lower levels
of nerve activity. Both low and high frequency regulation seemed to be
physiologically important, as mice lacking both ADRA2A and ADRA2C
receptor subtypes had elevated plasma noradrenaline concentrations and
developed cardiac hypertrophy with decreased left ventricular
contractility by 4 months of age.
MOLECULAR GENETICS
By PCR-SSCP analysis, Heinonen et al. (1999) screened the entire coding
sequence of the ADRA2B gene in 58 obese, nondiabetic Finns. They
identified a polymorphism that led to a deletion of 3 glutamic acids
from a glutamic acid repeat element (glu12, amino acids 297 to 309)
present in the third intracellular loop of the receptor protein. This
repeat element had been shown to be important for agonist-dependent
receptor desensitization. Of 166 genotyped subjects, 47 (28%) had 2
normal (long) alleles (glu12/glu12), 90 (54%) were heterozygous
(glu12/glu9), and 29 (17%) were homozygous for the short form
(glu9/glu9). The basal metabolic rate, determined by indirect
calorimetry and adjusted for fat-free body mass, fat mass, sex, and age,
was 94 calories/day (5.6%) lower (95% confidence interval for
difference, 32, 156) in subjects homozygous for the short allele than in
subjects with 2 long alleles (F = 4.84; P = 0.009, by ANOVA). The
authors concluded that a genetic polymorphism of the ADRA2B subtype
could partly explain the variation in basal metabolic rate in an obese
population and may therefore contribute to the pathogenesis of obesity.
Suzuki et al. (2003) investigated the association of the ADRA2B
3-glutamic acid deletion polymorphism (glu12, amino acids 297 to 309)
with autonomic nervous system (ANS) activity in 381 young healthy
Japanese male subjects by electrocardiogram R-R interval power spectral
analysis. One hundred sixty-eight (44.1%) were homozygous for the long
allele, 162 (42.5%) were heterozygous, and 51 (13.4%) were homozygous
for the short allele. The allele frequency of the short allele was 0.35.
In R-R spectral analysis of heart rate variability, homozygous carriers
of the short allele had significantly greater low frequency and very low
frequency than did homozygous carriers of the long allele, as well as a
higher sympathetic nervous system index. These findings suggested that
the ADRA2B deletion polymorphism might result in metabolic disorder by
altering ANS function.
DUSP2
| dbSNP name | rs1724120(T,C) |
| cytoBand name | 2q11.2 |
| EntrezGene GeneID | 1844 |
| EntrezGene Description | dual specificity phosphatase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4105 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Weight loss, progressive;
[Other];
Thin body habitus;
Marked cachexia
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural;
[Eyes];
External ophthalmoplegia, progressive (PEO);
Ptosis
ABDOMEN:
[Gastrointestinal];
Gastrointestinal dysmotility;
Malabsorption;
Intermittent diarrhea;
Chronic malnutrition;
Chronic intestinal pseudoobstruction;
Gastroparesis;
Abdominal pain;
Vomiting;
Constipation, chronic;
Diverticulosis;
Diverticulitis;
Intestinal perforation
MUSCLE, SOFT TISSUE:
Mitochondrial myopathy;
Distal limb muscle weakness (less common);
Distal limb muscle atrophy (less common);
Ragged red fibers seen on muscle biopsy;
mtDNA depletion see on muscle biopsy;
Multiple mitochondrial DNA (mtDNA) deletions seen on muscle biopsy;
Decreased activity of cytochrome c oxidase in most cases seen on muscle
biopsy;
Decreased activities of complexes I, III, and IV, variable;
Subsarcolemmal accumulations of abnormally shaped mitochondria seen
on electron microscopy
NEUROLOGIC:
[Central nervous system];
Leukoencephalopathy;
Hypodensity of cerebral white matter seen on MRI;
[Peripheral nervous system];
Peripheral neuropathy;
Loss of distal sensation;
Areflexia;
Sensorimotor axonal/demyelinating neuropathy
METABOLIC FEATURES:
Lactic acidosis
LABORATORY ABNORMALITIES:
Decreased activity of thymidine phosphorylase;
Increased serum thymidine;
Increased serum deoxyuridine
MISCELLANEOUS:
Onset in second to fifth decade;
Progressive disorder;
Early death in early adulthood often associated with diverticulitis
and intestinal perforation
MOLECULAR BASIS:
Caused by mutation in the thymidine phosphorylase gene (TYMP, 131222.0001)
OMIM Title
*603068 DUAL-SPECIFICITY PHOSPHATASE 2; DUSP2
;;PHOSPHATASE OF ACTIVATED CELLS 1; PAC1
OMIM Description
DESCRIPTION
Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous
subgroup of the type I cysteine-based protein-tyrosine phosphatase
superfamily. DUSPs are characterized by their ability to dephosphorylate
both tyrosine and serine/threonine residues. DUSP2 belongs to a class of
DUSPs, designated MKPs, that dephosphorylate MAPK (mitogen-activated
protein kinase) proteins ERK (see 601795), JNK (see 601158), and p38
(see 600289) with specificity distinct from that of individual MKP
proteins. MKPs contain a highly conserved C-terminal catalytic domain
and an N-terminal Cdc25 (see 116947)-like (CH2) domain. MAPK activation
cascades mediate various physiologic processes, including cellular
proliferation, apoptosis, differentiation, and stress responses (summary
by Patterson et al., 2009).
CLONING
Rohan et al. (1993) isolated mouse and human cDNAs encoding DUSP2, which
they called PAC1, a mitogen-induced 32-kD protein that contains a
sequence that is associated with enzymatic activity in previously
identified protein phosphotyrosine phosphatases. The predicted human
PAC1 protein has 314 amino acids. Northern blot analysis of human cell
lines and mouse tissues revealed that PAC1 is expressed predominantly in
hematopoietic tissues. By immunofluorescence of transfected cells and
mitogen-stimulated T cells, Rohan et al. (1993) localized PAC1 to the
nucleus.
GENE STRUCTURE
Yi et al. (1995) determined that the PAC1 (DUSP2) gene contains 4 exons
that span approximately 2.3 kb.
MAPPING
By somatic cell hybrid analysis, linkage analysis, and in situ
hybridization, Yi et al. (1995) mapped the PAC1 gene to chromosome
2p11.2-q11. Using fluorescence in situ hybridization, Martell et al.
(1994) refined the localization of the PAC1 gene to chromosome 2q11.
GENE FUNCTION
Ward et al. (1994) demonstrated that PAC1 is a dual-specific thr/tyr
phosphatase that is a physiologically relevant MAP kinase phosphatase.
Yin et al. (2003) showed that during apoptosis, p53 (191170) activates
transcription of PAC1 by binding to a palindromic site in the PAC1
promoter. PAC1 transcription is induced in response to serum deprivation
and oxidative stress, which results in p53-dependent apoptosis, but not
in response to gamma-irradiation, which causes cell cycle arrest.
Reduction of PAC1 transcription using small interfering RNA inhibits
p53-mediated apoptosis, whereas overexpression of PAC1 increases
susceptibility to apoptosis and suppresses tumor formation. Moreover,
Yin et al. (2003) found that activation of p53 significantly inhibited
MAP kinase (see 602425) activity. They concluded that, under specific
stress conditions, p53 regulates transcription of PAC1 through a new
p53-binding site, and that PAC1 is necessary and sufficient for
p53-mediated apoptosis.
ITPRIPL1
| dbSNP name | rs147974893(G,A); rs772174(A,G); rs141148427(G,A); rs2279105(C,T); rs1048675(A,G) |
| cytoBand name | 2q11.2 |
| EntrezGene GeneID | 150771 |
| EntrezGene Description | inositol 1,4,5-trisphosphate receptor interacting protein-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008264 |
COX5B
| dbSNP name | rs75630766(A,G); rs71429371(A,G) |
| ccdsGene name | CCDS2032.1 |
| cytoBand name | 2q11.2 |
| EntrezGene GeneID | 1329 |
| EntrezGene Description | cytochrome c oxidase subunit Vb |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COX5B:NM_001862:exon3:c.A254G:p.N85S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0698 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P10606 |
| dbNSFP Uniprot ID | COX5B_HUMAN |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.0264227642276 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.02315 |
| ESP All MAF | 0.007843 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002936 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Normal intrauterine growth
HEAD AND NECK:
[Face];
Midface hypoplasia;
[Ears];
Low-set, posteriorly rotated ears;
Preauricular skin furrows;
[Eyes];
Hypertelorism;
Proptosis;
Downslanting palpebral fissures;
[Nose];
Choanal atresia;
Choanal stenosis;
[Mouth];
Narrow palate
RESPIRATORY:
[Lung];
Respiratory distress
ABDOMEN:
[External features];
Prominent umbilical stump;
Anteriorly placed anus
GENITOURINARY:
[External genitalia, male];
Bifid scrotum;
Prominent scrotal raphe;
[External genitalia, female];
Rugose labia majora
SKELETAL:
[Skull];
Craniosynostosis;
Cloverleaf skull;
[Limbs];
Limited elbow extension
SKIN, NAILS, HAIR:
[Skin];
Cutis gyrata;
Acanthosis nigricans;
Cutaneous and mucosal skin tags;
Furrowed palms and soles;
[Nails];
Small nails
NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Agenesis of the corpus callosum;
Developmental delay
MISCELLANEOUS:
Reported cases all sporadic;
Increased paternal age;
Early death in patients with cloverleaf skull
MOLECULAR BASIS:
Caused by mutation in the fibroblast growth factor receptor-2 gene
(FGFR2, 176943.0015)
OMIM Title
*123866 CYTOCHROME c OXIDASE, SUBUNIT Vb; COX5B
OMIM Description
DESCRIPTION
Subunit Vb of mammalian cytochrome c oxidase (COX; EC 1.9.3.1) is
encoded by a nuclear gene and assembled with the other 12 COX subunits
encoded in both mitochondrial and nuclear DNA. COX, the terminal enzyme
of the electron transport chain, transfers electrons from reduced
cytochrome c to oxygen and, in the process, generates an electrochemical
gradient across the mitochondrial inner membrane. The enzyme is composed
of 13 polypeptide subunits, 3 of which are encoded in mitochondrial DNA
and 10 in nuclear DNA. The nuclear-coded COX subunits can be divided
into 2 groups: those with muscle-specific isoforms and those that are
identical in all tissues, such as COX5B (summary by Lomax et al., 1991).
CLONING
Lomax et al. (1991) reported the isolation and DNA sequence of the
expressed gene for human COX subunit Vb and the chromosomal location of
the expressed gene and 7 pseudogenes as determined by analysis of panels
of somatic cell hybrids with cDNA, genomic, and intron probes.
GENE STRUCTURE
Lomax et al. (1991) determined that the COX5B gene contains 5 exons and
4 introns. The 4 coding exons span a region of approximately 2.4 kb. The
5-prime end of the COX5B gene is GC-rich and contains many HpaII sites.
MAPPING
Using genomic Southern blot analysis of human DNA probed with the human
COX Vb cDNA, Lomax et al. (1991) identified 8 restriction fragments
containing COX Vb-related sequences that were mapped to different
chromosomes with panels of human/Chinese somatic cell hybrids. Because
only 1 of these fragments hybridized with a 210-bp probe from intron 4,
Lomax et al. (1991) concluded that there is a single expressed gene in
the human genome, which they mapped to 2cen-q13.
RFX8
| dbSNP name | rs115333912(G,A); rs6716306(G,A); rs7571125(G,T); rs4851432(T,C); rs4241206(C,T); rs4241207(C,T); rs111727217(C,A); rs72973915(C,T); rs908123(C,T); rs908124(T,C); rs4430974(A,T); rs11123876(G,A); rs2175968(A,G); rs111429443(C,T); rs908125(C,T); rs10865041(T,G); rs4851433(G,A); rs112538218(C,T); rs7577705(A,G); rs61577372(G,A); rs78217075(G,C); rs12997785(A,G); rs111897190(G,A); rs113640342(C,T); rs13388476(C,A); rs1554069(C,T); rs1554068(T,C); rs17804607(G,A); rs10202527(G,A); rs113198885(C,T); rs11686870(A,G); rs11689348(T,C); rs77875445(A,G); rs1554070(G,A); rs12620464(T,C); rs7603471(G,A); rs2871419(T,G); rs4851434(A,G); rs908136(T,C); rs75075027(C,G); rs183480435(G,A); rs908135(T,C); rs908134(T,C); rs7564703(G,A); rs114874574(T,C); rs4850971(G,A); rs6761866(T,C); rs12712098(C,T); rs181952753(A,T); rs6709913(C,T); rs58872878(A,C); rs7565429(C,T); rs7591334(G,C); rs7568697(C,A); rs2280124(T,C); rs4851436(T,A); rs7589943(T,G); rs6543043(A,G); rs147877512(T,C); rs11891816(C,T); rs17025544(A,G); rs2310127(A,G); rs4241208(A,G); rs6748663(T,C); rs139907358(T,C); rs78528652(A,C); rs17025554(G,A); rs181442086(G,A); rs7607798(T,C); rs6543045(C,A); rs6543046(A,C); rs7608371(T,C); rs112010451(C,T); rs6543047(C,T); rs17025577(C,T); rs6543048(C,T); rs2310114(C,T); rs6543049(A,G); rs6543050(A,G); rs13018312(T,C); rs6543051(A,T); rs2037083(T,C); rs2037082(G,C); rs17805225(T,C); rs62152841(A,T); rs2037080(A,G); rs7587252(C,T); rs4850972(G,T); rs13415012(C,T); rs12712099(C,T); rs13430896(T,C); rs4850973(G,A); rs4850974(T,G); rs4850975(T,C); rs17192350(C,T); rs2310113(C,T); rs925689(C,T); rs4851438(G,A); rs4851439(A,G); rs6543052(A,G); rs7598455(C,T); rs6713867(T,C); rs6713868(T,C); rs79135247(C,T); rs7602021(C,T); rs6543053(G,A); rs2037079(C,A); rs74689653(G,A); rs68021122(C,T); rs75501616(G,A); rs12470038(G,A); rs6728722(G,C); rs190669765(T,C); rs938304(C,T); rs938303(G,C); rs938302(A,G); rs938301(G,C); rs6732190(G,A); rs6732292(G,A); rs2871422(C,T); rs2871421(C,A); rs2871420(G,A); rs2310112(C,A); rs6543055(C,T); rs7556845(C,T); rs6543058(G,A); rs34411515(G,T); rs35798094(C,T); rs6744649(C,T); rs6759537(A,G); rs6708221(T,A); rs6718464(G,A); rs6705262(A,G); rs6708466(T,C); rs6708469(T,C); rs6708626(T,C); rs6748209(C,T); rs12988565(A,G); rs13012980(C,G); rs6543059(T,C); rs6543060(G,T); rs7561022(A,G); rs10865042(T,C); rs11123879(G,A); rs11123880(A,G); rs75868819(C,T); rs6710049(A,G); rs6723288(G,A); rs12712100(C,T); rs4851440(T,C); rs4851441(C,T); rs10865043(A,G); rs13014187(T,C); rs11123881(C,G); rs12478990(C,A); rs7571594(T,A); rs7568893(A,G); rs7571802(T,C); rs4851442(C,T); rs12712101(G,A); rs6543061(G,A); rs12712102(G,A); rs12712103(G,A); rs76392456(G,A); rs12712104(C,A); rs57129496(G,T); rs17034567(T,G); rs10191662(T,C); rs75355070(G,A); rs7587439(A,G); rs10180163(C,G); rs4851443(A,G); rs4851444(A,C); rs4851445(C,T); rs4851446(G,A); rs4851447(A,G); rs7583866(G,A); rs12712105(C,G); rs11123882(T,C); rs11123883(T,C); rs11682765(T,G); rs4850977(A,G); rs4850978(C,A); rs962469(T,C); rs3903293(G,A); rs4851448(A,T); rs74263247(C,T); rs7585228(T,C); rs7569018(C,G); rs7594697(G,C); rs7569143(C,T); rs12472242(T,C); rs7569232(C,G); rs7594911(G,A); rs10176171(C,T); rs12475133(G,C); rs10190868(T,C); rs61488668(C,T); rs7598092(G,A); rs7589052(T,G); rs7598326(G,A); rs113201217(C,T); rs7572879(C,G); rs7572882(C,G); rs7586609(A,G); rs7586620(A,G); rs4851449(T,A); rs4851450(T,C); rs4851451(T,C); rs67512011(G,A); rs200599307(G,A); rs60156228(C,T); rs66675251(A,G); rs67787993(A,T); rs112661677(G,A); rs150084371(T,G); rs150490612(A,G); rs7606443(G,A); rs7594460(A,G); rs7580925(C,A); rs7597733(A,G); rs7584240(C,T); rs7600922(T,C); rs7587668(C,G); rs142644118(G,T); rs146904177(T,C); rs141731900(G,A); rs150121061(G,A); rs6713474(G,A); rs6543063(C,T); rs139312244(G,A); rs7601191(G,A); rs7592380(T,C); rs7575923(C,T); rs7578899(C,T); rs7592741(A,G); rs6543064(A,G); rs6543065(A,G); rs6543066(G,A); rs6543067(A,G); rs6543068(A,G); rs13034485(G,A); rs6760956(G,A); rs11123885(C,T); rs17025682(T,C); rs73943484(T,C); rs11123886(A,G); rs76183411(C,T); rs11674781(G,A); rs11693239(T,C); rs2871423(T,C); rs6737357(C,T); rs144638701(G,A); rs72827019(T,A); rs6737507(C,T); rs75000785(C,T); rs2056064(C,T); rs2056065(G,A); rs6543069(G,C); rs4611660(A,G); rs2175964(A,G); rs2138001(C,T); rs2138002(T,C); rs2175965(A,G); rs6759881(A,C); rs6715786(G,A); rs6705707(T,A); rs9678978(C,T); rs11904192(A,C); rs79479402(G,C); rs11904250(A,G); rs11884154(T,C); rs11690908(C,T); rs11674398(A,G); rs11679468(G,A); rs11674434(A,G); rs11123887(G,T); rs66559596(C,T); rs4851454(C,A); rs6720584(G,A); rs7574003(G,A); rs147457849(C,T); rs148507205(C,T); rs4850979(C,T); rs12614464(T,C); rs10176042(T,C); rs4851455(T,C); rs202220240(G,A); rs115757451(G,A); rs10172545(G,C); rs977675(C,T); rs60960220(A,G); rs139268679(G,A); rs77226316(A,G); rs76913368(G,T); rs4629180(G,A); rs4851456(T,C); rs59246268(G,A); rs6707298(C,T); rs74396980(C,T); rs6707517(C,T); rs73943488(C,G) |
| cytoBand name | 2q11.2 |
| EntrezGene GeneID | 731220 |
| EntrezGene Description | RFX family member 8, lacking RFX DNA binding domain |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| dbNSFP LR score | 0.7292 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ExAC AF | 0.0001096 |
GPR45
| dbSNP name | rs56355385(G,C); rs35946826(C,T) |
| ccdsGene name | CCDS2066.1 |
| cytoBand name | 2q12.1 |
| EntrezGene GeneID | 11250 |
| EntrezGene Description | G protein-coupled receptor 45 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR45:NM_007227:exon1:c.G504C:p.T168T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.023388 |
| ESP All MAF | 0.010152 |
| ESP Eur/Amr MAF | 0.003373 |
| ExAC AF | 4.786e-03,3.256e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
NEUROLOGIC:
[Central nervous system];
See juvenile myoclonic epilepsy (606904)
OMIM Title
*604838 G PROTEIN-COUPLED RECEPTOR 45; GPR45
OMIM Description
DESCRIPTION
G protein-coupled receptors (GPCRs), such as GPR45, are integral
membrane proteins containing 7 putative transmembrane domains (TMs).
These proteins mediate signals to the interior of the cell via
activation of heterotrimeric G proteins that in turn activate various
effector proteins, ultimately resulting in a physiologic response
(summary by Marchese et al., 1999).
CLONING
By PCR amplification of human genomic DNA, using degenerate
oligonucleotides corresponding to transmembrane domains 3 and 7 of the
mouse delta-opioid receptor (165195) and somatostatin receptors (see
182451), Marchese et al. (1999) isolated a cDNA for a novel GPCR that
they designated GPR45. The 11-kb GPR45 gene encodes a 372-amino acid
protein that shows 70% amino acid sequence identity to the Xenopus
oocyte receptor PSP24, a putative lysophosphatidic acid receptor.
Northern blot analysis detected a 4.25-kb transcript in basal forebrain,
frontal cortex, and caudate, but not in thalamus, hippocampus, or
putamen. A 3.0-kb transcript was detected in liver.
MAPPING
By fluorescence in situ hybridization, Marchese et al. (1999) mapped the
GPR45 gene to chromosome 2q11.2-q12.
SLC5A7
| dbSNP name | rs1684070(G,T); rs2433718(A,G); rs4676168(C,T); rs333238(A,G); rs333236(G,A); rs3806531(T,C); rs114715828(G,A); rs143876748(C,T); rs62148704(T,C); rs73953528(A,G); rs6542746(C,T); rs17269265(A,G); rs333235(C,T); rs333234(T,C); rs2450280(T,C); rs2450279(T,C); rs147540759(C,A); rs13020429(C,G); rs10195701(T,C); rs77020121(T,A); rs4676169(A,G); rs78165178(T,C); rs10199155(T,A); rs333217(A,G); rs333216(G,A); rs17269272(G,T); rs10187415(G,A); rs10187243(C,A); rs11685873(G,A); rs141156642(G,A); rs333214(A,G); rs113238383(T,G); rs114237057(A,C); rs17269279(A,G); rs55729209(T,G); rs73953532(G,T); rs115633185(G,A); rs114128553(G,A); rs333213(C,G); rs140839667(C,G); rs3731684(C,T); rs3731683(G,A); rs72935213(C,T); rs2450282(T,C); rs333220(C,A); rs333221(C,G); rs333222(C,T); rs6759730(G,A); rs6720783(T,G); rs333223(G,T); rs111769050(G,A); rs333224(T,C); rs6753566(G,C); rs333225(C,T); rs6753886(G,A); rs333226(G,A); rs373325777(A,G); rs11889263(T,G); rs58143025(G,T); rs333227(G,A); rs2046510(A,C) |
| ccdsGene name | CCDS2074.1 |
| cytoBand name | 2q12.3 |
| EntrezGene GeneID | 60482 |
| EntrezGene Description | solute carrier family 5 (sodium/choline cotransporter), member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC5A7:NM_021815:exon2:c.C46T:p.L16F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7517 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9GZV3 |
| dbNSFP Uniprot ID | SC5A7_HUMAN |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.00123 |
| ESP Eur/Amr MAF | 0.001628 |
| ExAC AF | 2.033e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low weight;
[Other];
Intrauterine growth retardation;
Poor growth
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Deafness, sensorineural;
[Eyes];
Ptosis
SKELETAL:
Delayed bone age;
Osteopenia;
[Hands];
Clinodactyly
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Mental retardation;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Short attention span
LABORATORY ABNORMALITIES:
Increased serum growth hormone;
Decreased serum insulin-like growth factor-1 (IGF1)
MISCELLANEOUS:
Onset in utero
MOLECULAR BASIS:
Caused by mutation in the insulin-like growth factor-1 gene (IGF1,
147440.0001)
OMIM Title
*608761 SOLUTE CARRIER FAMILY 5 (CHOLINE TRANSPORTER), MEMBER 7; SLC5A7
;;CHOLINE TRANSPORTER; CHT; CHT1
OMIM Description
DESCRIPTION
Choline is a direct precursor of acetylcholine (ACh), a neurotransmitter
of the central and peripheral nervous system that regulates a variety of
autonomic, cognitive, and motor functions. SLC5A7 is a Na(+)- and Cl(-)-
dependent high-affinity transporter that mediates the uptake of choline
for acetylcholine synthesis in cholinergic neurons (Apparsundaram et
al., 2000).
CLONING
By searching a genomic database using rat Cht as query, followed by PCR
of a spinal cord cDNA library, Apparsundaram et al. (2000) cloned
SLC5A7, which they called CHT. The deduced 580-amino acid protein has a
calculated molecular mass of 63.2 kD. CHT has 13 transmembrane (TM)
domains, a short extracellular N terminus, and a long cytoplasmic C
terminus. It contains 3 putative N-glycosylation sites and several
phosphorylation sites. CHT shares 93% amino acid identity with rat Cht
and 51% amino acid identity with its nematode homolog, Cho1. Northern
blot analysis of several brain regions detected a 5.0-kb Cht transcript
in putamen, spinal cord, and medulla only, a pattern consistent with
distribution of CHT in cholinergic neurons.
By searching a genomic database using C. elegans Cho1 as query, followed
by 5-prime and 3-prime RACE of a brain cDNA library and screening a
spinal cord cDNA library, Okuda and Haga (2000) cloned CHT1. The deduced
580-amino acid protein contains 12 TM domains. Northern blot analysis
detected a 5.4-kb transcript in putamen, medulla, and spinal cord only.
Using immunofluorescence confocal microscopy of transfected COS-7 cells,
Okuda et al. (2002) found CHT in a punctate cytoplasmic distribution,
suggesting that most of the protein was retained in the cytoplasmic
compartment and was inefficiently targeted to the plasma membrane.
Western blot analysis detected major bands of about 45 and 80 kD in
lysates of transfected COS-7 cells.
GENE FUNCTION
Apparsundaram et al. (2000) found that CHT was expressed at the membrane
of transfected COS-7 cells and mediated choline uptake. Choline
transport was saturable, dependent upon Na(+) and Cl(-), and showed
single-site kinetics. Hemicholinium-3, an antagonist used to identify
CHT in human brain membranes, bound CHT expressed in COS-7 cell
membranes.
By expression of CHT1 in Xenopus oocytes, Okuda and Haga (2000)
confirmed that CHT1 is a choline transporter. CHT1-mediated choline
uptake increased with increasing concentrations of choline, Na(+), and
Cl(-). The characteristics of choline uptake were essentially the same
as those of high-affinity choline uptake in human brain synaptosomes.
GENE STRUCTURE
Okuda and Haga (2000) determined that the SLC5A7 gene contains 9 exons
and spans 25 kb. Okuda et al. (2002) identified a TATA box and a
putative Sp1 (189906)-binding site in the 5-prime flanking region.
MAPPING
By radiation hybrid and genomic sequence analyses, Apparsundaram et al.
(2000) mapped the SLC5A7 gene near the RANBP2 gene (601181) on
chromosome 2q12.
MOLECULAR GENETICS
By examining genomic DNA from 57 unrelated Ashkenazi Jewish donors,
Okuda et al. (2002) identified a nonsynonymous single-nucleotide
polymorphism (SNP) in the CHT1 gene. The SNP, an A-to-G transition at
nucleotide 265, resulted in an ile89-to-val substitution (I89V) within
the third TM domain. Seven of the 57 individuals showed heterozygous
alleles (A/G), and the allele frequency was estimated to be 0.06. Okuda
et al. (2002) transfected COS-7 cells with CHT1 containing the 265A-G
SNP and determined that it had no effect on protein expression,
intracellular localization, or choline affinity, but it reduced the
maximum rate of choline uptake by about 40%.
In affected members of a large multigenerational Welsh family with
autosomal dominant distal hereditary motor neuronopathy type VIIA
(HMN7A; 158580), Barwick et al. (2012) identified a heterozygous
truncating mutation in the SLC5A7 gene (608761.0001) that truncated the
encoded product just beyond the final transmembrane domain, eliminating
conserved cytosolic C terminus sequences known to regulate surface
transporter trafficking. The mutation, which was identified by exome
sequencing and segregated with the disorder in this family, was not
found in genomic databases. In vitro functional expression assays showed
that the mutation resulted in reduced protein levels and reduced choline
transport, and also exhibited a dominant-negative effect when
coexpressed with the wildtype cDNA. The phenotype was characterized by
onset in the second decade of nonfatiguing progressive distal muscle
wasting and weakness affecting the upper and lower limbs and associated
with vocal cord paresis. Given the role of SLC5A7 at the neuromuscular
junction (NMJ), Barwick et al. (2012) commented on the lack of features
usually associated with congenital myasthenic syndromes (see, e.g.,
608931), which are caused by mutations in genes involved in synaptic
transmission at the NMJ.
ANIMAL MODEL
Ferguson et al. (2004) disrupted the Cht gene in mice. Although
morphologically normal at birth, Cht -/- mice became immobile, breathed
irregularly, appeared cyanotic, and died within an hour. Hemicholinium
3-sensitive choline uptake and subsequent ACh synthesis were
specifically lost in Cht -/- mouse brains. There was also a
time-dependent loss of spontaneous and evoked responses at Cht -/-
neuromuscular junctions. Consistent with defects in synaptic ACh
availability, Cht -/- mice had developmental changes in neuromuscular
junction morphology reminiscent of changes in mutant mice lacking ACh
synthesis. Adult Cht +/- mice overcame reductions in Cht protein levels
and sustained choline uptake activity at wildtype levels through
posttranslational mechanisms.
SH3RF3-AS1
| dbSNP name | rs115246865(T,C) |
| cytoBand name | 2q12.3 |
| EntrezGene GeneID | 100287216 |
| snpEff Gene Name | SH3RF3 |
| EntrezGene Description | SH3RF3 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008264 |
SOWAHC
| dbSNP name | rs1560884(G,A); rs4953847(A,G); rs4953848(A,G); rs4953849(G,A); rs4953850(T,G); rs6726252(T,C); rs6594049(C,T); rs6594050(A,G); rs1046645(A,G) |
| ccdsGene name | CCDS33270.1 |
| cytoBand name | 2q13 |
| EntrezGene GeneID | 65124 |
| snpEff Gene Name | ANKRD57 |
| EntrezGene Description | sosondowah ankyrin repeat domain family member C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SOWAHC:NM_023016:exon1:c.G1131A:p.K377K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3278 |
| ESP Afr MAF | 0.273718 |
| ESP All MAF | 0.255805 |
| ESP Eur/Amr MAF | 0.246628 |
| ExAC AF | 0.29 |
LOC100499194
| dbSNP name | rs2279839(T,C); rs59002325(C,T); rs62617784(C,T); rs10199415(G,A) |
| cytoBand name | 2q14.1 |
| EntrezGene GeneID | 100499194 |
| snpEff Gene Name | AC010982.1 |
| EntrezGene Description | uncharacterized LOC100499194 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.36 |
TMEM185B
| dbSNP name | rs116561907(G,A); rs1437421(C,A); rs114547713(C,T); rs78235591(C,T); rs74823521(G,C); rs4848579(A,G); rs7564298(C,A); rs1965781(C,G); rs3820768(T,G); rs113116654(C,T); rs189836120(A,C); rs9644(T,C) |
| cytoBand name | 2q14.2 |
| EntrezGene GeneID | 79134 |
| snpEff Gene Name | AC012363.10 |
| EntrezGene Description | transmembrane protein 185B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01653 |
LINC01101
| dbSNP name | rs7585143(G,T); rs182643468(C,A); rs12992152(C,T); rs1880544(T,C) |
| cytoBand name | 2q14.2 |
| EntrezGene GeneID | 84931 |
| EntrezGene Description | long intergenic non-protein coding RNA 1101 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2571 |
SFT2D3
| dbSNP name | rs117566639(A,C); rs800859(G,A) |
| cytoBand name | 2q14.3 |
| EntrezGene GeneID | 84826 |
| snpEff Gene Name | WDR33 |
| EntrezGene Description | SFT2 domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01882 |
RAB6C
| dbSNP name | rs11674996(T,A); rs56994843(A,G) |
| cytoBand name | 2q21.1 |
| EntrezGene GeneID | 84084 |
| EntrezGene Description | RAB6C, member RAS oncogene family |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4128 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Posterior amorphous corneal dystrophy extending to the corneal limbus;
Hyperopia;
Flattened corneal topography;
Anterior iris surface and stromal abnormalities;
Fine iris processes extending to Schwalbe line for 360 degrees
MISCELLANEOUS:
Onset in infancy
OMIM Title
*612909 RAS-ASSOCIATED PROTEIN RAB6C; RAB6C
;;WTH3
OMIM Description
CLONING
By methylation-sensitive representational difference analysis, Shan et
al. (2002) isolated a DNA fragment of RAB6C that was hypermethylated in
a multidrug-resistant MCF7 breast cancer cell line. Using 3-prime RACE
of a combined human tissue cDNA library, they obtained full-length
RAB6C, which they called WTH3. The deduced 254-amino acid WTH3 protein
shares significant homology with 2 isoforms of RAB6A (179513), but it
has a C-terminal extension compared with these proteins.
GENE FUNCTION
Using quantitative RT-PCR, Shan et al. (2002) found that expression of
WTH3 was reduced in multidrug-resistant cancer cell lines compared with
the parental cell lines. Reexpression of WTH3 in multidrug-resistant
cell lines increased their sensitivity to several anticancer drugs,
including doxorubicin. Flow cytometry and fluorescence microscopy
suggested that WTH3 stimulated cellular uptake and retention of
doxorubicin.
Tian et al. (2005) found that the WTH3 promoter region was
hypermethylated in multidrug-resistant MCF7 cells compared with the
parental cell line. EMSA showed that different pools of nuclear proteins
were attracted to the hypermethylated and nonmethylated WTH3 probes.
Tian et al. (2005) concluded that expression of WTH3 is controlled by
both epigenetic modification and transcription factor modulation.
Tian et al. (2007) identified a p53 (TP53; 191170)-binding site in the
promoter region of the WTH3 gene and showed that WTH3 was upregulated by
p53 in vitro and in vivo. Overexpression of WTH3 promoted an apoptotic
phenotype in human cells. Tian et al. (2007) concluded that the
antiapoptotic effect of WTH3 is linked to p53 expression.
GENE STRUCTURE
Tian et al. (2005) determined that the RAB6C promoter region contains 2
atypical TATA boxes and 2 atypical CAATT boxes. They identified a
GC-rich region that includes a CpG island and extends from position -485
relative to the translation initiation site into the 5-prime coding
region. The promoter region contains several putative transcription
factor-binding sites.
MAPPING
Hartz (2009) mapped the RAB6C gene to chromosome 2q21.1 based on an
alignment of the RAB6C sequence (GenBank GENBANK AL136727) with the
genomic sequence (build 36.1).
GPR148
| dbSNP name | rs80008074(C,G); rs79432147(T,C); rs272128(A,C); rs11894380(A,C) |
| ccdsGene name | CCDS2163.1 |
| cytoBand name | 2q21.1 |
| EntrezGene GeneID | 344561 |
| EntrezGene Description | G protein-coupled receptor 148 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR148:NM_207364:exon1:c.C41G:p.A14G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8TDV2 |
| dbNSFP Uniprot ID | GP148_HUMAN |
| dbNSFP KGp1 AF | 0.0659340659341 |
| dbNSFP KGp1 Afr AF | 0.219512195122 |
| dbNSFP KGp1 Amr AF | 0.0414364640884 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0277044854881 |
| dbSNP GMAF | 0.06474 |
| ESP Afr MAF | 0.171584 |
| ESP All MAF | 0.076119 |
| ESP Eur/Amr MAF | 0.027209 |
| ExAC AF | 0.033 |
WTH3DI
| dbSNP name | rs6710474(A,G); rs6704669(C,G); rs6704678(C,T); rs6714228(T,A); rs113864773(A,C) |
| cytoBand name | 2q21.1 |
| EntrezGene GeneID | 150786 |
| snpEff Gene Name | AC073869.1 |
| EntrezGene Description | RAB6C-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03949 |
LOC401010
| dbSNP name | rs11892999(G,T); rs62176150(C,T); rs112041013(G,A); rs4522649(G,A); rs1317139(T,C); rs111435137(G,A); rs1806887(C,G); rs13413908(T,C) |
| cytoBand name | 2q21.1 |
| EntrezGene GeneID | 401010 |
| snpEff Gene Name | AC073869.20 |
| EntrezGene Description | nucleolar complex associated 2 homolog (S. cerevisiae) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retrotransposed |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4683 |
MIR3679
| dbSNP name | rs10175383(G,C); rs6430498(G,A) |
| cytoBand name | 2q21.2 |
| EntrezGene GeneID | 100500878 |
| snpEff Gene Name | MGAT5 |
| EntrezGene Description | microRNA 3679 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1589 |
| ExAC AF | 0.03 |
CXCR4
| dbSNP name | rs17848060(A,T); rs2680880(A,T) |
| cytoBand name | 2q22.1 |
| EntrezGene GeneID | 7852 |
| EntrezGene Description | chemokine (C-X-C motif) receptor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001377 |
OMIM Clinical Significance
Neuro:
Progressive hypertrophic polyneuritis
Misc:
Onset about age 50
Lab:
Paraprotein in serum, CSF, and urine;
Nerve demyelination with Schwann cell proliferation;
Delayed nerve conduction velocity
Inheritance:
Autosomal dominant
OMIM Title
*162643 CHEMOKINE, CXC MOTIF, RECEPTOR 4; CXCR4
;;NEUROPEPTIDE Y RECEPTOR Y3; NPY3R;;
FUSIN;;
D2S201E;;
LEUKOCYTE-DERIVED SEVEN-TRANSMEMBRANE-DOMAIN RECEPTOR; LESTR;;
SEVEN-TRANSMEMBRANE-SEGMENT RECEPTOR, SPLEEN;;
HM89;;
LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 3; LAP3;;
LPS-ASSOCIATED PROTEIN 3
OMIM Description
CLONING
Several receptors for neuropeptide Y (NPY; 162640) have been
demonstrated and shown to differ in pharmacologic characteristics,
tissue distribution, and structure of the encoding genes; see the NPY Y1
receptor (NPY1R; 162641) and the NPY Y2 receptor (NPY2R; 162642). Herzog
et al. (1993) cloned, sequenced, and mapped the human homolog of a
proposed bovine NPY Y3 receptor reported by Rimland et al. (1991). The
human cDNA clone was derived from a human lung cDNA library. The
1,670-bp sequence predicts a single open reading frame (ORF) of 352
amino acids, with 92% amino acid identity to the reported bovine
sequence. The amino acid sequence shares features common to many other G
protein-coupled receptors, including the 7-transmembrane regions and
putative glycosylation and phosphorylation sites. The receptor shows 36%
identity to the interleukin-8 receptor (IL8RA; 146929), which is located
on chromosome 2, and to the angiotensin II receptor (AGTR1; 106165), but
only 21% identity to the NPY Y1 receptor.
The recruitment of leukocytes to inflamed tissues involves interleukin-8
(IL8; 146930) and several related chemotactic cytokines that attract and
activate leukocytes. Loetscher et al. (1994) noted that these proteins
are similar in size, have marked sequence similarities, and are
characterized by 4 conserved cysteines that form 2 essential disulfide
bonds. Two subfamilies are distinguished according to the arrangement of
the first 2 cysteines, which are either adjacent (CC subfamily) or
separated by one amino acid (CXC subfamily). The CXC cytokines activate
primarily neutrophil leukocytes, while CC cytokines act on monocytes,
basophils, and eosinophils. These chemotactic agonists act via
7-transmembrane domain, G protein-coupled receptors, e.g., the 2
interleukin-8 receptors, IL8RA and IL8RB (146928). Chemotactic cytokines
of the CC subfamily do not bind to IL8 receptors. Loetscher et al.
(1994) isolated from a human blood monocyte cDNA library a cDNA clone
encoding a protein of 352 amino acids, corresponding to a receptor of
the 7-transmembrane domain, G protein-coupled type. They referred to the
gene and the deduced protein as LESTR for 'leukocyte-derived
seven-transmembrane domain receptor.' It shows 92.6% identity with a
bovine neuropeptide Y receptor. In the monocyte library, LESTR cDNA
fragments were about 20 times as frequent as cDNA coding for IL8RA and
IL8RB, and much higher levels of mRNA specific for LESTR than for IL8R
were found in human blood neutrophils and lymphocytes. Although the
ligand for LESTR could not be identified among a large number of
chemotactic cytokines, the high expression in white blood cells and the
marked sequence relation to IL8RA and IL8RB suggested to Loetscher et
al. (1994) that LESTR may function in the activation of inflammatory
cells.
The human CD4 molecule (186940) acts as the primary receptor for the
human immunodeficiency virus type 1 (HIV-1), but CD4 supports viral
entry into cells only when it is expressed on specific human cell types
(Clapham et al., 1991). Weiner et al. (1991) and Dragic and Alizon
(1993) presented evidence that the restriction of HIV-1 infection to
certain human cell types is the result of a specific cofactor, encoded
in the human genome, which is required for cell virus membrane fusion.
Feng et al. (1996) undertook the isolation and characterization of the
putative human HIV-1 fusion cofactor using an approach that made no
assumptions about the mode of action of the cofactor other than that the
cofactor would allow a CD4-expressing nonhuman cell to undergo viral
fusion. They transfected CD4-expressing NIH 3T3 cells with a HeLa cell
cDNA library and then incubated the transfected cells with an NIH 3T3
cell line expressing the HIV-1 Env gene (which is required by HIV-1 for
fusion); transfected CD4+ cells that fused with Env-expressing cells
could be distinguished by utilizing a lacZ biochemical marker specific
to such fusion products. Feng et al. (1996) isolated a 1.7-kb human cDNA
clone that allowed the CD4-expressing NIH 3T3 cells to undergo fusion.
The cDNA contained a 352-codon ORF whose predicted amino acid sequence
has 7 predicted transmembrane segments and resembles that of the G
protein-coupled receptor superfamily. The predicted molecular weight of
the protein is 39,745 Da and its primary sequence includes 2 potential
N-linked glycosylation sites. The cDNA had in fact been cloned
previously by Federsppiel et al. (1993) from a human fetal spleen cDNA
library and was designated D2S201E. The predicted protein has 37% amino
acid identity with the interleukin-8 receptor and is 93% identical to
that of a cDNA isolated from bovine locus ceruleus, which apparently
encodes a neuropeptide Y receptor.
GENE STRUCTURE
Wegner et al. (1998) determined the genomic organization and promoter
function of CXCR4. The gene contains 2 exons of 103 and 1,563 bp
separated by an intron of 2,132 bp between codons 5 and 6 of the coding
sequence. Sequence analysis predicted that the promoter region includes
a TATA box, a nuclear respiratory factor-1 (NRF1; 600879) site, and 2 GC
boxes. Deletion of the NRF1 site abolished CXCR4 promoter activity.
Electrophoretic mobility shift assay (EMSA) experiments demonstrated
that the transcriptional regulator NRF1 binds to the NRF1 site in the
CXCR4 promoter. Caruz et al. (1998) also reported the genomic structure
of CXCR4.
MAPPING
By PCR analysis of human/hamster hybrid cell DNA, Herzog et al. (1993)
showed that the NPY3R gene is located on human chromosome 2.
Federsppiel et al. (1993) localized D2S201E, the expressed segment
encoding fusin, to chromosome 2q21 by isotopic in situ hybridization.
This finding was corroborated by the mapping of the NPY3R gene to
chromosome 2 by Herzog et al. (1993).
BIOCHEMICAL FEATURES
- Crystal Structure
Wu et al. (2010) reported 5 independent crystal structures of CXCR4
bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at
2.5- to 3.2-angstrom resolution. All structures revealed a consistent
homodimer with an interface including helices V and VI that may be
involved in regulating signaling. The location and shape of the
ligand-binding sites differ from other G protein-coupled receptors and
are closer to the extracellular surface. Wu et al. (2010) concluded that
these structures provided new clues about the interactions between CXCR4
and its natural ligand CXCL12 (600835) and with the HIV-1 glycoprotein
gp120.
GENE FUNCTION
Herzog et al. (1993) reported that NPY and a number of other ligands
failed to induce any change in cytosolic calcium levels in transfected
cells, suggesting that this clone represented a novel neuropeptide
receptor. Jazin et al. (1993) independently found that the Y3 receptor
does not respond to NPY.
Feng et al. (1996) showed that transient expression of the CXCR4 gene
(called 'fusin' by the authors) allowed nonhuman cells coexpressing
recombinant CD4 to undergo Env-CD4-mediated cell fusion and productive
HIV-1 infection. The authors used Northern analysis to show that fusin
mRNA levels correlated with HIV-1 permissiveness in diverse human cell
types; Federsppiel et al. (1993) had previously found that D2S201E was
expressed in a variety of tissues, including brain and tissues of
hemopoietic origin. Feng et al. (1996) also showed that anti-fusin
antibodies strongly inhibited HIV-1 infection of normal human CD4+
target cells. The authors commented that the identification of fusin as
a fusion cofactor for T-cell line-tropic HIV-1 isolates provided a new
means of elucidating the mechanism of HIV-1 infection and suggested that
production of an effective small-animal model of HIV infection might be
possible.
Bleul et al. (1996) and Oberlin et al. (1996) reported that stromal
cell-derived factor-1 (SDF1; 600835), also known as CXCL12 and PBSF, is
a ligand for this receptor, which they referred to as CXCR4. Both groups
found that SDF1 is a potent inhibitor in vitro of infection by
lymphocyte-tropic HIV-1 strains. Oberlin et al. (1996) showed that the
CC chemokines MIP-1-alpha (182283), MIP-1-beta (182284), and RANTES
(187011), which inhibit monocyte-tropic HIV-1 infection via the CC
chemokine receptor CMKBR5 (CCR5; 601373), were inactive against
lymphocyte-tropic HIV-1 strains. Conversely, Bleul et al. (1996) showed
that SDF1 does not inhibit CMKBR5-mediated infection by
macrophage-tropic and dual-tropic HIV-1.
CCR5 is the major macrophage-tropic coreceptor for HIV-1, whereas CXCR4
serves the counterpart function for T cell-tropic viruses. Xiao et al.
(2000) provided an explanation for the mystery of why only R5-HIV-1 is
initially detected in new seroconvertors who are exposed to R5 and X4
viruses. Indeed, X4 virus emerges in a minority of patients and only in
the late stages of disease, suggesting that early negative selection
against HIV-1-CXCR4 interaction may exist. Xiao et al. (2000) reported
that the HIV-1 Tat protein (HTATIP; 601409), which is secreted from
virus-infected cells, is a CXCR4-specific antagonist. Soluble Tat
selectively inhibited the entry and replication of X4, but not R5, virus
in peripheral blood mononuclear cells. The authors proposed that one
functional consequence of secreted Tat is to select against X4 viruses,
thereby influencing the early in vivo course of HIV-1 disease.
Peled et al. (1999) demonstrated that SDF1 and its receptor CXCR4 are
critical for murine bone marrow engraftment by human SCID repopulating
stem cells. Treatment of human cells with anti-CXCR antibodies prevented
engraftment. They further demonstrated that CD34(+)CD38(-/low) cells
could be converted to CD34(+)CD38(-/low)CXCR4(+) stem cells by
pretreatment with IL6 (147620) and stem cell factor (KITLG; 184745),
which increased CXCR4 expression. This pretreatment potentiated
migration to SDF1 and engraftment in primary and secondary transplanted
mice.
Breast cancer metastasis occurs in a distinct pattern involving the
regional lymph nodes, bone marrow, lung, and liver, but rarely other
organs. By real-time quantitative PCR, immunohistochemistry, and flow
cytometric analysis, Muller et al. (2001) found that CXCR4 is highly
expressed in primary and metastatic human breast cancer cells but is
undetectable in normal mammary tissue, whereas CCR7 (600242) is
significantly expressed in normal tissue and is upregulated in breast
cancer cells. Quantitative PCR analysis also detected peak expression
levels of the CXCR4 ligand, CXCL12 (SDF1) in lymph nodes, lung, liver,
and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant
in lymph nodes, the organs to which primary breast cancer cells
preferentially migrate. Analysis of malignant melanomas determined that
in addition to CXCR4 and CCR7, these tumors also had high levels of
CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific
chemokine involved in the homing of memory T cells into the skin. Flow
cytometric analysis and confocal laser microscopy demonstrated that
either CXCL12 or CCL21 induces high levels of F-actin polymerization and
pseudopod formation in breast cancer cells. These chemokines, as well as
lung and liver extracts, also induce directional migration of breast
cancer cells in vitro, which can be blocked by antibodies to CXCR4 or
CCL21. Histologic and quantitative PCR analyses showed that metastasis
of intravenously or orthotopically injected breast cancer cells could be
significantly decreased in SCID mice by treatment with anti-CXCR4
antibodies. Muller et al. (2001) proposed that the nonrandom expression
of chemokine receptors in breast cancer and malignant melanoma, and
probably in other tumor types, indicates that small molecule antagonists
of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to
interfere with tumor progression and metastasis in tumor patients.
Chan et al. (2003) investigated the expression of chemokines and
chemokine receptors in eyes with primary intraocular B-cell lymphoma
(PIOL). All 3 PIOL eyes showed similar pathology, with typical diffuse
large B-lymphoma cells between the retinal pigment epithelium (RPE) and
Bruch membrane. The eyes also showed a similar chemokine profile with
the expression of CXCR4 and CXCR5 (BLR1; 601613) in the lymphoma cells.
CXCL13 (605149) and CXCL12 transcripts were found only in the RPE and
not in the malignant cells. No chemokine expression was detected on the
RPE cells of a normal control eye. Since chemokines and chemokine
receptors selective for B cells were identified in RPE and malignant B
cells in eyes with PIOL, inhibition of B-cell chemoattractants might be
a future strategy for the treatment of PIOL.
Liotta (2001) reviewed the theories explaining the bias of metastases
toward certain organs and addressed questions raised by the work of
Muller et al. (2001).
CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990)
are major receptors for LPS; however, binding analyses and TNF
production assays have suggested the presence of additional cell surface
receptors, designated LPS-associated proteins (LAPs), that are distinct
from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using
affinity chromatography, peptide mass fingerprinting, and fluorescence
resonance energy transfer, Triantafilou et al. (2001) identified 4
diverse proteins, heat-shock cognate protein (HSPA8; 600816), HSP90A
(HSPCA; 140571), chemokine receptor CXCR4, and growth/differentiation
factor-5 (GDF5; 601146), on monocytes that form an activation cluster
after LPS ligation and are involved in LPS signal transduction. Antibody
inhibition analysis suggested that disruption of cluster formation
abrogates TNF release. Triantafilou et al. (2001) proposed that heat
shock proteins, which are highly conserved from bacteria to eukaryotic
cells, are remnants of an ancient system of antigen presentation and
defense against microbial pathogens.
Levesque et al. (2003) demonstrated that the mobilization of
hematopoietic progenitor cells (HPCs) by granulocyte colony-stimulating
factor (GCSF; 138970) or cyclophosphamide was due to the disruption of
the CXCR4/CXCL12 chemotactic pathway. The mobilization of HPCs coincided
in vivo with the cleavage of the N terminus of the chemokine receptor
CXCR4 found on HPCs. This resulted in the loss of chemotactic response
of the HPCs to the CXCR4 ligand, CXCL12. The concentration of CXCL12 was
also decreased in vivo in the bone marrow of mobilized mice, and this
decrease coincided with the accumulation of serine proteases capable of
direct cleavage and inactivation of CXCL12. As both CXCL12 and CXCR4 are
essential for the homing and retention of HPCs in the bone marrow, the
proteolytic degradation of CXCL12 and CXCR4 may represent a critical
step in the mobilization of HPCs into the peripheral blood by GCSF or
cyclophosphamide.
Ichiyama et al. (2003) showed that a low molecular mass nonpeptide
compound, KRH-1636, efficiently blocked replication of various T cell
line-tropic HIV-1 in cultured cells and peripheral blood mononuclear
cells through the inhibition of viral entry and membrane fusion via the
CXCR4 receptor but not via CCR5. Furthermore, this compound was absorbed
into the blood after intraduodenal administration as judged by
anti-HIV-1 activity and liquid chromatography-mass spectrometry. Thus,
KRH-1636 seemed to be a promising agent for the treatment of HIV-1
infection.
Hwang et al. (2003) characterized the expression of CXCR4 and analyzed
its functions in ARO cells, a human anaplastic thyroid carcinoma (ATC)
cell line. Fluorescence-activated cell sorting (FACS) analysis of CXCR4
expression in normal and ATC cells showed that ARO cells expressed
significant levels of CXCR4. FRO, NPA (both human thyroid carcinoma cell
lines), and normal thyroid cells did not express membrane CXCR4, as
determined by FACS. The authors concluded that these findings suggested
that a subset of ATC cells expresses functional CXCR4, which may be
important in tumor cell migration and local tumor invasion.
Staller et al. (2003) demonstrated that the von Hippel-Lindau tumor
suppressor protein (VHL; see 608537) negatively regulates CXCR4
expression owing to its capacity to target hypoxia-inducible factor
(HIF1-alpha; 603348) for degradation under normoxic conditions. This
process is suppressed under hypoxic conditions, resulting in
HIF-dependent CXCR4 activation. An analysis of clear cell renal
carcinoma that manifests mutations in the VHL gene in most cases
revealed an association of strong CXCR4 expression with poor
tumor-specific survival. Staller et al. (2003) concluded that their
results suggest a mechanism for CXCR4 activation during tumor cell
evolution and imply that VHL inactivation acquired by incipient tumor
cells early in tumorigenesis confers not only a selective survival
advantage but also the tendency to home to selected organs.
Marchese et al. (2003) determined that AIP4 colocalized with CXCR4 at
the plasma membrane in transfected HEK293 cells and that it colocalized
with HRS (604375) on endosomes in transfected HeLa cells. AIP4, HRS, and
a vacuole sorting protein, VPS4, were required for targeting CXCR4 to
the degradative pathway.
The germinal center (GC) is organized into dark and light zones. B cells
in the dark zone, called centroblasts, undergo rapid proliferation and
somatic hypermutation of their antibody variable genes. Centroblasts
then become smaller, nondividing centrocytes and undergo selection in
the light zone based on the affinity of their surface antibody for the
inducing antigen. The light zone also contains helper T cells and
follicular dendritic cells that sequester antigen. Failure to
differentiate results in centrocyte apoptosis, whereas centrocytes that
bind antigen and receive T-cell help emigrate from the GC as long-lived
plasma cells or memory B cells. Some centrocytes may also return to the
dark zone for further proliferation and mutation. Using genetic and
pharmacologic approaches, Allen et al. (2004) showed that CXCR4 was
essential for GC dark and light zone segregation. In the presence of the
antiapoptotic BCL2 (151430), B cells had robust chemotactic responses to
the CXCR4 ligand, CXCL12, as well as to CXCL13, the ligand for CXCR5.
CXCL12 was more abundant in the dark zone, and CXCR4 was more abundant
on centroblasts than centrocytes. In contrast, CXCR5 helped direct cells
to the CXCL13-positive light zone, but was not essential for segregation
of the 2 zones. CXCL13 and CXCR5 were required for correct positioning
of the light zone. Allen et al. (2004) concluded that these chemokines
and their receptors are critical for movement of cells to different
parts of the GC and for creating the distinct histologic appearance of
the GC. They suggested that GC organization is likely to be disrupted in
individuals with WHIM syndrome (193670) resulting from C-terminal
truncation mutations in CXCR4.
Using immunofluorescence microscopy, Yeaman et al. (2004) examined
expression of the HIV receptors CD4 and galactosylceramide (see GALC;
606890) and the HIV coreceptors CXCR4 and CCR5 in ectocervical specimens
from hysterectomy patients with benign diseases. CD4 expression was
detected on epithelial cells at early and midproliferative stages of the
menstrual cycle, whereas galactosylceramide expression was uniform in
all stages of the menstrual cycle. CXCR4 was not detected on
ectocervical epithelial cells, whereas CCR5 was expressed on
ectocervical epithelial cells at all stages of the menstrual cycle.
CD4-positive leukocytes were present in the basal and precornified
layers of squamous epithelium during early and midproliferative phases
of the menstrual cycle, but were absent in later proliferative phases
and the secretory phase; the presence of CD4-positive leukocytes was not
related to inflammation. Yeaman et al. (2004) concluded that HIV
infection of the ectocervix most likely occurs through
galactosylceramide and CCR5.
Feng et al. (2006) found that beta-defensin-3 (HBD3, or DEFB103A;
606611) not only blocked HIV-1 replication via direct interaction with
virions and modulation of the CXCR4 coreceptor, but it also competed
with the CXCR4 ligand, SDF1, and promoted internalization of CXCR4
without inducing calcium flux, ERK (see MAPK3; 601795) phosphorylation,
or chemotaxis. HBD3 had no effect on other G protein-coupled receptors
(e.g., CCR5). Feng et al. (2006) proposed that HBD3 or its derivatives
may have potential for HIV and/or immunoregulatory therapy.
Jin et al. (2006) found that hematopoietic cytokines, particularly Kitlg
and Tpo (THPO; 600044), induced release of Sdf1 from mouse platelets and
enhanced neovascularization of ischemic hindlimbs through mobilization
of Cxcr4-positive/Vegfr (KDR; 191306)-positive hematopoietic progenitors
termed hemangiocytes. Revascularization was profoundly impaired in Mmp9
(120361)-deficient mice, which have impaired release of soluble Kitlg
from membrane Kitlg, as well as Tpo-deficient mice and Tpor (MPL;
159530)-deficient mice. Transplantation of Cxcr4-positive/Vegfr-positive
hemangiocytes restored revascularization in Mmp9-deficient mice. Jin et
al. (2006) concluded that hematopoietic cytokines, through graded
deployment of platelet-derived SDF1, support mobilization and
recruitment of CXCR4-positive/VEGFR-positive hemangiocytes.
Vasyutina et al. (2005) showed that migrating muscle progenitors express
Cxcr4 and noted that the Cxcr4 ligand Sdf1 is expressed in limb and
branchial arch mesenchyme, i.e., along the routes and at the targets of
migratory cells. Ectopic application of Sdf1 in chick limb attracted
muscle progenitor cells. In Cxcr4 mutant mice, the number of muscle
progenitors that colonized the anlage of the tongue and the dorsal limb
was reduced. Changes in the distribution of muscle progenitor cells was
accompanied by increased apoptosis, indicating that Cxcr4 signals
provide not only attractive cues, but also control survival. Vasyutina
et al. (2005) further found that muscle progenitors of Cxcr4/Gab1
(604439) double mutants did not reach the anlage of the tongue,
suggesting that these proteins interact during progenitor cell
migration.
Using immunohistochemistry, Lieberam et al. (2005) showed that mouse
ventral motor neurons (vMNs) transiently expressed Cxcr4 as they
followed their ventral trajectory, whereas Cxcl12 was expressed by
mesenchymal cells surrounding the ventral neural tube. In mice lacking
Cxcr4 or Cxcl12, vMNs adopted a dorsal motor neuron (dMN)-like
trajectory. Axons of Cxcr4-deficient vMNs frequently invaded sensory
ganglia, a characteristic dMN trajectory. Lieberam et al. (2005)
concluded that a G protein-coupled receptor signaling system controls
the precision of initial motor axon trajectories and that CXCR4 is a
crucial effector of the transcriptional pathway specifying vMN
connectivity.
By studying brains of mice and humans with West Nile virus (WNV; see
610379) encephalitis, McCandless et al. (2008) found downregulation of
the beta isoform of CXCL12, but not the alpha isoform, as well as a
decline of perivascular T cells and an increase in parenchymal T cells.
Treatment with a continuously administered Cxcr4 antagonist increased
the survival of WNV-infected mice and eventually caused a reduction in
WNV burden in the brain. Cxcr4 antagonism also enhanced T-cell
penetration in the brain after WNV encephalitis, increased
virus-specific Cd8-positive T-cell interaction with infected cells, and
decreased glial cell activation in infected brains. McCandless et al.
(2008) proposed that targeting CXCR4 may allow enhanced CD8-positive
T-cell infiltration without increased immunopathology in viral
infections of the central nervous system.
Ding et al. (2014) combined an inducible endothelial cell-specific mouse
gene deletion strategy and complementary models of acute and chronic
liver injury to show that divergent angiocrine signals from liver
sinusoidal endothelial cells stimulate regeneration after immediate
injury and provoke fibrosis after chronic insult. The profibrotic
transition of vascular niche results from differential expression of
stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 in liver
sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in
liver sinusoidal endothelial cells acts with CXCR4 to induce
transcription factor ID1 (600349), deploying proregenerative angiocrine
factors and triggering regeneration. Inducible deletion of Cxcr7 in
sinusoidal endothelial cells from the adult mouse liver impaired liver
regeneration by diminishing Id1-mediated production of angiocrine
factors. By contrast, after chronic injury inflicted by iterative
hepatotoxin (carbon tetrachloride) injection and bile duct ligation,
constitutive Fgfr1 (136350) signaling in liver sinusoidal endothelial
cells counterbalanced Cxcr7-dependent proregenerative response and
augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7
expression shifted angiocrine response of liver sinusoidal endothelial
cells, stimulating proliferation of desmin (125660)-positive hepatic
stellate-like cells and enforcing a profibrotic vascular niche.
Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice
restored the proregenerative pathway and prevented Fgfr1-mediated
maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7
activation in liver sinusoidal endothelial cells abrogated fibrogenesis.
Ding et al. (2014) demonstrated that in response to liver injury,
differential recruitment of proregenerative CXCR7-ID1 versus profibrotic
FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration
and fibrosis.
MOLECULAR GENETICS
WHIM syndrome (193670) is an immunodeficiency disease characterized by
neutropenia, hypogammaglobulinemia, and extensive human papillomavirus
(HPV) infection. Despite the peripheral neutropenia, bone marrow
aspirates from affected individuals contain abundant mature myeloid
cells, a condition termed myelokathexis (kathexis = retention). The
susceptibility to HPV is disproportionate compared with other
immunodeficiency conditions, suggesting that the product of the affected
gene may be particularly important in the natural control of this
infection. By genomewide scan, Hernandez et al. (2003) mapped the gene
mutant in WHIM syndrome to a region of roughly 12 cM on 2q21, and by
screening the most attractive positional candidate in this region,
CXCR4, they identified truncating mutations of the cytoplasmic tail
domain of the CXCR4 gene. One frameshift and 2 nonsense mutations were
identified in separate families.
Balabanian et al. (2005) identified a heterozygous mutation in the CXCR4
gene (162643.0004) in 2 sibs with WHIM syndrome.
NOMENCLATURE
Depending on what properties were being studied, this molecule has been
called neuropeptide Y receptor Y3, fusin, and leukocyte-derived
7-transmembrane-domain receptor, among various designations.
ANIMAL MODEL
Vascularization of organs generally occurs by remodeling of the
preexisting vascular system during their differentiation and growth to
enable them to perform their specific functions during development. The
molecules required for early vascular systems, many of which are
receptor tyrosine kinases and their ligands, are revealed by analysis of
mutant mice. As most of these mice die during early gestation before
many of their organs have developed, the molecules responsible for
vascularization during organogenesis are not identified by this
approach. CXCR4 is responsible for B-cell lymphopoiesis, bone marrow
myelopoiesis, and cardiac ventricular septum formation. CXCR4 also
functions as a coreceptor for HIV-1 and is a receptor for the CXC
chemokine PBSF/SDF1 (600835). Tachibana et al. (1998) showed that CXCR4
is expressed in developing vascular endothelial cells. Tachibana et al.
(1998) found that mice lacking either CXCR4 or PBSF/SDF1 have defective
formation of the large vessels supplying the gastrointestinal tract. In
addition, mice lacking CXCR4 die in utero and are defective in vascular
development, hematopoiesis and cardiogenesis, like mice lacking
PBSF/SDF1, indicating that CXCR4 is a primary physiologic receptor for
PBSF/SDF1. Tachibana et al. (1998) concluded that PBSF/SDF1 and CXCR4
define a new signaling system for organ vascularization.
Zou et al. (1998) pointed out that CXCR4 is broadly expressed in cells
of both the immune and the central nervous systems and can mediate
migration of resting leukocytes and hematopoietic progenitors in
response to its ligand, SDF1. They showed that mice lacking CXCR4
exhibit hematopoietic and cardiac defects identical to those of
SDF1-deficient mice (Nagasawa et al., 1996), indicating that CXCR4 may
be the only receptor for SDF1. Furthermore, fetal cerebellar development
in mutant animals was markedly different from that in wildtype animals,
with many proliferating granule cells invading the cerebellar anlage.
This appeared to be the first demonstration of the involvement of a G
protein-coupled chemokine receptor in neuronal cell migration and
patterning in the central nervous system. They suggested that the
results are important for designing strategies to block HIV entry into
cells and for understanding mechanisms of pathogenesis in AIDS dementia.
Ma et al. (1998) found that mice deficient for Cxcr4 or its ligand Sdf1
died perinatally with defects in both the hemopoietic and nervous
systems, whereas heterozygotes were normal. Reduced B-lymphopoiesis and
myelopoiesis were observed in fetal liver, and myelopoiesis was absent
in bone marrow; however, T-lymphopoiesis was normal. In the nervous
system, the cerebellum developed with an irregular external granule cell
layer, ectopically located Purkinje cells, and numerous chromophilic
cell clumps of granule cells that had migrated abnormally within the
cerebellar anlage.
CXCR4 mRNA is expressed at sites of neuronal and progenitor cell
migration in the hippocampus at late embryonic and early postnatal ages.
SDF1 mRNA, the only known ligand for the CXCR4 receptor, is expressed
close to these migration sites, in the meninges investing the
hippocampal primordium and in the primordium itself. In mice engineered
to lack the CXCR4 receptor, Lu et al. (2002) found that the morphology
of the hippocampal dentate gyrus was dramatically altered. Gene
expression markers for dentate gyrus granule neurons and
bromodeoxyuridine labeling of dividing cells showed an underlying defect
in the stream of postmitotic cells and secondary dentate progenitor
cells that migrate toward and form the dentate gyrus. In the absence of
CXCR4, the number of dividing cells in the migratory stream and in the
dentate gyrus itself was reduced, and neurons appeared to differentiate
prematurely before reaching their target. Thus, Lu et al. (2002)
concluded that the SDF1/CXCR4 chemokine signaling system has a role in
dentate gyrus morphogenesis. The dentate gyrus is unusual as a site of
adult neurogenesis. They found that both CXCR4 and SDF1 are expressed in
the adult dentate gyrus, suggesting an ongoing role in dentate gyrus
morphogenesis.
Knaut et al. (2003) applied genetics and in vivo imaging to show that
'odysseus,' a zebrafish homolog of the G protein-coupled chemokine
receptor Cxcr4, is required specifically in germ cells for their
chemotaxis. Odysseus mutant germ cells are able to activate the
migratory program, but fail to undergo directed migration toward their
target tissue, resulting in randomly dispersed germ cells. SDF1, the
presumptive cognate ligand for Cxcr4, showed a similar loss of function
phenotype and can recruit germ cells to ectopic sites in the embryo,
thus identifying a vertebrate ligand-receptor pair guiding migratory
germ cells at all stages of migration toward their target.
Ding et al. (2006) used the Cre-loxP system to delete the Vhl gene
(608537) from podocytes in the glomerular basement membrane of mice. At
about 4 weeks of age, the mice developed rapidly progressive renal
disease with hematuria, proteinuria, and renal failure with crescentic
glomerulonephritis with prominent segmental fibrin deposition and
fibrinoid necrosis. No immune deposits were present; the phenotype was
similar to human 'pauci-immune' rapidly progressive glomerulonephritis
(RPGN). Gene expression profiling showed increased expression of the
Cxcr4 gene in glomeruli from both mice and humans with RPGN. Treatment
of the mice with a Cxcr4 antibody resulted in clinical improvement, and
isolated overexpression of Cxcr4 was sufficient to cause glomerular
disease. Ding et al. (2006) hypothesized that upregulation of Cxcr4
allowed terminally differentiated podocytes to reenter the cell cycle,
proliferate, and form cellular crescents.
Kawai et al. (2007) transplanted human peripheral blood CD34
(142230)-positive stem cells expressing wildtype or WHIM-type mutated
CXCR4 into nonobese diabetic/SCID mice. Neither wildtype nor mutated
CXCR4 enhanced neutrophil apoptosis in stem cell cultures, even with
CXCL12 stimulation. However, mutated CXCR4 further enhanced bone marrow
engraftment and was associated with significantly increased apoptosis in
bone marrow and reduced release of transduced white cells into
peripheral blood. Kawai et al. (2007) concluded that increased apoptosis
of mature myeloid cells in WHIM is secondary to a failure of marrow
release and progression to normal myeloid cell senescence rather than a
direct effect of activation of mutated CXCR4.
Hirbe et al. (2007) created hematopoietic Cxcr4-null mice via fetal
liver transplant. Compared with controls, mice reconstituted with
Cxcr4-null hematopoietic cells exhibited elevated markers of bone
resorption, increased osteoclast perimeter along bone, and increased
bone loss. Cxcr4-null osteoclasts showed accelerated differentiation and
enhanced bone resorption in vitro. Bone tumor growth was significantly
increased in the mutant mice, and this enhanced bone tumor growth was
abrogated with the osteoclast inhibitor zoledronic acid.
Nair and Schilling (2008) showed that the chemokine Cxcl12b (see 600835)
and its receptor Cxcr4a restrict anterior migration of the endoderm
during zebrafish gastrulation, thereby coordinating its movements with
those of the mesoderm. Depletion of either gene product causes
disruption of integrin-dependent cell adhesion, resulting in separation
of the endoderm from the mesoderm; the endoderm then migrates farther
anteriorly than it normally would, resulting in bilateral duplication of
endodermal organs. Nair and Schilling (2008) suggested that this process
may have relevance to human gastrointestinal bifurcations and other
organ defects.
Repair of demyelinated lesions requires migration, proliferation, and
differentiation of oligodendrocyte precursor cells, which originate in
subventricular zones distant from white matter areas of the central
nervous system. Patel et al. (2010) used cuprizone exposure to induce
demyelination in adult mice and found that Cxcl12 and Cxcr4 were
required for remyelination after cessation of cuprizone exposure. Cxcl12
was upregulated within activated astrocytes and microglia during the
demyelination phase, followed by Cxcl12-induced upregulation of Cxcr4 in
oligodendrocyte precursors during recovery. Loss of Cxcr4 signaling via
either pharmacologic blockade or RNA silencing led to decreased
oligodendrocyte precursor maturation and failure of remyelination.
YY1P2
| dbSNP name | rs1351915(G,A); rs1485063(A,T); rs11886636(C,T); rs72879695(G,T); rs6728281(G,A) |
| cytoBand name | 2q22.1 |
| EntrezGene GeneID | 647012 |
| snpEff Gene Name | AC023468.2 |
| EntrezGene Description | YY1 transcription factor pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2897 |
PABPC1P2
| dbSNP name | rs115518761(G,A); rs114469788(C,T); rs7561768(G,A); rs75392513(A,C); rs114926701(T,C); rs144993809(A,C); rs111322931(G,C); rs34469404(A,G); rs115755486(G,A); rs115058901(G,A) |
| cytoBand name | 2q22.3 |
| EntrezGene GeneID | 728773 |
| EntrezGene Description | poly(A) binding protein, cytoplasmic 1 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
TNFAIP6
| dbSNP name | rs1046672(C,G); rs1046675(A,G) |
| cytoBand name | 2q23.3 |
| EntrezGene GeneID | 7130 |
| EntrezGene Description | tumor necrosis factor, alpha-induced protein 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1423 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Face];
Midface hypoplasia;
Prominent forehead;
Prominent supraorbital ridges;
[Nose];
Depressed nasal bridge (in childhood);
Small, upturned nose (in childhood);
[Teeth];
No abnormalities of teeth
CHEST:
[External features];
Pectus excavatum
SKIN, NAILS, HAIR:
[Skin];
No abnormalities of sweating;
[Nails];
Dysplastic nails (1st and 2nd toes) [Hair];
No abnormalities of hair
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Hypotonia;
Developmental delay, primarily motor, resolves in childhood
MISCELLANEOUS:
One family reported (as of May 2012)
OMIM Title
*600410 TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 6; TNFAIP6
;;TUMOR NECROSIS FACTOR-STIMULATED GENE 6; TSG6
OMIM Description
DESCRIPTION
TSG6 is a member of the hyaluronan (HA)-binding protein family, which
includes cartilage link protein (HAPLN1; 115435), proteoglycan core
protein (e.g., 118661), and the adhesion receptor CD44 (107269) (Lee et
al., 1992).
CLONING
Lee et al. (1992) isolated TSG6 from a library made from tumor necrosis
factor-alpha (TNF; 191160)-treated human fibroblasts. The predicted
polypeptide is 277 amino acids long and includes a typical cleavage
signal peptide. TSG6 is highly homologous to CD44, particularly in the
hyaluronic acid-binding domain. Western blots with antibodies made to a
TSG6 fusion protein detected a 39-kD glycoprotein in TNF-treated cells.
MAPPING
Lee et al. (1993) showed by Southern blot analysis that TSG6 is a
single-copy gene in humans and mice. They assigned the TSG6 gene to
chromosome 2 by use of a panel of somatic cell hybrids.
By radiation hybrid analysis, Nentwich et al. (2002) mapped the TSG6
gene to chromosome 2q23.3.
GENE FUNCTION
By coprecipitation analysis, Lee et al. (1992) showed that human TSG6
bound hyaluronate.
Lee et al. (1993) demonstrated that TSG6 is transcribed in normal
fibroblasts and activated by binding of the cytokines TNF and
interleukin-1 (IL1; 147720; 147760) at AP1 (JUN; 165160) and NF-IL6
(CEBPB; 189965) sites in its promoter.
Klampfer et al. (1994) showed that the CEBPB site is essential for
activation of the TSG6 promoter by TNF or IL1. The JUN site cooperates
with the CEBPB site in the activation of the TSG6 promoter by both TNFA
and IL1.
Klampfer et al. (1994) suggested that the presence of TSG6 in synovial
fluid suggests a possible role in rheumatoid arthritis.
Lesley et al. (2004) noted that the HA-binding domains of TSG6 and CD44
both contain a structural unit of about 100 amino acids called a Link
module. They showed that preincubation of HA with full-length
recombinant human TSG6 or its Link module enhanced or induced binding of
HA to cell surface CD44 on constitutive and inducible cell backgrounds,
respectively. TSG6 Link module mutants with impaired HA binding had
reduced ability to modulate ligand binding by cell surface CD44.
MOLECULAR GENETICS
Nentwich et al. (2002) identified a nonsynonymous SNP, 431G-A, resulting
in an arg144-to-gln change in the CUB domain of TSG6. Genotyping of 400
individuals with osteoarthritis (see 165720), which has been linked to
chromosome 2q, and 400 controls showed that gln144 is the major form of
TSG6 in Caucasians, with over 75% being gln144 homozygotes. Although
modeling indicated that the amino acid change might lead to functional
differences, no association was found between the polymorphism and
susceptibility to osteoarthritis.
ANIMAL MODEL
Nagyeri et al. (2011) found a significant correlation between serum Tsg6
concentration and arthritis severity in a cartilage proteoglycan
(aggrecan)-induced mouse model of rheumatoid arthritis (180300).
Immunoblot and fluorescence microscopy detected Tsg6 in arthritic joint
tissue together with the heavy chains of inter-alpha-trypsin inhibitor
(I-alpha-I) (see 147270). Highest levels of Tsg6 were found in the
secretory granules of mast cells, where it colocalized with mast cell
protease-6 (MCP6, or TPSB2; 191081). In vitro, Tsg6 formed complexes
with Mcp6 and Mcp7 (TPSAB1; 191080) via either heparin or HA. Tsg6
suppressed inflammatory tissue destruction by enhancing serine
protease-inhibitory activity of I-alpha-I against plasmin (173350) by
transferring I-alpha-I heavy chains to HA, thus liberating the I-alpha-I
light chain, bikunin (176870). Nagyeri et al. (2011) proposed that TSG6
promotes inhibition of tryptase activity via a mechanism similar to
inhibition of plasmin.
RPRM
| dbSNP name | rs1063728(C,G) |
| cytoBand name | 2q23.3 |
| EntrezGene GeneID | 56475 |
| EntrezGene Description | reprimo, TP53 dependent G2 arrest mediator candidate |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3007 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Constricted visual fields by age 20 years;
Night blindness by age 20 years;
Loss of central vision between ages 25-30 years;
Complete blindness between ages 40-50 years;
Fundus pigment lumps, bone-corpuscle/bone-spicule pattern;
Attenuation of retinal blood vessels;
Obliteration of peripheral retinal blood vessels (in some patients);
Pallid optic disc
MISCELLANEOUS:
One family reported (last curated July 2008)
OMIM Title
*612171 REPRIMO; RPRM
OMIM Description
CLONING
Using a differential display screening approach on mouse embryonal
fibroblasts to identify genes that are induced by p53 (191170) following
X-irradiation, Ohki et al. (2000) identified one, which they termed
Reprimo, that is involved in cell cycle regulation. Ohki et al. (2000)
cloned mouse and human Reprimo cDNAs, which encode deduced 109-amino
acid proteins sharing 98% sequence identity. The Reprimo protein is
N-glycosylated and localizes to the cytoplasm.
GENE STRUCTURE
Ohki et al. (2000) determined that the mouse Rprm gene is intronless.
MAPPING
By FISH, Ohki et al. (2000) mapped the RPRM gene to chromosome 2q23 in a
region that is frequently lost in lung cancer cells and neuroblastomas.
GENE FUNCTION
Ohki et al. (2000) determined that RPRM is induced following
x-irradiation in a p53-dependent manner and is a downstream mediator of
p53 action. Overexpression of RPRM in HeLa cells by transfection
resulted in G2 arrest of the cell cycle by inhibiting both CDC2 (116940)
activity and nuclear translocation of the CDC2-cyclin B1 (CCNB1; 123836)
complex.
MOLECULAR GENETICS
On the basis of alignment of human EST sequences, Ye and Parry (2002)
identified 2 candidate polymorphisms at nucleotides 824 (G-C) and 839
(C-G) in the 3-prime untranslated region of the RPRM gene. They
confirmed the presence of these polymorphisms in a Caucasian population.
Beasley et al. (2008) found no association between the 824G-C
polymorphism and colorectal cancer in a Caucasian population.
Using high-throughput microarray analysis of pancreatic cancer cell
lines, Sato et al. (2003) identified RPRM as a methylation-related gene
that is frequently methylated in pancreatic cancer cell lines and
tumors.
HISTORY
Takahashi et al. (2005) reported that aberrant methylation and loss of
expression of RPRM was common in several tumor cell lines and human
malignancies. However, the paper was retracted 'due to presentation of
an improperly manipulated figure (Figure 1A) in the article.'
LOC643072
| dbSNP name | rs13388082(C,T); rs1046496(A,T); rs68112803(T,C) |
| cytoBand name | 2q24.2 |
| EntrezGene GeneID | 643072 |
| snpEff Gene Name | BAZ2B |
| EntrezGene Description | uncharacterized LOC643072 |
| EntrezGene Type of gene | unknown |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4261 |
AHCTF1P1
| dbSNP name | rs3914096(A,G); rs113533703(A,G); rs12620974(T,C); rs111698321(C,G); rs113711566(G,C); rs73005088(A,T); rs113567366(T,A) |
| cytoBand name | 2q24.2 |
| EntrezGene GeneID | 285116 |
| snpEff Gene Name | SLC4A10 |
| EntrezGene Description | AT hook containing transcription factor 1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1056 |
GRB14
| dbSNP name | rs1051160(G,A); rs11765(T,C); rs142385994(T,C); rs9287850(T,C); rs3828191(C,T); rs13005055(T,C); rs13029398(C,T); rs1451892(C,T); rs773291(G,A); rs670396(C,T); rs670757(C,T); rs671689(G,A); rs557632(T,A); rs3791355(T,C); rs685769(C,T); rs551160(C,T); rs17353146(A,G); rs8192673(C,T); rs372519668(G,T); rs10497250(T,C); rs73018287(C,T); rs34581642(T,C); rs570657(A,G); rs150329237(A,G); rs1451900(A,G); rs7584035(T,A); rs4667463(A,G); rs4667464(T,C); rs150965104(G,C); rs6717338(G,T); rs73020250(T,C); rs1562934(C,G); rs8192674(G,A); rs582447(A,C); rs16849557(C,T); rs71426725(T,C); rs474066(C,A); rs192662276(T,C); rs7608392(T,C); rs655510(A,C); rs1451897(A,C); rs143030429(C,T); rs373411188(T,C); rs1451896(T,A); rs13015780(C,T); rs13426023(A,T); rs13426155(A,C); rs114778174(T,C); rs13035350(G,T); rs13035519(A,C); rs71426726(T,C); rs1584697(G,A); rs10210468(T,C); rs73020265(T,C); rs13015232(C,A); rs150922782(C,A); rs13027325(A,C); rs77588144(G,T); rs34734180(T,C); rs79223780(C,T); rs139717555(C,T); rs1521521(T,G); rs116475111(G,T); rs4667757(T,C); rs13023450(T,C); rs939643(T,G); rs1879630(A,G); rs71426727(G,A); rs113831997(G,A); rs16849569(A,G); rs138498704(T,C); rs28756905(A,G); rs11690448(G,T); rs147383905(G,A); rs12464825(T,G); rs1106257(C,T); rs148988054(A,T); rs11683488(A,G); rs59724456(T,C); rs11894526(A,G); rs11895606(T,C); rs10167297(A,T); rs12994144(C,T); rs76351813(C,T); rs3920334(C,T); rs16849574(T,C); rs4667465(G,A); rs1357119(A,G); rs1568506(C,T); rs7576322(T,C); rs3942459(A,C); rs1568505(C,G); rs1568504(A,T); rs1474249(T,C); rs138038542(G,A); rs66529941(T,C); rs4599138(T,A); rs13020041(A,G); rs10172080(T,C); rs16849583(T,C); rs16849588(A,G); rs16849591(A,C); rs16849594(G,C); rs7564873(C,A); rs1474248(A,G); rs1474247(G,C); rs1402698(G,A); rs17437781(A,G); rs114451955(G,A); rs16849597(T,C); rs73022005(T,A); rs7579712(C,G); rs111486745(A,G); rs73028047(A,G); rs1521527(G,C); rs73028048(G,A); rs149954121(T,A); rs73028051(G,C); rs11677541(G,A); rs147826682(T,A); rs75806499(C,A); rs1464438(T,C); rs73028052(C,A); rs73028055(T,C); rs73028060(C,A); rs58033673(T,C); rs60973542(G,A); rs73028064(T,C); rs13020404(T,C); rs6751937(T,C); rs17437830(G,T); rs57434784(C,T); rs59970768(A,C); rs77450803(G,A); rs73028068(A,G); rs185297673(T,A); rs73028069(T,C); rs11691134(A,G); rs73971050(C,A); rs57793166(A,G); rs1521522(C,G); rs1521523(A,G); rs13027837(A,G); rs12692723(C,G); rs188688560(C,T); rs4423615(G,A); rs2892923(T,C); rs73028077(C,A); rs6721995(T,C); rs76420780(C,T); rs56049666(T,C); rs12472920(T,C); rs6749902(T,C); rs12692724(T,C); rs73028084(C,T); rs72874854(G,A); rs76565562(C,T); rs12476305(T,C); rs6432798(G,A); rs72874858(T,C); rs146920119(C,T); rs115067645(T,C); rs116042535(C,A); rs59552259(T,C); rs6432799(C,T); rs7568923(T,C); rs12469622(A,G); rs13025322(A,G); rs11885631(A,G); rs72874860(G,C); rs59456464(A,T); rs6750775(G,C); rs6750879(G,A); rs4319945(C,T); rs66756157(G,C); rs72874866(C,A); rs75075566(C,A); rs28407407(A,G); rs13017796(G,T); rs10171103(T,G); rs73971060(T,C); rs12613292(T,C); rs13393278(T,C); rs10188993(A,T); rs10178226(T,A); rs4130269(C,T); rs4667760(A,G); rs12692725(T,C); rs140149060(C,T); rs10199140(A,C); rs73030003(T,C); rs6707635(G,T); rs6736540(A,G); rs9973968(G,T); rs79268155(A,C); rs10164764(G,A); rs62173874(C,A); rs62173875(T,C); rs13000232(C,G); rs140331349(T,A); rs12692726(C,A); rs10930131(C,T); rs10803792(G,A); rs11895467(T,G); rs4667761(C,T); rs4667762(G,A); rs4128205(A,C); rs11901750(A,G); rs13022195(A,C); rs6747829(T,A); rs11892553(C,T); rs13429320(A,G); rs4667763(A,C); rs4667764(A,G); rs149740505(T,G); rs4667765(G,A); rs6752075(T,G); rs6755113(T,C); rs4327248(T,C); rs4527220(C,G); rs10153754(G,A); rs7590013(C,G); rs7607177(T,G); rs7594088(G,A); rs12988420(T,C); rs184563790(T,C); rs73030029(A,T); rs4407262(C,T); rs375798982(G,C); rs4456722(A,G); rs4606947(C,T); rs12692728(A,G); rs6754749(T,C); rs10187406(C,G); rs13035032(G,A); rs13035071(G,A); rs113911280(T,C); rs116448520(G,A) |
| ccdsGene name | CCDS2222.1 |
| cytoBand name | 2q24.3 |
| EntrezGene GeneID | 2888 |
| EntrezGene Description | growth factor receptor-bound protein 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GRB14:NM_004490:exon11:c.C1268A:p.S423Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5722 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B7Z7F9 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 8.132e-06,4.066e-05 |
OMIM Clinical Significance
Oncology:
Prostate cancer
Inheritance:
Autosomal dominant form
OMIM Title
*601524 GROWTH FACTOR RECEPTOR-BOUND PROTEIN 14; GRB14
OMIM Description
Many intracellular targets for receptor tyrosine kinases (RTKs) contain
one or more SH2 (Src homology region 2) domains. These are conserved,
noncatalytic domains that bind to short peptide sequences containing
phosphotyrosine. After RTK activation, autophosphorylation occurs, and
SH2 proteins bind to specific RTKs. Proteins containing SH2 domains are
also thought to mediate other protein-protein interactions during signal
transduction.
CLONING
Daly et al. (1996) screened a human breast epithelial cell cDNA library
with the tyrosine-phosphorylated C terminus of the epidermal growth
factor receptor (EGFR) and identified GRB14. GRB14 is a member of the
GRB7 family, whose members include the mouse genes Grb7 (601522) and
Grb10 (601523). GRB14, Grb7 and Grb10 all contain a C-terminal SH2
domain and a central domain with similarity to the C. elegans protein
F10E9.6/mig10. Daly et al. (1996) identified a third region of
similarity, an N-terminal motif, P(S/A)IPNPFPEL, which contains the
consensus PXXP SH3 binding domain, suggesting that an SH3 protein may
bind to these proteins.
Daly et al. (1996) found that GRB14 gene expression was highest in the
testis, ovary, heart, liver, skeletal muscle, kidney, and pancreas.
Moderate expression was detected in the small intestine, colon,
peripheral blood leukocytes, brain, and placenta, while expression in
the spleen, thymus, prostate, and lung was low or undetectable. GRB14
expression was detected in some breast cancer cell lines and correlated
with estrogen receptor positivity. GRB14 expression was also observed in
human prostate cancer cell lines. Daly et al. (1996) speculated that
GRB14 is a target for a platelet-derived growth factor (PDGF)-regulated
serine kinase.
BIOCHEMICAL FEATURES
GBR14 is a tissue-specific negative regulator of insulin receptor (INSR;
147670) signaling, and INSR inhibition is mediated by the GRB14 BPS
region (between PH and SH2). In order to elucidate the molecular
mechanism by which human GRB14 negatively regulates insulin receptor
signaling, Depetris et al. (2005) determined the crystal structure of
the GRB14 BPS region in complex with the phosphorylated kinase domain of
INSR. The structure revealed that the N-terminal portion of the BPS
region binds as a selective pseudosubstrate inhibitor in the substrate
peptide binding groove of the kinase.
MAPPING
By sequence analysis, Dong et al. (1997) mapped the GRB14 gene to
chromosome 2.
COBLL1
| dbSNP name | rs41357247(A,G); rs77942883(G,C); rs190889193(G,A); rs6717858(T,C); rs12328675(T,C); rs73013644(A,G); rs11558902(C,A); rs151138537(C,G); rs73013645(G,A); rs3769869(A,G); rs145041048(C,T); rs142839135(G,A); rs6753142(T,C); rs141390807(A,T); rs6738627(G,A); rs75297654(C,T); rs115743734(G,A); rs112486804(C,T); rs17244444(G,A); rs10490694(G,A); rs16849663(A,G); rs113966187(C,T); rs111873163(C,G); rs7607980(T,C); rs73013650(T,C); rs116305649(C,T); rs6752978(G,T); rs62173936(C,T); rs78970517(C,T); rs12692737(C,A); rs9653282(A,T); rs7609045(G,A); rs79953491(A,G); rs2198550(A,C); rs183167192(G,A); rs6712203(C,T); rs7590140(A,T); rs12692738(T,C); rs73013656(G,A); rs35492512(A,G); rs73013657(T,C); rs66691695(G,A); rs10183656(A,C); rs6738916(A,G); rs79354434(C,T); rs73013660(C,T); rs6711241(G,A); rs145701325(T,C); rs13017482(T,C); rs80165581(G,A); rs10193724(A,G); rs3769870(A,G); rs73013666(G,A); rs184683671(A,C); rs13031132(T,C); rs75538334(C,G); rs3769871(C,T); rs17185226(T,A); rs3769872(C,T); rs3769873(C,G); rs149974128(T,C); rs59884845(C,T); rs112364621(C,T); rs7581168(C,T); rs147997410(A,G); rs6705646(A,G); rs17185379(T,G); rs3769874(G,T); rs3820982(C,A); rs3769876(T,C); rs3769877(G,A); rs7591813(C,A); rs61465784(T,C); rs13408169(T,A); rs28433634(C,T); rs143900359(A,G); rs3820984(A,G); rs35408742(A,G); rs6748833(T,G); rs13024606(C,T); rs149053731(A,C); rs7586858(C,T); rs73013677(C,A); rs1319213(C,T); rs3754954(G,T); rs3754955(A,G); rs3754956(T,C); rs11896289(G,A); rs73013682(G,A); rs2061006(G,C); rs112907175(C,G); rs75266181(T,G); rs13415816(C,T); rs10221833(G,C); rs7559737(T,A); rs3820985(T,C); rs58133528(G,A); rs1117982(T,C); rs1117983(A,G); rs13432915(T,A); rs6414069(A,G); rs140199954(C,T); rs10167778(T,G); rs6432802(G,C); rs116176868(T,C); rs190905837(A,G); rs11891636(A,C); rs11902283(C,T); rs11902357(G,A); rs12692741(A,C); rs13411183(C,T); rs58792598(G,A); rs13411409(C,T); rs147787082(T,C); rs12619501(C,A); rs35830477(G,A); rs12692742(A,G); rs148245103(T,C); rs3769883(G,T); rs3769884(C,T); rs3820986(A,T); rs12692743(C,T); rs12692744(G,A); rs79916544(C,T); rs1122004(C,T); rs3884521(C,A); rs13403694(A,C); rs28651164(A,T); rs13392281(T,C); rs13432439(C,T); rs61553904(T,C); rs13395130(T,G); rs13407176(A,G); rs76152698(A,T); rs145166332(C,T); rs12618677(A,G); rs13388969(C,T); rs116433344(T,C); rs6735389(T,C); rs56345787(G,T); rs141816201(C,A); rs7574791(C,T); rs34303889(T,C); rs2219120(T,C); rs6706945(C,G); rs3769885(G,A); rs11887512(A,G); rs151149474(C,T); rs74941438(T,G); rs57963710(A,G); rs116831299(T,C); rs77559767(C,T); rs143225472(C,T); rs59879549(A,G); rs79914110(C,T); rs3820987(T,C); rs3769886(C,G); rs3769887(G,T); rs144434844(C,A); rs13432056(C,T); rs13406767(A,T); rs12692745(A,G); rs12990772(C,T); rs35212788(C,G); rs3769888(A,G); rs191161259(T,G); rs77580324(T,G); rs10153726(T,C); rs56378634(T,C); rs3769889(T,C); rs2219118(T,G); rs6729466(G,A); rs75886074(C,T); rs3769891(A,G); rs10178921(T,C); rs76399861(T,A); rs12612633(C,G); rs12616075(T,C); rs12616116(T,C); rs12616168(T,C); rs113238768(G,A); rs7601375(T,C); rs35349581(T,C); rs73968243(T,C); rs112427414(T,A); rs150785043(T,C); rs78319871(C,G); rs74811287(A,C); rs73968244(G,T); rs73968245(T,C); rs3769893(C,G); rs50916(C,G); rs12470606(C,A); rs446315(T,C); rs111717679(G,A); rs401131(A,G); rs411069(G,A); rs6758679(C,T); rs57053249(C,T); rs55790532(C,T); rs6432803(T,C); rs366225(G,C); rs4667770(G,A); rs366965(G,C); rs430419(C,T); rs404682(A,G); rs1828213(T,G); rs355825(A,G); rs355826(A,C); rs355827(C,A); rs355828(C,T); rs369428742(G,T); rs113266087(G,A); rs191531444(G,A); rs355829(G,T); rs4667772(C,T); rs355830(C,G); rs6739705(A,G); rs355831(C,A); rs355832(C,T); rs355833(G,T); rs141440717(C,A); rs6715317(C,A); rs355834(G,A); rs13008381(A,T); rs73968248(T,G); rs355835(G,A); rs6748091(A,G); rs355836(G,A); rs355837(A,G); rs355838(T,G); rs355839(C,G); rs12616012(A,G); rs16849728(A,G); rs171392(T,C); rs187209963(G,A); rs355840(C,G); rs1157581(G,A); rs355841(G,A); rs355842(C,T); rs355843(A,G); rs355844(T,G); rs391915(A,G); rs402908(C,T); rs374356154(T,C); rs355845(T,A); rs355846(T,C); rs355847(A,G); rs650330(G,A); rs355848(T,C); rs10204250(C,T); rs10169786(T,C); rs355849(T,C); rs186429744(T,A); rs355850(C,T); rs146054793(T,C); rs3769897(T,A); rs355853(T,C); rs1509099(A,C); rs355854(T,C); rs62173943(T,C); rs355855(C,A); rs355856(T,A); rs355857(A,G); rs355858(G,A); rs355859(T,A); rs355860(T,G); rs355861(A,G); rs355862(A,G); rs355863(C,A); rs355864(A,T); rs355865(T,C); rs392050(G,A); rs422265(C,T); rs355866(G,A); rs355867(C,T); rs355868(C,T); rs355869(C,T); rs355870(C,T); rs355871(A,G); rs355872(T,C); rs355873(T,C); rs355874(G,A); rs355875(G,A); rs355876(T,G); rs355877(G,A); rs355878(T,C); rs355879(T,C); rs355880(C,T); rs10181235(T,A); rs355881(C,G); rs355882(T,C); rs355883(A,T); rs355884(C,A); rs355885(G,A); rs355886(G,A); rs355887(T,C); rs441640(C,T); rs429376(A,G); rs355888(A,G); rs355889(C,T); rs11677495(G,T); rs355890(T,G); rs355891(T,C); rs11688531(A,G); rs355892(A,G); rs355893(A,G); rs75999234(T,G); rs355894(T,A); rs355895(C,T); rs355896(G,A); rs355897(T,C); rs355898(C,T); rs3820989(C,T); rs355899(C,A); rs355900(T,C); rs113210370(C,T); rs355901(T,C); rs355902(C,A); rs11691338(T,G); rs58716267(T,C); rs355903(C,T); rs75409655(T,G); rs355904(A,T); rs355905(T,C); rs355906(G,A); rs66808012(G,A); rs62173947(C,T); rs4667773(T,C); rs355907(G,A); rs355908(T,C); rs62173955(C,A); rs168546(C,T); rs355909(T,C); rs35734740(G,C); rs4297904(C,T); rs61305746(C,G); rs355910(C,T); rs355911(G,A); rs76436074(A,G); rs10210613(T,C); rs114637292(C,A); rs141497070(G,A); rs73968263(A,G); rs74660150(A,C); rs115311825(T,C); rs10170193(T,A); rs182320029(T,C); rs11901922(G,A); rs73015535(A,G); rs7566032(A,C); rs3769908(T,A); rs3820990(T,C); rs966277(C,A); rs12619449(C,T); rs718573(T,C); rs3820991(C,T); rs355912(C,A); rs61189732(C,T); rs3769910(G,A); rs116268413(C,T); rs2123922(A,G); rs148213480(G,A); rs115082531(A,G); rs73968265(T,G); rs13402599(A,G); rs10930134(G,A); rs355914(G,C); rs149711654(T,C); rs75458208(A,T); rs7588491(A,C); rs355915(G,A); rs6726505(T,C); rs113509293(C,A); rs73968267(A,C); rs355793(A,T); rs13391278(C,A); rs142807444(C,G); rs187965203(A,G); rs74904468(G,C); rs994822(T,C); rs972157(C,T); rs355794(C,T); rs974745(C,T); rs974746(T,C); rs10930136(T,G); rs16849787(G,A); rs992121(A,T); rs62175562(G,A); rs186888096(T,G); rs12616174(T,C); rs355795(C,T); rs16849792(C,T); rs6736779(T,C); rs10173063(G,A); rs11892976(T,G); rs137921058(G,A); rs185711875(G,T); rs409125(T,A); rs1995793(A,T); rs13401856(G,C); rs59462340(A,G); rs721668(A,G); rs34478915(A,G); rs114699691(T,G); rs144378884(A,G); rs146616980(G,C); rs115072020(C,T); rs17248297(T,C); rs3769914(G,C); rs13422348(A,G); rs355796(G,A); rs1993292(C,T); rs149588562(G,T); rs1993291(C,A); rs139749032(T,C); rs200661313(A,G); rs11899722(T,C); rs1037501(G,A); rs441414(A,G); rs6759770(T,C); rs6715946(A,T); rs111508402(T,C); rs10930137(G,C); rs6749295(G,T); rs1848546(T,G); rs1509103(C,T); rs13007273(C,T); rs2123921(C,T); rs355806(A,C); rs78614345(C,A); rs10166371(A,G); rs78098784(T,C); rs6708934(T,C); rs355808(T,C); rs355809(G,A); rs144781411(G,A); rs6710005(T,G); rs76561516(G,A); rs142047070(T,C); rs3769917(G,T); rs3769918(A,T); rs76269124(G,A); rs115732846(G,C); rs3820993(T,A); rs140387143(G,A); rs73015557(T,C); rs355810(G,A); rs3769920(A,G); rs3769921(T,A); rs67970359(T,C); rs355811(G,T); rs355812(A,C); rs3769924(A,T); rs168545(C,T); rs28584669(T,C); rs355797(A,G); rs143350997(C,G); rs355798(A,G); rs10193185(G,T); rs11902000(T,C); rs10205572(T,C); rs10208785(T,G); rs144127291(A,G); rs10199932(C,T); rs10167887(T,G); rs355799(C,T); rs149450117(T,C); rs6722257(G,A); rs145947432(C,T); rs3769925(T,C) |
| ccdsGene name | CCDS2223.2 |
| cytoBand name | 2q24.3 |
| EntrezGene GeneID | 22837 |
| EntrezGene Description | cordon-bleu WH2 repeat protein-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COBLL1:NM_014900:exon6:c.G952A:p.A318T,COBLL1:NM_001278458:exon9:c.G1150A:p.A384T,COBLL1:NM_001278460:exon7:c.G1090A:p.A364T,COBLL1:NM_001278461:exon6:c.G952A:p.A318T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.005674 |
| ESP All MAF | 0.002076 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0005774 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Mild facial weakness;
[Ears];
Prominent ears;
[Mouth];
High-arched palate
SKELETAL:
[Spine];
Thoracolumbar scoliosis;
Lumbar lordosis;
[Limbs];
Cubitus valgus;
Limited elbow extension;
[Hands];
Clinodactyly;
[Feet];
Clinodactyly;
Syndactyly, bilateral (2nd and 3rd toes)
SKIN, NAILS, HAIR:
[Skin];
Paradoxical sweating response (sweating induced by cold exposure,
inability to sweat in hot weather)
NEUROLOGIC:
[Peripheral nervous system];
Sensorimotor peripheral neuropathy, mild
MISCELLANEOUS:
Feeding difficulties in infancy
MOLECULAR BASIS:
Caused by mutation in the cardiotrophin-like cytokine gene (CLCF1,
607672.0001)
OMIM Title
*610318 COBL-LIKE PROTEIN 1: COBLL1
;;COBL-RELATED PROTEIN 1; COBLR1;;
KIAA0977
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA
library, Nagase et al. (1999) cloned COBLL1, which they designated
KIAA0977. The deduced protein contains 1,166 amino acids. RT-PCR ELISA
detected high COBLL1 expression in lung, liver, kidney, pancreas, ovary,
spinal cord, brain, fetal liver, and all specific adult brain regions
examined. Intermediate expression was detected in skeletal muscle,
spleen, testis, and fetal brain.
By searching for sequences similar to mouse Cobl (610317), Carroll et
al. (2003) identified human and mouse COBLL1, which they called COBLR1.
The deduced mouse and human proteins are 63% identical. In situ
hybridization of mouse embryos during gastrulation detected Coblr1 in
extraembryonic tissues only. At embryonic days 8.5 and 9.0, it was also
detected in developing branchial arch 1, and by day 10.5 it was
expressed in branchial clefts, nasal placodes, and the forelimb bud.
MAPPING
By genomic sequence analysis, Carroll et al. (2003) mapped the COBLL1
gene to chromosome 2q24. They mapped the mouse Cobll1 gene to a syntenic
region of mouse chromosome 2C1.3.
LOC101929680
| dbSNP name | rs11884723(C,T); rs1381106(T,C); rs12998106(C,T); rs12999293(G,A); rs17744701(G,A); rs17744737(C,T); rs573936(T,C); rs60933734(G,A); rs59237858(C,T); rs60055328(T,C); rs10497280(A,G); rs17801404(T,C); rs487374(T,C); rs34268282(A,G); rs13393239(T,C); rs11903891(G,T); rs497594(A,G); rs17801482(A,G); rs11904006(C,T); rs12463754(C,G); rs80304563(G,A); rs11890028(T,G); rs114685190(C,T); rs6717932(C,A); rs11885663(C,T); rs79856826(C,T); rs118104394(T,C); rs11887412(G,C); rs13004083(A,G); rs1972712(T,C); rs1972713(C,T); rs1037890(T,A); rs77758570(C,T); rs34335864(T,C); rs141371555(C,T); rs11890251(C,G); rs114688154(A,C); rs506158(T,C); rs143888312(T,A); rs142263392(G,A); rs114051169(G,T); rs146594494(A,C); rs150107211(C,A); rs580041(C,T); rs498918(G,A); rs74807726(A,G); rs115903102(T,C); rs144456541(C,T); rs12469308(C,T); rs51195(T,C); rs115097544(G,T); rs489811(T,C); rs114054885(T,A); rs4667872(G,A); rs28768214(G,A); rs6714844(T,G); rs535533(T,C); rs147566015(T,C); rs567096(A,G); rs73972805(T,G); rs115420667(C,G); rs481757(C,G); rs116823035(T,A); rs7596593(G,A); rs145673997(T,C); rs34079906(G,A); rs114182139(T,G); rs503544(C,G); rs6731168(A,T); rs116306195(G,A); rs6731869(A,G); rs117812432(G,T); rs114255309(A,G); rs35123379(T,A); rs147760685(G,A); rs150988290(C,T); rs13035233(G,C); rs13034850(C,T); rs476585(T,C); rs115972331(A,G); rs475725(C,T); rs35684982(G,A); rs10930205(C,T); rs35831635(A,G); rs13388135(G,A); rs79987444(C,T); rs35894186(C,T); rs596139(T,C); rs12999167(C,A); rs115517012(A,G); rs10185842(T,G); rs16851533(A,G); rs572878(A,C); rs573834(A,C); rs544357(T,C); rs145041168(G,A); rs542501(C,T); rs585528(G,C); rs144055111(T,C); rs62177960(A,G); rs485760(G,A); rs192851097(T,C); rs10930206(T,C); rs503872(T,C); rs472793(A,G); rs115282625(G,C); rs76591597(G,A); rs538640(T,C); rs562343(T,C); rs77847942(C,T); rs7587026(C,A); rs592324(A,G); rs590478(T,C); rs571246(C,T); rs138003290(G,A); rs580243(G,C); rs13008617(G,A); rs61390066(A,G); rs497480(A,C); rs666833(C,T); rs533202(A,C); rs79062501(G,A); rs479250(C,T); rs149004627(G,A); rs75629463(A,G); rs534798(G,A); rs579425(C,T); rs17745375(C,G); rs490463(T,C); rs552161(A,G); rs515090(T,C); rs17745411(G,C); rs520516(T,C); rs471527(G,A); rs519110(C,T); rs518940(A,G); rs604016(G,A); rs514516(G,A); rs514358(T,C); rs491520(G,C); rs519624(T,C); rs52248(A,G); rs680450(C,G); rs76803694(A,C); rs569909(C,G); rs496422(G,C); rs1960242(G,T); rs79570811(C,G); rs10197983(A,G); rs488176(T,G); rs7593275(G,T); rs16851603(C,T); rs3919196(C,T); rs73972811(A,T); rs2226710(C,G); rs73972812(G,A); rs11681250(C,T); rs55668382(C,T); rs11692466(A,T); rs11896706(T,C); rs7561474(T,C); rs7600739(G,A); rs10196629(T,C); rs13428656(A,C); rs2212659(G,A); rs4667875(A,G); rs4667876(A,G); rs113881910(C,T); rs4368345(T,C); rs34208638(G,A); rs4578871(T,C); rs4309588(A,G); rs4667509(T,C); rs4667877(G,A); rs13384709(A,G); rs58563330(A,C); rs117659764(G,T); rs2187012(C,A); rs4233806(A,G); rs4233807(A,T); rs4322851(A,G); rs76425918(T,C); rs7562646(C,T); rs55950735(T,A); rs6432871(G,A); rs6432872(T,C); rs114756703(T,A); rs115076133(C,G); rs12613975(A,C); rs6432873(G,C); rs6432874(A,G); rs6432875(A,G); rs6432876(G,T); rs6432877(C,G); rs35548017(T,A); rs10201267(G,A); rs10201110(C,T); rs10201501(G,C); rs10201324(C,T); rs10803805(T,C); rs10803806(G,T); rs12053373(G,A); rs41400450(C,T); rs2155870(G,A); rs2155871(G,A); rs2155872(C,T); rs2212656(C,A); rs2155873(G,A); rs2155874(C,T); rs2155875(T,C); rs5029249(C,G); rs4473394(T,A); rs201809099(T,C); rs7558010(G,A); rs6414072(T,C); rs190726710(G,A); rs2212655(G,A); rs76121363(C,A); rs12619301(C,T); rs7564783(G,T); rs7564814(C,A); rs7578943(T,C); rs7591278(A,G); rs6714313(C,T); rs6717330(C,A); rs6745779(A,G); rs6745863(A,G); rs6732793(T,C); rs6717728(C,T); rs6746010(A,C); rs6746129(A,G); rs16851664(A,G); rs6749736(A,G); rs115370186(A,G); rs16851666(G,A); rs16851669(G,A); rs4319946(A,G); rs7606233(A,G); rs115086024(G,A); rs2212657(A,G); rs2212658(G,A); rs35837351(A,G); rs181853866(G,T); rs6432879(C,T); rs72877461(T,A); rs72877463(C,G); rs192035227(T,C); rs12613742(G,T); rs78704939(G,T); rs4399745(T,C); rs71426800(A,G); rs71426801(A,G); rs73972827(C,A); rs4630783(G,A); rs720087(G,T); rs720086(C,T); rs4386334(C,A); rs35433566(A,T); rs948472(A,G); rs744073(T,C); rs4667878(T,A); rs4667879(A,G); rs11678868(G,A); rs59524411(A,C); rs2226709(C,T); rs2212654(A,C); rs11681716(G,A); rs11687576(T,G); rs115904897(C,G); rs12999775(T,G); rs10197729(T,C); rs4364034(G,A); rs4341952(T,A); rs11900242(T,A); rs78177954(C,T); rs6743698(C,T); rs6715117(A,G); rs78055675(G,T); rs77964311(A,C); rs77621098(G,A); rs73972828(G,A); rs6756283(G,A); rs10190407(C,A); rs78516460(C,T); rs7584793(A,C); rs6738771(A,G); rs60084731(C,A); rs3919195(T,C); rs11897214(C,T); rs6714310(C,T); rs4667881(A,G); rs62176592(C,T); rs13418070(G,T); rs12620369(C,T); rs10210369(T,C); rs4667510(G,A); rs2212661(T,C); rs6719300(G,A); rs75500901(T,G); rs6737509(T,C); rs35040406(C,T); rs6737887(T,C); rs141511259(G,A); rs12990962(C,T); rs6738067(A,G); rs10196359(G,A); rs7578515(T,C); rs7578621(T,G); rs11898201(C,T); rs150917680(A,C); rs139406181(T,A); rs948473(G,A); rs6432880(A,T); rs6746272(A,T); rs6432881(T,C); rs6432882(A,G); rs11885235(T,C); rs114001869(A,G); rs56192406(C,T); rs6722166(G,A); rs149361732(C,G); rs13024248(A,T); rs73969608(C,T); rs76672514(C,G); rs192318920(C,T); rs61292866(A,C); rs7586913(C,A); rs10181960(T,A); rs10169846(G,A); rs13002788(A,T); rs6713141(A,G); rs12470470(T,C); rs73969610(T,C); rs71426802(A,G); rs11693281(G,T); rs139481105(T,A); rs7556913(G,A); rs74778159(C,G); rs6708619(G,A); rs11683404(A,G); rs6708566(C,T); rs7563811(G,A); rs35502562(T,A); rs9287865(T,C); rs148960124(G,C); rs4667511(A,G); rs189361670(C,T); rs78265699(C,A); rs9917323(A,G); rs73969611(G,A); rs73969612(A,G); rs11900364(A,T); rs10178515(G,A); rs73017531(C,T); rs13005825(A,G); rs16851744(T,C); rs16851748(G,A); rs73017538(A,G); rs13396526(C,T); rs17804037(G,C); rs77050817(G,C); rs16851751(G,A); rs11902920(A,C); rs200732899(A,G); rs16851754(G,A); rs140553451(A,G); rs111510277(C,T); rs16851759(G,A); rs111558968(G,A); rs4303728(G,A); rs56821066(T,C); rs114005355(C,T); rs28675022(T,C); rs28452110(A,G); rs10165613(T,C); rs16851772(C,G); rs10930210(T,A); rs12996382(T,C); rs113703749(G,T); rs10169523(T,C); rs10180721(A,T); rs16822862(C,G); rs34141377(T,C); rs192012663(T,A); rs6750719(G,C); rs6721909(A,T); rs188316159(G,A); rs6755487(G,A); rs144605695(G,A); rs16851792(C,T); rs10209609(C,A); rs4358132(G,A); rs7582791(T,A); rs73017552(A,T); rs2212662(C,T); rs73017554(C,T); rs143083657(A,T); rs74958673(T,A); rs6432885(C,T); rs7589835(A,G); rs6741250(A,G); rs12612267(C,T); rs113326547(A,G); rs7567947(C,T); rs7568090(C,A); rs140840053(A,G); rs180692545(G,A); rs4578872(T,G); rs4599136(G,A); rs6725008(C,T); rs7605012(A,G); rs56170951(G,T); rs57631328(T,C); rs7582397(C,A); rs4295022(T,C); rs4270359(A,G); rs35822124(A,G); rs56137674(G,T); rs7600169(A,G); rs192955571(T,C); rs7595255(T,C); rs138736567(T,C); rs6750196(T,C); rs3793936(C,T); rs13406236(C,T); rs58582570(G,C); rs16851799(C,T); rs56878447(A,G); rs10170041(A,T); rs10194106(C,T); rs7557805(T,C); rs4641950(G,T); rs113022673(C,G); rs11689456(G,C); rs73017585(C,T); rs10200828(C,A); rs61137139(C,T); rs722204(G,A); rs73019642(A,G); rs73019643(T,G); rs7592052(G,T); rs7592093(C,T); rs193089269(T,C); rs12614583(G,C); rs3793937(T,G); rs10200136(A,G); rs144333343(A,C); rs74532817(T,A); rs6758728(C,T); rs6758751(C,T); rs6716818(T,C); rs10199202(T,G); rs6432888(C,T); rs6705157(G,A); rs6432890(T,A); rs7557561(G,A); rs7571373(T,C); rs17748381(A,G); rs12621853(T,C); rs2155876(T,A); rs2155877(A,G); rs2155878(A,G); rs3949023(C,T); rs10930211(G,A); rs10930212(C,T); rs6746030(A,G); rs7598274(A,T); rs7586035(T,C); rs2155879(T,A); rs115709759(T,C); rs146664769(G,T); rs143456294(T,C); rs36073236(A,G); rs10930213(A,G); rs16851831(A,G); rs191020971(G,T); rs7563540(C,T); rs187465818(T,A); rs16851834(G,A); rs12692791(C,T); rs12692792(A,T); rs4564791(C,T); rs4564792(C,A); rs10803807(G,A); rs76665783(G,A); rs11884801(T,G); rs76547772(C,T); rs10930214(C,G); rs6756630(A,G); rs2226711(G,T); rs4477933(C,T); rs7604448(A,C); rs188572267(A,G); rs7607967(A,G); rs7581840(G,C); rs4633936(C,T); rs4491742(C,T); rs4371369(A,G); rs4493273(A,G); rs4318405(G,A); rs4569493(G,A); rs4561679(T,C); rs183939191(T,C); rs76581711(A,G); rs4426541(A,G); rs186458745(T,G); rs4331518(C,T); rs11897575(T,C); rs4443014(A,T); rs10754969(C,A); rs4453709(A,T); rs188855445(C,T); rs4358134(C,A); rs12619279(G,A); rs12619240(C,G); rs12478543(T,A); rs10173021(A,C); rs60205988(A,C); rs61567448(C,T); rs13395140(A,T); rs7586794(T,G); rs7582029(A,C); rs60899792(C,T); rs71428906(A,G); rs3935511(T,C); rs11896007(C,T); rs71428907(G,T); rs55929222(A,T); rs35664204(C,T); rs35459615(G,A); rs6432892(T,C); rs10930215(T,C); rs7597740(A,C); rs12477229(G,A); rs6739404(T,A); rs34474991(T,A); rs6724623(C,T); rs12465551(T,A); rs3924001(G,A); rs6432893(G,A); rs4525717(C,T); rs13007020(T,C); rs35825653(T,C); rs34695782(T,G); rs6432894(A,C); rs73969653(G,A); rs146812858(C,T); rs7607896(C,T); rs7608201(G,A); rs6706811(G,A); rs61357875(T,G); rs6722503(T,A); rs6722507(T,C); rs6722511(T,C); rs9917231(A,G); rs4278943(C,T); rs4284843(G,A); rs9917396(G,A); rs9917401(C,T); rs9917250(A,G); rs34566252(T,G); rs7596100(A,G); rs13402180(T,C); rs13414203(A,G); rs13402540(T,G); rs12474466(A,G); rs4500963(T,G); rs13007151(C,T); rs36023349(C,T); rs7591475(T,C); rs150810472(T,C); rs6742597(T,C); rs6728078(G,C); rs145989298(C,T); rs114210536(C,T); rs4359678(G,T); rs12477876(A,G); rs35286247(T,A); rs4128577(A,G); rs4522621(G,A); rs7588632(G,A); rs12475406(T,C); rs12471272(G,A); rs4597545(G,C); rs4335960(A,G); rs4340540(A,G); rs4387806(T,C); rs36090076(A,G); rs12692793(G,A); rs13408109(T,C); rs13408332(T,C); rs6741822(T,C); rs12471856(T,C); rs7594745(T,C); rs34714940(G,A); rs11688164(T,C); rs62178522(T,A); rs62178523(G,C); rs58925228(C,A); rs192354676(C,T); rs4632359(C,T); rs6754023(T,C); rs6754031(T,G); rs10803809(T,C); rs12619987(G,A); rs12620053(C,A) |
| ccdsGene name | CCDS46441.1 |
| cytoBand name | 2q24.3 |
| EntrezGene GeneID | 101929680 |
| snpEff Gene Name | SCN9A |
| EntrezGene Description | uncharacterized LOC101929680 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | SCN9A:NM_002977:exon27:c.C5746T:p.L1916F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5483 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EUN6 |
| dbNSFP KGp1 AF | 0.00457875457875 |
| dbNSFP KGp1 Afr AF | 0.020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.008019 |
| ESP All MAF | 0.002549 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001012 |
SCN7A
| dbSNP name | rs1046022(T,C); rs13406727(G,A); rs6716020(T,C); rs9679088(T,C); rs6739952(G,A); rs35106200(T,C); rs13035112(A,C); rs3579(C,T); rs16852112(T,G); rs35344714(T,C); rs3791251(C,G); rs33953730(A,G); rs34971284(T,A); rs36024626(A,T); rs3791252(A,C); rs34915827(A,G); rs74838693(C,T); rs142431895(A,C); rs150518525(T,A); rs7574361(A,C); rs34977626(T,G); rs1406276(C,T); rs1406275(G,T); rs1406274(C,T); rs71428922(C,A); rs71428923(A,G); rs16852124(C,T); rs13027893(G,C); rs112697228(A,T); rs6432912(A,T); rs7562525(G,A); rs16852131(T,C); rs138401673(C,A); rs75496810(C,T); rs33922582(T,G); rs34619171(A,G); rs114806316(G,A); rs149141059(G,A); rs1919180(T,C); rs35844932(C,T); rs10930221(C,G); rs7561953(C,A); rs60440264(C,G); rs11681682(T,A); rs11675847(C,T); rs10930222(C,T); rs72623153(T,C); rs73027626(G,T); rs6750134(A,C); rs13004313(G,A); rs7587041(T,C); rs72623154(A,G); rs11899387(A,T); rs13408253(T,C); rs6734211(G,A); rs7584051(G,A); rs72623155(A,G); rs6738031(C,A); rs140504782(T,A); rs1983499(T,C); rs1983498(C,T); rs13415889(A,G); rs5024296(T,C); rs34611879(G,A); rs79239728(C,T); rs76929648(T,C); rs13397124(G,T); rs7578830(C,G); rs145836806(T,C); rs4550683(C,G); rs13404431(G,T); rs3791253(A,G); rs7563854(A,G); rs71428925(C,A); rs7597971(G,A); rs114797993(C,T); rs139589165(A,T); rs34054879(C,T); rs11900439(C,A); rs185976043(T,G); rs7596356(C,T); rs2390415(G,C); rs10178010(C,T); rs4000995(T,G); rs144805281(T,C); rs10204196(A,C); rs10180790(C,T); rs11681524(G,T); rs7569250(T,A); rs76555737(C,T); rs72623156(C,T); rs72623157(G,A); rs115649817(G,A); rs76692995(A,G); rs7570201(C,A); rs7570585(G,T); rs35213258(A,G); rs113442768(G,T); rs115835523(G,A); rs75016896(G,A); rs34975670(G,A); rs6709223(C,T); rs6709684(G,A); rs114414205(G,A); rs6741870(A,T); rs34692869(A,T); rs34114198(G,A); rs36028931(G,A); rs73027641(A,G); rs72623158(A,T); rs74341820(A,T); rs143817721(C,T); rs16852148(T,G); rs9967700(T,C); rs78688751(C,A); rs6734499(C,T); rs6738638(C,A); rs11680374(A,T); rs13023734(C,A); rs111781767(G,A); rs57219451(A,G); rs11888208(T,C); rs34536818(G,A); rs13014266(T,C); rs13408742(A,G); rs72623159(T,C); rs114318828(A,G); rs142771013(G,T); rs7590673(G,A); rs35704933(G,A); rs12468323(G,A); rs145202339(T,C); rs13029092(C,T); rs116063969(T,A); rs35191874(A,G); rs4476366(C,T); rs13417885(A,G); rs371049060(G,A); rs12475889(A,C); rs35263513(A,G); rs13017982(T,C); rs12992062(A,G); rs114729877(G,A); rs34774689(C,T); rs2293567(C,T); rs36063236(C,T); rs73027647(C,T); rs13016836(T,C); rs35405768(A,G); rs16852172(G,A); rs7565062(G,T); rs16852181(T,C); rs1569160(A,C); rs116167855(C,T); rs13018705(A,T); rs13019413(C,G); rs7575915(G,C); rs114544851(T,C); rs2141384(T,G); rs2893022(T,C); rs116571441(T,C); rs11893208(A,G); rs11888329(T,C); rs35473442(T,C); rs115525811(A,C); rs140728180(T,C); rs115034006(A,C); rs35220533(C,T); rs115916574(C,T); rs34565090(C,T); rs11687273(A,G); rs58234218(C,A); rs182135080(T,C); rs11680498(A,G); rs115491820(C,T); rs1172384(C,T); rs2293568(A,G); rs1172383(T,C) |
| ccdsGene name | CCDS46442.1 |
| cytoBand name | 2q24.3 |
| EntrezGene GeneID | 6332 |
| EntrezGene Description | sodium channel, voltage-gated, type VII, alpha subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SCN7A:NM_002976:exon15:c.T2477A:p.L826H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5907 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q01118 |
| dbNSFP Uniprot ID | SCN7A_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.002418 |
| ESP All MAF | 0.000755 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002779 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Isolated cases
HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Midface hypoplasia;
Broad face;
[Ears];
Hearing loss (conductive and/or sensorineural);
[Nose];
Broad nasal bridge
CARDIOVASCULAR:
[Heart];
Congenital heart defect
GENITOURINARY:
[Kidneys];
Structural renal anomalies
SKELETAL:
[Spine];
Scoliosis;
[Hands];
Brachydactyly
NEUROLOGIC:
[Central nervous system];
Speech delay;
Mental retardation (IQ 20-78);
Sleep disturbance;
Structural brain abnormalities;
[Peripheral nervous system];
Peripheral neuropathy;
Decreased pain sensitivity;
Normal nerve conduction velocities;
Decrease/absent deep tendon reflexes;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Polyembolokoilamania (insertion of foreign bodies into body orifices);
Behavioral problems;
Self-destructive behavior;
Onychotillomania (pulling out nails);
Wrist-biting;
Head-banging
VOICE:
Hoarse voice
LABORATORY ABNORMALITIES:
Interstitial deletion of 17p11.2 (most common is 3.7Mb)
MISCELLANEOUS:
Most cases result from de novo mutation or deletion of RAI1 (607642)
MOLECULAR BASIS:
Caused by mutation in the retinoic acid-induced gene 1 (RAI1, 607642.0004);
Contiguous gene deletion syndrome caused by deletion (650kb-3.7Mb)
of 17p11.2
OMIM Title
*182392 SODIUM CHANNEL, VOLTAGE-GATED, TYPE VII, ALPHA SUBUNIT; SCN7A
;;SODIUM CHANNEL, NEURONAL TYPE VI, ALPHA SUBUNIT;;
SODIUM CHANNEL, VOLTAGE-GATED, TYPE VI, ALPHA SUBUNIT; SCN6A
OMIM Description
Voltage-dependent sodium channels are responsible for the initial
membrane depolarization that occurs during generation of action
potentials in most electrically excitable cells. These ion channel
proteins exist as heteromultimeric complexes of a large (approximately
260 kD) alpha subunit and 1 or 2 smaller (approximately 33-38 kD) beta
subunits.
CLONING
George et al. (1990) identified a sodium channel alpha-subunit isoform
that is expressed in human heart and uterus.
MAPPING
George et al. (1994) assigned the SCN7A gene, which the authors
symbolized SCN6A, to chromosome 2 by a PCR-based strategy applied to a
human/rodent somatic cell hybrid mapping panel. Confirmation of the
localization and regional assignment was achieved using chromosome
microdissection-PCR as described by Han et al. (1991). Giesma-banded
metaphase chromosomes were dissected with glass needles using a
micromanipulator. Microdissected chromosomal fragments were then used as
templates in PCR reactions. Thus the assignment of the SCN7A gene to
2q21-q23 was determined. This chromosomal assignment overlaps with that
defined for SCN2A (182390) and SCN3A (182391), indicating the existence
of a cluster of these genes on 2q.
ANIMAL MODEL
Watanabe et al. (2000) generated mice in which Scn6a (Scn7a) was
knocked-out by insertion of an in-frame lacZ gene. The knockout mice
were healthy and fertile. By analyzing targeted mice for lacZ
expression, Watanabe et al. (2000) found Scn6a expression in lung,
heart, dorsal root ganglia (DRG), and Schwann cells in the peripheral
nervous system as well as in neurons and ependymal cells in restricted
areas of the CNS. Within the CNS, expression was found in neurons of the
circumventricular organs, including the subfornical organ and organum
vasculosum laminae terminalis, which are important regions for the
control of body fluid ionic balance. Scn6a-deficient mice ingested
excessive salt and, under thirst conditions, showed hyperactivity of the
neurons in the subfornical organ and organum vasculosum laminae
terminalis. Watanabe et al. (2000) proposed that Scn6a functions in the
central sensing of body-fluid sodium level and regulation of salt intake
behavior.
From studies in Scn6a-deficient mice, Hiyama et al. (2002) concluded
that Scn6a is a sodium channel that is sensitive to an increase in the
extracellular sodium concentration and is likely to be the sodium-level
sensor of body fluids in the brain.
LRP2
| dbSNP name | rs79052831(A,G); rs34564141(C,T); rs73028998(G,A); rs7598209(T,C); rs1003456(A,T); rs74839579(T,A); rs73030803(T,G); rs75431141(A,G); rs6754932(T,C); rs73030805(A,C); rs74560435(G,A); rs11691854(T,C); rs139023066(C,G); rs150914001(C,A); rs142559558(T,A); rs144260784(A,G); rs11892075(A,G); rs147049056(G,A); rs72890405(C,A); rs6746604(G,C); rs990627(C,T); rs16856476(G,A); rs73970129(G,C); rs990626(G,A); rs73970130(A,C); rs2268380(G,A); rs2268379(A,G); rs2268378(G,A); rs6725805(A,G); rs16856488(A,G); rs66660630(G,A); rs2075253(G,A); rs6733111(A,G); rs72890417(T,C); rs6733122(A,G); rs146901930(G,A); rs2284681(C,A); rs68155726(G,T); rs2284680(C,A); rs62172578(C,T); rs4668122(A,G); rs2239592(T,C); rs73970136(G,C); rs2239591(T,C); rs2239590(A,T); rs2239589(G,T); rs41265945(C,T); rs4667591(T,G); rs41268687(G,A); rs114936025(G,C); rs4667592(G,A); rs72874703(T,C); rs55681838(T,C); rs6761244(G,A); rs1123904(C,A); rs1123905(C,T); rs12692892(A,G); rs13386120(A,T); rs142783441(C,G); rs72874714(C,A); rs10192078(C,T); rs741376(C,A); rs72874715(A,T); rs755631(A,C); rs116448138(T,G); rs17848195(G,A); rs10198527(G,A); rs143766473(T,C); rs3944004(A,C); rs4667593(G,A); rs4667594(T,A); rs11679947(A,G); rs10177799(A,T); rs141668801(T,C); rs10490132(A,C); rs9967871(C,T); rs10190601(C,T); rs2075252(T,C); rs10191176(C,G); rs2075251(T,A); rs114646035(A,T); rs16856530(T,C); rs3815573(A,G); rs17848192(A,G); rs10930346(T,A); rs13021137(G,T); rs6759013(A,G); rs6730825(C,T); rs13011165(T,C); rs13034796(G,A); rs77383185(C,T); rs2268377(C,A); rs2268376(T,C); rs9646777(G,A); rs9646778(T,C); rs115504097(C,T); rs3821124(T,G); rs115425860(G,C); rs17848191(A,C); rs115587365(A,G); rs116822920(C,T); rs72874736(C,A); rs114570354(C,G); rs2268375(A,G); rs2268374(G,T); rs147683523(G,T); rs73015607(C,T); rs11884342(G,A); rs2229268(A,G); rs2239602(C,T); rs115483533(G,C); rs2239601(G,A); rs4140872(C,T); rs7559094(T,A); rs115478315(A,G); rs67931300(T,C); rs4497843(G,A); rs114123637(A,G); rs144075834(A,T); rs17848190(T,C); rs17848189(C,A); rs116700365(C,T); rs144081819(C,T); rs193258071(G,T); rs2075250(T,C); rs2024481(C,A); rs143472307(C,T); rs116379597(C,T); rs2229265(C,T); rs148378668(C,T); rs141395053(C,T); rs2193196(C,T); rs7565788(T,C); rs72874761(C,T); rs13421129(T,C); rs73971197(T,C); rs741378(G,A); rs10191692(C,T); rs7421492(T,C); rs2892803(C,T); rs193250154(T,C); rs9789747(T,C); rs9287910(C,T); rs9287911(A,T); rs17848182(A,T); rs199584573(A,C); rs200691310(T,C); rs6744473(A,T); rs17848180(C,T); rs3213759(T,G); rs116570214(C,T); rs10169879(T,C); rs10204688(C,T); rs7588584(T,C); rs2024480(A,G); rs2284679(C,T); rs139489982(T,C); rs6744155(G,A); rs2284678(A,G); rs2284677(G,A); rs2284676(A,G); rs4287730(G,C); rs6747214(C,T); rs35734447(T,C); rs59363833(T,C); rs116568823(G,T); rs16856558(G,A); rs10210408(C,T); rs1548936(C,T); rs1972589(C,T); rs57926641(T,C); rs7565822(G,A); rs7592045(A,G); rs12104494(G,A); rs7592152(A,C); rs16856573(C,T); rs4331469(A,C); rs2389589(A,G); rs3770604(T,A); rs115009492(A,G); rs3821125(C,T); rs75421287(A,G); rs2075248(T,C); rs114120325(C,T); rs11886626(T,C); rs2075247(C,T); rs192493338(T,C); rs72876205(G,T); rs10490131(A,G); rs144773209(A,G); rs58687448(T,C); rs77463292(C,T); rs7557964(C,T); rs73033881(T,C); rs7578722(T,C); rs2228171(C,T); rs2302696(C,T); rs78745237(C,T); rs73033887(C,T); rs10169232(C,G); rs16856592(A,C); rs16856593(G,A); rs16856594(G,T); rs16856596(G,A); rs62172607(A,G); rs62172609(A,G); rs16823023(T,C); rs72876208(C,T); rs11898106(A,G); rs73033899(C,T); rs73971315(T,G); rs28454851(G,A); rs371363668(C,T); rs77726104(T,C); rs11687903(T,G); rs13401581(G,A); rs79399342(T,G); rs16856600(G,A); rs11893158(G,T); rs2239600(C,T); rs2284675(G,A); rs2239599(T,C); rs6709670(A,G); rs73035704(C,A); rs140698184(C,A); rs114702762(G,T); rs147112898(G,C); rs370035430(T,C); rs35114151(A,G); rs13417389(T,C); rs116018950(T,C); rs2268373(C,G); rs2268372(T,A); rs10200740(T,C); rs7563506(A,G); rs10200859(T,C); rs10188487(C,T); rs79503405(G,T); rs75569504(A,G); rs116247504(T,C); rs112172369(G,C); rs10170902(A,G); rs4668124(C,A); rs77711606(T,C); rs4001547(G,C); rs11689553(C,G); rs188087943(A,C); rs10201691(G,A); rs10201911(C,T); rs6718884(T,C); rs76592461(C,A); rs116602311(C,T); rs114072720(T,C); rs17848168(G,A); rs11886219(T,C); rs2302695(G,C); rs149313132(T,G); rs17848164(C,T); rs2052298(T,A); rs2052297(C,T); rs114862540(C,T); rs72876227(T,C); rs2052296(A,C); rs62172631(G,A); rs11886318(A,C); rs151079759(G,C); rs13417486(C,T); rs13431061(T,C); rs62172632(G,T); rs7600336(C,T); rs75241704(G,A); rs2300447(C,A); rs2300446(T,C); rs143294557(A,T); rs150795325(C,A); rs2193195(T,C); rs2193194(A,G); rs2193193(G,A); rs2216239(T,C); rs144259254(T,G); rs78833883(G,A); rs116671969(A,T); rs369998522(G,A); rs3815572(C,T); rs2268370(A,C); rs74688656(A,G); rs9283479(C,T); rs9646731(G,A); rs4606889(T,C); rs4302191(C,G); rs138660843(C,T); rs6719440(C,T); rs6747692(A,T); rs72876246(C,T); rs2268369(A,C); rs2268368(C,T); rs2268367(A,C); rs2268366(T,A); rs13389381(T,C); rs11902433(C,T); rs185887347(G,A); rs34951037(A,T); rs2075246(A,G); rs140482743(A,G); rs72876251(A,G); rs982810(A,G); rs13383183(C,A); rs35836996(A,T); rs116456291(C,T); rs115846598(T,C); rs112160178(C,A); rs72876254(A,G); rs6433109(A,C); rs141661189(A,T); rs142870933(G,A); rs142155669(C,T); rs4668127(G,A); rs4668128(G,A); rs184214264(T,C); rs2302694(G,A); rs2302693(T,C); rs2302692(T,C); rs3926693(C,T); rs77251020(G,A); rs116718746(T,C); rs4667597(G,A); rs3821126(G,A); rs1362996(A,G); rs3821127(A,G); rs72876264(C,T); rs3821128(T,C); rs2239598(A,G); rs72876271(G,A); rs2239597(A,C); rs2239596(T,C); rs2239595(G,A); rs78750385(C,G); rs2239594(C,T); rs143601179(C,T); rs6713797(A,T); rs151020693(T,C); rs6752778(A,C); rs6724600(G,T); rs114534086(T,C); rs4668129(A,G); rs114570913(A,C); rs115452726(C,A); rs148175287(G,A); rs114658487(C,T); rs2229267(A,G); rs74457112(C,G); rs12151603(A,T); rs78967293(G,T); rs78008770(T,A); rs116202304(C,A); rs12987817(A,G); rs2268365(T,C); rs77885658(A,T); rs115228222(C,T); rs78265059(C,T); rs830973(G,A); rs34915742(C,G); rs76714416(A,G); rs76838238(C,T); rs2239593(G,A); rs111495150(T,C); rs78828988(C,T); rs114215601(T,C); rs17848149(T,G); rs77416334(T,G); rs72876285(T,A); rs10490130(A,C); rs831040(C,T); rs74705514(A,C); rs831041(T,G); rs116697309(A,T); rs831042(T,C); rs148541367(C,G); rs2075255(A,C); rs2075254(G,A); rs150552608(G,A); rs139922642(T,C); rs56377101(G,A); rs116387136(C,T); rs115603768(C,A); rs12613980(G,T); rs140227448(G,A); rs116792402(T,A); rs149050875(T,G); rs114779248(A,T); rs831043(T,C); rs2075249(G,T); rs138299719(C,G); rs831044(T,A); rs56168972(G,C); rs57516605(A,C); rs191840384(T,C); rs16823029(C,A); rs115301040(C,A); rs830956(C,T); rs830957(C,T); rs370268078(A,T); rs830958(G,T); rs830959(C,T); rs830960(C,T); rs1421509(T,C); rs149524265(T,G); rs144193618(T,C); rs2241190(T,C); rs33954745(A,G); rs35583956(A,T); rs830982(G,A); rs13025890(C,G); rs830983(A,G); rs78830569(T,A); rs35994058(A,T); rs114346886(T,C); rs2544385(C,A); rs68108873(T,C); rs35853478(C,T); rs2673175(T,G); rs4667599(A,G); rs4613240(T,C); rs2544386(A,T); rs2673176(A,G); rs2544388(G,A); rs2544389(C,G); rs141248390(A,G); rs830992(A,G); rs830993(A,T); rs73035802(A,G); rs10515931(C,T); rs830994(G,A); rs830995(A,G); rs10515930(G,C); rs10490129(G,C); rs77612812(C,A); rs830996(T,G); rs111849729(C,T); rs3770607(G,T); rs830997(A,G); rs830998(A,C); rs830999(G,A); rs831000(T,C); rs831001(T,C); rs831002(T,C); rs831003(G,C); rs113568043(G,C); rs2673179(G,A); rs2544372(C,T); rs7568568(T,C); rs59076959(T,C); rs62173981(A,G); rs831004(C,T); rs115854094(A,G); rs12991585(A,C); rs12998030(C,G); rs112897661(A,G); rs831005(A,G); rs831006(G,C); rs831008(C,T); rs73971833(T,C); rs831009(G,A); rs831010(C,T); rs111704488(A,C); rs112238821(T,C); rs72878449(A,G); rs831011(A,G); rs831012(C,T); rs831013(T,G); rs56325975(G,C); rs831014(T,G); rs831015(T,C); rs145577206(G,A); rs73037817(C,T); rs55679014(T,G); rs112348713(A,C); rs58338106(C,T); rs78253750(A,C); rs2673180(C,G); rs185185849(A,C); rs831016(G,C); rs3770611(A,C); rs3770612(A,G); rs72878472(T,C); rs10754970(G,A); rs72878477(C,T); rs2161039(C,T); rs831017(G,A); rs144147038(C,T); rs16856748(G,A); rs831019(T,G); rs3770613(C,T); rs61219833(T,C); rs831020(A,G); rs59457398(T,C); rs72878487(G,A); rs62171262(A,G); rs189216637(T,C); rs62171263(G,A); rs831022(C,T); rs11887007(C,A); rs2229266(G,A); rs2673173(G,A); rs16856759(A,G); rs2673165(C,T); rs148297723(C,A); rs13396247(T,A); rs2673164(C,T); rs2673163(C,T); rs2673162(T,C); rs2222020(C,A); rs2222019(C,A); rs9287914(T,A); rs2544373(A,T); rs2544374(A,G); rs2244407(T,C); rs2390829(G,A); rs187819976(A,G); rs830962(A,G); rs830963(A,G); rs3770616(C,T); rs7575260(G,A); rs830964(T,C); rs4667600(T,A); rs3914468(A,G); rs830965(G,A); rs700549(G,A); rs700550(C,T); rs186596898(A,G); rs830966(G,C); rs830967(A,T); rs830968(T,C); rs830969(A,G); rs853988(C,A); rs10174058(G,A); rs830970(C,T); rs7600757(A,G); rs151305177(C,T); rs830971(G,C); rs73028131(C,T); rs830972(G,A); rs12622085(A,G); rs113462565(C,T); rs16856796(T,C); rs2247506(T,C); rs34104660(G,T); rs13403197(C,A); rs2673170(G,C); rs2673169(G,C); rs80083165(T,C); rs140014046(C,T); rs140478629(G,C); rs145261747(G,A); rs10177180(A,G); rs56902755(C,T); rs59816206(G,C); rs55693114(A,C); rs10169533(T,A); rs3845730(G,A); rs10165679(A,G); rs2544376(T,C); rs3770621(A,G); rs2544377(G,A); rs13409736(C,G); rs2673167(C,G); rs2544378(C,T); rs2544379(G,A); rs116424504(C,T); rs2544380(G,T); rs2544381(G,C); rs2544382(T,C); rs10173013(A,G); rs74342879(A,G); rs75290491(G,T); rs10221870(C,A); rs3770623(C,T); rs3770624(A,C); rs2544383(A,T); rs72880424(A,C); rs2544384(T,C); rs861239(T,C); rs2229263(T,C); rs830974(T,C); rs73971880(G,A); rs57764549(C,T); rs830976(T,C); rs830977(C,G); rs830979(A,G); rs2673178(G,A); rs2673177(A,G); rs60889754(G,C); rs56217955(A,G); rs113818579(C,T); rs112297484(A,G); rs3845731(G,A); rs116400101(T,C); rs13006076(T,G); rs831025(T,A); rs80122464(A,G); rs3770630(T,C); rs6433115(T,C); rs831027(C,T); rs74505905(C,T); rs831029(G,C); rs78991977(A,G); rs831030(T,C); rs831031(A,G); rs57989581(C,A); rs831032(G,A); rs79811865(A,G); rs60911566(A,G); rs831034(C,T); rs10930352(T,C); rs11889511(C,G); rs115433692(C,T); rs6751001(C,T); rs146041621(A,G); rs61555954(T,C); rs73971892(C,A); rs145135773(A,G); rs60641214(A,T); rs115674907(C,T); rs831036(C,G); rs831037(G,A); rs831038(C,T); rs831039(T,C); rs3770636(T,G); rs3770637(T,C); rs3729573(T,C); rs116772184(C,G); rs2673171(A,G); rs145706481(T,C); rs3821129(T,C); rs2673172(G,T); rs2544390(C,T); rs3770641(A,T); rs6730118(A,G); rs2544392(T,C); rs79672267(C,T); rs4668134(T,A); rs2389558(C,T); rs4668135(C,A); rs6713072(C,T); rs75193630(C,A); rs10199321(C,T); rs2544393(T,C); rs10199676(G,T); rs2673151(T,C); rs6721930(G,C); rs3909274(C,G); rs2389557(G,A); rs76358518(C,T); rs11685268(C,A); rs830943(A,G); rs10192423(C,A); rs10195737(C,T); rs10198558(G,C); rs16856843(G,A); rs830948(G,A); rs75619091(T,C); rs830950(G,A); rs4668136(C,T); rs3845732(T,C) |
| ccdsGene name | CCDS2232.1 |
| CosmicCodingMuts gene | LRP2 |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 4036 |
| EntrezGene Description | low density lipoprotein receptor-related protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LRP2:NM_004525:exon56:c.G10804A:p.A3602T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6892 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P98164 |
| dbNSFP Uniprot ID | LRP2_HUMAN |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.031094 |
| ESP All MAF | 0.010534 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.00296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Weight loss
HEAD AND NECK:
[Eyes];
Diplopia, intermittent
RESPIRATORY:
Apneic episodes
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation
GENITOURINARY:
[Bladder];
Urinary retention
SKIN, NAILS, HAIR:
[Skin];
Diaphoresis
NEUROLOGIC:
[Central nervous system];
Insomnia, refractory;
Sleep impairment, progressive;
Dysautonomia;
Myoclonus;
Ataxia;
Dysarthria;
Dream enactment;
Somniloquism;
Dementia;
Thalamic neuronal loss, especially in the medial dorsal nucleus;
Brainstem may show neuronal loss
METABOLIC FEATURES:
Fever
MISCELLANEOUS:
Onset in adulthood;
Rapid course;
Death within 12 months
MOLECULAR BASIS:
Caused by mutation in the prion protein gene (PRNP, 176640.0010)
OMIM Title
*600073 LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2
;;GLYCOPROTEIN 330;;
MEGALIN
OMIM Description
DESCRIPTION
Lipoprotein receptor-related protein-2 (LRP2), also called
glycoprotein-330 or megalin (Farquhar, 1995), is part of the Heymann
nephritis antigenic complex with RAP (LRPAP1; 104225) (Farquhar et al.,
1995) and is a member of a family of receptors with structural
similarities to the low density lipoprotein receptor (LDLR; 606945).
CLONING
LRP2 was originally identified as the target antigen of Heymann
nephritis, a rat model of membranous glomerulonephritis. Its location in
clathrin-coated pits suggested that gp330 is an endocytic receptor.
Gp330 is expressed in specialized epithelia, including those of the
inner ear (Farquhar et al., 1995), neural tube, lung airway, epididymis,
yolk sac, glomeruli, and proximal renal tubules (Kerjaschki and
Farquhar, 1983; Chatelet et al., 1986; Buc-Caron et al., 1987).
Raychowdhury et al. (1989) sequenced a partial cDNA clone which clearly
established that gp330 is a member of the LDL receptor gene family.
Saito et al. (1994) reported the complete amino acid sequence of the
517,715-Da megalin protein. Hjalm et al. (1996) determined the
nucleotide sequence of human gp330. They reported that the deduced
4,655-amino acid mature protein has a molecular mass of approximately
519,636 Da and consists of a probable 25-amino acid N-terminal signal
peptide, an extracellular region of 4,398 amino acids, a single
transmembrane-spanning domain of 23 amino acids, and an intracellular
C-terminal region of 209 amino acids. Three types of cysteine-rich
repeats characteristic of the LDLR superfamily are present in human
gp330. In the extracellular region, there are a total of 36 LDLR
ligand-binding repeats, comprising 4 distinct domains, 16 growth factor
repeats separated by 8 YWTD spacer regions, and 1 epidermal growth
factor-like repeat. Hjalm et al. (1996) detected no consensus cleavage
sequence for the processing endoprotease furin. The intracellular tail
contains 2 copies of the F(X)NPXY coated-pit mediated internalization
signal characteristic of LDLR superfamily members, as well as
potentially functional motifs including several Src-homology 3
recognition motifs, one Src-homology 2 recognition motif for the p85
regulatory subunit of phosphatidylinositol 3-kinase, and additional
sites for protein kinase C, casein kinase II, and cAMP-/cGMP-dependent
protein kinase. There is approximately 77% amino acid identity between
human and rat gp330, with minor differences between the extra- and
intracellular regions.
GENE FUNCTION
In kidney tubule epithelial cells, gp330 has been shown to bind in vitro
to lipoprotein lipase and apolipoprotein E-enriched beta-VLDL,
suggesting a role for this receptor in lipoprotein metabolism. Kounnas
et al. (1995) showed that gp330 can bind apolipoprotein J/clusterin
(CLU; 185430) with high affinity. Cells that express gp330 can mediate
APOJ endocytosis, leading to its lysosomal degradation.
Moestrup et al. (1995) demonstrated that the antifibrinolytic
polypeptide, aprotinin, and the nephro- and ototoxic antibiotics,
aminoglycosides and polymyxin B, compete for binding of radioiodinated
urokinase-plasminogen activator inhibitor type-1 complexes to purified
rabbit gp330. (Aprotinin, also known as bovine pancreatic trypsin
inhibitor, is a 6-kD protein used clinically in acute pancreatitis and
antifibrinolytic therapy. Intravenously administered aprotinin
accumulates in the lysosomes of kidney proximal tubules and is only very
slowly degraded.) Analyses of mutant aprotinins expressed in
Saccharomyces cerevisiae demonstrated that basic residues are essential
for the binding to gp330 and renal uptake. The polybasic drugs also
antagonized ligand binding to the human alpha-2-macroglobulin receptor
(107770). However, the rapid glomerular filtration of the drugs
suggested kidney gp330 to be the quantitatively most important target.
Thus, a novel role of gp330 as a drug receptor was demonstrated.
Moestrup et al. (1995) stated that the insight into the mechanism of
epithelial uptake of polybasic drugs might provide a basis for design of
drugs with reduced toxicity. Farquhar (1995) reviewed briefly the
literature on LRP2/gp330/megalin in light of these new findings.
Megalin, a member of the low density lipoprotein receptor family
abundant in kidney proximal tubules, mediates endocytic uptake of
complexes between the steroid 25(OH) vitamin D3 and vitamin D-binding
protein (DBP; 139200) filtered in the glomeruli. The receptor-mediated
uptake is required to prevent loss of 25(OH)D3 in the urine and to
deliver the precursor for generation of 1,25(OH)2 vitamin D3, a potent
regulator of calcium homeostasis and bone turnover. Nykjaer et al.
(1999) showed that accordingly, megalin knockout mice lose DBP and
25(OH)D3 in the urine and develop severe vitamin D deficiency and bone
disease. Megalin binds a large number of structurally unrelated ligands,
and coreceptors may confer ligand specificity by sequestering and
presenting their cargo to megalin. For example, the gastric intrinsic
factor (IF; 609342)-B12 complex is taken up in the intestine by a tandem
receptor-mediated mechanism: the complex is first bound to a receptor,
cubilin (602997), anchored to the outer leaflet of the plasma membrane
possibly by an amphipathic helix, followed by endocytosis of cubilin and
its cargo mediated by megalin (summary by Nykjaer et al., 2001).
Marino et al. (1999) searched for antimegalin antibodies in 78 patients
with autoimmune and nonautoimmune thyroid diseases. Significantly
elevated values were found in 18 patients, including 13 of 26 (50%)
patients with autoimmune thyroiditis and 2 of 19 (11%) patients with
Graves disease (275000). Furthermore, 2 of 19 (11%) patients with
nontoxic goiter and 1 of 14 (7%) patients with differentiated thyroid
cancer had mean fluorescence intensity (MFI) values greater than 50.62,
associated with the presence of circulating antithyroid autoantibodies.
Binding of serum IgGs to L2 cells was significantly reduced by
coincubation with purified megalin in 15 of 18 (83%) positive patients,
and by a rabbit antimegalin antibody in 11 (61%) patients.
Immunoprecipitation experiments provided further and more conclusive
evidence that positive tests (MFI less than 50.62) for binding to L2
cells were attributable to serum antimegalin antibodies. The authors
suggested that further studies are needed to determine whether
antimegalin antibodies have pathogenic significance or diagnostic value
in autoimmune thyroid diseases.
Using yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, Nagai
et al. (2003) found that rat Arh (LDLRAP1; 605747) bound the first
FxNPxY motif of megalin. Arh colocalized with megalin in clathrin-coated
pits and in recycling endosomes in the Golgi region of rat L2 cells.
Upon internalization of megalin, megalin and Arh colocalized in
clathrin-coated pits, followed by their colocalization in early
endosomes and tubular recycling endosomes in the pericentriolar region,
and then by their reappearance at the cell surface. Expression of Arh in
canine kidney cells expressing megalin minireceptors enhanced
megalin-mediated uptake of lactoferrin (LTF; 150210), a megalin ligand.
Nagai et al. (2003) concluded that ARH facilitates endocytosis of
megalin and escorts megalin along its endocytic route.
Albumin (ALB; 103600) does not readily cross the renal glomerular
filter, and the fraction that does is reabsorbed by proximal tubule
cells via clathrin- and receptor-mediated endocytosis. Overstressing
this endocytic system with prolonged excess of albumin, which is often
associated with kidney disease, is injurious to proximal tubule cells
and leads to albumin-induced apoptosis. Caruso Neves et al. (2006)
identified megalin as the sensor that determines whether cells will be
protected or injured by albumin. Using a porcine kidney cell line, they
showed that megalin bound protein kinase B (PKB; see 164730) in a
phosphoinositide 3-kinase (see 601232)-independent manner, anchoring PKB
in the luminal plasma membrane. Low doses of albumin led to activation
of PKB and phosphorylation of Bad (603167), an antiapoptotic protein. In
contrast, pathophysiologic levels of albumin reduced the interaction
between PKB and megalin, resulting in reduced Bad phosphorylation and
albumin-induced apoptosis.
Hammes et al. (2005) found that megalin internalized complexes of sex
steroids bound to sex hormone-binding globulin (SHBG; 182205) in
cultured rat carcinoma cells. Following internalization, the carrier was
degraded in lysosomes while the steroids were released to induce
steroid-responsive genes. Lack of megalin expression in knockout mice
impaired descent of the testes and blocked vaginal opening, processes
critically dependent on sex steroid signaling.
MAPPING
Korenberg et al. (1994) designed degenerate oligonucleotide primers
based on conserved regions of gp330, LDLR, and LRP1 (107770) and used
homology-PCR cloning to isolate cDNAs encoding human gp330. They then
used the human gp330 cDNA as a probe in fluorescence in situ
hybridization to map the gene to the border of bands 2q24-q31 (Korenberg
et al., 1994). By isotopic in situ hybridization, Chowdhary et al.
(1995) found that LRP2 maps to 2q31-q32.1 in human and to 15q22-q24 in
pig.
MOLECULAR GENETICS
In 4 affected sibs with Donnai-Barrow syndrome (DBS; 222448) from the
United Arab Emirates, Kantarci et al. (2007) identified a homozygous
mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also
identified pathogenic mutations in the LRP2 gene in affected individuals
reported by Donnai and Barrow (1993) (600073.0004-600073.0006) and
Chassaing et al. (2003) (see, e.g., 600073.0002-600073.0003). In
addition, Kantarci et al. (2007) identified mutations in the LRP2 gene
(600073.0007; 600073.0008) in a Belgian child reported by Devriendt et
al. (1998) as having faciooculoacousticorenal syndrome (FOAR). Urine
samples from affected individuals showed proteinuria with spillage of
retinol-binding proteins (see RBP1, 180260) and vitamin D-binding
proteins (see DBP, 139200). The findings confirmed that FOAR and
Donnai-Barrow syndrome are the same entity.
For discussion of a possible association between variation in the LRP2
gene and susceptibility to autism, see AUTS5 (606053).
ANIMAL MODEL
Willnow et al. (1996) constructed gp330/megalin knockout mice by
targeted disruption of the murine gene. Homozygous knockout mice
manifested abnormalities in epithelial tissues including lung and kidney
that normally express the protein. The mice died perinatally from
respiratory insufficiency. In brain, impaired proliferation of
neuroepithelium produced a holoprosencephalic syndrome, characterized by
lack of olfactory bulbs, forebrain fusion, and a common ventricular
system. Because megalin can bind lipoproteins, these investigators
proposed that the receptor is part of the maternal-fetal lipoprotein
transport system and mediates the endocytic uptake of essential
nutrients in the postgastrulation stage.
Although most megalin-deficient mice die perinatally from
holoprosencephaly, approximately 1 in 50 of these mice survive to
adulthood. Nykjaer et al. (1999) used surviving knockout animals to
study the role of megalin in the renal proximal tubules. They found that
complexes of 25-(OH) vitamin D3 and the 58-kD vitamin D-binding protein
(DBP) are filtered through the glomerulus and reabsorbed by megalin into
the proximal tubular cells. Abnormal urinary excretion of 25-(OH)
vitamin D3 and DBP in megalin knockout mice resulted in severe vitamin D
deficiency and bone disease. Thus, Nykjaer et al. (1999) identified a
renal uptake pathway that is essential to preserve vitamin D metabolites
and to deliver the precursor for generation of 1,25-(OH)2 vitamin D3.
Using the megalin-deficient mouse model, Schmitz et al. (2002) found
that megalin is a major contributor to renal aminoglycoside accumulation
and nephrotoxicity. In normal mice, they found that the aminoglycoside
gentamicin accumulated only in the kidney and in urine; within the
kidney, it accumulated exclusively within proximal tubular cells.
Megalin-deficient mice excreted similar amounts of labeled gentamicin
but exhibited no renal accumulation.
Similarly, Leheste et al. (1999) demonstrated that megalin-deficient
mice exhibit tubular resorption deficiency and excrete low molecular
mass plasma proteins in the urine. Proteins excreted included small
plasma proteins that carry lipophilic compounds including vitamin
D-binding protein, retinol-binding protein, alpha-1-microglobulin, and
odorant-binding protein. Megalin normally binds these proteins and
mediates their cellular uptake. Urinary loss of carrier proteins
resulted in concomitant loss of lipophilic vitamins bound to the
carriers. Leheste et al. (1999) showed that patients with Fanconi
syndrome, who have low molecular mass proteinuria, also excrete
vitamin/carrier complexes. Thus, these results identified a crucial role
of the proximal tubule in retrieval of filtered vitamin/carrier
complexes and the central role played by megalin in this process.
Tramontano and Makker (2004) showed that rats immunized with a soluble,
secreted 563-amino acid N-terminal sequence of megalin encoded by a
baculovirus construct elicited a response consistent with active Heymann
nephritis (AHN). In contrast, bacterial or nonsecreted insect cell
proteins induced a milder antimegalin response and no disease. All 3
recombinant proteins were detectable in Western blot analysis using
rabbit antimegalin antiserum, although the insect proteins reacted
preferentially with autoantibodies from rats with AHN induced by native
megalin. Lectin blot analysis detected only the secreted protein,
suggesting that it is glycosylated. Tramontano and Makker (2004)
proposed that the megalin N-terminal domain contains epitopes sufficient
for a pathogenic autoimmune response and that conformational B-cell
epitopes, as well as glycosidic posttranslational modifications, are
involved in nephritogenicity.
Naccache et al. (2006) found that synectin (GIPC1; 605072)-null mice,
like megalin-null mice, showed proteinuria. Urine from synectin-null
mice contained retinol-binding protein (see RBP1; 180260), a known
megalin ligand. Megalin expression in proximal tubules of synectin-null
mouse kidneys was normal compared to wildtype, suggesting that megalin
recycling is defective in synectin-null mice. Naccache et al. (2006)
concluded that synectin is required for proper megalin trafficking in
vivo.
LINC01124
| dbSNP name | rs3749038(C,T); rs72885464(C,T); rs7563812(C,G) |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 440925 |
| snpEff Gene Name | SP5 |
| EntrezGene Description | long intergenic non-protein coding RNA 1124 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1501 |
SP5
| dbSNP name | rs2287109(T,G) |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 389058 |
| EntrezGene Description | Sp5 transcription factor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2617 |
DLX2
| dbSNP name | rs10930504(C,A) |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 1746 |
| EntrezGene Description | distal-less homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06749 |
OMIM Clinical Significance
Skel:
Craniodiaphyseal osteosclerosis
Radiology:
Hyperostosis mainly in forearms and lower legs;
Mild cranial sclerosis
Inheritance:
Autosomal dominant
OMIM Title
*126255 DISTAL-LESS HOMEOBOX 2; DLX2
;;TES1
OMIM Description
CLONING
To isolate genes involved in forebrain development, Porteus et al.
(1992) used subtractive hybridization of cDNA libraries to enrich for
cDNAs that are encoded by genes preferentially expressed in mouse
gestational day-15 telencephalon. In an attempt to find genes that are
candidates for the regulation of forebrain development, the subtracted
cDNA library was screened with probes homologous to the homeobox, a
conserved motif found in transcriptional regulators that often control
development. A novel cDNA, named Tes1, that encodes a homeodomain was
identified. Its sequence showed that Tes1 was a member of the
'Distal-less' family of homeodomain-encoding genes. Related by amino
acid homology within their homeodomains, the known members of the family
are Tes1, Dlx1 (600029), and Dll (a Drosophila melanogaster gene).
McGuinness et al. (1996) reported the DNA sequence of the human DLX2
gene and compared it to the murine gene. The deduced sequence of the
human DLX2 protein shows that the human and mouse DLX2 proteins are 92%
identical. The human DLX2 protein is 330 amino acids in length, while
the mouse DLX2 protein contains 332 amino acids. The introns have 63 to
71% identity. Domains identified in the human and mouse DLX2 protein
include a homeodomain and short stretches of homology to several
transcription factors.
GENE STRUCTURE
McGuinness et al. (1996) determined that the human DLX2 gene has 3
exons.
MAPPING
Ozcelik et al. (1992) determined the chromosomal location of the DLX2
gene in mouse and human. By Southern analysis of somatic cell hybrid
lines, they assigned the human locus to chromosome 2cen-q33 and the
mouse locus to chromosome 2. An EcoRI dimorphism was used for
recombinant inbred strain mapping in the mouse. The results placed the
Dlx2 gene near the Hox4 cluster on mouse chromosome 2.
Simeone et al. (1994) found that the DLX1 and DLX2 genes are localized
to chromosome 2q32 near the HOXD (formerly HOX4; 142980-142989) cluster
at 2q31, as had previously been suggested for the mouse. The mapping was
done by study of rodent/human hybrid cells and by fluorescence in situ
hybridization. The genes were found to be closely linked, i.e., about 8
kb apart, in an inverted convergent (i.e., tail-to-tail) configuration.
Zerucha et al. (2000) reported that the vertebrate Dlx1 and Dlx2 genes
are organized in a conserved tail-to-tail arrangement.
GENE FUNCTION
Using retroviral labeling in organotypic slice cultures of the embryonic
human forebrain, Letinic et al. (2002) demonstrated the existence of 2
distinct lineages of neocortical GABAergic neurons. One lineage
expresses DLX1 and DLX2 and MASH1 (100790) transcription factors,
represents 65% of neocortical GABAergic neurons in humans, and
originates from MASH1-expressing progenitors of the neocortical
ventricular and subventricular zone of the dorsal forebrain. The second
lineage, characterized by the expression of DLX1 and DLX2 but not MASH1,
forms around 35% of the GABAergic neurons and originates from the
ganglionic eminence of the ventral forebrain. Letinic et al. (2002)
suggested that modifications in the expression pattern of transcription
factors in the forebrain may underlie species-specific programs for the
generation of neocortical local circuit neurons and that distinct
lineages of cortical interneurons may be differentially affected in
genetic and acquired diseases of the human brain.
PITX2 (601542) and DLX2 are transcription markers observed during early
tooth development. Espinoza et al. (2002) demonstrated that PITX2 binds
to bicoid and bicoid-like elements in the DLX2 promoter and activates
this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2
associated with Axenfeld-Rieger syndrome (see 180500) provided the first
link of this homeodomain transcription factor to tooth development. One
mutation produces Axenfeld-Rieger syndrome with iris hypoplasia but
without tooth anomalies; this allele has a similar DNA binding
specificity compared to wildtype PITX2 and transactivates the DLX2
promoter. In contrast, a different PITX2 mutation produces Rieger
syndrome with the full spectrum of developmental anomalies, including
tooth anomalies; this allele is unable to transactivate the DLX2
promoter. Since DLX2 expression is required for tooth and craniofacial
development, the lack of tooth anomalies in the patient with iris
hypoplasia may be due to the residual activity of this mutant in
activating the DLX2 promoter. The authors proposed a molecular mechanism
for tooth development involving DLX2 gene expression in Axenfeld-Rieger
patients.
Thomas et al. (2000) identified regulatory regions of the mouse Dlx2
upstream sequence that drove epithelial but not mesenchymal expression
of Dlx2 in the first branchial arch. Epithelial expression of Dlx2 was
regulated by planar signaling by Bmp4 (112262), which was coexpressed in
distal oral epithelium. Mesenchymal expression was regulated by a
different mechanism involving Fgf8 (600483), which was expressed in the
overlying epithelium. Fgf8 also inhibited expression of Dlx2 in the
epithelium by a signaling pathway that required the mesenchyme. Thomas
et al. (2000) concluded that Bmp4 and Fgf8 maintain the strict
epithelial and mesenchymal expression of Dlx2 in the first branchial
arch of developing mice.
Zerucha et al. (2000) found that, like DLX1 and DLX2, the mouse and
human DLX5 (600028) and DLX6 (600030) genes, as well as their zebrafish
orthologs, Dlx4 and Dlx6, respectively, are arranged in a tail-to-tail
orientation. The intergenic region between zebrafish, mouse, and human
DLX5 and DLX6 is highly conserved, with 2 nucleotide stretches reaching
about 85% nucleotide identity among these species. Using knockdown and
reporter gene assays, Zerucha et al. (2000) showed that the zebrafish
Dlx4/Dlx6 intergenic region drove expression of mouse Dlx5 and Dlx6
reporter genes in the ventral thalamus/hypothalamus and in basal
telencephalon in transgenic mouse forebrain. Although their expression
patterns overlapped, the Dlx5 reporter was more highly expressed in the
subventricular zone, whereas the Dlx6 reporter was more highly expressed
in the mantle zone, similar to endogenous mouse Dlx5 and Dlx6. Activity
of the zebrafish intergenic enhancer was reduced in the subventricular
zone, but not in the mantle zone, in mice lacking Dlx1 and Dlx2,
consistent with decreased endogenous Dlx5 and Dlx6 expression. In
zebrafish forebrain, Dlx1 and Dlx2 were expressed in more immature cells
than Dlx4 and Dlx6. Cotransfection and DNA-protein binding experiments
with mouse and zebrafish proteins suggested that Dlx1 and/or Dlx2 are
required for Dlx5 and Dlx6 expression in forebrain and that this
regulation is mediated by the intergenic enhancer sequence.
Glutamic acid decarboxylases (see GAD1; 605363) are required for
synthesis of gamma-aminobutyric acid (GABA) in GABAergic neurons. Using
electroporation to introduce Dlx1, Dlx2, and Dlx5 plasmids in embryonic
mouse cerebral cortex, Stuhmer et al. (2002) found that Dlx2 and Dlx5,
but not Dlx1, induced expression of the glutamic acid decarboxylases
Gad65 (GAD2; 138275) and Gad67 (GAD1) to variable degrees. Dlx2 induced
expression of endogenous Dlx5, but not Dlx6. Dlx2 and Dlx5 induced
expression of a mouse Dlx5/Dlx6 intergenic region reporter in all brain
regions examined, whereas Dlx1 induced expression of the reporter in a
more restricted pattern.
MOLECULAR GENETICS
For a discussion of a possible association between variation in the DLX2
gene and susceptibility to autism, see AUTS5 (606053).
ANIMAL MODEL
Qiu et al. (1995) utilized information about the genomic structure of
the murine Dlx2 gene to carry out gene targeting experiments and made
deletions in the Dlx2 gene in mouse embryonic stem cells for use in
transgenic mice. They reported that heterozygous mice appeared normal
and homozygous mice died on the day of birth. The mutant mice had
altered differentiation of interneurons in the olfactory bulb and
abnormal morphogenesis of the cranial neural crest-derived skeletal
structures formed from the proximal first and second branchial arches,
causing cleft palate.
Kraus and Lufkin (2006) reviewed mouse studies of Dlx gene family loss-
and gain-of-function mutations and the role of Dlx homeobox genes in
craniofacial, limb, and bone development.
HOXD11
| dbSNP name | rs863678(G,T); rs6745764(G,A) |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 3237 |
| snpEff Gene Name | HOXD10 |
| EntrezGene Description | homeobox D11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3719 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142986 HOMEOBOX D11; HOXD11
;;HOMEOBOX 4F; HOX4F;;
Hox-4.6, MOUSE, HOMOLOG OF
HOXD11/NUP98 FUSION GENE, INCLUDED
OMIM Description
MAPPING
As reviewed by Acampora et al. (1989), the homeobox region 4 includes at
least 6 homeobox genes in 70 kb of DNA located on chromosome 2. The
order of the genes, from 5-prime to 3-prime, is HOX4F (HOXD11), HOX4D
(HOXD10; 142984), HOX4C (HOXD9; 142982), HOX4E (HOXD8; 142985), HOX4B
(HOXD4; 142981), HOX4A (HOXD3; 142980). HOX4A is homologous to mouse
Hox-4.1. HOX4B (HOXD4) through HOX4G (HOXD1; 142987) are homologous to
mouse genes Hox-4.2 through Hox-4.7, respectively. Hox-4.2 through
Hox-4.7 were previously thought to be Hox-5 genes.
GENE FUNCTION
For a review of the role of this gene in limb development, see Johnson
and Tabin (1997).
Using RT-PCR, Woo et al. (2010) found that differentiation of human
embryonic stem cells (hESCs) into mesenchymal stem cells (MSCs), and
then into adipocytes or osteoblasts, was accompanied by differential up-
and downregulation of several HOX genes. Woo et al. (2010) identified a
1.8-kb intergenic region between HOXD11 and HOXD12 (142988), which they
called D11.12, that showed high chromatin plasticity. D11.12 contains a
CpG island surrounded by YY1 (600013)-binding sites and a 237-bp region
that is highly conserved from humans to flies. In differentiating hESCs,
D11.12 was occupied by histone H3 (see 602810) with trimethylated lys27
(H3K27me3), but not by nucleosomes, and it showed recruitment of the
polycomb group (PcG) proteins BMI1 (164831) and SUZ12 (606245), which
are essential for accurate axial body patterning during embryonic
development. The recruitment of PcG proteins during differentiation of
MSCs into adipocytes, but not osteoblasts, appeared to be mediated by
YY1. The isolated D11.12 region repressed expression of a reporter gene,
and D11.12 lacking the 237-bp conserved sequence did not recruit BMI1,
SUZ12, or H3K27me3 or show repressor function. Knockdown of PcG proteins
was associated with gene activation, suggesting that D11.12 also has an
activator function in the absence of PcG proteins.
Sheth et al. (2012) used mouse genetics to analyze how digit patterning
(an iterative digit/nondigit pattern) is generated and showed that the
progressive reduction in Hoxa13 (142959) and Hoxd11-Hoxd13 (142989)
genes (hereafter referred to as distal Hox genes) from the Gli3
(165240)-null background results in progressively more severe
polydactyly, displaying thinner and densely packed digits. Combined with
computer modeling, their results argued for a Turing-type mechanism
underlying digit patterning, in which the dose of distal Hox genes
modulates the digit period or wavelength. The phenotypic similarity of
fish-fin endoskeleton patterns suggested that the pentadactyl state has
been achieved through modification of an ancestral Turing-type
mechanism.
CYTOGENETICS
Taketani et al. (2002) found that the HOXD11 gene is fused to the NUP98
gene (601021) in acute myeloid leukemia associated with the
translocation t(2;11)(q31;p15). Four genes had been found to be fused to
a variety of partner genes in AML: AML1 (RUNX1; 151385), MLL (159555);
MOZ (601408); and TEL (ETV6; 600618), in addition to NUP98. Among the
partner genes of the NUP98 gene, HOXA9 (142956), HOXD13 (142989), and
PMX1 (167420) are homeobox genes and part of their DNA binding
homeodomain is fused in-frame to a domain encoding the NH2-terminal FG
repeat of the NUP98 gene.
Taketani et al. (2002) found that in the t(2;11) translocation 2
alternatively spliced 5-prime NUP98 transcripts were fused in-frame to
the HOXD11 gene. The NUP98/HOXD fusion genes encode similar fusion
proteins, suggesting that NUP98/HOXD11 and NUP98/HOXD13 fusion proteins
play a role in leukemogenesis through similar mechanisms.
ANIMAL MODEL
Kmita et al. (2002) used targeted meiotic recombination to produce
unequal recombination between the Hoxd13, Hoxd12, and Hoxd11 loci in
mice. Furthermore, some deletions and duplications were engineered along
with other mutations in cis. Kmita et al. (2002) found that HOXD genes
competed for a remote enhancer that recognized the locus in a polar
fashion, with a preference for the 5-prime extremity. Modifications in
either the number or topography of HOXD loci induced regulatory
reallocations affecting both the number and morphology of digits. These
results demonstrated why genes located at the extremity of the cluster
are expressed at the distal end of the limbs, following a gradual
reduction in transcriptional efficiency, and thus highlight the
mechanistic nature of collinearity in limbs. Kmita et al. (2002) also
found that RXII, a DNA fragment that displays sequence conservation with
the chicken genome and is located between Hoxd13 and Evx2 (142991), was
required along with the Hoxd13 locus to implement the
position-dependent, preferential activation. Removal of both RXII and
the Hoxd13 locus abrogated quantitative collinearity.
By using an inversion of and a large deficiency in the mouse HoxD
cluster, Zakany et al. (2004) found that a perturbation in the early
collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a
loss of asymmetry. Ectopic Hox gene expression triggered abnormal Shh
(600725) transcription, which in turn induced symmetrical expression of
Hox genes in digits, thereby generating double posterior limbs. Zakany
et al. (2004) concluded that early posterior restriction of Hox gene
products sets up an anterior-posterior prepattern, which determines the
localized activation of Shh. This signal is subsequently translated into
digit morphologic asymmetry by promoting the late expression of Hoxd
genes, 2 collinear processes relying on opposite genomic topographies,
upstream and downstream Shh signaling.
Spitz et al. (2005) engineered mice to carry a 7-cM inversion within the
Hoxd cluster, with the breakpoint between the Hoxd11 and Hoxd10 genes.
Control fetuses showed Hoxd11 and Hoxd10 expressed in 2 distinct domains
in both the distal and proximal limb buds, in the genital bud, and in
the intestinal hernia. After separating the cluster, there was a strict
and precise partition of the expression domains. Hoxd11 was still
expressed in the genital and distal limb buds, but was no longer
transcribed in the proximal limb bud or in the intestinal hernia. Hoxd10
showed a complementary pattern, being expressed in the intestinal hernia
and proximal limb bud, but was absent from the distal limb and genital
buds. Spitz et al. (2005) concluded that the Hoxd genes are controlled
by a set of global enhancer sequences located on both sides of the Hoxd
locus.
The anterior to posterior (A-P) polarity of the tetrapod limb is
determined by the confined expression of SHH at the posterior margin of
developing early limb buds, under the control of HOX proteins encoded by
gene members of both the HoxA and HoxD clusters. Tarchini et al. (2006)
used a set of partial deletions in mice to show that only the last 4 Hox
paralogy groups can elicit this response: i.e., precisely those genes
whose expression is excluded from most anterior limb bud cells owing to
their collinear transcriptional activation. Deletion of Hoxd10, Hoxd11,
Hoxd12, and Hoxd13 led to Hoxd9 (142982) upregulation in posterior
cells; however, even a robust dose of Hoxd9 was unable to trigger Shh
expression, demonstrating that HOXD10-HOXD13 expression is essential to
elicit Shh expression. Tarchini et al. (2006) proposed that the limb A-P
polarity is produced as a collateral effect of Hox gene collinearity, a
process highly constrained by its crucial importance during trunk
development. In this view, the co-option of the trunk collinear
mechanism, along with emergence of limbs, imposed an A-P polarity to
these structures as the most parsimonious solution. This in turn further
contributed to stabilize the architecture and operational mode of this
genetic system.
HOXD4
| dbSNP name | rs1063656(C,T); rs1063657(C,T) |
| cytoBand name | 2q31.1 |
| EntrezGene GeneID | 3233 |
| snpEff Gene Name | HOXD3 |
| EntrezGene Description | homeobox D4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1414 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142981 HOMEOBOX D4; HOXD4
;;HOMEOBOX 4B; HOX4B;;
Hox-4.2, MOUSE, HOMOLOG OF;;
HOMEOBOX X
OMIM Description
CLONING
Mavilio et al. (1986) described the HOXD4 gene, but designated it
homeobox X. Northern blot analysis detected multiple embryonic
transcripts, which were differentially expressed in spinal cord, brain,
backbone rudiments, limb buds, and heart in 5- to 9-week-old human
embryos and fetuses in a striking organ- and stage-specific pattern.
MAPPING
The homologous mouse Hoxd4 gene was at first designated a Hox5 gene.
Oliver et al. (1989) found by study of interspecific somatic cell
hybrids that the cluster of so-called HOX5 genes map to human chromosome
2. By in situ hybridization, they found that the localization was
2q31-q32 with a peak of grains at 2q32.3. The HOX5 gene is now
designated HOXD4, as a member of the HOXD gene cluster on 2q31.
GENE FUNCTION
On the basis of the expression pattern of the HOXD4 gene, Mavilio et al.
(1986) suggested that in early mammalian development, homeobox genes may
exert a wide spectrum of control functions in a variety of organs and
body parts in addition to the spinal cord.
Van Scherpenzeel Thim et al. (2005) noted that an excess of skeletal
congenital anomalies had been reported among children with hematologic
malignancies, pointing to involvement of developmental genes, such as
those of the HOX gene family. They stated that HOX transcription factors
are known to be regulators of proliferation and differentiation of
hematopoietic cells.
MOLECULAR GENETICS
- Possible Association with Susceptibility to Acute Lymphoblastic
Leukemia
To explore the possibility that germline alterations of HOX genes might
be involved in childhood acute lymphoid malignancies, van Scherpenzeel
Thim et al. (2005) studied a cohort of 86 children with acute lymphoid
malignancy, 20 of them concurrently presenting a congenital anomaly of
the skeleton. They screened for nucleotide changes within the HOX genes
of paralogous groups 4 to 13 in the 20 patients with skeletal defects
and subsequently extended the HOX mutation screening to the other 66
children with a malignant lymphoproliferative disorder without skeletal
defects. Sixteen germline mutations were identified. Although 13 changes
were also observed in healthy controls, 3 variants were found
exclusively in acute lymphoid malignancy cases. In 2 children with acute
lymphoblastic leukemia, van Scherpenzeel Thim et al. (2005) identified a
germline glu81-to-val mutation in the HOXD4 gene (E81V; 142981.0001) in
association with other specific HOX variants of cluster D on 2q31-q37,
defining a unique haplotype. Functional analysis of the mouse Hoxd4
homolog revealed that mutant Hoxd4 protein had lower transcriptional
activity than wildtype protein in vitro. Van Scherpenzeel Thim et al.
(2005) concluded that the missense mutation results in a partial loss of
function, which may be involved in childhood acute lymphoblastic
leukemia.
ANIMAL MODEL
Zakany and Duboule (1999) used a Hoxd minicomplex in mice to show that
an overlapping, yet different, set of Hoxd genes contributes to the
formation of the iliocecal sphincter, which divides the small intestine
from the large bowel.
TTC30B
| dbSNP name | rs1046370(C,T); rs376295230(C,T); rs115971389(G,A); rs11694988(C,T); rs11695035(C,T); rs113625626(T,C) |
| cytoBand name | 2q31.2 |
| EntrezGene GeneID | 150737 |
| EntrezGene Description | tetratricopeptide repeat domain 30B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02112 |
TTC30A
| dbSNP name | rs16865446(T,C); rs10497498(T,G); rs75910863(T,C); rs3821003(A,G); rs3731804(A,G); rs3731806(C,T); rs3821004(C,T); rs6736390(T,C); rs3821005(T,C); rs16865448(C,A); rs13020788(C,A); rs16865449(C,T); rs144716682(C,T); rs57691380(A,G); rs10497497(G,T); rs61743008(A,G); rs61164370(C,T); rs61742858(G,T); rs3813257(T,G); rs3813256(A,G); rs59353759(C,T); rs111468773(G,A); rs80201392(G,T); rs75024536(A,T) |
| cytoBand name | 2q31.2 |
| EntrezGene GeneID | 92104 |
| EntrezGene Description | tetratricopeptide repeat domain 30A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1074 |
PMS1
| dbSNP name | rs5742933(G,C); rs1899026(T,C); rs72547269(T,G); rs1899024(T,G); rs5742938(G,A); rs4666784(G,T); rs4666785(A,G); rs5742949(C,T); rs5742952(T,C); rs5742955(A,G); rs4667307(T,C); rs5742956(T,C); rs142215845(A,G); rs5742959(T,C); rs5742960(T,C); rs74590453(G,A); rs5742962(G,A); rs5742963(A,G); rs5742965(G,A); rs5742969(C,T); rs3762545(G,C); rs75492913(G,C); rs147651707(C,T); rs1233262(A,G); rs114237316(A,T); rs139364500(C,G); rs5742976(A,T); rs1233265(G,T); rs5742991(A,G); rs5742993(G,A); rs5742997(T,C); rs5742998(A,G); rs1233299(A,C); rs115396123(G,A); rs77295675(T,C); rs62184283(G,A); rs114394215(A,T); rs5743003(A,T); rs1233302(C,A); rs5743008(G,T); rs5743015(A,G); rs2066457(T,C); rs5743017(C,T); rs1317751(A,C); rs1233267(T,A); rs5743024(T,C); rs3791770(C,T); rs5743028(T,G); rs114746364(G,A); rs62184286(G,A); rs1234834(T,C); rs58147864(A,G); rs73054335(A,G); rs5743030(G,A); rs5743032(A,C); rs1233270(C,A); rs1233271(A,C); rs73054336(T,C); rs1233272(A,G); rs73054339(G,A); rs1233273(A,G); rs13396619(A,T); rs1233274(T,C); rs3791773(G,C); rs5743044(A,G); rs73054342(G,A); rs1233276(A,G); rs1233278(C,T); rs79831338(A,G); rs1233282(G,A); rs5743048(C,T); rs5743052(G,A); rs1233284(G,A); rs1233285(T,C); rs1233286(A,C); rs1233288(C,T); rs1233290(T,G); rs5743057(G,A); rs1233291(G,C); rs3791778(T,C); rs3791779(A,G); rs73042330(A,G); rs186130568(G,A); rs182727972(C,T); rs1233297(C,T); rs5743061(G,T); rs5743063(C,T); rs5743067(A,G); rs5743072(A,G); rs5743076(C,T); rs5743078(G,A); rs5743080(A,G); rs1233241(A,G); rs2544056(G,A); rs1238785(A,G); rs144325704(A,G); rs1233242(G,A); rs1233243(T,C); rs1233244(A,G); rs2017410(T,A); rs1233245(G,A); rs1233246(C,T); rs1233248(G,A); rs1233249(T,G); rs6753164(T,C); rs115831793(T,A); rs1233251(T,C); rs74462916(T,C); rs12617253(T,A); rs143975783(A,G); rs5743090(C,T); rs5743091(A,G); rs1233252(A,G); rs1233253(T,A); rs5743100(G,T); rs1233254(G,C); rs1233255(A,C); rs1233257(A,G); rs1233258(T,C); rs4920657(T,A); rs148374504(A,T); rs12618262(C,T); rs5743112(C,A); rs5743113(A,G); rs113168867(C,T); rs256580(G,A); rs79600438(G,A); rs112579153(C,T); rs13404927(G,A); rs5743116(T,C); rs5743117(T,C); rs5743118(A,G); rs60386871(G,C); rs5743127(G,A); rs5743130(T,C); rs256572(T,C); rs10210548(T,C); rs73042345(T,C); rs735558(G,A); rs735559(T,C); rs733318(T,C); rs256571(C,T); rs13432549(G,C); rs73042348(A,G); rs147672988(C,A); rs10183082(T,C); rs256567(C,T); rs55795880(A,G); rs61736573(G,A); rs256564(G,A); rs5743161(T,C); rs5743164(T,C); rs256563(A,G); rs5743168(A,G); rs5743169(C,G); rs5743173(A,C); rs5743175(G,A); rs73042354(G,A); rs7595425(G,A); rs256562(T,C); rs6721150(A,T); rs1030136(C,T); rs256558(T,C); rs256556(T,G); rs5743176(C,T); rs5743187(A,C); rs256554(C,A); rs5743189(C,G); rs5743191(C,T); rs5743192(T,C); rs5743193(T,A); rs5743195(C,T); rs16832146(T,C); rs116380374(A,C); rs41561515(A,G); rs5743199(T,A) |
| ccdsGene name | CCDS2302.1 |
| cytoBand name | 2q32.2 |
| EntrezGene GeneID | 5378 |
| EntrezGene Description | PMS1 postmeiotic segregation increased 1 (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PMS1:NM_001128143:exon9:c.G2050A:p.E684K,PMS1:NM_001289408:exon9:c.G1639A:p.E547K,PMS1:NM_001289409:exon8:c.G1639A:p.E547K,PMS1:NM_000534:exon10:c.G2167A:p.E723K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6177 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q4VAL4 |
| ESP Afr MAF | 0.001589 |
| ESP All MAF | 0.000538 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002196 |
OMIM Clinical Significance
Neuro:
Hydrocephalus
Ears:
Branchiootorenal (BOR) syndrome
Eyes:
Duane syndrome
Muscle:
Trapezius muscle aplasia
Lab:
Deletion of 8q12.2-q21.2
Inheritance:
Autosomal dominant contiguous gene syndrome
OMIM Title
*600258 POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 1; PMS1
;;MISMATCH REPAIR GENE PMSL1; PMSL1
OMIM Description
CLONING
Genomic instability in tumor DNA is a feature of hereditary nonpolyposis
colon cancer (HNPCC; see HNPCC1, 120435). Two types of HNPCC had been
tied to mismatch repair of dinucleotide and trinucleotide repeat
sequences: MSH2 (609309) on 2p and MLH1 (120436) on 3p. MLH1 (120436) is
a homolog of the bacterial DNA mismatch repair gene mutL. In screening a
database of human genes identified by the expressed sequence tag (EST)
method (Adams et al., 1991), Papadopoulos et al. (1994) identified 2
other ESTs with homology to bacterial and yeast mutL genes. The 2 had
greatest homology to the yeast PMS1 gene and therefore the human genes
were designated PMS1 and PMS2 (600259). Sequence analysis of human PMS1
cDNA identified an open reading frame (ORF) of 2,795 bp thought to
encode a 932-residue protein with 27% identity to yeast PMS1. Sequence
analysis of the human PMS2 clone identified a 2,586-bp ORF thought to
encode an 862-residue protein with 32% identity to yeast PMS1.
Horii et al. (1994) isolated and analyzed the human counterparts of
yeast PMSL genes. DNA sequencing analyses indicated that human PMSL
genes constitute a multiple gene family.
MAPPING
Nicolaides et al. (1994) regionalized the PMS1 gene to 2q31-q33 by
fluorescence in situ hybridization.
MOLECULAR GENETICS
In 22 patients with a family history of HNPCC who did not have
demonstrable mutations in MSH2 (609309) or MLH1 (120436), Nicolaides et
al. (1994) used an in vitro synthesized protein (IVSP) assay to detect
mutations that result in an altered size of the protein product. They
detected a deletion in the PMS1 gene that resulted in exon skipping. Liu
et al. (2001) demonstrated that this patient carried a germline mutation
in the MSH2 gene consistent with her microsatellite instability-positive
tumor. Another relative who developed colorectal cancer carried the MSH2
mutation but not the PMS1 mutation, demonstrating that MSH2 predisposes
to colorectal cancer in this family. The form of HNPCC in this family
had been known as HNPCC3.
MARS2
| dbSNP name | rs7592344(C,T) |
| cytoBand name | 2q33.1 |
| EntrezGene GeneID | 92935 |
| EntrezGene Description | methionyl-tRNA synthetase 2, mitochondrial |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2342 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, due to auditory neuropathy
ABDOMEN:
[Gastrointestinal];
Hiatal hernia;
Paraesophageal hernia;
Sliding hernia;
Persistent vomiting
GENITOURINARY:
[Bladder];
Detrusor muscle hyperactivity;
Urinary urgency;
Urge incontinence;
Nocturia;
Hesitancy;
Diminished force of urine stream
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
[Central nervous system];
Spastic paraplegia;
Lower limb spasticity;
Upper limb spasticity;
Hyperreflexia;
Clonus;
Extensor plantar responses;
[Peripheral nervous system];
Decreased vibratory sense (less common);
Decreased joint position sense (less common)
LABORATORY ABNORMALITIES:
Hyperbilirubinemia, neonatal
MISCELLANEOUS:
Mean age at onset 15.2 years;
Genetic anticipation
OMIM Title
*609728 METHIONYL-tRNA SYNTHETASE 2; MARS2
;;METHIONINE tRNA SYNTHETASE, MITOCHONDRIAL;;
MITOCHONDRIAL METRS
OMIM Description
CLONING
Using primers designed from EST sequences, Spencer et al. (2004)
amplified the human mitochondrial methionyl-tRNA synthetase (mtMetRS)
gene (MARS2) from HL-60 cDNA. The gene encodes a deduced 593-amino acid
protein with an 18-amino acid mitochondrial import signal sequence. The
protein shares a high degree of identity with methionyl-tRNA synthetases
from other mammals, but is less well conserved with the corresponding
enzymes of lower eukaryotes and does not share considerable sequence
similarity to the human cytoplasmic MetRS. The human mtMetRS protein and
the E. coli homolog share 19% sequence identity. The domain organization
of human mtMetRS closely resembles that of the S. cerevisiae and C.
albicans mitochondrial MetRSs. Human mtMetRS contains the signature
sequences HIGH and KMSKS that are present in all class I synthetases as
well as many of the residues that have been proposed to contribute to a
universal core in MetRS of all organisms. Unlike many MetRSs, however,
it has no zinc-binding site and lacks a C-terminal extension thought to
be important in dimerization. Gel filtration studies indicated that
human mtMetRS functions as a monomer with an apparent molecular mass of
67 kD.
GENE FUNCTION
Using a recombinant human enzyme affinity-purified from E. coli, Spencer
et al. (2004) determined the kinetic parameters for mtMetRS
aminoacylation. Like several of the characterized mitochondrial
aminoacyl RSs, human mtMetRS can aminoacylate the heterologous E. coli
tRNA.
GENE STRUCTURE
Bonnefond et al. (2005) determined that MARS2 is a single-exon gene and
spans 1.8 kb.
MAPPING
Gross (2014) mapped the MARS2 gene to chromosome 2q33.1 based on an
alignment of the MARS2 sequence (GenBank GENBANK AB107013) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 54 patients from 38 French Canadian families with autosomal recessive
spastic ataxia-3 (SPAX3; 611390), most of whom were originally reported
by Thiffault et al. (2006), Bayat et al. (2012) identified complex
duplication rearrangements of the MARS2 gene. Haplotype analysis
indicated that 3 duplication events (609728.0001-609728.0003) involving
the MARS2 gene had occurred in their SPAX3 cohort. All patients carried
these rearrangements in the homozygous or compound heterozygous state,
and the rearrangements segregated with the disorders in the families; in
addition, a Brazilian patient with a similar phenotype also carried a
homozygous duplication. The rearrangements were found using PCR, array
CGH, sequencing, and Southern blot analysis. These data suggested that
homologies among repeat elements were responsible for complex
rearrangements, and Bayat et al. (2012) hypothesized that the numerous
repetitive elements present in this gene induced genomic instability and
caused template switching during DNA replication, as well as
recombination errors. Cultured patient cells showed reduced complex I
activity, increased levels of reactive oxygen species, and decreased
cell proliferation rates compared to controls. Patient cells had
increased levels of MARS2 mRNA, but decreased protein levels. The
paradoxical decrease in protein levels may be due to an RNAi-mediated
mechanism. Knockdown of MARS2 in HEK293 cells using shRNA caused some
decreases in mitochondrial translation, with significant decreases only
when protein levels were reduced beyond a certain level.
Genotype/phenotype correlation analysis showed that patients with the
Dup-Del rearrangement (609728.0001) tended to have an earlier age at
onset, as did patients who were homozygous for the Dup1 rearrangement
(609728.0002).
ANIMAL MODEL
Bayat et al. (2012) identified a Drosophila strain homozygous for
mutations in the Drosophila homolog of the human MARS2 gene. Mutant
flies had age-dependent degeneration of photoreceptors in the eye,
consistent with defects in neuronal function and survival. Other
features of these flies included reduced life span, muscle degeneration
with abnormal myofibrils and abnormal mitochondria, and impaired cell
proliferation in epithelial tissues. Cellular studies of mutant flies
showed defects in oxidative phosphorylation, increased reactive oxygen
species, and an upregulation of the mitochondrial unfolded protein
response.
FZD7
| dbSNP name | rs13034206(C,T); rs13034579(G,T); rs4673222(G,A); rs36057115(A,G) |
| cytoBand name | 2q33.1 |
| EntrezGene GeneID | 8324 |
| EntrezGene Description | frizzled family receptor 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1892 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Small birth length
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Frontal bossing;
[Eyes];
Large eyes;
Blindness;
Pale optic nerves;
Wide palpebral fissures;
Eyelid ptosis;
[Nose];
Low bridge;
[Mouth];
Tent-shaped mouth;
Prominent philtral groove;
Submucous cleft palate (rare)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Vascular ring;
Mitral regurgitation, mild;
[Vascular]
GENITOURINARY:
[Kidneys];
Duplicated kidneys (rare)
SKELETAL:
[Spine];
Kyphosis;
S-scoliosis of thoracic spine;
[Limbs];
Flexion contractures at both knees;
[Hands];
Postaxial polydactyly
MUSCLE, SOFT TISSUE:
Muscle atrophy
NEUROLOGIC:
[Central nervous system];
Diffuse hypotonia;
Axial hypotonia;
Developmental delay;
Mental retardation, profound;
No language;
Increased tendon reflex;
Seizures;
Megalencephaly;
Thick corpus callosum;
Mildly thin corpus callosum;
Enlarged white matter;
Focal pachygyria;
Polymicrogyria;
Wide Sylvian fissures with incomplete opercularization;
Ventricles slightly enlarged;
Hydrocephalus;
Cavum septi pellucidi;
Cavum vergae;
Small cavum septum;
[Behavioral/psychiatric manifestations];
Asperger-like features
NEOPLASIA:
Increased risk of medulloblastoma (rare)
MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol 3-kinase, regulatory
subunit 2 gene (PIK3R2, 603157.0001)
OMIM Title
*603410 FRIZZLED, DROSOPHILA, HOMOLOG OF, 7; FZD7
;;FZE3
OMIM Description
CLONING
The APC tumor suppressor gene (611731), which is frequently mutated in
human polyps and colon carcinomas, appears to interact with beta-catenin
(116806), leading to beta-catenin degradation; mutant APC proteins found
in colon carcinomas are defective in this activity and result in
beta-catenin stabilization. The function of APC is inhibited by
signaling pathways initiated through the secreted Wnt oncoprotein (see
164975). Members of the 'frizzled' (Fz) family of 7-transmembrane
proteins act as receptors for Wnt proteins. To examine a potential role
of Fz in the development and progression of human esophageal carcinoma,
Tanaka et al. (1998) used a strategy based on differential display of
RT-PCR products to isolate several Fz genes that are expressed in
esophageal carcinoma tissue. They determined that 1 gene, designated
FzE3, was specifically expressed in esophageal carcinoma tissue compared
with the adjacent normal mucosa. RT-PCR analysis revealed that FzE3
expression was generally correlated with the development of poorly
differentiated tumors with high metastatic potential. The predicted
574-amino acid FzE3 protein contains an N-terminal signal sequence, 10
cysteine residues typical of the cysteine-rich extracellular domain of
Fz family members, 7 putative transmembrane domains, and an
intracellular C-terminal tail with a PDZ domain-binding motif. FzE3
shares 78% protein sequence identity with FZD2 (600667). Based on
functional studies in esophageal carcinoma cells, Tanaka et al. (1998)
suggested that FzE3 gene expression may downregulate APC function and
enhance beta-catenin-mediated signals in poorly differentiated human
esophageal carcinomas.
Sagara et al. (1998) isolated FZD7 cDNAs from a fetal lung library. They
stated that the FZD7 sequence had 20 nucleotide differences compared to
that reported for FzE3 by Tanaka et al. (1998), resulting in 9 predicted
amino acid substitutions. Sagara et al. (1998) noted that the
substituted amino acids are conserved between FZD7 and mouse Mfz7. They
suggested that the sequence differences between FZD7 and FzE3 resulted
from misincorporations during the PCR-based cloning of FzE3. Northern
blot analysis revealed that FZD7 is expressed as 5- and 4-kb mRNAs in
several human tissues, with the highest expression in adult skeletal
muscle and fetal kidney.
GENE FUNCTION
The frizzled-dependent signaling cascade comprises several branches
whose differential activation depends on specific Wnt ligands, frizzled
receptor isoforms, and the cellular context. In Xenopus embryos, the
canonical beta-catenin (116806) pathway contributes to the establishment
of the dorsal-ventral axis. A different branch, referred to as the
planar cell polarity pathway, is essential for cell polarization during
elongation of the axial mesoderm by convergent extension. Winklbauer et
al. (2001) demonstrated that a third branch of the cascade is
independent of dishevelled (see 601365) function and involves signaling
through trimeric G proteins and protein kinase C (PKC, see 176960).
During gastrulation, frizzled-7-dependent PKC signaling controls
cell-sorting behavior in the mesoderm. Loss of zygotic frizzled-7
function results in the inability of involuted anterior mesoderm to
separate from the ectoderm, which leads to severe gastrulation defects.
Winklbauer et al. (2001) concluded that their results provide a
developmentally relevant in vivo function for the frizzled/PKC pathway
in vertebrates.
MAPPING
By fluorescence in situ hybridization, Sagara et al. (1998) mapped the
FZD7 gene to 2q33.
GCSHP3
| dbSNP name | rs1052190(G,A) |
| cytoBand name | 2q33.3 |
| EntrezGene GeneID | 100329109 |
| snpEff Gene Name | AC007383.5 |
| EntrezGene Description | glycine cleavage system protein H (aminomethyl carrier) pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4141 |
FZD5
| dbSNP name | rs115875814(C,T); rs6435388(C,G); rs3731568(A,C); rs698910(G,T) |
| cytoBand name | 2q33.3 |
| EntrezGene GeneID | 7855 |
| snpEff Gene Name | CCNYL1 |
| EntrezGene Description | frizzled family receptor 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEMATOLOGY:
Moderate-severe bleeding tendencies (epistaxis, menorrhagia, hemarthrosis,
easy bruisability);
Thrombocytopenia, mild;
Mildly decreased to low-normal platelet count (80-150 x 10(9)/L);
Bleeding time normal to mildly prolonged;
Increased platelet content of PLAU;
Degraded platelet alpha-granule proteins;
Reduced platelet aggregation response to adenosine 5'-diphosphate
(ADP);
Absent platelet aggregation response to epinephrine;
Normal platelet aggregation response to ristocetin and arachidonic
acid (AA);
Normal platelet fibrinogen;
Normal von Willebrand factor;
Normal thrombospondin;
Normal beta-thromboglobulin;
Normal platelet morphology;
Decreased multimerin
MISCELLANEOUS:
Bleeding is usually delayed-onset after challenge;
Good response to fibrinolytic inhibitors;
Prevalence of 1 in 300,000 in Quebec
MOLECULAR BASIS:
Caused by tandem duplication of the urinary plasminogen activator
gene (PLAU, 191840.0002)
OMIM Title
*601723 FRIZZLED, DROSOPHILA, HOMOLOG OF, 5; FZD5
;;FRIZZLED 5
OMIM Description
CLONING
Wang et al. (1996) cloned and sequenced a large family of mammalian
homologs of the Drosophila polarity gene 'frizzled' (see 600667). One of
these was a human gene, termed 'frizzled 5,' isolated from a retina cDNA
library. Wang et al. (1996) determined that this gene encodes a
polypeptide of 585 amino acids.
GENE FUNCTION
He et al. (1997) showed that human frizzled 5 is the receptor for the
Wnt5A (164975) ligand.
MAPPING
Wang et al. (1996) used interspecific backcross analysis to map the gene
to mouse chromosome 1 between the markers Ctla4 (123890) and Fn1
(135600), which is syntenic to human chromosome 2q33-q34.
ACADL
| dbSNP name | rs116282254(A,G); rs1155845(C,T); rs188344670(C,T); rs67549871(C,T); rs7604292(T,C); rs2539005(G,C); rs263682(T,C); rs263681(G,C); rs148890762(G,A); rs1509567(C,G); rs5000481(A,T); rs12474872(G,T); rs263680(G,A); rs263679(G,C); rs263678(A,G); rs1509568(T,C); rs263677(G,A); rs146511220(C,G); rs1509572(A,T); rs1509571(C,T); rs1509570(A,G); rs62202972(T,C); rs181648799(A,G); rs6726602(C,A); rs10179268(C,T); rs16844213(C,T); rs13415601(T,A); rs141509750(T,G); rs72990901(G,A); rs148490181(C,T); rs147197980(G,A); rs71350736(G,T) |
| ccdsGene name | CCDS2389.1 |
| cytoBand name | 2q34 |
| EntrezGene GeneID | 33 |
| EntrezGene Description | acyl-CoA dehydrogenase, long chain |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACADL:NM_001608:exon6:c.G722C:p.G241A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9873 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P28330 |
| dbNSFP Uniprot ID | ACADL_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 1.610e-03,5.694e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Skull];
Symmetrical, oval parietal bone defects;
Cranium bifidum
SKIN, NAILS, HAIR:
[Skin];
Scalp defect
MISCELLANEOUS:
Genetic heterogeneity (see PFM1, 168500)
OMIM Title
*609576 ACYL-CoA DEHYDROGENASE, LONG-CHAIN; ACADL
;;LCAD
OMIM Description
DESCRIPTION
The ACADL gene encodes long-chain acyl-CoA dehydrogenase, an enzyme
involved in fatty acid beta-oxidation. See also short- (ACADS; 606885),
medium- (ACADM; 607008), and very long- (ACADVL; 609575) chain acyl-CoA
dehydrogenases.
CLONING
Indo et al. (1991) cloned the human ACADL gene, which encodes a mature
400-residue polypeptide with a molecular mass of approximately 44.4 kD.
The human ACADL protein shares 85.3% identity with the rat protein.
Hinsdale et al. (1995) cloned the mouse Acadl gene. The sequence of the
cDNA indicated that the deduced amino acid sequence had a high degree of
homology to those of the rat and human. Northern analysis of multiple
tissues showed 2 bands in all tissues examined. They found a total of 3
distinct mRNAs for Acadl, all encoded by a single gene. The 3
transcripts differed in the 3-prime untranslated region due to use of
alternative polyadenylation sites.
MAPPING
Using a cDNA probe for in situ hybridization, Yang-Feng et al. (1991)
mapped the ACADL gene to chromosome 2q34-q35; also see Indo et al.
(1991).
Hinsdale et al. (1995) mapped the Acadl gene to mouse chromosome 1 by
interspecific backcross methods.
GENE FUNCTION
Using Western blot analysis, Goetzman et al. (2014) detected ACADL in
human alveolar type II pneumocytes (ATII), which are specialized cells
in the alveolar epithelium that synthesize and secrete pulmonary
surfactant.
MOLECULAR GENETICS
For discussion of a possible association between variation in the ACADL
gene and pulmonary surfactant dysfunction leading to sudden infant death
(see 265120), see 609576.0001.
ANIMAL MODEL
Guerra et al. (1998) found that mice with targeted inactivation of the
long-chain acyl-CoA dehydrogenase gene (Acadl) are sensitive to the
cold, similar to BALB/cByJ mice who have mutations in the Acads gene
(see 201470). The cold sensitivity resembled that described for mice
with a defect in nonshivering thermogenesis due to the targeted
inactivation of the brown adipocyte-specific mitochondrial uncoupling
protein gene, Ucp1 (113730). Mutations in both the Acadl and Acads genes
attenuated the induction of genes normally responsive to adrenergic
signaling in brown adipocytes, suggesting that the mutant mice had a
perturbation in the action of fatty acids as regulators of gene
expression.
Kurtz et al. (1998) produced a mouse model of LCAD deficiency with
severely impaired fatty acid oxidation. Matings between heterozygous
mice yielded an abnormally low number of Lcad heterozygous and
homozygous deficient offspring, indicating frequent gestational loss.
Lcad -/- mice that reached birth appeared normal, but had severely
reduced fasting tolerance with hepatic and cardiac lipidosis,
hypoglycemia, elevated serum free fatty acids, and nonketotic
dicarboxylic aciduria. Approximately 10% of adult Lcad -/- males
developed cardiomyopathy, and sudden death was observed in 4 of 75 Lcad
-/- mice. These results demonstrated the crucial roles of mitochondrial
fatty acid oxidation and LCAD in vivo.
Zhang et al. (2007) found that Lcad-knockout mice developed hepatic
steatosis associated with hepatic insulin resistance. The defect in
insulin action was associated with reduced Irs2 (600797)-associated
PI3-kinase (see 601232) activity and reduced Akt2 (164731) activation.
These changes were associated with increased protein kinase C-epsilon
(PRKCE; 176975) activity and an aberrant increase in diacylglycerol
content after insulin stimulation. The increase in diacylglycerol
concentration was caused by de novo synthesis of diacylglycerol from
medium-chain acyl-CoA after insulin stimulation. Zhang et al. (2007)
concluded that primary defects in mitochondrial fatty acid oxidation
capacity can lead to diacylglycerol accumulation and hepatic insulin
resistance.
In mice, Hirschey et al. (2010) demonstrated that Sirt3 (604481)
expression is upregulated during fasting in liver and brown adipose
tissues. During fasting, livers from mice lacking Sirt3 had higher
levels of fatty acid oxidation intermediate products and triglycerides,
associated with decreased levels of fatty acid oxidation, compared to
livers from wildtype mice. Mass spectrometry of mitochondrial proteins
showed that Lcad was hyperacetylated at lysine-42 in the absence of
Sirt3. Lcad was deacetylated in wildtype mice under fasted conditions
and by Sirt3 in vitro and in vivo; and hyperacetylation of LCAD reduced
its enzymatic activity. Mice lacking Sirt3 exhibited hallmarks of fatty
acid oxidation disorders during fasting, including reduced ATP levels
and intolerance to cold exposure. Hirschey et al. (2010) concluded that
their findings identified acetylation as a novel regulatory mechanism
for mitochondrial fatty acid oxidation and demonstrated that Sirt3
modulates mitochondrial intermediary metabolism and fatty acid use
during fasting.
Goetzman et al. (2014) found that Acadl-null mice had altered lung
mechanics, including increased stiffness, increased resistance to
inflation, and decreased compliance. Pulmonary lavage fluid from mutant
mice showed decreased surfactant phospholipid content compared to
control, and this was associated with decreased amounts of surfactant
and impaired surfactant function in surface tension tests. Serum albumin
was increased in lavage fluid, suggesting increased epithelial
permeability.
HISTORY
In an abstract, Kelly et al. (1991) reported the identification of a
mutation in the ACADL gene (gln303-to-lys; Q303K) in 3 unrelated
patients with LCAD deficiency (see VLCAD deficiency, 201475). No
follow-up on this abstract was reported.
CPS1
| dbSNP name | rs17552879(G,A); rs7607222(G,A); rs7580462(A,G); rs35003355(C,G); rs62203674(T,C); rs114119938(C,T); rs111599400(T,G); rs7569252(G,A); rs74908656(C,A); rs28485712(T,C); rs13005638(G,C); rs13031561(T,A); rs60112891(G,T); rs72932418(A,G); rs7603241(A,G); rs72932421(A,G); rs114314134(C,T); rs2370960(A,G); rs73071716(C,G); rs72932424(G,A); rs73071719(C,G); rs114460526(T,G); rs62203678(A,C); rs6713472(G,C); rs12463895(G,A); rs12468052(T,C); rs72932427(C,T); rs72932430(A,G); rs6749711(A,C); rs17771664(G,A); rs72932437(A,C); rs72932439(C,T); rs16844534(A,G); rs16844536(T,G); rs6725303(C,A); rs6725770(G,A); rs6725979(C,T); rs13016272(A,G); rs6729280(C,A); rs72932447(G,A); rs7580046(G,A); rs72932449(G,C); rs17822981(A,G); rs112314380(G,A); rs10932336(A,G); rs111841370(T,C); rs138298082(A,T); rs759689(C,A); rs759688(G,A); rs2007748(C,T); rs60428496(A,G); rs60981818(A,G); rs16844550(T,C); rs16844551(A,G); rs10804184(G,A); rs73071732(G,C); rs113136438(G,A); rs112213397(A,T); rs74937471(T,C); rs74552364(G,A); rs28391483(T,C); rs7571893(A,C); rs1509816(C,T); rs73071736(C,A); rs10932337(G,T); rs4672580(T,C); rs4672581(A,G); rs4672582(T,C); rs142177935(C,T); rs1858195(A,G); rs1858194(T,C); rs1858193(T,C); rs76903192(G,A); rs10191395(G,A); rs2160851(G,A); rs12619519(G,A); rs6752530(C,T); rs12694200(T,C); rs3845634(C,G); rs141085501(G,A); rs17772042(A,T); rs112719666(C,T); rs1468957(G,A); rs72934330(C,G); rs2370962(G,A); rs11696008(G,C); rs10211666(C,T); rs6712000(C,T); rs7599872(C,T); rs115070972(G,A); rs78421188(T,C); rs138138870(C,T); rs918234(T,C); rs918233(C,T); rs9941507(G,T); rs115051322(G,A); rs918232(A,G); rs191002357(A,C); rs1396957(T,G); rs112417548(C,A); rs2370963(A,T); rs148772630(C,T); rs112096182(C,G); rs1588365(A,G); rs72934339(A,G); rs13399079(G,A); rs7594883(T,C); rs6713369(C,G); rs10932339(T,C); rs72934342(C,A); rs10932340(C,T); rs1544717(T,A); rs3915695(C,T); rs4372818(T,C); rs3915694(A,G); rs189844173(G,A); rs3915693(C,T); rs1912267(T,C); rs10205168(A,G); rs112092198(A,G); rs1509820(G,A); rs1509819(A,G); rs6752320(T,A); rs59337803(T,C); rs13405091(G,A); rs10188695(G,A); rs7590759(G,A); rs10165084(A,C); rs10189047(C,T); rs2664239(T,C); rs2664238(T,C); rs111558515(C,T); rs2544312(C,A); rs12611623(G,A); rs139448426(A,G); rs111935420(G,A); rs2544311(A,G); rs111503281(A,G); rs16844579(A,G); rs115669804(C,T); rs2664237(G,A); rs10184280(T,C); rs112699771(C,T); rs2247029(G,A); rs138404781(C,A); rs2664236(G,A); rs12472153(T,C); rs2664234(T,A); rs112626750(A,G); rs111468596(G,A); rs981024(G,A); rs56098529(C,T); rs62203712(G,A); rs2664233(A,T); rs10490318(G,C); rs2664232(G,A); rs2544310(A,G); rs145275962(G,T); rs2664231(G,C); rs10490319(T,C); rs2544309(C,T); rs6711129(G,A); rs2247708(C,G); rs2544308(C,T); rs10932341(T,A); rs2544307(G,A); rs951878(T,A); rs2012564(A,G); rs2544306(G,A); rs2250976(T,G); rs183374606(A,G); rs2544305(C,G); rs112244504(T,G); rs7569730(G,A); rs72934370(C,T); rs189877223(C,G); rs3914067(C,T); rs28699076(A,G); rs11904031(C,T); rs10932342(G,T); rs6745362(T,C); rs12475210(G,T); rs7571548(G,A); rs2544304(A,G); rs2664230(A,G); rs7560638(A,G); rs10172081(C,G); rs150071496(A,G); rs4016619(C,T); rs77792726(C,T); rs6749355(G,A); rs6749597(G,T); rs2887913(A,C); rs112377572(G,T); rs113230810(T,A); rs16844619(A,C); rs9789405(C,T); rs12466705(G,A); rs6744672(G,A); rs17824552(T,C); rs16844625(G,A); rs113841387(T,G); rs2287604(A,G); rs2287602(A,G); rs10932343(C,T); rs10804185(T,G); rs12694201(T,G); rs13414563(C,T); rs2370997(G,C); rs2370998(G,A); rs10203439(A,T); rs10180357(G,T); rs13399140(C,T); rs143275693(C,T); rs6755648(G,A); rs71420801(A,G); rs7583733(A,G); rs7583822(A,G); rs191833499(C,T); rs12694202(T,C); rs6714124(C,T); rs7582951(T,G); rs12694203(T,C); rs7573258(G,A); rs6435577(A,G); rs149111290(C,T); rs13416489(C,T); rs61291087(A,G); rs33949976(A,C); rs13031200(A,G); rs10165443(C,T); rs28499505(A,T); rs4312427(A,T); rs7576225(C,T); rs7593211(T,C); rs10191702(T,C); rs10211372(C,T); rs13385991(G,A); rs6435578(A,G); rs4309518(G,A); rs137915289(C,T); rs2302911(A,G); rs150778667(C,T); rs1047883(A,G); rs2229589(C,T); rs10184633(C,T); rs181202377(T,A); rs144478691(C,T); rs113899268(A,G); rs10167325(A,T); rs113132447(C,A); rs188058513(A,G); rs4396646(G,A); rs79318518(G,A); rs12694204(A,G); rs7422569(G,A); rs7598448(T,A); rs7588072(C,A); rs11684318(C,T); rs71422704(A,T); rs9752757(T,C); rs6742717(C,A); rs6743023(G,A); rs6743156(G,A); rs112724994(A,G); rs12991680(C,T); rs9288418(G,A); rs2371000(T,C); rs75782806(C,A); rs112393887(C,G); rs2371001(A,G); rs183537859(A,T); rs6721139(T,A); rs6734696(A,G); rs6721477(T,G); rs2277909(T,C); rs13010668(T,G); rs2371002(G,A); rs147454471(G,A); rs13415932(A,C); rs2287599(C,G); rs142700264(A,G); rs11680040(C,T); rs11685945(T,G); rs11685955(T,A); rs74583594(A,G); rs7607205(T,G); rs10176085(T,G); rs2887914(C,A); rs10804186(T,C); rs12468557(C,T); rs7568329(T,A); rs7607412(C,A); rs112302136(C,T); rs12694205(A,G); rs12694206(T,A); rs7558276(G,T); rs7587701(A,G); rs7587791(A,C); rs2371005(A,T); rs13401425(G,A); rs55930720(T,A); rs28469042(G,A); rs7606346(G,A); rs2302909(G,T); rs2302908(C,T); rs13409110(G,A); rs13408918(C,T); rs13383683(A,C); rs17775057(A,G); rs13429886(T,C); rs13391067(A,G); rs115591026(G,A); rs13416810(G,A); rs2371007(C,G); rs4356603(G,A); rs16844718(G,C); rs6724941(C,A); rs16844728(A,T); rs186899938(G,A); rs954499(C,T); rs10469763(T,C); rs61131132(C,G); rs10195256(C,T); rs2371008(G,C); rs2371009(G,A); rs34976026(A,T); rs4673540(C,T); rs76340296(G,A); rs58927072(C,T); rs2371010(C,A); rs13022335(C,T); rs2371011(A,G); rs79992801(G,A); rs34449727(G,T); rs3213784(A,T); rs113612213(T,C); rs11686101(A,G); rs62203741(C,T); rs11681045(T,C); rs7599931(T,G); rs10179212(T,C); rs6435579(C,T); rs191208274(T,C); rs2287598(A,G); rs6435580(C,T); rs2270476(G,A); rs2371013(C,A); rs6726148(A,T); rs7567836(T,C); rs77268067(A,G); rs12990908(C,T); rs4673542(C,T); rs116573496(A,T); rs114159907(G,A); rs4233981(G,C); rs142501744(C,G); rs2287596(C,T); rs10932347(A,G); rs181229489(G,T); rs78989095(C,A); rs12995914(G,A); rs16844777(C,T); rs4673544(T,C); rs16844781(C,G); rs4142154(G,A); rs16844782(A,G); rs115814250(A,G); rs4672587(A,G); rs142412414(A,G); rs10179039(A,G); rs10932348(A,G); rs79585301(A,G); rs11902281(G,A); rs4567871(C,T); rs4325692(A,G); rs116262806(T,A); rs1047891(C,A); rs6720137(A,G); rs6748782(C,A); rs6749137(G,A); rs17832175(A,G); rs715(T,C); rs10932349(C,G); rs7684(T,G); rs12476133(C,G) |
| ccdsGene name | CCDS46506.1 |
| cytoBand name | 2q34 |
| EntrezGene GeneID | 1373 |
| EntrezGene Description | carbamoyl-phosphate synthase 1, mitochondrial |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CPS1:NM_001122633:exon28:c.G3373A:p.A1125T,CPS1:NM_001875:exon27:c.G3355A:p.A1119T,CPS1:NM_001122634:exon17:c.G2002A:p.A668T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7427 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q59HF8 |
| dbNSFP KGp1 AF | 0.0114468864469 |
| dbNSFP KGp1 Afr AF | 0.0508130081301 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.047208 |
| ESP All MAF | 0.015993 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.261e-03,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Dolichocephaly;
[Face];
Prominent forehead;
[Eyes];
Amblyopia;
Ptosis;
Cataracts;
Microcornea;
[Nose];
Beaked nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum
SKELETAL:
[Skull];
Craniosynostosis;
[Feet];
Hypoplasia of the halluces;
Agenesis of the halluces;
Metatarsus adductus
NEUROLOGIC:
[Central nervous system];
Delayed development may occur;
Cognitive deficits may occur
MISCELLANEOUS:
Intrafamilial variability
OMIM Title
+608307 CARBAMOYL PHOSPHATE SYNTHETASE I; CPS1
VENOOCCLUSIVE DISEASE AFTER BONE MARROW TRANSPLANTATION, SUSCEPTIBILITY
TO, INCLUDED
OMIM Description
DESCRIPTION
Carbamoyl phosphate synthetase I (EC 6.3.4.16) is the rate-limiting
enzyme that catalyzes the first committed step of the hepatic urea cycle
by synthesizing carbamoyl phosphate from ammonia, bicarbonate, and 2
molecules of ATP (summary by Haberle et al., 2011).
The mitochondrial isozyme is designated CPS I and the cytoplasmic enzyme
CPS II. CPS II is part of a multifunctional enzyme, called the CAD
trifunctional protein of pyrimidine biosynthesis (CAD; 114010), which
has been mapped to 2p21.
CLONING
Lusty (1978) purified the carbamyl phosphate synthetase I enzyme from
rat liver mitochondria, and Pierson and Brien (1980) purified it from
human liver.
Haraguchi et al. (1991) cloned and sequenced a cDNA for CPS1 from a
human liver cDNA library. The full-length sequence encodes a 1,500-amino
acid precursor polypeptide with a deduced molecular mass of 165 kD that
shows 94.4% amino acid homology to the rat enzyme precursor. Hoshide et
al. (1993) corrected the cDNA nucleotide sequence for CPS1 reported by
Haraguchi et al. (1991). The 165-kD proenzyme is produced in the
cytoplasm and transported into the mitochondria where it is cleaved into
its mature 160-kD form. CPS1 is expressed in the liver and in epithelial
cells of the intestinal mucosa.
Nyunoya et al. (1985) characterized the rat CPS1 gene.
GENE STRUCTURE
Summar et al. (2003) determined that the CPS1 gene contains 38 exons.
Haberle et al. (2003) also reported the complete sequencing and
structure of the CPS1 gene.
MAPPING
The structural gene for carbamoyl phosphate synthetase was assigned to
the short arm of chromosome 2 using a cDNA gene probe in human-rodent
somatic cell hybrids (Adcock et al., 1984). Adcock and O'Brien (1984)
assigned CPS1 to 2p by somatic cell hybrid analysis using a 1.6-kb cDNA
fragment.
Summar et al. (1995) used fluorescence in situ hybridization for
physical mapping and CEPH families for linkage mapping of the CPS1 gene
to 2q34-q35. By fluorescence in situ hybridization, Hoshide et al.
(1995) mapped the CPS1 gene to 2q35.
Helou et al. (1997) mapped the mouse homolog to chromosome 1.
GENE FUNCTION
CPS I catalyzes the conversion of ammonia and bicarbonate to carbamyl
phosphate. The reaction requires a cofactor, N-acetylglutamate (NAG; see
608300).
Mitochondrial nucleoids are large complexes containing, on average, 5 to
7 mitochondrial DNA (mtDNA) genomes and several proteins involved in
mtDNA replication and transcription, as well as related processes.
Bogenhagen et al. (2008) had previously shown that CPS1 was associated
with native purified HeLa cell nucleoids. Using a formaldehyde
crosslinking technique, they found that CPS1 copurified with mtDNA and
was a core nucleoid protein.
MOLECULAR GENETICS
Summar et al. (2003) identified 14 polymorphisms in the CPS1 gene.
- Carbamoyl Phosphate Synthetase I Deficiency
In a newborn Japanese girl with CPS I deficiency (237300), Hoshide et
al. (1993) identified a homozygous missense mutation in the CPS1 gene
(608307.0001), causing a splice site alteration that resulted in a 9-bp
deletion in the coding region of the mRNA.
In a male infant who died at the age of 11 days from a severe form of
CPS I deficiency, Finckh et al. (1998) identified a homozygous mutation
in the CPS1 gene (608307.0002). The parents were consanguineous.
In 6 patients with CPS I deficiency, Haberle et al. (2003) identified 9
novel mutations in the CPS1 gene.
In 16 of 18 Japanese patients with a clinical diagnosis of CPS I
deficiency, Kurokawa et al. (2007) identified 25 different mutations in
the CPS1 gene, including 19 novel mutations (see, e.g.,
608307.0007-608307.0009). Two patients with confirmed CPS I deficiency
had later onset at ages 13 and 31 years, respectively.
Genotype/phenotype correlations were not observed.
By analyzing tissue and DNA samples from 205 individuals with CPS I
deficiency spanning 24 years, Haberle et al. (2011) identified 192
different pathogenic mutations in the CPS1 gene, including 130 novel
mutations. When combined with previously reported mutations, it was
clear that most mutations (90%) were private, occurring in only 1 family
each. The few recurrent mutations tended to occur at CpG dinucleotides.
Most missense mutations occurred around exon 24, at the boundary between
both homologous halves of the region encoding the 120-kD catalytic
moiety of the enzyme. Mutations also clustered at the bicarbonate and
carbamate phosphorylation domains, at the NAG cofactor binding domain,
and at the interface between the large and small subunit-like moieties.
Comparative modeling using the E. coli enzyme showed that the location
of missense mutations correlated with evolutionary importance and
included internal residues, suggesting that they affect protein folding.
- Neonatal Pulmonary Hypertension, Susceptibility to
Pearson et al. (2001) reported an association between a T1405N
polymorphism in the CPS1 gene (608307.0006) and plasma levels of
arginine/citrulline with a risk of persistent pulmonary hypertension in
newborns (PHN; 615371). The same polymorphism was implicated as a risk
factor for venoocclusive disease after bone marrow transplantation
(Summar et al., 2004).
EVOLUTION
In E. coli, carbamoyl phosphate synthetase is a dimer of 2 structurally
different polypeptides, alpha and beta (Trotta et al., 1971). Nyunoya et
al. (1985) found that the amino acid sequence in the rat CPS1 protein is
homologous to the sequences of carbamyl phosphate synthetase of E. coli
and yeast, and encompasses the entire sequences of both the small and
large subunits of the E. coli and yeast enzymes. The data provided
strong evidence that these genes were derived from common ancestral
genes, and that the mammalian CPS1 gene arose from fusion of loci from 2
separate ancestral units or duplication (see also Schofield, 1993).
LOC101928103
| dbSNP name | rs12478396(G,A); rs16852821(G,A); rs112488105(A,C); rs717548(G,A); rs6744811(A,C); rs76233667(C,T); rs146407277(A,T); rs73989374(G,C); rs73084588(T,C); rs111996226(A,T); rs10190149(T,C); rs2166459(C,G); rs12617559(A,G); rs10176190(T,G); rs145090987(T,G); rs1838807(C,G); rs2372426(A,G); rs58351646(A,G); rs141544997(C,T); rs72946209(C,T); rs150881255(T,C); rs140038482(T,G); rs2053709(G,A); rs2053708(T,C); rs58483425(A,G); rs58219082(A,G); rs113323749(A,G); rs16852840(T,C); rs6758178(T,C); rs4673907(A,G); rs6705457(T,C); rs9989787(T,A); rs2121287(T,C); rs2121286(T,C); rs1550842(A,T); rs73989378(C,A); rs7591408(C,T); rs60650883(G,A); rs9789570(T,G); rs79456983(G,A); rs115509888(G,A); rs10176354(C,T); rs113400653(A,G); rs73989379(T,C); rs73989380(C,A); rs73989381(A,G); rs79499158(A,G); rs73989382(C,G); rs34560341(C,T); rs10182771(C,T); rs73989384(A,C); rs13427566(A,G); rs13031306(C,G); rs34330242(G,A); rs148940750(G,T); rs4571053(C,G); rs4234008(G,A); rs4234009(C,T); rs10193901(T,C); rs116049063(C,T); rs73989386(G,A); rs115610029(C,G); rs6728252(A,T); rs77856887(T,A); rs6757370(C,T); rs6728876(A,G); rs113255258(C,T); rs113352821(A,G); rs4672730(T,A); rs73987704(C,T); rs4673910(C,T); rs140743188(A,G); rs56124285(T,C); rs1446363(A,T); rs1446362(G,A); rs1530537(A,G); rs1530536(T,C); rs77258021(C,T); rs2121283(C,T); rs114770257(C,T); rs2121282(G,A); rs2121281(G,A); rs79364910(G,A); rs6730415(T,G); rs1446361(G,A); rs55967731(C,A); rs146632191(G,A); rs77362163(A,G); rs2888310(C,T); rs12233219(G,A); rs34962596(T,C); rs1963469(C,T); rs62202034(T,A); rs115282736(T,G); rs1026020(A,G); rs75218197(G,A); rs2166458(C,T); rs73987707(G,A); rs146853805(G,A); rs148550759(A,G); rs73987711(T,C); rs12472016(T,C); rs78475343(A,G); rs13009232(T,G); rs13431492(G,A); rs6704642(A,C); rs115563179(C,T); rs76336966(G,C); rs62202037(G,A); rs79096661(T,A); rs2592234(A,C); rs13029929(T,C); rs10932574(G,A); rs11677798(C,T); rs2592233(A,G); rs2766515(C,T); rs1831029(G,A); rs73987713(A,G); rs2592232(G,A); rs1831028(A,G); rs112804746(C,T); rs4428014(G,A); rs146407208(C,A); rs2592231(T,C); rs150667981(A,G); rs12468492(C,T); rs12472805(T,C); rs777300(C,A); rs192344265(C,T); rs1083274(A,G); rs145027637(T,G); rs115455118(T,C); rs1083275(T,C); rs140351314(G,A); rs140330724(G,C); rs1083276(A,G); rs189032963(A,G); rs78153064(C,G); rs1083277(G,C); rs79025198(A,G); rs1083278(C,A); rs2766513(C,T); rs2592223(G,A); rs777303(C,T); rs777304(T,C); rs777305(A,G); rs777307(G,A); rs777308(C,A); rs777309(G,A); rs73987715(G,T); rs777311(C,A); rs62202047(C,T); rs895457(C,T); rs13030316(A,G); rs1031219(T,C); rs707285(G,A); rs12994273(C,T); rs777313(A,G); rs75846391(G,A); rs777314(T,C); rs777317(C,G); rs62202048(C,T); rs777320(G,A); rs777321(A,G); rs777323(A,G); rs73987717(T,C); rs57694645(A,G); rs777325(T,G); rs10173839(T,C); rs149204601(A,G); rs10932575(G,C); rs78085738(A,G); rs190853294(A,T); rs777327(C,A); rs1326750(A,G); rs777328(A,G); rs777329(A,G); rs372824939(A,G); rs10932576(C,G); rs73987730(C,G); rs73987732(G,A); rs10175925(T,C); rs62202052(C,T); rs16852904(T,C); rs115459277(A,G); rs13401954(T,C); rs12474361(A,G); rs10498024(C,T); rs10498026(G,A); rs144638409(G,A); rs114318638(C,T); rs16852918(C,T); rs10169626(G,A); rs10182158(T,G); rs6733692(T,G); rs78408124(C,A); rs7602290(A,G); rs114801476(G,T); rs4673915(A,C); rs943294(T,C); rs737453(T,C); rs11890522(G,A); rs11902136(A,G); rs724183(A,G); rs7560809(A,C); rs11899149(T,C); rs10932577(T,G); rs10166035(A,G); rs116040465(G,A); rs11895311(T,C); rs13396950(G,A); rs2038960(T,C); rs10932578(G,A); rs59235410(G,A); rs10205105(A,G); rs2225062(C,A); rs141381234(A,G); rs1575927(T,C); rs1575926(G,A); rs10197966(T,C); rs9288501(A,G); rs55796204(G,A); rs187559610(A,G); rs13389211(A,C); rs13389629(A,G); rs943293(T,C); rs149912289(C,A); rs1536420(T,G); rs11898828(G,A); rs73987736(A,G); rs10201174(C,G); rs2372428(T,C); rs7605128(G,A); rs75431027(C,T); rs147758894(C,T); rs4361128(G,A); rs75690174(A,G); rs1887168(A,G); rs1887167(G,A); rs73987737(G,A); rs55766838(C,G); rs12478515(G,A); rs12465305(A,C); rs12477655(T,G); rs73987738(T,G); rs16852954(T,G); rs16852956(A,G); rs1952224(G,A); rs115338005(C,T); rs60055523(G,A); rs73987739(G,A); rs1326749(C,T); rs111356357(A,G); rs1831027(A,C); rs73987740(A,T); rs765161(G,A); rs1831026(A,C); rs6739178(A,G); rs12614543(T,C); rs138325659(T,G); rs4672731(C,T); rs142762175(G,A); rs4672732(C,T); rs6435865(A,C); rs6756170(A,G); rs6737675(A,G); rs2094280(T,C); rs10932579(A,G); rs7578941(T,G); rs7565159(G,C); rs73987742(G,T); rs112321420(G,A); rs6718099(C,T); rs6718199(C,T); rs10196159(A,G); rs2148532(T,C); rs4673917(C,A); rs58493437(T,C); rs113232116(C,T); rs11683658(C,T); rs11683799(C,G); rs115735199(T,A); rs114105962(A,G); rs11901973(T,C); rs78198970(C,T); rs113876729(T,A); rs79896015(G,T); rs76334788(G,C); rs10932580(A,G); rs11895717(C,T); rs12612329(A,G); rs1326751(A,T); rs111985420(T,A); rs4672734(A,G); rs7563922(A,G); rs7566779(A,G); rs12614872(A,G); rs12694349(T,C); rs17426207(C,T); rs1409611(A,C); rs7578759(A,G); rs10208498(G,A); rs943295(A,C); rs146834697(G,A); rs146431242(T,C); rs4672735(G,A); rs143205680(T,C); rs148271569(A,G); rs4673918(A,T); rs76560247(C,G); rs1409612(G,A); rs111989918(T,A); rs138088617(A,G); rs147480122(A,G); rs3738884(G,A); rs33932423(T,C); rs148800117(T,C); rs4381786(A,C); rs116269691(G,A); rs148909327(C,T); rs2225064(A,G); rs2209657(G,A); rs2225063(C,T); rs141872037(A,G); rs11679293(G,T); rs3920623(G,A); rs144312353(G,C); rs200488843(C,T); rs4673920(C,T); rs2274412(G,A); rs143277541(A,G); rs17879522(C,T); rs148307792(T,C); rs77010286(C,A); rs73088462(T,A); rs113250545(T,C); rs56102372(A,G); rs4672738(T,G); rs4672739(C,T); rs6758451(A,G); rs11694964(A,G); rs13013391(T,C); rs10153765(C,T); rs10153865(T,C); rs16852981(C,G); rs10171780(A,G); rs10208383(T,C); rs6760738(T,C); rs10498027(G,A); rs10084163(T,G); rs1980847(G,A); rs17492577(T,C); rs16852994(G,A); rs10498028(T,C); rs13423832(T,C); rs956132(C,T); rs956133(A,G); rs10498029(T,C); rs4673923(G,A); rs4673924(A,G); rs4672740(C,T); rs4672741(G,A); rs16853007(T,G); rs114385349(T,C); rs12998290(T,C) |
| ccdsGene name | CCDS33372.1 |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 101928103 |
| snpEff Gene Name | ABCA12 |
| EntrezGene Description | uncharacterized LOC101928103 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | ABCA12:NM_173076:exon52:c.C7631T:p.T2544I,ABCA12:NM_015657:exon44:c.C6677T:p.T2226I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5424 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86UK0 |
| dbNSFP Uniprot ID | ABCAC_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.001999 |
| ESP Eur/Amr MAF | 0.002442 |
| ExAC AF | 0.001399 |
PKI55
| dbSNP name | rs207897(C,T); rs114287004(C,T); rs207898(C,T); rs697447(C,G) |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 150967 |
| EntrezGene Description | DKFZp434H1419 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2686 |
TNS1
| dbSNP name | rs3747(T,G); rs9579(T,G); rs111276801(A,G); rs1559595(C,T); rs11898620(T,C); rs4674215(G,A); rs3791979(T,C); rs3088214(G,A); rs1063281(C,T); rs182851722(G,A); rs75156815(A,G); rs78909193(G,A); rs74897150(A,G); rs2552520(C,T); rs2571461(T,G); rs972229(T,G); rs972230(A,G); rs972231(T,C); rs116716385(A,G); rs34831382(A,G); rs35136714(T,C); rs1035671(C,T); rs918950(G,A); rs1035672(G,A); rs62183753(C,T); rs1035673(T,C); rs11692329(C,T); rs1991161(C,T); rs76043829(G,A); rs13026442(A,G); rs78297591(G,A); rs75274377(T,G); rs11695740(G,A); rs2161967(T,G); rs2161968(G,A); rs2161969(G,A); rs41383244(A,G); rs35955543(C,T); rs2552523(G,T); rs2552524(C,T); rs4674216(C,T); rs4674217(G,C); rs12476660(C,G); rs13424201(C,A); rs12694422(A,G); rs34291329(G,A); rs2571445(A,G); rs2552525(C,T); rs2571442(A,G); rs34144104(C,T); rs149785174(G,A); rs12466972(T,C); rs13394030(T,C); rs62183755(G,C); rs76857989(G,A); rs2571434(T,C); rs13022333(T,C); rs34681173(G,A); rs34572447(T,G); rs35833791(G,A); rs35949566(G,A); rs75793379(C,T); rs2552527(T,G); rs34085205(C,G); rs11897815(T,C); rs7582112(T,C); rs80062932(G,A); rs4674218(T,C); rs2571435(C,T); rs2571436(C,A); rs2552528(T,G); rs2571437(G,A); rs2571438(G,A); rs2571439(G,A); rs6729308(G,A); rs6744219(T,C); rs6729330(C,T); rs6729561(G,A); rs55694913(T,G); rs16858298(A,G); rs10188605(A,G); rs4674219(C,A); rs10165160(C,G); rs3796028(G,A); rs2571440(T,C); rs2552529(A,G); rs10168611(G,A); rs10168454(C,A); rs2552530(A,G); rs114121710(C,T); rs11677276(G,A); rs56724923(C,G); rs2571443(T,C); rs138731715(T,C); rs2571444(T,C); rs16858320(G,A); rs145753994(G,A); rs2571449(T,C); rs1008835(A,G); rs73992637(T,C); rs1122986(G,A); rs1122987(T,G); rs2571452(T,G); rs2552534(T,C); rs55764538(C,T); rs1000980(T,C); rs1000979(C,T); rs1000978(C,A); rs2571454(G,A); rs918951(G,T); rs918952(T,C); rs11899788(T,C); rs41497947(T,G); rs55840817(C,A); rs55763753(T,C); rs4643515(G,C); rs1364637(A,G); rs1364638(A,G); rs1364639(G,A); rs1364640(G,C); rs929936(C,T); rs929937(T,C); rs190853596(C,T); rs59997697(C,T); rs12474617(G,A); rs7566566(G,C); rs7566504(C,T); rs1559590(G,A); rs929938(T,C); rs58343915(A,G); rs987336(T,C); rs4519498(A,G); rs987337(T,G); rs987338(C,A); rs987339(G,C); rs55763335(A,G); rs1004814(C,T); rs1364641(G,A); rs1364642(A,G); rs3796033(G,A); rs200009331(G,A); rs7587518(A,G); rs11902263(T,G); rs11902267(T,C); rs10170040(A,T); rs12998464(C,T); rs16858371(C,T); rs3791978(A,C); rs3791977(G,A); rs3791976(T,A); rs3791975(A,G); rs17733847(A,C); rs3791973(A,G); rs56096813(A,G); rs3791972(A,G); rs3791970(A,G); rs3791969(T,A); rs3791968(A,C); rs3828291(C,T); rs2059409(C,T); rs3791967(A,G); rs3791966(G,A); rs3791965(G,A); rs3791964(G,A); rs3791963(G,A); rs3791962(T,C); rs7594104(A,C); rs7581920(T,C); rs7568256(G,A); rs3791961(A,C); rs3791960(C,A); rs3791959(C,G); rs3791958(G,A); rs3791957(A,G); rs3791955(A,C); rs6725482(C,A); rs3791953(C,A); rs3828288(T,A); rs370452071(C,T); rs749386(G,A); rs749387(T,C); rs1424915(G,A); rs6760625(T,G); rs2373223(A,G); rs116791662(G,A); rs3791950(C,A); rs1863132(A,G); rs1863133(T,C); rs2113768(G,C); rs56203324(T,C); rs77147469(A,G); rs17790748(A,G); rs17790760(A,G); rs1035674(A,G); rs17790821(G,A); rs112941127(G,A); rs3791949(T,C); rs3828287(G,A); rs10204348(A,G); rs17790839(T,A); rs2042541(T,C); rs2042542(A,G); rs13407109(G,T); rs1991162(T,C); rs3791948(C,T); rs3791947(A,G); rs1424916(T,C); rs1424918(G,A); rs4674220(G,A); rs3791944(A,T); rs3791943(A,G); rs890048(C,T); rs56886627(A,G); rs11898107(C,T); rs890049(C,T); rs57512321(T,C); rs55718126(C,T); rs2288164(G,T); rs10199795(G,A); rs7421896(A,G); rs2888521(C,T); rs3791941(G,A); rs2303383(T,C); rs2373224(T,C); rs13427550(G,T); rs13390002(T,C); rs13428061(G,A); rs12694423(T,C); rs4672853(G,A); rs4674222(G,A); rs3791940(G,A); rs2288165(T,C); rs6742531(A,G); rs6729299(T,A); rs6714429(G,A); rs6714587(G,A); rs12990490(C,T); rs2288166(C,T); rs2288167(G,C); rs2288168(T,A); rs10211238(T,C); rs3791938(C,T); rs10174633(T,C); rs76131299(G,A); rs975441(C,T); rs6436018(A,G); rs1345989(T,G); rs56217129(C,A); rs1808466(A,G); rs79783479(C,A); rs4334476(C,T); rs2288169(G,C); rs148779339(C,T); rs183946516(T,A); rs75951541(A,G); rs184284069(A,C); rs1559594(G,A); rs1549590(A,C); rs111905134(G,C); rs3791936(T,G); rs3791935(G,A); rs3791934(C,T); rs7600493(G,A); rs111728465(C,A); rs1863798(A,G); rs2288170(C,T); rs78693972(G,A); rs4674223(C,T); rs4674224(C,T); rs6739316(G,C); rs4674225(C,A); rs3791930(A,T); rs3791929(A,G); rs1863799(G,A); rs3791928(G,A); rs3791927(C,A); rs732660(G,A); rs6436019(T,C); rs3791926(G,A); rs6755375(C,T); rs12612462(T,C); rs66515744(T,C); rs73990612(T,A); rs3791924(C,T); rs3791923(G,A); rs113495808(A,G); rs3791922(C,T); rs78798799(C,T); rs918947(C,T); rs918948(C,T); rs3828282(C,G); rs73990627(G,A); rs12623944(G,A); rs12623951(C,A); rs10165875(C,T); rs4672855(T,C); rs3828281(C,A); rs10199479(G,A); rs73990629(C,A); rs890051(C,T); rs1863796(G,A); rs28403309(T,C); rs2888530(C,A); rs13426335(G,A); rs13022785(C,T); rs890052(G,A); rs35855182(C,T); rs35597949(C,A); rs16858459(G,C); rs77510646(G,A); rs3791919(A,G); rs3791918(T,C); rs3791917(C,T); rs3791916(A,G); rs3791914(G,C); rs3828280(T,C); rs2288172(C,G); rs2288173(G,C); rs2288175(A,G); rs2288176(T,A); rs367671365(C,T); rs7590152(A,G); rs11883929(C,T); rs11883936(C,T); rs11890796(T,C); rs6731585(T,C); rs74467849(C,A); rs78313063(G,A); rs76649728(T,C); rs3791913(A,G); rs114952420(C,G); rs6725612(G,A); rs62182181(T,A); rs34134227(C,G); rs4672859(C,T); rs10191332(T,C); rs150404355(T,G); rs61088813(G,A); rs116484130(T,C); rs35593161(C,T); rs10197671(A,G); rs74842411(T,A); rs1427669(T,G); rs4672861(C,T); rs4674231(G,A); rs1427668(G,C); rs7585036(C,G); rs56372827(A,T); rs11895557(G,A); rs78232484(T,C); rs74572248(T,C); rs76694365(C,G); rs3791910(G,A); rs4672862(C,T); rs1365964(G,A); rs1365963(G,C); rs3791907(T,A); rs113077169(T,G); rs11894803(C,T); rs61203898(A,G); rs77385765(C,T); rs4674232(C,T); rs72951918(C,A); rs112931109(C,T); rs980675(A,G); rs1006980(C,G); rs3791906(T,C); rs3791905(T,C); rs185466056(G,A); rs3791904(T,C); rs13389514(T,A); rs1820321(G,C); rs3828278(T,G); rs3791902(A,C); rs6705554(C,T); rs735061(T,C) |
| ccdsGene name | CCDS2407.1 |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 7145 |
| EntrezGene Description | tensin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TNS1:NM_022648:exon24:c.C3281T:p.P1094L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7824 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PF55 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001383 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Weight loss
HEAD AND NECK:
[Eyes];
Diplopia, intermittent
RESPIRATORY:
Apneic episodes
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation
GENITOURINARY:
[Bladder];
Urinary retention
SKIN, NAILS, HAIR:
[Skin];
Diaphoresis
NEUROLOGIC:
[Central nervous system];
Insomnia, refractory;
Sleep impairment, progressive;
Dysautonomia;
Myoclonus;
Ataxia;
Dysarthria;
Dream enactment;
Somniloquism;
Dementia;
Thalamic neuronal loss, especially in the medial dorsal nucleus;
Brainstem may show neuronal loss
METABOLIC FEATURES:
Fever
MISCELLANEOUS:
Onset in adulthood;
Rapid course;
Death within 12 months
MOLECULAR BASIS:
Caused by mutation in the prion protein gene (PRNP, 176640.0010)
OMIM Title
*600076 TENSIN 1; TNS1
;;TENSIN; TNS
OMIM Description
DESCRIPTION
Tensin is an actin-binding protein that is concentrated in some
submembranous cytoskeletal focal contacts (Weigt et al., 1992). In
addition to its 3 actin-binding domains, the 200-kD tensin protein
contains an Src homology 2 (SH2) motif that mediates protein-protein
contacts and is shared by a variety of signal transduction molecules. In
addition, tensin can bind to phosphotyrosine-containing proteins and can
itself be phosphorylated, suggesting that tensin may be a link between
the cytoskeleton and a signal transduction pathway. Tensin
phosphorylation occurs during cell adhesion to extracellular matrix
proteins.
CLONING
Using avian tensin as probe, Chen et al. (2000) obtained overlapping
clones of tensin from human heart and bovine pericyte cDNA libraries.
The deduced 1,735-amino acid protein has a calculated molecular mass of
185 kD. Human and bovine tensins share 82% amino acid identity. In
addition to the actin-binding domains and SH2 domain, tensin contains a
region similar to PTEN (601728) and a 9-amino acid sequence that is
repeated 4 times. Northern blot analysis revealed a major 10-kb
transcript expressed in most tissues, with highest levels in heart,
skeletal muscle, kidney, and lung. Heart and skeletal muscle also
expressed a 9-kb transcript. Western blot analysis revealed an apparent
molecular mass of 220 kD, and mutation analysis revealed that the
discrepancy between the calculated and the apparent molecular masses was
due to the reduced electrophoretic mobility of the central region of the
tensin polypeptide. Expression of tensin in mouse fibroblasts resulted
in staining at focal adhesions.
GENE FUNCTION
Katz et al. (2000) presented evidence that overexpression of mammalian
tensin activates both the JNK (601158) and p38 MAPK (600289) pathways.
Tensin-mediated JNK activation was independent of the activities of Rac
(602048) and Cdc42 (116952), but did depend on Sek (601335).
Chen et al. (2002) determined that stable overexpression of both
tensin-1 and -2 (TENC1; 607717) in HEK293 cells promoted cell migration
on fibronectin (135600) in a cell migration assay. Fibroblasts from
tensin-1-null mice migrated significantly slower than their normal
counterparts in the cell migration assay, and tensin-2 expression was
not upregulated to compensate for loss of tensin-1 function.
Chen et al. (2000) found that tensin expression was reduced or absent in
several prostate and breast cancer cell lines, while the levels of talin
(186745) and focal adhesion kinase (600758) remained at normal levels.
They also found that tensin is a substrate for a focal adhesion
protease, calpain II (114230), and that incubation of cells with a
calpain inhibitor prevented tensin cleavage and induced morphologic
change. Chen et al. (2002) hypothesized that cleavage of tensin and
other focal adhesion constituents by calpain disrupts maintenance of
normal cell shape.
GENE STRUCTURE
Chen et al. (2002) determined that the tensin gene contains 33 exons and
spans about 150 kb. Exon 6 contains the putative start codon.
MAPPING
Jankowski and Gumucio (1995) demonstrated that, in the mouse, genes for
tensin, villin (193040), and desmin (125660) are closely linked on
chromosome 1. This region is homologous to human chromosome 2; in the
human, the desmin gene maps to 2q35 and the villin-1 gene to 2q35-q36.
Jankowski and Gumucio (1995) used a rat DNA probe to study human/rodent
somatic cell hybrids and obtained results consistent with location of
the human TNS gene on chromosome 2. Homology of synteny would suggest
that it is located in the 2q35-q36 region.
ANIMAL MODEL
Lo et al. (1997) generated tensin-null mice. These mice appeared normal
and healthy for several months, but eventually developed cystic kidneys.
Progressive cyst formation led to kidney degeneration and death from
renal failure. The authors concluded that tensin is not necessary for
mouse embryogenesis, but it is required for the maintenance of normal
renal function.
CXCR2P1
| dbSNP name | rs73082355(A,G); rs180703996(G,A); rs6725761(A,C); rs1593782(A,G); rs73082358(C,G); rs6758271(G,A); rs59564632(A,G); rs3181380(G,A); rs60743553(A,C); rs16858606(T,C); rs114610787(C,A) |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 285180 |
| EntrezGene Symbol | RUFY4 |
| snpEff Gene Name | RUFY4 |
| EntrezGene Description | RUN and FYVE domain containing 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09183 |
CXCR1
| dbSNP name | rs2234671(C,G) |
| ccdsGene name | CCDS2409.1 |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 3577 |
| EntrezGene Description | chemokine (C-X-C motif) receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CXCR1:NM_000634:exon2:c.G827C:p.S276T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P25024 |
| dbNSFP Uniprot ID | CXCR1_HUMAN |
| dbNSFP KGp1 AF | 0.114468864469 |
| dbNSFP KGp1 Afr AF | 0.264227642276 |
| dbNSFP KGp1 Amr AF | 0.0939226519337 |
| dbNSFP KGp1 Asn AF | 0.0944055944056 |
| dbNSFP KGp1 Eur AF | 0.0422163588391 |
| dbSNP GMAF | 0.1143 |
| ESP Afr MAF | 0.195188 |
| ESP All MAF | 0.101492 |
| ESP Eur/Amr MAF | 0.053488 |
| ExAC AF | 0.091 |
OMIM Clinical Significance
Immunology:
Immune suppression;
Control of suppressor T cell generation
Inheritance:
Autosomal dominant
OMIM Title
*146929 CHEMOKINE, CXC MOTIF, RECEPTOR 1; CXCR1
;;INTERLEUKIN 8 RECEPTOR, ALPHA; IL8RA;;
INTERLEUKIN 8 RECEPTOR, TYPE 1; IL8R1
OMIM Description
CLONING
Interleukin-8 (IL8; 146930) is a proinflammatory cytokine involved in
chemoattraction and activation of neutrophils. Holmes et al. (1991)
isolated a cDNA encoding an IL8 receptor, IL8RA, from human neutrophils.
The deduced amino acid sequence of IL8RA showed that it belongs to the
superfamily of receptors that couple to guanine nucleotide-binding
proteins (G proteins). The sequence is 29% identical to that of
receptors for the other neutrophil chemoattractants, fMet-Leu-Phe and
C5a.
GENE FUNCTION
Palter et al. (2001) characterized the IL8 system, which includes IL8,
its receptors IL8RA and IL8RB (146928), and its degradative enzyme
aminopeptidase N (151530), in the human fallopian tube by
immunohistochemistry. IL8 was found in the human fallopian tube
predominantly in the epithelial cells and was present in greater amounts
in the distal compared with the proximal tube. IL8RA and IL8RB localized
in the tube in similar patterns. Aminopeptidase N was found in tubal
stromal tissue at the epithelial-stromal border and perivascularly. The
authors concluded that the IL8 system may be an active component of
tubal physiology and that aminopeptidase N may limit the systemic
effects of epithelial IL8.
Weathington et al. (2006) reported that the collagen- or extracellular
matrix (ECM)-derived PGP peptide shares sequence and structural homology
with neutrophil chemokines, such as CXCL1 (155730) and CXCL2 (139110).
In vivo studies in mice and in vitro studies using human cells showed
that PGP was chemotactic for neutrophils. PGP chemotactic activity could
be blocked by antibodies to CXCR1 and CXCR2 (IL8RB) in vivo and in
vitro, and neutrophils failed to accumulate in Cxcr2 -/- mice after PGP
challenge. Mass spectrometric analysis showed that mouse airways
inflamed after exposure to lipopolysaccharide produced PGP peptides,
resulting in neutrophil recruitment. Chronic exposure to PGP caused
alveolar enlargement and right ventricular hypertrophy in mice.
Weathington et al. (2006) found that individuals with chronic
obstructive pulmonary disease (COPD; see 606963) had detectable PGP in
bronchoalveolar lavage fluid. They concluded that PGP activity links ECM
degradation with neutrophil recruitment in airway inflammation.
Hartl et al. (2007) showed that IL8 promoted killing of Pseudomonas
aeruginosa through CXCR1, but not CXCR2. Bacterial killing and CXCR1
expression were significantly reduced in bronchoalveolar lavage (BAL)
and induced sputum neutrophils in patients with cystic fibrosis (CF;
219700) and, to a lesser extent, in patients with chronic obstructive
pulmonary disease (COPD; see 606963) and bronchiectasis, regardless of
P. aeruginosa infection status. The loss of CXCR1 expression and
bacterial killing was greater in older CF patients. Inhibition of serine
proteases in BAL inhibited or prevented CXCR1 loss. CXCR1 cleavage
released glycosylated CXCR1 fragments that stimulated IL8 production via
TLR2 (603028). Inhalation of alpha-1-antitrypsin (PI; 107400) by CF
patients decreased the abundance of free elastase, increased CXCR1 and
CD35 (CR1; 120620) expression on airway neutrophils, improved bacterial
killing, and reduced P. aeruginosa numbers in sputum. Hartl et al.
(2007) concluded that CXCR1 cleavage and its functional consequences
represent an important pathophysiologic mechanism in CF and other
neutrophilic airway diseases.
MAPPING
Morris et al. (1992) mapped the IL8RA gene to chromosome 2q35. Mollereau
et al. (1993) assigned the IL8RA gene to the same region by in situ
hybridization. Lloyd et al. (1993) assigned both the IL8RA and the IL8RB
genes to chromosome 2 by polymerase chain reaction amplification and by
Southern analysis of a panel of human/rodent somatic cell hybrid DNAs.
The IL8R genes were further localized by in situ hybridization to 2q35.
MOLECULAR GENETICS
Vasilescu et al. (2007) identified a CXCR1 haplotype (CXCR1-Ha;
146929.0001) carrying 2 SNPs that resulted in nonsynonymous amino acid
changes: 92T-G (dbSNP rs16858811), which caused a met31-to-arg change
(M31R) in the N-terminal extracellular domain, and 1003C-T (dbSNP
rs1658808), which caused an arg335-to-cys change (R335C) in the
C-terminal intracellular domain. Flow cytometric, RT-PCR, and Western
blot analysis showed that expression of CXCR1-Ha in different cell lines
led to reduced expression of CD4 (186940) and CXCR4 (162643) compared
with cell lines transfected with the alternative haplotype. Human
immunodeficiency virus (HIV)-1 (see 609423) isolates preferentially
using the CXCR4 receptor were less efficient in infecting cells
expressing CXCR1-Ha than those expressing the alternative haplotype.
Patients infected with HIV-1 who progressed rapidly to acquired
immunodeficiency syndrome (AIDS) were significantly less likely to have
CXCR1-Ha compared with patients who progressed slowly to AIDS. Vasilescu
et al. (2007) concluded that the CXCR1-Ha allele protects against rapid
progression to AIDS by modulating CD4 and CXCR4 expression.
CATIP-AS1
| dbSNP name | rs3845833(C,T); rs7608923(C,A); rs144442656(C,T) |
| ccdsGene name | CCDS2414.1 |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 375307 |
| EntrezGene Symbol | C2orf62 |
| snpEff Gene Name | C2orf62 |
| EntrezGene Description | chromosome 2 open reading frame 62 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CATIP:NM_198559:exon8:c.C816T:p.P272P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.009642 |
| ESP Afr MAF | 0.008398 |
| ESP All MAF | 0.003152 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.999 |
LINC00608
| dbSNP name | rs114379371(T,G); rs359964(G,A) |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 151300 |
| snpEff Gene Name | FEV |
| EntrezGene Description | long intergenic non-protein coding RNA 608 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0101 |
GLB1L
| dbSNP name | rs180863263(C,T); rs72955452(C,T); rs116252189(C,T); rs148493267(G,A); rs192758062(G,A); rs73991428(A,T); rs10208108(G,A); rs55778922(C,T); rs10211319(G,A); rs115974036(T,C); rs3755049(A,G); rs3755050(A,C); rs11552796(T,C); rs35328001(C,T); rs10194492(A,G) |
| ccdsGene name | CCDS2437.1 |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 79411 |
| EntrezGene Description | galactosidase, beta 1-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GLB1L:NM_001286427:exon8:c.C691T:p.R231C,GLB1L:NM_024506:exon11:c.C961T:p.R321C,GLB1L:NM_001286423:exon11:c.C961T:p.R321C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7805 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6UWU2-2 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.002724 |
| ESP All MAF | 0.000923 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.000431 |
MIR4268
| dbSNP name | rs4674470(C,T) |
| cytoBand name | 2q35 |
| EntrezGene GeneID | 100422959 |
| snpEff Gene Name | AC008281.1 |
| EntrezGene Description | microRNA 4268 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2052 |
| ExAC AF | 0.658 |
KCNE4
| dbSNP name | rs13031825(G,A); rs10201907(T,C); rs12621643(T,G); rs10189762(C,G); rs3795884(T,C); rs41313545(G,A); rs116696122(A,T); rs10208429(T,C); rs10172380(A,G) |
| cytoBand name | 2q36.1 |
| EntrezGene GeneID | 23704 |
| EntrezGene Description | potassium voltage-gated channel, Isk-related family, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0101 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
ABDOMEN:
[External features];
Intrahepatic cholestasis;
Jaundice;
Hepatomegaly;
Giant cell hepatitis shown on biopsy;
Nonspecific inflammation shown on biopsy;
Fibrosis shown on biopsy;
Cirrhosis;
Progressive liver failure;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea;
Steatorrhea;
Discolored, acholic stools;
Malabsorption of fat and fat-soluble vitamins
SKIN, NAILS, HAIR:
[Skin];
Jaundice
HEMATOLOGY:
Coagulopathy secondary to liver disease
LABORATORY ABNORMALITIES:
Increased serum bilirubin;
Abnormal liver function tests;
Decreased serum cholesterol;
Normal serum levels of gamma-GGT (231950)
MISCELLANEOUS:
Neonatal onset;
Caused by inborn error in bile acid synthesis;
Favorable response to oral bile acid therapy
MOLECULAR BASIS:
Caused by mutation in the 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase
gene (HSD3B7, 607764.0001)
OMIM Title
*607775 POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 4;
KCNE4
;;MINIMUM POTASSIUM ION CHANNEL-RELATED PEPTIDE 3; MIRP3;;
MINK-RELATED PEPTIDE 3
OMIM Description
DESCRIPTION
Voltage-dependent K+ (Kv) channels contain 4 pore-forming alpha subunits
that sense and respond to voltage change and mediate ion permeation.
KCNE accessory subunits, such as KCNE4, are small, single transmembrane
domain-containing proteins that interact with and regulate the activity
of Kv channels.
CLONING
Grunnet et al. (2002) cloned mouse Kcne4. RT-PCR detected low expression
of Kcne4 in mouse uterus, 14-day embryo tissue, kidney, small intestine,
lung, and heart. With increased cycle number, RT-PCR detected expression
of Kcne4 in all tissues examined.
Using the mouse sequence as query in a database search, followed by
RT-PCR and 5-prime and 3-prime RACE of fetal and adult heart cDNA
libraries, Teng et al. (2003) cloned full-length KCNE4. The deduced
170-amino acid protein has a calculated molecular mass of 19 kD. KCNE4
has a typical single membrane-spanning domain at its N terminus, a
characteristic PKC (see 176960) phosphorylation site following the
transmembrane region, and an intracellular C terminus. It shares 90%
identity with mouse Kcne4 and 38% identity with KCNE1 (176261). Northern
blot analysis detected a 4.4-kb transcript expressed at high levels in
heart, skeletal muscle, and kidney, at lower levels in placenta, lung,
and liver, and weakly in brain and peripheral blood leukocytes.
GENE FUNCTION
By coexpression of mouse Kcne4 and Kcnq1 (607542) in Xenopus oocytes and
CHO-K1 cells, Grunnet et al. (2002) determined that Kcne4 completely
inhibited the Kcnq1 current. Kcne4 expression did not alter currents
generated by other Kcnq channels.
Teng et al. (2003) determined that KCNE4 altered the activation time
constant of KCNQ1 following heterologous expression in Xenopus oocytes.
GENE STRUCTURE
Teng et al. (2003) determined that the KCNE4 gene contains 4 exons.
MAPPING
By electronic PCR, Teng et al. (2003) mapped the KCNE4 gene to
chromosome 2q35-q36.
DNER
| dbSNP name | rs57056068(G,A); rs4972896(C,G); rs7594321(T,C); rs9653373(G,T); rs7607057(A,G); rs6436860(C,T); rs11884730(G,A); rs4973191(G,A); rs74906344(T,C); rs35104975(T,C); rs4972897(A,G); rs73096238(G,A); rs4973192(G,A); rs62190329(A,C); rs79275603(A,G); rs181939058(A,C); rs12694809(G,A); rs6722278(A,G); rs58350190(G,A); rs13415396(T,C); rs73096239(A,G); rs4973193(A,G); rs7564004(T,C); rs7602905(C,T); rs7564014(T,C); rs12464994(G,A); rs74488906(G,C); rs2302769(A,T); rs192093139(G,A); rs10184832(T,C); rs34197095(C,T); rs145803107(T,G); rs59140604(C,A); rs192753872(C,A); rs10933292(A,C); rs10933293(T,G); rs116813815(T,C); rs55851318(A,G); rs2396644(A,G); rs2396645(C,A); rs139626476(G,A); rs721941(G,A); rs721942(A,C); rs721943(T,A); rs74681808(A,G); rs114662865(G,A); rs4973194(G,A); rs6436861(T,C); rs79375017(G,A); rs13001246(C,G); rs6712134(C,G); rs6712337(G,A); rs11677239(A,G); rs6712621(C,A); rs116432085(G,A); rs13432559(T,C); rs933602(T,C); rs112008718(T,G); rs207651(A,C); rs115258479(G,A); rs207654(C,T); rs10194205(C,T); rs61403582(C,A); rs200315143(A,G); rs4972898(T,A); rs207657(A,G); rs116071287(G,A); rs113302423(G,A); rs9712102(G,T); rs4972899(T,G); rs142656151(G,C); rs207660(C,T); rs6706971(C,T); rs142677831(A,G); rs145841005(T,C); rs207663(G,A); rs207664(A,C); rs56326135(A,G); rs114328750(G,A); rs6755840(G,T); rs11885456(T,C); rs207666(G,A); rs207667(T,C); rs207668(G,A); rs11695607(G,C); rs56224856(C,T); rs207669(C,A); rs207670(G,A); rs7591720(A,G); rs143887376(C,T); rs7579543(T,C); rs112013473(C,T); rs207671(G,A); rs79792473(T,C); rs79103720(T,A); rs11678000(G,A); rs112761160(T,A); rs207672(T,G); rs58219993(T,C); rs207673(C,A); rs62190335(A,G); rs6734386(G,A); rs111860189(C,T); rs111468460(G,T); rs10196190(T,C); rs10192168(A,G); rs73098300(G,T); rs73100207(A,G); rs10172172(C,T); rs2216337(A,T); rs6753786(A,T); rs59482982(G,C); rs73100225(C,A); rs6733289(G,C); rs78458076(C,G); rs207674(A,T); rs4508585(G,A); rs1862106(G,A); rs76299479(C,A); rs183278457(A,C); rs145147208(A,G); rs2059025(T,A); rs113575183(C,T); rs76957712(A,G); rs3085430(G,A); rs13393630(A,G); rs13432641(T,C); rs13432655(T,G); rs10164537(T,C); rs10207587(A,G); rs10184352(G,A); rs973322(A,G); rs10933295(T,C); rs7562609(A,G); rs112587768(T,C); rs6712266(A,G); rs6759486(T,C); rs114973663(A,T); rs13019241(T,C); rs12694811(A,C); rs112478912(C,T); rs12999104(A,C); rs115633080(C,T); rs76633817(C,T); rs12999879(C,T); rs12999920(C,T); rs11688074(G,A); rs7597467(C,G); rs7574590(A,G); rs6436863(T,G); rs6753093(C,T); rs7604025(C,A); rs7604135(C,T); rs6436864(G,A); rs112159740(G,A); rs13020740(G,T); rs6760330(C,T); rs6731881(A,G); rs6732014(A,G); rs6761181(G,T); rs6761102(C,A); rs116217431(G,A); rs113583700(G,C); rs2396661(T,G); rs10207909(G,A); rs60401340(G,A); rs6436865(T,C); rs6436866(A,T); rs10176118(T,C); rs6739440(A,G); rs6739449(A,T); rs2396662(A,T); rs6711664(G,A); rs111616887(C,T); rs113675701(G,A); rs6712150(G,A); rs2216532(T,C); rs7589774(A,G); rs113462798(C,T); rs58244502(C,T); rs1030147(C,T); rs111842989(T,C); rs112010984(A,G); rs372284620(T,C); rs12694812(A,G); rs13011469(A,G); rs35658974(C,T); rs116216004(T,C); rs6760224(G,A); rs199948718(T,C); rs6735031(A,G); rs6738575(A,C); rs141731266(C,G); rs4973199(G,A); rs6710468(G,A); rs4972900(C,T); rs114469901(C,G); rs13409256(A,G); rs139776497(C,G); rs10192937(A,G); rs145530338(T,C); rs2080801(T,C); rs6719008(C,G); rs6719349(G,T); rs73100266(C,G); rs73100267(T,C); rs73100268(C,T); rs6750605(A,G); rs75775276(T,A); rs148289395(G,A); rs16826019(A,G); rs13417042(A,G); rs139972818(C,T); rs144035056(C,A); rs141044995(A,G); rs13398165(C,T); rs145859373(A,T); rs2161075(C,A); rs7580533(G,A); rs79415686(C,T); rs12105722(A,G); rs12473837(T,G); rs6749306(T,C); rs114161670(G,C); rs6705613(A,G); rs59739122(G,A); rs75320419(T,A); rs55839948(C,G); rs146477702(C,G); rs150175870(C,G); rs7584775(C,A); rs189778812(A,G); rs7568173(G,A); rs4973200(A,C); rs140956451(T,G); rs12468240(A,G); rs7571817(G,A); rs11885159(T,C); rs191372156(G,A); rs149669570(C,T); rs7601566(A,G); rs4973201(C,A); rs144022378(G,T); rs10206153(G,T); rs10206239(G,A); rs6725862(G,A); rs77559069(G,A); rs75210022(G,A); rs6757904(A,G); rs190274628(T,C); rs76306842(C,A); rs77999461(C,A); rs78704018(T,C); rs16826024(G,A); rs10178629(T,C); rs16826025(C,T); rs13416229(A,C); rs6713048(A,C); rs6741786(C,T); rs12466167(G,A); rs11678824(G,A); rs76262463(G,A); rs63635062(G,A); rs12694813(A,C); rs17580751(G,A); rs34188301(T,G); rs4973202(T,C); rs74352267(G,A); rs10519380(C,G); rs80094592(T,C); rs4973203(C,T); rs78757025(G,A); rs6436867(T,A); rs13006734(A,C); rs79992161(T,C); rs75011786(G,A); rs11893863(T,A); rs77839802(C,T); rs75098367(A,G); rs6752093(C,T); rs17580786(C,T); rs7561981(T,A); rs6436868(T,C); rs6436869(C,T); rs75791716(A,G); rs1019441(T,C); rs186342337(G,A); rs75075788(G,A); rs80267723(C,T); rs77376424(C,T); rs113986168(A,G); rs149982045(A,G); rs1811289(T,G); rs6718937(T,C); rs111868934(A,T); rs6722404(T,C); rs10933296(A,T); rs6707324(C,T); rs112433178(C,G); rs16826027(A,G); rs16826028(G,T); rs12694814(A,C); rs12694815(T,C); rs16826032(T,C); rs35032874(T,G); rs2396664(C,G); rs73101878(G,A); rs34836319(C,T); rs17620300(G,T); rs10490181(A,T); rs140576705(G,A); rs2193899(T,C); rs60500900(G,A); rs34680221(G,A); rs12473438(G,A); rs116215807(T,C); rs9711829(C,T); rs79627851(G,A); rs6714349(C,A); rs6743257(A,G); rs6717853(C,G); rs12611671(T,C); rs61025829(G,A); rs59861927(C,T); rs61610064(T,C); rs6750496(A,G); rs6722651(G,T); rs111781343(C,T); rs62191988(A,C); rs720916(G,A); rs369188521(T,A); rs720915(T,G); rs7577257(G,A); rs17483785(G,A); rs7594132(T,C); rs17483806(T,C); rs1966469(A,C); rs73998236(T,C); rs6749425(T,C); rs16826034(T,C); rs16826035(C,T); rs55889076(G,A); rs6731978(T,C); rs6745220(A,G); rs73101894(C,T); rs4973205(C,T); rs58879014(T,C); rs7572143(C,T); rs7575055(C,T); rs144802086(T,C); rs4508586(A,T); rs72986904(A,C); rs1024956(G,A); rs6761543(A,C); rs6733371(C,T); rs6733485(C,T); rs12615146(T,C); rs10192000(A,G); rs16826047(C,A); rs114514264(C,T); rs11675728(C,T); rs10933297(C,T); rs11891316(T,C); rs11896385(A,T); rs11885654(C,G); rs7604082(T,A); rs2112104(C,A); rs2112105(C,T); rs35767843(A,G); rs7590678(C,T); rs9967719(G,T); rs2396665(C,T); rs918345(T,C); rs67150264(T,C); rs36091574(T,A); rs35834872(C,T); rs34433763(T,C); rs4494732(C,T); rs4246634(C,A); rs4246635(G,A); rs4246636(A,G); rs4246637(T,C); rs4535033(C,T); rs17483944(T,C); rs13017464(A,G); rs12994299(T,C); rs13017642(A,G); rs13023083(G,A); rs10439280(A,C); rs12616203(G,C); rs58437855(G,C); rs11688148(T,C); rs11680954(T,C); rs11675160(C,T); rs11681072(T,C); rs77337707(C,T); rs12464613(G,C); rs10933300(A,G); rs13385992(C,T); rs11686561(A,G); rs1862105(C,T); rs116083733(C,T); rs114602305(A,G); rs149931206(G,T); rs11689674(A,G); rs11678693(G,C); rs2017940(T,C); rs759796(T,C); rs2396666(T,C); rs759797(G,A); rs140975579(G,A); rs12621550(A,G); rs13015627(A,G); rs13021049(G,A); rs13020519(A,T); rs13020947(C,T); rs6709876(T,C); rs6723327(A,C); rs4453679(A,G); rs146168137(G,A); rs55792064(C,T); rs6710578(T,C); rs34999103(A,G); rs11903122(A,G); rs11903125(A,G); rs35277260(T,C); rs35653766(A,G); rs35153017(T,C); rs56414048(A,G); rs77698083(C,A); rs12623475(A,G); rs10933301(A,T); rs6757193(G,A); rs6760197(G,A); rs114528058(C,T); rs151274077(T,C); rs13424063(T,C); rs4973206(C,T); rs4973207(A,G); rs2894683(G,C); rs57018215(G,T); rs6707345(C,T); rs13414163(C,G); rs6739318(A,G); rs6711090(G,T); rs6711463(G,A); rs11887777(A,G); rs60195609(A,G); rs58630604(G,T); rs60886461(A,G); rs57580439(G,T); rs6715897(G,A); rs6735048(G,C); rs6750269(T,C); rs6706264(A,G); rs141340727(T,C); rs78338686(G,A); rs77151342(G,T); rs78897145(A,G); rs12464136(A,G); rs75353413(C,T); rs78961607(A,T); rs145588387(C,T); rs115754080(T,G); rs62191993(G,A); rs35792147(T,G); rs7569251(A,G); rs7569493(A,C); rs369397933(G,A); rs77981657(T,C); rs74315837(G,C); rs1013437(C,T); rs79129733(T,C); rs35265916(G,T); rs35037304(C,T); rs35913968(A,G); rs35604710(G,A); rs35001624(A,G); rs34421466(C,T); rs35954449(G,A); rs34885955(C,A); rs74779058(G,A); rs12463621(T,C); rs55948854(G,A); rs12475538(C,T); rs12475633(G,A); rs12464761(T,C); rs12476571(C,T); rs12476610(C,A); rs6717075(T,C); rs13424219(G,A); rs2193901(C,T); rs2193902(C,T); rs73103753(A,G); rs12465019(T,G); rs12468751(A,G); rs6705870(G,A); rs6721121(T,A); rs6705812(C,T); rs6721342(T,C); rs79603144(G,A); rs17620481(G,T); rs2193903(T,C); rs2193904(G,T); rs59605241(A,C); rs2216534(A,G); rs2216535(C,T); rs78003086(A,G); rs7576358(T,A); rs7562276(C,T); rs2193905(T,C); rs7565085(C,A); rs2193906(G,A); rs11890081(T,C); rs13384217(C,T); rs978958(G,A); rs978959(T,C); rs977040(A,T); rs150389039(C,T); rs12475099(C,G); rs74952932(C,T); rs114710090(G,T); rs12479377(T,G); rs977041(G,A); rs977042(T,A); rs74727444(T,G); rs77153663(A,C); rs77489683(G,A); rs12464732(T,C); rs12477357(C,T); rs7570424(T,C); rs7609541(C,T); rs7556846(G,A); rs7583086(A,C); rs7570739(T,C); rs12477612(G,C); rs62191995(G,A); rs12470420(A,G); rs57790472(T,A); rs79971039(G,A); rs78793984(C,G); rs75297485(G,A); rs55942296(G,T); rs741560(G,A); rs741561(G,T); rs741562(T,C); rs741563(C,G); rs76247640(A,G); rs36044071(G,A); rs741564(G,A); rs741565(T,A); rs2098577(T,C); rs2080802(G,A); rs2080803(T,G); rs12464934(G,T); rs12464905(C,A); rs150122166(C,G); rs75175791(T,A); rs76376503(A,C); rs375773601(T,C); rs60437114(C,G); rs77496542(C,T); rs76549545(G,C); rs80014430(C,G); rs78130428(C,T); rs77028133(G,A); rs12467146(C,T); rs12467233(G,C); rs139283771(T,C); rs12475270(A,T); rs79734202(T,C); rs2042138(G,A); rs10933302(C,A); rs114716843(T,G); rs62191997(G,A); rs6748056(T,C); rs7597072(T,C); rs12052301(C,T); rs75694758(G,A); rs2161076(T,G); rs6745008(A,T); rs6723969(C,T); rs10187046(T,C); rs13007913(G,A); rs59199836(G,A); rs10177861(G,A); rs12467839(C,T); rs146071079(A,T); rs56395401(C,T); rs116602555(A,C); rs2894684(G,A); rs2396667(G,T); rs4449119(T,C); rs186722773(A,C); rs12468972(C,T); rs75242787(G,A); rs59358579(A,G); rs61211340(T,C); rs60409302(C,T); rs62192046(T,C); rs4972901(C,A); rs6750972(T,C); rs61036626(T,C); rs9789656(T,C); rs77857410(A,T); rs6736464(C,G); rs6736466(C,T); rs114224224(T,C); rs6736713(C,T); rs6754970(T,A); rs13035309(C,T); rs55728123(A,T); rs56029598(C,T); rs56079234(A,G); rs79545201(T,C); rs56137664(T,C); rs75352906(C,A); rs56049535(A,G); rs62192048(G,A); rs759791(G,A); rs17620535(G,C); rs150460352(T,C); rs138287848(T,C); rs74202774(G,C); rs6744847(C,T); rs6747968(G,A); rs759793(G,T); rs973440(A,G); rs1987684(A,G); rs1987685(A,G); rs2894685(T,C); rs2396668(G,A); rs2006726(T,C); rs4246638(T,C); rs17484035(A,T); rs140562611(A,G); rs11689225(C,T); rs77823047(G,T); rs10197959(C,A); rs6749788(T,C); rs7598686(T,G); rs72988854(G,A); rs137989339(A,T); rs62192049(C,T); rs62192050(C,A); rs6436872(T,C); rs6738730(C,T); rs34916899(G,A); rs13033846(A,G); rs75657127(A,C); rs13410136(G,C); rs10193281(C,T); rs6718834(A,G); rs2013672(T,C); rs73998257(C,T); rs769269(G,A); rs73998258(C,T); rs769268(G,A); rs140103217(T,C); rs6755403(G,A); rs7606954(G,A); rs6759186(G,C); rs6730758(A,T); rs6717730(T,C); rs12694816(T,G); rs115505565(G,T); rs114461787(T,C); rs6735195(A,C); rs116144766(G,A); rs4973212(T,C); rs13010630(T,C); rs6729009(T,A); rs6743025(A,G); rs55662405(C,T); rs6730117(T,C); rs6436873(C,T); rs77211260(G,A); rs58264625(A,G); rs115308758(C,T); rs2216531(A,C); rs17581255(T,G); rs9679608(C,T); rs11695055(C,A); rs76311377(C,T); rs34877621(G,A); rs76403312(G,A); rs142399529(G,A); rs958110(C,T); rs142762727(G,A); rs12614243(C,T); rs72983889(G,C); rs76381883(G,C); rs13394533(G,C); rs13410501(T,A); rs1030148(T,C); rs75116838(T,C); rs74536651(C,T); rs10210785(T,C); rs13419323(G,C); rs11900286(C,G); rs13388601(T,C); rs13426012(C,T); rs113007809(A,T); rs72983898(G,C); rs7581546(C,T); rs112461776(T,A); rs17620716(C,T); rs72985904(A,T); rs73105609(T,C); rs7589154(C,T); rs13013785(A,G); rs115539044(C,T); rs7584721(G,A); rs56754501(G,A); rs10182787(T,C); rs10170426(C,T); rs113366841(C,T); rs4355098(T,A); rs111518795(A,T); rs17677341(T,C); rs10490183(C,G); rs112533189(C,A); rs141355278(C,T); rs76727601(G,A); rs114947712(C,G); rs115999853(T,C); rs146884000(C,A); rs76409546(A,G); rs116164862(G,A); rs76418701(T,C); rs55691530(G,A); rs78515761(G,T); rs11891640(G,A); rs11891593(C,T); rs77974876(T,C); rs7420119(T,A); rs2396669(G,C); rs4519513(T,C); rs5010430(G,A); rs113857349(C,T); rs146673499(T,G); rs11893306(G,A); rs11893229(C,T); rs150074395(G,A); rs28616295(T,C); rs28624660(T,C); rs962127(G,A); rs962126(G,A); rs962125(G,A); rs962128(T,C); rs115884449(A,T); rs114470318(T,C); rs115953372(G,A); rs115986956(A,G); rs114746621(G,A); rs142902392(G,A); rs75289638(A,C); rs116606626(T,A); rs141956252(A,G); rs2059026(T,C); rs2059027(A,G); rs2059028(T,C); rs58110232(C,A); rs1477111(T,G); rs60028805(C,T); rs116378380(A,G); rs11694957(C,T); rs149900584(G,A); rs76891986(G,A); rs74371718(G,A); rs76672647(C,T); rs78364077(T,C); rs16826179(G,T); rs79543002(T,C); rs2216251(T,G); rs68133819(T,C); rs150372891(G,A); rs16826186(T,G); rs4973213(C,T); rs16826188(A,G); rs68150706(T,C); rs67240011(C,T); rs6760456(A,T); rs115613551(A,G); rs78500574(G,A); rs17677491(G,A); rs72985999(T,G); rs72987903(C,T); rs12694817(A,C); rs2894686(C,T); rs1861614(A,T); rs1861615(A,T); rs6751176(C,T); rs6754996(G,T); rs11695348(A,G); rs6759455(G,T); rs6759476(C,T); rs17621000(C,T); rs2396691(A,G); rs2396692(T,C); rs4972903(C,T); rs6706536(G,A); rs6724721(T,A); rs113994694(A,G); rs58430280(G,A); rs6710000(C,T); rs2396693(T,C); rs2111191(G,A); rs2216250(G,A); rs10490184(C,A); rs6436874(T,C); rs2052310(G,T); rs2052311(C,T); rs2160545(T,C); rs6436875(T,A); rs11893092(G,A); rs1968183(G,A); rs1968184(G,A); rs10519389(A,G); rs115877419(G,A); rs114551736(G,C); rs73998281(G,A); rs13429440(T,C); rs76900680(G,A); rs56722619(A,T); rs73998282(A,G); rs10211320(T,C); rs10175534(A,T); rs73998283(A,C); rs77843923(A,G); rs16826224(C,T); rs7574727(T,C); rs60506636(T,C); rs7562651(T,C); rs7601543(C,T); rs764410(A,G); rs7604611(C,T); rs764408(C,T); rs17581619(G,A); rs17677612(C,T); rs6436876(T,C); rs56156768(C,T); rs10183252(T,C); rs73998286(G,A); rs10171278(G,A); rs114716201(G,A); rs2052299(T,C); rs6724108(C,G); rs6724241(C,T); rs13013362(A,G); rs12614918(C,T); rs6436877(T,C); rs13410334(T,C); rs75484200(A,T); rs11891200(G,A); rs137882680(C,T); rs116365609(C,T); rs113693430(C,A); rs12998709(T,C); rs12373570(G,A); rs12373571(C,A); rs10166515(C,T); rs888175(A,G); rs888176(G,T); rs888177(G,A); rs114002969(C,T); rs10193150(A,C); rs10182101(T,C); rs2052300(G,A); rs10933303(G,A); rs10933304(G,A); rs2052301(G,A); rs2052303(C,T); rs2052304(C,T); rs17581710(C,T); rs1861616(G,A); rs1108310(A,T); rs2075256(A,G); rs2075257(G,C); rs759534(C,T); rs77987384(G,A); rs2396694(A,G); rs2396695(G,C); rs759535(A,G); rs759536(G,A); rs17677744(T,C); rs759537(T,A); rs74426531(T,C); rs759538(C,T); rs6751880(A,G); rs78528532(T,C); rs114823573(C,G); rs10176645(C,T); rs2052305(T,C); rs2052306(A,G); rs7591410(T,C); rs79053853(A,G); rs77527469(T,C); rs79267008(T,G); rs1990706(G,C); rs116223979(T,C); rs115406452(C,T); rs759539(A,T); rs741379(C,G); rs741380(A,G); rs741381(G,C); rs75357806(G,A); rs7587967(C,T); rs7588236(G,C); rs7588346(G,A); rs7588294(C,T); rs17621264(T,C); rs74622106(T,G); rs79730615(C,T); rs76550120(A,T); rs115319600(A,G); rs114250880(G,C); rs116477474(A,C); rs6743564(C,A); rs115916447(G,T); rs12619180(G,A); rs2894688(G,T); rs7599546(C,A); rs1465345(A,C); rs980005(G,A); rs1465346(A,G); rs1465347(G,A); rs1006739(C,G); rs114209523(T,A); rs1006740(T,G); rs77606099(A,G); rs11891909(G,A); rs7583906(C,T); rs11891954(G,A); rs7597895(T,C); rs7557517(A,C); rs11892985(C,T); rs36010441(G,A); rs16826257(A,G); rs78700886(T,A); rs41459545(C,G); rs6738620(G,A); rs6709611(A,C); rs12471720(G,A); rs16826262(G,A); rs11900303(T,A); rs11900304(T,C); rs75696870(A,G); rs75111173(A,T); rs114239487(C,T); rs6742437(C,T); rs6745606(G,A); rs6745738(G,A); rs6745860(G,A); rs11896391(G,A); rs77694161(G,A); rs16826265(C,G); rs78003892(T,G); rs17621306(T,C); rs150926879(A,G); rs116184471(A,G); rs114688038(G,A); rs6436878(A,T); rs7426347(C,T); rs116277740(G,A); rs77474560(G,A); rs6705299(C,T); rs75611426(T,G); rs4625897(G,C); rs4414668(G,A); rs2052307(T,C); rs2052308(A,G); rs10933306(C,T); rs11898749(C,T); rs372715164(G,C); rs10174833(A,G); rs10490186(C,T); rs2052309(A,G); rs13421700(G,T); rs4972904(C,T); rs1990707(G,C); rs4972905(A,C); rs114172382(T,G); rs151213722(G,A); rs375658086(A,G); rs73998299(C,T); rs11694665(G,A); rs6727393(T,G); rs12986692(C,T); rs7593572(A,C); rs4542838(A,G); rs376682450(A,G); rs150463400(C,T); rs13389510(G,C); rs13389566(C,T); rs4375853(T,C); rs13392383(G,A); rs12474631(A,G); rs13392878(G,T); rs111235069(G,A); rs13393112(C,T); rs57716199(C,A); rs55667324(T,A); rs13396586(C,T); rs7607763(A,G); rs6436879(C,T); rs6436880(C,G); rs6436881(G,A); rs12474401(C,T); rs13392007(A,T); rs11678266(A,G); rs2024484(A,C); rs13383968(T,C); rs1861617(A,G); rs7570081(G,A); rs1861618(C,T); rs2024485(C,T); rs10169481(T,A); rs888178(A,C); rs190084551(T,A); rs6726280(C,A); rs62191164(T,C); rs7591419(T,C); rs113016068(T,C); rs72993226(C,T); rs6735187(G,C); rs13388208(G,A); rs17621398(A,C); rs13006528(G,A); rs77130106(C,T); rs72993233(C,T); rs78913406(T,C); rs13421262(A,G); rs72993235(G,A); rs6750904(G,A); rs13399244(C,T); rs4972907(C,T); rs59434242(C,T); rs1986253(A,G); rs6436882(A,G); rs6436883(C,T); rs6754103(G,A); rs7605496(G,T); rs2007965(A,G); rs7557015(C,T); rs6704918(C,T); rs34056484(C,T); rs35596599(C,T); rs34851081(C,T); rs28555092(A,G); rs6713110(G,A); rs10196161(C,T); rs6436884(G,A); rs7565407(T,C); rs7604951(G,A); rs116499184(G,A); rs35392477(T,C); rs115726119(T,G); rs7562942(C,T); rs138850626(T,A); rs74001406(G,A); rs11901716(G,A); rs11676294(T,G); rs72993258(A,G); rs6752370(A,G); rs2080485(G,A); rs2080486(T,C); rs2894689(A,G); rs16826294(C,A); rs115736376(C,T); rs1544673(C,T); rs1544674(C,A); rs1544675(C,G); rs1544676(T,C); rs7591557(A,G); rs10197480(C,T); rs10933307(G,T); rs4973214(T,C); rs4973215(G,T); rs4972908(T,C); rs4972909(C,T); rs72977204(T,C); rs56242730(T,C); rs13012870(C,T); rs9646889(A,G); rs1861612(G,A); rs6436885(A,T); rs1861613(G,A); rs13424801(G,T); rs79449403(T,C); rs768975(C,T); rs115047818(C,T); rs7576516(C,T); rs7576948(G,A); rs10172673(T,C); rs12469914(A,G); rs12052464(T,G); rs6742213(T,C); rs4491719(T,C); rs11695483(G,A); rs11678962(T,C); rs144506834(C,T); rs116295634(T,A); rs16826316(T,C); rs114239527(A,C); rs116688996(A,G); rs7587835(C,T); rs2193216(A,C); rs74723553(A,G); rs17678034(C,T); rs888172(T,A); rs888173(C,T); rs888174(T,C); rs57351570(T,G); rs1023594(T,C); rs77169594(G,A); rs185331192(C,T); rs13400117(T,C); rs13386895(C,T); rs13387114(C,T); rs13400648(T,C); rs13400767(T,A); rs13387731(G,A); rs13387568(C,T); rs13400996(T,C); rs55986303(G,T); rs189812406(C,T); rs60405027(T,C); rs6712401(A,G); rs10188714(T,C); rs78072044(G,A); rs13422868(A,G); rs10191393(T,C); rs10179055(C,T); rs114844819(T,C); rs10182640(G,A); rs74337721(C,T); rs6754246(C,T); rs12470575(C,T); rs10185857(G,T); rs10198320(T,C); rs10185900(G,A); rs10186123(G,A); rs6761364(C,G); rs2011781(G,A); rs147870691(C,T); rs115705863(C,T); rs111947825(A,G); rs75197587(C,T); rs35950189(A,G); rs36074934(T,A); rs74001413(G,A); rs13022074(C,A); rs13022561(G,T); rs13022072(A,G); rs75153883(C,T); rs77512224(T,A); rs17582010(T,C); rs75967091(C,T); rs78056129(A,T); rs17484908(C,T); rs75099438(A,G); rs16826329(C,G); rs16826331(T,C); rs35849655(T,C); rs112267006(G,C); rs34845702(A,T); rs115204367(G,A); rs147418327(A,G); rs2216248(T,C); rs2193217(A,G); rs2193218(A,G); rs2216249(T,C); rs10195162(C,T); rs116351529(C,T); rs10207750(T,C); rs7558924(T,C); rs13392868(A,G); rs7574501(A,G); rs7574506(A,T); rs7574520(A,C); rs13418598(C,T); rs7562346(T,C); rs7562449(T,C); rs6724560(A,C); rs10201955(G,A); rs985002(A,G); rs2396697(A,G); rs2396698(T,G); rs12466507(T,A); rs7589153(A,G); rs76910713(C,T); rs9288650(T,C); rs76346197(A,C); rs112727818(G,A); rs115250784(G,A); rs4973218(C,T); rs4973219(T,C); rs208788(T,G); rs208789(C,T); rs208790(G,C); rs116613978(T,C); rs59968882(G,A); rs116769130(C,G); rs114815651(T,G); rs208791(A,G); rs79456621(G,A); rs208792(A,G); rs208793(A,G); rs35131486(C,A); rs721528(A,G); rs2761119(A,T); rs79564979(C,T); rs187940339(G,A); rs721529(T,C); rs192783514(A,G); rs963898(C,T); rs2253704(A,G); rs59541630(C,A); rs12991349(C,T); rs2761121(T,G); rs1548940(A,T); rs2193219(T,C); rs2193220(A,T); rs142127364(G,T); rs2193221(T,C); rs11899738(A,G); rs13408959(T,C); rs10933308(T,C); rs208781(C,T); rs208782(T,C); rs208783(C,A); rs7568451(G,T); rs73097208(C,G); rs80257173(T,C); rs208784(G,A); rs208785(G,C); rs114538016(C,T); rs208786(A,C); rs1323595(G,A); rs208787(G,A); rs1407974(A,G); rs10175956(C,T); rs11900796(A,G); rs6758674(A,G); rs116658461(G,A); rs2894690(C,T); rs368618959(G,A); rs7560653(A,T); rs4973220(A,G); rs146507230(A,G); rs115380872(G,A); rs12473075(G,T); rs12473885(G,T); rs12465803(A,G); rs4972911(G,A); rs6761377(A,C); rs4972912(G,A); rs208780(C,A); rs75972869(C,A); rs4331494(A,G); rs6749279(G,C); rs115813061(C,G); rs2100(A,T); rs6753309(C,T); rs6756478(G,A); rs57461282(C,T); rs77263106(T,C); rs76362200(G,A); rs73097225(C,A); rs73097226(T,A); rs73097228(T,C); rs73097229(T,A); rs73097231(G,A); rs73097232(A,G); rs73097236(C,A); rs73097239(C,T); rs73097243(T,G); rs73097244(C,T) |
| ccdsGene name | CCDS33390.1 |
| cytoBand name | 2q36.3 |
| EntrezGene GeneID | 92737 |
| EntrezGene Description | delta/notch-like EGF repeat containing |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DNER:NM_139072:exon9:c.A1574G:p.N525S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9536 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NFT8 |
| dbNSFP Uniprot ID | DNER_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 2.44e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
RESPIRATORY:
[Nasopharynx];
[Airways];
Reactive airway disease;
Asthma;
[Lung];
Pneumonia
ABDOMEN:
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea, chronic
SKIN, NAILS, HAIR:
[Skin];
Eczema
IMMUNOLOGY:
Lymphadenopathy;
Recurrent sinopulmonary infections;
Herpes simplex virus infection, mucocutaneous;
Defective CD95-induced apoptosis of peripheral blood lymphocytes;
No response to pneumococcal vaccination;
Defective T cell activation;
Defective B cell activation;
Defective natural killer cell (NK) activation;
Decreased cellular caspase-8 levels
MOLECULAR BASIS:
Caused by mutation in the caspase 8 gene (CASP8, 601763.0001)
OMIM Title
*607299 DELTA- AND NOTCH-LIKE EPIDERMAL GROWTH FACTOR-RELATED RECEPTOR; DNER
;;DELTA- AND NOTCH-LIKE EGF-RELATED RECEPTOR
OMIM Description
DESCRIPTION
The DNER gene encodes a transmembrane protein carrying extracellular EGF
repeats and is strongly expressed in Purkinje cells in the cerebellum.
DNER functions as a Notch (190198) ligand and mediates signaling through
neuron-glia interactions (Eiraku et al., 2002, 2005).
CLONING
Using subtractive hybridization to identify genes that are
differentially expressed during the development of mouse cerebellar
granule cells, Eiraku et al. (2002) identified and cloned Dner, which
was strongly expressed during formation of dendrites and axons. Using
the mouse cDNA as probe, Eiraku et al. (2002) cloned human DNER from a
brain cDNA library. The deduced human and mouse proteins contain 737
amino acids and share 90% identity. DNER contains an N-terminal signal
sequence and 10 distinct EGF (131530)-like motifs. The final EGF-like
repeat displays a typical signature of a calcium-binding domain
important for molecular orientation. DNER also has a single
transmembrane region and an intracellular C-terminal region containing
potential tyrosine kinase phosphorylation sites, a typical
tyrosine-based sorting signal (YEEF), and a dileucine-type sorting
signal (LI). Northern blot analysis of several mouse tissues revealed a
3.7-kb transcript that was predominantly expressed in brain. Western
blot analysis of mouse brain lysates revealed a molecular mass of about
90 kD, with 2 higher molecular mass species occasionally detected. In
situ hybridization revealed that Dner mRNA was almost exclusively
expressed in the mouse central nervous system as early as embryonic day
14.5. Immunolocalization of Dner protein revealed expression in several
types of neurons, including cortical and hippocampal pyramidal neurons,
cerebellar granule cells, and Purkinje cells. Dner localized to the
dendritic plasma membrane and within endosomes, and it was excluded from
the axons even when experimentally overexpressed.
GENE FUNCTION
Using deletion and mutation analysis, Eiraku et al. (2002) determined
that the YEEF tyrosine-based motif is required for somatodendritic
targeting of mouse Dner. Using coimmunoprecipitation techniques, they
found direct binding between Dner and the clathrin coat-associated
protein complex Ap1 (see 603534), and they colocalized Dner and Ap1
within mouse Purkinje cells. Eiraku et al. (2002) concluded that Dner
undergoes Ap1-dependent sorting to the somatodendritic compartments from
the trans-Golgi network.
Differentiation of glia in the central nervous system is regulated by
Notch (see NOTCH1; 190198) signaling through neuron-glia interaction.
Eiraku et al. (2005) identified Dner as a ligand of Notch during
cellular morphogenesis of Bergmann glia in the mouse cerebellum. Dner
bound to Notch1 at cell-cell contacts and activated Notch signaling in
vitro. In the developing cerebellum, Dner was highly expressed in
Purkinje cell dendrites, which were tightly associated with radial
fibers of Bergmann glia expressing Notch. Dner specifically bound to
Bergmann glia in culture and induced process extension by activating
gamma-secretase (see PSEN1; 104311)- and Dtx1 (602582)-dependent Notch
signaling. Inhibition of Dtx1-dependent but not Rbpj (RBPSUH;
147183)-dependent Notch signaling in Bergmann glia suppressed formation
and maturation of radial fibers in organotypic slice cultures.
Additionally, deficiency of Dner retarded the formation of radial fibers
and resulted in abnormal arrangement of Bergmann glia.
- Paraneoplastic Tr Antibody
Graus et al. (1997) characterized the anti-Tr antibody found in the
serum and cerebrospinal fluid of 5 patients with paraneoplastic
cerebellar degeneration and Hodgkin lymphoma. The name 'Tr' was given
because the antibody was first identified by Trotter et al. (1976) in a
woman with subacute cerebellar degeneration associated with Hodgkin
lymphoma. The antibody reacted with cerebellar Purkinje cells. Graus et
al. (1997) found that anti-Tr antibodies labeled the cytoplasm of
Purkinje cells of human and rat cerebellum. The molecular layer of rat
cerebellum showed a characteristic dotted pattern suggestive of
immunoreactivity of dendritic spines of Purkinje cells. Anti-Tr
antibodies were not found in 159 patients with cerebellar disorders
without Hodgkin disease or in 30 patients with Hodgkin disease without
cerebellar disorders. Thus, anti-Tr antibodies appeared specific for
Hodgkin-associated paraneoplastic cerebellar degeneration.
De Graaff et al. (2012) identified DNER as the antigen for the anti-Tr
antibody that can cause paraneoplastic cerebellar degeneration and is
usually associated with Hodgkin lymphoma. The protein was identified by
mass spectrometry analysis of immunopurified rat brain treated with
anti-Tr-positive sera. All 12 anti-Tr-positive sera stained
DNER-expressing HeLa cells, and all but 1 of 246 control sera samples
did not stain DNER-expressing HeLa cells. Studies with deletion
constructs localized the main epitope to the extracellular domain.
Knockdown of endogenous DNER in the hippocampus and N-glycosylation
mutations abolished the anti-Tr staining, indicating that glycosylation
of DNER is required for it to be recognized by the antibody. Western
blotting was an unreliable method for diagnosing anti-Tr antibodies.
MAPPING
By genomic sequence analysis, Eiraku et al. (2002) mapped the DNER gene
to chromosome 2q37.
ANIMAL MODEL
Tohgo et al. (2006) found that Dner-knockout mice showed motor
incoordination in the fixed bar and rotarod tests. The cerebellum from
these mice was small with hypoplasia of the cerebellar fissure and
folia, indicating impaired development. Histochemical and
electrophysiologic analyses showed that Purkinje cells had normal
differentiation and formation of synapses, but there was irregular
multiple innervation of Purkinje cells by climbing fibers and irregular
parallel fiber/Purkinje cell transmission. This was associated with
impaired glutamate clearance at the parallel fiber-Purkinje cell
synapses, likely resulting from reduced GLAST (SLC1A3; 600111) content
in Bergmann glia. The findings indicated that DNER takes part in
stimulation of maturation of the cerebellum via intercellular
communication between Purkinje cells and Bergmann glia and is essential
for precise cerebellar functional and morphologic development.
FBXO36
| dbSNP name | rs1617328(C,T); rs2439570(A,G); rs140623876(G,A); rs144483970(C,T); rs73103541(A,G); rs36075200(G,C); rs111541029(C,T); rs147197907(T,A); rs140531916(T,C); rs73103544(A,T); rs7607428(A,C); rs6734667(C,T); rs116832753(T,C); rs147973238(A,G); rs35547214(A,T); rs62191699(A,C); rs3856526(C,T); rs553536(T,C); rs62191700(C,T); rs112498064(G,A); rs481567(G,A); rs62191701(C,T); rs536707(A,G); rs73103553(G,T); rs76206252(C,T); rs62191702(G,A); rs144260276(T,A); rs7605745(C,G); rs114329924(C,A); rs6720609(T,A); rs182036534(T,C); rs77601194(C,T); rs11683062(A,G); rs2439571(G,A); rs6722477(T,C); rs112263477(G,A); rs2433733(G,A); rs2162524(T,C); rs77408380(A,G); rs2396701(C,T); rs6720455(C,A); rs537428(T,C); rs181190618(C,T); rs500016(G,A); rs560304(C,T); rs16826498(G,T); rs78483999(C,T); rs17325374(A,G); rs36092235(C,T); rs144043541(A,G); rs76065987(C,T); rs79295772(G,A); rs2042802(G,T); rs375964305(C,T); rs35484873(C,T); rs34869673(G,T); rs2247164(G,C); rs116788437(A,G); rs113604116(G,A); rs519707(T,C); rs6748770(T,A); rs7590645(C,G); rs6745417(G,A); rs73103594(C,T); rs4973241(G,A); rs6746407(G,A); rs78721367(C,T); rs13030629(G,A); rs548289(T,C); rs553957(G,A); rs61753284(C,T); rs499449(C,T); rs73103599(A,T); rs375570431(A,C); rs10169734(T,C); rs555865(G,A); rs10204772(G,A); rs62191707(A,G); rs34257474(G,A); rs526475(G,A); rs6710926(G,A); rs59217414(A,G); rs112961026(G,A); rs114579661(G,C); rs35392774(C,T); rs7577278(C,A); rs74748308(G,A); rs61706380(A,G); rs72993088(T,C); rs2396702(G,A); rs191381934(T,C); rs141937059(A,G); rs57594845(T,C); rs62191712(T,C); rs11679182(C,T); rs149319800(C,T); rs2396703(T,A); rs66549147(A,G); rs34124733(T,A); rs34473288(G,A); rs6436893(T,C); rs73105408(C,T); rs76327152(A,G); rs144654977(T,C); rs12694822(C,T); rs13420478(G,T); rs1035834(G,T); rs61049183(A,G); rs16826505(C,A); rs12618849(C,T); rs71415740(G,A); rs74188614(G,A); rs28821930(C,T); rs4973242(T,C); rs4972923(G,A); rs11900583(C,T); rs140227946(G,A); rs73105414(C,T); rs7582815(A,G); rs1978590(A,G); rs72993102(C,T); rs140938355(A,G); rs6727194(T,C); rs377572716(G,A); rs111949012(A,G); rs11675466(G,A); rs73105424(C,T); rs6732130(T,C); rs2114663(G,T); rs7608112(C,T); rs34012856(C,T); rs720041(A,G); rs720042(C,T); rs184959043(G,A); rs13035433(A,G); rs115277725(A,C); rs148428810(G,T); rs2059716(T,C) |
| ccdsGene name | CCDS2472.1 |
| cytoBand name | 2q36.3 |
| EntrezGene GeneID | 130888 |
| EntrezGene Description | F-box protein 36 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FBXO36:NM_174899:exon2:c.C151T:p.P51S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6335 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B3KVQ6 |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00923482849604 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.001589 |
| ESP All MAF | 0.00569 |
| ESP Eur/Amr MAF | 0.007791 |
| ExAC AF | 0.004725 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEMATOLOGY:
High blood oxygen saturation of hemoglobin (10% higher mean than the
lowest values of population studied)
OMIM Title
*609105 F-BOX ONLY PROTEIN 36; FBXO36
;;FBX36
OMIM Description
DESCRIPTION
Members of the F-box protein family, such as FBXO36, are characterized
by an approximately 40-amino acid F-box motif. SCF complexes, formed by
SKP1 (601434), cullin (see CUL1; 603134), and F-box proteins, act as
protein-ubiquitin ligases. F-box proteins interact with SKP1 through the
F box, and they interact with ubiquitination targets through other
protein interaction domains (Jin et al., 2004).
CLONING
Jin et al. (2004) reported that the FBXO36 protein contains an F box in
its C-terminal half.
MAPPING
Jin et al. (2004) stated that the FBXO36 gene maps to chromosome 2q37.1
and the mouse Fbxo36 gene maps to chromosome 1C5.
B3GNT7
| dbSNP name | rs2290130(G,A); rs10445830(C,T); rs10445831(A,G); rs13025087(G,T); rs11903772(C,T) |
| ccdsGene name | CCDS46540.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 93010 |
| EntrezGene Description | UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | B3GNT7:NM_145236:exon2:c.G697A:p.V233I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NFL0 |
| dbNSFP Uniprot ID | B3GN7_HUMAN |
| dbNSFP KGp1 AF | 0.237637362637 |
| dbNSFP KGp1 Afr AF | 0.182926829268 |
| dbNSFP KGp1 Amr AF | 0.21270718232 |
| dbNSFP KGp1 Asn AF | 0.230769230769 |
| dbNSFP KGp1 Eur AF | 0.290237467018 |
| dbSNP GMAF | 0.2374 |
| ESP Afr MAF | 0.151344 |
| ESP All MAF | 0.213162 |
| ESP Eur/Amr MAF | 0.244101 |
| ExAC AF | 0.246 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Depigmented iris;
Nystagmus;
Photophobia;
Albinotic fundus;
Foveal hypoplasia;
Impaired visual acuity
SKIN, NAILS, HAIR:
[Skin];
White skin;
[Hair];
Golden-colored hair
MISCELLANEOUS:
One consanguineous Pakistani family reported (last curated August
2013)
OMIM Title
*615313 BETA-1,3-N-ACETYLGLUCOSAMINYLTRANSFERASE 7; B3GNT7
OMIM Description
DESCRIPTION
Beta-1,3-N-acetylglucosaminyltransferases, such as B3GNT7, catalyze the
transfer of N-acetylglucosamine (GlcNAc) residues from UDP-GlcNAc to the
C-3 position of nonreducing terminal galactose (Gal) or GalNAc by
beta-linkage (Seko and Yamashita, 2004).
CLONING
Kataoka and Huh (2002) cloned mouse B3gnt7 from a placenta cDNA library;
by database analysis, they identified human B3GNT7. Mouse and human
B3GNT7 encode proteins of 397 and 401 amino acids, respectively, and the
proteins share 87% identity. Mouse B3gnt7 is a type II transmembrane
protein with a short N-terminal signal/transmembrane domain and an
approximately 200-amino acid galactosyltransferase domain. It also has a
single putative N-glycosylation site and 5 cysteine residues, both of
which are conserved in the deduced human ortholog. Northern blot
analysis of mouse tissues detected variable expression of a 3-kb
transcript in all tissues examined except liver and skeletal muscle.
Highest expression was detected in mature placenta and colon.
Seko and Yamashita (2004) cloned human B3GNT7 from a colon cDNA library.
GENE FUNCTION
Using an antisense oligonucleotide, Kataoka and Huh (2002) found that
knockdown of B3gnt7 enhanced motility and invasiveness of mouse lung
cancer cells. Using the crude membrane fraction from COS-7 cells
expressing B3GNT7 to measure the enzyme's activity, Seko and Yamashita
(2004) found that B3GNT7 efficiently elongated keratan sulfate-related
glycans by the addition of GlcNAc to the C-3 position of the distal Gal.
The optimal pH with keratan sulfates was 6.5 to 7.0, and the reaction
required manganese chloride (MnCl2). B3GNT7 also recognized internal
6-O-sulfated GlcNAc. Lacto-N-tetraose and lacto-N-neo-tetraose were poor
substrates.
GENE STRUCTURE
Kataoka and Huh (2002) determined that the B3GNT7 gene contains 2 exons.
MAPPING
By genomic sequence analysis, Kataoka and Huh (2002) mapped the B3GNT7
gene to chromosome 2q37.1.
SNORA75
| dbSNP name | rs13019380(T,G) |
| ccdsGene name | CCDS33397.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 654321 |
| snpEff Gene Name | AC017104.2 |
| EntrezGene Description | small nucleolar RNA, H/ACA box 75 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07438 |
| ESP Afr MAF | 0.018836 |
| ESP All MAF | 0.0797 |
| ESP Eur/Amr MAF | 0.106479 |
| ExAC AF | 0.084 |
C2orf57
| dbSNP name | rs10933378(T,C) |
| ccdsGene name | CCDS2487.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 165100 |
| EntrezGene Description | chromosome 2 open reading frame 57 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C2orf57:NM_152614:exon1:c.T781C:p.S261P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q53QW1 |
| dbNSFP Uniprot ID | CB057_HUMAN |
| dbNSFP KGp1 AF | 0.937271062271 |
| dbNSFP KGp1 Afr AF | 0.928861788618 |
| dbNSFP KGp1 Amr AF | 0.92817679558 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.899736147757 |
| dbSNP GMAF | 0.06198 |
| ESP Afr MAF | 0.069224 |
| ESP All MAF | 0.084807 |
| ESP Eur/Amr MAF | 0.092791 |
| ExAC AF | 0.921,8.133e-06 |
ECEL1P2
| dbSNP name | rs3748971(C,T); rs55781386(G,C); rs12328730(C,T); rs116068897(A,T) |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 347694 |
| snpEff Gene Name | ALPP |
| EntrezGene Description | endothelin converting enzyme-like 1, pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07025 |
ALPPL2
| dbSNP name | rs142232440(G,T); rs2678517(G,A); rs180766761(G,A) |
| ccdsGene name | CCDS2491.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 251 |
| EntrezGene Description | alkaline phosphatase, placental-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ALPPL2:NM_031313:exon3:c.G286T:p.V96L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5907 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P10696 |
| dbNSFP Uniprot ID | PPBN_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ExAC AF | 8.946e-05,8.133e-06 |
OMIM Clinical Significance
Lab:
Elevated serum alkaline phosphatase with no disease
Inheritance:
? Autosomal dominant
OMIM Title
*171810 ALKALINE PHOSPHATASE, PLACENTAL-LIKE 2; ALPPL2
;;ALKALINE PHOSPHATASE, GERM CELL; ALPG; GCAP;;
ALKALINE PHOSPHATASE, TESTICULAR AND THYMUS;;
NAGAO ISOENZYME
OMIM Description
CLONING
With monoclonal antibodies, Goldstein et al. (1981) demonstrated a form
of alkaline phosphatase seemingly distinct from the placental,
intestinal, and liver forms. It was present in trace amounts in testis
and thymus. Millan et al. (1982) found that human testes contain trace
amounts of heat-stable placentallike alkaline phosphatase. From
reactivity with a monoclonal antibody to placental alkaline phosphatase
and from study of enzyme inhibitors, they concluded that the testicular
enzyme is separate from the placental enzyme.
Millan and Manes (1988) studied the PLAP (171800)-like isozyme called
the Nagao isozyme which shows enhanced expression in germ-cell tumors of
the testis, especially seminomas, and demonstrated that it is encoded by
the germ-cell alkaline phosphatase gene.
MAPPING
Knoll et al. (1988) concluded that 3 closely related alkaline
phosphatase genes reside on the long arm of chromosome 2 in man.
Martin et al. (1987) mapped the placentallike alkaline phosphatase gene
to 2q37.
GENE FAMILY
Knoll et al. (1988) summarized the 3 closely related alkaline
phosphatase genes. One of these genes (the placental ALP1, in their
symbology; 171800) encodes the classic heat-stable placental alkaline
phosphatase; a second, which they referred to as placental ALP2, is
closely related to the first, and may encode the so-called placental
ALP-like enzyme of the testis and thymus; the third member of this gene
family, the intestinal ALP gene, encodes intestinal alkaline phosphatase
(171740). The expression of the intestinal and placental genes is highly
tissue-specific in spite of nearly 90% sequence similarity within their
exons. Knoll et al. (1988) compared the placental alkaline phosphatase
gene with the placentallike gene.
OTHER FEATURES
Cloning and sequencing of the placental alkaline phosphatase, intestinal
alkaline phosphatase, and germ-cell alkaline phosphatase genes indicated
a high degree of homology; in particular, 98% amino acid sequence
identity had been demonstrated between placental and germ-cell forms of
the enzyme. In a study of a Finnish population, Beckman et al. (1991)
described a PstI RFLP strongly correlated with electrophoretic placental
alkaline phosphatase types and believed to be caused by a variable
restriction site at position 367 in exon 2 of the ALPP gene. However,
Beckman et al. (1992) demonstrated that in fact the RFLP involves the
germ-cell alkaline phosphatase and that the correlation with the
placental alkaline phosphatase type was the result of linkage
disequilibrium.
CHRNG
| dbSNP name | rs12996322(G,C); rs13003665(G,T); rs1190434(C,T); rs1656388(G,C); rs1656389(A,G); rs1881492(T,G); rs6761667(T,A); rs2697782(G,C); rs13018423(C,T); rs73995686(C,T); rs72991926(A,T); rs2250451(G,A); rs117196251(G,A); rs142273229(G,T); rs744159(G,A); rs729941(G,C); rs16829216(G,A); rs2099489(C,T); rs11690038(T,C); rs59295139(C,A); rs72991939(C,T) |
| ccdsGene name | CCDS33400.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 1146 |
| EntrezGene Description | cholinergic receptor, nicotinic, gamma (muscle) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CHRNG:NM_005199:exon12:c.G1421A:p.R474H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8178 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14DU4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0001138 |
OMIM Clinical Significance
Limbs:
Arachnodactyly
Joints:
Joint laxity limited to hands and feet
Skull:
Broad skull
Head:
Brachycephaly;
Micrognathia
Misc:
Normal body proportions
Inheritance:
Autosomal dominant
OMIM Title
*100730 CHOLINERGIC RECEPTOR, NICOTINIC, GAMMA POLYPEPTIDE; CHRNG
;;ACETYLCHOLINE RECEPTOR, MUSCLE, GAMMA SUBUNIT; ACHRG
OMIM Description
DESCRIPTION
For background information on the acetylcholine receptor (AChR), see
CHRNA1 (100690). Two forms of AChR are found in mammalian skeletal
muscle cells. The mature form is predominant in innervated adult muscle
and the embryonic form is present in fetal and denervated muscle.
Embryonic and mature AChR differ by the replacement of the gamma subunit
in the pentameric glycoprotein complex by its isoform, the epsilon
subunit (100725), which is specific to the mature AChR subtype. This
switch is mediated by ARIA (acetylcholine receptor-inducing activity;
142445).
GENE FUNCTION
- Role in Myasthenia Gravis
Transient neonatal myasthenia gravis occurs in approximately 20% of
infants born to mothers with myasthenia gravis (see 601462). Symptoms
usually appear within hours after birth and disappear after 2 or 3
weeks. The severity of neonatal MG is highly variable, ranging from mild
hypotonia to respiratory distress requiring assisted mechanical
ventilation. Antenatal onset leading to multiple joint contractures,
hydramnios, and decreased fetal movements is rare. The disease severity
is not correlated to the clinical status of the mother. Vernet-der
Garabedian et al. (1994) studied 22 mothers with myasthenia gravis and
their newborns. Twelve mothers had transmitted MG to their neonates
with, in 3 cases, antenatal injury. A clear correlation was found
between occurrence of neonatal MG and high overall levels of anti-AChR
antibodies. However, a strong correlation was also found between
occurrence of neonatal MG and the ratio of anti-embryonic AChR to
anti-adult muscle AChR antibodies. Taken together, the data suggested
that autoantibodies directed against the embryonic form of AChR, which
contains the gamma subunit, may play a predominant role in the
pathogenesis of neonatal MG. Paradoxically, the 3 cases with antenatal
injury, presumably the most severe form of the disorder, were not
associated with high ratio of anti-embryonic ACh to anti-adult AChR
antibodies.
MAPPING
See CHRND (100720) for a discussion of the probable close linkage of the
genes for the gamma and delta subunits and their possible location on
chromosome 2q. Shibahara et al. (1985) showed that the genes encoding
the gamma and delta subunits of CHRN are contained in an EcoRI
restriction fragment of approximately 20 kb. Cohen-Haguenauer et al.
(1989) used a murine full-length 1,900-bp-long cDNA encoding the gamma
subunit to map the gene to chromosome 2 in human/rodent somatic cell
hybrids. (They used conditions of low stringency to favor cross-species
hybridization, and prehybridization with rodent DNA to prevent rodent
background.) The use of a chromosomal translocation t(X;2)(p22;q32.1)
served to localize the CHRNG gene to 2q32-qter.
Schurr et al. (1990) mapped this gene to mouse chromosome 1 (symbol
Acrg) at a position between Vil (193040) proximally and Col6a3 (120250)
distally.
MOLECULAR GENETICS
Hoffmann et al. (2006) and Morgan et al. (2006) demonstrated that
mutations in the CHRNG gene cause Escobar syndrome (EVMPS; 265000) and
the lethal form of multiple pterygium syndrome (LMPS; 253290). These are
autosomal recessive forms of arthrogryposis multiplex congenita
characterized by excessive webbing (pterygia), congenital contractures
(arthrogryposis), and scoliosis. The congenital contractures may be
caused by reduced fetal movements at sensitive times of development
(Hoffmann et al., 2006). The CHRNG gene encodes the gamma subunit of the
acetylcholine receptor (AChR) and is expressed before the 33rd week of
gestation in humans but is replaced by the epsilon subunit (100725) in
the late fetal and perinatal period, thereby forming the adult AChR. The
fetal AChR helps to establish the primary encounter of muscle and axon
(Koenen et al., 2005). Thus, the gamma subunit not only contributes to
neuromuscular signal transduction but is also important for
neuromuscular organogenesis. The importance of the fetal AChR subtype
for neuromuscular development is underscored by the lethal phenotype of
gamma inactivation in mice (Takahashi et al., 2002).
Vogt et al. (2012) identified 20 different homozygous or compound
heterozygous CHRNG mutations (see, e.g., 100730.0008) in 11 (27%) of 41
families with nonlethal multiple pterygium syndrome and 5 (8%) of 59
families with lethal multiple pterygium syndrome. The mutations were
found by direct sequencing of the coding exons only. Most patients
(87.5%) with a CHRNG mutation had pterygia; none with CHRNG mutations
had central nervous system anomalies. The mutation spectrum was similar
in EVMPS and LMPS kindreds, and both phenotypes were observed in
different families with the same CHRNG mutation. Based on these
findings, Vogt et al. (2012) proposed a molecular genetic diagnostic
pathway for the investigation of MPS.
TIGD1
| dbSNP name | rs4973539(A,G); rs72991949(G,A); rs6752614(C,T); rs11681785(G,A); rs11692919(A,G); rs4973540(C,T); rs4973541(G,A); rs11683262(C,T); rs11689217(T,G) |
| ccdsGene name | CCDS2495.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 200765 |
| EntrezGene Description | tigger transposable element derived 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TIGD1:NM_145702:exon1:c.T1773C:p.D591D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1414 |
| ESP Afr MAF | 0.129616 |
| ESP All MAF | 0.17643 |
| ESP Eur/Amr MAF | 0.203335 |
| ExAC AF | 0.144 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial weakness;
[Neck];
Neck weakness
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, restrictive;
Cardiomyopathy, hypertrophic
RESPIRATORY:
Respiratory insufficiency;
Reduced forced vital capacity
CHEST:
[Diaphragm];
Diaphragmatic paralysis
SKELETAL:
[Spine];
Scoliosis;
Rigid spine;
Stiff spine;
[Limbs];
Contractures of the knees and ankles;
Valgus ankle deformity;
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness, severe, diffuse;
Muscle atrophy, diffuse;
Easy fatigability;
Skeletal muscle biopsy shows dystrophic changes;
Necrotic fibers;
Internal nuclei;
Variation in fiber size;
Apoptotic nuclei;
Myofibrillar myopathy;
Sarcoplasmic accumulation of electron-dense granulofilamentous material;
Myopathic and neurogenic changes seen on EMG;
Z-disk streaming;
Z-disk degeneration
NEUROLOGIC:
[Central nervous system];
Toe-walking in early childhood;
Clumsy gait;
Loss of ambulation;
[Behavioral/psychiatric manifestations];
Axonal and demyelinating peripheral neuropathy;
Chronic denervation;
Distal sensory impairment;
Hyporeflexia;
Giant axonal neuropathy;
Axonal loss;
Thin myelin sheaths
VOICE:
Hypernasal speech
LABORATORY ABNORMALITIES:
Markedly increased serum creatine kinase
MISCELLANEOUS:
Onset in late childhood or early teens;
Rapidly progressive;
Early death may occur;
Most mutations occur de novo
MOLECULAR BASIS:
Caused by mutation in the BCL2-associated athanogene 3 gene (BAG3,
603883.0001)
OMIM Title
*612972 TIGGER TRANSPOSABLE ELEMENT-DERIVED GENE 1; TIGD1
OMIM Description
DESCRIPTION
DNA transposons are repetitive elements that move in the genome by
excision and reintegration without an RNA intermediate. Tiggers are
ancestral transposons that appear to be the source of several medium
reiterated frequency repeats (MERs) in the human genome. TIGD1 belongs
to a family of genes derived from Tiggers (Smit and Riggs, 1996; Dou et
al., 2004).
MAPPING
Hartz (2009) mapped the TIGD1 gene to chromosome 2q37.1 based on an
alignment of the TIGD1 sequence (GenBank GENBANK AK056329) with the
genomic sequence (build 36.1).
EVOLUTION
- Tigger Transposons
DNA transposons are characterized by terminal inverted repeats (TIRs) of
10 to 500 bp, and they encode a transposase that binds to the TIRs and
catalyzes the cutting and pasting of the element. By searching the human
genome for repetitive elements containing TIRs, followed by database
analysis, Smit and Riggs (1996) identified 2 related elements with
coding capacity that they designated Tigger1 and Tigger2. The deduced
Tigger1 and Tigger2 products share 48% amino acid identity, and both are
related to the Drosophila pogo transposase. Smit and Riggs (1996)
identified several MERs within the genome that appeared to arise by
Tigger duplication. Tigger1 was represented primarily by full-length
elements, whereas most elements related to Tigger2 were partial copies
or included an internal deletion.
INPP5D
| dbSNP name | rs4073603(C,T); rs34218488(T,G); rs4246649(A,G); rs6759288(T,C); rs77391586(G,A); rs4973063(G,A); rs6759511(T,C); rs11888284(C,T); rs80235131(T,C); rs4439944(T,C); rs3935584(T,C); rs4257390(T,C); rs4073363(G,A); rs114958979(T,G); rs4075306(C,A); rs3935583(G,C); rs4075305(T,A); rs139757925(A,C); rs4581888(A,G); rs13035797(A,G); rs11673758(A,G); rs11677752(C,G); rs55749303(C,T); rs72982218(C,T); rs72982221(C,G); rs4973064(A,C); rs72982225(A,C); rs141425069(C,T); rs72982227(C,T); rs58913593(C,T); rs114586452(T,C); rs72982230(C,T); rs138952311(T,C); rs4594431(C,T); rs60486020(G,A); rs4566354(C,T); rs113554688(C,T); rs116779412(C,T); rs6717971(A,G); rs6746785(C,T); rs6704675(T,C); rs6704948(T,C); rs184795888(G,A); rs72982235(G,A); rs72982236(C,T); rs79550752(T,C); rs6747425(C,T); rs114979093(G,A); rs72982239(T,G); rs6721932(A,C); rs6750656(C,G); rs151198509(A,G); rs140494190(A,G); rs73094968(G,A); rs73094970(C,T); rs184732869(G,A); rs6722679(A,G); rs12694924(G,A); rs72982242(T,C); rs72982244(G,A); rs28649756(C,T); rs55816734(G,A); rs28605384(C,G); rs11892111(C,T); rs55827216(G,A); rs56359974(T,A); rs181886158(G,C); rs7576582(A,G); rs186567614(C,T); rs61487211(G,C); rs4973065(G,A); rs12617651(G,A); rs6759488(C,T); rs12617622(C,T); rs6717732(T,C); rs34370170(G,A); rs6734548(A,G); rs72982255(G,A); rs56065581(C,T); rs181235673(C,G); rs77089222(C,T); rs4586623(T,C); rs145330887(A,G); rs4597514(C,T); rs115943460(T,C); rs143536198(G,A); rs4383322(T,C); rs6708049(T,C); rs35350746(G,C); rs7601830(C,T); rs13419542(C,T); rs10199700(G,A); rs79795989(C,T); rs4246650(C,G); rs4603757(T,G); rs7425956(C,T); rs7606583(C,T); rs9679425(G,A); rs7583618(A,G); rs4260233(T,A); rs4335936(C,T); rs4075111(A,C); rs4353640(G,A); rs13387054(G,A); rs56404114(T,C); rs4356648(C,A); rs7608422(G,A); rs140201133(C,T); rs3922950(G,C); rs7590141(A,C); rs7566856(G,A); rs12233023(T,A); rs4335931(T,C); rs35481789(C,T); rs57905758(A,G); rs6756729(A,T); rs10933428(T,C); rs10201551(A,G); rs6746738(T,C); rs6437088(C,G); rs11683143(C,A); rs7423246(G,A); rs12694925(A,G); rs4284824(G,A); rs4289181(G,A); rs74775430(G,A); rs6711326(A,G); rs6740376(C,T); rs6740385(C,T); rs9288678(T,G); rs12474242(A,T); rs13005673(G,A); rs6723093(C,T); rs6723294(C,T); rs4973602(G,A); rs4973069(C,A); rs4973603(G,A); rs4973604(A,C); rs4973605(T,A); rs4973606(A,G); rs4973607(A,C); rs6437089(G,A); rs6437090(G,A); rs6727609(C,T); rs6437091(A,G); rs6437092(A,G); rs6437093(A,G); rs6437094(T,C); rs6437095(C,T); rs6437096(C,T); rs6437097(A,C); rs72984219(C,G); rs10195662(T,C); rs10195664(T,C); rs78931617(A,T); rs4973609(G,A); rs182058167(A,G); rs57371118(A,G); rs56159726(C,T); rs187457991(G,A); rs79270030(G,T); rs111935646(G,C); rs113209490(C,T); rs76116774(G,A); rs9288684(C,T); rs61669959(C,T); rs10804385(T,C); rs191430365(G,A); rs67588496(C,A); rs9752615(G,A); rs9750891(A,G); rs114546788(G,A); rs61068452(A,G); rs60178340(G,A); rs111749074(C,G); rs78933842(C,G); rs78309527(C,T); rs115107477(G,A); rs10933429(C,G); rs75276944(T,C); rs114511196(A,G); rs79974003(T,C); rs13016591(A,T); rs370441595(T,A); rs186121487(C,T); rs141205949(T,C); rs79446057(G,T); rs13427129(C,T); rs13427156(C,A); rs13404184(A,C); rs13392343(T,A); rs149760525(C,T); rs114088072(T,G); rs11903669(G,C); rs7570061(G,A); rs11888199(T,A); rs7599330(C,A); rs11903887(G,A); rs6705834(T,C); rs6712973(A,T); rs6605277(A,C); rs7602833(C,T); rs66493939(T,C); rs72984266(C,T); rs68147208(A,G); rs111502414(T,C); rs72984271(G,A); rs72984274(C,T); rs112715011(A,G); rs139271555(T,C); rs10171658(C,T); rs66905949(G,C); rs60697246(G,A); rs6708745(C,T); rs116572811(A,G); rs145270249(C,A); rs7569598(T,C); rs112878010(C,T); rs10181541(A,G); rs10933431(G,C); rs10933432(C,G); rs7421448(T,C); rs59397833(A,G); rs61672111(C,T); rs13432536(C,T); rs13432627(C,T); rs111489634(G,C); rs73996040(A,G); rs115373923(C,T); rs11885054(G,C); rs138187520(T,C); rs73996041(A,G); rs35368576(T,C); rs6717453(T,C); rs13013293(C,T); rs143304277(T,C); rs9288685(T,C); rs10201557(A,C); rs10193128(T,C); rs148173423(A,G); rs13021947(G,A); rs13022011(C,T); rs144057364(C,T); rs72984294(C,T); rs72984297(C,T); rs72984298(T,A); rs181573526(C,T); rs73105541(A,G); rs73105542(T,A); rs7587242(T,C); rs113623476(C,G); rs7605743(G,T); rs12694926(T,G); rs12694927(G,A); rs111470212(G,T); rs113393739(A,G); rs189160359(T,C); rs113059328(G,A); rs12694928(T,A); rs112716577(T,C); rs6704603(G,A); rs113597069(T,C); rs141088596(T,G); rs12694929(T,C); rs113389798(C,T); rs112031050(A,T); rs10176163(T,A); rs7597516(T,A); rs144431134(A,G); rs7589369(C,G); rs111891260(C,G); rs112629607(C,G); rs148412203(A,C); rs182791720(T,C); rs184562428(G,A); rs113774622(A,C); rs13388142(C,T); rs112236849(T,C); rs113634501(T,C); rs190730343(G,C); rs182223656(G,C); rs111727354(C,T); rs10174016(G,A); rs10173878(C,T); rs10174028(G,A); rs11893401(T,C); rs28376818(G,A); rs193239226(C,T); rs10199951(A,G); rs10176895(G,A); rs10176909(G,A); rs10189300(T,A); rs10200271(A,C); rs10189488(T,C); rs11681000(C,T); rs10933433(C,G); rs10933434(G,T); rs10933435(A,G); rs73105553(C,T); rs144545098(A,G); rs10933436(C,A); rs6738961(C,T); rs11693862(A,G); rs11682791(G,A); rs58884803(C,G); rs11682728(C,T); rs11682798(G,A); rs56265336(G,A); rs56143615(T,C); rs56307293(A,G); rs7557877(A,G); rs79625383(C,T); rs11677508(C,T); rs6756920(T,C); rs6719575(G,A); rs6759973(T,C); rs77868397(C,T); rs13419717(A,C); rs12617905(T,A); rs10202748(A,C); rs7421653(G,A); rs7419666(T,C); rs144181925(T,C); rs140053128(T,G); rs147786898(G,A); rs1135173(G,A); rs36180605(T,G); rs36189208(T,C); rs36181881(A,G); rs149355571(A,G); rs371452221(G,A); rs36171341(A,G); rs146744645(C,T); rs140450451(C,T); rs144125196(G,A); rs140885928(A,G); rs36157180(C,T); rs36134067(G,A); rs148640837(A,G); rs146680237(C,T); rs146523041(C,T); rs140803184(G,C); rs148967109(G,A); rs143850273(G,A); rs148377885(G,T); rs141500584(T,C); rs150889436(G,A); rs149701000(G,A); rs146178696(A,G); rs138410813(T,C); rs142317393(G,A); rs146382281(G,A); rs36142114(C,T); rs36129046(G,T); rs142339885(C,A); rs150521622(T,C); rs149754149(T,G); rs36146561(G,C); rs36131515(A,G); rs36171197(C,G); rs142911999(G,A); rs145129423(C,T); rs137933594(G,C); rs148602645(T,C); rs145226909(G,A); rs36138569(T,C); rs36172244(T,C); rs145770967(C,A); rs36148770(T,C); rs36149367(T,C); rs36149390(G,A); rs36180389(G,A); rs36130536(C,T); rs139326470(A,G); rs141410484(C,A); rs143865234(C,T); rs36194657(A,G); rs36151663(C,T); rs36136502(G,A); rs137945009(C,A); rs143436458(A,C); rs149294471(A,G); rs144572050(C,T); rs142888286(T,C); rs146095751(G,A); rs150035249(A,T); rs145368672(T,A); rs148846867(T,C); rs147595122(T,C); rs141917895(A,G); rs138923135(C,T); rs150345441(G,A); rs138015578(A,G); rs149515675(A,G); rs146077639(C,A); rs36131511(G,A); rs36162295(C,G); rs36130256(C,T); rs142110920(C,A); rs145742767(C,T); rs148827642(G,T); rs143588376(C,T); rs36136752(G,A); rs36145835(G,T); rs36195783(G,A); rs36153144(G,A); rs36183661(C,G); rs36138480(G,A); rs36172148(T,A); rs36131975(T,C); rs144804244(G,A); rs36129915(G,T); rs36142198(A,C); rs138713068(C,T); rs36127492(C,G); rs148118779(A,G); rs36165346(A,G); rs36153082(T,C); rs36181983(T,C); rs145579957(G,A); rs144478195(C,T); rs150943557(A,G); rs36164374(G,A); rs36177526(G,A); rs36133610(G,A); rs74222529(C,T); rs67498812(A,G); rs75322627(T,A); rs62192874(G,A); rs35349669(C,T); rs28669088(C,T); rs28534487(C,A); rs74523514(T,C); rs140005135(T,C); rs28655385(C,A); rs28459768(A,C); rs28478933(C,A); rs28429042(C,T); rs28631646(C,T); rs28539971(G,A); rs35877172(C,T); rs28605534(G,C); rs28609111(G,A); rs28576692(T,C); rs28751960(A,T); rs28437902(T,C); rs145096292(A,G); rs7607812(G,A); rs55801407(G,A); rs7568027(A,G); rs7559212(A,C); rs4430948(A,G); rs13385791(C,T); rs141642539(T,C); rs6715810(C,T); rs149130511(G,A); rs10182902(G,A); rs6715767(G,A); rs10175286(C,T); rs7558417(C,T); rs7583176(A,G); rs111974734(C,T); rs7570320(C,A); rs7570656(A,T); rs148742517(T,C); rs12052961(A,G); rs145835056(T,C); rs7577360(G,A); rs7581787(A,C); rs62192877(G,T); rs7569837(T,C); rs10754947(G,A); rs147572692(C,T); rs6431237(A,G); rs6741388(C,T); rs59836591(G,A); rs6431239(G,A); rs13408647(G,A); rs73105592(C,T); rs13385922(C,T); rs141013376(T,C); rs7568389(C,G); rs7597763(A,C); rs10193017(G,A); rs10179304(T,A); rs148646263(C,T); rs113807511(C,G); rs62192878(G,C); rs61225971(A,G); rs60886467(C,T); rs72972242(T,A); rs113059868(C,T); rs78674368(C,T); rs6720896(T,C); rs6737719(G,A); rs148127775(T,A); rs150736244(G,A); rs113848123(T,C); rs182128489(T,G); rs4585024(A,G); rs11684564(T,C); rs113230465(T,C); rs73111445(G,T); rs62192879(T,G); rs4395246(C,A); rs4571051(T,C); rs72972259(T,C); rs10208466(G,T); rs4503982(T,C); rs77206203(G,A); rs4436949(A,G); rs6431381(C,G); rs6740918(G,A); rs115685855(A,G); rs11686233(C,G); rs151110318(C,G); rs7584458(A,G); rs12612322(G,T); rs144468389(C,T); rs76413167(C,T); rs117684491(C,A); rs147479628(G,A); rs75961839(T,C); rs7605022(G,C); rs4663221(C,G); rs3890760(T,C); rs7603087(A,G); rs79330248(G,A); rs73111456(C,T); rs56063952(A,G); rs4663643(A,G); rs3924334(T,A); rs10176734(G,T); rs10168693(A,G); rs10203185(C,T); rs11675867(A,T); rs115296980(T,A); rs11681058(G,T); rs116293005(C,T); rs34888825(C,T); rs116792876(C,A); rs3924336(T,G); rs62192895(C,G); rs73111460(G,A); rs6706611(G,A); rs13027728(G,C); rs59929577(C,T); rs138009423(C,T); rs34587266(T,C); rs11674483(C,T); rs11680711(A,G); rs10929185(C,T); rs146315925(C,T); rs77443371(C,T); rs7569134(G,C); rs7569827(G,A); rs144190615(T,C); rs6719549(G,A); rs6722529(G,A); rs191450043(T,C); rs12692197(G,A); rs7577111(G,C); rs6760912(A,G); rs4468807(C,T); rs6761018(A,C); rs34865199(A,G); rs116594323(G,A); rs7609436(T,C); rs7346(G,A); rs9247(C,T); rs374411309(C,T); rs1135727(A,G); rs28505715(G,C); rs4663784(C,T); rs116061588(A,G); rs13408498(T,C); rs7609307(C,T); rs3792117(G,A); rs187622749(C,A); rs7559281(C,T); rs1057258(C,T); rs14243(A,G) |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 3635 |
| EntrezGene Description | inositol polyphosphate-5-phosphatase, 145kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7156 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q92835-2 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.005335 |
| ESP All MAF | 0.001712 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0004655 |
OMIM Clinical Significance
Eyes:
Severe glaucoma;
Exophthalmia
Limbs:
Severe micromelia;
Contractures of elbow and hip
Head:
Dolichocephaly;
Large anterior fontanel
Facies:
Malar hypoplasia
Mouth:
Cleft palate
Radiology:
Short, broad long bones with flared metaphyses;
Detailed epiphyseal ossification;
Flat vertebral bodies
Inheritance:
? Autosomal recessive
OMIM Title
*601582 INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 145-KD; INPP5D
;;SH2-CONTAINING INOSITOL PHOSPHATASE; SHIP;;
SHIP1
OMIM Description
CLONING
The phosphatidylinositols serve as precursors for a number of different
messenger molecules. Agonist stimulation of cells results in
phosphatidylinositol turnover and the generation of inositol
1,4,5-triphosphate (Ins(1,4,5)P3), which mobilizes intracellular
calcium. The inositol-polyphosphate 5-phosphatase (INPP5) enzymes
hydrolyze Ins(1,4,5)P3 in a signal-terminating reaction. Known INPP5s
include the 40-kD INPP5A (600106), the 75-kD INPP5B (147264), and the
enzyme associated with Lowe oculocerebrorenal syndrome (300535). Damen
et al. (1996) cloned and sequenced a cDNA encoding a 145-kD protein from
a mouse hematopoietic cell line; the protein became tyrosine
phosphorylated and associated with SHC (600560) after cytokine
stimulation. Based on its domains and enzymatic activity, Damen et al.
(1996) named this protein SHIP for 'SH2-containing inositol
phosphatase.'
Ware et al. (1996) described the cloning of the human homolog of murine
Ship from a human megakaryocytic cell line cDNA library using 2
nonoverlapping mouse Ship cDNA fragments as probes. Northern blot
analysis suggested that human SHIP is expressed as a 5.3-kb mRNA in bone
marrow and a wide variety of other tissues. Sequence analysis of the
cDNA predicted a protein of 1,188 amino acids exhibiting 87.2% overall
sequence identity with mouse Ship. Contained within the defined open
reading frame was an N-terminal, group I src homology (SH2) domain; 3
NXXY motifs that, if phosphorylated, could be bound by
phosphotyrosine-binding (PTB) domains; a C-terminal proline-rich region;
and 2 centrally located inositol polyphosphate 5-phosphatase motifs.
Using the sequences of known inositol and phosphatidylinositol
polyphosphate 5-phosphatases, Drayer et al. (1996) designed degenerate
oligonucleotides and subsequently cloned a novel 5-phosphatase, which
they called 51CN. They cloned a full-length cDNA from a human placenta
library and found that it encodes a 1,188-amino acid protein with a
predicted molecular mass of 133 kD. The sequence predicted an N-terminal
region containing an SH2 domain, a central 5-phosphatase domain, and a
C-terminal proline-rich region with consensus sites for SH3-domain
interactions. Northern blot analysis revealed a 5-kb message expressed
strongly in placenta and heart and weakly in brain and lung tissues. The
authors also noted the presence of an 8-kb transcript in heart and
skeletal muscle. Following expression in COS-7 cells, Drayer et al.
(1996) showed that this enzyme has a specificity for substrates
phosphorylated at the 3-position. Kavanaugh et al. (1996) found 3 splice
variants of the 51CN gene which, based on their molecular masses, they
termed SIP-110, SIP-130, and SIP-145. The SIP-110 protein was isolated
based on its binding to the SH3 domain of GRB2 (108355). The SIP-130 and
SIP-145 proteins were isolated based on their binding to the PTB domain
of SHC. The authors stated that INPP5s may be associated with GRB2- and
SHC-mediated signal transduction.
By using a modified yeast 2-hybrid system to find proteins that bind the
SHC phosphotyrosine-binding domain, Lioubin et al. (1996) independently
cloned INPP5D and designated it p150(Ship).
GENE FUNCTION
Liu et al. (1998) studied the expression of the Ship gene during mouse
development. They found that the gene is expressed in late
primitive-streak stage embryos (7.5 days postcoitum), when hematopoiesis
is thought to begin, and the expression is restricted to the
hematopoietic lineage. In adult mice, Ship expression continues in most
cells of hematopoietic origin, including granulocytes, monocytes, and
lymphocytes, and is also found in the spermatids of the testis.
Furthermore, the level of Ship expression is developmentally regulated
during T-cell maturation. These results suggested a possible role for
Ship in the differentiation and maintenance of the hematopoietic
lineages and in spermatogenesis.
Valderrama-Carvajal et al. (2002) studied the signaling pathway
activated by inhibin (147290) and TGF-beta (TGFB1; 190180) during
apoptosis in mouse and human hematopoietic cell lines. They determined
that the downstream effectors include SMAD (see 601595) and SHIP.
Activation of the SMAD pathway induced SHIP expression, resulting in
intracellular changes in phospholipid pools and inhibited
phosphorylation of protein kinase B (AKT1; 164730).
Using microarray analysis, O'Connell et al. (2009) identified Ship1
among transcripts repressed by stable expression of human MIR155
(609337) in a mouse macrophage cell line. Transgenic mice expressing
human or mouse MIR155 or a small interfering RNA directed to Ship1
showed similar myeloproliferative disorder phenotypes in spleen and bone
marrow. Bone marrow was pale and contained an elevated population of
granulocyte/monocyte progenitors, and spleen showed splenomegaly with
abnormal architecture and expanded interfollicular regions containing
developing myeloid populations, erythroid precursors, and
megakaryocytes. O'Connell et al. (2009) concluded that repression of
SHIP1 is a critical aspect of MIR155 function in the hematopoietic
system.
Sly et al. (2009) noted that gram-negative bacterial infections do not
protect against subsequent viral infections, even though
lipopolysaccharide (LPS), like double-stranded RNA (dsRNA), activates
the TRIF (TICAM1; 607601) pathway and stimulates production of type I
IFN (e.g., IFNA; 147660). They found that Ship protein levels were
dramatically increased in murine macrophages via the Myd88
(602170)-dependent pathway by upregulating Tgfb. Increased Ship, via
inhibition of PI3K, mediated CpG- and LPS-induced tolerance and
restrained Ifnb (147640) production induced by subsequent exposure to
LPS or dsRNA. Ship -/- mice overproduced Ifnb in response to LPS,
responded well against virus, and exhibited severe hypothermia rather
than fever after low- or high-dose LPS challenge. Sly et al. (2009)
concluded that upregulation of SHIP in response to gram-negative
bacterial infections explains the inability of such infections to
protect against subsequent viral infections.
Khalil et al. (2012) showed that most proliferating germinal center B
cells do not demonstrate active B cell receptor signaling. Rather,
spontaneous and induced signaling was limited by increased phosphatase
activity. Accordingly, both SH2 domain-containing phosphatase-1 (SHP1;
176883) and SHIP1 were hyperphosphorylated in germinal center cells and
remained colocalized with B cell receptors after ligation. Furthermore,
SHP1 was required for germinal cell maintenance. Intriguingly, germinal
center B cells in the cell cycle G2 period regained responsiveness to B
cell receptor stimulation.
MAPPING
Liu et al. (1997) mapped the mouse INPP5D homolog to 1C5 by fluorescence
in situ hybridization (FISH). By FISH, using the full-length human SHIP
cDNA as a probe, Ware et al. (1996) mapped SHIP to the border of 2q36
and 2q37.
ANIMAL MODEL
Helgason et al. (1998) generated mice homozygous for a targeted
disruption of the SHIP gene. Although viable and fertile, the SHIP-null
mice failed to thrive, and survival was only 40% by 14 weeks of age. The
mice exhibited a myeloproliferative-like syndrome with consolidation of
the lungs caused by infiltration of macrophages. Helgason et al. (1998)
concluded that SHIP plays a crucial role in modulating cytokine
signaling within the hematopoietic system.
To clarify the role that SHIP plays in mast cell degranulation, Huber et
al. (1998) disrupted the SHIP gene in mice by homologous recombination
in embryonic stem cells. Homozygous SHIP -/- mast cells were found to be
far more prone to degranulation, after the crosslinking of IgE preloaded
cells, than SHIP +/- or +/+ cells. IgE alone also stimulated massive
degranulation in SHIP -/- but not +/+ mast cells. This degranulation
with IgE alone, which may be due to low levels of IgE aggregates,
correlated with a higher and more sustained intracellular calcium level
than that observed with SHIP +/+ cells and was dependent on the entry of
extracellular calcium. The results showed the critical role that SHIP
plays in setting the threshold for degranulation and demonstrated that
SHIP directly modulates a 'positive-acting' receptor.
Wang et al. (2002) generated mice with a targeted mutation in SHIP,
resulting in Ship -/- mice. Flow cytometric analysis demonstrated that
natural killer (NK) cells develop normally in juvenile Ship-deficient
mice, but that adult mice express 10-fold higher levels of NK1.1
receptor and an overall increase in NK cell levels due to prolonged
survival. The prolonged survival is accompanied by significantly altered
levels of Ly49 (see 604274) and CD94 (602894) receptors, indicating that
Ship-deficient mice express a repertoire of inhibitory receptors that
are both self-specific and promiscuous for other ligands. Western blot
analysis showed significant increases in Akt (164730) and Akt
phosphorylation, as well as increased Bcl2 (151430), in the NK cells of
Ship-deficient mice, indicating the activation of the PIK3 (see 171834)
pathway. Wang et al. (2002) noted that the recruitment of Ship by Ly49
in mice is analogous to SHIP recruitment by KIR (604936) in humans and
that this may limit the in vivo survival of NK cells and limit NK
effector function. Transplantation experiments determined that fully
MHC-mismatched bone marrow is rejected by wildtype, but not Ship -/-,
mice. The mutant mice, however, were able to reject B2M (109700) -/-
marrow, suggesting that the NK compartment of Ship-deficient mice is not
broadly disabled. In addition, most of the mutant mice did not develop
graft-versus-host disease (GVHD; see 614395), whereas most wildtype mice
did not survive the mismatched transplant. Wang et al. (2002) proposed
that inhibiting SHIP activity prior to bone marrow transplant can
restrict the NK inhibitory repertoire, such that selecting a donor with
an appropriate MHC ligand or ligands might enable engraftment in the
absence of GVHD.
Because Ship -/- mice contain increased numbers of osteoclast
precursors, i.e., macrophages, Takeshita et al. (2002) examined bones
from these animals and found that osteoclast number was increased
2-fold. The increased number was the result of prolonged life span of
these cells and hypersensitivity of precursors to macrophage
colony-stimulating factor (MCSF; 120420) and receptor activator of
nuclear factor-kappa-B ligand (RANKL; 602642). Similar to the
osteoclasts of Paget disease of bone (602080), Ship -/- osteoclasts were
enlarged, containing upwards of 100 nuclei, and exhibited enhanced
resorptive activity. Moreover, as in Paget disease, serum levels of
interleukin-6 (IL6; 147620) were markedly increased in Ship -/- mice.
Consistent with accelerated resorptive activity, a 22% loss of
bone-mineral density and a 49% decrease in fracture energy were
observed. Thus, SHIP negatively regulates osteoclast formation and
function, and the absence of this enzyme results in severe osteoporosis.
Severin et al. (2007) found that Ship1 deficiency in mice affected
platelet aggregation in response to several agonists, with minor effects
of fibrinogen (see 134820) binding and beta-3 integrin (ITGB3; 173470)
tyrosine phosphorylation. Accordingly, Ship1-null mice showed defects in
arterial thrombus formation in response to localized laser-induced
injury, and these mice had prolonged tail bleeding time. Upon
stimulation, Ship1-deficient platelets showed large membrane extensions,
abnormalities in the open canalicular system, and a dramatic decrease in
close cell-cell contacts. Ship1 appeared to be required for platelet
contractility, thrombus organization, and fibrin clot retraction.
Antignano et al. (2010) observed increased numbers of splenic dendritic
cells (DCs) in Ship -/- mice and increased expansion of DCs from Ship
-/- DC precursors ex vivo in response to Gmcsf (CSF2; 138960). However,
Ship -/- DCs had an immature phenotype, characterized by lower
expression of MHC class II, Cd40 (109535), Cd80 (112203), and Cd86
(601020), and they produced less Il12 (see 161560) and Il10 (124092),
but more Tnf (191160) and Il6, compared with wildtype DCs. Ship -/- DCs
were also less able to stimulate antigen-specific T-cell proliferation
and Th1 cytokine production. The immature phenotype of Ship -/- DCs
could be reversed by phosphatidylinositol 3-kinase (PI3K; see 601232)
inhibitors, suggesting that SHIP promotes DC maturation by reducing PI3K
second messenger levels. Antignano et al. (2010) concluded that SHIP is
a negative regulator of GMCSF-derived DC generation, but a positive
regulator of GMCSF-derived maturation and function.
Using Ship -/- mice and mice with a conditional deletion of Ship in
hemopoietic stem cells (HSCs), Hazen et al. (2009) showed that the
reconstitution capacity of the HSCs was not compromised if resident in a
Ship-competent bone marrow milieu. The same cells in Ship -/- mice were
functionally compromised for repopulation. Hazen et al. (2009) concluded
that SHIP is required in bone marrow for functionally competent HSCs.
By flow cytometric analysis, Collazo et al. (2009) showed that Ship -/-
mice had increased Cd4-positive/Cd25-positive/Foxp3 (300292)-positive
regulatory T (Treg) cells, as well as
Cd4-positive/Cd25-negative/Foxp3-positive naive T cells. Ship -/-
Cd4-positive/Cd25-negative T cells, like conventional Treg cells, were
unresponsive to MHC-mismatched stimulator cells and suppressed
allogeneic T-cell responses in vitro. In addition, Ship -/-
Cd4-positive/Cd25-negative T cells mediated reduced lethal GVHD on
adoptive transfer to MHC-mismatched hosts. Hosts with induced Ship
deficiency had delayed rejection of mismatched heart grafts. Collazo et
al. (2009) concluded that SHIP is required for robust GVHD and
host-versus-graft responses, suggesting that SHIP could be targeted in
clinical transplantation.
DNAJB3
| dbSNP name | rs3796088(T,C) |
| ccdsGene name | CCDS2509.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 100286922 |
| EntrezGene Symbol | LOC100286922 |
| snpEff Gene Name | UGT1A10 |
| EntrezGene Description | DnaJ (Hsp40) homolog, subfamily B, member 3 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.112 |
LOC100286922
| dbSNP name | rs1054804(C,T); rs10929301(C,G) |
| ccdsGene name | CCDS2509.1 |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 101927831 |
| EntrezGene Symbol | LOC101927831 |
| snpEff Gene Name | UGT1A10 |
| EntrezGene Description | dnaJ homolog subfamily B member 3-like |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02571 |
ARL4C
| dbSNP name | rs115792278(G,T); rs1043029(T,C); rs10194289(G,T); rs200533981(T,G); rs201518427(T,A); rs6719230(T,A); rs8245(C,G) |
| cytoBand name | 2q37.1 |
| EntrezGene GeneID | 10123 |
| EntrezGene Description | ADP-ribosylation factor-like 4C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Dilation of dermal capillaries
SKIN, NAILS, HAIR:
[Skin];
Collodion membrane at birth (in some patients);
Fine white or greyish-white scales;
Erythroderma (in some patients);
Hyperlinearity of palms (in some patients);
Palmoplantar keratoderma (in some patients);
Scales on scalp (in some patients);
HISTOLOGY:;
Hyperkeratosis;
Orthokeratosis (in some patients);
Thickening of stratum corneum, mild;
Acanthosis, moderate;
Parakeratosis, moderate;
Granular layer normal or slightly prominent;
Perivascular lymphocytic infiltrate, dermal, mild;
Dilation of dermal capillaries
MISCELLANEOUS:
Disease complicated by recurrent sepsis in some patients
MOLECULAR BASIS:
Caused by mutation in the cytochrome P450, family 4, subfamily F,
polypeptide 22 gene (CYP4F22, 611495.0001)
OMIM Title
*604787 ADP-RIBOSYLATION FACTOR-LIKE 4C; ARL4C
;;ADP-RIBOSYLATION FACTOR-LIKE 7; ARL7
OMIM Description
CLONING
ADP-ribosylation factors (ARFs; see ARF1, 103180) regulate diverse
cellular functions, such as vesicle traffic, endocytosis, and
phospholipase D activity. ARFs and ARF-like (ARL) proteins, which share
sequence similarity with ARFs, form a subfamily of the Ras-related
GTPase superfamily. By searching EST databases for sequences that are
similar to murine Arl4 (604786), Jacobs et al. (1999) identified human
ESTs corresponding to a novel ARL, ARL7. Using RT-PCR, they isolated a
human bladder epithelium ARL7 cDNA containing a full-length coding
sequence. The predicted 192-amino acid ARL7 protein contains the motifs
that are presumably involved in nucleotide binding and hydrolysis in
other Ras-related GTPases. ARL7 also has the highly conserved residues
typical of members of the ARF subfamily. Jacobs et al. (1999)
demonstrated that the C terminus of ARL7 harbors a functional nuclear
localization signal. ARL7 shares 71% amino acid identity with rat ARL4,
59% identity with human ARL6 (608845), 49% identity with human ARF1, and
43% identity with rat ARL1 (603425). Recombinant ARL7 had a considerably
higher rate of guanine nucleotide exchange activity than ARF1 and ARP
(ARFRP1; 604699). Northern blot analysis detected a 3.6-kb ARL7
transcript at high levels in brain and at lower levels in spleen,
thymus, esophagus, stomach, intestine, and uterus.
GENE FUNCTION
Ji et al. (2010) examined 4.6 million CpG sites throughout the mouse
genome for multipotent progenitors (MPPs), common lymphoid progenitors
(CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage
progenitors (GMPs), and thymocyte progenitors. Many examples of genes
and pathways not previously known to be involved in choice between
lymphoid/myeloid differentiation were identified, such as Arl4c and Jdp2
(608657). Ji et al. (2010) concluded that their data provided a
comprehensive map of the methylome during myeloid and lymphoid
commitment from hematopoietic progenitors.
IQCA1
| dbSNP name | rs13431281(A,T); rs6431452(C,A); rs7608734(G,A); rs7596805(A,C); rs10168914(T,G); rs7609398(G,T); rs13425394(C,T); rs6708050(G,A); rs13391313(A,G); rs13402890(G,A); rs6759477(T,A); rs199815380(T,C); rs6431453(G,A); rs6431454(A,G); rs6716112(G,A); rs6705889(T,G); rs6745692(C,T); rs7570322(G,T); rs13410280(G,A); rs72978603(A,G); rs2046284(A,G); rs62191029(G,A); rs7585499(C,T); rs7601923(T,C); rs58529851(C,A); rs6431455(T,C); rs71424910(G,A); rs6758666(A,C); rs6714545(G,T); rs6704601(T,C); rs6431456(T,C); rs7566079(G,A); rs6431457(C,T); rs7557194(T,C); rs7593746(C,T); rs377559100(T,C); rs62191032(C,T); rs72978613(C,G); rs58127588(T,C); rs56692031(G,A); rs56942260(C,G); rs60242756(C,T); rs55865650(G,A); rs2167879(C,T); rs80206374(C,G); rs77534044(C,T); rs72978619(G,A); rs77704052(C,T); rs147905533(G,A); rs62192361(A,G); rs74533213(T,G); rs72978633(G,A); rs62192362(T,C); rs62192363(C,G); rs55848659(T,C); rs7563187(C,T); rs374357858(G,A); rs74941416(C,T); rs62192365(T,C); rs4060823(C,T); rs56259145(G,A); rs116562332(C,T); rs72978641(T,C); rs116042492(G,A); rs60050750(G,A); rs72978644(G,A); rs372523410(C,T); rs146494641(C,A); rs72978647(C,A); rs139964368(A,G); rs149749687(G,A); rs375047481(G,A); rs62192368(T,C); rs62192369(A,G); rs62192370(A,G); rs150800328(G,C); rs147569288(G,A); rs62192371(A,G); rs62192372(T,C); rs77466706(C,A); rs77514864(C,T); rs13428016(T,A); rs7576763(C,T); rs76879666(C,T); rs7593458(T,C); rs144572338(A,G); rs62192374(C,T); rs62192375(A,G); rs66808092(T,C); rs116709114(T,C); rs6748498(T,G); rs6758710(G,A); rs6734045(C,T); rs144254887(C,T); rs62192376(A,G); rs67796631(G,A); rs59403004(G,A); rs57364322(C,T); rs74598509(T,G); rs55675564(G,A); rs62192377(T,C); rs62192378(C,T); rs72980696(T,G); rs1078913(C,T); rs10200884(C,A); rs115655308(G,A); rs193070529(C,T); rs56012891(A,C); rs55796341(T,C); rs55789711(T,C); rs72982610(G,A); rs141678102(G,C); rs2046286(G,A); rs143605386(T,C); rs114424648(T,C); rs62192388(C,A); rs187512383(T,C); rs141624764(C,T); rs139716141(C,T); rs6724356(C,T); rs78775391(T,C); rs72982618(G,A); rs145473335(T,C); rs72982621(A,G); rs6743420(A,G); rs138534842(C,T); rs56017702(A,C); rs6740905(C,T); rs116366222(T,C); rs144664353(T,G); rs62192392(A,G); rs142604029(A,G); rs62192393(T,C); rs62192394(A,G); rs189869149(A,G); rs62192395(C,T); rs73125863(G,A); rs372100075(C,T); rs62192396(T,C); rs62192398(T,A); rs62192400(A,G); rs60501707(T,A); rs73125868(T,G); rs114767609(G,A); rs115235647(G,C); rs114279184(G,T); rs192330871(G,T); rs183628806(C,T); rs150115774(C,T); rs13399907(A,G); rs13386822(C,T); rs7576576(G,A); rs147235905(C,G); rs189631095(C,T); rs114728138(A,G); rs149036249(A,G); rs142083575(G,A); rs13405611(T,C); rs7563323(A,G); rs147084500(T,G); rs7566807(A,T); rs146905082(A,G); rs6733348(G,T); rs113822881(T,C); rs116051132(T,C); rs116786902(G,C); rs55830125(C,T); rs139664273(A,G); rs116658935(C,G); rs141193805(C,T); rs10204742(T,C); rs1384580(G,A); rs1384581(T,C); rs62189775(G,T); rs116474177(C,T); rs115802011(G,T); rs1482959(G,A); rs1482960(T,C); rs67765089(C,A); rs115268007(G,A); rs142823391(G,A); rs6728418(C,T); rs6728422(C,A); rs6742962(A,G); rs6728779(C,T); rs6746336(A,G); rs6759530(G,T); rs6749502(T,C); rs13382640(A,G); rs62189776(C,T); rs11885437(A,G); rs72984714(C,T); rs62189777(G,T); rs6431459(A,G); rs6431460(C,T); rs74413598(G,T); rs55997105(T,C); rs111886813(G,A); rs3738986(G,A); rs6719078(G,A); rs6748813(C,T); rs6748933(C,T); rs141457001(C,T); rs62189780(C,T); rs73996893(C,T); rs2046280(G,C); rs2046281(G,T); rs2046282(A,G); rs2046283(T,G); rs150361605(G,A); rs7585175(C,T); rs73996895(C,T); rs138665750(C,T); rs148442277(A,G); rs146134094(G,A); rs140164571(T,C); rs143924908(A,G); rs114600570(C,T); rs148284155(C,T); rs141150478(C,T); rs6431461(A,G); rs7603314(C,T); rs146113778(G,A); rs187616880(C,T); rs55718468(C,T); rs56140319(C,T); rs147604626(T,A); rs146057336(T,C); rs148911981(A,C); rs143427754(G,T); rs138620354(A,G); rs35136956(T,G); rs114173352(T,C); rs6709427(C,T); rs144872333(T,C); rs140790157(C,T); rs73996899(G,A); rs6752563(G,A); rs142978256(A,G); rs6431462(C,G); rs139943716(T,G); rs148458381(C,T); rs373621111(T,C); rs140273238(G,A); rs74748794(G,T); rs72984735(A,C); rs11899054(A,G); rs62189785(C,T); rs150236457(T,C); rs1871988(A,C); rs1905236(C,T); rs149561369(C,T); rs115481673(T,A); rs75311722(T,C); rs1871990(G,C); rs144901707(C,A); rs73996902(G,A); rs58636821(G,T); rs146253678(C,G); rs6750125(A,G); rs76246561(T,C); rs6431463(T,C); rs1586094(T,A); rs145536314(G,A); rs151237326(A,C); rs145662766(G,A); rs10929179(T,C); rs1384578(T,C); rs1384579(A,C); rs35954558(G,C); rs140829205(C,T); rs143478893(C,G); rs143946461(A,G); rs6719264(T,C); rs11896490(A,G); rs11896685(A,T); rs11897843(T,C); rs191257270(C,T); rs75181222(G,A); rs11892411(C,T); rs11900652(T,C); rs151251705(G,T); rs146996104(C,T); rs149120665(A,G); rs2317638(A,G); rs137971441(C,T); rs6743304(T,C); rs146134376(G,A); rs192118719(C,T); rs59150836(G,T); rs140165383(C,G); rs59375752(C,T); rs73127814(T,C); rs111890705(A,G); rs73127815(G,A); rs6731334(A,G); rs75373936(A,T); rs148823732(A,G); rs75753478(G,C); rs7591054(T,G); rs112521322(C,T); rs368672540(G,A); rs73998616(A,G); rs147237811(T,G); rs79499851(C,T); rs57597567(C,T); rs73998617(G,C); rs143676246(C,T); rs372490414(C,G); rs113542405(C,T); rs7591215(G,A); rs7582440(T,C); rs113030155(T,C); rs72988877(G,A); rs28527781(G,A); rs150968425(T,C); rs900439(A,C); rs113495272(A,T); rs28424021(A,G); rs28608629(A,G); rs111725017(T,C); rs141371257(C,T); rs112452976(C,T); rs35432941(C,T); rs60012516(T,C); rs111887800(C,A); rs56895846(G,A); rs112571137(C,T); rs55838320(C,T); rs13430726(C,A); rs148067900(A,T); rs115341207(C,T); rs10166015(C,T); rs147144592(G,A); rs10201525(C,T); rs73998619(A,G); rs56044945(A,G); rs2873519(A,C); rs376634314(T,C); rs2317639(A,C); rs62189794(T,A); rs6706805(T,C); rs78627877(C,T); rs78484260(T,G); rs115029312(G,T); rs111665518(G,T); rs13408545(T,G); rs75696399(C,A); rs376482102(C,G); rs62189795(C,T); rs111785697(T,A); rs28858705(A,G); rs28865871(T,C); rs74475733(T,C); rs184217129(T,C); rs76020172(A,G); rs138976163(T,C); rs142684912(C,T); rs115553277(T,G); rs59244680(T,C); rs11891900(A,C); rs137964384(T,C); rs149489336(T,G); rs376128897(T,C); rs2317907(T,C); rs2317908(C,T); rs370314640(A,G); rs13415559(A,T); rs13402598(C,T); rs73998624(G,A); rs13402878(C,A); rs372354354(T,C); rs142168986(T,C); rs10201507(T,C); rs373094224(A,G); rs1986381(C,G); rs78506565(C,A); rs61754936(A,C); rs6751722(G,A); rs112574671(C,A); rs113318210(T,C); rs60508202(T,C); rs7604255(G,A); rs72988893(C,A); rs6749746(T,A); rs56213437(C,T); rs58280998(C,T); rs73127838(A,G); rs61014078(T,C); rs58519633(A,G); rs147271498(A,G); rs183455822(C,T); rs1807773(T,C); rs144005162(G,A); rs73127841(C,G); rs3761713(G,A); rs73998636(G,C); rs3761714(G,A); rs73998637(G,A); rs73127846(A,C); rs2317644(T,G); rs139563860(C,T); rs73127849(T,C); rs6748779(T,G); rs6749165(T,A); rs140549745(A,T); rs59003890(A,G); rs4663648(C,T); rs4663649(T,C); rs12328446(G,C); rs6709076(G,A); rs73127855(A,G); rs60545079(A,G); rs111264846(T,C); rs78518051(C,T); rs77048153(G,A); rs2317640(T,C); rs5028467(T,A); rs7562715(T,C); rs4281859(T,C); rs73127861(C,T); rs4505467(C,T); rs144916683(C,T); rs6431464(C,T); rs13421791(C,T); rs59024700(G,T); rs73127866(G,A); rs183167805(C,T); rs73127867(G,A); rs11885826(T,C); rs11885828(T,C); rs11901661(C,T); rs77898878(C,T); rs13390666(T,C); rs13391228(T,G); rs73998662(G,C); rs147176858(C,T); rs4427967(A,G); rs13432714(C,T); rs76557076(A,G); rs10179669(T,C); rs10167317(C,A); rs10179644(A,C); rs1962309(A,C); rs73127878(G,C); rs115291079(C,G); rs73127879(C,T); rs73127880(A,G); rs73127881(G,A); rs11893167(T,A); rs79543813(C,T); rs73127884(C,G); rs1922798(C,T); rs73127885(G,A); rs73127887(T,A); rs4663650(A,G); rs80148244(C,T); rs57200920(C,T); rs73127891(A,G); rs75774242(G,T) |
| ccdsGene name | CCDS46549.1 |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 79781 |
| EntrezGene Description | IQ motif containing with AAA domain 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IQCA1:NM_001270585:exon8:c.A1048G:p.I350V,IQCA1:NM_024726:exon8:c.A1027G:p.I343V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7056 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| ExAC AF | 0.0001403 |
COL6A3
| dbSNP name | rs7436(T,A); rs4663722(C,G); rs4663724(C,A); rs4414631(A,G); rs4641892(G,A); rs6720773(T,C); rs12998915(T,G); rs10191631(A,T); rs13018020(C,T); rs13018217(C,T); rs6722463(A,C); rs6431536(G,A); rs6431537(C,T); rs75586091(A,C); rs1039155(A,G); rs1039156(G,C); rs1566153(C,T); rs115510139(A,T); rs13403106(A,G); rs12692201(T,C); rs13403733(A,G); rs56033985(C,T); rs10201060(G,A); rs113074221(C,T); rs2270671(G,A); rs10201909(G,A); rs2270669(C,G); rs7561606(C,G); rs11682162(C,T); rs113295051(T,G); rs11687877(A,G); rs10929226(G,C); rs4233631(T,C); rs11690358(T,C); rs111859552(C,T); rs111668515(T,A); rs111597227(T,G); rs112208903(G,C); rs112995858(G,T); rs28709058(A,G); rs112737490(T,C); rs72984184(T,C); rs112315665(T,C); rs113746649(C,A); rs111232447(G,A); rs112523013(A,G); rs112384249(G,C); rs112538848(A,C); rs112557330(C,T); rs111671687(G,A); rs112589267(G,A); rs111410929(C,T); rs57074977(G,A); rs113907246(A,T); rs35763271(T,C); rs80193928(T,G); rs4433949(C,T); rs111595697(G,A); rs112818200(C,G); rs10202434(T,G); rs6735032(T,G); rs12105222(C,T); rs12105619(A,C); rs12105704(T,C); rs10929227(A,G); rs6748526(G,A); rs6748910(G,A); rs11885964(G,C); rs11897148(C,G); rs2646258(G,A); rs10084221(G,A); rs113448987(C,T); rs2256485(A,G); rs111940831(G,A); rs111428562(T,G); rs78148457(G,A); rs2270656(C,T); rs35902696(T,G); rs6761147(G,A); rs7586225(C,A); rs7586434(C,T); rs376142209(C,A); rs13398955(G,A); rs2645767(C,T); rs77941529(C,T); rs35993209(T,C); rs57728742(T,C); rs13402341(G,A); rs2646265(G,A); rs3790990(C,A); rs2646264(C,G); rs2646263(A,G); rs113165342(G,A); rs11889732(T,C); rs2645766(G,T); rs2646262(C,T); rs3790993(C,G); rs10167181(C,T); rs75838380(A,G); rs2646261(A,G); rs3790995(G,A); rs112307296(C,T); rs73998881(G,T); rs3790996(G,C); rs185894227(G,A); rs3790998(C,A); rs11901326(C,A); rs2645765(T,C); rs2646257(T,C); rs36117715(G,A); rs2645764(C,T); rs2646256(A,G); rs2646255(A,C); rs2645763(C,A); rs73998887(G,A); rs10178599(A,G); rs148602333(G,A); rs74805426(T,C); rs10929228(C,T); rs2645777(C,T); rs7577192(G,C); rs4663731(G,A); rs112752569(G,A); rs59437067(G,A); rs2646254(C,T); rs73998889(G,A); rs111638541(G,A); rs12622722(G,A); rs73998890(A,G); rs2645769(C,G); rs3736341(T,C); rs7597795(A,G); rs10202497(C,A); rs7598394(A,G); rs10167850(A,C); rs10205605(C,T); rs111808145(T,C); rs73998892(C,T); rs146355600(G,A); rs2645770(C,A); rs75148159(G,A); rs34340053(C,T); rs2645771(A,G); rs2645772(A,G); rs61526536(C,T); rs35970577(T,G); rs73998893(C,T); rs2645773(A,G); rs2645774(C,A); rs114736729(T,A); rs2646260(A,G); rs77444546(T,G); rs2645775(G,A); rs140319915(C,T); rs1463796(T,C); rs34503558(G,A); rs78380978(A,G); rs59334109(G,A); rs375341787(G,A); rs3791001(G,A); rs60654577(T,G); rs35489467(C,T); rs12622093(G,A); rs73998896(C,T); rs11896721(A,G); rs11901587(G,A); rs67210443(G,A); rs10929229(A,G); rs73093761(C,T); rs6727774(A,G); rs375269838(G,C); rs34367758(G,A); rs1826873(T,C); rs7579816(T,C); rs140662372(T,C); rs143643111(C,T); rs10929230(T,C); rs74428365(C,T); rs2646253(A,G); rs114750216(G,A); rs146855272(C,T); rs73093782(C,T); rs12052967(G,A); rs12052971(G,A); rs1874573(G,A); rs2645778(A,G); rs58672130(G,T); rs73093795(C,T); rs73093799(A,G); rs1553032(C,T); rs76129358(A,G); rs76117790(T,C); rs6720283(G,A); rs4663256(C,A); rs2645779(C,T); rs2645780(C,G); rs4663745(C,G); rs13431876(G,A); rs13407339(C,T); rs80074272(C,T); rs116361793(T,C); rs10205682(T,C); rs2645781(A,T); rs2645782(A,C); rs113082599(T,C); rs12477690(A,T); rs2646259(A,G); rs4663747(G,A); rs139670348(C,G); rs2646252(G,A); rs2645783(G,A); rs7579936(T,G); rs74001309(A,T); rs2325812(C,G); rs372463081(C,T); rs12692202(C,A); rs12476069(T,C); rs10929231(G,A); rs12692203(G,A); rs10929232(C,T); rs10929233(G,T); rs115727053(G,A); rs78202506(G,T); rs2291794(A,G) |
| ccdsGene name | CCDS33409.1 |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 1293 |
| EntrezGene Description | collagen, type VI, alpha 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL6A3:NM_057167:exon9:c.A3830T:p.D1277V,COL6A3:NM_057166:exon7:c.A2627T:p.D876V,COL6A3:NM_004369:exon10:c.A4448T:p.D1483V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6346 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
Eyes:
Coloboma of iris, choroid and retina
Inheritance:
Autosomal dominant
OMIM Title
*120250 COLLAGEN, TYPE VI, ALPHA-3; COL6A3
OMIM Description
The COL6A3 gene encodes the alpha-3 chain of type VI collagen. See also
COL6A1 (120220).
CLONING
Chu et al. (1990) isolated and sequenced human cDNA clones corresponding
to the COL6A3 gene.
Klewer et al. (1998) studied COL6A3 gene expression in the developing
mammalian heart. The pattern of expression was identical to that of
COL6A1.
By microarray analysis, Jun et al. (2001) demonstrated expression of the
COL6A3 gene in human donor corneas.
GENE STRUCTURE
Stokes et al. (1991) reported information on the exons for part of the
COL6A3 gene.
MAPPING
Weil et al. (1987, 1988) localized the COL6A3 gene to chromosome 2q37 by
Southern blot analysis of somatic cell hybrids and by in situ
hybridization. At least 3 other extracellular matrix genes are also
located on 2q: 2 collagen genes, COL3A1 (120180) and COL5A2 (120190),
and the fibronectin gene (135600).
Using fluorescence in situ hybridization, Speer et al. (1996) localized
the COL6A3 gene to chromosome 2q37 within a 17-cM region spanned by
D2S336 and D2S395. By linkage analysis, they mapped a candidate gene for
Bethlem myopathy (158810) to the same chromosomal region.
MOLECULAR GENETICS
Pan et al. (1998) identified a mutation in the COL6A3 gene (120250.0001)
in affected members of a large American pedigree with Bethlem myopathy
(158810), a rare autosomal dominant proximal myopathy characterized by
early childhood onset and joint contractures.
Ullrich congenital muscular dystrophy (UCMD; 254090) is an autosomal
recessive disorder characterized by generalized muscular weakness,
contractures of multiple joints, and distal hyperextensibility. Demir et
al. (2002) demonstrated linkage of UCMD to 2q37 in 3 families, each of
which demonstrated homozygous mutation in the COL6A3 gene (see, e.g.,
120250.0002 and 120250.0003). One family had a phenotype of intermediate
severity, a second an unusually mild phenotype, and a third with a
severe phenotype as previously described in patients with UCMD. This was
the first description of mutations in COL6A3 in UCMD; previously
mutations had been described in COL6A2 (120240).
Lampe et al. (2005) developed a method for rapid direct sequence
analysis of all 107 coding exons of the COL6 genes (COL6A1, COL6A2,
COL6A3) using single condition amplification/internal primer (SCAIP)
sequencing. They sequenced all 3 COL6 genes from genomic DNA in 79
patients with UCMD or Bethlem myopathy, and found putative mutations in
1 of the COL6 genes in 62% of patients. Some patients showed changes in
more than one of the COL6 genes, and some UCMD patients appeared to have
dominant rather than recessive disease. Lampe et al. (2005) concluded
that these findings may explain some or all of the cases of UCMD that
are unlinked to the COL6 genes under a recessive model.
In 2 unrelated patients with Bethlem myopathy, Baker et al. (2007)
identified 2 different heterozygous mutations in the COL6A3 gene
(120250.0005; 120250.0006).
Nadeau et al. (2009) identified a heterozygous COL6A3 mutation
(120250.0004) in 2 unrelated individuals with autosomal dominant UCMD.
LOC643387
| dbSNP name | rs13419960(T,C); rs13419980(T,C); rs115643647(G,T); rs11694487(G,C); rs11689432(A,G); rs11695827(G,A); rs138745161(A,C); rs11692007(T,C); rs11696058(G,A); rs55808641(C,A); rs56200201(G,T); rs56269782(T,C); rs148797104(A,G) |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 643387 |
| snpEff Gene Name | AC016757.3 |
| EntrezGene Description | TAR DNA binding protein pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02893 |
| ExAC AF | 0.019 |
HES6
| dbSNP name | rs8835(C,G); rs7240(T,C); rs9776(C,G); rs77852620(G,A) |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 55502 |
| EntrezGene Description | hes family bHLH transcription factor 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2034 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, postnatal
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Photophobia;
Decreased visual acuity;
Strabismus;
[Teeth];
Amelogenesis imperfecta (in 1 patient);
[Neck];
Short neck
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Short ribs;
Wide ribs;
Short clavicles;
Wide clavicles
SKELETAL:
Normal bone age;
[Spine];
Scoliosis, severe;
Biconcave vertebral bodies;
Narrowed lumbar canal;
[Pelvis];
Irregular sacro-iliac joints;
[Limbs];
Rhizomelic shortening of the long bones, particularly the upper limbs;
Short humeri;
Prominent deltoid tuberosities;
Short distal ulnae;
Sloping epiphyses of the radii;
Short femoral necks
OMIM Title
*610331 HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 6; HES6
OMIM Description
DESCRIPTION
HES6 belongs to the basic helix-loop-helix (bHLH) family of
transcription factors, which regulate several key developmental pathways
(Gao et al., 2001).
CLONING
By searching an EST database for sequences similar to mouse Hes6, Bae et
al. (2000) identified human HES6. The mouse and human proteins contain
224 amino acids and have an N-terminal basic helix-loop-helix domain, a
central orange domain, and a C-terminal proline-rich region. This
structure is generally conserved in HES family proteins; however, the
loop region of HES6 is shorter than that of other HES proteins. Northern
blot analysis detected high Hes6 expression in all adult mouse tissues
examined. In mouse embryos, expression was first detected at embryonic
day 10.5, and Hes6 was highly expressed in all later developmental
stages tested. In situ hybridization revealed Hes6 expression restricted
to the developing mouse nervous system at embryonic day 8.5, and Hes6
was widely expressed in nonneural tissues by embryonic day 11.5.
GENE FUNCTION
Bae et al. (2000) found that mouse Hes6, unlike Hes1 (139605), did not
directly bind E- or N-box DNA elements. However, Hes6 coprecipitated
with Hes1 in COS-7 cells, and it prevented Hes1-mediated transcriptional
repression from the N-box in a mouse fibroblast cell line. Furthermore,
Hes6-Hes1 interaction prevented Hes1-mediated inhibition of Mash1
(ASCL1; 100790)-E47 (TCF3; 147141) heterodimer formation, allowing Mash1
and E47 to bind E-box DNA and upregulate transcription in the presence
of Hes1. Misexpression of Hes6 in developing retina promoted rod
photoreceptor differentiation. Interchanging the loop regions of Hes6
and Hes1 interchanged the role of the proteins in transcriptional
repression, suggesting that the loop region in HES proteins plays a
specific role in transcriptional control.
Gao et al. (2001) found that Hes6 bound Tle1 (600189) through its
C-terminal WRPW tetrapeptide and repressed transcription from
N-box-containing promoters in a mouse myoblast cell line. Hes6 did not
antagonize Hes1 in myoblasts, but cooperated in an additive manner to
further repress transcription. Constitutive expression of Hes6 in
myoblasts inhibited expression of a repressor of myogenesis, Myor (MSC;
603628), and induced differentiation. On the other hand, blocking
endogenous Hes6 with a WRPW-deleted dominant-negative Hes6 mutant led to
increased expression of Myor and complete blockage of the muscle
development program.
Gratton et al. (2003) found that Hes6 antagonized Hes1 function in
embryonic mouse cortical neural progenitor cells by inhibiting
interaction of Hes1 with its transcriptional corepressor Tle1 and by
promoting proteolytic degradation of Hes1. The effect was maximal when
both Hes1 and Hes6 contained the WRPW motif. Repression of Hes1 was
reduced when Hes6 was mutated to eliminate a conserved phosphorylation
site (ser183) used by protein kinase CK2 (see CSNK2A1; 115440).
Consistent with these findings, Hes6 inhibited Hes1-mediated
transcriptional repression in cortical neural progenitor cells and
promoted their differentiation, a process that is normally inhibited by
Hes1. Mutation of ser183 impaired the neurogenic effect of Hes6.
By mutation analysis, Kang et al. (2005) determined that the WRPW motif
of mouse Hes6 is a degradation motif that directs proteasome-mediated
Hes6 degradation.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the HES6
gene to chromosome 2 (TMAP RH69252).
MGC16025
| dbSNP name | rs11692243(A,G); rs11685604(G,A); rs13419799(C,T); rs13419802(C,T); rs3791568(G,A); rs115075751(A,G); rs6739116(G,A); rs625839(C,T); rs145081090(A,G); rs12105700(C,T); rs3791575(C,T); rs631292(A,G); rs79239997(T,C); rs115889836(G,A) |
| ccdsGene name | CCDS2529.1 |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 85009 |
| snpEff Gene Name | HDAC4 |
| EntrezGene Description | uncharacterized LOC85009 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.27 |
OR6B2
| dbSNP name | rs61730683(C,T) |
| ccdsGene name | CCDS46559.1 |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 389090 |
| EntrezGene Description | olfactory receptor, family 6, subfamily B, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6B2:NM_001005853:exon1:c.G10A:p.E4K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IFH4 |
| dbNSFP Uniprot ID | OR6B2_HUMAN |
| dbNSFP KGp1 AF | 0.0105311355311 |
| dbNSFP KGp1 Afr AF | 0.0467479674797 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01056 |
| ESP Afr MAF | 0.038196 |
| ESP All MAF | 0.012454 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.003502 |
OR6B3
| dbSNP name | rs201522340(G,A); rs13389099(C,G) |
| ccdsGene name | CCDS42837.1 |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 150681 |
| EntrezGene Description | olfactory receptor, family 6, subfamily B, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6B3:NM_173351:exon1:c.C933T:p.A311A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.002704 |
| ESP All MAF | 0.000841 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002125 |
CAPN10-AS1
| dbSNP name | rs1133352(C,T); rs1133353(A,T); rs1133354(T,C); rs2975754(G,A); rs73108034(A,G); rs2953173(T,A); rs73108040(T,C); rs2975755(G,A); rs78807390(C,A); rs2953172(C,T); rs3749164(G,A) |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 101752400 |
| snpEff Gene Name | RNPEPL1 |
| EntrezGene Description | CAPN10 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2176 |
AQP12A
| dbSNP name | rs76463197(C,T) |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 375318 |
| EntrezGene Description | aquaporin 12A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AQP12A:NM_198998:exon2:c.C298T:p.L100L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1212 |
| ESP Afr MAF | 0.082609 |
| ESP All MAF | 0.190149 |
| ESP Eur/Amr MAF | 0.242478 |
| ExAC AF | 0.197 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataract, congenital;
Cataract, nuclear (in some patients);
Cataract, posterior polar (in some patients);
Cataract, anterior polar (in some patients);
Cataract, cortical (in some patients);
Glaucoma (in some patients)
MISCELLANEOUS:
Two Pakistani families with a homozygous CRYBB3 mutation have been
reported (last curated August 2014);
One 4-generation Caucasian Italian family with a heterozygous CRYBB3
mutation has been reported (last curated August 2014)
MOLECULAR BASIS:
Caused by mutation in the beta-B3 crystallin gene (CRYBB3, 123630.0001)
OMIM Title
*609789 AQUAPORIN 12A; AQP12A
;;AQP12;;
AQPX2
OMIM Description
CLONING
Ishibashi et al. (2000) isolated human AQP12A, which they called AQPX2,
from a pancreas cDNA library. Northern blot analysis detected a 1.5-kb
AQP12A transcript only in human pancreas. RNA dot blot analysis of 71
human and mouse tissues showed AQP12A expression only in pancreas.
Using a rat EST with homology to AQP11 (609914) to screen human and
mouse pancreas cDNA libraries, Itoh et al. (2005) identified AQP12A,
which they designated AQP12. Human AQP12A encodes a deduced 295-amino
acid protein with a calculated molecular mass of about 31 kD. The mouse
and human AQP12A proteins share 72% sequence homology. Whereas typical
members of the AQP family have 2 asparagine-proline-alanine (NPA)
motifs, the human and mouse AQP12A proteins have 1 NPA motif and a
variant asparagine-proline-threonine (NPT) motif. RNA dot blot analysis
of multiple mouse tissues revealed expression only in the pancreas. In
situ hybridization of mouse pancreas sections showed expression in the
acinar cells, but not in the duct or islet cells. When expressed in
Xenopus oocytes, AQP12A was retained in the cytoplasm and was not
targeted to the plasma membrane. Transient transfection of EGFP-tagged
AQP12A in HEK293 and COS-7 cells showed an intracellular granular
staining pattern.
GENE STRUCTURE
Ishibashi et al. (2000) determined that the AQP12A gene contains 5
exons.
MAPPING
By genomic sequence analysis, Ishibashi et al. (2000) mapped the AQP12A
gene to chromosome 2. Morishita et al. (2005) stated that the human
AQP12A gene maps to chromosome 2q34-q37.
AGXT
| dbSNP name | rs34116584(C,T); rs66494441(A,G); rs35698882(C,T); rs34995778(C,T); rs11681134(G,T); rs78377431(C,T); rs71428471(G,A); rs34134404(C,T); rs10196315(C,T); rs12997245(G,A); rs11687303(G,C); rs11691745(C,G); rs33958047(G,A); rs11693280(C,T); rs10933640(G,A); rs10933641(T,C); rs12478859(C,T); rs12464426(A,G); rs4675793(C,T); rs13030904(G,A); rs5013752(G,T); rs5013751(G,A); rs6732985(C,T); rs61729604(G,A); rs4073370(G,T); rs10199038(C,T); rs4426527(A,G); rs148485020(C,T); rs35566646(G,A); rs4273214(C,A); rs4344931(A,C) |
| ccdsGene name | CCDS2543.1 |
| CosmicCodingMuts gene | AGXT |
| cytoBand name | 2q37.3 |
| EntrezGene GeneID | 189 |
| EntrezGene Description | alanine-glyoxylate aminotransferase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AGXT:NM_000030:exon9:c.G866A:p.R289H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6561 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UJX1 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.001733 |
| ESP All MAF | 0.000759 |
| ESP Eur/Amr MAF | 0.000256 |
| ExAC AF | 0.000402 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Growth retardation
HEAD AND NECK:
[Eyes];
Cataract;
Corneal opacities;
Glaucoma;
Band keratopathy
GENITOURINARY:
[Kidneys];
Proximal renal tubular acidosis;
Renal bicarbonate wasting;
Normal distal tubule acid excretion
NEUROLOGIC:
[Central nervous system];
Mental retardation
METABOLIC FEATURES:
Hyperchloremic acidosis
HEMATOLOGY:
Increased red cell osmotic resistance
MOLECULAR BASIS:
Caused by mutations in the solute carrier family 4, sodium bicarbonate
cotransporter, member 4 gene (SLC4A4, 603345.0001)
OMIM Title
*604285 ALANINE-GLYOXYLATE AMINOTRANSFERASE; AGXT
;;AGXT1;;
AGT;;
SERINE-PYRUVATE AMINOTRANSFERASE; SPT; SPAT
OMIM Description
DESCRIPTION
The AGXT gene encodes alanine:glyoxylate aminotransferase (AGT; EC
2.6.1.44), whose activity is largely confined to peroxisomes in the
liver. AGT also shows serine:pyruvate aminotransferase activity (EC
2.6.1.51) (Noguchi et al., 1978).
CLONING
Takada et al. (1990) isolated clones corresponding to the AGT gene from
a human liver cDNA library. The deduced 392-residue protein had a
calculated molecular mass of 43 kD. The human peroxisomal AGT showed
about 78% amino acid sequence identity with rat mitochondrial AGT. The
putative pyridoxal phosphate-binding lysine residue at position 209 is
conserved. A comparison of the 5-prime sequences indicated that the
N-terminal 22 amino acids of the rat translation product are absent from
the human protein. The loss of this mitochondrial targeting sequence
(MTS) signal during evolution may partly explain the species differences
in intracellular localization of AGT.
Purdue et al. (1990) isolated a clone encoding human liver-specific
peroxisomal AGT, also called AGXT. The nucleotide sequences corresponded
to the sequence of the AGT cDNA characterized by Takada et al. (1990).
The results of genomic Southern blotting indicated that the human AGT
gene is a probably single copy.
Cellini et al. (2009) noted that AGT functions as a dimer, and each AGT
monomer consists of an N-terminal arm involved in dimer formation, a
large catalytic domain containing an active site lys209, and a smaller
C-terminal domain. One pyridoxal 5-prime-phosphate (PLP) cofactor binds
per subunit and is present in a Schiff base linkage with lys209.
GENE STRUCTURE
Purdue et al. (1990) determined that the coding sequence of the AGXT
gene spans 10 kb and contains 11 exons.
MAPPING
By in situ hybridization and PCR analysis of rodent/human somatic cell
hybrids, Purdue et al. (1991) mapped the AGXT gene to chromosome
2q36-q37.
Mori et al. (1992) showed by in situ hybridization that a single gene
for this enzyme in the rat, symbolized SPT/AGT, is located on chromosome
9q34-q36.
MOLECULAR GENETICS
Primary hyperoxaluria type 1 (259900) is an autosomal recessive disorder
caused by deficiency of alanine:glyoxylate aminotransferase (AGT),
characterized by progressive kidney failure due to renal deposition of
calcium oxalate. In about one-third of patients residual enzyme activity
is up to 60% of mean normal, but in most of these patients AGT is
mistargeted to mitochondria instead of peroxisomes. The mistargeting
mutation gly170-to-arg (G170R; 604285.0013) is the most common mutation
among Caucasian patients, with a frequency of 23 to 27%. The G170R
mutation always occurs on the background of the minor allele (see
604285.0002), with which it interacts synergistically (summary by
Coulter-Mackie and Rumsby, 2004).
Danpure and Jennings (1986) demonstrated that total AGXT levels were
reduced in 2 patients with type I primary hyperoxaluria (259900).
In a patient with primary hyperoxaluria type I (HP1; 259900), Nishiyama
et al. (1991) identified a mutation in the AGXT gene (S205P;
604285.0001). SPT activity was approximately 1% of that in control
liver.
The intermediary metabolic enzyme AGT contains a pro11-to-leu (P11L;
604285.0002) polymorphism that decreases its catalytic activity by a
factor of 3 and causes a small proportion to be mistargeted from its
normal intracellular location in the peroxisomes to the mitochondria.
These changes were predicted to have significant effects on the
synthesis and excretion of the metabolic end-product oxalate and the
deposition of insoluble calcium oxalate in the kidney and urinary tract
(summary by Danpure, 1997).
In 15 unrelated Italian patients with type I primary hyperoxaluria,
Pirulli et al. (1999) 8 novel mutations in the AGXT gene (see, e.g.,
G158R, 604285.0012). The most frequent mutation was G170R (604285.0013),
accounting for 30% of alleles, followed by G158R, with a 13% frequency.
Ten of the 15 patients were homozygotes; in only 1 case were the parents
identified as first cousins.
In a mutation update of the AGXT gene, Williams et al. (2009) stated
that 146 mutations had been identified, with all exons of the AGXT gene
represented. The authors identified 50 novel mutations in patients with
HP1. There were no apparent genotype/phenotype correlations.
Fargue et al. (2013) showed that 3 disease-causing missense mutations,
I244T (604285.0007), F152I (604285.0006), and G41R (604285.0005), which
occur on the background of the minor allele characterized by the P11L
polymorphism, can, like G170R, unmask the cryptic P11L-generated
mitochondrial targeting sequence and result in AGT protein being
mistargeted to mitochondria. These 4 missense mutations together
constitute 40% of HP1 alleles.
POPULATION GENETICS
Based on the evolution of AGT targeting in mammals, Danpure (1997)
hypothesized that the common P11L polymorphism would be advantageous for
individuals who have a meat-rich diet, but disadvantageous for those who
do not. If true, the frequency of distribution of P11L in different
extant human populations should have been shaped by their dietary
history so that it should be more common in populations with
predominantly meat-eating ancestral diets than it is in populations in
which the ancestral diet was predominantly vegetarian. In a study of
frequency of P11L in 11 different human populations with divergent
ancestral dietary lifestyles, Caldwell et al. (2004) found evidence in
support of the hypothesis: the highest allelic frequency, 27.9%, was
found in the Saami, a population with a very meat-rich ancestral diet;
the lowest, 2.3%, was found in Chinese, who were likely to have had a
more mixed ancestral diet. The differences in P11L frequency between
some populations (particularly Saami vs Chinese) was very high when
compared with neutral loci, suggesting that its frequency might have
been shaped by dietary selection pressure.
Fargue et al. (2013) stated that the minor allele characterized by the
P11L polymorphism occurs in 15 to 20% of European and North American
populations.
ANIMAL MODEL
Salido et al. (2006) found that Agt1-null mice grew and developed
normally; however they developed hyperoxaluria and crystalluria. About
half of the male mice in mixed genetic background developed calcium
oxalate urinary stones. Severe nephrocalcinosis and renal failure
developed after pharmacologic enhancement of oxalate production. Hepatic
expression of human AGT1 by adenoviral vector-mediated gene transfer in
Agt1 -/- mice normalized urinary oxalate excretion and prevented oxalate
crystalluria. Subcellular fractionation and immunofluorescence studies
revealed that, as in the human liver, the expression of transgenic AGT1
was predominantly localized to hepatocellular peroxisomes.
LOC102723448
| dbSNP name | rs73093420(T,C); rs73009220(G,A); rs9713920(T,C); rs35007339(C,G) |
| cytoBand name | 3p26.3 |
| snpEff Gene Name | AY269186.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03765 |
ITPR1
| dbSNP name | rs304076(T,G); rs304074(C,T); rs13319720(A,G); rs304073(A,C); rs177441(C,T); rs184233(C,G); rs77817661(A,G); rs142142166(A,C); rs116245246(T,C); rs304072(G,A); rs304071(C,T); rs141482388(C,A); rs304070(A,G); rs147884986(T,C); rs189545618(T,A); rs901871(G,C); rs901872(C,A); rs145221907(G,A); rs17706522(T,C); rs304069(G,A); rs373945718(T,C); rs142274194(G,A); rs35886654(A,T); rs2131458(G,A); rs151033652(A,G); rs304068(A,G); rs9838575(T,A); rs304067(A,C); rs304066(A,G); rs304064(C,G); rs9843389(T,C); rs304063(G,A); rs304062(T,G); rs115231963(A,G); rs116728445(G,A); rs369960068(G,A); rs11130036(A,G); rs17757503(T,C); rs58994349(T,G); rs694385(C,G); rs694507(G,A); rs56269779(G,A); rs55647430(G,A); rs304026(T,C); rs143539141(A,G); rs304027(G,C); rs304028(C,T); rs304029(A,C); rs113317912(G,C); rs304031(C,G); rs304032(G,C); rs114506187(A,G); rs111274783(T,C); rs304036(C,G); rs304038(A,G); rs304039(T,G); rs304040(G,A); rs304041(G,T); rs184232(G,C); rs304042(C,T); rs374406215(C,T); rs304043(C,G); rs1488465(T,G); rs304045(T,C); rs4685755(T,G); rs304046(T,C); rs115996081(G,A); rs11716573(C,A); rs420944(T,G); rs442741(A,G); rs56262140(G,A); rs437037(C,T); rs79761408(C,T); rs60785740(T,C); rs62231447(G,A); rs9871469(C,G); rs9871636(C,G); rs9819848(T,C); rs55742503(C,T); rs62231449(C,T); rs304047(A,G); rs141017017(G,A); rs113895575(A,G); rs9829878(T,C); rs73807272(C,G); rs304008(G,A); rs140421913(A,G); rs184018803(C,T); rs115060668(G,A); rs304009(G,A); rs73127266(G,T); rs304010(G,A); rs304011(G,A); rs73807276(T,C); rs73127268(T,A); rs143254643(G,A); rs304012(T,C); rs304014(C,A); rs1038639(T,G); rs304015(G,C); rs146476230(G,A); rs141495659(C,T); rs304016(C,T); rs60146603(G,A); rs73005403(A,G); rs304018(G,A); rs304019(G,A); rs304020(C,T); rs304021(T,C); rs304022(C,A); rs4684418(A,G); rs304023(C,T); rs304024(G,T); rs150716570(G,A); rs73005414(T,C); rs78384(T,C); rs113006668(G,A); rs873768(C,G); rs17040842(C,T); rs9784254(T,A); rs76223102(T,G); rs6796205(T,G); rs6784152(C,T); rs304061(A,C); rs304060(G,A); rs304059(G,A); rs77473283(G,A); rs304058(G,A); rs304057(A,C); rs304056(C,T); rs113130321(G,A); rs7635739(C,T); rs6766061(G,C); rs17030584(C,G); rs141091869(G,A); rs76336723(T,A); rs304054(G,T); rs304053(T,C); rs304052(G,A); rs304051(T,C); rs304050(G,A); rs304049(T,C); rs6783234(G,A); rs34253984(C,G); rs111479135(A,G); rs149068840(C,T); rs68161849(A,G); rs2639810(T,A); rs2633849(A,G); rs2639809(G,T); rs304048(C,T); rs184231(G,A); rs304003(C,T); rs76879760(C,T); rs304004(T,A); rs17040880(T,C); rs304005(G,C); rs304006(G,A); rs372171816(A,G); rs304007(G,T); rs406909(A,G); rs7616234(C,T); rs4684419(C,T); rs13068939(C,T); rs115693442(T,C); rs142477746(A,G); rs116793168(A,G); rs7636025(T,G); rs12639183(A,C); rs114000487(C,T); rs6802929(G,A); rs4621315(T,C); rs6792272(A,G); rs73007716(C,T); rs6776513(A,G); rs6764083(C,T); rs12495382(T,C); rs11130057(C,T); rs902982(A,G); rs10510294(T,C); rs11720109(T,C); rs7618458(C,G); rs7642560(G,T); rs11130058(G,A); rs74460086(A,G); rs11130059(G,A); rs73109212(A,G); rs372979377(T,C); rs11709199(G,T); rs7635333(A,G); rs7624224(C,G); rs9865200(C,G); rs186893069(A,G); rs185726899(G,C); rs7651919(G,T); rs115959858(G,A); rs7647089(T,A); rs6442886(A,C); rs6803663(T,G); rs13096859(G,A); rs80151924(G,A); rs190149510(C,T); rs931502(G,C); rs7637311(C,T); rs76335939(A,C); rs1565700(G,A); rs9816891(T,A); rs6781052(C,T); rs76499153(T,C); rs4685758(C,T); rs4685759(C,G); rs4685760(G,C); rs9822773(T,C); rs4685761(A,T); rs4685763(A,T); rs11130064(C,G); rs9832410(T,C); rs145839464(G,A); rs6794363(C,G); rs9834340(A,G); rs9838462(T,C); rs4685764(C,A); rs4684420(G,A); rs4685765(C,T); rs4684421(A,G); rs4685766(G,A); rs11130068(A,G); rs62231456(G,A); rs17758821(C,G); rs17040924(C,T); rs13087672(G,C); rs56073408(G,A); rs13089179(C,G); rs13088247(G,T); rs147767762(A,G); rs11923960(A,C); rs75837807(G,C); rs56359217(A,T); rs73807293(G,A); rs1038898(G,A); rs1038897(C,T); rs1389162(A,C); rs75321780(A,C); rs4685767(G,C); rs11130069(T,C); rs12488824(C,A); rs77827932(C,G); rs73102466(T,C); rs12492889(A,G); rs931504(G,T); rs2101695(A,G); rs2087870(C,T); rs6774037(A,G); rs73102474(C,T); rs73102477(G,A); rs6785564(G,A); rs140419283(A,G); rs6442887(G,A); rs17040941(T,G); rs7637687(G,A); rs7627633(A,G); rs10510295(C,T); rs9875660(A,G); rs9809124(T,A); rs9837857(C,T); rs1353045(G,A); rs7646719(G,C); rs6442888(G,A); rs7622912(A,G); rs11926353(T,G); rs6764946(C,A); rs11705928(G,A); rs11717970(A,G); rs11718824(T,C); rs13083200(A,G); rs116792445(T,G); rs73102490(G,A); rs73102492(C,T); rs73102493(A,G); rs7642352(G,T); rs116252990(G,A); rs1873850(G,A); rs1873849(C,T); rs114955259(T,C); rs112587162(G,A); rs6804671(G,A); rs1493115(A,C); rs4685770(G,C); rs4685771(C,T); rs4684422(T,C); rs4684423(C,T); rs114423214(G,A); rs4684424(C,A); rs4684425(T,C); rs12633680(G,A); rs35593371(C,A); rs137864435(G,A); rs9846866(G,C); rs6791713(C,T); rs6806554(T,C); rs35154162(C,T); rs9823834(G,C); rs79634491(C,G); rs6442889(G,A); rs11709910(G,A); rs2172450(A,G); rs6808180(A,G); rs146842580(G,A); rs4685772(A,G); rs4685773(C,T); rs149574109(A,G); rs144222046(T,C); rs6784607(C,T); rs116238352(T,G); rs2322734(C,A); rs114311247(T,G); rs2686623(T,G); rs9832099(T,C); rs9809167(C,T); rs4684426(C,G); rs9846619(G,A); rs17041001(A,G); rs17041005(C,T); rs9815192(C,A); rs9856060(G,A); rs62233665(G,A); rs62233666(C,T); rs9856921(G,A); rs9857030(G,A); rs9857199(G,A); rs112404295(A,G); rs9861106(G,A); rs9861380(G,A); rs17041023(G,A); rs17041028(A,C); rs17041030(C,T); rs73104420(A,G); rs73104421(T,C); rs2686622(C,A); rs9871881(G,A); rs73104425(C,T); rs73104427(C,T); rs73104430(A,G); rs2686621(C,T); rs116511353(T,C); rs2639808(C,T); rs114077304(G,A); rs73104435(T,C); rs2686620(C,A); rs11717313(G,C); rs11709872(C,A); rs112873765(C,G); rs2322735(A,G); rs13317699(C,T); rs76581126(T,A); rs6804103(C,A); rs2322737(G,T); rs72622153(A,T); rs56098012(A,C); rs62231563(A,G); rs142081350(G,A); rs6782233(G,A); rs4685775(G,A); rs4685776(A,G); rs111734004(T,C); rs11719619(G,A); rs55650819(C,A); rs4685777(G,A); rs11719669(G,A); rs11716943(T,A); rs11712103(C,G); rs4684427(C,A); rs4685778(T,C); rs114328330(G,A); rs73104456(T,A); rs6765127(C,T); rs150871267(G,A); rs111766469(C,G); rs2101694(C,A); rs9850086(C,T); rs56685673(C,T); rs114311460(T,C); rs9816389(G,A); rs9816390(G,A); rs113858504(T,G); rs57342612(C,G); rs73809705(A,G); rs9860924(C,A); rs9880304(A,C); rs28520334(G,T); rs9874201(G,C); rs148794539(G,A); rs1879817(T,C); rs13327131(G,A); rs55986749(C,T); rs10084763(T,C); rs2470502(T,A); rs2639805(G,A); rs2686617(G,T); rs114911504(G,A); rs60852742(T,C); rs11709423(G,A); rs2686616(C,T); rs11707535(T,C); rs2639804(C,T); rs60558681(A,G); rs57907751(C,T); rs6794384(A,C); rs111377589(G,A); rs2686613(T,C); rs35054010(C,G); rs75891979(G,A); rs2686612(A,G); rs9828126(T,A); rs2686611(C,A); rs2686610(T,C); rs9825366(A,T); rs9842451(G,A); rs9810214(C,T); rs9847184(G,A); rs114416364(T,C); rs11130084(C,G); rs1008826(C,T); rs2686609(G,A); rs2639803(C,G); rs2639802(T,C); rs2322806(G,A); rs2686607(C,T); rs2639801(G,A); rs113686917(C,G); rs62231565(G,T); rs9871287(T,G); rs115054628(C,T); rs1008825(G,A); rs62231566(C,T); rs9818621(G,C); rs9881021(T,C); rs146607488(G,A); rs9857776(C,G); rs931503(T,C); rs185423954(G,T); rs1873848(A,G); rs7638474(C,A); rs12487945(G,T); rs12494610(C,T); rs11716996(C,T); rs2029665(A,G); rs17041043(A,G); rs17041046(T,G); rs6797564(C,G); rs6810292(A,G); rs77400890(G,A); rs9834888(G,C); rs9822791(T,C); rs150933996(C,G); rs34427272(A,G); rs146988553(T,A); rs9845318(G,A); rs9832246(T,C); rs57917131(G,A); rs9828379(A,C); rs2307066(G,C); rs143162276(A,G); rs6774937(A,G); rs6762740(C,G); rs13080068(G,A); rs902985(C,G); rs902984(G,A); rs34394878(A,T); rs902983(G,A); rs113047754(A,G); rs9820962(T,G); rs56310584(C,G); rs58494218(C,T); rs17041075(T,A); rs114086016(C,T); rs9818111(C,A); rs13315765(C,G); rs78421649(A,T); rs62231568(C,T); rs34652697(T,C); rs375673541(C,A); rs4234560(C,T); rs6442892(T,A); rs369178236(T,C); rs78663073(G,A); rs4074087(C,A); rs4074088(T,G); rs4073665(G,A); rs4073664(A,T); rs149149920(C,T); rs7613276(T,A); rs11717002(G,T); rs4685783(C,T); rs11717037(G,A); rs4685784(G,C); rs4685785(C,T); rs4685786(G,A); rs4685787(C,A); rs7652764(C,A); rs7652864(C,T); rs59079559(T,G); rs4594601(C,T); rs2686606(A,G); rs41289624(T,A); rs4271897(A,G); rs4303850(A,G); rs17760545(T,G); rs4293683(T,C); rs376007473(G,A); rs113464760(A,C); rs145345067(T,C); rs78041264(A,G); rs377494274(A,G); rs2686605(A,C); rs4630930(A,G); rs4402917(G,C); rs4685789(G,T); rs374853382(T,C); rs4685790(A,T); rs77826702(A,G); rs114013637(A,G); rs11130090(A,G); rs11716699(A,T); rs11720328(G,A); rs6442893(T,G); rs74407032(C,T); rs7614107(C,T); rs4685792(A,T); rs4234561(C,A); rs4685793(T,C); rs9871670(A,G); rs7616864(C,A); rs377667787(C,T); rs7630678(T,C); rs17041104(C,T); rs149347290(G,T); rs3796336(C,A); rs6442894(C,T); rs28461825(C,T); rs28562557(G,A); rs6442896(A,C); rs56896093(G,A); rs6442897(C,G); rs13315712(G,A); rs192233574(G,A); rs17041109(A,G); rs145997583(C,T); rs13316843(G,A); rs17041113(A,C); rs80349654(G,C); rs17709863(T,C); rs56378886(T,C); rs115675437(C,T); rs10510296(G,A); rs11916179(A,G); rs4560283(C,G); rs12486970(A,G); rs7630009(C,A); rs7643701(A,G); rs7632260(C,G); rs7643879(A,G); rs73807108(A,G); rs78465078(T,C); rs78366681(G,A); rs2306871(T,C); rs2306870(T,C); rs2306869(G,A); rs2306868(C,G); rs17041133(A,C); rs4685794(C,A); rs149627982(A,G); rs7616631(G,C); rs115271323(A,G); rs116099794(G,A); rs148424429(A,G); rs60038939(G,A); rs6783245(C,T); rs114149274(C,G); rs111246613(G,T); rs6801424(T,C); rs6801563(T,C); rs79145630(A,G); rs143765102(A,G); rs79567473(T,C); rs113513187(G,A); rs34252981(G,A); rs116494988(A,G); rs11721069(C,T); rs149892865(T,C); rs115569023(A,G); rs41289628(G,A); rs35047189(A,G); rs80123990(G,A); rs74971639(A,G); rs115092972(C,T); rs146764774(T,A); rs143612902(A,G); rs112462259(A,G); rs73807112(C,G); rs17041141(G,A); rs57206214(G,C); rs181790466(T,C); rs17041147(G,A); rs7625003(G,T); rs7650467(C,T); rs114291927(A,T); rs7620485(A,G); rs59444586(A,G); rs73807115(A,G); rs2306874(C,A); rs78163413(G,A); rs77927338(C,T); rs75642054(T,C); rs147901616(G,A); rs141803744(T,C); rs1994500(G,A); rs112999071(T,C); rs2306875(G,A); rs2306876(A,T); rs3792487(A,G); rs3792488(A,C); rs3792489(A,G); rs3792490(A,G); rs9846505(A,G); rs74889905(T,C); rs3828433(A,T); rs901856(T,C); rs150040255(T,A); rs145319823(A,T); rs750712(C,T); rs145220403(T,A); rs3804984(T,C); rs73807116(G,A); rs13082052(T,C); rs73807117(T,G); rs2306877(A,C); rs35826345(G,A); rs4685796(C,G); rs4685797(G,A); rs4684433(T,C); rs4684434(A,G); rs4684436(G,A); rs76242092(T,C); rs12487282(G,C); rs111296528(C,G); rs3804985(A,G); rs3828434(G,A); rs12715418(C,G); rs17041165(G,T); rs13325766(G,A); rs13322592(A,G); rs13322594(A,T); rs13322595(A,G); rs34917285(T,G); rs6786478(G,C); rs6786687(G,A); rs3804986(C,T); rs3804987(C,T); rs9866640(A,G); rs2633722(T,G); rs41289638(C,T); rs4684437(C,T); rs4684438(A,G); rs7628064(A,G); rs6442898(G,T); rs6782811(A,G); rs6785591(T,G); rs9876460(T,C); rs74826855(T,C); rs2054869(G,A); rs6773688(C,T); rs2306879(A,G); rs733018(T,G); rs78245904(A,G); rs72995451(A,G); rs3804989(G,A); rs140009611(C,T); rs2633761(G,A); rs6787391(C,T); rs4685798(C,G); rs11709648(T,C); rs4684439(T,A); rs6805394(T,G); rs13059394(C,T); rs13059562(C,T); rs2686625(T,C); rs2686624(A,G); rs4685799(C,T); rs4685800(C,T); rs140996110(A,G); rs28391200(G,A); rs9866837(C,T); rs6802947(G,A); rs9828130(G,A); rs6803045(G,A); rs6803046(G,A); rs6792465(A,G); rs6803382(G,C); rs6792539(A,G); rs6803471(G,A); rs9815748(A,G); rs9833138(G,T); rs4684440(A,G); rs6786081(C,G); rs12715419(G,T); rs11918796(T,C); rs9311394(T,C); rs77448239(C,T); rs10440145(T,A); rs10440146(G,A); rs76850135(C,A); rs9682063(A,G); rs9682208(T,A); rs6442899(G,A); rs6442900(T,G); rs9682380(T,G); rs3749381(T,C); rs3749382(A,G); rs4685802(A,T); rs4685803(A,G); rs4685804(G,A); rs9311395(A,G); rs7652028(A,G); rs17762078(A,T); rs77255589(C,T); rs6762558(A,G); rs6762644(A,G); rs17041228(G,T); rs6765702(T,C); rs6774180(G,A); rs9846046(T,C); rs9841951(A,G); rs3828435(G,C); rs6802366(C,G); rs113619952(C,G); rs34953856(G,A); rs9831844(C,T); rs17041233(G,A); rs2322830(T,C); rs73112420(A,G); rs4510365(C,T); rs6784635(G,A); rs6784839(G,A); rs9862943(A,T); rs9866934(T,C); rs60871539(G,A); rs188820204(A,G); rs9880424(G,A); rs73112423(C,G); rs9871443(T,G); rs9867580(A,C); rs13313995(G,A); rs55895837(G,A); rs34548572(G,A); rs17711545(T,C); rs146876632(G,C); rs12330193(G,A); rs62231595(G,T); rs73112429(C,T); rs6774387(C,T); rs6798315(G,A); rs6798320(G,A); rs3804992(A,G); rs7637793(T,C); rs17762542(A,G); rs3804993(A,G); rs3804994(T,C); rs12330816(G,A); rs12330423(C,T); rs3804995(C,T); rs72997390(G,T); rs9877680(G,T); rs7631642(G,A); rs7631664(G,A); rs3816835(T,G); rs147645928(C,A); rs6781893(T,C); rs17041262(C,T); rs9813210(G,A); rs2306881(A,G); rs9880562(T,C); rs7641327(G,C); rs7634227(T,G); rs140823046(A,G); rs722367(G,A); rs722368(G,A); rs9829279(G,T); rs9830067(G,A); rs2054870(C,G); rs9816936(A,C); rs2054871(G,A); rs73095823(G,A); rs9822274(T,C); rs59713853(C,A); rs7645905(T,G); rs58109310(A,T); rs9876432(G,A); rs9859826(A,C); rs142780729(A,C); rs901851(T,C); rs9812100(G,A); rs9311399(A,C); rs76976210(C,A); rs7643344(A,G); rs148746986(C,T); rs9311400(A,G); rs9311401(A,G); rs13075137(C,T); rs9809576(T,A); rs7651990(T,C); rs9823748(G,A); rs9866867(C,T); rs77484874(G,T); rs7613447(T,C); rs7611336(A,G); rs55946983(G,A); rs2054872(C,A); rs11721101(C,T); rs7620729(A,G); rs17041308(G,A); rs13080185(C,A); rs12715422(C,A); rs73807141(G,A); rs4685806(T,C); rs184624713(G,C); rs189465458(C,A); rs77052686(C,T); rs9824272(T,C); rs76907489(A,T); rs11922422(G,C); rs6792995(C,T); rs11920824(T,G); rs11920001(A,G); rs11921036(A,G); rs931389(T,C); rs4685807(A,G); rs931390(C,T); rs3804997(G,C); rs3804998(A,G); rs4685808(G,A); rs9852752(A,G); rs3804999(A,G); rs76420881(T,C); rs79621767(G,T); rs78540583(G,A); rs17728633(C,T); rs13092274(T,C); rs4685810(C,T); rs76404484(G,A); rs923353(C,T); rs72999385(C,T); rs3805002(C,T); rs3828436(T,G); rs74519297(T,A); rs11714054(T,C); rs6776938(G,A); rs6765970(A,T); rs141212637(A,C); rs6769031(A,G); rs12638018(G,A); rs12496244(G,A); rs113162004(C,G); rs1866999(A,G); rs4684441(T,A); rs4684442(A,T); rs78566789(C,A); rs1846436(G,A); rs112561304(G,A); rs113119861(T,C); rs4685812(A,G); rs148009421(G,C); rs9880589(T,G); rs6786487(A,C); rs79520093(T,A); rs79204890(C,T); rs3828437(G,A); rs1866998(G,C); rs1866997(T,C); rs13068994(C,A); rs2874877(G,C); rs901849(A,G); rs79322395(A,G); rs6785305(A,G); rs4685813(T,C); rs746039(G,A); rs61455902(T,C); rs17041369(G,A); rs3805004(G,T); rs77986810(A,G); rs74720729(A,G); rs3805005(A,C); rs4685814(A,T); rs11706308(A,G); rs11710644(G,A); rs68048957(C,T); rs2279748(G,C); rs2279749(C,T); rs13077184(T,C); rs2633719(A,G); rs12490375(G,T); rs2015714(T,G); rs2322831(T,C); rs3792495(C,T); rs11712971(G,A); rs56160460(C,T); rs35689220(C,T); rs4685815(T,C); rs1962325(C,G); rs9860324(C,G); rs3805006(T,C); rs11717244(C,T); rs79746927(A,G); rs3792496(G,A); rs3792497(T,C); rs3792498(C,T); rs7627280(C,T); rs9870554(C,T); rs9831960(G,A); rs9871052(C,T); rs60179040(A,G); rs2633714(G,A); rs77085038(C,G); rs10510297(C,T); rs11720655(C,T); rs3792499(C,T); rs11712551(G,C); rs62231613(G,A); rs4685816(A,G); rs4685817(C,T); rs6764292(G,T); rs3805008(A,C); rs3805009(A,G); rs3805010(A,G); rs3805011(A,G); rs11715842(G,A); rs11712379(A,G); rs11713227(T,C); rs3805012(C,T); rs148623078(C,T); rs2291863(G,A); rs6766817(A,C); rs34152940(A,G); rs6772040(T,C); rs55990720(G,A); rs71313896(G,A); rs11130135(A,G); rs11130136(A,G); rs183664145(G,C); rs17041401(T,C); rs13086334(T,G); rs2053501(C,T); rs181612870(C,T); rs143553956(A,T); rs1550559(G,A); rs13066557(C,G); rs3792501(G,A); rs2171537(C,T); rs12493142(T,C); rs13079371(T,C); rs4575882(T,C); rs6442905(T,C); rs17729477(T,C); rs4684443(T,C); rs35840266(C,T); rs1145126(A,T); rs3805015(G,A); rs3805016(C,T); rs13098920(G,A); rs7624085(A,G); rs7615779(C,T); rs6442906(T,C); rs6442907(T,C); rs4685818(A,G); rs2119803(T,A); rs13060980(A,G); rs34758081(C,T); rs2839768(G,A); rs1018107(A,G); rs13086041(G,C); rs1018108(A,T); rs1018109(A,G); rs3805017(A,G); rs4685819(G,A); rs2633716(T,G); rs6801569(T,C); rs2633760(A,G); rs4685820(A,G); rs11712938(G,A); rs13079522(A,G); rs6442908(A,G); rs11721322(T,C); rs7649566(A,G); rs7652212(T,C); rs7637819(T,C); rs4684444(T,C); rs4685821(T,C); rs17041451(C,T); rs149545468(C,G); rs73807153(C,T); rs2165624(T,A); rs13070473(A,G); rs13075170(T,C); rs6763424(G,A); rs11917686(A,T); rs142554534(A,G); rs7634198(C,T); rs7645608(A,G); rs2633715(A,G); rs2270748(C,T); rs11713160(T,G); rs931387(C,T); rs931388(C,T); rs62231623(G,A); rs6802582(C,T); rs3805018(G,T); rs6442909(A,G); rs6442910(C,A); rs4142942(G,A); rs2291862(C,T); rs2291861(G,T); rs114806495(C,G); rs80129583(A,T); rs11717863(G,A); rs116439772(G,A); rs2119802(A,G); rs115321910(C,G); rs114704329(G,A); rs17729838(G,C); rs144075248(A,G); rs3792508(G,A); rs3792509(G,A); rs874130(C,G); rs874131(C,T); rs7612703(C,T); rs878135(A,C); rs731915(T,C); rs731914(A,G); rs901853(T,G); rs17041462(A,G); rs73807164(T,G); rs6800071(G,A); rs711631(T,C); rs901854(G,A); rs76604555(G,A); rs3816252(G,A); rs2304820(T,C); rs6442911(C,G); rs6798160(T,C); rs12638626(C,G); rs11130153(G,C); rs4685822(G,T); rs4685823(A,G); rs1386943(A,G); rs1386944(G,A); rs10865950(C,G); rs1386945(C,T); rs2322832(A,G); rs2322833(G,A); rs60868772(T,C); rs901855(G,A); rs9844268(G,A); rs6768192(G,A); rs6768493(G,C); rs9838930(C,T); rs6802133(G,A); rs9858749(A,G); rs9858750(A,C); rs3805021(A,C); rs1873020(A,G); rs1873021(T,C); rs2053504(G,A); rs1546228(C,T); rs4685827(C,T); rs2053503(G,C); rs9883291(T,C); rs3792511(T,G); rs367736206(C,T); rs2053502(C,T); rs191833013(C,G); rs73006921(G,A); rs1051559(A,G); rs189521239(G,C); rs1867000(T,C); rs17041493(G,A); rs55767618(C,G); rs113448493(C,G); rs111976679(G,T); rs56386567(C,T); rs17786757(G,A); rs6766684(A,G); rs1472468(A,T); rs4685828(A,G); rs3805024(C,A); rs12491098(G,A); rs3805027(T,G); rs3805029(C,G); rs75634085(C,T); rs1470212(G,A); rs1470211(T,C); rs73098074(T,G); rs7432768(G,T); rs2874879(T,G); rs112695811(C,A); rs4685829(A,G); rs2291859(C,T); rs3828439(G,A); rs3805030(T,C); rs56244927(T,G); rs7651812(G,A); rs13096481(C,T); rs11708908(A,G); rs17041507(T,C); rs114305493(C,T); rs61611742(G,T); rs17041517(G,A); rs11711879(T,G); rs56092942(G,A); rs3792514(A,G); rs4685830(C,T); rs3792515(T,C); rs12493413(G,A); rs185804814(G,T); rs116502474(T,C); rs3805032(A,G); rs4685831(C,G); rs12634562(T,C); rs11130159(A,G); rs11130160(T,C); rs2270747(T,C); rs73098087(C,A); rs41290678(C,T); rs10865951(T,C); rs77092017(G,A); rs9853970(T,C); rs6768569(A,G); rs6779719(G,T); rs3805034(A,C); rs3805035(T,C); rs9311419(T,C); rs11711554(T,C); rs1039245(A,T); rs9842419(T,C); rs3805036(T,C); rs1473298(T,G); rs73098093(G,C); rs9824167(C,G); rs7355847(T,A); rs4685832(G,A); rs4684445(T,C); rs4684446(C,G); rs4685833(T,A); rs1822223(A,C); rs11714953(A,T); rs4685834(T,C); rs4685835(A,G); rs4685836(A,G); rs9840922(C,G); rs75289994(C,T); rs74998763(G,C); rs77764633(T,G); rs41304181(G,A); rs367636150(C,T); rs9817206(G,T) |
| ccdsGene name | CCDS46740.2 |
| cytoBand name | 3p26.1 |
| EntrezGene GeneID | 3708 |
| EntrezGene Description | inositol 1,4,5-trisphosphate receptor, type 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ITPR1:NM_002222:exon15:c.G1435A:p.V479I,ITPR1:NM_001168272:exon15:c.G1435A:p.V479I,ITPR1:NM_001099952:exon16:c.G1480A:p.V494I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7621 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EPX7 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.002035 |
| ESP All MAF | 0.005058 |
| ESP Eur/Amr MAF | 0.006486 |
| ExAC AF | 0.004859 |
OMIM Clinical Significance
Teeth:
Fused mandibular deciduous incisors
Inheritance:
Autosomal dominant
OMIM Title
*147265 INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1
;;IP3R;;
IP3R1
OMIM Description
DESCRIPTION
The ITPR1 gene encodes the inositol 1,4,5-triphosphate (IP3) receptor,
an intracellular IP3-gated calcium channel that modulates intracellular
calcium signaling (Berridge, 1993; Hirota et al., 2003).
CLONING
Ross et al. (1991) cloned a cDNA for the human type 1 inositol
1,4,5-triphosphate receptor. Nucifora et al. (1995) studied the
expression of alternatively spliced forms. The long form appears to
create an additional consensus protein kinase C phosphorylation site.
The long form predominates in most brain regions except for the
cerebellum, while the short form predominates in peripheral tissues.
GENE FUNCTION
Inositol 1,4,5-triphosphate is an intracellular second messenger
produced by phospholipase C through a G protein-dependent mechanism. It
releases calcium from endoplasmic reticulum by binding to specific
receptors that are coupled to calcium channels. These receptors are
abundant in neuronal and nonneuronal tissues. The neuronal form of the
receptor is abundant in the cerebellum, particularly the perikaryon of
the Purkinje cells. Matsumoto et al. (1996) noted that the product of
the ITPR1 gene is predominantly enriched in cerebellar Purkinje cells
but is also concentrated in neurons in the hippocampal CA1 region,
caudate-putamen, and cerebral cortex. The inositol triphosphate receptor
shares sequence and functional homology with the ryanodine receptor
(180901); they both trigger the release of calcium from intracellular
stores. The primary structure of the inositol triphosphate receptor
contains 3 domains: an inositol triphosphate binding domain near the N
terminus, a coupling domain in the middle of the molecule, and a
transmembrane spanning domain near the C terminus. In addition, there
are at least 2 consensus protein kinase A phosphorylation sites and at
least 1 consensus ATP-binding site (Nucifora et al., 1995).
Boehning et al. (2003) presented evidence that mammalian cytochrome c
(123970) binds to inositol 1,4,5-trisphosphate receptors during
apoptosis. The addition of 1 nanomolar cytochrome c blocked
calcium-dependent inhibition of ITPR1 function in ITPR1-transfected COS
cells. Early in apoptosis, cytochrome c translocated to the endoplasmic
reticulum, where it selectively bound ITPR1, resulting in sustained
oscillatory cytosolic calcium increases. These calcium events were
linked to the coordinated release of cytochrome c from all mitochondria.
In mouse brain, Hirota et al. (2003) identified Carp (CA8; 114815) as an
ITPR1-binding protein. Western blot and immunohistochemical studies
showed that Carp colocalized and interacted with ITPR1 predominantly in
the cytoplasm of cerebellar Purkinje cells. Mutagenesis studies showed
that residues 45 to 291 of Carp were essential for its association with
the modulatory domain of ITPR1 (residues 1387 to 1647). Carp functioned
as an inhibitor of IP3 binding to ITPR1 by reducing the affinity of the
receptor for IP3.
Higo et al. (2005) found that ERp44 (TXNDC4; 609170), an endoplasmic
reticulum (ER) luminal protein of the thioredoxin family, interacted
directly with the third luminal loop of IP3R1. The interaction was
dependent on pH, Ca(2+) concentration, and redox state, with the
presence of free cysteine residues in the loop of IP3R1 required.
Ca(2+)-imaging experiments and single-channel recording of IP3R1
activity with a planar lipid bilayer system demonstrated that IP3R1 was
directly inhibited by ERp44. Higo et al. (2005) concluded that ERp44
senses the environment in the ER lumen and modulates IP3R1 activity
accordingly, which in turn contributes to regulating both intraluminal
conditions and the complex patterns of cytosolic Ca(2+) concentrations.
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was ITPR1. These 37 genes included several
splicing factors for which knockdown generates mitotic spindle defects.
In addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
IP3R1 localizes to dendrites and is thought to be locally translated in
response to synaptic activity. Iijima et al. (2005) showed that the
3-prime UTR of mouse Ip3r1 was required as a cis element for its
dendritic localization, and they identified Hzf (ZNF385A; 609124) as a
trans-acting factor. Moreover, dendritic Ip3r1 mRNA in Purkinje cells
and Bdnf (113505)-induced protein synthesis were both reduced in
Hzf-deficient mice.
Inositol 1,4,5-trisphosphate receptors release calcium ions from
intracellular stores. Dellis et al. (2006) found that inositol
trisphosphate stimulated opening of very few (1.9 +/- 0.2 per cell)
calcium-ion permeable channels in whole-cell patch-clamp recording of
DT40 chicken or mouse B cells. Activation of the B-cell receptor in
perforated-patch recordings evoked the same response. Inositol
trisphosphate failed to stimulate intracellular or plasma membrane
channels in cells lacking IP3R. Expression of IP3R restored both
responses. Mutations in the pore affected the conductances of inositol
triphosphate-activated plasma membrane and intracellular channels
similarly. An impermeant pore mutant abolished B cell receptor-evoked
calcium ion signals, and plasma membrane IP3Rs were undetectable. After
introduction of an alpha-bungarotoxin binding site near the pore, plasma
membrane IP3Rs were modulated by extracellular alpha-bungarotoxin. IP3Rs
are unusual among endoplasmic reticulum proteins in being also
functionally expressed at the plasma membrane, where very few IP3Rs
contribute substantially to the calcium ion entry evoked by the B-cell
receptor.
Using nuclear patch-clamp recording, Taufiq-Ur-Rahman et al. (2009)
demonstrated that inositol-1,4,5-trisphosphate receptors are initially
randomly distributed with an estimated separation of about 1 micron. Low
concentrations of inositol-4,4,5-trisphosphate (Insp3) cause InsP3Rs to
aggregate rapidly and reversibly into small clusters of about 4 closely
associated InsP3Rs. At resting cytosolic calcium ion concentration,
clustered InsP3Rs open independently, but with lower open probability,
shorter open time, and less InsP3 sensitivity than lone InsP3Rs.
Increasing cytosolic calcium ion concentration reverses the inhibition
caused by clustering, InsP3R gating becomes coupled, and the duration of
multiple openings is prolonged. Clustering both exposes InsP3Rs to local
calcium rises and increases the effects of calcium. Dynamic regulation
of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and calcium
ion, facilitating hierarchical recruitment of the elementary events that
underlie all InsP3-evoked calcium signals.
Wang et al. (2012) showed in mice that glucagon stimulates CRTC2
(608972) dephosphorylation in hepatocytes by mobilizing intracellular
calcium stores and activating the calcium/calmodulin-dependent PPP3CA
(114105). Glucagon increased cytosolic calcium concentration through the
PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors
(InsP3Rs) (ITPR1; ITPR2, 600144; ITPR3, 147267), which associated with
CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene
expression by promoting the calcineurin-mediated dephosphorylation of
CRTC2. During feeding, increases in insulin signaling reduced CRTC2
activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R
activity was increased in diabetes, leading to upregulation of the
gluconeogenic program. As hepatic downregulation of InsP3Rs and
calcineurin improved circulating glucose levels in insulin resistance,
these results demonstrated how interactions between cAMP and calcium
pathways at the level of the InsP3R modulate hepatic glucose production
under fasting conditions and in diabetes.
BIOCHEMICAL FEATURES
Bosanac et al. (2002) presented the 2.2-angstrom crystal structure of
the inositol triphosphate-binding core of mouse Itpr1 in complex with
inositol triphosphate. The asymmetric, boomerang-like structure consists
of an N-terminal beta-trefoil domain and a C-terminal alpha-helical
domain containing an 'armadillo repeat'-like fold. The cleft formed by
the 2 domains exposes a cluster of arginine and lysine residues that
coordinate the 3 phosphoryl groups of inositol triphosphate. Putative
calcium-binding sites were identified in 2 separate locations within the
inositol triphosphate-binding core.
MAPPING
Ozcelik et al. (1991) used an M13 clone for a type 1 receptor and
another for a type 3 receptor as probes for assignment of their loci to
human chromosomes by Southern blot analysis of DNA from human/rodent
somatic cell hybrids. The ITPR1 cDNA probe was found to be associated
with the presence of human chromosome 3 in all hybrids. Furthermore, it
was not present in 2 hybrids that contained an isochromosome of 3q,
without an intact copy of this chromosome, thus localizing ITPR1 to 3p.
By isotopic in situ hybridization, Yamada et al. (1994) localized the
ITPR1 gene to 3p26-p25. They found that the gene is widely expressed in
human tissues and thus may play critical roles in various kinds of
cellular functions.
CYTOGENETICS
Cargile et al. (2002) studied a patient with clinical findings
consistent with 3p- syndrome (613792), a rare contiguous gene disorder
characterized by developmental delay, growth retardation, and dysmorphic
features. They noted that all reported cases had, at a minimum, the loss
of chromosomal material telomeric to 3p25.3. Their patient had an
interstitial deletion involving a 4.5-Mb interval between markers
D3S3630 and D3S1304. They suggested the ITPR1 gene as a candidate for
the mental retardation found in this syndrome.
MOLECULAR GENETICS
- Spinocerebellar Ataxia 15
Van de Leemput et al. (2007) identified heterozygous deletions involving
the ITPR1 gene in affected members of 3 unrelated families with
adult-onset autosomal dominant spinocerebellar ataxia-15 (SCA15;
606658), including the SCA15 family of Australian origin used to map the
locus to 3p26-p25 (Knight et al., 2003). Using high-density genomewide
SNP genotyping, Van de Leemput et al. (2007) found a large deletion
removing the first 3 exons of the neighboring SUMF1 gene (607939) and
the first 10 exons of the ITPR1 gene in the family reported by Knight et
al. (2003). Affected members of 2 additional families were found to have
even larger deletions removing the first 3 exons of SUMF1 and 44 and 40
exons of the ITPR1 gene, respectively. The deletions were not observed
in a control population. As homozygous mutations in the SUMF1 gene lead
to a different phenotype (MSD; 272200) and heterozygous carriers of
SUMF1 mutations do not exhibit a movement disorder, the authors
concluded that deletions of the ITPR1 gene underlie the ataxia phenotype
of SCA15. Van de Leemput et al. (2007) noted that direct gene sequencing
failed to identify mutations in the ITPR1 gene and that gene dosage
studies were required for accurate diagnosis.
In affected members of a large 4-generation Japanese family with SCA15,
originally designated as SCA16, Iwaki et al. (2008) identified a
heterozygous deletion of exons 1 to 48 of the ITPR1 gene (147265.0001).
The SUMF1 gene was not affected. The findings indicated that SCA15 is
due to haploinsufficiency of ITPR1. Iwaki et al. (2008) concluded that
the CNTN4 (607280) transition previously identified in this family was
likely a rare polymorphism that was not responsible for the disease.
In affected members of a Japanese family with SCA15 originally reported
by Hara et al. (2004), Hara et al. (2008) identified a 414-kb deletion
of chromosome 3p26 including all of the ITPR1 gene and exon 1 of the
SUMF1 gene. Breakpoint analysis indicated that the deletion was mediated
by nonhomologous end joining. RT-PCR showed that expression levels of
both ITPR1 and SUMF1 in the patients were half of levels in normal
controls. In affected members of a second unrelated Japanese family
reported by Hara et al. (2004), Hara et al. (2008) identified a
heterozygous mutation in the ITPR1 gene (147265.0002).
Synofzik et al. (2011) identified pathogenic ITPR1 deletions in 5 (8.9%)
of 56 European families with autosomal dominant SCA who were negative
for common SCA repeat expansions. All deletions detected by multiplex
ligation-dependent probe amplification (MLPA) were confirmed by SNP
array and spanned approximately 183 to 423 kb, and each family had a
unique deletion. In 3 families, the deletions affected partly both the
ITPR1 and SUMF1 genes, without including the 3-prime region of the ITPR1
gene. One family had a deletion preserving exons 1 and 2 in the 5-prime
untranslated region of the ITPR1 gene.
- Spinocerebellar Ataxia 29
By exome sequencing of a member of the family with autosomal dominant
spinocerebellar ataxia-29 (SCA29; 117360) reported by Dudding et al.
(2004), Huang et al. (2012) identified a heterozygous mutation in the
ITPR1 gene (V1553M; 147265.0003). The mutation was confirmed by Sanger
sequencing and segregated with the disorder in this family. Direct
sequencing of the ITPR1 gene in a Canadian family with a similar
disorder identified a different heterozygous missense mutation (N602D;
147265.0004). Both mutations occurred at highly conserved residues in
the coupling/regulatory domain that modulates channel function, possibly
resulting in dysregulation of intracellular calcium signaling. The
phenotype of SCA29 was distinguished from that of SCA15 by onset in
infancy, delayed motor development, and mild cognitive impairment.
ANIMAL MODEL
Matsumoto et al. (1996) found that most Itpr1-deficient mice generated
by gene targeting die in utero, and that most animals that are born
alive have severe ataxia and tonic or tonic-clonic seizures and die by
the weaning period. Electroencephalograms showed that they suffer from
epilepsy, indicating that ITPR1 is essential for proper brain function.
However, observation by light microscope of the hematoxylin-eosin
staining of the brain and peripheral tissues of deficient mice showed no
abnormality and the unique electrophysiologic properties of the
cerebellar Purkinje cells of deficient mice were not severely impaired.
In the mouse the Intp3r locus is closely situated to the 'opisthotonos'
mutant locus (opt), and Opt homozygous mutant mice exhibit phenotypes
similar to those described for the knockout mice. The opt locus is on
mouse chromosome 6.
Street et al. (1997) determined that the Opt mouse has a homozygous
in-frame deletion of exons 43 and 44 of the Itpr1 gene.
Ogura et al. (2001) found that heterozygous Itpr1 knockout mice (Itpr1
+/-) demonstrated impaired motor coordination compared to wildtype mice
as shown on the rotarod test.
Van de Leemput et al. (2007) identified a homozygous spontaneous 18-bp
deletion in exon 18 of the Itpr1 gene that caused a recessive movement
disorder in mice similar to that observed in Opt mice. The deletion
mutation resulted in markedly decreased levels of Itpr1 in cerebellar
Purkinje cells.
BHLHE40-AS1
| dbSNP name | rs58358486(A,C) |
| cytoBand name | 3p26.1 |
| EntrezGene GeneID | 100507582 |
| snpEff Gene Name | AC018816.4 |
| EntrezGene Description | BHLHE40 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2062 |
LINC00312
| dbSNP name | rs17728877(A,C); rs181419(G,A); rs355134(A,G); rs146719075(C,T); rs164965(T,C); rs11539927(G,T); rs55806758(G,A); rs12497104(G,A); rs164966(G,A); rs15734(A,G); rs165172(T,C) |
| cytoBand name | 3p26.1 |
| EntrezGene GeneID | 29931 |
| snpEff Gene Name | LMCD1 |
| EntrezGene Description | long intergenic non-protein coding RNA 312 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3705 |
SETD5
| dbSNP name | rs9842540(C,T); rs62246275(A,T); rs56324368(A,T); rs2251166(G,A); rs112833191(A,G); rs188648834(T,A); rs56915664(G,A); rs111451827(G,A); rs6443238(C,T); rs7650141(T,C); rs62246277(A,C); rs17746498(T,C); rs60465913(A,C); rs181820917(G,A); rs115705755(C,A); rs4328788(A,T); rs4308263(A,G); rs374643260(C,T); rs11922615(A,G); rs374796824(C,G); rs7615424(A,T); rs113862276(G,A); rs373570080(T,C); rs3885755(A,G); rs3885754(A,G); rs192269726(G,C); rs374093434(G,A); rs141405783(A,C); rs2728934(A,G); rs78349086(A,G); rs34665459(T,C); rs113225651(T,G); rs115968566(A,G); rs9832810(A,T); rs112326060(T,C); rs80208369(A,G); rs78981946(T,C); rs7634081(G,A); rs56782786(T,C); rs2648587(A,T); rs370725282(A,T); rs111511558(G,A); rs904467(G,A); rs7613389(A,C); rs141617620(A,G); rs6769174(T,C); rs3912330(A,G); rs11921561(C,G); rs150269792(A,T); rs2442825(G,A); rs73811484(T,G); rs2596937(T,C); rs60193959(A,G); rs113836389(A,T); rs113039421(G,A); rs112573190(C,G); rs59049946(C,G); rs57892443(G,A); rs77446386(T,G); rs6803966(G,A); rs2290164(T,C); rs74787011(C,A); rs200418836(G,A); rs2258735(T,C); rs73130110(G,A); rs41352751(T,C); rs6792674(A,T); rs1973243(T,C); rs1152314(T,C); rs58803356(T,G); rs6798598(A,G); rs6786197(C,T); rs10510399(G,A); rs2625164(G,A); rs7646012(A,G); rs75387294(C,T); rs112544371(G,T); rs3898759(G,A); rs3898760(C,A); rs2648580(A,G); rs34867485(G,A); rs62246310(C,T); rs11924980(G,A); rs11918316(C,T); rs11923091(T,C); rs62246311(G,A); rs112380819(G,A); rs2648579(T,C); rs138721491(G,A); rs111429675(G,A); rs7617427(A,G); rs181136292(C,T); rs60848685(G,A); rs113424691(A,G); rs79364135(G,C); rs73130117(A,C); rs57949682(C,T); rs9845420(T,C); rs62246314(G,A); rs61337449(C,A); rs7652415(C,T); rs41491550(T,C); rs59790119(A,G); rs57176531(T,C); rs17050371(C,T); rs1060894(A,C); rs73811489(C,T); rs73130123(G,A); rs73130124(G,A); rs115104912(C,T); rs78119175(C,T); rs79921329(C,T); rs3774063(C,T); rs62246320(G,A); rs3872707(G,A); rs17050383(G,A); rs3915844(G,A); rs115699611(G,A); rs62246321(C,T); rs17747739(C,T); rs2279440(C,T); rs17081119(G,C) |
| ccdsGene name | CCDS46741.1 |
| cytoBand name | 3p25.3 |
| EntrezGene GeneID | 55209 |
| EntrezGene Description | SET domain containing 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SETD5:NM_001080517:exon23:c.C4115T:p.T1372I,SETD5:NM_001292043:exon25:c.C3821T:p.T1274I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6495 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B3KXG4 |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.00543 |
| ESP All MAF | 0.002282 |
| ESP Eur/Amr MAF | 0.000708 |
| ExAC AF | 0.001158 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Mouth];
Mild leukokeratosis of buccal bite line (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Palmoplantar keratoderma, focal;
Palmoplantar keratoderma, diffuse (in some patients);
Plantar blistering;
Hyperhidrosis of plantar surface (in some patients);
Clavus formation (rare);
HISTOLOGY:;
Nonepidermolytic orthohyperkeratosis;
Acanthosis;
[Nails];
Hypertrophic nail changes, mild (in some patients);
Splinter hemorrhages of nails (in some patients)
MISCELLANEOUS:
Some patients have only plantar surface involvement
MOLECULAR BASIS:
Caused by mutation in the keratin-6C gene (KRT6C, 612315.0001)
OMIM Title
*615743 SET DOMAIN-CONTAINING PROTEIN 5; SETD5
;;KIAA1757
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated human fetal brain
cDNA library, Nagase et al. (2000) obtained a partial SETD5 clone, which
they designated KIAA1757. RT-PCR ELISA detected highest SETD5 expression
in adult brain, followed by spinal cord, most isolated adult brain
regions, and ovary. Much lower expression was detected in other adult
peripheral tissues and in fetal brain and liver.
The SETD5 gene encodes a 1,442-residue protein that is a putative
methyltransferase (summary by Grozeva et al., 2014).
MAPPING
Hartz (2014) mapped the SETD5 gene to chromosome 3p25.3 based on an
alignment of the SETD5 sequence (GenBank GENBANK AB051544) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 7 unrelated boys with moderate to severe mental retardation-23
(MRD23; 615761), Grozeva et al. (2014) identified 7 different de novo
heterozygous truncating or frameshift mutations in the SETD5 gene (see,
e.g., 615743.0001-615743.0005), consistent with a loss of function and
haploinsufficiency. The patients were ascertained from a larger cohort
of 996 individuals with intellectual disability who were screened for
mutations in 565 known or candidate genes using a targeted
next-generation sequencing approach. All of the mutations were confirmed
by Sanger sequencing, and molecular evidence was compatible with de novo
occurrence. None were found in the dbSNP, 1000 Genomes Project, or Exome
Sequencing Project databases. The patients accounted for 0.7% of the
cohort, suggesting that SETD5 mutations may be relatively common causes
of intellectual disability.
FGD5P1
| dbSNP name | rs6791183(C,T); rs11128668(G,A); rs12490233(G,A); rs6772864(A,G); rs9647360(A,T) |
| cytoBand name | 3p25.1 |
| EntrezGene GeneID | 100132526 |
| snpEff Gene Name | TPRXL |
| EntrezGene Description | FYVE, RhoGEF and PH domain containing 5 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01331 |
SGOL1-AS1
| dbSNP name | rs73818859(G,A) |
| cytoBand name | 3p24.3 |
| EntrezGene GeneID | 100874028 |
| snpEff Gene Name | SGOL1 |
| EntrezGene Description | SGOL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009642 |
VENTXP7
| dbSNP name | rs409972(A,C); rs409974(G,A); rs371532(C,A); rs4857993(G,A); rs366161(G,A); rs11718548(C,T); rs800605(A,G); rs776644(C,T); rs72625843(C,A) |
| cytoBand name | 3p24.3 |
| EntrezGene GeneID | 391518 |
| EntrezGene Description | VENT homeobox pseudogene 7 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4656 |
MIR4792
| dbSNP name | rs11714172(G,T); rs372550739(C,A) |
| cytoBand name | 3p24.2 |
| EntrezGene GeneID | 100616448 |
| EntrezGene Description | microRNA 4792 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3751 |
| ExAC AF | 0.347 |
EPM2AIP1
| dbSNP name | rs1055095(C,A); rs1133661(A,G); rs139834071(T,C); rs200607906(A,T); rs4678923(A,T); rs74903284(G,A); rs9311149(C,A); rs141275247(A,G); rs79081918(T,A); rs1046512(A,C); rs3172297(T,C); rs34566456(G,C) |
| cytoBand name | 3p22.2 |
| EntrezGene GeneID | 9852 |
| EntrezGene Description | EPM2A (laforin) interacting protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4435 |
ACVR2B-AS1
| dbSNP name | rs112514383(A,G); rs9871059(C,T); rs2366123(G,A); rs3792527(T,C); rs3792528(T,C); rs75221584(C,T); rs3762788(C,A); rs62239933(C,T); rs1870914(T,C); rs1870915(G,C); rs3749388(C,T) |
| cytoBand name | 3p22.2 |
| EntrezGene GeneID | 100128640 |
| snpEff Gene Name | ACVR2B |
| EntrezGene Description | ACVR2B antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07163 |
SCN10A
| dbSNP name | rs142653846(G,A); rs6599241(T,C); rs6599242(A,G); rs62243861(G,A); rs11714394(T,G); rs62243862(T,C); rs78881985(C,T); rs11129799(T,C); rs75559840(G,A); rs149102632(C,T); rs11129800(C,T); rs72864380(G,A); rs140870671(T,C); rs78136603(C,T); rs7628873(T,C); rs6422143(C,G); rs6599243(C,T); rs6599244(A,G); rs6599245(G,C); rs6599246(G,C); rs6599247(T,C); rs6790627(T,C); rs6599248(T,A); rs112208946(G,A); rs7430283(C,G); rs11129801(A,G); rs11129802(T,C); rs9861456(C,T); rs11710006(A,T); rs6783110(A,G); rs11129803(T,C); rs6781740(C,T); rs62242430(T,C); rs9818087(T,C); rs141878212(C,T); rs11928905(T,C); rs11924846(C,T); rs6794914(C,T); rs145298386(G,C); rs6599249(G,A); rs185763094(G,A); rs9990137(A,G); rs62242434(C,T); rs62242435(G,A); rs139638446(A,G); rs7617547(G,C); rs61487238(C,T); rs4076737(G,T); rs75660637(G,A); rs7430477(C,T); rs9825762(T,C); rs62242438(T,C); rs6795970(A,G); rs6791171(C,T); rs11129804(A,G); rs74792924(G,A); rs6801957(T,C); rs6799257(A,G); rs59858965(A,C); rs59468016(G,A); rs57326399(T,C); rs73825883(G,C); rs12636153(A,C); rs147989553(G,A); rs34786326(C,T); rs7433306(C,G); rs11129805(A,T); rs11710461(C,G); rs11710462(C,A); rs6780103(G,A); rs6797763(T,C); rs9836859(C,G); rs6790396(C,G); rs72866235(A,G); rs9874633(A,G); rs13096893(G,A); rs9809798(A,C); rs6800541(C,T); rs9874436(C,G); rs144546246(C,T); rs9828737(T,C); rs62242444(C,T); rs58684946(T,C); rs10428132(T,G); rs7428167(T,C); rs9820042(C,T); rs10428168(T,C); rs62242447(T,C); rs62242448(C,A); rs72866253(G,A); rs73826310(A,G); rs9830687(G,A); rs146410320(T,A); rs7615140(T,C); rs3923696(T,A); rs7426951(A,G); rs60554541(A,G); rs3923697(G,A); rs72866259(G,A); rs11129806(C,T); rs62242450(A,G); rs58141279(G,C); rs60847476(G,A); rs6599250(T,C); rs7618620(A,C); rs185526823(A,T); rs72866265(T,G); rs72866267(A,G); rs72866270(G,A); rs7433723(G,A); rs6599251(G,T); rs57203624(G,A); rs56704765(T,C); rs72866278(C,A); rs62242453(C,T); rs371609091(A,G); rs60969309(T,C); rs56128837(A,G); rs7430323(A,G); rs9844265(C,T); rs12634001(G,A); rs55779957(G,T); rs9844577(C,A); rs12491593(C,T); rs7430861(A,C); rs6599252(T,A); rs76984993(G,A); rs9816817(A,G); rs56206213(T,C); rs60349808(T,A); rs12494065(C,T); rs56824318(T,G); rs57803396(G,A); rs56654680(A,T); rs58410551(A,G); rs58802016(T,C); rs7373595(T,A); rs7630989(A,G); rs7431144(T,C); rs6599253(A,C); rs55849713(C,T); rs6784303(C,T); rs7430451(C,G); rs143708033(G,C); rs6599254(A,G); rs6599255(A,C); rs368807551(G,C); rs7374030(C,T); rs62244070(C,T); rs6798015(C,T); rs7433958(T,C); rs7432727(C,T); rs72867808(G,A); rs62244071(T,C); rs62244072(C,T); rs12496750(G,A); rs6763876(T,C); rs6809264(A,C); rs9637536(G,A); rs6599256(G,T); rs57122706(A,G); rs9847662(A,G); rs7641844(A,G); rs185622522(A,T); rs7432804(A,G); rs59640942(C,T); rs7430438(G,A); rs7430439(G,A); rs62244074(G,A); rs62244075(G,C); rs7651106(T,C); rs7635221(G,T); rs7635325(G,T); rs6599257(C,T); rs7433352(A,C); rs113906876(G,C); rs73826327(C,G); rs12497173(G,T); rs113350292(T,A); rs13095477(G,T); rs76354991(G,A); rs145847820(C,T); rs62244077(A,G); rs7610489(A,G); rs7650384(C,T); rs7641702(G,A); rs7644332(G,A); rs11129807(T,A); rs140129291(C,A); rs77136813(A,G); rs148525974(G,A); rs112167921(G,A); rs4676479(G,A); rs12635859(A,G); rs12635869(A,G); rs13071311(G,T); rs4676597(T,C); rs62244078(T,C); rs4629274(T,A); rs4417808(G,A); rs11917835(G,A); rs56040630(C,T); rs4676596(C,T); rs12631918(C,T); rs9872482(A,C); rs113702854(C,T); rs62244079(T,C); rs62244080(G,A); rs113795932(C,T); rs4414778(C,T); rs10212338(G,A); rs4420804(C,T); rs62244081(T,C); rs148138968(G,T); rs7611456(C,T); rs4369974(G,A); rs143024212(A,G); rs11929645(A,G); rs4426622(C,T); rs148450274(T,C); rs4426623(C,T); rs28523323(C,G); rs114543527(G,A); rs62244105(A,G); rs11716467(A,G); rs11716493(A,G); rs4072090(G,T); rs113641258(C,T); rs11711860(C,A); rs12490478(G,T); rs7430726(T,C); rs59856101(C,A); rs62244106(T,C); rs62244107(C,T); rs187154278(C,G); rs11927856(T,C); rs6777775(A,G); rs73064540(T,A); rs11926158(C,G); rs62244108(G,A); rs73064548(C,G); rs4622847(A,G); rs9848976(C,A); rs147938089(A,G); rs9878604(T,C); rs11129808(T,C); rs12172966(T,G); rs13085808(G,A); rs116083182(C,T); rs9836531(A,G); rs73064557(C,T); rs12172962(G,A); rs73064559(T,C); rs9875610(G,A); rs114346323(C,T); rs4676595(A,G); rs4676594(G,T); rs58883392(C,T); rs55791366(G,C); rs73826357(T,G); rs62244110(G,T); rs62244111(C,G); rs73826358(C,G); rs73064564(A,G); rs9815891(C,T); rs6599259(T,C); rs6599260(C,T); rs73826359(T,A); rs6599261(T,A) |
| ccdsGene name | CCDS33736.1 |
| cytoBand name | 3p22.2 |
| EntrezGene GeneID | 6336 |
| EntrezGene Description | sodium channel, voltage-gated, type X, alpha subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SCN10A:NM_001293306:exon27:c.C5654T:p.A1885V,SCN10A:NM_001293307:exon26:c.C5363T:p.A1788V,SCN10A:NM_006514:exon27:c.C5657T:p.A1886V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5832 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5Y9 |
| dbNSFP Uniprot ID | SCNAA_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.010213 |
| ESP All MAF | 0.003537 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001179 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Irritable bowel syndrome
SKELETAL:
Intermittent sterile, pauciarticular, peripheral erosive arthritis
(elbow, knee, ankle);
Synovial tissue biopsy shows polymorphonuclear infiltrate without
presence of immunoglobulin or complement deposits
SKIN, NAILS, HAIR:
[Skin];
Pyoderma gangrenosum;
Severe cystic acne;
Sterile abscesses at site of parenteral injection
HEMATOLOGY:
Normocytic pancytopenia following sulfa use
MISCELLANEOUS:
PAPA syndrome is an acronym for Pyogenic sterile Arthritis, Pyoderma
gangrenosum, Acne;
Onset of arthritis in early childhood;
Onset of acne in adolescence, persists into adulthood
MOLECULAR BASIS:
Caused by mutation in the proline/serine/threonine phosphatase-interacting
protein 1 (PSTPIP1, 606347.0001)
OMIM Title
*604427 SODIUM CHANNEL, VOLTAGE-GATED, TYPE X, ALPHA SUBUNIT; SCN10A
;;NAV1.8;;
PN3;;
SENSORY NEURON-SPECIFIC SODIUM CHANNEL; SNS
OMIM Description
DESCRIPTION
The SCN10A gene encodes the alpha subunit of a voltage-gated sodium
channel. Voltage-gated sodium channels are integral membrane
glycoproteins that are responsible for the initial rising phase of
action in most excitable cells. They are composed of a large alpha
subunit that may be associated with one or more smaller beta subunits.
Sodium channels can be differentiated by their primary structure,
kinetics, and relative sensitivity to the neurotoxin tetrodotoxin (TTX).
Sodium channels, particularly those with TTX-resistant currents, have
been found to accumulate in the region of peripheral nerve injury and
may be important in chronic pain. SCN10A encodes a TTX-resistant channel
that is restricted to the peripheral sensory nervous system (Rabert et
al., 1998).
CLONING
Sangameswaran et al. (1996) and Akopian et al. (1996) independently
identified a sodium channel that produced TTX-resistant currents in rat
dorsal root ganglion (DRG). Sangameswaran et al. (1996) called the
channel Pn3, and Akopian et al. (1996) called the channel Sns. Rabert et
al. (1998) obtained the full-length coding sequence for human PN3,
symbolized SCN10A, from a human DRG cDNA library. The predicted
1,956-amino acid SCN10A protein contains all the features of a
voltage-gated sodium channel: 4 homologous domains consisting of 6
putative alpha-helical transmembrane segments, positively charged
residues in the voltage-sensor transmembrane segments, and the
ile-phe-met sequence within the highly conserved interdomain region. The
amino acid sequence is 90.2% similar to rat PN3 and 70.4% similar to the
human cardiac channel, SCN5A (600163). By RT-PCR analysis, PN3 is
expressed in the peripheral sensory nervous system (i.e., DRG and
sciatic nerve) but not in spinal cord, brain, skeletal muscle, or heart.
MAPPING
By analysis of a panel of somatic cell hybrids, Rabert et al. (1998)
mapped the SCN10A gene to chromosome 3p24.2-p22.
Gross (2013) mapped the SCN10A gene to chromosome 3p22.2 based on an
alignment of the SCN10A sequence (GenBank GENBANK AF117907) with the
genomic sequence (GRCh37).
GENE FUNCTION
Okuse et al. (2002) noted earlier work with rats indicating that SCN10A,
which they called NAV1.8/SNS, is restricted to small-diameter
C-fiber-associated rat sensory neurons and appears to have a role in
pain pathways. By a yeast 2-hybrid screen of a rat sensory neuron cDNA
library, they found that the annexin II light chain, p11 (S100A10;
114085), interacts with the N-terminal intracellular domain of rat
Nav1.8. Transfection of p11 into Chinese hamster ovary (CHO) cells
stably expressing rat Nav1.8 demonstrated that p11 can behave as an
accessory beta subunit, promoting the translocation of Nav1.8 to the
plasma membrane and generating functional sodium channels.
Zimmermann et al. (2007) showed the continuation of nociceptors to
function at low temperatures is achieved by endowing superficial endings
of slowly conducting nociceptive fibers with the tetrodotoxin-resistant
voltage-gated sodium channel NAV1.8. This channel is essential for
sustained excitability of nociceptors when the skin is cooled.
Zimmermann et al. (2007) showed that cooling excitable membranes
progressively enhanced the voltage-dependent slow inactivation of
tetrodotoxin-sensitive voltage-gated sodium channels. In contrast, the
inactivation properties of NAV1.8 were entirely cold-resistant.
Moreover, low temperatures decreased the activation threshold of the
sodium currents and increased the membrane resistance, augmenting the
voltage change caused by any membrane current. Thus, in the cold, NAV1.8
remains available as the sole electrical impulse generator in
nociceptors that transmits nociceptive information to the central
nervous system. Consistent with this concept was the observation that
Nav1.8-null mutant mice (developed by Akopian et al., 1999) showed
negligible responses to noxious cold and mechanical stimulation at low
temperatures. Zimmermann et al. (2007) concluded that their data
provided strong evidence for a specialized role of NAV1.8 in nociceptors
as the critical molecule for the perception of cold pain and pain in the
cold.
The rate of action potential firing in nociceptors is a major
determinant of the intensity of pain. Possible modulators of action
potential firing include the hyperpolarization-activated cyclic
nucleotide-gated (HCN) ion channels, which generate an inward current,
I-h, after hyperpolarization of the membrane. Emery et al. (2011) found
that genetic deletion of HCN2 (602781) removed the cAMP-sensitive
component of I-h and abolished action potential firing caused by an
elevation of cAMP in nociceptors. Mice in which HCN2 was specifically
deleted in nociceptors expressing Nav1.8 had normal pain thresholds, but
inflammation did not cause hyperalgesia to heat stimuli. After a nerve
lesion, these mice showed no neuropathic pain in response to thermal or
mechanical stimuli. Emery et al. (2011) concluded that neuropathic pain
is therefore initiated by HCN2-driven action potential firing in
NAV1.8-expressing nociceptors.
Chiu et al. (2013) demonstrated that bacteria directly activate
nociceptors and that the immune response mediated through TLR2 (603028),
MYD88 (602170), T cells, B cells, and neutrophils and monocytes is not
necessary for Staphylococcus aureus-induced pain in mice. Mechanical and
thermal hyperalgesia in mice is correlated with live bacterial load
rather than tissue swelling or immune activation. Bacteria induce
calcium flux and action potentials in nociceptor neurons, in part via
bacterial N-formylated peptides and the pore-forming toxin
alpha-hemolysin, through distinct mechanisms. Specific ablation of
Nav1.8-lineage neurons, which include nociceptors, abrogated pain during
bacterial infection, but concurrently increased local immune
infiltration and lymphadenopathy of the draining lymph node. Chiu et al.
(2013) concluded that bacterial pathogens produce pain by directly
activating sensory neurons that modulate inflammation.
Riol-Blanco et al. (2014) exposed the skin of mice to imiquimod, which
induces IL23 (see 605580)-dependent psoriasis-like inflammation, and
showed that a subset of sensory neurons expressing the ion channels
TRPV1 (602076) and NAV1.8 is essential to drive this inflammatory
response. Imaging of intact skin revealed that a large fraction of
dermal dendritic cells (DDCs), the principal source of IL23, is in close
contact with these nociceptors. Upon selective pharmacologic or genetic
ablation of nociceptors, DDCs failed to produce IL23 in
imiquimod-exposed skin. Consequently, the local production of
IL23-dependent inflammatory cytokines by dermal gamma-delta-T17 cells
and the subsequent recruitment of inflammatory cells to the skin were
markedly reduced. Intradermal injection of IL23 bypassed the requirement
for nociceptor communication with DDCs and restored the inflammatory
response. Riol-Blanco et al. (2014) concluded that
TRPV1-positive/NAV1.8-positive nociceptors, by interacting with DDCs,
regulate the IL23/IL17 (603149) pathway and control cutaneous immune
responses.
MOLECULAR GENETICS
In a father and son with adult-onset familial episodic pain syndrome-2
(FEPS2; 615551), Faber et al. (2012) identified a heterozygous missense
mutation in the SCN10A gene (L554P; 604427.0001). An unrelated woman
with a similar disorder carried a different heterozygous mutation
(A1304T; 604427.0002). In vitro functional expression studies in mouse
dorsal root ganglia neurons showed that both mutations caused enhanced
channel electrical activities and induced hyperexcitability of DRG
neurons. The findings indicated that gain-of-function mutations in
SCN10A can cause an episodic pain disorder.
- Associations Pending Confirmation
For discussion of a possible association between variants in the SCN5A
(600163), SCN10A, and HEY2 (604674) genes and Brugada syndrome, see
601144.
ANIMAL MODEL
Akopian et al. (1999) found that Sns-null mice were viable, fertile, and
apparently normal. However, they showed lowered thresholds of electrical
activation of C fibers and increased current densities of TTX-sensitive
channels, indicating compensatory upregulation of TTX-sensitive currents
in sensory neurons. Behavioral studies demonstrated a pronounced
analgesia to noxious mechanical stimuli, small defects in noxious
thermoreception, and delayed development of inflammatory hyperalgesia.
Akopian et al. (1999) concluded that SNS is involved in pain perception.
Abrahamsen et al. (2008) tested pain responses in mice treated with
diphtheria toxin to kill all postmitotic sensory neurons expressing the
Nav1.8 sodium channel. They found that Nav1.8-expressing neurons were
essential for mechanical, cold, and inflammatory pain sensitivity, but
not for neuropathic pain or heat sensing.
CYP8B1
| dbSNP name | rs12494055(T,C); rs3732860(T,C); rs62247911(G,A); rs148984634(T,C); rs2888271(G,T); rs2888272(C,G); rs6782601(T,C); rs9865715(A,G) |
| cytoBand name | 3p22.1 |
| EntrezGene GeneID | 1582 |
| EntrezGene Description | cytochrome P450, family 8, subfamily B, polypeptide 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3237 |
OMIM Clinical Significance
Eyes:
Retinitis pigmentosa;
Eyelid ptosis;
Enophthalmos
Endocrine:
Hypopituitarism;
Growth hormone deficiency;
Thyroid stimulating hormone deficiency
GU:
Nephronophthisis;
Renal failure
Skel:
Skeletal dysplasia
GI:
Liver fibrosis
Ears:
Conduction deafness
Inheritance:
? Autosomal recessive
OMIM Title
*602172 CYTOCHROME P450, SUBFAMILY VIIIB, POLYPEPTIDE 1; CYP8B1
;;CYP12;;
STEROL 12-ALPHA-HYDROXYLASE
OMIM Description
DESCRIPTION
Sterol 12-alpha-hydroxylase (CYP8B1) is a hepatic cytochrome P450 that
controls the ratio of cholic acid over chenodeoxycholic acid in bile and
thus controls the solubility of cholesterol (summary by Gafvels et al.,
1999).
CLONING
From rabbit liver, Eggertsen et al. (1996) cloned a cDNA, which they
termed CYP12, coding for sterol 12-alpha-hydroxylase. Northern blot
analysis revealed that CYP12 is expressed exclusively in human and
rabbit liver tissue. Fasting of rats and mice increased CYP12 enzyme
activity and mRNA levels.
Gafvels et al. (1999) obtained cDNAs encoding human and mouse CYP8B1.
The deduced 501-amino acid human CYP8B1 protein is approximately 75%
identical to the mouse and rabbit proteins. It contains a hydrophobic,
membrane-spanning N terminus and conserved oxygen-binding,
steroidogenic, and heme-binding segments. Northern blot analysis
revealed expression of a 3.9-kb CYP8B1 transcript in liver. In mouse,
expression was restricted to liver.
BIOCHEMICAL FEATURES
Zhang and Chiang (2001) showed that hepatocyte nuclear factor-4-alpha
(HNF4A; 600281) strongly activates CYP8B1 promoter activity, whereas
CYP7A promoter-binding factor (CPF, or NR5A2; 604453) has much less
effect. The promoter activities were strongly repressed by bile acid.
EMSA and site-directed mutagenesis analysis indicated that HNF4A, CPF,
and the bile acid response element have overlapping binding sites in
CYP8B1. Mammalian 2-hybrid analysis demonstrated interaction of HNF4A
with the small heterodimer partner (SHP; 604630). Functional analysis
determined that SHP represses HNF4A-induced CYP8B1 transcription. Zhang
and Chiang (2001) concluded that bile acids repress human CYP8B1
transcription by reducing the transactivation activity of HNF4A through
the interaction of HNF4A with SHP and a reduction of HNF4A expression in
liver.
GENE STRUCTURE
By PCR and genomic sequence analyses, Gafvels et al. (1999) determined
that the CYP8B1 gene lacks introns. Primer extension and database
analyses indicated that the promoter region of CYP8B1 contains multiple
regulatory motifs, including a possible TATA box 51 bp from the
transcriptional start site.
MAPPING
By FISH and radiation hybrid analysis, Gafvels et al. (1999) mapped the
CYP8B1 gene to chromosome 3p22-p21.3. They mapped the mouse gene to
chromosome 9qF4
SNRK-AS1
| dbSNP name | rs78701056(G,A); rs4682684(T,C) |
| cytoBand name | 3p22.1 |
| EntrezGene GeneID | 100873954 |
| snpEff Gene Name | ANO10 |
| EntrezGene Description | SNRK antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0303 |
TMEM42
| dbSNP name | rs10429(A,G) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 131616 |
| snpEff Gene Name | KIF15 |
| EntrezGene Description | transmembrane protein 42 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intragenic |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1979 |
CCRL2
| dbSNP name | rs11574439(G,A); rs11574440(G,A); rs11574441(G,A); rs111863112(G,A); rs11266744(A,C); rs3204849(T,A); rs137877836(A,C); rs35212534(G,T) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 9034 |
| EntrezGene Description | chemokine (C-C motif) receptor-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05969 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Nonsyndromic sensorineural hearing loss;
Progressive hearing loss;
Initially, hearing loss is moderate for low (120-250 Hz) and mid (500-2000
Hz) frequencies;
By fourth decade, there is severe hearing loss for mid frequencies
and moderate hearing loss for high frequencies (4000-8000 Hz) (U-shaped
audiometric profile);
Approximately 0.7dB per year hearing loss at all frequencies
MISCELLANEOUS:
Onset in first decade
OMIM Title
*608379 CHEMOKINE, CC MOTIF, RECEPTOR-LIKE PROTEIN 2; CCRL2
;;HCR;;
CRAM
OMIM Description
DESCRIPTION
CCRL2 is an atypical chemokine receptor that may have a role in
modulating chemokine-triggered immune responses (Hartmann et al., 2008).
CLONING
By searching an EST database for significant homology to chemokine
receptors, followed by library screening, Fan et al. (1998) obtained a
genomic clone of CCRL2, which they designated HCR. The deduced 345-amino
acid protein has a calculated molecular mass of 39.5 kD. CCRL2 contains
a 7-transmembrane topography and 2 potential N-glycosylation sites. It
shares 43.1% amino acid identity with CKR1 (601159) and 40.5 to 42.7%
identity with several other cytokine receptors. Northern blot analysis
detected a 1.7-kb transcript expressed predominantly in spleen, fetal
liver, lymph node, bone marrow, lung, and heart. Expression was lower in
thymus and placenta, marginal in skeletal muscle, and was not detected
in several other tissues.
Hartmann et al. (2008) noted that 2 CCLR2 splice variants exist, one
encoding a 345-amino acid protein referred to as CCRL2B, CRAMB, CKRX, or
HCR, and the other encoding a 357-amino acid protein referred to as
CCRL2A or CRAMA.
GENE FUNCTION
Using RT-PCR and flow cytometry, Hartmann et al. (2008) showed that CCL5
(187011) induced ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948)
phosphorylation and expression of CRAMA and CRAMB, but not other
CCL5-binding molecules, in a pre-B cell line. CCL5 did not induce
calcium mobilization or migratory responses in the cell lines. Hartmann
et al. (2008) suggested that CCRL2 may be involved in immunomodulatory
functions together with CCL5.
Zabel et al. (2008) identified chemerin (RARRES2; 601973) as a protein
that interacted with, but was not internalized by, mouse and human
CCRL2. They proposed that CCRL2 focuses chemerin localization and
thereby contributes to inflammatory processes mediated by the chemerin
receptor, CMKLR1 (602351).
By screening for proteins that could bind human CCRL2, Leick et al.
(2009) identified the homeostatic chemokine CCL19 (602227) as a CCRL2
ligand. CCL19 bound to CCRL2-expressing cells with an affinity
comparable to its binding of CCR7 (600242), but binding to CCRL2 did not
result in cellular activation for calcium mobilization or migration.
Confocal microscopy showed that CCRL2 was constitutively recycled via
clathrin-coated pits and could internalize CCL19, as well as anti-CCRL2
antibodies. Leick et al. (2009) concluded that CCRL2 is a nonclassical
chemokine receptor that may be involved in modulating CCL19-mediated
lymphocyte and dendritic cell trafficking.
ANIMAL MODEL
Zabel et al. (2008) found that Ccrl2-knockout mice displayed no overt
phenotype and had normal numbers of mast cells in all tissues analyzed.
Analysis of Ccrl2-knockout mice showed that Ccrl2 was not required for
expression of IgE-mediated mast cell-dependent passive cutaneous
anaphylaxis. However, Ccrl2 was required for development of optimal
cutaneous tissue swelling and leukocyte infiltrates after sensitization
with low doses of antigen-specific IgE.
MAPPING
By FISH, Fan et al. (1998) mapped the CCRL2 gene to chromosome X.
However, Hartz (2004) mapped the CCRL2 gene to chromosome 3p21 based on
an alignment of the CCRL2 sequence (GenBank GENBANK U97123) with the
genomic sequence.
NRADDP
| dbSNP name | rs2278963(C,A) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 100129354 |
| snpEff Gene Name | NBEAL2 |
| EntrezGene Description | neurotrophin receptor associated death domain, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3163 |
TREX1
| dbSNP name | rs11797(C,T); rs3135946(T,C) |
| ccdsGene name | CCDS59451.1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 84126 |
| EntrezGene Symbol | ATRIP |
| EntrezGene Description | ATR interacting protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TREX1:NM_007248:exon2:c.C501T:p.Y167Y,TREX1:NM_016381:exon1:c.C696T:p.Y232Y,TREX1:NM_033629:exon2:c.C531T:p.Y177Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | low |
| dbSNP GMAF | 0.331 |
| ESP Afr MAF | 0.274626 |
| ESP All MAF | 0.393126 |
| ESP Eur/Amr MAF | 0.453837 |
| ExAC AF | 0.37 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Hands];
Claw hand deformities (in severe cases);
[Feet];
Pes cavus
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Upper limb involvement occurs later;
'Steppage' gait;
Foot drop;
Distal sensory impairment;
Hyporeflexia;
Areflexia;
Fasciculations;
Muscle cramps;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Sural nerve biopsy shows chronic axonal neuropathy
MISCELLANEOUS:
Variable age at onset (range 15 to 60 years);
Usually begins in feet and legs (peroneal distribution);
Genetic heterogeneity (see CMT2A, 118210)
MOLECULAR BASIS:
Caused by mutation in the heat-shock 27-kD protein (HSPB1, 602195.0001)
OMIM Title
*606609 3-PRIME @REPAIR EXONUCLEASE 1; TREX1
;;DNase III
OMIM Description
DESCRIPTION
The multistep processes of DNA replication, repair, and recombination
require the excision of nucleotides from DNA 3-prime termini. Enzymes
containing 3-prime-to-5-prime exonuclease activity remove mismatched,
modified, fragmented, and normal nucleotides to generate the appropriate
3-prime termini for subsequent steps in the DNA metabolic pathways
(Mazur and Perrino, 1999).
CLONING
By micropeptide sequence analysis of the 30-kD bovine Trex1 protein, PCR
with degenerate primers, and EST database searching, Mazur and Perrino
(1999) obtained cDNAs encoding mouse and human TREX1 and TREX2 (300370).
Sequence analysis predicted that the 304-amino acid TREX1 protein is 44%
identical to TREX2 (Mazur and Perrino (2001) corrected the TREX1
sequence to 314 amino acids). TREX1 contains 3 conserved exonuclease
motifs, with an HxAxxD sequence in the third motif. Functional analysis
confirmed that the 3-prime-to-5-prime exonuclease activity of the
recombinant protein is comparable to that of the native protein and
prefers mismatched 3-prime termini. Mazur and Perrino (1999) concluded
that the TREX proteins are small, independent 3-prime excision enzymes,
whereas the multifunctional p53 (191170) and WRN (RECQL2; 604611)
proteins, which also have 3-prime-to-5-prime exonuclease activity, are
much larger.
Using rabbit Trex1 to search an EST database, Hoss et al. (1999) also
isolated human TREX1, which they termed DNase III. Northern blot
analysis revealed expression of a 1.15-kb TREX1 transcript in all
tissues tested.
Mazur and Perrino (2001) used 5-prime RACE to identify the flanking
region of TREX1. Genomic sequence analysis suggested that TREX1 open
reading frames are produced by a variety of mechanisms, including
alternate promoter usage, alternative splicing, and varied sites for
3-prime cleavage. RT-PCR analysis detected ubiquitous expression of
TREX1.
GENE STRUCTURE
The TREX1 gene contains a single exon (Hoss et al., 1999; Mazur and
Perrino, 2001).
MAPPING
Hoss et al. (1999) and Mazur and Perrino (2001) identified clones
containing the TREX1 gene that map to chromosome 3p21.3-p21.2.
GENE FUNCTION
SET (600960) and NM23H1 (NME1; 156490) reside in an endoplasmic
reticulum-associated complex, the SET complex, that translocates to the
nucleus in response to superoxide generation by granzyme A (GZMA;
140050). Chowdhury et al. (2006) identified TREX1 as a component of the
SET complex. TREX1 bound SET and colocalized and translocated with the
SET complex. On its own, TREX1 did not damage intact DNA, but it acted
in concert with NM23H1 to destroy DNA during granzyme A-mediated cell
death. After NM23H1 nicked 1 strand, TREX1 removed bases from the free
3-prime end to enhance the damage and prevent DNA end reannealing and
repair.
Using mass spectrometry and Western blot analysis, Stetson et al. (2008)
identified mouse Trex1 as a protein involved in recognition of
interferon stimulatory DNA (ISD) BrdU-labeled intracellular
oligonucleotides. Microarray analysis showed that Trex1 was upregulated
in response to ISD stimulation. However, Trex1 -/- cells retained an
intact ISD response, ruling out Trex1 as the ISD sensor. In contrast
with Trex1 -/- mice, which succumb to lethal autoimmunity (see ANIMAL
MODEL), Trex1 -/- mice lacking Irf3 (603734), Ifnar1 (107450), or Rag2
(179616) survived and regained normal body weight through amelioration
of disease at discrete phases, indicating that TREX1 substrates are
ligands of the ISD pathway. Single-stranded DNA derived from endogenous
retroelements accumulated in Trex1 -/- cells, and Trex1 metabolized
reverse-transcribed DNA. Stetson et al. (2008) concluded that TREX1 is
an essential negative regulator of the ISD response and represents a
mechanism to prevent autoimmunity caused by endogenous retroelements.
Using mutation analysis with recombinant human TREX1, Fye et al. (2011)
found that arg174 and lys175 within the flexible loop and arg128 in the
catalytic core contributed to single-stranded DNA (ssDNA) and
double-stranded DNA (dsDNA) degradation. TREX1 degraded
endonuclease-treated hamster liver nuclei, suggesting that TREX1
contributes to apoptosis-associated DNA degradation.
MOLECULAR GENETICS
- Aicardi-Goutieres Syndrome 1
In affected members of 10 families with Aicardi-Goutieres syndrome
(AGS1; 225750), Crow et al. (2006) identified 5 different mutations in
the TREX1 gene in homozygous or compound heterozygous state (see, e.g.,
606609.0001-606609.0004). One of the mutations, R114H (606609.0001), was
identified in 7 European pedigrees. Crow et al. (2006) identified a
homozygous mutation in the TREX1 gene (606609.0002) in a patient
originally diagnosed with Cree encephalitis, indicating that Cree
encephalitis is essentially the same disorder as AGS1.
Rice et al. (2007) described a de novo heterozygous TREX1 mutation,
affecting a critical catalytic residue in TREX1 (D200N; 606609.0006),
that resulted in typical Aicardi-Goutieres syndrome, thus defining a
dominant form of the disorder.
Haaxma et al. (2010) reported a second patient with Aicardi-Goutieres
syndrome and a de novo heterozygous TREX1 mutation (D18N; 606609.0007).
The D18N mutation had previously been identified in heterozygosity by
Lee-Kirsch et al. (2007) in a family with chilblain lupus.
- Susceptibility to Systemic Lupus Erythematosus
Aicardi-Goutieres syndrome shows overlap with systemic erythematosus
(SLE; 152700) at both clinical and pathologic levels. Lee-Kirsch et al.
(2007) analyzed the TREX1 gene in 417 patients with SLE and 1,712
controls and identified heterozygosity for a 3-prime UTR variant and 11
nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They
found only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7),
relative risk = 25.3). In vitro studies of 2 frameshift mutations
revealed that both caused altered subcellular distribution.
- Chilblain Lupus
Rice et al. (2007) reported a heterozygous TREX1 mutation (606609.0005)
causing familial chilblain lupus (CHBL; 610448), a rare cutaneous form
of SLE.
In affected members of the large 5-generation German family with
chilblain lupus in which the disease was mapped to chromosome 3p21-p14
by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified
heterozygosity for a missense mutation (D18N; 606609.0007) in the TREX1
gene.
- Retinal Vasculopathy with Cerebral Leukodystrophy
In 9 families with autosomal dominant retinal vasculopathy with cerebral
leukodystrophy (192315), Richards et al. (2007) identified 5 different
heterozygous frameshift mutations at the C terminus of the TREX1 gene
(see, e.g., 606609.0008 and 606609.0009). In expression studies, the
truncated proteins retained exonuclease activity but lost normal
perinuclear localization.
GENOTYPE/PHENOTYPE CORRELATIONS
The TREX1 D200N and D18N dominant heterozygous mutations are associated
with AGS1 and CHBL, respectively. Using exonuclease enzyme analysis,
Lehtinen et al. (2008) showed that TREX1 heterodimers containing
wildtype TREX1 and either D200N or D18N mutant proteins were completely
deficient in degrading dsDNA and degraded ssDNA at an approximately
2-fold lower rate than wildtype TREX1. In addition, D200N- and
D18N-containing homo- and heterodimers inhibited the dsDNA degradation
activity of wildtype TREX1, providing an explanation for the dominant
phenotype of the mutant alleles. In contrast, the R114H mutation, which
causes AGS1 when present as a homozygous mutation and SLE when present
as a heterozygous mutation, had dysfunctional dsDNA and ssDNA
degradation activities as a homodimer, but it was functional as a
heterodimer. The R114H homodimer lacked inhibitory activity against
wildtype TREX1, supporting the recessive genetics of the R114H mutation
in AGS1. Lehtinen et al. (2008) concluded that the dysfunctional dsDNA
activities of the disease-related TREX1 mutants could account for
persistent dsDNA from dying cells leading to an aberrant autoimmune
response in these disorders.
ANIMAL MODEL
Morita et al. (2004) found that Trex1 -/- mice developed inflammatory
myocarditis, suggesting a role for this enzyme in immune regulation.
PRKAR2A-AS1
| dbSNP name | rs11709092(A,C); rs9830636(A,C) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 100506637 |
| snpEff Gene Name | PRKAR2A |
| EntrezGene Description | PRKAR2A antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05142 |
WDR6
| dbSNP name | rs6781790(C,T); rs141268742(G,A); rs8926(T,A) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 11180 |
| snpEff Gene Name | P4HTM |
| EntrezGene Description | WD repeat domain 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2755 |
| ESP Afr MAF | 0.433526 |
| ESP All MAF | 0.385896 |
| ESP Eur/Amr MAF | 0.365179 |
| ExAC AF | 0.634 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Gaze-evoked nystagmus;
Saccadic smooth pursuit;
Strabismus (13 to 30% of patients);
Oculomotor apraxia (56% of patients);
Conjunctival telangiectasia (reported in 1 family)
SKELETAL:
[Spine];
Scoliosis (22% of patients);
[Feet];
Pes cavus (less common)
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Distal amyotrophy;
Distal muscle weakness
NEUROLOGIC:
[Central nervous system];
Gait ataxia, progressive;
Limb ataxia, progressive;
Spinocerebellar ataxia;
Dysarthria;
Tremor (57% of patients);
Head tremor (14% of patients);
Dystonic hand posturing (44% of patients);
Dystonia (14% of patients);
Choreic movements (10 to 22% of patients);
Pyramidal signs (21% of patients);
Cerebellar atrophy (96% of patients);
Pontocerebellar atrophy;
[Peripheral nervous system];
Polyneuropathy (98% of patients);
Decreased distal vibration sense;
Decreased distal proprioception (74% of patients);
Decreased distal touch sense (57% of patients);
Areflexia;
Absence of sensory action potentials;
Decreased motor nerve conduction velocity (NCV);
Sural nerve biopsy shows chronic axonal neuropathy;
Sural nerve biopsy shows loss of large myelinated fibers
LABORATORY ABNORMALITIES:
Increased serum alpha-fetoprotein;
Increased serum gamma-globulin;
Increased serum creatine kinase (less common)
MISCELLANEOUS:
Onset usually in mid-teens, average 15 years (range 2 to 20 years);
Progressive disorder;
Variable severity;
High frequency in the French-Canadian population
MOLECULAR BASIS:
Caused by mutations in the senataxin gene (SETX, 608465.0001)
OMIM Title
*606031 WD REPEAT-CONTAINING PROTEIN 6; WDR6
OMIM Description
DESCRIPTION
A conserved core of 4 or more modular repeat units defines a group of
functionally diverse regulatory proteins in eukaryotes known as the WD
repeat family. WD repeats are minimally conserved regions of
approximately 40 amino acids typically bracketed by gly-his and trp-asp
(GH-WD), which may facilitate formation of heterotrimeric or
multiprotein complexes. Proteins belonging to the WD repeat family are
involved in a variety of cellular processes, including cell cycle
progression, signal transduction, apoptosis, and gene regulation
(summary by Claudio et al., 1999).
CLONING
Using a cDNA fragment obtained with a differential display/PCR technique
to screen a human atrial cDNA library, Li et al. (2000) obtained a novel
WD repeat-containing cDNA, designated WDR6. WDR6 encodes a 1,121-amino
acid protein with 11 WD repeat units clustered into 2 distinct groups
that are separated by a putative transmembrane domain. Northern blot
analysis detected ubiquitous expression of a major 4.4-kb transcript,
with prominent expression in pancreas.
MAPPING
By FISH, Li et al. (2000) mapped the WDR6 gene to chromosome 15q21.
However, Gross (2011) mapped the WDR6 gene to chromosome 3p21.31 based
on an alignment of the WDR6 sequence (GenBank GENBANK AF099100) with the
genomic sequence (GRCh37).
DALRD3
| dbSNP name | rs7100(A,G); rs3087866(T,C) |
| ccdsGene name | CCDS2783.1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 55152 |
| snpEff Gene Name | WDR6 |
| EntrezGene Description | DALR anticodon binding domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1221 |
| ESP Afr MAF | 0.12256 |
| ESP All MAF | 0.201599 |
| ESP Eur/Amr MAF | 0.242093 |
| ExAC AF | 0.828 |
MST1
| dbSNP name | rs3197999(G,A); rs13085791(C,A); rs142690032(G,A) |
| ccdsGene name | CCDS33757.2 |
| CosmicCodingMuts gene | MST1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 4485 |
| EntrezGene Description | macrophage stimulating 1 (hepatocyte growth factor-like) |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/pubmed?term=18587394,20228799,21102463,21151127,23128233 |
| Annovar Function | MST1:NM_020998:exon18:c.C2107T:p.R703C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3XAK1 |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/pubmed?term=18587394,20228799,21102463,21151127,23128233 |
| dbNSFP KGp1 AF | 0.216117216117 |
| dbNSFP KGp1 Afr AF | 0.241869918699 |
| dbNSFP KGp1 Amr AF | 0.223756906077 |
| dbNSFP KGp1 Asn AF | 0.0646853146853 |
| dbNSFP KGp1 Eur AF | 0.310026385224 |
| dbSNP GMAF | 0.2153 |
| ESP Afr MAF | 0.235134 |
| ESP All MAF | 0.273797 |
| ESP Eur/Amr MAF | 0.293605 |
| ExAC AF | 0.255 |
OMIM Clinical Significance
Thorax:
Hiatus hernia;
Congenital short esophagus;
Partial thoracic stomach
Inheritance:
Autosomal dominant
OMIM Title
*142408 MACROPHAGE STIMULATING 1; MST1
;;HEPATOCYTE GROWTH FACTOR-LIKE PROTEIN; HGFL;;
MACROPHAGE STIMULATING PROTEIN; MSP
OMIM Description
CLONING
Han et al. (1991) isolated an MST1 cDNA from a human liver cDNA library.
The deduced protein contains 4 kringle domains followed by a serine
protease domain. Because this domain structure was identical to that
found in hepatic growth factor (HGF; 142409), Han et al. (1991) proposed
that the protein be called HGF-like (HGFL). The 2 proteins share about
50% sequence identity.
GENE STRUCTURE
Han et al. (1991) determined that the HGFL gene contains 18 exons and
spans approximately 47 kb.
MAPPING
Han et al. (1991) identified the HGFL gene at the DNF15S2 locus on human
chromosome 3 (3p21). The gene for acylpeptide hydrolase (APH; 102645)
was located 444 bp downstream of the HGFL gene, but on the complementary
strand. The DNF15S2 locus had been proposed to code for one or more
tumor suppressor genes since this locus is deleted in DNA from small
cell lung carcinoma, renal cell carcinoma, and von Hippel-Lindau
syndrome.
Degen et al. (1992) demonstrated that the mouse Hgfl gene is on
chromosome 9, distal to the transferrin locus. The region surrounding
the Hgfl locus shows homology of synteny to 3p21. Yoshimura et al.
(1993) assigned the human gene for macrophage stimulating protein to
chromosome 3. They also found that a cDNA identified a unique sequence
on chromosome 1, suggesting the location there of a member of the same
gene family.
GENE FUNCTION
Sakamoto et al. (1997) showed that the RON tyrosine kinase (600168), the
receptor for MSP, is expressed on the ciliated epithelia of the
mucociliary transport apparatus of the lung. Furthermore, they showed
that MSP stimulated ciliary motility in these cells by activating RON.
MOLECULAR GENETICS
For discussion of an association between variation in the MST1 gene and
inflammatory bowel disease, see IBD12 (612241).
For discussion of an association between variation in the MST1 gene and
primary sclerosis cholangitis, see PSC (613806).
ANIMAL MODEL
To assess the in vivo effects of total loss of HGFL, Bezerra et al.
(1998) generated mice with targeted disruption of the gene resulting in
loss of the protein. Embryogenesis proceeded normally and followed a
mendelian pattern of genetic transmission. Mice homozygous for the
targeted allele, Hgfl -/- mice, were fertile and grew to adulthood
without obvious phenotypic abnormalities in unchallenged animals, except
for development of lipid-containing cytoplasmic vacuoles in hepatocytes
throughout the liver lobules. The histologic changes were not
accompanied by discernible changes in synthetic or excretory hepatic
functions. Hematopoiesis appeared unaltered, and although macrophage
activation was delayed in the absence of Hgfl, migration to the
peritoneal cavity upon challenge with thioglycollate was similar in null
and in wildtype mice. Challenged with incision to skin, null mice
displayed normal wound healing. These data demonstrated that HGFL is not
essential for embryogenesis, fertility, or wound healing. The mice will
provide a valuable means to assess the role of HGFL in hepatic and
systemic responses to inflammatory and infectious stimuli in vivo.
AMIGO3
| dbSNP name | rs7628207(T,C) |
| ccdsGene name | CCDS33758.1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 386724 |
| snpEff Gene Name | GMPPB |
| EntrezGene Description | adhesion molecule with Ig-like domain 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1607 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial nerve palsies;
[Eyes];
Ophthalmoplegia;
Optic atrophy (1 patient)
CARDIOVASCULAR:
[Vascular];
Stroke, ischemic;
Stroke, hemorrhagic;
Small-vessel disease;
Polyarteritis nodosa;
Aneurysms;
Stenosis;
Hypertension (in some patients)
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Gastrointestinal pain
GENITOURINARY:
[Kidneys];
Renal artery aneurysms
SKELETAL:
Arthritis;
[Hands];
Ischemic digital necrosis;
[Feet];
Ischemic digital necrosis
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa;
Livedo reticularis;
Erythema nodosum;
Urticarial rash;
Purpura;
HISTOLOGY:;
Vasculitis in the reticular dermis;
Inflammatory infiltrate;
Interstitial neutrophils and macrophages;
Perivascular T lymphocytes;
Leukocytoclastic vasculitis;
Panniculitis
MUSCLE, SOFT TISSUE:
Myalgia
NEUROLOGIC:
[Central nervous system];
Neurologic sequelae of stroke;
Altered mental status;
Hemiplegia;
Headache;
Ataxia;
Agitation;
Cranial nerve dysfunction;
Aphasia;
Lacunar infarcts in the deep-brain nuclei, brainstem, internal capsule
seen on imaging;
[Peripheral nervous system];
Raynaud phenomenon;
Neuropathy
METABOLIC FEATURES:
Fever, recurrent
HEMATOLOGY:
Lupus anticoagulant (in some patients);
Anemia (in some patients);
Thrombocytosis (in some patients)
IMMUNOLOGY:
Immunodeficiency;
Hypogammaglobulinemia (in some patients);
Leukopenia;
Leukocytosis
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Acute-phase reactants during fever
MISCELLANEOUS:
Variable age at onset, usually in first decade, but can occur later;
Variable manifestations;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0001)
OMIM Title
*615691 ADHESION MOLECULE WITH Ig-LIKE DOMAIN 3; AMIGO3
;;AMPHOTERIN-INDUCED GENE AND OPEN READING FRAME 3; AMIGO3;;
ALIVIN 3; ALI3
OMIM Description
DESCRIPTION
AMIGO3 belongs to a family of cell surface transmembrane proteins that
interact with one another. These proteins are predicted to function in
cell adhesion (Kuja-Panula et al., 2003).
CLONING
By searching databases for sequences similar to rat Ali1 (AMIGO2;
615690), Ono et al. (2003) identified human AMIGO3, which they called
ALI3. The deduced protein contains an N-terminal signal sequence,
followed by a cysteine-rich domain, 7 leucine-rich repeats (LRRs), a
second cysteine-rich domain, an immunoglobulin C2-like loop, a
transmembrane region, and a C-terminal intracellular domain. Human ALI3
shares 32% and 34% amino acid identity with human ALI1 and ALI2 (AMIGO1;
615689), respectively.
By searching an EST database for sequences similar to AMIGO (AMIGO1;
615689), followed by 5-prime RACE of HEK293 cells, Kuja-Panula et al.
(2003) cloned AMIGO3. The deduced protein contains 504 amino acids.
Kuja-Panula et al. (2003) reported that the AMIGO proteins contain 6
LRRs. The AMIGO protein family shares highest similarity with the SLIT
family of extracellular axon-guiding proteins (see 603742) and with the
NOGO66 receptor (RTN4R; 605566). RT-PCR analysis of 12 mouse tissues
showed ubiquitous Amigo3 expression.
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (2001) obtained a clone, which they designated
KIAA1851, containing 2 coding regions separated by 2.4 kb. They
identified the upstream coding region as that of GMPPB (615320) and
suggested that KIAA1851 may represent a read-through transcript of the
GMPPB gene. Hartz (2014) determined that the KIAA1851 sequence (GenBank
GENBANK AB058754) includes the sequence of AMIGO3 (GenBank GENBANK
AY237003) in addition to that of GMPPB.
MAPPING
Hartz (2014) mapped the AMIGO3 gene to chromosome 3p21.31 based on an
alignment of the AMIGO3 sequence (GenBank GENBANK AY237003) with the
genomic sequence (GRCh37).
GMPPB
| dbSNP name | rs1466685(T,C) |
| ccdsGene name | CCDS2802.1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 29925 |
| EntrezGene Description | GDP-mannose pyrophosphorylase B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GMPPB:NM_013334:exon5:c.A551G:p.Q184R,GMPPB:NM_021971:exon5:c.A551G:p.Q184R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5P6-2 |
| dbNSFP KGp1 AF | 0.989010989011 |
| dbNSFP KGp1 Afr AF | 0.95325203252 |
| dbNSFP KGp1 Amr AF | 0.997237569061 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.031548 |
| ESP All MAF | 0.010841 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.997 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Low anterior hairline (in some patients);
[Ears];
Minor ear anomalies (in some patients);
[Eyes];
Strabismus (in some patients);
Blepharoptosis (in some patients);
[Teeth];
Malocclusion, class I/II (in some patients)
SKELETAL:
[Skull];
Coronal synostosis, unilateral or bilateral;
Sagittal synostosis;
[Hands];
Transverse palmar crease (in some patients);
Brachydactyly (in some patients);
[Feet];
Hallux valgus (in some patients);
Syndactyly between adjacent toes (in some patients)
SKIN, NAILS, HAIR:
[Hair];
Low anterior hairline (in some patients)
NEUROLOGIC:
[Central nervous system];
Learning disability (in some patients);
Developmental delay (in some patients);
Asperger syndrome (rare);
Autism (rare);
Prominent ventricles (in some patients);
Prominent CSF spaces (in some patients);
Agenesis of corpus callosum, partial or complete (rare)
MOLECULAR BASIS:
Caused by mutation in the transcription factor-12 gene (TCF12, 600480.0001)
OMIM Title
*615320 GDP-MANNOSE PYROPHOSPHORYLASE B; GMPPB
;;GDP-MANNOSE PYROPHOSPHORYLASE, BETA SUBUNIT;;
GMPP-BETA
OMIM Description
DESCRIPTION
The GMPPB gene encodes the beta subunit of an essential enzyme,
GDP-mannose pyrophosphorylase (EC 2.7.7.13), that catalyzes the
conversion of mannose-1-phosphate and GTP to inorganic diphosphate and
GDP-mannose, a major mannosyl donor for mannose-containing polymers
(Ning and Elbein, 2000). GDP-mannose is required in 4 glycosylation
pathways, including O-mannosylation of membrane and secretory
glycoproteins, such as alpha-dystroglycan (DAG1; 128239) (summary by
Carss et al., 2013).
CLONING
By searching databases for sequences similar to porcine Gmpp-beta, Ning
and Elbein (2000) identified human GMPPB, as well as GMPPB orthologs in
several lower species, including nematode, yeast, and plants. The
360-amino acid human protein shares 96% identity with porcine Gmpp-beta.
The GMPPB protein contains 2 main functional domains: a nucleotidyl
transferase domain and a bacterial transferase hexapeptide domain. Carss
et al. (2013) determined that the GMPPB gene is transcribed as 2
isoforms in human tissues. The longer isoform (GenBank GENBANK
NM_021971.1) was strongly expressed in all fetal and adult tissues
tested, including brain and skeletal muscle, whereas the shorter isoform
(GenBank GENBANK NM_013334.2) was weakly expressed in the tissues
tested. There appeared to be no developmental difference in the
expression of the 2 isoforms.
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (2001) obtained a clone, which they designated
KIAA1851, containing 2 coding regions separated by 2.4 kb. They
identified the upstream coding region as that of GMPPB and suggested
that KIAA1851 may represent a read-through transcript of the GMPPB gene.
Hartz (2014) determined that the KIAA1851 sequence (GenBank GENBANK
AB058754) includes the sequence of AMIGO3 (615691) (GenBank GENBANK
AY237003) in addition to that of GMPPB.
GENE STRUCTURE
The coding DNA sequence of one isoform of the GMPPB gene (GenBank
GENBANK NM_021971.1) contains 10 exons, whereas that of another isoform
(GenBank GENBANK NM_013334.2) contains 8 exons (Carss et al., 2013).
MAPPING
Hartz (2013) mapped the GMPPB gene to chromosome 3p21.31 based on an
alignment of the GMPPB sequence (GenBank GENBANK AB058754) with the
genomic sequence (GRCh37).
GENE FUNCTION
Ning and Elbein (2000) found that recombinant porcine Gmpp-beta
catalyzed bidirectional conversion of mannose-1-phosphate and GTP to
inorganic diphosphate and GDP-mannose. Compared with purified pig liver
Gmpp, which was a dimer of alpha and beta subunits, recombinant
Gmpp-beta showed much lower activity as a GDP-glucose pyrophosphorylase
(EC 2.7.7.34). Divalent cations, particularly Mn(2+), enhanced the
Gmpp-beta reaction, whereas Mg(2+) was the preferred cofactor for the
endogenous dimeric enzyme.
MOLECULAR GENETICS
By exome sequencing combined with Sanger sequencing of 8 unrelated
patients with various forms of congenital muscular dystrophy, Carss et
al. (2013) identified 8 different mutations in the GMPPB gene (GenBank
GENBANK NM_02197.1) (615320.0001-615320.0008). All mutations occurred in
homozygous or compound heterozygous state and segregated with the
disorder in the families in whom parental DNA was available. All
affected individuals had at least 1 mutation affecting the highly
conserved nucleotidyl transferase domain. The phenotype was highly
variable. The most severely affected patient had muscle weakness at
birth with severely delayed psychomotor development, retinal
dysfunction, and pontocerebellar hypoplasia, reminiscent of
muscle-eye-brain disease and consistent with congenital muscular
dystrophy-dystroglycanopathy with brain and eye anomalies type A14
(MDDGA14; 615350). Four patients presented with a slightly milder
phenotype with onset of muscle weakness in the first months of life with
milder intellectual disability with or without cerebellar hypoplasia,
consistent with congenital muscular dystrophy-dystroglycanopathy with
mental retardation type B14 (MDDGB14; 615351). The least severe
phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14
(MDDGC14; 615352), was present in 3 unrelated patients, 1 of whom had
onset at age 4 and normal intellectual function. Variable features seen
in some patients included microcephaly, seizures, cataracts, and cardiac
dysfunction. All patients had dystrophic features on muscle biopsy, and
immunohistochemical and flow cytometric analysis of patient cells showed
reduced glycosylation of alpha-dystroglycan. Overexpression of wildtype
GMPPB in fibroblasts from an affected individual partially restored
glycosylation of DAG1. Whereas wildtype GMPPB localized to the
cytoplasm, 5 of the identified missense mutations caused formation of
aggregates in the cytoplasm or near membrane protrusions. Knockdown of
the GMPPB ortholog in zebrafish caused structural muscle defects with
decreased motility, eye abnormalities, and reduced glycosylation of
DAG1. None of the patients had evidence of abnormal serum transferrin
glycoforms.
ANIMAL MODEL
Carss et al. (2013) found that zebrafish gmppb is expressed throughout
development. Morpholino knockdown of gmppb in zebrafish resulted in
smaller embryos with multiple anomalies, including bent tails,
hypopigmentation, microphthalmia, hydrocephalus, and reduced motility.
Muscle fibers in mutant zebrafish were sparse and disorganized, and the
myosepta were damaged or incompletely developed. There was also evidence
of sarcolemmal damage. Immunostaining showed defective glycosylation of
DAG1 associated with abnormal structure of the basement membrane. These
findings were reminiscent of the muscular dystrophy phenotype found in
humans with GMPPB mutations.
RBM5-AS1
| dbSNP name | rs73835203(A,T) |
| ccdsGene name | CCDS2810.1 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 100775107 |
| snpEff Gene Name | RBM5 |
| EntrezGene Description | RBM5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03581 |
GNAT1
| dbSNP name | rs11919418(T,G); rs13064381(C,T); rs114828382(G,A); rs34877766(A,G) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 2779 |
| EntrezGene Description | guanine nucleotide binding protein (G protein), alpha transducing activity polypeptide 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3237 |
OMIM Clinical Significance
Thorax:
Gynecomastia
Inheritance:
Male-limited autosomal dominant vs. autosomal recessive or X-linked
OMIM Title
*139330 GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-TRANSDUCING ACTIVITY POLYPEPTIDE
1; GNAT1
;;G PROTEIN, ALPHA-TRANSDUCING 1;;
TRANSDUCIN, ROD-SPECIFIC, ALPHA POLYPEPTIDE
OMIM Description
CLONING
By physical cloning methodologies and bioinformatic computational
analyses, Lerman and Minna (2000) identified a number of genes,
including GNAT1, in a region of chromosome 3p21.3 that is associated
with a putative lung cancer tumor suppressor gene. The deduced 350-amino
acid transducin protein, which is 100% identical to the mouse protein,
contains a G-alpha domain and an ARF domain. Northern blot analysis
revealed abundant expression of a 1.5-kb transcript in retina and fetal
heart and in T-cell lines. No expression was detected in lung or lung
cancer cell lines, and no mutations were found in any lung cancer cell
lines. Lerman and Minna (2000) concluded that GNAT1 is an unlikely
candidate for functional tumor suppressor gene studies.
GENE STRUCTURE
By genomic sequence analysis, Lerman and Minna (2000) determined that
the 3.5-kb GNAT1 gene contains 7 exons.
Bourne et al. (1991) analyzed the conserved structure of the GTPase
superfamily which includes the 21-kD (relative molecular mass, 21,000)
products of the ras oncogenes (e.g., 190020, 190070) and the alpha
subunits of the heterotrimeric signal-transducing G proteins. All such
GTPases go through the same unidirectional cycle, in which exchange of
GDP for GTP turns on the switch and GTP hydrolysis turns it off.
Structures of the GTPases resemble one another not only in overall
design, but also in detail.
MAPPING
Sparkes et al. (1987) and Blatt et al. (1988) hybridized cDNA probes for
subunits of different G proteins against a mouse/human somatic cell
hybrid panel. This permitted assignment of the gene for the
alpha-transducing G protein, polypeptide-1, to human chromosome 3.
Sparkes et al. (1987) mapped the corresponding gene in the mouse to
chromosome 9. Using a cDNA clone for the alpha subunit of bovine rod
transducin, Danciger et al. (1989) also mapped the corresponding gene,
Gnat1, to mouse chromosome 9 with a panel of Chinese-hamster somatic
cell hybrid DNAs. By in situ hybridization, Wilkie et al. (1992)
demonstrated that the GNAT1 gene is on 3p21. They confirmed that the
mouse equivalent is on chromosome 9. Transducin is involved in the
stimulation of cGMP-phosphodiesterase when light hits the rod
photoreceptors. Danciger et al. (1989) concluded that the primary defect
in the retinal degeneration of mice, called rd, cannot reside in this
gene inasmuch as the disease maps to mouse chromosome 5. Ngo et al.
(1993) placed GNAT1 on 3p22 by in situ hybridization. In conjunction
with earlier work, the localization could be said to be 3p22-p21.3.
Bourne et al. (1991) noted that the GNAT1 and GNAI2 (139360) genes are
closely situated on human 3p21 and on mouse chromosome 9, consistent
with the notion that they were generated by tandem gene duplication that
occurred prior to the divergence of rodents and primates. Similarly,
GNAI3 (139370) and GNAT2 (139340) are apparently closely linked on human
1p13 and murine chromosome 3.
Wilkie et al. (1992) pointed out that in mammals, 15 G protein
alpha-subunit genes can be grouped by sequence and functional
similarities into 4 classes: Gs, Gi, Gq, and G12. From the chromosomal
location of these 15 genes, in combination with mapping studies in
humans, they proposed a phylogenetic tree for the genes.
Lerman and Minna (2000) identified the human GNAT1 gene in a region of
chromosome 3p21.3 that is associated with a putative lung cancer tumor
suppressor gene.
GENE FUNCTION
Ruiz-Avila et al. (1995) demonstrated that rod transducin is not limited
to retinal cells but is also present in vertebrate taste cells, where it
specifically activates a phosphodiesterase isolated from taste tissue.
Other results suggested that rod transducin tranduces bitter taste by
coupling a taste receptor(s) to taste-cell phosphodiesterase. Gustducin
(139395), a G protein specific to taste receptor cells, is closely
related to the transducins. Taste can be divided into 4 primary
sensations: salty, sour, sweet, and bitter. Salty and sour are directly
transduced by apical channels, whereas sweet and bitter utilize cyclic
nucleotide second messengers. The role of rod transducin in bitter taste
is an example of the latter mechanism.
Nair et al. (2005) identified the presence of leu-gly-asn
repeat-enriched protein (LGN; 609245), a putative binding partner of
transducin, in rod photoreceptors.
MOLECULAR GENETICS
Dryja et al. (1996) reported that affected descendants of Jean Nougaret
(1637-1719) who suffer from congenital stationary night blindness (see
610444) carry a missense mutation in the GNAT1 gene. Sequence analysis
in 2 affected sibs revealed a point mutation in codon 38 (139330.0001)
resulting in a G38D amino acid change. No other changes in the coding
region or flanking intron sequences were found by SSCP. Dryja et al.
(1996) reported that subsequent analysis of 27 relatives revealed that
the mutation was present only in affected family members. Dryja et al.
(1996) noted that gly38 is a highly conserved residue among heteromeric
G proteins including p21(RAS) (see 190020).
ANIMAL MODEL
Hattar et al. (2003) investigated whether photoreceptor systems besides
rod-cone and melanopsin participate in pupillary reflex, light-induced
phase delays of the circadian clock, and period lengthening of the
circadian rhythm in constant light. Using mice lacking rods and cones,
Hattar et al. (2003) measured the action spectrum for phase-shifting the
circadian rhythm of locomotor behavior. This spectrum matched that for
the pupillary light reflex in mice of the same genotype, and that for
the intrinsic photosensitivity of the melanopsin-expressing retinal
ganglion cells. Hattar et al. (2003) also generated triple-knockout mice
(for Gnat, Cnga3, 600053, and Opn4, 606665) in which the rod-cone and
melanopsin systems were both silenced. These animals had an intact
retina but failed to show any significant pupil reflex, to entrain to
light/dark cycles, and to show any masking response to light. Thus,
Hattar et al. (2003) concluded that the rod-cone and melanopsin systems
together seem to provide all of the photic input for these accessory
visual functions.
Inactivating mutations in the RPE65 gene (180069) and LRAT gene (604863)
cause forms of Leber congenital amaurosis (LCA). Maeda et al. (2009)
investigated human RPE65-LCA patients and mice with visual cycle
abnormalities to determine the impact of chronic chromophore deprivation
on cones. Young patients with RPE65 mutations showed foveal cone loss
along with shortened inner and outer segments of remaining cones; cone
cell loss also was dramatic in young mice lacking Rpe65 or Lrat gene
function. To selectively evaluate cone pathophysiology, the authors
eliminated the rod contribution to electroretinographic (ERG) responses
by generating double-knockout mice lacking Lrat or Rpe65 together with
an inactivated Gnat1 gene. Cone ERG responses were absent in
Gnat1-null/Lrat-null mice, which also showed progressive degeneration of
cones. Cone ERG responses in Gnat1-null/Rpe65-null mice were markedly
reduced and declined over weeks. Treatment of these mice with an
artificial chromophore prodrug, 9-cis-retinyl acetate, partially
protected inferior retinal cones as evidenced by improved ERGs and
retinal histochemistry. Gnat1-null mice chronically treated with
retinylamine, a selective inhibitor of RPE65, also showed a decline in
the number of cones that was ameliorated by 9-cis-retinyl acetate. Maeda
et al. (2009) suggested that chronic lack of chromophore may lead to
progressive loss of cones in mice and humans, and that therapy for LCA
patients could be geared toward early adequate delivery of chromophore
to cone photoreceptors.
HYAL2
| dbSNP name | rs709210(A,C) |
| ccdsGene name | CCDS2818.1 |
| CosmicCodingMuts gene | HYAL2 |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 8692 |
| EntrezGene Description | hyaluronoglucosaminidase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HYAL2:NM_003773:exon2:c.T52G:p.S18A,HYAL2:NM_033158:exon3:c.T52G:p.S18A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q12891 |
| dbNSFP Uniprot ID | HYAL2_HUMAN |
| dbNSFP KGp1 AF | 0.77380952381 |
| dbNSFP KGp1 Afr AF | 0.947154471545 |
| dbNSFP KGp1 Amr AF | 0.801104972376 |
| dbNSFP KGp1 Asn AF | 0.79020979021 |
| dbNSFP KGp1 Eur AF | 0.635883905013 |
| dbSNP GMAF | 0.2264 |
| ESP Afr MAF | 0.117099 |
| ESP All MAF | 0.274854 |
| ESP Eur/Amr MAF | 0.355548 |
| ExAC AF | 0.656,8.182e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Midface hypoplasia
SKELETAL:
Spondyloepimetaphyseal dysplasia;
Joint laxity;
[Spine];
Scoliosis;
Caudal narrowing of interpedicular distances;
Vertebral endplate irregularity;
Posterior vertebral body scalloping;
Sacral spinal dysraphism;
[Pelvis];
Congenital hip dislocation;
Small flattened capital femoral epiphyses;
Narrow femoral necks;
Tapered ischia;
[Limbs];
Large joint dislocations (especially knees);
Small, flattened irregular epiphyses;
Irregular, flared metaphyses with streaky sclerosis;
Radial head dislocation;
Genu valgum;
Severely delayed patellae ossification;
[Hands];
Gracile metacarpals;
Long, slender middle and proximal phalanges;
Broad, square ends of distal phalanges;
Prominent distal phalangeal tufts;
Small carpal bones;
Severe delay in phalangeal epiphyseal bone maturation
SKIN, NAILS, HAIR:
[Skin];
Velvety skin;
Normal wound healing
NEUROLOGIC:
[Central nervous system];
Hypotonia
OMIM Title
*603551 HYALURONOGLUCOSAMINIDASE 2; HYAL2
;;LUCA2;;
HYALURONIDASE 2
OMIM Description
DESCRIPTION
Hyaluronidases degrade hyaluronic acid (HA), a glycosaminoglycan present
in the extracellular matrix of vertebrates. However, hyaluronidase-2
exhibits very low hyaluronidase activity.
CLONING
By searching an EST database for sequences related to the PH-20 (600930)
hyaluronidase, Lepperdinger et al. (1998) identified HYAL2 cDNAs. The
HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide. The
predicted 452-amino acid mature protein is 36.5% identical to PH-20.
Northern blot analysis indicated that HYAL2 was expressed in all human
tissues tested except adult brain, and Western blot analysis detected
Hyal2 protein in all mouse tissues examined except adult brain.
Strobl et al. (1998) characterized Hyal2, the mouse homolog of HYAL2.
The deduced proteins are 82% identical.
GENE FUNCTION
Lepperdinger et al. (1998) found that, unlike HYAL1 (607071), whose
properties suggested that it was membrane associated, a fusion protein
of HYAL2 and green fluorescent protein (GFP) localized to lysosomes of
mammalian cells. HYAL2 hyaluronidase activity had a pH optimum below 4.
Also in contrast to HYAL1, the HYAL2 enzyme hydrolyzed only HA of high
molecular mass, yielding intermediate-sized HA fragments of
approximately 20 kD, which were further hydrolyzed to small
oligosaccharides by PH-20. The authors noted that the intermediate-sized
HA fragments have specific biologic functions. Lepperdinger et al.
(1998) concluded that HYAL2 encodes a lysosomal hyaluronidase that is
present in many cell types.
Rai et al. (2001) and Dirks et al. (2002) showed that HYAL2 is a
glycosylphosphatidylinositol (GPI)-anchored protein on the cell surface
and serves as a receptor for entry into the cell of the jaagsiekte sheep
retrovirus (JSRV). In sheep, JSRV causes a contagious form of lung
cancer that arises from epithelial cells in the lower airway, including
type II aveolar and bronchiolar epithelial cells. De las Heras et al.
(2000) reported that antiserum directed against the JSRV capsid protein
crossreacted with 30% of human pulmonary adenocarcinoma samples but not
with normal lung tissue or adenocarcinomas from other tissues. These
findings supported the possibility of a viral etiology of some human
lung cancers, particularly the bronchioloalveolar adenocarcinoma type,
which is morphologically very similar to the sheep tumors. The viral
envelope (Env) protein alone can transform cultured cells, and
Danilkovitch-Miagkova et al. (2003) hypothesized that Env could bind and
sequester the HYAL2 receptor and thus liberate a potential oncogenic
factor bound and negatively controlled by HYAL2. They showed that the
HYAL2 receptor protein is associated with the RON receptor tyrosine
kinase, also called macrophage stimulating-1 receptor (MST1R; 600168),
rendering it functionally silent. In human cells expressing a JSRV Env
transgene, the Env protein physically associated with HYAL2. RON
liberated from the association with HYAL2 becomes functionally active
and consequently activates the AKT1 (164730) and mitogen-activated
protein kinase-1 (MAPK1; 176948) pathways, leading to oncogenic
transformation of immortalized human bronchial epithelial cells.
Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a
subset of human bronchioloalveolar carcinoma tumors, suggesting RON
involvement in this type of human lung cancer.
Miller (2002) provided an explanation for the discrepancy between the
conclusions of Lepperdinger et al. (1998) and Rai et al. (2001), the
former that HYAL2 is a lysosomal enzyme and the latter that it is a cell
surface enzyme. Lepperdinger et al. (1998) linked GFP to the carboxy end
of HYAL2 and found GFP in the lysosome, leading to the conclusion that
HYAL2 is also in the lysosome. The findings of Rai et al. (2001) that
HYAL2 is a GPI-anchored protein on the cell surface showed that GFP
would likely be cleaved from HYAL2 during GPI addition, leaving HYAL2 on
the cell surface and resulting in GFP transit to the lysosome for
degradation. Rai et al. (2001) also showed that HYAL2 has very low
hyaluronidase activity, if any, compared to serum hyaluronidase HYAL1,
and that HYAL2 serves as a receptor for JSRV.
Using hyaluronan as substrate, Vigdorovich et al. (2007) demonstrated
that recombinant soluble HYAL2 had hyaluronidase activity, with a sharp
pH optimum of 5.6. Mutation analysis showed that hyaluronidase activity
was not required for HYAL2 to function as JSRV receptor.
GENE STRUCTURE
Strobl et al. (1998) found that the human and mouse HYAL2 genes contain
4 exons and have the same exon-intron organization.
MAPPING
Lepperdinger et al. (1998) stated that the HYAL2 gene is identical to
LUCA2, which Wei et al. (1996) positioned on a contig of human
chromosome 3p21.3, a region frequently deleted in lung cancer (see
182280). Wei et al. (1996) observed that LUCA2 is located near LUCA1
(HYAL1; 607071). By analysis of an interspecific backcross, Strobl et
al. (1998) mapped the Hyal2 gene to mouse chromosome 9 in a region
showing homology of synteny with human 3p21.
ANIMAL MODEL
Jaagsiekte sheep retrovius (JSRV) causes a contagious lung cancer in
sheep and goats, with significant animal health and economic
consequences. The host range of JSRV is in part limited by
species-specific differences in the virus entry receptor,
hyaluronidase-2 (Hyal2), which is not functional as a receptor in mice
but is functional in humans. Sheep are immunotolerant of JSRV because of
expression of closely related endogenous retroviruses, which are not
present in humans and most other species, and that may facilitate
oncogenesis. Using a replication-incompetent adeno-associated virus
vector, Wootton et al. (2005) showed that expression of the JSRV
envelope (Env) protein alone in lungs of mice results in tumors with a
brochioloalveolar localization like those seen in sheep. Whereas lethal
disease was observed in immunodeficient mice, tumor development was
almost entirely blocked in immunocompetent mice. Wootton et al. (2005)
concluded that their results provided a rare example of an oncogenic
viral structural protein, showed that interaction of the viral Env
protein with the virus entry receptor Hyal2 is not required for
tumorigenesis, and indicated that immune recognition of Env can protect
against JSRV tumorigenesis.
The naked mole rat (Heterocephalus glaber) displays exceptional
longevity, with a maximum life span exceeding 30 years. In addition, it
is unusually resistant to cancer. Tian et al. (2013) identified a
mechanism responsible for the cancer resistance. Tian et al. (2013)
found that naked mole rat fibroblasts secrete extremely high molecular
mass hyaluronan (HA), which is over 5 times larger than human or mouse
HA. This high molecular mass HA accumulates abundantly in naked mole rat
tissues owing to the decreased activity of HA-degrading enzymes and a
species-specific sequence of hyaluranan synthase-2 (HAS2; 601636).
Furthermore, the naked mole rat cells are more sensitive to HA
signaling, as they have a higher affinity to HA compared to mouse or
human cells. Perturbation of the signaling pathways sufficient for
malignant transformation of mouse fibroblasts failed to transform naked
mole rat cells. However, once high molecular mass HA was removed by
either knocking down HAS2 or overexpressing the HA-degrading enzyme
HYAL2, naked mole rat cells became susceptible to malignant
transformation and readily formed tumors in mice. Tian et al. (2013)
speculated that naked mole rats have evolved a higher concentration of
HA in the skin to provide skin elasticity needed for life in underground
tunnels and that this trait may have then been coopted to provide cancer
resistance and longevity to this species.
TUSC2
| dbSNP name | rs11549673(G,A) |
| cytoBand name | 3p21.31 |
| EntrezGene GeneID | 11334 |
| snpEff Gene Name | RASSF1 |
| EntrezGene Description | tumor suppressor candidate 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03811 |
RBM15B
| dbSNP name | rs113714267(G,A); rs3804766(A,C); rs112644740(T,C); rs57831708(C,T); rs4687569(T,C) |
| ccdsGene name | CCDS33764.1 |
| cytoBand name | 3p21.2 |
| EntrezGene GeneID | 29890 |
| EntrezGene Description | RNA binding motif protein 15B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RBM15B:NM_013286:exon1:c.G1377A:p.Q459Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.003631 |
| ESP All MAF | 0.001307 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.000431 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Colorectal adenomas;
Colorectal polyps;
Colorectal carcinoma
GENITOURINARY:
[Internal genitalia, female];
Endometrial carcinoma
NEOPLASIA:
Colorectal carcinoma;
Endometrial carcinoma
MISCELLANEOUS:
Tumors are microsatellite stable;
Onset usually before age 40 years;
Patients develop multiple tumors
MOLECULAR BASIS:
Caused by mutation in the polymerase (DNA-directed), delta 1, catalytic
subunit gene (POLD1, 174761.0001)
OMIM Title
*612602 RNA-BINDING MOTIF PROTEIN 15B; RBM15B
;;ONE TWENTY TWO PROTEIN 3; OTT3;;
HUMAGCGB
OMIM Description
DESCRIPTION
Members of the SPEN (Split-end) family of proteins, including RBM15B,
have repressor function in several signaling pathways and may bind to
RNA through interaction with spliceosome components (Hiriart et al.,
2005).
CLONING
By yeast 2-hybrid screening of a human B-cell cDNA library using
Epstein-Barr virus (EBV) mRNA export factor EB2 as bait, followed by
sequence database analysis, Hiriart et al. (2005) cloned RBM15B, which
they called OTT3. The deduced 890-amino acid protein contains 3
N-terminal RNA recognition motifs and a conserved SPOC (SPEN paralog and
ortholog C-terminal) domain. RBM15B shares 58% and 30% amino acid
identity with RBM15 (606077) and human SPEN (also known as SHARP) over
the SPOC domain. Northern blot analysis of human tissues detected strong
expression of a 3.5-kb transcripts in heart, placenta, brain, kidney,
and thymus with moderate expression in peripheral blood leukocytes,
lung, small intestine, liver, spleen, colon, and muscle. A longer 7.5-kb
transcript was detected with weak expression in all tissues examined.
Western blot analysis of epithelial cells and EBV-positive Burkitt
lymphoma cells detected RBM15B as a 120-kD species. Confocal microscopy
colocalized RBM15B and EB2 to the nucleus in a granular staining pattern
excluded from the nucleolus. Heterokaryon analysis demonstrated that,
unlike EB2, RBM15B was not a shuttling protein and displayed restricted
localization to the nucleus even in the presence of EB2.
GENE FUNCTION
Hiriart et al. (2005) demonstrated that RBM15B binds EBV EB2 protein by
coimmunoprecipitation and yeast 2-hybrid studies, and they showed that
the RBM15B SPOC domain interacted with the EB2 N-terminal 51 amino
acids. Overexpression of RBM15B repressed accumulation of alternatively
spliced beta-thalassemia transcripts without affecting the
constitutively spliced beta-globin (HBB; 141900) transcripts, suggesting
that RBM15B plays a role in splicing regulation.
MAPPING
By genomic sequence analysis, Hiriart et al. (2005) mapped the RBM15B
gene to chromosome 3p21.1.
IQCF5-AS1
| dbSNP name | rs7635409(A,G); rs1505403(T,C); rs6794320(T,C); rs1983106(T,C); rs1857800(G,C); rs76923764(G,A) |
| cytoBand name | 3p21.2 |
| EntrezGene GeneID | 101928999 |
| EntrezGene Symbol | LOC101928999 |
| snpEff Gene Name | IQCF5 |
| EntrezGene Description | uncharacterized LOC101928999 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2511 |
| ESP Afr MAF | 0.434971 |
| ESP All MAF | 0.302015 |
| ESP Eur/Amr MAF | 0.187618 |
| ExAC AF | 0.726 |
GPR62
| dbSNP name | rs60649028(C,T) |
| cytoBand name | 3p21.2 |
| EntrezGene GeneID | 118442 |
| snpEff Gene Name | PCBP4 |
| EntrezGene Description | G protein-coupled receptor 62 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Teeth];
Dental pulp stones;
Microdontia
SKELETAL:
[Skull];
Narrowed zygomatic arch;
[Hands];
Short fingers;
Distal symphalangism;
Aplastic/hypoplastic middle phalanges (fingers 2-5);
Aplastic/hypoplastic distal phalanges (fingers 2-5);
Cone-shaped epiphyses of middle phalanges;
Absent scaphoid bone;
Absent trapezium bone;
Absent trapezoid bone;
Absent pisiform bone;
[Feet];
Distal symphalangism;
Aplastic/hypoplastic middle phalanges (toes 2-5);
Aplastic/hypoplastic distal phalanges (toes 2-5)
SKIN, NAILS, HAIR:
[Nails];
Absent nails;
Hypoplastic nails
OMIM Title
*606917 G PROTEIN-COUPLED RECEPTOR 62; GPR62
OMIM Description
DESCRIPTION
G protein-coupled receptors (GPCRs, or GPRs) contain 7 transmembrane
domains and transduce extracellular signals through heterotrimeric G
proteins.
CLONING
Lee et al. (2001) identified GPR62 within human genomic DNA using GPR61
(606916) as probe. Primers to the intronless sequence were synthesized,
and GPR62 cDNA was amplified by PCR and cloned. The deduced 368-amino
acid protein shares 44% sequence similarity with GPR61 in the
transmembrane domain. Northern blot analysis revealed a single 2.3-kb
transcript in all brain regions examined, including basal forebrain,
frontal cortex, thalamus, hippocampus, caudate, and putamen. No
expression was detected in liver.
GENE STRUCTURE
Lee et al. (2001) determined that the GPR62 gene contains a single exon.
MAPPING
Lee et al. (2001) mapped the human GPR62 gene to chromosome 3p21.3-p21.1
based on sequence similarity between the GPR62 sequence and a PAC
(GenBank GENBANK AC006255) localized to this region.
LINC00696
| dbSNP name | rs9860982(T,C); rs111780761(C,T); rs57335685(C,T) |
| cytoBand name | 3p21.2 |
| EntrezGene GeneID | 100128378 |
| snpEff Gene Name | C3orf74 |
| EntrezGene Description | long intergenic non-protein coding RNA 696 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1226 |
ERC2-IT1
| dbSNP name | rs115748214(C,T); rs2231384(A,G); rs1179359(C,A) |
| cytoBand name | 3p14.3 |
| EntrezGene GeneID | 26059 |
| EntrezGene Symbol | ERC2 |
| snpEff Gene Name | ERC2 |
| EntrezGene Description | ELKS/RAB6-interacting/CAST family member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007805 |
CCDC66
| dbSNP name | rs73079894(C,A); rs17056889(C,G); rs185565127(A,T); rs200386928(A,G); rs2054987(G,C); rs2054988(G,A); rs17235670(A,G); rs12486047(C,A); rs11130525(T,C); rs11130526(T,C); rs73079902(A,G); rs17056892(A,G); rs55960262(C,T); rs62255966(A,G); rs62255967(C,T); rs9822876(G,A); rs17825529(T,C); rs17216678(A,G); rs190152916(G,C); rs59897254(C,T); rs111349193(G,C); rs6781056(A,C); rs6792321(G,C); rs77970474(A,C); rs74707994(G,A); rs6781293(A,G); rs71309962(G,C); rs186629692(A,T); rs2035798(G,A); rs62255971(T,C); rs73081810(T,C); rs55831745(G,C); rs6799086(G,A); rs75285999(A,C); rs73081811(T,G); rs76533482(C,T); rs10865997(G,A); rs71309963(G,A); rs55865922(T,C); rs112310084(T,C); rs62255972(G,A); rs73081816(T,A); rs4974218(A,G); rs4974219(T,C); rs4974220(C,T); rs78399921(C,T); rs74884919(C,T); rs4974222(A,G); rs4974223(C,T); rs73081819(T,A); rs7628343(T,C); rs79593029(A,G); rs7626378(A,T); rs36029237(G,T); rs145205237(T,C); rs13097030(G,A); rs73081823(C,T); rs73081825(G,T); rs141697411(A,T); rs62255973(C,G); rs9881005(A,T); rs12636773(T,C); rs35689307(C,T); rs34171578(A,G); rs71309964(C,T); rs6778373(C,A); rs35564119(G,T); rs73081836(C,T); rs13089169(A,G); rs9873754(A,G); rs13090343(G,A); rs138000397(C,T); rs9842283(G,T); rs11130527(A,G); rs147542831(A,G); rs79734005(C,T); rs144141027(A,G); rs139982089(T,C); rs10865998(A,C); rs137879941(C,G); rs147499222(C,T); rs147102665(C,T); rs6784100(C,T); rs139975912(G,C); rs141543888(C,G); rs148455337(T,C); rs142085144(C,G); rs147766149(G,A); rs114175521(C,T); rs4974224(A,C); rs4974225(A,G); rs1812347(A,G); rs4093514(G,T); rs955248(G,T); rs6764730(T,C); rs111419101(C,T); rs7621290(T,C); rs55938093(G,T); rs77315462(A,T); rs116758226(A,G); rs35995233(A,T); rs56190096(T,C); rs9881789(C,T); rs73081850(T,C); rs9881961(C,T); rs56204053(A,C); rs62255981(G,T); rs1352766(G,A); rs73081851(A,T); rs143348331(C,T); rs7617331(T,C); rs12631156(G,A); rs7612510(C,T); rs1388256(A,G); rs9985317(G,T); rs1491170(A,G); rs7637449(G,A); rs73081854(A,T); rs7630094(A,G); rs9985253(G,C); rs9985254(G,T); rs34720351(T,C); rs282522(A,G); rs13072654(G,A); rs282523(C,T); rs282524(G,T); rs282525(A,C); rs75296869(C,T); rs6805469(G,T); rs282526(T,C); rs13080003(C,A); rs62256011(G,A); rs149520122(G,A); rs282536(G,A); rs4681951(A,G); rs282535(G,T); rs9862490(T,C); rs62256014(A,G); rs282534(G,A); rs6798118(G,C); rs282543(G,A); rs282542(G,A); rs282541(G,A); rs140948433(A,G); rs282540(T,A); rs282539(T,A); rs4060982(A,T); rs61456176(G,A); rs140364365(T,G); rs7431634(A,G); rs282538(G,C); rs114096928(C,T); rs182898270(C,G); rs144163234(T,C); rs6785479(C,T); rs140442708(C,T); rs146797364(A,C); rs116328709(C,G); rs151312808(G,A); rs282537(T,C); rs115438128(A,G); rs139349486(C,T); rs9841851(C,G); rs9846282(G,T); rs282528(T,C); rs115141624(G,A); rs35803417(T,A); rs35728519(C,T); rs56356916(G,T); rs62256018(G,A); rs62256019(G,C); rs62256020(G,T); rs145896133(G,C); rs282529(T,C); rs7629559(C,T); rs116378681(A,G); rs114797443(T,C); rs282530(A,G); rs282531(A,G); rs282532(G,A); rs62256022(G,A); rs282533(G,C); rs2004199(G,A); rs6810125(A,G); rs17216685(T,C); rs2317133(G,A); rs2317134(T,C); rs62256023(T,C); rs6807338(C,T); rs6445801(C,T); rs4681903(T,C); rs4681904(G,C); rs9833926(A,G); rs58457441(A,G); rs151107400(G,A); rs75531148(T,C); rs3732505(C,A); rs79095236(T,C); rs79211940(T,A); rs61747991(A,T); rs61747994(T,C); rs2291501(C,T); rs6556(T,C); rs1045926(C,G); rs17288852(T,C); rs10865999(C,G); rs184595678(G,A); rs9823108(C,A); rs34284682(A,C); rs73083715(A,C); rs200563279(G,A); rs114427213(A,G) |
| ccdsGene name | CCDS46852.1 |
| cytoBand name | 3p14.3 |
| EntrezGene GeneID | 285331 |
| EntrezGene Description | coiled-coil domain containing 66 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC66:NM_001141947:exon2:c.A14G:p.D5G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9785 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A2RUB6 |
| dbNSFP Uniprot ID | CCD66_HUMAN |
| ExAC AF | 0.0005878 |
FLNB
| dbSNP name | rs1658338(T,A); rs11712230(C,T); rs11920912(C,G); rs192919533(C,T); rs839245(G,A); rs9828717(C,T); rs839246(T,C); rs858217(C,T); rs56124659(C,T); rs10470696(G,T); rs12715519(C,A); rs839239(C,T); rs55749066(C,T); rs6764184(G,T); rs1718460(A,G); rs839241(G,A); rs7634753(C,T); rs56697644(T,C); rs11927339(C,T); rs7652117(T,C); rs6796697(C,T); rs145757177(G,A); rs1658345(G,A); rs1658343(T,C); rs1658342(G,C); rs17058743(A,T); rs1718459(C,T); rs116430285(A,T); rs112484968(C,T); rs1658350(C,T); rs148489110(A,C); rs1718458(G,A); rs12629815(T,C); rs116074945(C,G); rs76540305(C,T); rs1658351(C,T); rs75115040(C,T); rs6802104(C,T); rs11130609(G,C); rs7428893(G,A); rs145412957(T,C); rs76240547(T,C); rs6780437(G,A); rs75111254(G,C); rs2686637(T,C); rs145182846(T,C); rs56886540(T,C); rs1658397(G,C); rs79377960(A,C); rs9819106(T,C); rs839238(A,C); rs865726(C,T); rs839237(C,T); rs839236(G,C); rs839235(T,C); rs112654490(A,G); rs839234(G,C); rs11130610(G,A); rs1658393(C,T); rs1718483(C,T); rs9682171(A,C); rs839233(C,T); rs9681058(G,A); rs839232(T,A); rs9681051(C,T); rs113071168(T,A); rs839231(T,C); rs143853205(G,A); rs79576484(A,T); rs111336058(G,T); rs116719554(C,T); rs6781727(T,A); rs115202399(C,T); rs77976744(G,A); rs1718482(T,C); rs1718481(C,T); rs9681990(G,A); rs9681987(C,A); rs9311663(T,C); rs1623879(A,G); rs1658335(G,A); rs839247(C,A); rs116151871(C,T); rs9847392(G,C); rs9823764(G,A); rs113850147(C,T); rs9828322(G,A); rs376479453(G,A); rs11130611(T,G); rs11130612(C,T); rs9829520(G,A); rs9866947(A,G); rs9829566(C,T); rs9833870(C,T); rs77493781(C,T); rs28537238(T,A); rs1718479(A,G); rs9839449(C,G); rs187678074(G,T); rs144841849(G,A); rs7340704(G,A); rs9850554(C,T); rs6779340(C,G); rs11707429(A,T); rs4681780(G,T); rs78068601(G,T); rs12494328(G,A); rs9881472(T,A); rs76291946(C,G); rs114850118(A,G); rs704529(T,C); rs839230(C,T); rs858215(A,G); rs732527(T,C); rs732526(C,T); rs56374442(G,T); rs10049126(A,G); rs10049407(C,T); rs116521170(G,C); rs10048979(T,C); rs10049213(G,A); rs138357558(G,C); rs13314130(A,C); rs13324916(T,C); rs13321163(C,G); rs13321311(G,T); rs13314263(A,G); rs13321292(C,T); rs12634644(G,A); rs2033740(C,A); rs839228(C,T); rs370893922(C,T); rs7643775(C,T); rs7620995(G,C); rs839227(G,A); rs78591755(C,G); rs9311664(A,G); rs9311665(T,C); rs9859627(C,A); rs9879767(T,C); rs9879941(T,C); rs77792829(G,A); rs138443581(C,T); rs13317295(A,T); rs9870239(C,T); rs75644027(C,T); rs113163034(A,G); rs79246522(T,C); rs79501872(T,A); rs76176791(A,G); rs74627337(T,A); rs9824672(T,C); rs9824706(T,A); rs75723950(A,C); rs9825005(T,G); rs9880585(G,A); rs76619909(C,G); rs6765354(T,C); rs6799323(C,G); rs6763256(A,G); rs143338599(C,T); rs1718468(T,C); rs6783821(G,C); rs1658346(G,A); rs6445941(C,T); rs6445942(A,G); rs1658347(A,C); rs13096731(G,A); rs4681782(A,G); rs9884078(C,T); rs9809315(C,T); rs2686639(G,A); rs140094031(G,A); rs1658389(T,C); rs1718454(A,G); rs6795015(G,C); rs9852396(A,G); rs1658388(T,G); rs13071918(G,A); rs1718480(G,A); rs2686641(C,G); rs1718476(A,G); rs1718475(G,A); rs1658387(T,C); rs1658386(G,A); rs111950172(G,C); rs55809752(T,C); rs112187779(A,T); rs77043875(C,T); rs9836278(G,A); rs6770198(C,T); rs1658385(T,C); rs1718462(C,T); rs9841884(G,A); rs113364171(C,T); rs80014093(C,T); rs190429416(A,C); rs9822918(G,T); rs112561544(C,T); rs34859978(C,T); rs3852008(G,A); rs182052292(G,A); rs4681659(G,C); rs13318633(C,T); rs13072796(T,C); rs13073359(T,G); rs13073391(T,C); rs9840244(G,A); rs9881512(A,G); rs13099206(G,T); rs12715520(C,G); rs4681783(T,C); rs6805521(G,A); rs9850519(G,C); rs13063266(G,C); rs13062947(C,T); rs13063457(G,A); rs13085609(T,C); rs12715521(G,T); rs2033739(G,A); rs116551325(A,T); rs2033741(G,A); rs57337941(A,G); rs77246628(G,A); rs3772998(C,T); rs6768856(T,C); rs6802426(C,T); rs2049239(A,G); rs139236158(T,A); rs6445943(T,A); rs13072975(A,G); rs13073525(C,A); rs9865341(G,A); rs4681784(C,A); rs3914955(G,A); rs12638392(C,T); rs55729263(C,T); rs7616482(A,T); rs141978875(A,C); rs114051170(G,A); rs150996432(C,T); rs7610839(C,G); rs7632156(G,A); rs7622448(A,G); rs141905843(A,G); rs190788736(A,G); rs9883669(G,A); rs839224(G,A); rs839223(G,A); rs6785667(T,C); rs80242857(T,A); rs7644723(G,T); rs13316820(G,A); rs12491415(T,A); rs1522383(C,T); rs1522384(T,C); rs9834312(G,A); rs3772995(G,A); rs939882(G,A); rs3732638(A,G); rs6785672(A,C); rs13091926(T,C); rs11719557(A,G); rs75294566(A,G); rs76489676(T,G); rs74712521(A,C); rs6445945(A,G); rs6445946(T,A); rs1522385(G,A); rs1522386(A,G); rs7638552(C,T); rs2686629(A,G); rs2246601(T,C); rs2257266(A,C); rs114667821(C,T); rs2259091(A,G); rs2708317(G,A); rs116668062(G,A); rs7634236(C,T); rs2708318(G,T); rs2686635(G,T); rs9820773(T,G); rs2362241(T,C); rs77450973(G,C); rs78859332(C,T); rs7615893(T,C); rs145348201(G,A); rs79495046(G,A); rs13327831(T,G); rs56143512(G,A); rs7616838(A,G); rs151228150(A,G); rs55905032(T,C); rs192640778(G,A); rs7428240(A,G); rs74518310(G,A); rs7653042(C,T); rs77527258(G,T); rs58110788(G,A); rs12630504(T,G); rs13095627(C,T); rs77213664(G,A); rs13096736(G,T); rs9880603(G,A); rs9808999(C,T); rs77549946(C,G); rs114372417(G,C); rs3732636(T,C); rs190666282(A,G); rs76192684(C,T); rs3732635(G,C); rs74403943(G,A); rs3732634(G,A); rs78381674(C,A); rs13077017(C,T); rs11130613(C,A); rs139257182(C,T); rs7625646(A,C); rs12488636(T,C); rs12488642(T,C); rs1131356(G,A); rs201254275(C,T); rs4681800(T,A); rs4681799(A,G); rs3732633(T,G); rs4681798(G,A); rs4681797(C,T); rs9829490(G,A); rs368157239(C,T); rs12495232(A,G); rs2362903(A,G); rs2362904(C,T); rs2362905(G,C); rs2362906(G,A); rs11718801(A,G); rs4681796(G,C); rs6784426(T,C); rs2362907(G,A); rs9311669(G,A); rs3772993(C,T); rs3772992(G,C); rs3772991(T,C); rs79814779(T,C); rs1573890(A,G); rs4475005(C,T); rs2362908(C,G); rs6445947(A,G); rs111781714(A,G); rs4254629(T,G); rs9832565(G,A); rs60183346(G,A); rs111827177(C,G); rs12632362(G,A); rs12632456(G,A); rs12638356(A,G); rs13098199(G,C); rs2885646(A,G); rs6445948(T,A); rs2363684(T,C); rs2001972(C,A); rs80271551(G,T); rs9875647(G,T); rs4284952(A,C); rs34336464(C,T); rs9863375(G,C); rs9826147(A,G); rs2362911(A,G); rs9869210(G,C); rs2362910(T,C); rs111492947(C,T); rs7355798(C,T); rs113525232(C,A); rs13095822(C,T); rs9809281(G,A); rs67418699(C,T); rs74733805(T,G); rs111703309(C,T); rs77315011(C,T); rs4681795(T,C); rs9867527(A,G); rs113331896(G,A); rs12715522(A,G); rs28428734(A,G); rs28729432(A,G); rs9884098(G,A); rs76757704(C,T); rs113600161(G,T); rs77285652(G,A); rs113689782(T,C); rs112208738(A,T); rs147638609(T,C); rs113239180(A,G); rs71311841(C,T); rs13075863(C,T); rs75907585(C,T); rs3821566(C,T); rs112947322(G,T); rs9835147(G,T); rs6787425(T,C); rs12634123(G,A); rs76944895(C,T); rs17058924(T,A); rs9817209(A,G); rs9855529(G,A); rs139455117(G,A); rs67476047(C,T); rs34502586(C,T); rs17058927(T,C); rs11710658(G,A); rs73075934(G,A); rs17058931(G,A); rs76818141(T,C); rs4234386(C,T); rs34366007(A,C); rs2362901(C,G); rs2362902(A,C); rs4299451(A,G); rs114857924(T,A); rs73075938(G,A); rs4343595(A,C); rs2885645(A,G); rs55759213(C,T); rs8640(C,T); rs66869903(C,G); rs4681787(T,C); rs73075944(G,C); rs2362899(A,G); rs111281532(C,T); rs9870243(C,G); rs4681660(G,A); rs1131264(G,C) |
| ccdsGene name | CCDS2885.1 |
| cytoBand name | 3p14.3 |
| EntrezGene GeneID | 2317 |
| EntrezGene Description | filamin B, beta |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FLNB:NM_001164317:exon21:c.C3476T:p.S1159L,FLNB:NM_001457:exon21:c.C3476T:p.S1159L,FLNB:NM_001164319:exon21:c.C3476T:p.S1159L,FLNB:NM_001164318:exon21:c.C3476T:p.S1159L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7293 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B2ZZ83 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 3.253e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmar telangiectasias (described in 1 family)
NEUROLOGIC:
[Central nervous system];
Cerebral cavernous malformations;
Seizures;
Recurrent headaches;
Hemorrhagic stroke
MISCELLANEOUS:
Genetic heterogeneity (see 116800 for summary);
Sporadic cases often single lesions versus multiple lesions in familial
cases
MOLECULAR BASIS:
Caused by mutation in the CCM2 gene (CCM2, 607929.0001)
OMIM Title
*603381 FILAMIN B; FLNB
;;FILAMIN, BETA;;
ACTIN-BINDING PROTEIN 276/278; ABP276/278
TRUNCATED ACTIN-BINDING PROTEIN, INCLUDED; TABP, INCLUDED;;
ACTIN-BINDING PROTEIN, TRUNCATED, INCLUDED;;
FILAMIN HOMOLOG 1, INCLUDED; FH1, INCLUDED
OMIM Description
DESCRIPTION
Filamins, such as FLNB, are actin-binding proteins that also interact
with multiple receptors and intracellular proteins that regulate
cytoskeleton-dependent cell proliferation, differentiation, and
migration (Hu et al., 2014).
CLONING
The platelet GpIb complex (see 138720) mediates the adherence of
platelets at the site of vascular injury through the binding of
GpIb-alpha (231200) to subendothelial von Willebrand factor (VWF;
613160). In platelets, the GpIb complex is tightly bound to the actin
cytoskeleton via an interaction of GpIb-alpha with ABP280 (filamin A;
300017). Using a yeast 2-hybrid screen with the cytoplasmic tail of
GpIb-alpha as bait, Takafuta et al. (1998) isolated partial cDNAs
encoding a novel filamin homolog that they designated beta-filamin. They
used the partial cDNAs to screen a placenta library and recovered
additional cDNAs corresponding to the entire beta-filamin coding region.
Like ABP280, the predicted 2,602-amino acid protein contains an
N-terminal actin-binding domain, a backbone of 24 tandem repeats, and 2
hinge regions. Excluding the unique first hinge region of beta-filamin,
the sequences of beta-filamin and ABP280 are 70% identical. Antibodies
against beta-filamin detected a 280-kD protein on Western blots of human
umbilical vein endothelial cell (HUVEC) extracts and stained normal
human endothelial cells in culture and in situ. Takafuta et al. (1998)
determined that the GpIb-alpha-binding domain in beta-filamin is in
repeats 17-20, a region that corresponds to the GpIb-alpha-binding
domain in ABP280. Northern blot analysis revealed that beta-filamin is
expressed as 2 approximately 9.5-kb mRNAs in many adult tissues. The 2
different transcripts appear to result from use of alternative
polyadenylation signals. Takafuta et al. (1998) concluded that
beta-filamin is a new member of the filamin family that may have
significance for GpIb-alpha function in endothelial cells and platelets.
Independently, Xu et al. (1998) isolated cDNAs encoding beta-filamin,
which they referred to as ABP278. These authors also identified
alternatively spliced mRNAs encoding ABP276, a beta-filamin isoform
missing the first hinge region. RT-PCR analysis indicated that the 2
isoforms were expressed at different relative levels in various human
tissues.
The addition of thyroid-stimulating hormone (TSH; see 188540) to
cultured thyroid follicular cells induces rapid and profound disruption
of actin microfilaments. Using serum from a Graves disease (275000)
patient, Leedman et al. (1993) identified a thyroid cDNA encoding TABP
(truncated actin-binding protein), a predicted 195-amino acid protein
with homology to the C terminus of ABP280. Both Xu et al. (1998) and
Takafuta et al. (1998) considered TABP to be a truncated form of
beta-filamin.
MAPPING
By analysis of somatic cell hybrids, Zhang et al. (1998) mapped the FH1
gene to chromosome 3. Takafuta et al. (1998) refined the map position to
3p21.1-p14.3 based on inclusion of a previously mapped STS within the
beta-filamin sequence. By FISH, Brocker et al. (1999) assigned the FLNB
gene to 3p14.3. Chakarova et al. (2000) mapped FLNB to 3p14 by radiation
hybrid analysis.
GENE FUNCTION
Using antigen-capture ELISA, Takafuta et al. (1998) found that
beta-filamin associates with GpIb-alpha in both platelets and HUVEC
extracts.
Mutations in the presenilin genes PS1 (104311) and PS2 (600759) account
for approximately 50% of early-onset familial Alzheimer disease (AD;
104300). Zhang et al. (1998) identified beta-filamin as filamin homolog
1 (FH1), a filamin-related protein that interacts with the loop regions
of PS1 and PS2. A monoclonal antibody recognizing both ABP280 and FH1
bound to blood vessels and astrocytes in the normal brain. In the brains
of AD patients, Zhang et al. (1998) observed staining also in
neurofibrillary tangles, neuropil threads, and dystrophic neurites
within some senile plaques. The authors stated that detection of these
presenilin-interacting proteins in these brain structures suggests that
ABP280 and FH1 may be involved in the development of AD and that
interactions between presenilins and ABP280/FH1 may be functionally
significant. Takafuta et al. (1998) noted that the FH1 sequence is
identical to the C-terminal 291 amino acids of beta-filamin except for 2
residues, making it very likely that FH1 represents the C-terminal
region of beta-filamin.
Krakow et al. (2004) found that FLNB is expressed in human growth plate
chondrocytes and in developing vertebral bodies in the mouse. The
authors concluded that FLNB plays a role in vertebral segmentation,
joint formation, and endochondral ossification.
Mutation in the X-linked gene filamin A (FLNA) can cause the neurologic
disorder periventricular heterotopia (300049). Although periventricular
heterotopia is characterized by a failure in neuronal migration into the
cerebral cortex with consequent formation of nodules in the ventricular
and subventricular zones, many neurons appear to migrate normally, even
in males, suggesting compensatory mechanisms. Sheen et al. (2002) showed
that, in mice, Flna mRNA was widely expressed in all brain cortical
layers, whereas a homolog, Flnb, was most highly expressed in the
ventricular and subventricular zones during development. In adulthood,
widespread but reduced expression of Flna and Flnb persisted throughout
the cerebral cortex. Flna and Flnb proteins were highly expressed in
both the leading processes and somata of migratory neurons during
corticogenesis. Postnatally, Flna immunoreactivity was largely localized
to the cell body, whereas Flnb was localized to the soma and neuropil
during neuronal differentiation. The putative Flnb homodimerization
domain strongly interacted with itself or the corresponding homologous
region of Flna, as shown by yeast 2-hybrid interaction. The 2 proteins
colocalized within neuronal precursors by immunocytochemistry, and the
existence of Flna-Flnb heterodimers could be detected by
coimmunoprecipitation. Sheen et al. (2002) suggested that FLNA and FLNB
may form both homodimers and heterodimers, and that their interaction
could potentially compensate for the loss of FLNA function during
cortical development within patients with periventricular heterotopia.
Using yeast 2-hybrid and immunoprecipitation analyses, Hu et al. (2014)
found that mouse Flnb and Flna interacted directly with the actin
nucleating-protein Fmn1 (136535). The filamins and Fmn1 colocalized in
cytoplasm and, to a lesser extent, nucleus, and they were coexpressed in
chondrocytes.
MOLECULAR GENETICS
Krakow et al. (2004) identified mutations in the FLNB gene in 4 human
skeletal disorders: spondylocarpotarsal syndrome (SCT; 272460), Larsen
syndrome (LRS; 150250), type I atelosteogenesis (AO1; 108720), and type
III atelosteogenesis (AO3; 108721).
Biesecker (2004) commented that from the standpoint of the clinical
geneticist, 4 distinct disorders result from mutation in the FLNB gene.
In contrast, a basic scientist might view them as a single disorder with
inconsequential phenotypic differences. The information concerning the
multiple disorders caused by mutations in the FLNB gene followed closely
on the heels of reports of mutations in the FLNA gene (300017) as the
cause of 5 distinct disorders. This was of interest because there are
overlapping phenotypic features in the disorders associated with FLNA
and FLNB. Biesecker (2004) pointed out that the 'FLNB story' used
information from the International Skeletal Dysplasia Registry (ISDR),
which is maintained by a skilled group of clinical scientists and
includes information on more than 12,000 cases of individuals with
disorders that fall into 50 diagnostic groups. One reason for the
success of the registry is that it combines clinical service with
research archives. The motivation for a clinician to submit cases to the
registry is that he or she can receive an expert opinion on the
diagnosis (which is useful for medical care and estimating recurrence
risks) and, as in the FLNB story, contribute to research.
In a 22-week male fetus previously studied by Krakow et al. (2004) and a
17-week male fetus previously described by Wessels et al. (2003), both
diagnosed with boomerang dysplasia (112310), Bicknell et al. (2005)
identified heterozygosity for mutations in the FLNB gene, leu171 to arg
(L171R; 603381.0009) and ser235 to pro (S235P; 603381.0010),
respectively.
Farrington-Rock et al. (2006) found 14 novel missense mutations in FLNB
in 15 unrelated patients with atelosteogenesis I and/or atelosteogenesis
III. Most of the mutations resided in exons 2 and 3, which encode the
CH2 domain of the actin-binding region of filamin B. The remaining
mutations were found in exon 28 and exon 29, which encode repeats 14 and
15 of filamin B. Clinical and radiographic data were used to confirm the
diagnosis of atelosteogenesis in all the patients. The diagnosis of type
I was given to patients showing classic findings of absent, shortened,
or distally tapered humeri and femora; absent, shortened, or bowed
radii; shortened and bowed ulnae and tibiae; and absent fibulae. Other
findings included vertebral hypoplasia with coronal clefts, 11 ribs,
shortened wide distal phalanges, and unossified or partially ossified
metacarpals and middle and proximal phalanges. In addition, most type I
patients showed evidence of a hypoplastic pelvis, dislocations of the
hips, elbows, and knees, and clubbed feet. With the exception of 1
patient where the pregnancy was terminated after 24 weeks' gestation,
the patients given the diagnosis of type I either died in the neonatal
period or were stillborn. The diagnosis of type III was given to
patients when all bones were present in the extremities, when there was
distal tapering of the humeri or femora, and where the small tubular
bones of the hands and feet were shortened and broad. In 2 patients with
type III, the fibulae were absent. Dislocation of the elbows, hips, and
knees and clubbed feet were also present in the type III patients, as
was vertebral hypoplasia with coronal clefting. Cartilage of these
patients showed acellular areas within the growth plate and the presence
of large multinuclear cells ('giant cells') within the resting zone as
had been described previously.
Bicknell et al. (2007) identified heterozygous mutations in the FLNB
gene (see, e.g., 603381.0011; 603381.0012) in 20 unrelated patients with
Larsen syndrome. The distribution of mutations within the gene was
nonrandom, with clusters of mutations in the actin-binding domains and
filamin repeats 13 through 17 being the most common.
In a female infant with atelosteogenesis who died 3 hours after birth
due to respiratory failure, Jeon et al. (2014) performed postmortem
exome sequencing and identified heterozygosity for a de novo A173T
mutation (603381.0015) in the FLNB gene that was not found in 50 healthy
controls. The authors noted that most lethal FLNB-related disorders are
caused by de novo mutations, and thus there is a low risk of recurrence
in subsequent pregnancies.
ANIMAL MODEL
Zhou et al. (2007) detected strong expression of the mouse Flnb gene in
vascular endothelial cells and chondrocytes. In Flnb -/- mice, the
authors observed a phenotype that resembled those of human skeletal
disorders with mutations in the FLNB gene. Less than than 3% of Flnb -/-
embryos reached term, indicating that the Flnb gene is important in
embryonic development, whereas Flnb +/- mice were indistinguishable from
their wildtype sibs. Flnb -/- embryos had impaired development of
microvasculature and skeletal systems. The few that were born were very
small and had scoliotic and kyphotic spines, lack of intervertebral
discs, fusion of vertebral bodies, and reduced hyaline matrix in bones
of the extremities, thorax, and vertebrae.
Farrington-Rock et al. (2008) generated Fnlb -/- mice and observed a
phenotype of short stature and skeletal abnormalities similar to those
of individuals with spondylocarpotarsal synostosis syndrome (SCT;
272460). Newborn Flnb -/- mice had fusions between the neural arches of
the vertebrae in the cervical and thoracic spine. At postnatal day 60,
the vertebral fusions were more widespread and involved the vertebral
bodies as well as the neural arches. In addition, fusions were seen in
sternum and carpal bones. Analysis of the Flnb -/- mice phenotype showed
that an absence of filamin B causes progressive vertebral fusions, in
contrast to the previous hypothesis that SCT results from failure of
normal spinal segmentation. Farrington-Rock et al. (2008) suggested that
spinal segmentation can occur normally in the absence of filamin B, but
that the protein is required for maintenance of intervertebral, carpal,
and sternal joints, and the joint fusion process commences antenatally.
Hu et al. (2014) found that knockout (KO) of both Flnb and Fmn1 in mice
resulted in a more severe reduction in body size, weight, and growth
plate length than that observed in mice with KO of either gene alone. In
Flnb/Fmn1 double-KO mice, shortening of long bones was associated with
decreased chondrocyte proliferation and an overall delay in
ossification. Comparison of Fmn1 KO mice with Flnb/Fmn1 double-KO mice
revealed nonoverlapping functions for Fmn1 and Flnb in the
prehypertrophic zone, with loss of Fmn1 resulting in a decrease in the
width of the prehypertrophic zone, and loss of Flnb causing premature
differentiation of the prehypertrophic zone.
LMOD3
| dbSNP name | rs9816032(G,A); rs3796213(C,T); rs6784228(A,G); rs60230066(A,G); rs57119184(C,T); rs115396901(G,A); rs17005368(C,T); rs9824846(A,G); rs9832917(T,C); rs56264601(G,A); rs17005369(A,G); rs72924884(A,G); rs116257053(T,C); rs9815992(C,T); rs7610262(A,C); rs7620430(G,A); rs7613159(T,C); rs9844987(T,C); rs4855548(A,G); rs937863(T,C) |
| ccdsGene name | CCDS46862.1 |
| cytoBand name | 3p14.1 |
| EntrezGene GeneID | 56203 |
| EntrezGene Description | leiomodin 3 (fetal) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LMOD3:NM_198271:exon2:c.A1226G:p.Q409R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5887 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q0VAK6 |
| dbNSFP Uniprot ID | LMOD3_HUMAN |
| dbNSFP KGp1 AF | 0.00869963369963 |
| dbNSFP KGp1 Afr AF | 0.0345528455285 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.035787 |
| ESP All MAF | 0.011552 |
| ESP Eur/Amr MAF | 0.000121 |
| ExAC AF | 0.003994 |
PROS1
| dbSNP name | rs6123(T,C); rs11926689(C,T); rs114640812(C,T); rs73846069(C,T); rs12488200(A,G); rs143341429(T,C); rs151228573(T,G); rs186805658(G,A); rs62266144(C,A); rs12634349(A,G); rs145895474(G,C); rs141598188(T,C); rs186018349(G,T); rs150582727(C,A); rs141180990(G,A); rs8178644(T,G); rs71326805(C,T); rs199796557(C,A); rs184045014(C,T); rs188192803(A,T); rs8178635(T,G); rs8178633(G,C); rs8178630(G,T); rs4417906(G,A); rs4857037(G,A); rs8178626(A,T); rs8178623(C,T); rs148200391(A,G); rs137920921(T,C); rs183916733(T,C); rs8178616(G,T); rs150073780(G,T); rs7641886(T,C); rs115404275(G,A); rs9826711(G,C); rs8178615(C,T); rs148147636(C,T); rs7428007(A,G); rs7616142(T,C); rs4133534(C,T); rs6773487(T,C); rs8178613(G,A); rs4857343(T,C); rs13080445(C,T); rs13089004(A,T); rs61519199(A,C); rs73846070(G,A); rs8178610(C,T); rs146512766(C,T); rs34557251(C,T); rs73846072(C,T); rs6803590(G,A); rs6795524(A,G); rs71326806(G,A); rs146518390(G,A); rs8178607(G,A); rs141770679(A,G); rs13092355(G,A); rs4414894(T,G); rs62266146(G,A); rs146011610(T,C); rs140447807(C,T); rs13085785(C,T); rs142899735(C,A); rs147151353(C,T); rs8178603(C,T); rs75801216(C,A); rs139668862(T,C); rs7609644(A,G); rs7615840(A,G); rs75944758(T,C); rs143942968(A,C); rs141215857(G,A); rs6764203(C,T); rs6441600(C,G); rs6441601(C,A); rs116285815(C,T); rs187398962(C,G); rs5013930(T,C); rs8178592(T,A); rs79348279(G,A); rs8178591(C,T); rs13062355(G,A); rs68145886(T,C) |
| ccdsGene name | CCDS2923.1 |
| cytoBand name | 3q11.1 |
| EntrezGene GeneID | 5627 |
| EntrezGene Description | protein S (alpha) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PROS1:NM_000313:exon2:c.C227T:p.P76L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9581 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P07225 |
| dbNSFP Uniprot ID | PROS_HUMAN |
| dbNSFP KGp1 AF | 0.00457875457875 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.004591 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.002307 |
| ESP Eur/Amr MAF | 0.001744 |
| ExAC AF | 0.001708 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Superficial thrombophlebitis;
Deep venous thrombosis
RESPIRATORY:
[Lung];
Pulmonary embolism
SKIN, NAILS, HAIR:
[Skin];
Warfarin-induced skin necrosis
NEUROLOGIC:
[Central nervous system];
Cerebral thrombosis (e.g. 612283.0014 protein C deficiency)
LABORATORY ABNORMALITIES:
Plasma protein C deficiency
MISCELLANEOUS:
Vast majority of heterozygotes are asymptomatic;
Protein C deficiency is found in 3-4% of patients with venous thromboembolism;
Acquired protein C deficiency seen in liver disease, DIC, and following
surgery;
See also autosomal recessive form (612304)
MOLECULAR BASIS:
Caused by mutation in the protein C gene (PROC, 612283.0001)
OMIM Title
*176880 PROTEIN S; PROS1
;;PROTEIN S, ALPHA; PSA
PROTEIN S PSEUDOGENE, INCLUDED; PROSP, INCLUDED;;
PROTEIN S, BETA, INCLUDED; PSB, INCLUDED;;
PROS2, INCLUDED
OMIM Description
DESCRIPTION
Protein S is a vitamin K-dependent plasma protein that inhibits blood
clotting by serving as a nonenzymatic cofactor for activated protein C
(PROC; 612283) in the inactivation of procoagulant factors V (F5;
612309) and VIII (F8; 300841). Protein S exists in 2 forms in plasma:
the free, functionally active form, and the inactive form complexed with
C4b-binding protein (C4BPA; 120830) (Dahlback and Stenflo, 1981).
CLONING
Lundwall et al. (1986) isolated and sequenced cDNA clones for protein S.
Human protein S is a single-chain protein of 635 amino acids with 82%
homology to bovine protein S. Hoskins et al. (1987) isolated cDNA for a
protein S precursor.
Edenbrandt et al. (1990) isolated clones corresponding to the 3-prime
part of the PROS1 gene, including the thrombin (F2; 176930)-sensitive
region, 4 domains that are homologous to the epidermal growth factor
(EGF; 131530) precursor, the COOH-terminal part of protein S that is
homologous to a plasma sex hormone binding globulin (SHBG; 182205), and
the 3-prime untranslated region.
GENE FUNCTION
In human plasma, around 40% of protein S circulates as a free protein,
while the remaining 60% forms a noncovalent 1:1 stoichiometric complex
with the beta-chain of the complement C4b-binding protein (C4BPB;
120831) (Dahlback, 1991). This interaction is of high affinity and
abolishes the anticoagulant properties of protein S. Therefore, in
plasma, only the molar excess of protein S over C4BPB circulates in a
free form and is active as a cofactor of activated protein C (APC) in
the inactivation of the procoagulant factors Va and VIIIa (Griffin et
al., 1992).
Maillard et al. (1992) studied protein S synthesis and secretion by
human osteosarcoma cell lines and by normal adult human osteoblast-like
cells. They showed that protein S is synthesized by osteoblasts in an
active form and incorporated in the mineralized matrix of bone.
Previously, protein S was known to be synthesized mostly by hepatocytes.
Heeb et al. (1994) presented data that demonstrated mechanisms of
anticoagulant action for protein S that are independent of activated
protein C and that involve direct binding to factors Xa and Va and
direct inhibition of factor Xa.
Anderson et al. (2003) identified protein S as the factor in serum that
mediates serum-stimulated macrophage phagocytosis of apoptotic cells, a
process thought to limit the development of inflammation and autoimmune
disease. Flow cytometric and competitive inhibition analyses
demonstrated that protein S binds exclusively to
phosphatidylserine-positive apoptotic cells in a calcium-dependent
manner. Anderson et al. (2003) concluded that protein S is a
multifunctional protein that facilitates the clearance of early
apoptotic cells in addition to regulating blood coagulation.
GENE STRUCTURE
Schmidel et al. (1990) determined that the PROS1 gene contains 15 exons
and spans more than 80 kb.
MAPPING
By Southern blot analysis of DNA from somatic cell hybrids, Naylor et
al. (1987) and Long et al. (1988) assigned the protein S gene to
chromosome 3p21-q21. By study of somatic cell hybrids with cDNA probes,
including hybrids with rearranged chromosomes, Watkins et al. (1987,
1988) assigned the protein S gene to 3p21-q21; see Stanislovitis et al.
(1987).
By in situ hybridization, Watkins et al. (1988) assigned the PROS gene
to chromosome 3p11.1-q11.2, the region immediately surrounding the
centromere.
Hartz (2008) mapped the PROS1 gene to chromosome 3q11.2 based on an
alignment of the PROS1 sequence (GenBank GENBANK AK292994) with the
genomic sequence (build 36.1).
- Pseudogene
By Southern analysis of the protein S locus, with cDNA probes
encompassing the 3-prime untranslated region of protein S mRNA, Ploos
van Amstel et al. (1987) determined that there are 2 protein S genes,
both situated on chromosome 3. Conservation of restriction sites
suggested that the 2 genes are highly homologous.
Ploos van Amstel et al. (1988) reported the nucleotide sequence of the
complete 3-prime untranslated regions of the 2 protein S genes, which
they designated PS-alpha (PSA) and PS-beta (PSB). Comparison of the 2
genes with the reported protein S liver cDNAs showed that the latter all
originated from the PSA gene. Therefore, PSA appeared to be the major
locus for synthesis of liver protein S mRNA.
Edenbrandt et al. (1990) isolated and mapped genomic clones
corresponding to the protein S beta-gene, which was found to contain
stop codons and a 2 bp-deletion introducing a frameshift, suggesting
that it is a pseudogene.
The protein S beta locus represents a pseudogene (PROSP) on chromosome
3.
MOLECULAR GENETICS
- Autosomal Dominant Thrombophilia due to Protein S Deficiency
Ploos van Amstel et al. (1989) used Southern blot analysis to identify a
heterozygous deletion in the PROS1 gene in a patient with familial
thrombophilia associated with protein S deficiency (THPH5; 612336). The
deletion segregated with the disorder in this family. The findings
indicated that this specific disorder is directly the result of a defect
in the protein S gene.
Formstone et al. (1995) identified 7 different heterozygous mutations in
the PROS1 gene (see, e.g., 176880.0002) in patients with protein S
deficiency.
In affected members of 22 Spanish families with protein S deficiency,
Espinosa-Parrilla et al. (1999) identified 10 different mutations in the
PROS1 gene (see, e.g., 176880.0007; 176880.0008). One of these
mutations, Q238X (176880.0007), cosegregated with both type I and type
III protein S-deficient phenotypes coexisting in a type I/type III
pedigree. By contrast, Espinosa-Parrilla et al. (1999) found no
cosegregating PROS1 mutations in any of the 6 families with only type
III phenotypes. From these results, Espinosa-Parrilla et al. (1999)
concluded that while mutations in PROS1 are the main cause of type I
protein S deficiency, the molecular basis of the type III phenotype may
be more complex.
Beauchamp et al. (2004) stated that over 200 mutations in the PROS1 gene
had been identified in patients with protein S deficiency.
Using multiplex ligation-dependent probe amplification (MLPA) analysis,
Pintao et al. (2009) identified copy number variation (CNV) involving
the PROS1 gene in 6 (33%) of 18 probands with protein S deficiency who
did not have point mutations by direct sequencing. The results were
confirmed by PCR analysis. Three probands were found to have complete
deletion of the PROS1 gene; all had type I deficiency with quantitative
deficiency of total and free PROS1 antigen. Two probands had partial
deletion, and 1 proband had partial duplication. Three probands with CNV
had positive family history and the CNV cosegregated with protein S
deficiency in family members.
- Autosomal Recessive Thrombophilia due to Protein S Deficiency
In a Thai infant with autosomal recessive thrombophilia due to protein S
deficiency (THPH6; 614514) (Mahasandana et al., 1990), Pung-amritt et
al. (1999) identified compound heterozygosity for 2 mutations in the
PROS1 gene (176880.0010 and 176880.0011). The patient presented with
neonatal purpura fulminans. Each parent, who was found by ELISA studies
to have about 50% of protein S free antigen, was heterozygous for 1 of
the mutations.
In an infant, born of Albanian parents, with autosomal recessive
thrombophilia due to protein S deficiency, Fischer et al. (2010)
identified a homozygous mutation in the PROS1 gene (176880.0012). The
patient presented with seizures and hemorrhagic shock associated with a
massive intracranial bleed and laboratory evidence of disseminated
intravascular coagulation. After stabilization, laboratory studies
showed thrombophilia due to severe protein S deficiency (less than 10%).
Each parent was heterozygous for the mutation and showed about 50%
protein S activity.
ANIMAL MODEL
Burstyn-Cohen et al. (2009) generated several lines of transgenic mice
with conditional knockout of the Pros1 gene in (1) all cells, (2) in
hepatocytes, (3) in endothelial and hematopoietic cells, and (4) in
vascular smooth muscle cells. Complete knockout of Pros1 in all cells
was embryonic lethal. Pros1 -/- mice died between E15.5 and E17.5 from
massive coagulopathy with large blood clots and associated hemorrhage
throughout the body. The embryonic vasculature of Pros1 -/- mice showed
defects in vessel development, integrity, and function, with reduction
of smooth muscle staining. Pros1 +/- mice showed milder defects in
vessel morphology, with permeability defects, and also showed shorter
clot times than wildtype, consistent with a prothrombotic state.
However, this effect was independent of protein C, suggesting that
protein S can inhibit clotting on its own. Vascular smooth
muscle-specific Pros1 -/- mice showed mild defects similar to Pros1 +/-
mice. Hepatocyte-specific Pros1 -/- mice were viable and had normal
vessel morphology, although about 15% showed focal fibrin deposition in
blood vessels. Vascular endothelial and hematopoietic cell-specific
Pros1 -/- mice were also viable, but had vessel defects. They also had
approximately 57% circulating protein S compared to wildtype, indicating
that these cells contribute to circulating protein S levels.
Burstyn-Cohen et al. (2009) suggested that PROS1 may have a direct
anticoagulant function in the blood coagulation cascade as well as a
role in vascular development and function, most likely via its ability
to bind to and activate TAM receptors, such as AXL (109135).
Saller et al. (2009) found that Pros -/- embryos died late in gestation
with consumptive coagulopathy. Pros +/- mice were viable and appeared
normal, and they did not present abnormal mortality or signs of
thrombosis with age. Pros +/- blood cell counts and plasma levels of
coagulation factors were normal, although plasma protein S concentration
was half normal. However, Pros +/- mice exhibited reduced plasma
activated protein C cofactor (F5) activity, reduced anticoagulant
activity, and increased sensitivity to development of tissue factor (F3;
134390)-induced thromboembolism.
DHFRL1
| dbSNP name | rs115816763(G,C); rs368555054(T,C); rs142093204(T,C); rs17855824(C,T); rs369311923(C,G) |
| cytoBand name | 3q11.1 |
| EntrezGene GeneID | 200895 |
| snpEff Gene Name | ARL13B |
| EntrezGene Description | dihydrofolate reductase-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02801 |
OR5AC2
| dbSNP name | rs76549762(C,A); rs76417121(G,T); rs4518168(G,A); rs77322229(A,C); rs80220955(T,C) |
| ccdsGene name | CCDS33796.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 81050 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AC, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AC2:NM_054106:exon1:c.C159A:p.N53K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NZP5 |
| dbNSFP Uniprot ID | O5AC2_HUMAN |
| dbNSFP KGp1 AF | 0.0499084249084 |
| dbNSFP KGp1 Afr AF | 0.0731707317073 |
| dbNSFP KGp1 Amr AF | 0.0552486187845 |
| dbNSFP KGp1 Asn AF | 0.0856643356643 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.04913 |
| ESP Afr MAF | 0.084884 |
| ESP All MAF | 0.036983 |
| ESP Eur/Amr MAF | 0.012442 |
| ExAC AF | 0.034,2.440e-05,4.879e-05 |
OR5H1
| dbSNP name | rs75688383(G,A); rs72926074(G,A); rs9849637(T,A) |
| ccdsGene name | CCDS33797.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 26341 |
| EntrezGene Description | olfactory receptor, family 5, subfamily H, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5H1:NM_001005338:exon1:c.G355A:p.A119T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0098 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NKK0 |
| dbNSFP Uniprot ID | OR5H1_HUMAN |
| dbNSFP KGp1 AF | 0.0187728937729 |
| dbNSFP KGp1 Afr AF | 0.0772357723577 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.01882 |
| ESP Afr MAF | 0.050863 |
| ESP All MAF | 0.01769 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.006189 |
OR5H14
| dbSNP name | rs77954988(T,C); rs4241468(G,A); rs111228762(A,G); rs372260126(A,T); rs4857076(A,G); rs72927996(T,C); rs12639519(T,A); rs75547468(C,A) |
| ccdsGene name | CCDS33798.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 403273 |
| EntrezGene Description | olfactory receptor, family 5, subfamily H, member 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5H14:NM_001005514:exon1:c.T189C:p.L63L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.02938 |
| ESP Afr MAF | 0.059918 |
| ESP All MAF | 0.020837 |
| ESP Eur/Amr MAF | 0.000814 |
| ExAC AF | 0.01 |
OR5H15
| dbSNP name | rs146412623(G,A); rs4133320(G,A); rs4133321(T,A); rs7623031(C,T); rs138282085(G,A); rs13082608(C,T) |
| ccdsGene name | CCDS33799.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 403274 |
| EntrezGene Description | olfactory receptor, family 5, subfamily H, member 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5H15:NM_001005515:exon1:c.G290A:p.C97Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0067 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NDH6 |
| dbNSFP Uniprot ID | O5H15_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.001538 |
| ESP Eur/Amr MAF | 0.00221 |
| ExAC AF | 0.001757 |
OR5H6
| dbSNP name | rs2132894(C,G); rs2173236(C,T); rs9289564(G,C); rs16846784(C,T); rs58475490(C,A); rs9853887(T,C); rs146724389(C,G); rs9853906(A,G); rs9871143(G,A) |
| ccdsGene name | CCDS33800.1 |
| CosmicCodingMuts gene | OR5H6 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 79295 |
| EntrezGene Description | olfactory receptor, family 5, subfamily H, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5H6:NM_001005479:exon1:c.C129G:p.L43L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2847 |
| ESP Afr MAF | 0.141852 |
| ESP All MAF | 0.259074 |
| ESP Eur/Amr MAF | 0.319144 |
| ExAC AF | 0.681 |
OR5H2
| dbSNP name | rs72487753(G,C); rs138288586(A,G); rs16839214(A,G); rs72934924(C,T) |
| ccdsGene name | CCDS33801.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 79310 |
| EntrezGene Description | olfactory receptor, family 5, subfamily H, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5H2:NM_001005482:exon1:c.G46C:p.E16Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGV7 |
| dbNSFP Uniprot ID | OR5H2_HUMAN |
| dbNSFP KGp1 AF | 0.158424908425 |
| dbNSFP KGp1 Afr AF | 0.15243902439 |
| dbNSFP KGp1 Amr AF | 0.196132596685 |
| dbNSFP KGp1 Asn AF | 0.22027972028 |
| dbNSFP KGp1 Eur AF | 0.0976253298153 |
| dbSNP GMAF | 0.1589 |
| ESP Afr MAF | 0.150704 |
| ESP All MAF | 0.130709 |
| ESP Eur/Amr MAF | 0.120465 |
| ExAC AF | 0.147,1.626e-05 |
OR5K4
| dbSNP name | rs9822460(A,G) |
| ccdsGene name | CCDS33802.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 403278 |
| EntrezGene Description | olfactory receptor, family 5, subfamily K, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5K4:NM_001005517:exon1:c.A616G:p.I206V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NMS3 |
| dbNSFP Uniprot ID | OR5K4_HUMAN |
| dbNSFP KGp1 AF | 0.20467032967 |
| dbNSFP KGp1 Afr AF | 0.235772357724 |
| dbNSFP KGp1 Amr AF | 0.21546961326 |
| dbNSFP KGp1 Asn AF | 0.141608391608 |
| dbNSFP KGp1 Eur AF | 0.22691292876 |
| dbSNP GMAF | 0.2043 |
| ESP Afr MAF | 0.272129 |
| ESP All MAF | 0.22728 |
| ESP Eur/Amr MAF | 0.204302 |
| ExAC AF | 0.212 |
OR5K3
| dbSNP name | rs13068323(G,A) |
| ccdsGene name | CCDS33803.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 403277 |
| EntrezGene Description | olfactory receptor, family 5, subfamily K, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5K3:NM_001005516:exon1:c.G131A:p.G44D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NET4 |
| dbNSFP Uniprot ID | OR5K3_HUMAN |
| dbNSFP KGp1 AF | 0.165750915751 |
| dbNSFP KGp1 Afr AF | 0.140243902439 |
| dbNSFP KGp1 Amr AF | 0.138121546961 |
| dbNSFP KGp1 Asn AF | 0.199300699301 |
| dbNSFP KGp1 Eur AF | 0.17018469657 |
| dbSNP GMAF | 0.1653 |
| ESP Afr MAF | 0.134816 |
| ESP All MAF | 0.14278 |
| ESP Eur/Amr MAF | 0.14686 |
| ExAC AF | 0.149 |
OR5K1
| dbSNP name | rs200654905(T,C); rs111771929(C,T) |
| ccdsGene name | CCDS43115.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 26339 |
| EntrezGene Description | olfactory receptor, family 5, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5K1:NM_001004736:exon1:c.T134C:p.L45S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0034 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHB7 |
| dbNSFP Uniprot ID | OR5K1_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.008151 |
| ESP Eur/Amr MAF | 0.011747 |
| ExAC AF | 6.506e-03,8.132e-06 |
OR5K2
| dbSNP name | rs59427166(C,A) |
| ccdsGene name | CCDS33804.1 |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 402135 |
| EntrezGene Description | olfactory receptor, family 5, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5K2:NM_001004737:exon1:c.C526A:p.H176N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHB8 |
| dbNSFP Uniprot ID | OR5K2_HUMAN |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0528455284553 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.063323 |
| ESP All MAF | 0.021452 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.005343 |
GPR15
| dbSNP name | rs140101017(C,T); rs2230344(C,T); rs35320046(A,G) |
| cytoBand name | 3q11.2 |
| EntrezGene GeneID | 2838 |
| snpEff Gene Name | CPOX |
| EntrezGene Description | G protein-coupled receptor 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intragenic |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002296 |
OMIM Clinical Significance
Cardiac:
Lethal complex congenital heart defect
Facies:
Flat facial profile
Mouth:
Bilateral cleft lip/palate;
Macrosomia;
Tongue anomaly
Eyes:
Hypertelorism
Head:
Flat occiput
GI:
Malrotation of the intestine;
Visceromegaly
Growth:
Large for gestational age
Limbs:
Bifid thumbs;
Minor hand anomalies;
Short broad hands
Lab:
Normal chromosomes;
Hypertrophic pancreatic islets
Inheritance:
Autosomal recessive
OMIM Title
*601166 G PROTEIN-COUPLED RECEPTOR 15; GPR15
OMIM Description
CLONING
Using primers based on conserved regions of the opioid-related receptors
(e.g., 165196), Heiber et al. (1996) isolated a PCR product that they
then used to locate the full-length coding region of a novel human
receptor gene, GPR15. GPR15 shares sequence identity with the
angiotensin II receptors type 1 (106165) and type 2 (300034), the
interleukin 8 b receptor (146928), and the orphan receptors GPR1
(600239) and angiotensin receptor-like 1 (600052).
MAPPING
By fluorescence in situ hybridization, Heiber et al. (1996) mapped GPR15
to 3q11.2-q13.1.
GENE FUNCTION
Kim et al. (2013) showed that GPR15, an orphan heterotrimeric guanine
nucleotide-binding protein (G protein)-coupled receptor, controlled the
specific homing of T cells, particularly FOXP3 (300292)-positive
regulatory cells (T-regs), to the large intestine lamina propria. GRP15
expression was modulated by gut microbiota and transforming growth
factor beta-1 (TGFB1; 190180), but not by retinoic acid. GPR15-deficient
mice were prone to develop more severe large intestine inflammation,
which was rescued by the transfer of GPR15-sufficient T-regs. Kim et al.
(2013) concluded that their findings described a T-cell homing receptor
for the large intestine lamina propria and indicated that GPR15 plays a
role in mucosal immune tolerance largely by regulating the influx of
T-regs.
ZBTB11-AS1
| dbSNP name | rs3806654(G,C); rs77504794(G,T); rs3806653(T,C); rs3806652(G,A); rs3864012(T,C); rs1056579(T,G) |
| cytoBand name | 3q12.3 |
| EntrezGene GeneID | 100009676 |
| snpEff Gene Name | AC084198.1 |
| EntrezGene Description | ZBTB11 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3365 |
CCDC54
| dbSNP name | rs709564(G,A); rs117360444(A,G) |
| ccdsGene name | CCDS2949.1 |
| cytoBand name | 3q13.12 |
| EntrezGene GeneID | 84692 |
| EntrezGene Description | coiled-coil domain containing 54 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC54:NM_032600:exon1:c.G113A:p.R38Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NEL0 |
| dbNSFP Uniprot ID | CCD54_HUMAN |
| dbNSFP KGp1 AF | 0.466117216117 |
| dbNSFP KGp1 Afr AF | 0.313008130081 |
| dbNSFP KGp1 Amr AF | 0.450276243094 |
| dbNSFP KGp1 Asn AF | 0.886363636364 |
| dbNSFP KGp1 Eur AF | 0.255936675462 |
| dbSNP GMAF | 0.4669 |
| ESP Afr MAF | 0.327281 |
| ESP All MAF | 0.267107 |
| ESP Eur/Amr MAF | 0.236279 |
| ExAC AF | 0.367 |
TMPRSS7
| dbSNP name | rs73216064(G,A); rs73216065(A,C); rs73216066(T,C); rs4682346(T,C); rs4682347(T,C); rs4682348(G,C); rs11928544(G,A); rs9840207(A,C); rs1844925(A,G); rs774774(A,G); rs11929695(C,T); rs11914332(G,C); rs6438026(C,T); rs113801793(A,G); rs79483275(G,T); rs1688286(A,C); rs62280175(G,T); rs56163753(G,T); rs7625219(A,C); rs4682080(A,C); rs4682081(G,A); rs4682349(C,T); rs7650263(G,A); rs4682350(C,T); rs7650559(G,T); rs79231988(G,A); rs73216078(G,A); rs774778(T,C); rs2120093(G,A); rs9829318(G,A); rs1561911(G,A); rs1318554(A,G); rs1688304(T,G); rs7630245(T,C); rs1662265(A,C); rs7622025(G,A); rs9826973(C,A); rs2399403(T,C); rs7625159(G,A); rs774768(A,G); rs774769(T,G); rs12489437(G,A); rs10934131(G,A); rs11927988(A,G); rs56071730(G,A); rs11928025(A,G); rs774770(A,G); rs11711986(G,A); rs11711987(G,A); rs11720631(A,G); rs10934132(C,T); rs10934133(G,A); rs9288935(T,C); rs920708(G,A); rs11713084(G,A); rs11713897(C,G); rs774771(A,C); rs17443294(C,A); rs16859113(T,C); rs811808(A,G); rs16859114(G,C); rs17502804(A,G); rs774772(G,C); rs16859115(T,C); rs16859117(T,A); rs58878074(G,T); rs11715228(C,T); rs17443498(A,G); rs115010615(G,A); rs55971748(T,A); rs56039551(T,G); rs17443548(C,T); rs17503000(G,A); rs77230791(A,C); rs77767840(A,G); rs73853294(G,T); rs11716665(T,C); rs4682351(C,T); rs4682352(T,C); rs4682353(C,T); rs774773(A,G); rs16859126(A,G); rs73853296(G,C); rs73853297(T,C); rs73853298(G,A); rs60361907(G,C); rs16859128(A,G); rs58414055(G,A); rs36047004(G,A); rs116215899(G,A); rs55913382(G,A); rs16859129(C,T); rs16859130(A,G); rs73853300(G,A); rs73856305(T,C); rs340143(T,A); rs60746737(C,A); rs55968036(A,C); rs9864383(G,A); rs60031977(G,A); rs116542268(G,A); rs340145(G,A); rs145166872(A,C); rs7650076(T,C); rs112815638(C,T); rs340146(T,C); rs111401430(C,T); rs74966366(G,A); rs11715561(G,A); rs9876878(T,C); rs340149(A,C); rs76798375(C,T); rs340150(T,C); rs141757986(G,C); rs4682354(G,A); rs143694039(G,A); rs4544583(A,C); rs150710326(T,C); rs16859140(T,C); rs114361557(A,G); rs191454(G,T); rs1907639(A,G); rs79325822(G,A); rs76703900(A,G); rs115133099(G,A); rs1075618(G,A); rs112458085(C,G); rs168151(C,T); rs902854(C,T); rs168150(C,T); rs3082393(C,T); rs77017561(C,T); rs340151(A,T); rs78489211(T,C) |
| ccdsGene name | CCDS43129.2 |
| cytoBand name | 3q13.2 |
| EntrezGene GeneID | 344805 |
| EntrezGene Description | transmembrane protease, serine 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMPRSS7:NM_001042575:exon10:c.G1102A:p.G368S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.649 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0284552845528 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.026588 |
| ESP All MAF | 0.008622 |
| ESP Eur/Amr MAF | 0.000241 |
| ExAC AF | 0.002638 |
LINC01279
| dbSNP name | rs2668222(A,G); rs3732815(C,T); rs2172196(A,G); rs2668223(T,C); rs986883(C,A); rs2280066(T,A); rs2705518(T,C) |
| cytoBand name | 3q13.2 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.264 |
ZNF80
| dbSNP name | rs73235934(A,G); rs73235935(A,G); rs3732782(T,G); rs3732781(A,C); rs6438190(G,A); rs6438191(C,T); rs3732780(G,C); rs76061345(C,T); rs6770874(G,A) |
| cytoBand name | 3q13.31 |
| EntrezGene GeneID | 7634 |
| EntrezGene Description | zinc finger protein 80 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2544 |
OMIM Clinical Significance
Lab:
Elevated plasma zinc;
Increased zinc binding to albumin;
Copper and iron not increased
Inheritance:
Autosomal dominant;
? albumin gene (103600) mutation
OMIM Title
*194553 ZINC FINGER PROTEIN 80; ZNF80
OMIM Description
MAPPING
Huebner et al. (1993) mapped the ZNF80 gene to chromosome 3p12-qter by
analysis of its segregation pattern in a rodent/human hybrid panel.
HGD
| dbSNP name | rs804976(A,G); rs200226427(T,C); rs140354298(G,A); rs113975133(C,A); rs804974(C,T); rs61799339(C,A); rs112229599(T,C); rs991912(C,G); rs384136(C,A); rs388554(G,C); rs144140050(G,T); rs113499557(G,C); rs111264757(C,A); rs41452145(C,T); rs3755560(G,A); rs804973(C,A); rs804972(T,C); rs142840881(A,G); rs111784242(G,A); rs113762162(G,A); rs113778129(C,T); rs17829440(G,T); rs61799346(C,T); rs4676810(G,C); rs2075505(C,T); rs804971(T,C); rs138872539(C,T); rs140512565(G,A); rs16849176(C,G); rs10511397(A,G); rs804967(G,T); rs10511396(T,G); rs140205901(G,A); rs909078(A,T); rs1862942(G,A); rs2293735(T,C); rs111258955(C,T); rs2551622(G,T); rs112488469(C,T); rs34975956(G,T); rs2551617(C,T); rs111699823(C,T); rs2432696(T,C); rs113514515(C,T); rs2551614(G,C); rs3817627(T,G); rs17829608(T,C); rs17239827(C,T); rs2551607(G,A); rs7652072(G,A); rs3732367(A,G); rs2551605(T,A); rs7610838(G,T); rs17140342(G,T); rs3753090(A,G); rs149376104(A,C); rs144182886(T,C); rs35447032(T,C); rs111374013(C,T); rs150983540(C,T); rs17140347(C,T); rs35002954(A,G); rs1862941(T,C); rs1862940(T,A); rs1862939(C,T); rs1862938(A,G); rs61799866(C,G); rs726267(T,C); rs2194423(T,C); rs61799868(C,T); rs113007421(G,A); rs2551598(G,C); rs34574908(C,T); rs145756258(C,G); rs2551595(A,C); rs2081312(G,A); rs2081311(G,A); rs111226618(G,A); rs2098781(T,C); rs1013765(T,A); rs2113470(A,T); rs6796584(T,C); rs6783720(C,T); rs2015444(A,T); rs113869017(C,T); rs2551583(G,C); rs113612658(C,T); rs138273450(C,T); rs3819375(C,T); rs2551575(G,T); rs113657571(C,T); rs2551573(G,A); rs3821356(G,A); rs112089657(C,T); rs2551570(A,C); rs2551569(G,T); rs2733795(C,G); rs35360713(G,A); rs147684399(A,C); rs113888182(A,G); rs34807255(C,T); rs112879202(G,A); rs111286424(A,G); rs139366703(T,C); rs2059332(G,A); rs112615156(C,T); rs34002526(G,A); rs112522711(G,A); rs2236994(G,A); rs2204994(G,A); rs35982446(C,T); rs71618038(G,A); rs148900835(A,G); rs148212806(A,G); rs2298958(G,T); rs112788906(C,T); rs2298956(G,C); rs144140750(A,C); rs61795572(G,A); rs61795573(A,G); rs3819373(T,C); rs3819372(T,C); rs3819371(A,G); rs61795577(C,T); rs146031279(G,A); rs1800722(T,C); rs2255543(T,A); rs17140269(A,G); rs148221793(T,C); rs111294844(A,G); rs4676815(C,T); rs61795582(A,G); rs4676816(C,T); rs17140364(T,C); rs17140367(T,C); rs74356584(A,G); rs79072367(C,T); rs2236993(C,A); rs4676817(T,G); rs4676818(G,C); rs4676819(G,A); rs2236992(C,T); rs141091610(C,T); rs112331122(G,A); rs149141143(T,C); rs147202203(A,C); rs138846036(C,A); rs149888385(G,A); rs2042482(A,T); rs2733828(G,A); rs61795590(T,C); rs2551557(T,C); rs2733827(C,T); rs17140396(T,C); rs2733825(T,A); rs17140398(G,C); rs4143446(A,G); rs144450825(G,A); rs147025012(C,G); rs150357284(C,T); rs17140408(T,C); rs2141991(A,C); rs3755563(A,C); rs150684685(C,T); rs4676821(C,T); rs4676704(T,C); rs2251584(T,C); rs2733806(A,G); rs61795599(T,C); rs2236991(G,A); rs1862937(C,T) |
| ccdsGene name | CCDS3000.1 |
| cytoBand name | 3q13.33 |
| EntrezGene GeneID | 3081 |
| EntrezGene Description | homogentisate 1,2-dioxygenase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HGD:NM_000187:exon3:c.G142T:p.A48S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8765 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q93099 |
| dbNSFP Uniprot ID | HGD_HUMAN |
| dbNSFP KGp1 AF | 0.010989010989 |
| dbNSFP KGp1 Afr AF | 0.0447154471545 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.031548 |
| ESP All MAF | 0.011002 |
| ESP Eur/Amr MAF | 0.000466 |
| ExAC AF | 0.003033 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Sensorineural hearing loss;
Vestibular dysfunction;
[Eyes];
Nystagmus;
Upward gaze paresis;
Blepharoptosis;
Ophthalmoparesis, progressive, external;
Cataracts (less common)
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy (less common)
ABDOMEN:
[Gastrointestinal];
Gastroparesis (less common);
Intestinal pseudo-obstruction (less common)
MUSCLE, SOFT TISSUE:
Proximal muscle weakness, mild;
Dysarthria;
Ragged red fibers seen on muscle biopsy;
Increased variation in fiber size;
Necrotic and atrophic fibers with centralized nuclei;
Multiple mitochondrial DNA (mtDNA) deletions (in most cases);
Decreased activity of cytochrome c oxidase (in most cases);
Subsarcolemmal accumulations of abnormally shaped mitochondria seen
on electron microscopy
NEUROLOGIC:
[Central nervous system];
Gait ataxia, progressive;
Ataxia worsens in the dark;
Positive Romberg sign;
Hyporeflexia;
Areflexia;
Myoclonus (less common);
Migraine;
Seizures (less common);
Cognitive impairment, mild;
Bilateral thalamic lesions on MRI;
Cerebellar white matter lesions on MRI;
Atrophic and degenerative changes in the spinal cord;
[Peripheral nervous system];
Sensory ataxic neuropathy;
Distal sensory impairment to vibration and proprioception;
Sensory axonal neuropathy;
Sural nerve biopsy shows loss of large and small myelinated axons;
[Behavioral/psychiatric manifestations];
Memory difficulties;
Lack of concentration;
Withdrawal;
Depression
LABORATORY ABNORMALITIES:
Mildly increased serum lactate;
Mildly increased serum creatine kinase
MISCELLANEOUS:
Young-adult onset (18-30 years) of sensory ataxia;
Later onset of ophthalmoparesis;
Highly variable phenotype
MOLECULAR BASIS:
Caused by mutation in the DNA polymerase-gamma gene (POLG, 174763.0002)
OMIM Title
*607474 HOMOGENTISATE 1,2-DIOXYGENASE; HGD
;;HOMOGENTISIC ACID OXIDASE; HGO
OMIM Description
DESCRIPTION
The HGD gene encodes homogentisate 1,2-dioxygenase (HGD; EC 1.13.11.5),
an enzyme involved in the catabolism of phenylalanine and tyrosine
(summary by Vilboux et al., 2009).
CLONING
Fernandez-Canon et al. (1996) cloned the gene for homogentisate
1,2-dioxygenase. Characterization of the human HGD gene came from work
with the ascomycete fungus Aspergillus nidulans in which a gene encoding
an HGD enzyme, hmgA, had been cloned. The deduced amino acid sequence of
its encoded protein product was used to identify EST clones putatively
corresponding to the human HGD gene. HGD encodes a 445-amino acid
polypeptide with high homology to the Aspergillus hmgA. By Northern blot
analysis, Fernandez-Canon et al. (1996) found highest expression of HGD
in the prostate, small intestine, colon, and liver.
Schmidt et al. (1997) cloned the homogentisate 1,2-dioxygenase gene in
the mouse.
GENE STRUCTURE
Fernandez-Canon et al. (1996) determined that the HGD gene contains 14
exons.
MAPPING
Fernandez-Canon et al. (1996) mapped the HGD gene to chromosome 3q21-q23
by a preliminary PCR screen of hamster/human somatic cell hybrid genomic
DNA samples and by fluorescence in situ hybridization.
Gross (2014) mapped the HGD gene to chromosome 3q13.33 based on an
alignment of the HGD sequence (GenBank GENBANK AF000573) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In patients with alkaptonuria (AKU; 203500), Fernandez-Canon et al.
(1996) identified missense mutations in the HGD gene that cosegregated
with the disease (607474.0001, 607474.0002), and provided biochemical
evidence that at least one of these missense mutations is a
loss-of-function mutation.
Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a
notably high frequency, Gehrig et al. (1997) found 2 novel mutations in
the HGD gene. In 2 apparently unrelated patients, a 481G-A substitution
was found leading to a gly161-to-arg amino acid substitution
(607474.0003). Both patients were the only affected members of their
families and both were homozygous for this missense mutation. In another
pedigree, 2 brothers were homozygous for a 1-basepair insertion
(454-457insG) leading to a premature translational stop 26 codons
downstream (607474.0004); other relatives were heterozygous for the
mutation.
Beltran-Valero de Bernabe et al. (1998) reported haplotype and mutation
analysis of the HGO gene in 29 previously unstudied AKU chromosomes.
They identified 12 novel mutations. Eight were missense mutations, 1 was
a frameshift mutation, 2 were intronic mutations, and 1 was a splice
site mutation. They also characterized 5 polymorphic sites in HGO and
described the haplotypic associations of alleles at these sites in
normal and AKU chromosomes.
Beltran-Valero de Bernabe et al. (1999) stated that a total of 17
different AKU mutations had been described. Most of these were missense
mutations changing amino acid residues that are conserved between human
and other species. Only 3 had been found in more than 1 patient. This
remarkable allelic heterogeneity was further demonstrated by analysis of
7 new AKU pedigrees, which uncovered 6 novel AKU mutations and 2
single-nucleotide polymorphisms. Reexamination of all 29 mutations and
polymorphisms in the HGO gene described to that time showed that these
nucleotide changes were not randomly distributed; the CCC sequence motif
and its inverted complement, GGG, were preferentially mutated. These
analyses also demonstrated that the nucleotide substitutions in the HGO
gene did not involve CpG dinucleotides, which illustrates important
differences between the HGO gene and other genes for the occurrence of
mutation at specific short-sequence motifs. Because the CCC sequence
motifs comprise a significant proportion (34.5%) of all mutated bases
that have been observed in the HGO gene, Beltran-Valero de Bernabe et
al. (1999) concluded that the CCC triplet is a mutation hotspot in HGO.
Beltran-Valero de Bernabe et al. (1999) reported 3 novel mutations
(607474.0006, 607474.0007, and 607474.0008) and 1 previously reported
mutation, met368 to val (607474.0009), in 2 Finnish alkaptonuria
pedigrees. Using haplotype analysis, they predicted that the 3 novel
mutations were most likely specific to the Finnish population and had
arisen recently, in light of the low prevalence of alkaptonuria in
Finland and the finding of homozygosity for these mutations in 3
individuals.
Muller et al. (1999) reported on the molecular defects in 30 AKU
patients from central Europe. In addition to 5 mutations described
previously, they detected 5 novel HGO mutations. In Slovakia, the
country with the highest incidence of AKU, they found that 2 recurrent
mutations, 183-1G to A (607474.0005) and gly161 to arg (607474.0003),
were found on more than 50% of AKU chromosomes. An analysis of the
allelic association with intragenic DNA markers and of the geographic
origins of the AKU chromosomes suggested that several independent
founders had contributed to the gene pool, and that subsequent genetic
isolation was probably responsible for the high prevalence of
alkaptonuria in Slovakia.
Rodriguez et al. (2000) reported 7 novel AKU and 22 fungal mutations,
and correlated mutational information with HGO crystal structure and
function using kinetic assays of AKU mutant enzymes. HGO is a
topologically complex structure which assembles as a functional hexamer
arranged as a dimer of trimers. The authors showed how the intra- and
intersubunit interactions and the extensive surfaces required for
subunit folding and association can be inactivated at multiple levels by
single-residue substitutions.
Zatkova et al. (2000) identified 9 different mutations in 32 chromosomes
in 17 Slovak patients with alkaptonuria. Four mutations (2 missense, a
frameshift, and a splice site mutation) were novel. Gly161 to arg
(607474.0003) and the 1-bp insertion at nucleotide 621 (607474.0010)
were each seen in 8 of 32 chromosomes.
Phornphutkul et al. (2002) identified 23 new HGO mutations. In 57
patients, at least 1 HGO mutation was identified; 23 of these mutations
had not previously been reported. Thirty-six patients were compound
heterozygotes. In total, mutations were identified in 104 of 116
alleles. At least 1 M368V mutation (607474.0009) occurred in 14
patients. Seven patients were also either homozygous or heterozygous for
H80Q, which is considered a common polymorphism.
Zatkova et al. (2003) stated that 43 HGO mutations had been identified
in approximately 100 patients. In Slovakia, the incidence of the
disorder was estimated at 1 in 19,000, and 10 different AKU mutations
had been identified in this relatively small country.
Vilboux et al. (2009) provided an extensive update of published HGD
mutations associated with AKU and identified 52 variants in 93
additional patients. Twenty-two novel mutations were identified,
yielding a total of 91 identified HGD variants associated with the
disorder. Most of the variants occurred in exons 3, 6, 8, and 13.
ANIMAL MODEL
In the course of an ethylnitrosourea mutation study, Guenet (1990) and
his group detected a mutation for alkaptonuria in the mouse by the
finding of black wood shavings in the mouse boxes.
Manning et al. (1999) demonstrated that the mutation causing
alkaptonuria in mice that was created by ethylnitrosourea mutagenesis
was a single base change in a splice donor consensus sequence, causing
exon skipping and frame-shifted products.
POLQ
| dbSNP name | rs149864930(A,G); rs2306211(G,A); rs3218634(G,C); rs12629829(G,T); rs6800901(C,T); rs1381057(T,C); rs2030531(C,T); rs16832303(A,G); rs1522357(G,A); rs78593942(A,G); rs148945914(G,A); rs9883968(G,A); rs6769377(G,A); rs112196344(A,G); rs148046764(T,G); rs4676677(G,A); rs6806191(C,T); rs13076688(G,A); rs7621376(T,A); rs143144587(A,G); rs6765310(G,A); rs146211654(A,G); rs72969951(T,C); rs140009334(G,A); rs7618570(C,T); rs6785417(T,C); rs6438630(A,C); rs116472990(A,G); rs11709726(G,A); rs185862343(T,A); rs3218650(G,A); rs143042326(A,C); rs191657010(T,G); rs141598142(G,A); rs150904129(A,G); rs6438631(G,T); rs118069544(G,T); rs630138(G,A); rs10934550(G,C); rs552404(C,T); rs11707252(A,G); rs3843345(C,T); rs650469(A,G); rs3856578(A,G); rs7645869(C,T); rs669277(T,C); rs7613752(T,C); rs181419263(G,A); rs74837046(C,G); rs6438633(C,A); rs4676722(A,G); rs6797376(G,A); rs77029095(A,G); rs11705939(G,T); rs11713643(A,G); rs11713696(A,C); rs7645027(G,A); rs7644962(C,T); rs148519413(G,C); rs524026(G,A); rs532411(G,A); rs532326(T,C); rs1381058(A,G); rs3218630(A,G); rs73193612(G,A); rs541818(A,G); rs12634017(A,T); rs76287450(C,T); rs3772120(G,A); rs41545720(T,C); rs34815002(A,T); rs12496163(A,G); rs58473385(T,C); rs7615529(G,C); rs6784324(T,C); rs1381059(C,T); rs3772122(T,C); rs6778684(C,T); rs13080007(C,G); rs12632308(G,A); rs12635218(T,C); rs143921963(G,T); rs575913(G,A); rs3772124(C,G); rs3821367(A,G); rs72969983(T,C); rs142138752(C,T); rs35775179(C,A); rs3218651(T,C); rs3218649(G,C); rs507353(G,A); rs11711667(G,A); rs532464(C,G); rs4555467(A,G); rs13097659(G,C); rs7622897(C,T); rs143579841(G,A); rs11719937(A,G); rs41548518(T,C); rs35362700(A,G); rs148240231(G,C); rs13098567(T,A); rs114903786(A,C); rs66922316(A,G); rs28406368(A,G); rs11718918(C,G); rs10934551(G,A); rs6793252(G,C); rs3911713(A,G); rs115164121(C,T); rs138000344(C,T); rs71329222(C,T); rs693403(C,T); rs3732406(A,C); rs487848(G,A); rs7618539(G,A); rs34624267(G,A); rs115477598(T,G); rs513380(T,C); rs13085365(C,T); rs604231(C,T); rs482920(G,C); rs2877516(G,A); rs140388138(A,G); rs73179904(C,T); rs3886541(G,T); rs187478812(T,A); rs13077305(C,T); rs12488196(G,C); rs702018(G,A); rs702019(G,A); rs111868689(T,C); rs13059229(C,G); rs11714746(G,C); rs494140(G,A); rs13077237(C,T); rs149408529(C,T); rs59260884(T,C); rs73179913(T,G); rs502643(G,A); rs149932961(G,C); rs11717597(T,C); rs2331962(A,G); rs7645050(G,C); rs7622867(A,T); rs7622881(A,G); rs486725(G,T); rs697019(T,C); rs10451895(C,T); rs2169301(G,T); rs794323(G,A); rs13100579(A,G); rs501099(T,C); rs11706583(C,T); rs116370248(T,G); rs7628081(A,G); rs7617748(T,C); rs7633930(A,G); rs7612018(C,T); rs149003604(G,A); rs138727117(G,A); rs13095550(T,C); rs187638702(T,C); rs144166929(C,T); rs111976946(T,C); rs702017(C,A); rs114619601(G,A); rs61729716(C,G) |
| ccdsGene name | CCDS33833.1 |
| cytoBand name | 3q13.33 |
| EntrezGene GeneID | 10721 |
| EntrezGene Description | polymerase (DNA directed), theta |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POLQ:NM_199420:exon29:c.C7640T:p.A2547V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5546 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75417 |
| dbNSFP Uniprot ID | DPOLQ_HUMAN |
| dbNSFP KGp1 AF | 0.0247252747253 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0559440559441 |
| dbNSFP KGp1 Eur AF | 0.0158311345646 |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.002951 |
| ESP All MAF | 0.01261 |
| ESP Eur/Amr MAF | 0.017558 |
| ExAC AF | 0.026 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Irritable bowel syndrome
SKELETAL:
Intermittent sterile, pauciarticular, peripheral erosive arthritis
(elbow, knee, ankle);
Synovial tissue biopsy shows polymorphonuclear infiltrate without
presence of immunoglobulin or complement deposits
SKIN, NAILS, HAIR:
[Skin];
Pyoderma gangrenosum;
Severe cystic acne;
Sterile abscesses at site of parenteral injection
HEMATOLOGY:
Normocytic pancytopenia following sulfa use
MISCELLANEOUS:
PAPA syndrome is an acronym for Pyogenic sterile Arthritis, Pyoderma
gangrenosum, Acne;
Onset of arthritis in early childhood;
Onset of acne in adolescence, persists into adulthood
MOLECULAR BASIS:
Caused by mutation in the proline/serine/threonine phosphatase-interacting
protein 1 (PSTPIP1, 606347.0001)
OMIM Title
*604419 POLYMERASE, DNA, THETA; POLQ
OMIM Description
CLONING
DNA polymerases can participate in both replication of the genome and
DNA repair processes. The human genome contains multiple DNA polymerase
genes. By searching sequence databases with the translated sequences of
the human POLG (174763) and Drosophila mus308 DNA polymerase genes,
Sharief et al. (1999) identified the novel human DNA polymerase theta
(POLQ). They isolated human fetal spleen and human T-cell cDNAs
representing the complete POLQ coding sequence. The predicted
1,762-amino acid POLQ protein contains an N-terminal ATP-binding domain
and C-terminal DNA polymerase motifs A, B, and C, which classify POLQ as
a family A-type DNA polymerase. The C-terminal regions of POLQ and the
Drosophila mus308 gene product share 40% sequence identity; their
N-terminal regions have no significant similarity. PCR detected POLQ
cDNAs in human cerebellum, KB cell, and HeLa cell cDNA libraries.
MAPPING
By radiation hybrid mapping, Sharief et al. (1999) mapped the POLQ gene
to 3q, between proximal marker D3S1303 and distal marker D3S3576. Based
on its proximity to the GOLGB1 gene (602500), they tentatively localized
the POLQ gene to 3q13.31.
ANIMAL MODEL
Masuda et al. (2005) noted that, unlike other low-fidelity DNA
polymerases, which are ubiquitously expressed, POLQ is specifically
expressed in lymphoid tissues in human and mouse. Masuda et al. (2005)
generated mice devoid of Polq polymerase activity by deleting exons 25
and 26, leaving the helicase and other potentially important domains
intact. Polq-inactive mice showed a moderate decrease in overall
mutation frequency in the JH4 intronic region of responding B cells,
which is unaffected by antigen-selection bias. However, only C/G
mutations, both transitions and transversions, were reduced in
Polq-inactive mice, whereas A/T mutations were unaffected. Masuda et al.
(2005) noted that Polh (603968) deficiency produces the opposite effect,
with reduced A/T mutations and no effect on C/G mutations. They proposed
that POLQ introduces mutations at C/G by replicating over abasic sites
generated by uracil-DNA glycosylase (UNG; 191525).
WDR5B
| dbSNP name | rs11553085(T,C); rs9843165(G,C); rs3828362(C,G); rs111928394(C,T); rs1067(G,A); rs182779658(T,C); rs6777596(C,T); rs3749213(T,G) |
| cytoBand name | 3q21.1 |
| EntrezGene GeneID | 54554 |
| snpEff Gene Name | FAM162A |
| EntrezGene Description | WD repeat domain 5B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4766 |
LOC100129550
| dbSNP name | rs9864868(G,A); rs6438769(T,A); rs28375649(T,A); rs12637688(C,T); rs12632212(A,G); rs112577971(G,A); rs12629869(T,C); rs55889467(A,G); rs12638324(G,A); rs79680123(G,C); rs142240975(A,C); rs13091327(C,T); rs111397316(T,C); rs9875741(C,T); rs114656579(C,T); rs4677974(G,C); rs9289207(A,T); rs77147700(C,T); rs80042954(C,A); rs1560485(A,G); rs77605121(G,A); rs7629631(T,C); rs2116320(G,A) |
| cytoBand name | 3q21.1 |
| EntrezGene GeneID | 100129550 |
| EntrezGene Description | uncharacterized LOC100129550 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4403 |
| ExAC AF | 0.323 |
SLC12A8
| dbSNP name | rs2981486(G,A); rs2981485(C,T); rs2948818(T,C); rs13975(T,C); rs1140122(G,A); rs2002242(G,A); rs1574340(A,G); rs2981483(A,G); rs2981482(C,T); rs3732502(G,T); rs2981481(G,A); rs3732500(C,G); rs2981480(A,T); rs2981479(C,T); rs2948817(G,A); rs9861952(C,A); rs2948816(T,C); rs2981478(A,G); rs2948815(G,A); rs17239028(T,G); rs2948814(A,C); rs2981477(T,A); rs4679324(T,G); rs9867868(C,T); rs2981533(T,C); rs2688992(A,C); rs9818560(C,A); rs2670172(T,G); rs2688991(T,C); rs9834177(C,T); rs78175392(C,T); rs2948808(T,C); rs1828684(C,T); rs2788466(G,A); rs74619178(C,T); rs651630(G,A); rs650718(G,A); rs2948828(A,G); rs2333042(T,C); rs1624326(T,C); rs3965994(G,T); rs2981526(C,T); rs16836420(A,C); rs564065(C,G); rs535575(G,A); rs532106(T,C); rs75686195(G,A); rs628788(G,A); rs628716(G,C); rs2993639(A,G); rs614347(G,A); rs2076727(C,T); rs7643017(G,T); rs4679346(G,C); rs2688994(G,A); rs2788464(C,T); rs2688993(A,G); rs2670170(G,A); rs2788463(T,C); rs2788462(C,T); rs13325275(G,A); rs79427359(T,C); rs115065302(A,G); rs74643118(G,C); rs2089986(C,A); rs624886(G,C); rs35237061(G,C); rs72963844(T,C); rs370780074(T,C); rs11914961(T,C); rs10934707(C,T); rs1877579(C,T); rs816144(T,G); rs6808008(C,A); rs10512635(T,C); rs6773138(T,C); rs72963849(G,A); rs62265706(C,T); rs2948803(C,T); rs481018(A,T); rs62265707(T,C); rs72963853(C,T); rs115301299(C,T); rs702059(G,C); rs78546063(T,G); rs658971(A,G); rs2993638(T,C); rs2993637(T,C); rs946244(G,A); rs2788459(C,G); rs1712466(T,C); rs11714323(T,C); rs1712465(C,G); rs10512636(A,G); rs1712464(G,A); rs619432(C,T); rs816154(C,T); rs2948797(A,G); rs816155(T,C); rs2993636(A,G); rs631640(T,G); rs4679362(C,T); rs56118182(C,T); rs539533(C,T); rs591803(G,A); rs62265708(G,A); rs62265709(G,A); rs72480430(G,A); rs373819548(G,A); rs621383(T,C); rs585058(G,A); rs11927069(A,G); rs73191223(G,C); rs2942819(G,T); rs77644453(G,T); rs79332788(C,T); rs863642(G,A); rs6789966(C,G); rs6790154(G,A); rs816156(T,C); rs2945116(C,T); rs1554241(T,A); rs570253(A,G); rs2948805(A,G); rs2037236(G,C); rs2037235(G,A); rs1877581(A,C); rs590037(A,G); rs6791617(T,G); rs36073986(G,A); rs2333043(C,T); rs2945120(G,A); rs59337767(C,T); rs16836458(A,G); rs2942811(T,A); rs12486816(A,G); rs28589555(G,C); rs2942812(C,G); rs112118546(G,C); rs2945119(A,C); rs2945118(C,T); rs2942813(G,A); rs860112(G,A); rs2948796(G,A); rs2948795(A,C); rs2981515(C,T); rs72480431(T,G); rs2948794(C,T); rs139565224(A,G); rs78777213(T,A); rs2945113(G,T); rs7611635(A,G); rs2981514(T,G); rs74534074(C,T); rs2948793(A,G); rs1971407(T,A); rs1971408(A,T); rs7634309(C,G); rs580492(T,C); rs1890407(C,T); rs9868033(T,C); rs2945114(A,C); rs11706126(A,G); rs546672(T,C); rs9815838(A,G); rs516355(T,C); rs11716082(G,C); rs35795291(G,A); rs489699(A,G); rs16836484(G,A); rs2228677(C,T); rs486178(A,G); rs57563086(A,G); rs816146(T,C); rs816147(C,T); rs2981513(G,T); rs12233556(C,T); rs702045(G,A); rs702046(G,C); rs702047(A,T); rs2993635(A,G); rs9831295(A,G); rs2981512(G,A); rs502345(G,C); rs2981511(G,C); rs56273571(C,A); rs2948825(T,C); rs28986278(G,A); rs652746(A,G); rs2942814(C,T); rs2981510(T,C); rs816149(A,C); rs2945121(A,G); rs816150(T,C); rs11929067(G,A); rs2981509(G,T); rs2981508(T,C); rs9809701(C,T); rs2981507(G,A); rs1068926(C,T); rs2981505(C,T); rs9814968(C,T); rs2981504(C,T); rs702048(T,C); rs2981503(A,T); rs640717(A,G); rs628562(G,C); rs504255(C,T); rs613500(T,C); rs4679158(C,A); rs28478427(T,A); rs7375050(G,C); rs531740(T,C); rs612968(G,T); rs7375044(C,T); rs532549(A,G); rs558940(T,C); rs2942815(A,G); rs1818638(A,T); rs510348(G,C); rs55769410(C,G); rs674526(T,C); rs673693(C,T); rs537749(A,G); rs537800(A,C); rs1712458(C,G); rs816151(T,C); rs816152(C,T); rs1416218(C,G); rs555915(C,T); rs11925247(A,T); rs11917613(C,T); rs10934708(C,T); rs10934709(T,C); rs10804569(C,T); rs11714072(T,C); rs653526(G,A); rs28361505(T,C); rs28677078(C,T); rs683120(A,G); rs684030(C,A); rs502057(A,G); rs2333044(C,G); rs588190(G,A); rs606656(G,C); rs552609(G,C); rs547902(G,A); rs1538355(C,G); rs692744(A,G); rs73191246(C,T); rs999731(C,T); rs2175756(G,C); rs28505072(T,C); rs9847619(T,A); rs7625590(G,C); rs7637299(T,C); rs7625624(C,T); rs938226(C,T); rs2176444(G,A); rs1000716(G,A); rs1000715(G,A); rs1467208(G,C); rs13067346(T,C); rs9834609(G,A); rs6786220(C,T); rs6786622(C,T); rs6764841(A,G); rs7634448(G,A); rs3772217(C,T); rs3772216(C,T); rs679990(C,T); rs11713052(C,G); rs596950(A,G); rs55907992(A,G); rs73191256(C,T); rs581557(A,G); rs570340(C,A); rs860976(T,A); rs568456(G,A); rs678197(A,G); rs677412(C,G); rs564809(C,T); rs630439(T,C); rs539135(G,A); rs4679367(A,G); rs533925(T,C); rs373826977(G,T); rs1464172(A,G); rs2945115(G,A); rs6785677(C,T); rs7611512(A,G); rs633055(T,C); rs28986274(C,T); rs142679733(G,A); rs78219403(G,C); rs631691(C,T); rs113161688(G,C); rs183734380(C,A); rs113983169(G,C); rs2993634(A,G); rs115947407(T,C); rs114275828(C,A); rs114994349(A,C); rs16836571(T,G); rs60552957(G,A); rs76347838(A,G); rs11924526(C,G); rs11928563(T,C); rs116059701(G,A); rs11916785(A,T); rs115763604(G,A); rs73191260(C,T); rs62265727(G,T); rs491058(A,C); rs816324(C,A); rs632682(T,C); rs9869183(C,T); rs631333(A,C); rs567432(A,G); rs628380(C,G); rs9870310(G,A); rs484728(A,C); rs486571(A,G); rs816325(A,G); rs1548194(C,T); rs9837500(A,C); rs816326(A,G); rs816327(C,T); rs816328(C,T); rs816329(C,T); rs147926015(C,A); rs6798307(G,A); rs587926(C,A); rs587856(G,A); rs9814903(G,A); rs9852163(A,G); rs559637(T,C); rs2076726(A,G); rs114611061(T,C); rs76446910(G,A); rs58926570(C,T); rs658717(A,G); rs1708337(C,T); rs6763338(C,A); rs694828(A,T); rs35032707(G,A); rs1767087(T,C); rs682870(C,T); rs682815(A,T); rs669532(T,C); rs515234(A,G); rs681268(T,G); rs140308984(T,C); rs491370(T,C); rs1708338(G,C); rs1398759(G,C); rs2981497(A,G); rs1708339(C,T); rs587899(G,C); rs537748(T,C); rs13316796(C,A); rs62265743(G,T); rs6762089(G,A); rs6810352(C,A); rs6786383(A,C); rs6762297(G,A); rs503875(A,G); rs28886643(C,T); rs34093528(T,C); rs114267974(A,T); rs148244346(G,A); rs524325(T,C); rs79021934(G,A); rs17319456(G,C); rs13074637(T,C); rs518109(T,C); rs2993633(C,T); rs144005249(A,C); rs2993632(T,C); rs2993631(G,A); rs545103(C,G); rs112439637(C,T); rs2945117(C,T); rs12637135(A,T); rs146358577(G,A); rs554404(T,C); rs78111621(A,T); rs59736653(T,C); rs55990322(A,G); rs7634656(C,A); rs6438882(A,G); rs11713166(C,A); rs6782235(A,G); rs6770908(T,A); rs62265746(G,A); rs62265747(C,G); rs79205279(G,A); rs9860000(G,A); rs9859758(C,G); rs6777718(T,G); rs12636353(G,C); rs693970(T,C); rs58490484(C,A); rs59434204(G,A); rs58404348(T,C); rs139471950(G,A); rs77645586(G,A); rs1708332(T,C); rs6784701(T,C); rs9816529(C,T); rs12630700(C,A); rs76901101(G,A); rs79885949(G,A); rs586273(C,T); rs76742851(C,T); rs111834267(C,T); rs114632443(C,G); rs867805(C,T); rs77570110(C,A); rs1464065(A,C); rs4679368(T,C); rs702043(T,C); rs146507502(G,A); rs76554709(A,G); rs1980080(C,T); rs57544447(C,T); rs13322132(C,T); rs4254601(C,A); rs74628012(T,C); rs1980079(A,G); rs640403(C,G); rs655593(G,A); rs145993761(C,T); rs76322037(T,A); rs2137599(A,G); rs78638448(T,C); rs683902(T,C); rs62265750(C,T); rs816342(T,C); rs816341(T,C); rs816340(G,A); rs816339(A,C); rs111964726(T,A); rs118106565(C,T); rs816338(T,C); rs591267(T,A); rs77831694(T,C); rs503104(T,G); rs843823(C,T); rs6798073(G,A); rs475155(G,A); rs475147(C,T); rs474365(T,C); rs579296(A,G); rs6801331(C,T); rs6801517(C,T); rs1260471(G,A); rs6766250(T,G); rs28986276(C,T); rs4679370(T,C); rs115210195(G,A); rs78854722(G,T); rs9873519(C,T); rs67623005(C,T); rs667718(A,G); rs13315685(T,C); rs12497133(G,A); rs140946575(G,C); rs35305102(T,C); rs13100784(G,A); rs13101034(A,C); rs146686808(C,T); rs595907(C,T); rs560015(G,A); rs62270293(T,A); rs816344(C,T); rs56077477(A,C); rs13080851(A,G); rs9870956(C,T); rs569255(G,A); rs9815815(T,A); rs9833435(A,G); rs9833476(A,T); rs9816151(T,C); rs11710899(A,C); rs11710930(A,T); rs649961(T,C); rs11718838(C,T); rs11718913(G,A); rs11711022(A,G); rs9872582(G,C); rs9838559(A,G); rs1767090(T,G); rs6762589(G,A); rs1563294(C,T); rs1563293(G,A); rs6789711(A,C); rs6778311(T,C); rs6438883(T,C); rs644751(A,C); rs113252482(T,C); rs1712468(A,T); rs573046(A,G); rs657371(C,G); rs593358(G,A); rs605516(G,A); rs79739632(T,G); rs671064(G,A); rs607784(A,G); rs9832863(T,C); rs1712469(A,T); rs673881(A,G); rs686088(A,G); rs754202(T,G); rs651490(T,G); rs71325819(G,A) |
| ccdsGene name | CCDS43143.1 |
| cytoBand name | 3q21.2 |
| EntrezGene GeneID | 84561 |
| EntrezGene Description | solute carrier family 12, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC12A8:NM_024628:exon5:c.C541T:p.R181C,SLC12A8:NM_001195483:exon4:c.C541T:p.R181C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.755 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0306776556777 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0690607734807 |
| dbNSFP KGp1 Asn AF | 0.00874125874126 |
| dbNSFP KGp1 Eur AF | 0.0448548812665 |
| dbSNP GMAF | 0.03076 |
| ESP Afr MAF | 0.011068 |
| ESP All MAF | 0.035607 |
| ESP Eur/Amr MAF | 0.04767 |
| ExAC AF | 0.053 |
LOC90246
| dbSNP name | rs28634748(A,G); rs55714314(C,G); rs2713586(G,A); rs113684529(C,T); rs9854674(C,A); rs4550835(G,A); rs58951374(G,A); rs2335660(G,T); rs62273171(G,A); rs79070372(G,A); rs1136444(C,A) |
| cytoBand name | 3q21.3 |
| EntrezGene GeneID | 90246 |
| EntrezGene Description | uncharacterized LOC90246 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02847 |
ACAD9
| dbSNP name | rs789225(G,A); rs789226(G,C); rs789227(C,G); rs114156198(T,C); rs789228(A,G); rs13323787(G,T); rs789229(C,T); rs789230(G,A); rs789231(A,G); rs789232(T,G); rs789233(G,T); rs75748817(T,C); rs6439147(T,C); rs13076403(G,C); rs58943552(C,T); rs115893744(G,A); rs114417154(C,T); rs6786847(C,T); rs62268188(G,A); rs2929859(T,G); rs6790091(G,C); rs113519807(C,T); rs184937941(T,G); rs62268189(A,G); rs112298396(C,G); rs6791451(T,C); rs1683811(A,C); rs10460833(A,G); rs113316898(G,A); rs1680780(G,C); rs1680781(C,A); rs79986808(G,A); rs150053865(C,T); rs140879975(C,G); rs144311840(T,C); rs1683791(C,T); rs1680778(A,C); rs62268191(C,T); rs1680779(G,A); rs111716284(C,T); rs113585764(C,T); rs1683804(C,T); rs789213(C,G); rs79398737(T,G); rs1979528(T,G); rs112750943(C,T); rs813732(C,T); rs142564404(G,T); rs16852133(T,C); rs1680795(T,C); rs115920138(C,T); rs115385161(T,C); rs7639482(C,T); rs62268195(T,C); rs1683776(G,T); rs115532916(G,A); rs61096019(C,T); rs2630252(T,C); rs1683777(T,G); rs7652295(C,T); rs1680788(C,T); rs62265263(C,T); rs1680789(G,T); rs1680790(G,T); rs62265264(G,T); rs62265265(A,G); rs1683786(T,C); rs1683787(A,G); rs62265266(G,A); rs62265267(G,C); rs116630465(A,G); rs876756(G,A); rs876754(T,C); rs876755(C,T); rs72973231(T,G); rs6797917(A,G); rs6774021(G,C); rs141633386(C,T); rs62265268(C,G); rs62265269(G,A); rs789240(T,C); rs74888113(C,T); rs116106966(C,T); rs114763241(T,G) |
| ccdsGene name | CCDS3053.1 |
| cytoBand name | 3q21.3 |
| EntrezGene GeneID | 28976 |
| EntrezGene Description | acyl-CoA dehydrogenase family, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACAD9:NM_014049:exon10:c.G976A:p.A326T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8946 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H9W4 |
| dbNSFP KGp1 AF | 0.0100732600733 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0224274406332 |
| dbSNP GMAF | 0.0101 |
| ESP Afr MAF | 0.00227 |
| ESP All MAF | 0.015224 |
| ESP Eur/Amr MAF | 0.02186 |
| ExAC AF | 0.018,4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural (bilateral, prelingual)
GENITOURINARY:
[Internal genitalia, male];
Asthenoteratozoospermia
MOLECULAR BASIS:
A contiguous gene syndrome caused by deletion of the stereocilin gene
(STRC, 606440) and the sperm-associated cation channel-2 gene (CATSPER2,
607249) gene
OMIM Title
*611103 ACYL-CoA DEHYDROGENASE FAMILY, MEMBER 9; ACAD9
OMIM Description
DESCRIPTION
Mitochondrial fatty acid beta-oxidation is one of the main
energy-producing metabolic pathways in eukaryotes. Acyl-CoA
dehydrogenases (ACADs; EC 1.3.99.13) are mitochondrial enzymes that
catalyze the initial rate-limiting step in the beta-oxidation of fatty
acyl-CoA. ACAD9 belongs to a group of ACADs that act on fatty acids
containing 14 to 20 carbons (Zhang et al., 2002).
CLONING
By large-scale random sequencing of cDNAs obtained from a dendritic cell
cDNA library, Zhang et al. (2002) cloned ACAD9. The deduced 621-amino
acid protein has a calculated molecular mass of 68.8 kD. It has an
N-terminal leader sequence, 2 conserved motifs shared by all ACAD family
members, and a potential N-glycosylation site. Northern blot analysis
detected a 2.6-kb transcript in all tissues examined except peripheral
blood leukocytes.
Ensenauer et al. (2005) demonstrated that epitope-tagged ACAD9 localized
to the mitochondria of transfected human liver cells.
Using in situ hybridization and enzymatic studies, Oey et al. (2006)
showed that ACAD9 is the long-chain acyl-CoA dehydrogenase in human
embryonic and fetal brain and central nervous tissue.
GENE STRUCTURE
Zhang et al. (2002) determined that the ACAD9 gene contains 18 exons.
MAPPING
By genomic sequence analysis, Zhang et al. (2002) mapped the ACAD9 gene
to chromosome 3q26.
GENE FUNCTION
Zhang et al. (2002) demonstrated that human ADAC9, expressed in
transfected COS-7 cells, catalyzed the oxidation of stearoyl-CoA (C18:0)
and palmitoyl-CoA (C16:0), but not n-octanoyl-CoA (C8:0), n-butyryl-CoA
(C4:0), or isovaleryl-CoA (C5:0).
Ensenauer et al. (2005) demonstrated that ACAD9 undergoes 2-step
mitochondrial processing, resulting in the cleavage of the first 37
amino acids from the precursor protein and leaving ala38 as the
N-terminal amino acid of the mature form of the enzyme. Gel filtration
analysis indicated that ACAD9 is a dimer, in contrast to other ACADs,
which are tetramers. Purified recombinant mature ACAD9, expressed in E.
coli, had maximal activity with long-chain unsaturated acyl-CoAs as
substrates, including C16:1-, C18:1-, C18:2-, and C22:6-CoA.
MOLECULAR GENETICS
He et al. (2007) reported 3 cases of ACAD9 deficiency (611126). Defects
in ACAD9 mRNA were identified in the first 2 patients, and all patients
manifested marked defects in ACAD9 protein. Despite a significant
overlap of substrate specificity, it appeared that ACAD9 and very
long-chain acyl-CoA dehydrogenase (ACADVL; 609575) are unable to
compensate for each other in patients with either deficiency. Studies of
the tissue distribution and gene regulation of ACAD9 and ACADVL
identified the presence of 2 independently regulated functional pathways
for long-chain fat metabolism, indicating that these 2 enzymes are
likely to be involved in different physiologic functions. In the first
of the patients with ACAD9 deficiency reported by He et al. (2007), they
demonstrated a 4-bp insertion 44 bp upstream of the first ATG on 1
allele (611103.0001). Only a minimal signal corresponding to this
insertion was visible when fragments amplified from cDNA made from
patient liver mRNA were directly sequenced, suggesting a transcriptional
defect in this allele. Although a minimal amount of ACAD9 antigen was
detected in samples from patient 1, it was thought that it was probably
enzymatically inactive, since none was appropriately targeted to
mitochondria. Instead, residual ACAD9 protein in patient 1 was
predominantly cytoplasmic.
In 4 patients, including 2 sibs, with mitochondrial complex I deficiency
due to ACAD9 deficiency (611126), Haack et al. (2010) identified
compound heterozygosity for mutations in the ACAD9 gene
(611103.0002-611103.0006, respectively).
MIR6826
| dbSNP name | rs6771809(T,C) |
| ccdsGene name | CCDS33851.1 |
| cytoBand name | 3q21.3 |
| EntrezGene GeneID | 22820 |
| EntrezGene Symbol | COPG1 |
| snpEff Gene Name | COPG |
| EntrezGene Description | coatomer protein complex, subunit gamma 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.23 |
| ExAC AF | 0.162 |
COL6A5
| dbSNP name | rs75868828(A,C); rs116372003(C,T); rs1869319(T,C); rs6797052(T,C); rs79858757(T,A); rs74666537(T,C); rs6790871(C,A); rs78325830(C,T); rs6791196(G,T); rs144586727(C,A); rs142542153(G,C); rs139617141(C,T); rs139667023(T,C); rs4688876(C,T); rs73870607(A,G); rs77830466(A,G); rs78449469(G,T); rs150385188(C,A); rs9811896(T,C); rs1453262(T,G); rs76242080(G,A); rs80235967(G,A); rs75007671(G,T); rs75671962(T,C); rs76811948(T,C); rs75108562(G,A); rs12633371(A,G); rs77338654(G,A); rs78457124(C,T); rs77400627(G,T); rs78289031(G,A); rs78910553(G,A); rs77521823(A,T); rs78424115(T,C); rs80139537(C,T); rs79799002(A,G); rs73212702(C,T); rs75337292(A,C); rs79399881(A,C); rs76948045(C,T); rs76809474(A,G); rs9833122(A,T); rs78279408(A,T); rs77956853(G,T); rs28537535(C,T); rs1453263(T,C); rs74281833(G,C); rs12485916(C,T); rs4688878(T,C); rs80288350(A,G); rs9843331(T,C); rs75675043(T,G); rs11925891(A,G); rs1453244(T,A); rs16826828(T,C); rs17737623(G,A); rs1545521(A,T); rs79963650(C,T); rs2219025(T,C); rs77972907(G,A); rs6439228(T,C); rs79208858(G,A); rs2034664(A,T); rs2034663(G,A); rs78097668(T,C); rs55658704(T,C); rs76747696(C,T); rs77660128(C,T); rs186829428(T,A); rs78241424(C,T); rs11914702(A,G); rs76078186(C,T); rs1453243(A,G); rs80153586(G,C); rs9835065(C,T); rs9841662(G,A); rs16826933(A,G); rs16826935(A,G); rs76383732(G,A); rs28488776(G,T); rs16826951(A,G); rs74387849(A,G); rs16845861(G,A); rs2167809(C,T); rs74632921(A,G); rs137859226(A,G); rs1391057(A,G); rs9868060(G,T); rs1391060(T,C); rs77435007(G,A); rs62284290(C,T); rs77065964(A,C); rs1453242(C,T); rs1453241(G,A); rs10212241(T,C); rs10212372(A,G); rs10212618(C,T); rs2123566(A,G); rs4688794(C,T); rs35388315(A,G); rs2403349(G,A); rs1391062(T,C); rs76481399(G,A); rs9878012(A,G); rs9864310(T,G); rs57575291(A,G); rs1391061(A,G); rs77949734(T,C); rs1497320(G,A); rs9817834(A,G); rs924193(G,T); rs11917356(A,G); rs60460040(C,A); rs16827238(C,G); rs115108223(C,A); rs148872921(A,G); rs10934938(T,G); rs9859068(G,C); rs2132826(A,G); rs193284052(G,A); rs2003948(C,A); rs77995367(C,T); rs149928802(A,G); rs79867908(G,A); rs12488457(A,C); rs74695611(C,T); rs9875661(C,T); rs56196458(G,A); rs74553528(A,C); rs2198387(C,T); rs2123567(C,T); rs11711373(T,C); rs1497314(A,C); rs10934939(G,A); rs114408026(A,G); rs6773017(T,C); rs1497313(A,G); rs116398954(G,A); rs10934940(G,A); rs4688761(C,T); rs1497312(G,C); rs1391056(A,C); rs11713675(A,G); rs4494971(G,T); rs12635836(A,G); rs4688796(T,G); rs2403348(C,T); rs1987493(A,C); rs116656604(T,C); rs1812696(C,T); rs113202510(C,A); rs77856467(G,A); rs62284292(C,T); rs78763082(A,G); rs79394681(A,G); rs115199195(A,C); rs77968090(G,A); rs2173187(C,T); rs1497311(G,A); rs11917803(C,A); rs1497310(G,A); rs80258586(G,T); rs35886424(G,C); rs35688409(C,T); rs16827427(C,T); rs6439230(T,C); rs1566139(A,G); rs1566137(G,A); rs74336538(T,G); rs13094766(C,G); rs4688797(C,T); rs13094994(A,G); rs77577667(G,A); rs13100417(A,G); rs111608039(C,T); rs11713398(C,T); rs75935321(C,G); rs11717623(T,A); rs11713542(G,T); rs2219026(A,G); rs1391053(G,C); rs10512767(A,G); rs10512768(G,A); rs185668313(C,T); rs1497309(T,C); rs35694754(C,A); rs16827474(G,A); rs1497308(G,A); rs1497307(T,C); rs1497306(C,T); rs112137948(A,G); rs16827497(T,C); rs7628563(G,A); rs77178989(C,A); rs78022895(G,T); rs6439231(G,A); rs7629023(C,T); rs75681439(G,A); rs6439233(T,C); rs76820193(G,A); rs4688798(A,T); rs1391047(T,C); rs2403344(A,C); rs79207147(T,G); rs76540728(T,G); rs1542829(G,A); rs13062453(G,A); rs6769205(A,G); rs6806491(T,G); rs9813099(A,C); rs12636289(C,T); rs79075848(T,A); rs6785340(C,T); rs976323(C,T); rs976325(A,G); rs2173186(C,G); rs76376162(T,G); rs976558(C,T); rs78292211(C,T); rs976559(G,T); rs16827618(A,G); rs13093230(G,A); rs80115788(G,A); rs13326724(G,C); rs16827628(C,T); rs16827630(A,G); rs75625622(G,C); rs6774465(A,G); rs12330914(C,T); rs61454857(A,G); rs1874599(G,C); rs9859372(G,A); rs4688762(G,A); rs9821748(A,G); rs981548(A,G); rs981549(A,G); rs66743633(G,A); rs7647248(G,C); rs1497303(T,C); rs1497304(T,C); rs12637622(G,C); rs1497305(G,A); rs11926930(G,T); rs6770893(T,C); rs11926934(G,A); rs16827679(A,C); rs11927775(C,G); rs9875499(C,T); rs9879929(C,T); rs16827721(A,G); rs16827728(T,C); rs1391050(C,A); rs61744488(A,C); rs67891747(G,T); rs12486483(C,T); rs6802378(G,A); rs62281866(C,T); rs7648579(G,T); rs1566135(G,A); rs1566136(G,A); rs140926262(T,G); rs78842698(C,A); rs2403343(G,A); rs143680261(G,A); rs9289373(A,G); rs146774760(C,A); rs80080629(C,G); rs75216871(G,T); rs1846029(A,G); rs9857509(A,G); rs2403340(C,T); rs78410669(G,A); rs142408473(T,C); rs7629719(G,T); rs7652023(A,G); rs4688764(C,T); rs1846030(A,G); rs77949652(A,G); rs9840472(G,A); rs1391046(T,A); rs114486684(G,A); rs9883988(A,G); rs34340548(C,T); rs147588439(C,T); rs35742965(C,T); rs4688765(A,G); rs4688766(T,A); rs7628395(C,T); rs7631888(G,A); rs12636109(T,C); rs143841270(C,T); rs1846031(C,T); rs9844861(G,A); rs4353839(A,T); rs6765939(A,G); rs2896543(G,C); rs2173189(C,A); rs76721981(G,A); rs56121417(T,C); rs77628167(G,T); rs188913(G,A); rs186518(A,T); rs2645970(T,G); rs113121144(C,T); rs322123(A,G); rs6800797(G,T); rs75671953(A,G); rs2661941(A,G); rs322121(T,C); rs172815(G,A); rs322120(G,A); rs113979277(A,G); rs322119(A,G); rs34253740(G,A); rs150566852(A,G); rs58996900(G,A); rs864701(A,G); rs819086(G,A); rs819085(G,A); rs819084(G,A); rs819083(G,A); rs819082(T,C); rs819081(A,G); rs819080(G,C); rs2047366(G,A); rs819079(A,C); rs59688446(G,A); rs58399309(C,T); rs819076(G,C); rs12485492(G,C); rs113151073(C,T); rs819077(T,A); rs9682426(A,G); rs75856723(C,T); rs6791107(A,T); rs139421738(G,T); rs113127151(G,A); rs322113(T,C); rs75328271(G,A); rs322114(T,A); rs76464675(G,A); rs201292581(C,T); rs322115(T,A); rs191217(G,A); rs7375010(A,G); rs322116(G,T); rs322117(G,A); rs73868680(G,A); rs322118(G,A); rs924194(A,G); rs2661943(C,T); rs11915195(A,C); rs11923015(G,T); rs112026551(G,A); rs819088(T,A); rs819089(C,T); rs10804599(T,A); rs57032488(A,G); rs12495856(A,C); rs819090(A,G); rs819091(A,G); rs77746940(G,T); rs819092(C,A); rs819093(A,G); rs61583674(C,T); rs819094(C,A); rs819095(A,G); rs78547065(G,A); rs2935463(T,G); rs2935464(A,C); rs2971565(A,G); rs2935465(G,A); rs2935466(T,C); rs2971564(A,G); rs55865558(C,A); rs142592069(C,T); rs143414720(A,G); rs144493585(T,G); rs3112293(A,G); rs16828578(A,C); rs1497322(G,A) |
| cytoBand name | 3q22.1 |
| EntrezGene GeneID | 256076 |
| EntrezGene Description | collagen, type VI, alpha 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL6A5:NM_153264:exon13:c.A4268G:p.E1423G,COL6A5:NM_001278298:exon13:c.A4268G:p.E1423G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.523 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A8TX70-2 |
| dbNSFP KGp1 AF | 0.0123626373626 |
| dbNSFP KGp1 Afr AF | 0.0467479674797 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.040462 |
| ESP All MAF | 0.012484 |
| ESP Eur/Amr MAF | 0.000314 |
| ExAC AF | 0.003761 |
NUDT16
| dbSNP name | rs2874(C,T); rs3749390(C,A); rs13073793(C,T) |
| cytoBand name | 3q22.1 |
| EntrezGene GeneID | 131870 |
| EntrezGene Description | nudix (nucleoside diphosphate linked moiety X)-type motif 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03673 |
NPHP3-ACAD11
| dbSNP name | rs72998114(A,G); rs112272900(A,T); rs6777072(G,A); rs72998120(G,C); rs74543320(T,A); rs111501580(C,T); rs74338180(G,A); rs28607463(A,C); rs377012370(G,A); rs58855069(T,A); rs6799862(G,A); rs111656391(C,T); rs9818117(C,T); rs72998134(G,A); rs6777846(T,C); rs12487584(C,T); rs72998140(T,A); rs79987789(A,G); rs1869862(A,C); rs11927882(G,A); rs72998147(T,C); rs370530045(T,G); rs57506813(G,A); rs10804608(C,G); rs10804610(C,T); rs58614702(G,A); rs74339247(C,T); rs72998157(C,T); rs72998159(G,C); rs55993287(A,G); rs56111069(T,C); rs61070597(A,G); rs113349774(T,G); rs7626429(G,C); rs7626622(G,C); rs57009048(G,C); rs61748105(A,C); rs6779298(C,T); rs7652793(T,C); rs58044355(A,G); rs10935021(A,G); rs139315513(C,A); rs140496418(C,G); rs11920197(T,C); rs61249633(G,C); rs56245927(G,A); rs7629689(A,T); rs56772913(T,C); rs150866170(T,C); rs6776576(C,A); rs57632080(T,C); rs2305627(C,T); rs16839460(C,T); rs61151161(T,A); rs10804611(G,A); rs201632256(T,G); rs12492476(C,T); rs60539887(T,C); rs11918640(A,G); rs11915025(T,C); rs75265262(G,A); rs61364254(C,T); rs144649560(G,A); rs6778812(A,C); rs56881289(T,G); rs10935025(A,T); rs140262698(A,G); rs113942550(A,G); rs821572(C,T); rs9826414(T,C); rs73002026(C,T); rs1079367(T,C); rs73002028(A,T); rs16839475(T,C); rs115837674(G,A); rs6776500(T,C); rs139029285(T,C); rs10935026(C,G); rs58869763(C,T); rs1001122(C,T); rs73220108(C,T); rs13096279(G,A); rs57439039(G,T); rs59426843(T,C); rs2168435(C,T); rs73000577(G,C); rs6792511(T,C); rs73000581(G,T); rs61437184(C,T); rs6786305(C,T); rs6799695(T,C); rs6799696(T,C); rs1378807(C,G); rs1378808(A,G); rs116724502(C,G); rs73000586(G,A); rs73000590(G,A); rs12495862(C,A); rs2305629(T,C); rs12635575(A,T); rs73000594(G,T); rs7340563(G,T); rs16839512(T,C); rs111957675(G,A); rs6774366(C,T); rs11925495(A,G); rs6792074(G,A); rs377494658(G,C); rs57252488(T,A); rs11708051(G,C); rs1812334(G,T); rs201015677(A,G); rs62292470(T,A); rs10804612(A,C); rs10935028(T,C); rs12636390(T,C); rs6772409(G,C); rs6439362(C,T); rs75934653(C,A); rs76055795(A,G); rs75789016(T,C); rs77147476(T,G); rs73002521(G,A); rs79953884(C,T); rs3860501(A,G); rs9842176(C,T); rs112934128(T,A); rs73002527(G,C); rs3901917(G,A); rs56832953(C,T); rs114663747(T,A); rs1382670(T,A); rs149590891(A,G); rs59376040(A,G); rs12636883(C,A); rs7340663(G,A); rs12486323(T,C); rs4123899(C,A); rs1479103(C,T); rs142676203(A,T); rs16839527(T,C); rs114431392(T,C); rs61080008(T,A); rs147932449(A,T); rs67092166(C,T); rs11718115(C,T); rs72628561(A,G); rs74657284(C,T); rs77344670(T,A); rs7652305(G,T); rs112553920(C,G); rs56214742(G,A); rs66564593(A,G); rs79108863(G,C); rs2369832(C,T); rs3860502(C,T); rs3860503(T,C); rs12631786(T,C); rs149236243(A,C) |
| ccdsGene name | CCDS3074.1 |
| cytoBand name | 3q22.1 |
| EntrezGene GeneID | 100532724 |
| snpEff Gene Name | ACAD11 |
| EntrezGene Description | NPHP3-ACAD11 readthrough (NMD candidate) |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | ACAD11:NM_032169:exon6:c.A833C:p.E278A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7016 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 8.132e-06 |
C3orf36
| dbSNP name | rs3811662(C,T) |
| cytoBand name | 3q22.1 |
| EntrezGene GeneID | 80111 |
| snpEff Gene Name | SLCO2A1 |
| EntrezGene Description | chromosome 3 open reading frame 36 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.045 |
SOX14
| dbSNP name | rs201718(G,T); rs12497608(G,C); rs73225431(T,C) |
| cytoBand name | 3q22.3 |
| EntrezGene GeneID | 8403 |
| EntrezGene Description | SRY (sex determining region Y)-box 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.444 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, bilateral, progressive;
Hearing loss begins with loss of high frequencies;
Audiogram shows sloping configuration;
Deafness, profound, by 6th decade
MISCELLANEOUS:
Onset in first or second decades;
Variable rate of progression
MOLECULAR BASIS:
Caused by mutation in the gamma-1 actin gene (ACTG1, 102560.0001)
OMIM Title
*604747 SRY-BOX 14; SOX14
;;SRY-RELATED HMG-BOX GENE 14;;
SOX28
OMIM Description
DESCRIPTION
SRY-related HMG-box (SOX) genes encode a family of DNA-binding proteins
containing a 79-amino acid HMG (high mobility group) domain that shares
at least 50% sequence identity with the DNA-binding HMG box of the SRY
protein (480000). SOX proteins are divided into 6 subgroups based on
sequence similarity within and outside of the HMG domain. For additional
background information on SOX genes, see SOX1 (602148).
CLONING
By PCR of human genomic DNA using highly degenerate oligonucleotides
designed to amplify HMG box-related sequences, Cremazy et al. (1998)
identified several novel SOX proteins, including SOX14, which they
called SOX28. The partial SOX14 sequence encodes a deduced protein with
an HMG box-like domain sharing 57% sequence identity with the SRY HMG
box. Like the HMG box of SRY, the HMG box-like domain of SOX28 contains
a putative nuclear localization signal.
By screening a genomic library using a SRY box-containing probe, Arsic
et al. (1998) isolated the human SOX14 gene, which contains an HMG box
identical to that of the partially characterized mouse Sox14 gene. The
human SOX14 gene encodes a deduced 240-amino acid, proline-rich protein
that contains several phosphorylation sites and a potential
N-glycosylation site. The protein shows high similarity (87 to 92%) to
the HMG-box region of other SOX proteins of the B subfamily, but lacks
any similarity to those proteins outside of the HMG box. Northern blot
analysis revealed expression of an approximately 1.8-kb SOX14 transcript
in the liver-derived HepG2 cell line. With RT-PCR, expression was
detectable in fetal brain, spinal cord, and thymus, with a lower level
of expression in fetal adrenals and adult heart, liver, gut, kidney, and
testes.
Hargrave et al. (2000) also reported the cloning and sequencing of the
human ortholog of mouse and chick Sox14. They found that human SOX14
showed remarkable sequence conservation compared with orthologs from
other vertebrate species and probably mirrored the expression of these
genes in the developing brain and spinal cord.
Wilmore et al. (2000) stated that the SOX14 gene most closely resembles
SOX21 (604974) with respect to nucleotide and amino acid sequence (Malas
et al., 1999). Wilmore et al. (2000) found that the SOX14 amino acid
sequence is highly conserved across human, mouse, and chicken orthologs,
suggesting an important role for this protein in vertebrate development.
SOX14 is expressed in the neural tube and apical ectodermal ridge of the
developing chicken limb. Wilmore et al. (2000) stated that SOX14 is the
only SOX gene known to be expressed in the apical ectodermal ridge, a
structure that directs outgrowth of the embryonic limb bud.
GENE STRUCTURE
Wilmore et al. (2000) stated that both the SOX14 and SOX21 genes appear
to be encoded by a single exon. Arsic et al. (1998) determined that the
SOX14 gene is intronless.
MAPPING
By fluorescence in situ hybridization (FISH), Arsic et al. (1998) mapped
the SOX14 gene to chromosome 3q22-q23. By radiation hybrid analysis,
they mapped the gene 3.46 cR distal to D3S1549 and proximal to D3S1576.
Using radiation hybrid mapping and FISH, Hargrave et al. (2000)
localized the SOX14 gene close to marker D3S1576 on 3q23. By FISH,
Wilmore et al. (2000) mapped the SOX14 gene to 3q and further narrowed
the assignment by screening a panel of YAC clones. They found that the
SOX14 gene is localized to a 1.15-Mb YAC on 3q23, close to loci for
blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES;
110100) and Moebius syndrome (MBS2; 601471).
FOXL2
| dbSNP name | rs76490864(A,T); rs72976936(G,A) |
| cytoBand name | 3q22.3 |
| EntrezGene GeneID | 668 |
| snpEff Gene Name | C3orf72 |
| EntrezGene Description | forkhead box L2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0877 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Progressive high-frequency hearing loss (onset 20-30 years);
Tinnitus;
[Teeth];
Dentinogenesis imperfecta
MISCELLANEOUS:
Allelic with dentinogenesis imperfecta 1 (125490) and dentin dysplasia,
type II (125420)
MOLECULAR BASIS:
Caused by mutation in the dentin sialophosphoprotein gene (DSPP, 125485.0003)
OMIM Title
*605597 FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2
;;PITUITARY FORKHEAD FACTOR, MOUSE, HOMOLOG OF; PFRK
OMIM Description
DESCRIPTION
Transcription factors belonging to the evolutionarily conserved forkhead
box (FOX) superfamily contain a DNA-binding motif known as the forkhead
box or winged-helix domain. The forkhead box domain is about 100 amino
acids long and folds into a structure containing 3 N-terminal alpha
helices, 3 beta strands, and 2 loop regions near the C-terminal end of
the domain. In contrast with the highly conserved forkhead box domain,
FOX proteins are highly divergent in other parts of their sequences. FOX
proteins vary widely in their expression patterns, regulation, and
physiologic functions, with roles in eye organogenesis, language
acquisition, stress response, aging regulation, and tumor suppression.
FOXL2 plays a crucial role in ovarian development and female fertility
(summary by Benayoun et al., 2008).
CLONING
Crisponi et al. (2001) positionally cloned a novel putative winged
helix/forkhead transcription factor gene, FOXL2, in the
blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; 110100)
critical region on chromosome 3q23. Consistent with an involvement in
BPES, FOXL2 was selectively expressed in the mesenchyme of developing
mouse eyelids and in adult ovarian follicles; in adult humans, it
appeared predominantly in the ovary.
Cocquet et al. (2002) found that the FOXL2 coding region is highly
conserved in human, goat, mouse, and pufferfish. They showed that the
number of alanine residues is strictly conserved among the mammals
studied, suggesting the existence of strong functional or structural
constraints. They provided immunohistochemical evidence indicating that
FOXL2 is a nuclear protein specifically expressed in eyelids and in
fetal and adult ovarian follicular cells. It does not undergo any major
posttranslational maturation. They pointed out that FOXL2 is the
earliest known marker of ovarian differentiation in mammals and may play
a role in ovarian somatic cell differentiation and in further follicle
development and/or maintenance.
Udar et al. (2003) sequenced the mouse homolog for the FOXL2 gene and
identified the Fugu rubripes (pufferfish) ortholog by screening the
Joint Genome Institute database (Aparicio et al., 2002) with the mouse
genomic sequence. By alignment of the human, mouse, and pufferfish
sequences, they found an almost complete conservation of the forkhead
domain in the 3 species. There is 95% and 61% conservation at the
protein level between human-mouse and human-pufferfish, respectively.
The polyalanine and polyproline tracts within the gene are absent in
pufferfish.
Beysen et al. (2008) stated that the 376-amino acid FOXL2 protein has a
DNA-binding forkhead domain (FHD) of about 110 amino acids and a
polyalanine tract of 14 residues.
GENE STRUCTURE
Crisponi et al. (2004) determined that mouse and human FOXL2 are
single-exon genes.
MAPPING
By genomic sequence analysis, Crisponi et al. (2001) mapped the FOXL2
gene to chromosome 3q23.
GENE FUNCTION
More than 99% of ovarian germ cells undergo atresia. Lee et al. (2005)
found that overexpression of human FOXL2 caused apoptosis in Chinese
hamster ovary cells and in primed rat granulosa cells in a
dose-dependent manner. Apoptosis was prevented by cotransfection of a
baculoviral caspase inhibitor. Yeast 2-hybrid analysis revealed that
FOXL2 interacted with the C-terminal domain of mouse Dp103 (DDX20;
606168), an ATP-dependent RNA helicase. The region of Dp103 that
interacted with FOXL2 lacks the helicase domain, but it also interacts
with SF1 (NR5A1; 184757), a nuclear factor involved in sex
determination. Dp103 had no effect on cell viability alone, but
cotransfection studies showed that Dp103 enhanced the apoptotic effect
of FOXL2.
By PCR selection using a library of double-stranded DNA fragments and
nuclear extracts of a mouse granulosa cell line, Benayoun et al. (2008)
identified a Foxl2 response element (FLRE) that differed significantly
from other FOX protein-binding sites. The common 7-bp FLRE was
5-prime-GT(C/G)AAGG-3-prime, or its reverse complement. By transfecting
mouse and human granulosa-like cells with artificial promoter reporters,
Benayoun et al. (2008) found that 4 tandem copies of FLRE resulted in
higher reporter activity than 2, and that replacement of Gs with Ts in
the FLRE core sequence resulted in an FLRE with lower FOXL2 affinity and
weaker reporter activity. In addition, poly(A) expansion of FOXL2,
notably expansion to 24 alanines (FOXL2-ala24), resulted in lower
reporter activity when the reporter had fewer FLREs or when the FLRE had
lower FOXL2 affinity. FOXL2-ala24 functioned in a dominant-negative
fashion when coexpressed with wildtype FOXL2, but only with a reporter
of low FOXL2 affinity. Benayoun et al. (2008) concluded that the impact
of poly(A) expansion on expression of FOXL2-dependent genes depends on
both the number and specific sequences of FLREs in FOXL2-responsive
promoters.
Benayoun et al. (2009) showed that cell stress upregulated FOXL2
expression in an ovarian granulosa cell model. The response of FOXL2 to
stress correlated with a dramatic remodeling of its posttranslational
modification profile. Upon oxidative stress, there was increased
recruitment of FOXL2 to several stress-response promoters, notably
mitochondrial manganese superoxide dismutase, MnSOD (SOD2; 147460).
FOXL2 activity was repressed by the SIRT1 (604479) deacetylase. SIRT1
transcription was, in turn, directly upregulated by FOXL2, which closed
a negative-feedback loop. Treatment with the sirtuin inhibitor
nicotinamide increased FOXL2 transcription. Eleven disease-causing
mutations in the ORF of FOXL2 induced aberrant regulation of FOXL2
and/or the FOXL2 stress-response target gene MnSOD. Benayoun et al.
(2009) concluded that FOXL2 is an actor of the stress response.
MOLECULAR GENETICS
- Blepharophimosis, Ptosis, and Epicanthus Inversus, Types
I and II
There are 2 forms of the blepharophimosis/ptosis/epicanthus inversus
syndrome (BPES; 110100). In type I, eyelid abnormalities are associated
with ovarian failure. In type II, only the eyelid defects are found.
Crisponi et al. (2001) identified mutations in the FOXL2 gene that
produced truncated proteins in type I families and larger proteins in
type II families. Because of the variable phenotypes produced by
mutations in forkhead transcription factor genes, Crisponi et al. (2001)
proposed that some mutations in the FOXL2 gene may be associated with
other phenotypes, including nonsyndromic premature ovarian failure (POF;
see 608996). FOXL2 was the third forkhead gene found to be involved in
the pathogenesis of inherited developmental human disorders. A
single-exon gene, FOXE1 (602617), is mutated in cases of thyroid
agenesis, and FOXC1 (601090) is mutated in eye defects associated with
congenital glaucoma.
In a study in Korean patients, Cha et al. (2003) identified FOXL2
mutations in 5 of 9 BPES families and 3 of 7 sporadic cases. No causal
mutation was found in the other BPES families or sporadic cases,
suggesting that the genetic defect in some BPES patients may reside in
the noncoding region of the FOXL2 gene or in other genes.
Vincent et al. (2005) reported an 18-month-old girl with sporadic BPES
and bilateral type 1 Duane syndrome (see 126800), in whom they
identified a heterozygous duplication of 10 alanine residues in the
FOXL2 gene (605597.0002).
In an Indian cohort comprising 6 familial and 2 sporadic cases of BPES
type I or type II, Kaur et al. (2011) identified 6 heterozygous
mutations in the FOXL2 gene, 3 of which were novel (see, e.g.,
605597.0020). In 1 family, an affected female also had polycystic
ovarian disease. Kaur et al. (2011) noted that mutations in the region
downstream of the forkhead domain were predominantly responsible for
BPES among Indian patients.
- Premature Ovarian Failure
Harris et al. (2002) detected heterozygous FOXL2 mutations in 2 patients
with isolated POF (608996). One mutation removed 10 of the 14 alanines
in the polyalanine tract downstream of the winged helix/forkhead domain
(605597.0016). The other was a single-nucleotide substitution predicted
to result in a tyr258-to-asn amino acid change (605597.0017).
In a 26-year-old Tunisian patient with nonsyndromic premature ovarian
failure, Laissue et al. (2009) identified a heterozygous mutation in the
FOXL2 gene (G187D; 605597.0019). Although the transactivation capacity
of FOXL2-G187D was significantly lower than that of wildtype FOXL2, the
mutant was able to strongly activate a reporter construct driven by the
OSR2 (611297) promoter, believed to be a crucial target of FOXL2 in the
craniofacial region. Laissue et al. (2009) noted that this is compatible
with the absence of BPES in this patient.
- Ovarian Granulosa-Cell Tumors
Shah et al. (2009) analyzed 4 adult-type ovarian granulosa-cell tumor
(GCT) specimens for GCT-specific mutations and identified a somatic
point mutation, 402C-G (C134W), in the FOXL2 gene in all 4 specimens.
The C134W mutation was present in 86 (97%) of 89 additional adult-type
GCTs, in 3 (21%) of 14 thecomas, and in 1 (10%) of 10 juvenile-type
GCTs. The mutation was absent in 49 sex cord/stromal tumors of other
types and in 329 unrelated ovarian or breast tumors. Shah et al. (2009)
concluded that mutant FOXL2 is a potential driver in the pathogenesis of
adult-type GCTs.
- FOXL2 Mutation Database
Beysen et al. (2004) described a locus-specific human FOXL2 mutation
database available on the Internet. The database contained approximately
135 intragenic mutations and variants of FOXL2, but did not include
variants residing outside the coding region of FOXL2 or molecular
cytogenetic rearrangements of the FOXL2 locus. Beysen et al. (2004)
stated that at least 1 mutation in the FOXL2 gene with a putative
pathogenic effect had been found in patients affected with isolated
primary ovarian failure (Harris et al., 2002).
- Pathogenic Effects of FOXL2 Mutations
Moumne et al. (2005) showed that premature stop codons in the FOXL2 gene
(e.g., 605597.0008) may lead to the production of N-terminally truncated
proteins by reinitiation of translation downstream of the stop codon.
Truncated proteins strongly aggregated in the nucleus, partially
localized in the cytoplasm, and retained a fraction of the wildtype
protein. A complete deletion of the polyalanine tract of FOXL2 induced
significant intranuclear aggregation.
Moumne et al. (2008) noted that polyalanine expansions of +10 residues
(i.e., 24 alanines) in FOXL2 have been identified in approximately 30%
of BPES patients and are mainly responsible for BPES type II. By
transfecting COS-7 and KGN cells with a series of FOXL2 polyalanine
variants, Moumne et al. (2008) found that the wildtype allele with 14
alanines was expressed exclusively in the nucleus. Cytoplasmic staining
became statistically significant for FOXL2 containing 19 alanines, and
it reached 100% for 37 alanines. FOXL2 proteins with 24 alanines or more
showed aggregation in both nuclear and cytoplasmic compartments. FRAP
analysis showed that wildtype FOXL2 was highly mobile within the nuclear
compartment, while FOXL2 with 17 alanines showed reduced mobility, and
FOXL2 with 19 alanines was virtually immobile. Reporter gene assays
using the promoter regions of several FOXL2 target genes showed that
alanine expansion had variable effects on promoter activity. Moumne et
al. (2008) suggested that promoters with more FOXL2-binding sites or
higher FOXL2 affinity would be less sensitive than other promoters to
reduced FOXL2 availability due to protein aggregation or
mislocalization.
By expression in COS-7 and KGN cells, Beysen et al. (2008) examined the
consequences of 16 missense mutations within the DNA-binding FHD of
FOXL2 and another mutation outside the FHD. The mutations had variable
effects on subcellular localization, aggregation, and transactivation of
a reporter gene.
Dipietromaria et al. (2009) dissected the molecular and functional
effects of 10 FOXL2 mutants, known to induce BPES with or without
premature ovarian failure (POF). There was a correlation between the
transcriptional activity of FOXL2 variants on 2 different reporter
promoter assays (4XFLRE-luc and SIRT1-luc) and the type of BPES.
Application of this functional framework to 18 BPES missense mutations
allowed classification as type I or II mutation based on transactivation
abilities. They also found a loose correlation between intranuclear
aggregation and cytoplasmic mislocalization of mutant FOXL2 and the type
of BPES. Dipietromaria et al. (2009) suggested that a FOXL2 mutant
completely lacking activity on the 2 reporter assays used in this study
is likely to lead to BPES with POF.
GENOTYPE/PHENOTYPE CORRELATIONS
De Baere et al. (2001) identified FOXL2 mutations in 21 of 34 patients
with BPES types I and II. A genotype-phenotype correlation was evident,
wherein mutations predicted to result in a truncated protein either
lacking or containing the forkhead domain led to BPES type I. In
contrast, duplications within or downstream of the forkhead domain and a
frameshift downstream of them, all predicted to result in an extended
protein, caused BPES type II. In 30 unrelated patients with isolated
premature ovarian failure, no causal mutations were identified in FOXL2.
The initial association of BPES type I and mutations in the FOXL2 gene
raised the question of whether mutations in FOXL2 could lead to isolated
POF (Prueitt and Zinn, 2001).
De Baere et al. (2003) described 21 FOXL2 mutations, 16 of which were
novel, and stated that 53 mutations in the FOXL2 had been reported. Two
mutation hotspots were identified: 30% of FOXL2 mutations led to
polyalanine expansions, and 13% were novel out-of-frame duplications.
They demonstrated intra- and interfamilial phenotypic variability, with
both BPES types caused by the same mutation (see 605597.0006 and
605597.0009). They found exceptions to their previously constructed
genotype-phenotype correlation, which required revision. They assumed
that for predicted proteins with a truncation before the polyalanine
tract, the risk for development of POF was high. For mutations leading
to a truncated or extended protein containing an intact forkhead and
polyalanine tract, no predictions were possible, because some of these
mutations led to both types of BPES, even within the same family.
Polyalanine expansions may lead to BPES type II (see 605597.0010). For
missense mutations, no correlations could be made. Microdeletions were
associated with mental retardation.
CYTOGENETICS
Boccone et al. (1994) described a de novo, apparently balanced,
reciprocal translocation between the long arms of chromosomes 3 and 7 in
a 2-year-old male with BPES; the breakpoints were 3q23 and 7q32.
Crisponi et al. (2004) found that the chromosome 3 breakpoint in this
patient was located about 170 kb upstream of the FOXL2 gene, within exon
6 of the MRPS22 gene (605810), which is transcribed in the opposite
orientation. They identified regions within introns 6, 11, and 12 of the
MRPS22 gene that may regulate FOXL2 expression, including a winged-helix
transcription factor-binding site in intron 11. Crisponi et al. (2004)
reviewed other examples of distant defects that alter gene function,
including a translocation 120 kb from the FOXC2 (602402) gene that
causes lymphedema-distichiasis syndrome (153400) and a translocation
more than 150 kb from the PAX6 gene (607108) that causes aniridia
(106210). They suggested several models for long-range regulation of
FOXL2 gene expression, including higher order genome structures that
bring distant regulatory sequences within proximity of gene
transcription start sites.
In 2 sporadic patients and 2 families with BPES, Beysen et al. (2005)
identified 4 overlapping extragenic microdeletions, ranging from 126 kb
to 1.9 Mb in size, 230 kb upstream of the FOXL2 gene. The shortest
region of deletion overlap contains several conserved nongenic sequences
harboring putative transcription factor-binding sites and representing
potential long-range cis-regulatory elements. In another family with
BPES, Beysen et al. (2005) identified an approximately 188-kb
microdeletion downstream of the FOXL2 gene. The father of the 2 affected
half-sisters was unaffected, suggestive of germinal mosaicism;
quantitative analysis using 3 SNPs located in the deletion showed that
about 10% of paternal germ cells and 5% of somatic peripheral blood
lymphocytes carried the mutation.
ANIMAL MODEL
Crisponi et al. (2001) pointed out that polled/intersex syndrome (PIS)
in the goat has been suggested to be an animal model of human BPES
(Vaiman et al., 1999). It maps to 1q31 in the goat, a region homologous
to human 3q23. Thus, the authors hypothesized that the goat FOXL2 gene
may be the site of the mutation causing PIS.
Pailhoux et al. (2001) found by a positional cloning approach that the
mutation underlying PIS in the goat is the deletion of a critical
11.7-kb DNA element containing mainly repetitive sequences. This
deletion was shown to affect the transcription of at least 2 genes:
PISRT1, encoding a 1.5-kb mRNA devoid of open reading frame, and FOXL2.
These 2 genes are located 20 and 200 kb telomeric from the deletion,
respectively.
Uda et al. (2004) reported that mice lacking Foxl2 recapitulated
relevant features of human BPES: males and females were small and showed
distinctive craniofacial morphology with absent upper eyelids.
Furthermore, in mice as in humans, sterility was confined to females:
all major somatic cell lineages failed to develop around growing oocytes
from the time of primordial follicle formation.
Ottolenghi et al. (2005) found that mouse XX gonads lacking Foxl2 formed
meiotic prophase oocytes, but then activated the genetic program for
somatic testis determination. Pivotal Foxl2 action repressed the male
gene pathway at several stages of female gonadal differentiation. The
authors proposed a continued involvement of sex-determining genes in
maintaining ovarian function throughout female reproductive life.
Ottolenghi et al. (2007) observed formation of testis-like tubules and
spermatogonia in the ovaries of Wnt4/Foxl2 double-knockout XX mice,
demonstrating that female sex-determining genes, the putative 'ovary
organizer,' are required to suppress an alternative male fate in the
ovary and act as a female equivalent of SRY (480000). Forced expression
of Foxl2 impaired testis tubule differentiation in XY transgenic mice,
and germ cell-depleted XX mice lacking Foxl2 and harboring a Kit
(164920) mutation underwent partial female-to-male sex reversal.
Ottolenghi et al. (2007) stated that the results were all consistent
with an anti-testis role for FOXL2.
Uhlenhaut et al. (2009) found that Foxl2 was required to prevent
transdifferentiation of an adult mouse ovary to a testis. Foxl2
repressed testis differentiation in vivo mainly through repression of
the Sox9 (608160) cis-regulatory sequence TESCO. Foxl2 and estrogen
receptor (ESR1; 133430) cooperated in Sox9 repression in vivo, thus
providing a mechanism by which loss of estrogen signaling could lead to
gonadal sex reversal.
Using piggyBac (PB) insertional mutagenesis, Shi et al. (2014) created a
line of mice with a modest yet significant reduction in Foxl2 expression
and a BPES-like phenotype. Homozygous PB/PB mice began to lose weight
approximately 2 weeks after birth, and most died within the first month
of life. At 3 weeks of age, they showed significant overgrowth of
mandibular incisors with malocclusion, and some showed palpebral
anomalies and periocular hair loss. Surviving female PB/PB mice were
subfertile, with smaller than normal ovaries and uteri. Shi et al.
(2014) mapped the PB insertion site to a region approximately 160 kb
upstream of the Foxl2 transcription start site and approximately 10 kb
upstream of an element, ECF1, that showed a high degree of conservation
among goat, mouse, and human. ECF1 functioned as an enhancer in reporter
gene assays and interacted directly with the Foxl2 promoter in
chromosome conformation capture assays. Shi et al. (2014) noted that
BPES patients with balanced translocations and chromosome breakpoints
130, 160, or 171 kb upstream of FOXL2 have been reported. The authors
hypothesized that these translocations may isolate transcription
regulatory elements, including the human ECF1 ortholog, leading to FOXL2
misregulation.
NOMENCLATURE
See Kaestner et al. (2000) for a unified nomenclature for winged
helix/forkhead transcription factors.
PRR23A
| dbSNP name | rs1553877(C,G) |
| cytoBand name | 3q23 |
| EntrezGene GeneID | 729627 |
| snpEff Gene Name | MRPS22 |
| EntrezGene Description | proline rich 23A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1042 |
PRR23C
| dbSNP name | rs60709982(T,C); rs74940990(C,T); rs77314243(A,T); rs57750225(C,T); rs113775738(C,T); rs60944880(A,G); rs12637621(C,G); rs12632179(A,G); rs7636403(C,G) |
| cytoBand name | 3q23 |
| EntrezGene GeneID | 389152 |
| snpEff Gene Name | MRPS22 |
| EntrezGene Description | proline rich 23C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1538 |
CHST2
| dbSNP name | rs75421180(G,C); rs6664(C,T); rs4149495(T,A); rs4149496(G,C); rs2292509(T,C) |
| cytoBand name | 3q24 |
| EntrezGene GeneID | 9435 |
| EntrezGene Description | carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01745 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Brachycephaly;
Cranium bifidum, anterior;
[Eyes];
Hypertelorism;
Telecanthus;
Myopia (in some patients);
Ptosis (in some patients);
Corneal dermoid cyst (rare);
Glaucoma (rare);
Optic nerve hypoplasia, segmental (rare);
Persistent primary vitreous (rare);
[Nose];
Bifid nose;
Nostril notching;
Broad nasal tip;
Separation of nostrils;
[Mouth];
Carp-shaped mouth (in some patients);
Cleft lip;
Cleft palate
RESPIRATORY:
[Airways];
Upper airway obstruction, severe (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism (in some patients)
SKELETAL:
[Skull];
Persistent craniopharyngeal canal (rare);
Vertical clivus (in some patients);
[Limbs];
Patellar hypoplasia or aplasia (in some patients);
Tibial hypoplasia;
[Hands];
Preaxial polydactyly;
Preaxial polysyndactyly;
[Feet];
Preaxial polydactyly;
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Vertical creases of plantar surface between first and second toes;
[Nails];
Clubbed, thickened nails of halluces (1 patient)
NEUROLOGIC:
[Central nervous system];
Encephalocele;
Agenesis of corpus callosum;
Hypoplasia of corpus callosum;
Ventricular dilatation;
Mental retardation;
Periventricular nodular heterotopia;
Choroid plexus cyst;
Septum pellucidum deficient or cavum;
Calcification of the falx;
Interhemispheric lipoma;
Absent olfactory bulbs;
Enlarged sella turcica;
Absence of anterior pituitary;
Fenestrated basilar artery;
Persistent falcine venous sinus;
Retrocerebellar cyst;
Seizures
ENDOCRINE FEATURES:
Hypopituitarism (in some patients)
MISCELLANEOUS:
Brain anomalies variable;
Four unrelated patients with ZSWIM6 mutations have been described
(last curated September 2014)
MOLECULAR BASIS:
Caused by mutation in the zinc finger SWIM domain-containing protein
6 (ZSWIM6, 615951.0001)
OMIM Title
*603798 CARBOHYDRATE SULFOTRANSFERASE 2; CHST2
;;N-ACETYLGLUCOSAMINE-6-O-SULFOTRANSFERASE 1;;
GlcNAc-6-O-SULFOTRANSFERASE;;
GlcNAc6ST1;;
GST2
OMIM Description
DESCRIPTION
N-acetylglucosamine-6-O-sulfotransferases, such as CHST2, catalyze the
transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate
(PAPS) to position 6 of a nonreducing N-acetylglucosamine (GlcNAc)
residue (Uchimura et al., 1998).
CLONING
Chicken chondroitin 6-sulfotransferase (C6ST; see 603799) is a Golgi
membrane-bound sulfotransferase. To identify sulfotransferases expressed
in human umbilical vascular endothelial cells (HUVECs), Li and Tedder
(1999) identified human ESTs homologous to chicken C6ST and used them to
screen HUVEC libraries. They isolated cDNAs encoding CHST1 (603797) and
a novel protein, CHST2. The predicted 530-amino acid CHST2 protein
contains a hydrophobic region in the N terminus that may function as a
transmembrane domain for a type II protein or as a Golgi retention
signal.
Uchimura et al. (1998) cloned a mouse cDNA encoding
GlcNAc-6-O-sulfotransferase. Uchimura et al. (1998) identified CHST2 as
the human homolog of the mouse GlcNAc-6-O-sulfotransferase gene. These
authors reported that GlcNAc-6-O-sulfotransferase cDNAs could be
translated to yield a deduced 484-amino acid protein as well as a longer
isoform. Northern blot analysis detected expression of the major 3.6-kb
GlcNAc-6-O-sulfotransferase mRNA in all tissues tested. A minor
additional 5.6-kb transcript was observed in some organs. However, using
the same technique, Li and Tedder (1999) found CHST2 expression as a
major 2.8- and a minor 1.8-kb mRNA in several human tissues, with the
highest expression in brain. A low-abundance 7-kb transcript was
observed in some tissues.
GENE FUNCTION
Uchimura et al. (1998) found that, when expressed in mammalian cells,
the human GlcNAc-6-O-sulfotransferase protein exhibited
GlcNAc-6-O-sulfotransferase activity and was involved in biosynthesis of
6-sulfosialyl Lewis X antigen (see 111100).
MAPPING
Based on sequence similarity to an STS (GenBank GENBANK G14605), Li and
Tedder (1999) tentatively mapped the CHST2 gene to chromosome 3q24.
However, by fluorescence in situ hybridization, Uchimura et al. (1998)
mapped the CHST2 gene to chromosome 7q31.
ANIMAL MODEL
Uchimura et al. (2005) found that double-knockout mice lacking both
Chst2 and Chst4 exhibited elimination of both peripheral lymph node
addressin (PNAd) and sialyl 6-sulfo Lewis X in high endothelial venules
(HEVs), along with reduced lymphocyte homing to peripheral lymph nodes
and reduced sticking of lymphocytes along HEVs. Uchimura et al. (2005)
concluded that CHST2 and CHST4 are critical to formation of PNAd and
sialyl 6-sulfo Lewis X.
LOC646903
| dbSNP name | rs61616747(C,G) |
| cytoBand name | 3q25.1 |
| EntrezGene GeneID | 646903 |
| snpEff Gene Name | PFN2 |
| EntrezGene Description | uncharacterized LOC646903 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3848 |
P2RY13
| dbSNP name | rs6440735(T,C); rs12497019(C,T); rs1388628(C,G); rs1388627(A,G); rs11712291(A,G); rs1491980(G,C); rs200506425(G,C); rs1466684(G,A); rs3732757(G,T) |
| ccdsGene name | CCDS33876.1 |
| cytoBand name | 3q25.1 |
| EntrezGene GeneID | 116931 |
| EntrezGene Symbol | MED12L |
| snpEff Gene Name | MED12L |
| EntrezGene Description | mediator complex subunit 12-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1924 |
IGSF10
| dbSNP name | rs16863388(T,C); rs2172250(T,C); rs114975613(A,G); rs16863390(A,C); rs41401648(G,A); rs6781302(G,A); rs9864533(A,C); rs78115932(C,T); rs12635091(T,C); rs937127(G,A); rs9874403(A,G); rs9836790(C,A); rs116007625(A,G); rs151294883(G,T); rs937126(A,T); rs937125(G,A); rs16863393(A,G); rs9866874(T,C); rs6792496(G,A); rs138216107(T,C); rs9867982(T,C); rs9810389(A,G); rs148243882(A,G); rs62284460(T,C); rs4435614(T,A); rs12487205(A,G); rs9863400(C,T); rs9825817(A,C); rs9871952(T,C); rs6798252(C,T); rs4680440(C,T); rs9824609(A,G); rs6769246(T,C); rs4679830(A,G); rs4680442(T,C); rs4680443(A,G); rs13088575(G,A); rs9873499(G,A); rs9877298(C,T); rs9289838(T,C); rs7610769(C,T); rs7619322(A,C); rs7621591(A,G); rs9812989(C,T); rs2172248(G,T); rs138267408(G,A); rs12496967(G,T); rs9843590(A,T); rs142214363(A,G) |
| ccdsGene name | CCDS3160.1 |
| cytoBand name | 3q25.1 |
| EntrezGene GeneID | 285313 |
| EntrezGene Description | immunoglobulin superfamily, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IGSF10:NM_001178145:exon2:c.T1649C:p.I550T,IGSF10:NM_001178146:exon2:c.T1505C:p.I502T,IGSF10:NM_178822:exon6:c.T7568C:p.I2523T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5535 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6WRI0 |
| dbNSFP Uniprot ID | IGS10_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.014753 |
| ESP All MAF | 0.004998 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001171 |
MBNL1-AS1
| dbSNP name | rs113269927(T,C); rs2288295(C,T); rs383278(C,T); rs391173(T,C); rs58013705(C,T); rs842049(C,T); rs76601968(C,G) |
| cytoBand name | 3q25.1 |
| EntrezGene GeneID | 401093 |
| snpEff Gene Name | MBNL1 |
| EntrezGene Description | MBNL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009183 |
P2RY1
| dbSNP name | rs701265(A,G); rs7643597(T,C) |
| ccdsGene name | CCDS3169.1 |
| cytoBand name | 3q25.2 |
| EntrezGene GeneID | 5028 |
| EntrezGene Description | purinergic receptor P2Y, G-protein coupled, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | P2RY1:NM_002563:exon1:c.A786G:p.V262V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3375 |
| ESP Afr MAF | 0.322969 |
| ESP All MAF | 0.32708 |
| ESP Eur/Amr MAF | 0.147791 |
| ExAC AF | 0.215 |
OMIM Clinical Significance
Cardiac:
Lethal complex congenital heart defect
Facies:
Flat facial profile
Mouth:
Bilateral cleft lip/palate;
Macrosomia;
Tongue anomaly
Eyes:
Hypertelorism
Head:
Flat occiput
GI:
Malrotation of the intestine;
Visceromegaly
Growth:
Large for gestational age
Limbs:
Bifid thumbs;
Minor hand anomalies;
Short broad hands
Lab:
Normal chromosomes;
Hypertrophic pancreatic islets
Inheritance:
Autosomal recessive
OMIM Title
*601167 PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 1; P2RY1
;;PURINOCEPTOR P2Y1; P2Y1
OMIM Description
CLONING
P2 purinoceptors have been broadly classified as P2X receptors (e.g.,
600843), which are ATP-gated channels; P2Z receptors, which mediate
nonselective pores in mast cells; and P2Y receptors, a family of G
protein-coupled receptors. Based on the recommendation for nomenclature
of P2 purinoceptors, the P2Y purinoceptors were numbered in the order of
cloning. Ayyanathan et al. (1996) noted that P2Y1, P2Y2 (PR2Y2; 600041),
and P2Y3 have been cloned from a variety of species. P2Y1 responds to
both ADP and ATP. The P2Y2 receptor cDNA was cloned in the human and
this receptor was known as P2U under previous nomenclature. Ayyanathan
et al. (1996) cloned the human P2Y1 receptor (P2RY1) and its 2
alternately polyadenylated forms of mRNA. The P2Y1 purinoceptor was also
cloned from a human placenta cDNA library by Leon et al. (1996). They
found that the gene encodes a 372-amino acid polypeptide. Northern blot
analysis revealed 2 transcripts of 4.6 and 7.5 kb which were expressed
in many tissues.
GENE FUNCTION
Leon et al. (1997) expressed the cloned P2Y1 gene in Jurkat T
lymphocytes, a cell line that is not naturally responsive to
nucleotides. They treated the transfected cells with ATP and measured
Ca(2+) fluxes and responses to agonists. The pharmacologic properties of
the P2Y1 receptor are similar to those of the P2T ADP receptor that is
responsible for platelet aggregation. They showed that the P2Y1 receptor
is expressed by human platelets and megakaryoblasts. The authors
suggested that the P2Y1 receptor may be the P2T receptor.
Adrian et al. (2000) analyzed the expression of several purinergic
receptors during differentiation in a promyelocytic leukemia cell line.
Granulocytic differentiation was induced by dimethylsulfoxide, and a
monocytic/macrophage phenotype was induced by phorbol esters. No change
from the moderate basal expression of P2Y1 was detected during
granulocytic differentiation. During monocytic differentiation,
expression was transiently upregulated about 3-fold and returned to
preinduction levels after 36 hours.
Mutafova-Yambolieva et al. (2007) identified P2ry1 as a receptor for
beta-nicotinamide adenine dinucleotide (beta-NAD) by measuring
receptor-mediated responses in HEK293 cells transfected with guinea pig
P2ry1. They found that beta-NAD behaved as an inhibitory
neurotransmitter in mouse colonic muscle. Beta-NAD was released by
stimulation of enteric nerves of mouse gastrointestinal muscles, and
release of beta-NAD depended on the frequency of nerve stimulation.
Responses to beta-NAD and inhibitory junction potentials were blocked by
a P2Y1-selective antagonist and by nonselective P2 receptor antagonists
in mouse colonic muscles.
Masse et al. (2007) determined that ectonucleoside triphosphate
diphosphohydrolase-2 (ENTPD2; 602012), an ectoenzyme that converts ATP
to ADP, acts upstream of the eye field transcription factors Pax6
(607108), Rx1, and Six3 (603714). To test whether ADP, the product of
ENTPD2, might act to trigger eye development through P2Y1 receptors,
selective in Xenopus for ADP, Masse et al. (2007) simultaneously knocked
down expression of the genes encoding ENTPD2 and the P2Y1 receptor. This
prevented the expression of Rx1 and Pax6 and eye formation completely.
GENE STRUCTURE
Ayyanathan et al. (1996) amplified the genomic region encoding the P2RY1
receptor and found that the gene contains no introns.
MAPPING
Using oligonucleotide primers specific for the human P2Y1 purinergic
receptor, Ayyanathan et al. (1996) amplified a region from genomic DNA
from a panel of mouse/human somatic cell hybrid cell lines and localized
the P2Y1 gene to human chromosome 3.
By sequence tagged site (STS) mapping utilizing the National Center for
Biotechnology Information (NCBI) database, Somers et al. (1997) mapped
the P2RY1 gene between flanking markers D3S1279 and D3S1280 at a
position 173 to 174 cM from the most telomeric markers on the short arm
of chromosome 3.
Ayyanathan et al. (1996) localized the P2RY1 gene to chromosome 3q25 by
PCR of a subchromosomal hybrid panel.
ANIMAL MODEL
Leon et al. (1999) generated P2Y1-null mice to define the physiologic
role of the P2Y1 receptor. These mice were viable with no apparent
abnormalities affecting their development, survival, reproduction, or
morphology of platelets, and the platelet count in these animals was
identical to that of wildtype mice. However, platelets from
P2Y1-deficient mice were unable to aggregate in response to usual
concentrations of ADP and displayed impaired aggregation to other
agonists, while high concentrations of ADP induced platelet aggregation
without shape change. In addition, ADP-induced inhibition of adenylyl
cyclase still occurred, demonstrating the existence of an ADP receptor
distinct from P2Y1. P2Y1-null mice had no spontaneous bleeding tendency
but were resistant to thromboembolism induced by intravenous injection
of ADP or collagen and adrenaline. Hence, the P2Y1 receptor plays an
essential role in thrombotic states and represents a potential target
for antithrombotic drugs.
RAP2B
| dbSNP name | rs114197684(A,G); rs61252895(A,G); rs6785014(A,T); rs6809490(G,A); rs3821547(A,G); rs74349115(A,G); rs73872933(G,A) |
| cytoBand name | 3q25.2 |
| EntrezGene GeneID | 5912 |
| EntrezGene Description | RAP2B, member of RAS oncogene family |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03076 |
OMIM Clinical Significance
Skin:
Bilateral, symmetrical, sharply localized raindrop-shaped hypopigmentation
of upper chest
Inheritance:
Autosomal dominant
OMIM Title
*179541 RAS-RELATED PROTEIN 2B; RAP2B
OMIM Description
CLONING
Ohmstede et al. (1990) screened a platelet cDNA library with monoclonal
antibody that recognizes a highly conserved epitope of Ras p21 (see
190020) involved in GTP binding. They identified a protein that is
structurally and functionally similar to but distinct from RAP1A
(179520), RAP1B (179530), and RAP2A (179540). RAP2B has a characteristic
Ras-type C-terminal motif for polyisoprenylation, and 2 C-terminal
cysteines suggesting that it may also be palmitoylated. Recombinant
RAP2B had an apparent molecular mass of 22 kD. The deduced RAP2B protein
contains 183 amino acids (Farrell et al., 1990). By RT-PCR, Greco et al.
(2006) detected RAP2B in purified human reticulocytes. Western blot
analysis of fractionated cells revealed the association of RAP2B with
cell membranes.
GENE FUNCTION
Ohmstede et al. (1990) demonstrated that recombinant RAP2B bound GTP. By
cell fractionated and Western blot analysis, Torti et al. (1993) found
that RAB2B was detergent soluble in resting platelets, but a significant
amount of RAP2B was associated with the cytoskeleton in platelets
aggregated with thrombin (176930), a thromboxane analog, or a
Ca(2+)-ATPase inhibitor. Translocation of RAP2B to the cytoskeleton was
strictly dependent on platelet aggregation. Inhibition of fibrinogen
(see FGA, 134820) binding to the glycoprotein IIb (607759)-IIIa (173470)
complex completely prevented the interaction of RAP2B with the
cytoskeleton.
Greco et al. (2006) found that membrane-associated RAP2B was activated
upon treatment of normal human reticulocytes with calcium and a calcium
ionophore. RAP2B was enriched in microvesicles released by
calcium-activated reticulocytes, suggesting a role for RAP2B in membrane
shedding.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RAP2B
gene to chromosome 3 (TMAP SHGC-77468).
TIPARP-AS1
| dbSNP name | rs1510269(T,C); rs1510270(G,A); rs66538320(G,A); rs6441095(T,C) |
| cytoBand name | 3q25.31 |
| EntrezGene GeneID | 100287227 |
| snpEff Gene Name | TIPARP |
| EntrezGene Description | TIPARP antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03076 |
C3orf80
| dbSNP name | rs146766340(G,A); rs139400428(G,A); rs4680571(A,T); rs6800035(A,G); rs62272163(A,C); rs61416438(G,C) |
| cytoBand name | 3q25.33 |
| EntrezGene GeneID | 401097 |
| snpEff Gene Name | AC112641.1 |
| EntrezGene Description | chromosome 3 open reading frame 80 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006428 |
ARL14
| dbSNP name | rs1879797(A,G); rs35633732(C,A); rs74781289(G,A) |
| cytoBand name | 3q25.33 |
| EntrezGene GeneID | 80117 |
| EntrezGene Description | ADP-ribosylation factor-like 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3797 |
| ESP Afr MAF | 0.344247 |
| ESP All MAF | 0.432712 |
| ESP Eur/Amr MAF | 0.31833 |
| ExAC AF | 0.312,7.515e-05,2.505e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Fetal overgrowth (in some patients)
HEAD AND NECK:
[Head];
Microcephaly (rare);
[Face];
Prominent forehead;
Prominent premaxilla;
Micrognathia;
[Ears];
Dysplastic ears;
Low-set ears;
[Eyes];
Prominent eyes;
Small palpebral fissures;
Downslanting palpebral fissures;
Hypertelorism, mild;
[Nose];
Bulbous nasal tip (in some patients);
Hooked nose (in some patients);
Depressed nasal bridge (in some patients);
[Mouth];
High-arched palate
CARDIOVASCULAR:
[Heart];
Thickened myocardium (rare);
Bradycardia (rare);
[Vascular];
Aortic aneurysm;
Pulmonary artery aneurysm;
Arterial aneurysms, multiple;
Arterial tortuosity, general;
Venous tortuosity;
Arterial stenoses, multiple;
Vascular fragility;
Vascularization increased in upper dermis
RESPIRATORY:
[Lung];
Emphysema
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum;
[Diaphragm];
Hypoplastic diaphragm;
Diaphragmatic hernia
GENITOURINARY:
[External genitalia, male];
Inguinal hernia
SKELETAL:
Joint hypermobility, generalized;
Fractures at birth;
[Hands];
Arachnodactyly;
Contractures of third to fifth fingers;
[Feet];
Arachnodactyly
SKIN, NAILS, HAIR:
[Skin];
Cutis laxa;
Velvety skin;
Normal scarring;
HISTOLOGY:;
Collagen bundles smaller than normal;
Vascularization increased in upper dermis;
Underdeveloped elastic fibers, severe
NEUROLOGIC:
[Central nervous system];
Hypotonia;
Brain hemorrhage
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios (in some patients)
MISCELLANEOUS:
Relatively mild cutis laxa, associated with severe vascular abnormalities;
Massive aortic aneurysm can cause airway compression in affected infants
MOLECULAR BASIS:
Caused by mutation in the EGF-containing fibulin-like extracellular
matrix protein-2 gene (EFEMP2, 604633.0001)
OMIM Title
*614439 ADP-RIBOSYLATION FACTOR-LIKE 14; ARL14
;;ADP-RIBOSYLATION FACTOR 7; ARF7
OMIM Description
DESCRIPTION
ADP-ribosylation factors (ARFs) and related proteins are regulators of
trafficking of intracellular proteins and membranes and of cytoskeletal
remodeling (review by Colicelli, 2004). ARL14 is a small GTPase that is
selectively expressed in immune cells. ARL14 uses PSD4 as a guanine
exchange factor (GEF) and is involved in controlling major
histocompatibility complex (MHC) II transport in dendritic cells (Paul
et al., 2011).
CLONING
Using a genomewide flow cytometry-based RNA interference screen in human
melanoma cells, Paul et al. (2011) identified ARL14 as a controller of
MHC II transport. Microarray and database analyses showed that ARL14 was
selectively expressed in immune cells. Confocal microscopy detected
ARL14 on MHC II vesicles in immature human dendritic cells.
GENE FUNCTION
Paul et al. (2011) used yeast 2-hybrid analysis, protein pull-down
assays, immunoprecipitation analysis, and confocal microscopy in human
cells to elucidate the pathway through which ARL14 controlled MHC II
transport. ARL14 recruited MYO1E (601479) via ARF7EP (C11ORF46; 612295).
PSD4 (614439) promoted GTP loading of ARF6 (600464) and ARL14. ARL14
belonged to a pathway where PIP5K1A (603275) and PIK3R2 (603157) created
phosphatidylinositol phosphate species that were required for
recruitment or activation of PSD4, which activated ARL14. The complex
controlled the movement of MHC II vesicles along the actin cytoskeleton
in human dendritic cells.
MAPPING
Gross (2012) mapped the ARL14 gene to chromosome 3q25.33 based on an
alignment of the ARL14 sequence (GenBank GENBANK BC034354) with the
genomic sequence (GRCh37).
SI
| dbSNP name | rs73018867(A,G); rs73018868(C,T); rs184209740(T,A); rs41273561(C,T); rs58103898(C,T); rs41273563(C,T); rs3762796(C,T); rs6788812(G,A); rs6548381(A,T); rs73018876(C,T); rs7615513(C,T); rs111378337(C,T); rs6781688(A,G); rs6785316(A,C); rs61110204(C,G); rs1457801(G,T); rs150256534(G,A); rs61603801(G,C); rs76160724(A,T); rs144303324(A,T); rs6776765(A,G); rs6788137(G,T); rs9863015(A,C); rs35640635(A,G); rs57398359(G,T); rs57366872(C,T); rs73877369(G,A); rs76385959(G,T); rs16848834(G,A); rs78540900(G,C); rs75982521(C,T); rs16848837(T,C); rs78437999(C,T); rs4855271(C,T); rs73877372(C,T); rs73877373(T,A); rs73018887(C,T); rs73877375(A,G); rs7636760(T,C); rs11925035(T,G); rs73018890(A,G); rs73163446(T,C); rs80169417(G,A); rs12107524(G,A); rs112977346(T,C); rs56676342(G,A); rs185797553(G,A); rs75845711(T,G); rs16848841(G,A); rs139013937(T,C); rs78963184(C,A); rs73018896(A,G); rs114497682(G,T); rs13063336(C,T); rs7618643(A,G); rs79622667(A,C); rs76393796(T,C); rs76037217(C,T); rs73018900(T,C); rs73020903(G,A); rs7653429(C,T); rs112690415(T,C); rs115782229(G,A); rs74648160(T,C); rs116493318(T,G); rs6789556(G,T); rs6781045(A,G); rs2290738(G,A); rs9838256(G,C); rs6779543(T,C); rs115920716(T,A); rs73877382(C,T); rs146943741(G,A); rs1817263(C,T); rs1817264(T,C); rs1817265(C,T); rs10936429(C,T); rs4557160(T,C); rs13069479(C,T); rs9862106(C,T); rs9866707(G,A); rs116481785(T,C); rs7611384(T,A); rs10936430(T,C); rs142360844(T,C); rs73877386(T,G); rs187505044(C,T); rs9682815(G,A); rs57544581(T,C); rs9825917(T,C); rs142468874(C,T); rs9290250(G,A); rs13099130(G,A); rs12634609(A,T); rs12632092(T,C); rs192480472(G,A); rs13062602(G,A); rs13089592(T,C); rs13067828(G,T); rs13067553(C,T); rs13067742(A,C); rs149393096(G,A); rs12381230(T,C); rs142789249(T,C); rs144485111(C,A); rs11712612(T,C); rs11716302(A,T); rs73020927(A,G); rs13091748(A,C); rs9838509(C,A); rs9814939(G,A); rs150885876(C,T); rs9290251(G,T); rs9290252(T,G); rs9681959(T,G); rs9821196(C,A); rs9290253(T,C); rs111263785(T,C); rs144521002(T,C); rs9290254(C,T); rs73020937(A,C); rs9290255(T,C); rs73020939(C,T); rs9758713(A,C); rs9757571(T,A); rs9878803(A,G); rs9841730(C,G); rs28726340(A,G); rs9883965(A,G); rs138999592(T,C); rs10755123(T,C); rs12186083(T,C); rs12185917(A,T); rs9714197(T,C); rs9290256(C,T); rs9290257(G,A); rs9857996(G,A); rs73020955(A,G); rs9858331(G,T); rs190732763(T,C); rs12494492(C,T); rs9290258(C,T); rs113143426(G,A); rs9878023(A,C); rs9845334(G,A); rs9882556(A,G); rs9290259(T,G); rs12496714(T,A); rs9290260(A,G); rs9290261(G,T); rs145798125(A,G); rs9829467(A,G); rs9812124(T,A); rs9833589(A,T); rs9871649(C,T); rs11718901(G,A); rs13093090(C,T); rs112139700(G,A); rs9290262(T,A); rs9756012(T,C); rs9813876(G,A); rs76463353(C,T); rs9865476(G,A); rs62280366(G,A); rs9758471(C,T); rs9758479(C,A); rs9754967(T,C); rs9756068(A,G); rs12630624(T,A); rs12497787(G,A); rs9810916(G,A); rs9811133(C,A); rs6774370(C,T); rs6782776(G,A); rs9812016(C,G); rs9831933(T,C); rs9835781(T,C); rs9816353(C,A); rs9290263(A,G); rs9827104(G,A); rs9865161(A,G); rs6783643(A,C); rs6444945(C,A); rs6788314(C,T); rs7430654(C,A); rs7430656(C,A); rs7432386(G,T); rs73880014(C,A); rs9290264(C,A); rs113303008(G,A); rs7626281(T,C); rs7639496(C,G); rs6794306(A,G) |
| ccdsGene name | CCDS3196.1 |
| cytoBand name | 3q26.1 |
| EntrezGene GeneID | 6476 |
| EntrezGene Description | sucrase-isomaltase (alpha-glucosidase) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SI:NM_001041:exon17:c.A1919G:p.E640G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6539 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P14410 |
| dbNSFP Uniprot ID | SUIS_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 0.0001709 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, severe to profound
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the TRIO- and F-actin-binding protein (TRIOBP,
609761.0001)
OMIM Title
*609845 SUCRASE-ISOMALTASE; SI
OMIM Description
DESCRIPTION
The SI gene encodes sucrase-isomerase, an enzyme composed of 2 highly
similar sucrase and isomaltase subunits, originating from a single
polypeptide precursor, pro-SI. It is a type II transmembrane
glycoprotein with preferential expression in the apical membranes of the
polarized enterocytes of the intestinal brush border membrane, where it
is essential for the processing of dietary carbohydrates. The mature
intestinal protein is a heterodimer, generated through proteolytic
cleavage in the intestinal lumen, in which both sucrase and isomaltase
domains remain associated by noncovalent interactions (summary by
Rodriguez et al., 2013).
CLONING
Hauser and Semenza (1983) reviewed the isolation and purification of
sucrase-isomaltase and its mode of association with the brush border
membrane.
Davis et al. (1987) isolated a cDNA clone from a human jejunal lambda
gt11 library coding for the N-terminal isomaltase region of human
sucrase-isomaltase (EC 3.2.1.48). The enzyme consists of 2 subunits
which are synthesized as a single chain mannose-rich precursor. From
studies of the cDNA, Chantret et al. (1992) showed that the human
protein has 83% identity with the rabbit enzyme. In addition to the
previously reported homology with lysosomal alpha-glucosidase (606800),
the sucrase and isomaltase subunits appear to be homologous to a yeast
glucoamylase.
GENE FUNCTION
Sander et al. (2006) noted that the SI gene encodes a bifunctional
protein, with the isomaltase subunit comprising amino acids 1 through
1007 and the sucrase subunit contained within amino acids 1008 through
1827. Therefore, mutations in the 3-prime part of the SI gene do not
necessarily affect isomaltase activity.
MAPPING
Using a cDNA probe to study somatic cell hybrids and for in situ
hybridization, Davis et al. (1987) localized the SI gene to chromosome
3q22-q26. See also Green et al. (1987). West et al. (1988) arrived at
the regional assignment 3q25-q26 by in situ hybridization. Swallow et
al. (1991) demonstrated linkage to DNA markers on 3q. Wu et al. (1992)
cloned and sequenced 3.6 kb of the 5-prime-flanking region of the human
SI gene. Linkage to reported genes demonstrated that transcription of
the gene involves both proximal and distal regulatory elements.
Birkenmeier et al. (1993) concluded that in the mouse the structural
gene for sucrase-isomaltase (Si-s) is closely linked to a regulatory
gene (Si-r) on chromosome 3.
MOLECULAR GENETICS
In a patient with phenotype II of sucrase-isomaltase deficiency (CSID;
222900), which is characterized by intracellular accumulation of
mannose-rich SI in the Golgi, Ouwendijk et al. (1996) identified a
homozygous mutation in the SI gene (Q1098P; 609845.0001). CSID is an
example of a disease in which mutation results in transport-incompetent
molecules. Ouwendijk et al. (1996) noted that SI is not transported to
the brush border membrane but accumulates as a mannose-rich precursor in
the endoplasmic reticulum (ER), ER-Golgi intermediate compartment, and
the cis-Golgi, where it is finally degraded.
Jacob et al. (2000) identified an L340P mutation (609845.0002) in the SI
gene that resulted in an unusual intracellular cleavage of SI in the ER.
Spodsberg et al. (2001) identified a Q117R mutation (609845.0003) in teh
SI gene that elicited missorting of the enzyme to the basolateral
membrane. Ritz et al. (2003) detected an L620P mutation (609845.0004)
that caused a block in the ER.
Sander et al. (2006) analyzed the SI gene in 11 patients of Hungarian
origin with congenital sucrase-isomaltase deficiency who had none of the
previously identified mutations. Their analyses revealed 43 SI variants
in total, 15 within exons and 1 at a splice site. Amino acid exchanges
resulted from 8 of the exonic mutations, causing hypomorphic or null
alleles. The splice site mutation was predicted to result in a null
allele. All potential pathologic alterations were present on 1 allele
only. In 6 of the 11 patients, the phenotype of CSID could be explained
by compound heterozygosity.
- Somatic Mutations
By whole-exome analysis, Rodriguez et al. (2013) identified somatic
heterozygous mutations in the SI gene in 4 of 105 patients with chronic
lymphocytic leukemia (CLL; 151400). Three of the 4 somatic mutations
(D1193N, W1493C, and T1680I) were located in the C-terminal sucrase
domain, whereas the remaining mutation, R91T, was located N-terminal to
the isomaltase domain. In vitro transfection studies of 3 of the
mutations showed that they caused a loss of sucrase activity compared to
wildtype: D1193N showed a 25% decrease in activity, R91T showed a 4-fold
decrease in activity, and W1493C had essentially no residual activity.
Immunoblotting and immunofluorescence studies indicated that the mutant
proteins had variable decreases in complex glycosylation as well as
abnormal accumulation in the endoplasmic reticulum, which correlated
with decreased activity. The findings suggested that the somatic
mutations impaired SI by altering intracellular trafficking, resulting
in intracellular accumulation of enzyme precursors and eventually
reducing or completely abrogating the sorting of mature SI to the cell
surface. Gene expression profiling of tumor cells provided evidence of a
unique signature of metabolic reprogramming, including changes in
carbohydrate metabolism, cofactor biosynthesis, and oxidative
phosphorylation.
MIR6828
| dbSNP name | rs149589357(G,T) |
| ccdsGene name | CCDS3213.1 |
| cytoBand name | 3q26.2 |
| EntrezGene GeneID | 5010 |
| EntrezGene Symbol | CLDN11 |
| snpEff Gene Name | CLDN11 |
| EntrezGene Description | claudin 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
| ESP Afr MAF | 0.017703 |
| ESP All MAF | 0.005997 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001691 |
MIR4789
| dbSNP name | rs78831152(C,T) |
| ccdsGene name | CCDS46960.1 |
| cytoBand name | 3q26.31 |
| EntrezGene GeneID | 100616395 |
| snpEff Gene Name | NAALADL2 |
| EntrezGene Description | microRNA 4789 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1203 |
| ExAC AF | 0.037 |
MCCC1
| dbSNP name | rs12486983(T,C); rs13326155(G,T); rs9879377(C,A); rs6786878(C,A); rs2292056(T,G); rs1135365(A,T); rs6443842(A,G); rs9834143(A,C); rs10937106(G,A); rs10937107(T,C); rs9877655(C,T); rs11928508(C,G); rs77458140(G,T); rs138480247(G,T); rs1948799(A,G); rs75534595(C,T); rs7640612(C,A); rs149886657(G,A); rs4859151(A,G); rs2134427(A,T); rs34822404(C,T); rs1056565(A,G); rs7651093(T,C); rs10937108(A,T); rs4859264(T,C); rs1540736(T,G); rs1566705(C,T); rs4859265(A,G); rs76262213(C,T); rs4859266(T,C); rs80115013(G,A); rs75187429(G,A); rs12330492(G,A); rs6443844(C,A); rs6443845(G,A); rs1540735(T,C); rs76849505(C,T); rs10937109(A,G); rs10937110(C,A); rs12496512(T,C); rs2270969(A,G); rs2270968(T,G); rs140957052(G,A); rs2270967(G,A); rs9861464(T,C); rs10937111(A,G); rs4859267(T,C); rs2292057(C,T); rs10513789(T,G); rs60260096(A,G); rs141710933(A,C); rs4859153(T,C); rs4859154(T,C); rs4859268(C,T); rs12637471(G,A); rs13088830(C,T); rs1502762(G,A); rs3772721(C,A); rs116378168(T,G); rs28793315(T,C); rs13097765(T,C); rs9861225(C,T); rs187742604(C,T); rs6806354(T,C); rs11927250(C,T); rs6443846(T,A); rs13072934(T,C); rs9821577(T,C); rs9877289(G,A); rs6806512(A,G); rs116112273(C,T); rs6801522(T,C); rs6801608(T,C); rs7432920(T,C); rs11711666(T,G); rs4859269(C,G); rs13075011(G,C); rs77329096(A,C); rs113566442(C,T); rs7646991(C,T); rs7616810(T,C); rs67514336(T,C); rs7649701(G,A); rs4859270(A,G); rs4859271(T,C); rs10212195(C,T); rs374094865(G,A); rs75623499(C,T); rs13078931(G,A); rs1604586(A,G); rs1970864(A,G); rs1970863(C,T); rs13066020(T,C); rs6443847(A,G); rs7632904(A,C); rs2314737(C,T); rs55811245(A,G); rs74343531(A,G); rs75540648(C,T); rs4859272(G,T); rs4859273(T,C); rs4859274(C,T); rs58210189(T,C); rs6785680(T,C); rs6443848(T,C); rs7622479(G,A); rs78297829(C,A); rs7624867(C,T); rs6443849(T,G); rs6443850(G,C); rs6806390(A,G); rs6782692(G,A); rs1995426(G,A); rs1995427(C,A); rs11712267(A,G); rs9823766(T,C); rs80083845(T,C); rs116132570(T,C); rs2314738(C,T); rs77775631(G,C); rs9810968(T,G); rs13061424(T,A); rs79456945(G,A); rs12638619(C,T); rs9882050(C,T); rs12497989(G,A); rs12498020(G,A); rs10937112(T,G); rs9812846(G,T); rs9822789(G,T); rs12491196(T,C); rs16833689(C,T); rs6806083(G,A); rs7611168(C,T); rs11716229(G,C); rs66468736(G,T); rs12495806(G,T); rs9838514(A,G); rs111716486(A,G); rs3732604(T,G); rs116291701(C,G); rs4859155(A,G); rs4859275(A,T); rs113118565(T,A); rs4859276(G,C); rs4859156(T,G); rs73178986(G,A); rs10513790(T,C); rs13059375(G,A); rs937652(C,G) |
| ccdsGene name | CCDS3241.1 |
| cytoBand name | 3q27.1 |
| EntrezGene GeneID | 56922 |
| EntrezGene Description | methylcrotonoyl-CoA carboxylase 1 (alpha) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MCCC1:NM_020166:exon16:c.C1792A:p.L598M,MCCC1:NM_001293273:exon14:c.C1441A:p.L481M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8699 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PG35 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.000461 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0004066 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Other];
Marfanoid body habitus;
Reduced upper-lower segment ratio
HEAD AND NECK:
[Face];
Prognathism;
Long face;
Myopathic facies;
[Eyes];
Lens subluxation;
Myopia
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Aortic regurgitation;
Dextrocardia;
Pulmonic stenosis;
[Vascular];
Aortic root dilatation;
Azygous connection;
Persistent left superior vena cava
RESPIRATORY:
Obstructive sleep apnea
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum
ABDOMEN:
Situs inversus
SKELETAL:
[Spine];
Scoliosis;
Kyphosis;
[Limbs];
Genu recurvatum;
[Hands];
Arachnodactyly;
Hyperextensible fingers
OMIM Title
*609010 3-@METHYLCROTONYL-CoA CARBOXYLASE 1; MCCC1
;;3-@METHYLCROTONYL-CoA CARBOXYLASE, ALPHA; MCCA;;
3-@METHYLCROTONYL-CoA CARBOXYLASE, BIOTIN-CONTAINING SUBUNIT
OMIM Description
DESCRIPTION
The MCCC1 gene encodes the alpha subunit of 3-methylcrotonyl-CoA
carboxylase (EC 6.4.1.4), a biotin-dependent mitochondrial enzyme
essential for the catabolism of leucine.
Also see MCCC2 (609014), which encodes the beta subunit.
CLONING
Obata et al. (2001) identified a cDNA clone corresponding to the MCCC1
gene in an expressed sequence tag (EST) database. The deduced 725-amino
acid protein has a molecular mass of 76 kD and contains a biotin
carboxylase domain and a biotin carboxyl carrier domain. The N terminus
showed 46.5% homology to the N terminus of human propionyl-CoA
carboxylase (PCCA; 232000). Northern blot analysis detected a 2.6-kb
mRNA transcript in brain, heart, liver, skeletal muscle, and kidney,
among other tissues.
Simultaneously and independently, Baumgartner et al. (2001) and Gallardo
et al. (2001) cloned the human MCCA cDNA. The MCC alpha subunit contains
an N-terminal biotin carboxylation domain and a C-terminal biotin
carrier domain. Biotin is covalently attached to lysine-681 (Baumgartner
et al., 2001).
Lau et al. (1979) determined that the bovine 3-MCC molecule contains
dissimilar alpha and beta subunits.
GENE STRUCTURE
Obata et al. (2001) determined that the MCCC1 gene contains 19 exons and
spans approximately 70 kb. Baumgartner et al. (2001) also determined
that the MCCA gene contains 19 exons.
MAPPING
By FISH, Obata et al. (2001) and Gallardo et al. (2001) mapped the MCCA
gene to chromosome 3q27 and 3q25-q27, respectively.
GENE FUNCTION
Gallardo et al. (2001) constructed a fungal model carrying an mccA-null
allele and used it to demonstrate, in vivo, the involvement of MCC in
leucine catabolism.
MOLECULAR GENETICS
In 2 patients with MCC1 deficiency (210200) with less than 10% normal
MCC activity, Gallardo et al. (2001) identified 2 different mutations in
the MCCA gene (609010.0001; 609010.0002). In 4 patients with MCC1
deficiency with less than 10% normal MCC activity, Baumgartner et al.
(2001) identified homozygous mutations in the MCCA gene (see, e.g.,
609010.0002-609010.0004). One of the patients had been reported by Steen
et al. (1999). Both Gallardo et al. (2001) and Baumgartner et al. (2001)
were able to categorize their MCC-deficient patients into 2
complementation groups corresponding to mutations in the MCCC1 or the
MCCC2 gene.
Uematsu et al. (2007) identified compound heterozygous or homozygous
mutations in the MCCA gene (see, e.g., 609101.0007) in 2 unrelated
Japanese patients with MCC1 deficiency. One of the patients was a
severely affected woman who had been reported by Murayama et al. (1997).
Uematsu et al. (2007) stated that 28 different mutations had been
reported in the MCCA gene.
MAGEF1
| dbSNP name | rs9872799(T,G); rs10937187(C,A) |
| ccdsGene name | CCDS3269.1 |
| cytoBand name | 3q27.1 |
| EntrezGene GeneID | 64110 |
| EntrezGene Description | melanoma antigen family F, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEF1:NM_022149:exon1:c.A707C:p.E236A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HAY2 |
| dbNSFP Uniprot ID | MAGF1_HUMAN |
| dbNSFP KGp1 AF | 0.569139194139 |
| dbNSFP KGp1 Afr AF | 0.50406504065 |
| dbNSFP KGp1 Amr AF | 0.544198895028 |
| dbNSFP KGp1 Asn AF | 0.398601398601 |
| dbNSFP KGp1 Eur AF | 0.751978891821 |
| dbSNP GMAF | 0.4302 |
| ESP Afr MAF | 0.472084 |
| ESP All MAF | 0.328387 |
| ESP Eur/Amr MAF | 0.254767 |
| ExAC AF | 0.645 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss (uncommon);
[Eyes];
Optic atrophy (uncommon)
SKELETAL:
Contractures (in those with early onset);
[Spine];
Scoliosis (in those with early onset);
[Feet];
Pes cavus;
Hammer toes;
Foot deformities
NEUROLOGIC:
[Central nervous system];
Cognitive decline (1 family);
Spasticity (1 family);
Pyramidal features (rare);
Tremor (rare);
Fatal subacute encephalopathy (1 family);
Pain;
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
'Steppage' gait;
Foot drop;
Distal sensory impairment;
Predominant loss of pain and temperature sensation;
Less severe loss of vibration and position sensation;
Hyporeflexia;
Areflexia;
Pyramidal signs (less common);
Increased muscle tone (less common);
Hyperreflexia (less common);
Extensor plantar responses (less common);
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Absent nerve conduction velocities (in those with early onset);
Axonal atrophy on nerve biopsy;
Axonal degeneration/regeneration on nerve biopsy;
Small 'onion bulbs' may be present;
Decreased number of myelinated fibers may be found;
Mitochondrial abnormalities in nerve biopsy
MISCELLANEOUS:
Variable age at onset (childhood to age 50);
Earlier onset is associated with a more severe disorder;
Usually begins in feet and legs (peroneal distribution), but may
progress to upper limbs;
Variable severity;
One family with a fatal subacute encephalopathy has been reported;
Slowly progressive;
Up to 25% of patients are asymptomatic or mildly affected, suggesting
incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the mitofusin 2 gene (MFN2, 608507.00001)
OMIM Title
*609267 MELANOMA ANTIGEN, FAMILY F, 1; MAGEF1
OMIM Description
CLONING
Stone et al. (2001) cloned MAGEF1 from an ovarian tumor cDNA library.
The deduced 308-amino acid protein contains a C-terminal MAGE motif and
shares extensive homology with the MAGE superfamily of tumor antigens
(e.g., MAGEA1; 300016). By EST database analysis, Stone et al. (2001)
identified MAGEF1 clones containing either 6 or 7 GGA trinucleotide
microsatellite repeats encoding glutamic acids. They also identified a
separate set of 2 GGAs encoding 2 glycine resides. The trinucleotide
repeats appeared to be unique to MAGEF1. Northern blot analysis detected
a 1.7-kb transcript in normal ovary and peripheral blood leukocytes and
in 6 of 7 ovarian tumors examined. RNA dot blot analysis detected MAGEF1
expression in all tissues examined.
GENE STRUCTURE
Stone et al. (2001) determined that a single exon contains the coding
region of the MAGEF1 gene.
MAPPING
By PCR of chromosome-specific DNA from rodent/human hybrid cell lines,
Stone et al. (2001) mapped the MAGEF1 gene to chromosome 3.
LPP-AS2
| dbSNP name | rs13318958(T,A); rs967718(T,A); rs7616349(G,C); rs62289742(C,T); rs374677426(G,A) |
| cytoBand name | 3q27.3 |
| EntrezGene GeneID | 339929 |
| snpEff Gene Name | LPP |
| EntrezGene Description | LPP antisense RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3926 |
TP63
| dbSNP name | rs28673064(A,T); rs13064999(G,A); rs13087793(T,C); rs11928222(T,G); rs36021505(G,A); rs35837956(T,G); rs35867177(A,G); rs6763020(T,C); rs73889790(A,G); rs12107970(G,A); rs12107966(C,T); rs11927406(C,T); rs12374182(G,A); rs4687079(G,A); rs55779747(A,C); rs73889793(T,A); rs34951828(T,C); rs11720249(C,T); rs75068794(A,T); rs4396880(G,A); rs4488809(T,C); rs4381914(A,G); rs4396881(G,A); rs4327365(T,C); rs10513839(T,G); rs7636839(A,G); rs13080835(G,T); rs13080545(A,G); rs13314271(T,C); rs12696594(A,G); rs73194170(A,C); rs59794299(C,A); rs13325621(C,T); rs12107251(A,G); rs78167181(G,A); rs149760040(G,A); rs141824209(A,G); rs147122316(C,A); rs55862124(T,C); rs12107025(T,A); rs7619517(T,C); rs73063892(T,A); rs7629983(A,G); rs80169435(G,A); rs13084874(T,C); rs6766775(C,G); rs9837544(T,C); rs12630321(G,C); rs36092415(G,A); rs9827354(C,T); rs9827487(C,A); rs9827991(C,T); rs9824378(T,G); rs9879965(G,T); rs11708944(T,C); rs16848825(C,G); rs1920236(A,T); rs1920235(A,G); rs4687080(G,A); rs4687081(G,A); rs4600801(A,T); rs4627739(A,T); rs4234611(G,A); rs4686521(G,C); rs115262691(G,T); rs115257365(G,T); rs9811174(G,A); rs9811214(C,T); rs6807954(A,T); rs76600814(A,C); rs75077200(A,G); rs13088465(T,C); rs13065852(A,C); rs6784251(G,A); rs6808068(A,G); rs79251530(C,A); rs13089021(T,G); rs28612247(C,A); rs17504410(C,T); rs9816523(G,A); rs9816277(C,T); rs8179917(C,A); rs9821164(G,A); rs4426661(T,A); rs4011820(A,T); rs4011821(G,T); rs6772378(G,A); rs146612909(A,G); rs12330526(T,C); rs10937398(G,A); rs6785679(T,C); rs9826717(G,A); rs74674764(C,A); rs9864161(A,T); rs12330765(A,T); rs56310892(C,T); rs1920275(C,G); rs150165178(T,C); rs9869716(A,G); rs1920271(G,A); rs1920270(A,G); rs143905890(T,C); rs1920267(T,C); rs1920266(C,A); rs1920265(T,C); rs1881993(C,T); rs1881992(G,T); rs1920252(T,G); rs9862450(T,C); rs1920251(A,T); rs9842604(C,T); rs9847400(G,T); rs151149456(C,G); rs9847439(C,A); rs9847440(C,G); rs9847745(G,A); rs13082542(T,C); rs9867687(T,C); rs9848040(G,C); rs9290902(G,T); rs4491878(C,G); rs1920250(T,C); rs4491879(C,T); rs1920249(A,G); rs1920248(T,A); rs1920247(G,A); rs1920245(G,T); rs4505678(T,A); rs112034496(C,T); rs9853796(G,C); rs9873650(T,C); rs9853686(C,T); rs146166332(C,G); rs138960240(T,G); rs9829846(G,A); rs9829884(C,G); rs113168912(C,G); rs9867905(A,C); rs9830903(G,A); rs9830662(C,T); rs114252996(A,T); rs9872452(A,G); rs9834994(C,T); rs34729753(A,G); rs10937401(G,A); rs4362700(A,G); rs9835487(C,T); rs4513433(T,G); rs113913438(C,T); rs12638113(A,G); rs9835923(G,C); rs145295752(G,C); rs4504152(C,T); rs1920269(C,A); rs9840662(C,G); rs13095135(A,C); rs115376581(A,G); rs115676522(G,A); rs9865635(T,G); rs6809573(A,G); rs1920272(A,G); rs34239723(G,A); rs13321778(C,G); rs1920273(G,A); rs1920274(A,G); rs74543052(T,G); rs73194199(C,A); rs73195959(G,A); rs73195961(G,A); rs73195962(G,T); rs13075719(G,A); rs62291707(G,A); rs1920276(C,T); rs10155001(G,T); rs113369253(G,A); rs10937403(A,G); rs114024501(C,G); rs10937404(G,A); rs12495269(C,G); rs6774934(A,G); rs9816619(T,C); rs9872590(G,A); rs10937405(C,T); rs4600802(C,T); rs2378507(A,G); rs1920277(A,G); rs2378508(T,C); rs79913345(C,T); rs74699520(A,G); rs10155037(C,T); rs10154920(A,G); rs9840974(A,G); rs115285978(A,C); rs9874407(T,A); rs9855034(G,A); rs12635590(G,A); rs140709368(C,T); rs76872857(A,T); rs12493249(C,T); rs149625368(A,G); rs9817932(A,G); rs9856057(G,A); rs9985415(C,T); rs116629195(T,C); rs78396810(G,A); rs141343369(G,A); rs1920279(G,A); rs78880854(A,T); rs75709115(T,A); rs60116225(C,A); rs143734986(A,C); rs148941599(A,G); rs143813639(A,G); rs4011816(C,G); rs3954248(G,T); rs75311801(C,A); rs1920280(T,C); rs62289999(A,G); rs148475163(C,A); rs141796379(C,A); rs79606561(C,A); rs76078569(G,A); rs6794898(G,C); rs139934163(C,T); rs79246760(C,T); rs115481265(A,C); rs13085052(T,G); rs76440101(C,G); rs9849964(A,G); rs9812737(G,A); rs9812619(C,A); rs183391117(C,A); rs59641946(T,G); rs76554798(A,G); rs13067268(A,G); rs1920282(A,G); rs116408427(G,A); rs35913385(A,C); rs6444390(T,C); rs6780531(A,G); rs6804873(C,G); rs6805171(C,A); rs28536004(T,C); rs28407489(A,G); rs28820407(A,G); rs73056143(T,C); rs7649341(G,A); rs13080141(A,G); rs73195971(A,G); rs7629326(A,G); rs28887633(C,T); rs111702573(C,A); rs10049472(C,A); rs13097576(A,G); rs79692229(G,A); rs2378509(T,C); rs113193980(G,T); rs55669201(G,A); rs9811339(G,C); rs78494480(A,G); rs71308971(G,T); rs1920243(G,A); rs59897638(T,A); rs60045731(T,C); rs1920242(T,C); rs6776687(A,G); rs6801312(C,A); rs73195974(A,G); rs9846059(T,C); rs73892306(G,A); rs11709407(G,A); rs1920283(A,G); rs12637443(A,G); rs2141612(G,A); rs2141613(T,C); rs16848860(T,C); rs73056161(C,T); rs6790659(A,G); rs2378512(A,C); rs4396878(C,T); rs2103354(C,T); rs6769332(C,G); rs6797174(A,T); rs7622471(G,A); rs7644839(A,G); rs144412756(A,G); rs185751431(T,G); rs139857100(C,T); rs16864723(G,A); rs9834524(T,A); rs75375616(A,G); rs1950084(G,A); rs80085129(T,G); rs180739732(G,A); rs2889918(C,T); rs7618742(C,T); rs2378514(A,G); rs17445898(A,G); rs79931736(G,A); rs55755345(C,T); rs2378515(G,A); rs74364260(T,A); rs79568440(C,G); rs2889919(T,C); rs4274726(T,A); rs9830997(C,T); rs73195984(A,C); rs79815404(G,A); rs9835321(G,A); rs12635562(T,C); rs140873374(C,G); rs17445954(G,A); rs9840152(C,G); rs79670660(A,G); rs56382677(G,A); rs114739418(C,A); rs146128669(C,T); rs73195987(T,C); rs1920239(T,G); rs9829330(C,T); rs9870855(A,G); rs1920238(A,G); rs73195990(G,C); rs4687084(A,T); rs12696596(C,T); rs73892309(A,G); rs10513840(A,C); rs146117240(A,G); rs2141608(G,A); rs9812576(A,G); rs73892310(T,C); rs9855645(C,T); rs185493823(T,C); rs4575879(A,G); rs6773555(A,G); rs75106747(T,G); rs77458386(T,C); rs4450788(G,A); rs76274605(C,A); rs4589906(C,A); rs73892313(C,T); rs78390975(A,T); rs73056186(C,T); rs75613372(A,T); rs7623877(A,G); rs11707283(T,C); rs11718770(C,A); rs7615946(T,C); rs4687085(A,T); rs76130555(G,T); rs9839197(A,C); rs4687086(A,G); rs76860898(T,C); rs73892315(G,A); rs73892316(T,C); rs9873352(T,A); rs67814458(C,A); rs55708425(A,G); rs7340529(C,T); rs67758342(C,T); rs73892324(C,G); rs79740233(C,G); rs79438791(C,T); rs73195998(T,C); rs6763902(G,A); rs4687087(T,C); rs4687088(G,C); rs143883565(A,T); rs4687089(T,C); rs79418982(C,T); rs6444391(A,T); rs6444392(G,A); rs9832021(A,G); rs79155799(T,G); rs73065446(T,G); rs6804480(G,T); rs144645915(A,G); rs55876846(A,T); rs58677043(C,G); rs73892326(A,C); rs62290041(A,G); rs186926238(A,G); rs75873691(A,T); rs11915751(C,T); rs115835645(C,A); rs35427436(G,A); rs4561809(G,C); rs116881234(A,G); rs7616178(C,T); rs9840944(T,A); rs11709314(G,A); rs71633254(A,T); rs6444393(T,G); rs6444394(T,G); rs13095039(A,C); rs10937406(G,A); rs10937407(C,A); rs11713345(A,T); rs56157362(G,A); rs76863114(A,G); rs117192977(G,A); rs6783038(C,T); rs6783229(G,T); rs6783042(C,G); rs55739282(G,A); rs9815203(G,A); rs7615280(G,A); rs56165954(A,G); rs79951788(G,A); rs7637305(A,G); rs10804919(G,A); rs10804920(T,C); rs4687090(A,G); rs117294724(G,A); rs117713100(C,T); rs10937408(T,A); rs116501411(G,A); rs62279900(T,A); rs78956444(G,C); rs11710119(C,T); rs11710127(C,T); rs35639049(A,C); rs11711225(G,A); rs11711203(C,T); rs11715334(T,G); rs62279901(C,T); rs77744581(C,T); rs115453744(G,A); rs10937409(A,G); rs11925908(T,C); rs9942139(A,C); rs4374508(A,G); rs9942065(C,T); rs6789055(G,A); rs73065473(C,A); rs4635683(G,C); rs75182346(C,A); rs149969511(C,A); rs9834380(G,A); rs113218159(T,A); rs74918774(G,T); rs4591486(C,A); rs4602364(T,A); rs12374133(T,G); rs146368926(C,A); rs4234612(A,G); rs4234613(C,T); rs4687091(G,A); rs9811463(A,C); rs9849184(C,T); rs10937410(C,T); rs11922764(G,T); rs11714257(C,T); rs11715415(G,A); rs115059156(A,T); rs80020321(T,C); rs4607088(C,T); rs77175656(C,T); rs13434202(C,T); rs13434203(C,G); rs56069876(C,T); rs28418876(C,T); rs11914582(T,C); rs11926051(G,A); rs11926083(G,A); rs9870676(G,C); rs188245060(G,C); rs73197812(C,T); rs6777607(A,G); rs74332415(A,G); rs7651838(G,A); rs75548317(A,G); rs74612319(C,G); rs76980033(T,G); rs4686525(C,G); rs9883548(T,G); rs34641720(A,G); rs113214211(C,T); rs79659066(G,C); rs6800495(G,T); rs77071188(T,C); rs78253230(G,A); rs6765015(T,A); rs6779677(A,C); rs73197818(G,A); rs146783742(C,T); rs9290904(A,T); rs140468705(G,C); rs9290905(A,T); rs6774831(T,C); rs114745183(A,C); rs62279903(G,C); rs78864350(A,C); rs74983845(C,A); rs6444395(T,C); rs79388935(C,A); rs6785054(T,A); rs78477878(A,G); rs78957269(T,C); rs7619526(G,A); rs79108234(C,T); rs7634242(T,A); rs7625113(G,C); rs12487895(T,C); rs62279904(G,A); rs28817057(G,A); rs79021066(T,C); rs62279905(G,T); rs78861023(A,C); rs7614997(G,A); rs62279906(G,A); rs62279907(G,A); rs6444397(C,G); rs73055259(A,T); rs9819938(G,A); rs140216199(A,G); rs7618682(C,T); rs74286996(A,C); rs13082345(G,T); rs76458431(C,T); rs76186802(C,G); rs4476481(A,T); rs4456839(C,T); rs62279908(T,A); rs6794551(T,G); rs6781804(G,A); rs6782443(G,C); rs77685903(G,A); rs6785424(G,A); rs78075098(C,T); rs7653252(A,G); rs7631262(G,A); rs76738198(A,G); rs76378134(A,G); rs79596360(A,T); rs4532112(G,A); rs62279909(A,G); rs62279910(A,G); rs62279911(T,G); rs80281161(G,A); rs79819757(G,A); rs73197825(G,A); rs7433868(T,C); rs7431810(G,A); rs4261858(T,C); rs78647045(G,A); rs11920456(G,A); rs35042961(T,C); rs73055278(C,G); rs62279913(T,C); rs115092314(G,A); rs62279914(T,C); rs76130289(C,G); rs7633192(G,C); rs149438436(T,A); rs67799575(T,G); rs4479568(G,A); rs4284956(T,C); rs9821822(A,G); rs34703486(A,G); rs4618206(G,A); rs6797860(G,A); rs4075773(T,A); rs62279916(G,A); rs73055285(T,C); rs6765473(T,C); rs13086640(G,A); rs13086840(G,A); rs56097670(G,A); rs9871604(C,T); rs147622078(A,G); rs6780467(A,T); rs11708278(T,C); rs113229129(T,A); rs74442502(G,A); rs80270222(G,A); rs75030757(T,C); rs66579885(T,C); rs9830137(T,C); rs13065563(A,G); rs60059444(T,C); rs57113330(G,A); rs62279936(A,G); rs13095322(G,A); rs111945918(G,A); rs6765754(C,G); rs71310836(T,C); rs4686529(A,G); rs62279937(A,G); rs11708052(G,T); rs17505775(G,A); rs73197834(A,G); rs17446303(G,A); rs9849766(T,C); rs1515502(C,T); rs73197835(A,G); rs10937411(C,A); rs143583504(G,A); rs73197837(A,T); rs148801452(G,A); rs55807849(G,A); rs2138247(C,T); rs6775277(G,A); rs62279940(G,A); rs1464118(T,C); rs1464117(C,A); rs59307720(T,G); rs1515498(A,G); rs1515497(T,C); rs9854771(G,A); rs1515496(T,C); rs73197843(T,G); rs183198764(G,C); rs150943038(T,C); rs144839213(G,C); rs9832339(A,G); rs6778036(G,A); rs150354054(A,G); rs113057004(C,A); rs113454268(G,A); rs10513843(G,A); rs13083021(A,G); rs869546(G,A); rs873595(T,C); rs75882530(A,C); rs1515499(C,T); rs71310837(A,G); rs7638319(G,A); rs11715710(A,G); rs17506395(T,G); rs7638864(G,T); rs7638725(C,T); rs139044046(C,A); rs111794153(G,A); rs7619549(A,G); rs146200523(G,A); rs13063446(G,A); rs13063521(A,T); rs1399772(G,A); rs141006314(C,A); rs149767941(C,T); rs7624774(T,C); rs147422540(C,T); rs191585818(C,T); rs7340541(T,C); rs4687094(C,A); rs9871386(A,G); rs4687095(G,A); rs73197850(T,C); rs4687096(C,A); rs67528643(T,A); rs17506500(G,A); rs73889828(C,T); rs16864809(C,T); rs7650138(C,T); rs16864811(A,G); rs73197854(C,A); rs9812549(A,G); rs112656013(A,C); rs114423791(C,T); rs62279946(A,G); rs79243809(T,C); rs11715216(C,T); rs9817297(A,G); rs13091309(T,C); rs12486772(A,G); rs182476316(A,G); rs9817608(A,G); rs12630260(A,C); rs5028799(A,G); rs17447076(C,G); rs4553956(C,T); rs13074619(G,C); rs16864812(A,C); rs34848400(G,A); rs34421332(C,T); rs35446946(A,G); rs35842958(C,A); rs9861259(G,A); rs13075375(A,G); rs11720810(T,C); rs13075892(C,A); rs56197129(C,A); rs10937415(A,G); rs6775391(G,A); rs7432936(A,G); rs4558735(A,G); rs2378524(T,C); rs9881595(A,G); rs6795002(T,A); rs6795465(T,C); rs9869075(T,C); rs56413159(G,C); rs56104635(C,T); rs1399775(A,G); rs73199730(T,G); rs73199732(C,G); rs55851920(T,C); rs9879356(T,C); rs9859681(G,A); rs10804923(T,C); rs11717319(G,A); rs4687097(T,G); rs115632979(G,A); rs139406203(T,C); rs6777728(G,A); rs28620689(T,A); rs28578142(C,T); rs73199738(G,A); rs12696597(T,C); rs144801075(A,T); rs9810322(C,T); rs9290906(A,G); rs13083327(T,G); rs16864819(G,A); rs1515493(T,G); rs9882798(T,A); rs4686530(C,T); rs147509082(A,C); rs9873617(C,G); rs1515492(T,C); rs1515491(A,G); rs73199745(A,G); rs17447411(A,G); rs6810297(A,G); rs2037130(T,C); rs2037129(A,G); rs2037128(G,A); rs7616437(A,G); rs73889839(T,C); rs7619370(A,G); rs7653443(T,C); rs7619556(A,G); rs7644113(C,T); rs7621997(A,G); rs6444399(C,T); rs17447607(C,T); rs6444400(G,T); rs6444401(A,G); rs11710350(C,A); rs12490015(G,A); rs12493420(T,G); rs16864828(G,C); rs4687098(T,C); rs2056126(G,T); rs12490194(T,C); rs67906287(A,G); rs76303197(A,G); rs55980479(A,G); rs140649859(G,A); rs7610858(T,C); rs74885811(G,C); rs11709973(G,C); rs11717720(A,G); rs2138244(G,A); rs73199755(C,G); rs62279957(C,T); rs73889852(A,G); rs373917834(A,G); rs185822901(C,A); rs6789212(A,C); rs145765652(A,T); rs6780540(T,C); rs6781069(T,C); rs9817981(A,G); rs9818301(A,T); rs6784696(T,A); rs116854647(G,C); rs6787482(T,C); rs73199758(A,G); rs141756350(C,T); rs6799352(A,G); rs6775002(C,A); rs34799513(C,A); rs11927955(A,G); rs17447782(A,C); rs16864837(A,G); rs7633378(T,C); rs73199761(A,G); rs7624251(G,A); rs13327249(A,C); rs9844142(C,G); rs114766353(C,A); rs6779454(T,C); rs2056124(G,C); rs2056125(C,T); rs58246207(G,A); rs78482149(G,A); rs2176085(T,G); rs116665369(A,G); rs13059768(T,C); rs7648781(A,G); rs11719667(G,A); rs16864848(G,C); rs12106692(C,T); rs12107107(T,C); rs16864850(G,A); rs76618242(T,A); rs2378526(C,G); rs145440947(C,T); rs79895390(A,G); rs1913719(T,G); rs1913720(A,G); rs9848905(A,G); rs6444402(G,A); rs953781(T,C); rs7642420(C,T); rs79038157(T,C); rs7628486(C,A); rs73199771(A,T); rs11720358(G,A); rs16864856(G,A); rs6783767(G,A); rs73199773(C,A); rs79236509(T,G); rs2378527(G,T); rs17448036(G,A); rs7612589(A,G); rs73199778(C,G); rs75015787(T,G); rs2138246(C,T); rs144129552(C,A); rs151270340(C,T); rs6803332(T,C); rs6790791(G,A); rs16864864(T,C); rs6444403(C,T); rs6444404(G,A); rs1913721(A,G); rs11924151(A,G); rs2378528(G,T); rs16864872(A,G); rs9820129(G,A); rs9820283(G,C); rs17514215(T,G); rs2276792(G,A); rs11716871(A,G); rs56059400(G,A); rs3773926(A,G); rs147697050(T,G); rs3773928(T,C); rs3773929(A,G); rs6807129(G,A); rs6783043(A,G); rs7653848(C,T); rs7624324(T,C); rs6789961(A,G); rs6790167(A,G); rs114031124(A,G); rs137933136(T,C); rs58609680(G,A); rs59825104(C,T); rs9840359(G,C); rs9840360(G,A); rs111843185(G,A); rs9844653(G,T); rs9882348(A,C); rs938425(G,C); rs6796401(G,A); rs115960078(C,T); rs9812089(A,G); rs76844400(C,T); rs74647875(A,G); rs7610966(T,C); rs28672730(A,T); rs6806662(G,A); rs111829356(C,G); rs7631107(A,C); rs151049723(G,A); rs143862910(C,T); rs7633861(A,G); rs76548419(C,A); rs75239772(C,T); rs7613791(T,C); rs115714764(T,A); rs12107036(A,G); rs16864889(T,C); rs73889902(C,T); rs116699731(G,A); rs55654591(C,A); rs76618690(G,T); rs1554132(G,C); rs1554131(T,G); rs1345186(T,C); rs35530903(C,T); rs2166815(A,G); rs73892203(T,C); rs3911034(A,G); rs147759295(G,A); rs150367949(G,A); rs6790554(T,G); rs73892204(C,T); rs148076109(C,A); rs35558939(G,A); rs140087205(G,A); rs6790068(A,G); rs11923292(C,T); rs3856775(C,A); rs74842599(G,C); rs140346057(T,C); rs60599136(T,G); rs4687100(A,G); rs9681004(T,C); rs143267775(T,G); rs78233713(C,T); rs73199799(G,A); rs115660354(A,G); rs35861864(G,A); rs35592567(C,T) |
| ccdsGene name | CCDS46978.1 |
| cytoBand name | 3q28 |
| EntrezGene GeneID | 8626 |
| EntrezGene Description | tumor protein p63 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TP63:NM_001114981:exon10:c.C1249A:p.P417T,TP63:NM_001114978:exon12:c.C1531A:p.P511T,TP63:NM_003722:exon12:c.C1531A:p.P511T,TP63:NM_001114980:exon10:c.C1249A:p.P417T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9777 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H3D4-10 |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.000908 |
| ESP All MAF | 0.002922 |
| ESP Eur/Amr MAF | 0.003953 |
| ExAC AF | 0.002846 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)
ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism
LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration
MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)
MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)
OMIM Title
*603273 TUMOR PROTEIN p63; TP63
;;TUMOR PROTEIN p73-LIKE; TP73L;;
p53-RELATED PROTEIN p63; p63;;
KET
OMIM Description
CLONING
Yang et al. (1998) described the cloning of tumor protein p63, which
shows strong homology to the tumor suppressor p53 (191170) and the
p53-related protein p73 (601990). p63 was detected in a variety of human
and mouse tissues, including proliferating basal cells of epithelial
layers in the epidermis, cervix, urothelium, and prostate. The p63 gene
encodes multiple isotypes with remarkably divergent abilities to
transactivate p53 reporter genes and induce apoptosis. The predominant
p63 isoforms in many epithelial tissues lack an acidic N terminus
corresponding to the transactivation domain of p53. The full-length p63
protein contains 448 amino acids. Isoforms of p63 are due to alternative
promoters in exons 1 or 3 and alternative splicing of exons at the
3-prime end. These truncated p63 variants can act as dominant-negative
agents toward transactivation by p53 and p63. Yang et al. (1998)
suggested the possibility of physiologic interactions among members of
the p53 family.
Augustin et al. (1998) also cloned a cDNA, which they termed KET, that
is related to the tumor suppressor p53. They stated that the 4,846-bp
KET cDNA encodes a protein of 680 amino acids that shares 98% identity
with the rat homolog. The remarkable degree of conservation lent support
to the notion that KET proteins have important basic functions in
development and differentiation.
Di Iorio et al. (2005) stated that the p63 gene generates 6 isoforms.
The transactivating isoforms are generated by the activity of an
upstream promoter, and the N-terminally truncated (delta-N) isoforms,
which lack the transactivation domain, are produced from a downstream
intronic promoter. For both transcripts, alternative splicing gives rise
to 3 different C termini, designated alpha, beta, and gamma.
Deutsch et al. (2011) stated that full-length TAp63-alpha contains an
N-terminal transactivation domain, followed by a DNA-binding domain, an
oligomerization domain, a sterile-alpha motif (SAM) domain, and a
C-terminal transactivation inhibitory (TI) domain.
GENE STRUCTURE
Yang et al. (1998) determined that the TP63 gene contains 15 exons.
MAPPING
By fluorescence in situ hybridization, Yang et al. (1998) localized the
human TP63 gene to chromosome 3q27-q29. Using linkage analysis, they
mapped the mouse gene to chromosome 16 in a region known to be syntenic
with human 3q27-q29.
By radiation hybrid analysis, Augustin et al. (1998) mapped the TP63
gene to human chromosome 3q27. KET (TP63) is located between the
somatostatin gene (SST; 182450) proximally and the apolipoprotein D gene
(APOD; 107740) distally. By means of an interspecific backcross panel,
Augustin et al. (1998) mapped the murine homolog, Ket, to chromosome 16
in a region that is deleted in early stages of tumorigenesis of mouse
islet cell carcinomas and contains the Loh2 gene, a putative suppressor
of angiogenesis. Augustin et al. (1998) inferred from mapping data that
KET may act as a tumor suppressor and should be considered a candidate
for Loh2.
GENE FUNCTION
Hibi et al. (2000) stated that p53 (191170) homologs known variously as
p40, p51, p63, and p73L (Trink et al., 1998, Yang et al., 1998, Osada et
al., 1998, Senoo et al., 1998) are isoforms of the same gene, which Hibi
et al. (2000) referred to as AIS for 'amplified in squamous cell
carcinoma.' The main difference between the various transcripts is the
presence or absence of the N-terminal transcriptional activation domain;
p40, delta-Np63, and p73L lack this domain. Though no evidence of a
tumor suppressor function was found, Hibi et al. (2000) observed
overexpression of this gene in head and neck cancer cell lines and
primary lung cancers associated with a low increase of its copy number.
Amplification of the AIS locus was accompanied by RNA and protein
overexpression of a variant p68(AIS) lacking the terminal
transactivation domain. Protein overexpression in primary lung tumors
was limited to squamous cell carcinoma and tumors known to harbor a high
frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells
led to an increase in soft agar growth and tumor size in mice. Results
were interpreted as indicating that AIS transcripts lacking the
N-terminal transcriptional activation domain play an oncogenic rather
than a suppressive role in certain cancers.
Flores et al. (2002) explored the role of p63 and p73 in DNA
damage-induced apoptosis. Mouse embryo fibroblasts deficient for 1 or a
combination of these p53 family members were sensitized to undergo
apoptosis through the expression of the adenovirus E1A oncogene. While
using the E1A system facilitated the performance of biochemical
analyses, the authors also examined the functions of p63 and p73 using
an in vivo system in which apoptosis had been shown to be dependent on
p53. Using both systems, Flores et al. (2002) demonstrated that the
combined loss of p63 and p73 results in the failure of cells containing
functional p53 to undergo apoptosis in response to DNA damage.
Benard et al. (2003) suggested that the 2 homologs of TP53, TP73 and
TP63, must not have a typical tumor suppressor gene role in human
cancers, given the lack of demonstrated mutations in either of these 2
genes. Nevertheless, TP73 and TP63 seem strongly involved in malignancy
acquisition and maintenance.
Using DNA microarray analysis with transfected human SAOS2 osteosarcoma
cells, Wu et al. (2003) found that both delta-Np63-alpha and TAp63-alpha
could activate gene transcription. A comparison of gene profiles
revealed that these p63 isoforms influenced a wide variety of partly
overlapping targets involved in cell cycle control, stress, and signal
transduction. Delta-Np63-alpha and TAp63-alpha often influenced
expression of specific genes in an opposite manner.
Di Iorio et al. (2005) found that, depending on the conditions, limbal
and corneal keratinocytes may contain all 3 delta-N isoforms of p63. In
the uninjured surface of the eye, delta-N p63-alpha was present in the
limbus but was absent from the corneal epithelium. Delta-N p63-beta and
delta-N p63-gamma appeared upon wounding, and their expression
correlated with limbal cell migration and corneal regeneration and
differentiation. Di Iorio et al. (2005) concluded that the alpha isoform
is necessary for maintenance of the proliferative potential of limbal
stem cells and their ability to migrate over the cornea. The beta and
gamma isoforms, being suprabasal and virtually absent from the resting
limbus, likely play a role in epithelial differentiation during corneal
regeneration.
Suh et al. (2006) showed that p63, and specifically the TAp63 isoform,
is constitutively expressed in female germ cells during meiotic arrest
and is essential in a process of DNA damage-induced oocyte death not
involving p53. They also showed that DNA damage induced both the
phosphorylation of p63 and its binding to p53 cognate DNA sites and that
these events are linked to oocyte death. Suh et al. (2006) concluded
that their data supported a model whereby p63 is the primordial member
of the p53 family and acts in a conserved process of monitoring the
integrity of the female germline, whereas the functions of p53 are
restricted to vertebrate somatic cells for tumor suppression.
Yi et al. (2008) showed that miR203 (611899) is induced in the skin
concomitantly with stratification and differentiation. By altering
miR203's spatiotemporal expression in vivo, they showed that miR203
promotes epidermal differentiation by restricting proliferative
potential and inducing cell cycle exit. Yi et al. (2008) identified p63
as one of the conserved targets of miR203 across vertebrates. Notably,
p63 is an essential regulator of stem cell maintenance in stratified
epithelial tissues. Yi et al. (2008) showed that miR203 directly
represses the expression of p63; it fails to switch off suprabasally
when either Dicer1 (606241) or miR203 is absent and it becomes repressed
basally when miR203 is prematurely expressed. The authors concluded that
miR203 defines a molecular boundary between proliferative basal
progenitors and terminally differentiating suprabasal cells, ensuring
proper identity of neighboring layers.
Su et al. (2010) showed that TAp63 suppresses tumorigenesis and
metastasis, and coordinately regulates Dicer (606241) and miR130b
(613682) to suppress metastasis. Metastatic mouse and human tumors
deficient in TAp63 express Dicer at very low levels, and Su et al.
(2010) found that modulation of expression of Dicer and miR130b markedly
affected the metastatic potential of cells lacking TAp63. TAp63 binds to
and transactivates the Dicer promoter, demonstrating direct
transcriptional regulation of Dicer by TAp63. Su et al. (2010) concluded
that their data provided a novel understanding of the roles of TAp63 in
tumor and metastasis suppression through the coordinate transcriptional
regulation of Dicer and miR130b, and may have implications for the many
processes regulated by miRNAs.
Deutsch et al. (2011) found that TAp63-alpha was maintained in a closed
dimeric and inactive conformation in nonstressed murine oocytes.
Phosphorylation opened the dimer and permitted formation of the active
tetramer from 2 activated dimers. Dephosphorylation did not affect the
oligomerization equilibrium. Mutation analysis showed that a helix
within the oligomerization domain of TAp63-alpha was crucial for
tetramer stabilization and essentially made the activation process
irreversible.
By Western blot analysis of transfected 5637 human bladder cancer cells,
Scheel et al. (2009) found that expression of a plasmid containing
tandem sequences of all 4 MIR302 family members (see MIR302A; 614596)
and MIR367 (614600) downregulated p63 expression. Mutation analysis
identified 2 functional MIR302 binding sites in the 3-prime UTR of the
p63 transcript. Western blot analysis showed that transfection of GH
testicular cancer cells with antagonizing oligonucleotides that blocked
all MIR302 subspecies resulted in elevated p63 protein levels. RT-PCR
confirmed that synthetic MIR302B (614597) downregulated p63 mRNA
expression.
Using mouse knockout models and transfected human cell lines, Restelli
et al. (2014) found that DLX5 (600028) and TP63, which both can cause
split hand/foot malformations when mutated, are involved in a regulatory
loop during limb development. Proteasome-mediated degradation of delta-N
p63-alpha was induced by the cis/trans isomerase PIN1 (601052). FGF8
(600483), a downstream DLX5 effector, countered delta-N p63-alpha
degradation. Restelli et al. (2014) noted that both the Tp63 and
Dlx5/Dlx6 (600030) mouse models of split hand/foot malformations show
reduced Fgf8 expression in the apical ectodermal ridge.
MOLECULAR GENETICS
- Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate
Syndrome 3
Celli et al. (1999) mapped EEC3 (604292), an autosomal dominant disorder
characterized by ectrodactyly, ectodermal dysplasia, and facial clefts,
to a region of 3q27 where an EEC-like disorder, limb-mammary syndrome
(LMS; 603543), had been mapped. Analysis of the p63 gene, which is
located in the critical LMS/EEC3 interval, revealed heterozygous
mutations in 9 unrelated EEC3 families. (see, e.g.,
603273.0001-603273.0004). Eight mutations resulted in amino acid
substitutions that were predicted to abolish the DNA binding capacity of
p63; the ninth was a frameshift mutation. Six of the 9 mutations were
C-to-T transversions at CpG dinucleotides. Transactivation studies with
these mutant p63 isotypes provided a molecular explanation for the
dominant character of p63 mutations in EEC3.
- Split-Hand/Foot Malformation 4
To assess the potential of p63 as a candidate gene for split-hand/foot
malformation (SHFM4; 605289), Ianakiev et al. (2000) analyzed the p63
gene in 2 multigenerational families with SHFM in which segregation
analysis had excluded linkage to all previously identified autosomal
regions. Two missense mutations, 724A-G in exon 5, which predicted a
lys194-to-glu substitution (603273.0005), and 982T-C in exon 7, which
predicted an arg280-to-cys substitution (603273.0006). Ianakiev et al.
(2000) also identified mutations in the TP63 gene in families with EEC3;
see 603273.0007 and 603273.0008.
- Ankyloblepharon-Ectodermal Defects-Clefting (AEC) Syndrome
Hay-Wells syndrome, also known as ankyloblepharon-ectodermal
dysplasia-clefting (AEC) syndrome (106260), is a rare autosomal dominant
disorder characterized by congenital ectodermal dysplasia, including
alopecia, scalp infections, dystrophic nails, hypodontia,
ankyloblepharon, and cleft lip and/or cleft palate. This constellation
of clinical signs is unique, but some overlap can be recognized with
other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal
dysplasia-cleft lip/palate (EEC; 604292), limb-mammary syndrome (LMS;
603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; 103285),
and recessive cleft lip/palate-ectodermal dysplasia (CLPED1; 225060).
McGrath et al. (2001) analyzed the p63 gene in AEC syndrome patients and
identified missense mutations in 8 families (see, e.g.,
603273.0009-603273.0010).
In a patient who displayed an overlapping phenotype with features of
both AEC and Rapp-Hodgkin syndrome (RHS; 129400), Prontera et al. (2008)
identified heterozygosity for an 11-bp duplication in the TP63 gene
(603273.0027).
Rinne et al. (2009) analyzed the TP63 gene in 24 individuals from 12
different AEC families, and identified mutations in 21 of those tested;
the 3 individuals without an identified mutation included 2 unaffected
relatives and 1 patient with a phenotype slightly different than
AEC/RHS. Of the 11 different mutations identified, 8 were within the
coding region of the sterile alpha motif (SAM) domain, and 3 were
located in the exon 14 sequence encoding the transactivation inhibitory
(TI) domain.
Using luciferase reporter assays, Beaudry et al. (2009) demonstrated
compromise of PERP (609301) induction with some (see 603273.0009) but
not all AEC-patient derived TP63 mutants. Skin biopsy analysis of AEC
patients revealed a subset displaying aberrant PERP expression,
suggesting that PERP dysregulation might be involved in the pathogenesis
of this disease. Beaudry et al. (2009) concluded that distinct AEC TP63
mutants could differentially compromise expression of downstream
targets, providing a rationale for the variable spectra of symptoms seen
in AEC patients.
Using humanized mouse cDNAs expressed in regenerated human epidermal
tissue and keratinocytes in culture, Zarnegar et al. (2012) found that
AEC-related mutations within the SAM domain of Tp63 repressed expression
of transcriptional activators and markers of epidermal differentiation
compared with wildtype Tp63. AEC-mutant Tp63 did not induce apoptosis or
alter keratinocyte proliferation. ZNF750 (610226), KLF4 (602253), and
GRHL3 (608317) were among a group of epidermal genes significantly
downregulated by AEC-related mutations. Chromatin immunoprecipitation
analysis and sequencing showed that both wildtype and AEC-mutant Tp63
bound 2 canonical TP63-binding sites near the ZNF750 transcriptional
start site. Expression of exogenous ZNF750 in AEC model tissue rescued
expression of the majority of TP63 target genes. Introduction of Tp63
variants lacking the SAM domain did not alter expression of epidermal
differentiation markers.
- ADULT Syndrome
Amiel et al. (2001) reported a missense mutation (603273.0011) in the
TP63 gene in an isolated case of acro-dermato-ungual-lacrimal-tooth
(ADULT) syndrome (103285), which maps to chromosome 3q27. The mutation
was inherited from the healthy father, in whom freckling of the back and
shoulders was the only feature of ADULT syndrome. Amiel et al. (2001)
considered incomplete penetrance as the most likely explanation.
In affected members of a 2-generation family with ADULT syndrome, Duijf
et al. (2002) identified a heterozygous mutation in the TP63 gene
(R298Q; 603273.0014). Rinne et al. (2006) identified the R298Q mutation
in affected members of 2 unrelated families with ADULT syndrome; 1 was
Italian, and the other was Dutch. A third family of Finnish origin had a
different mutation at the same codon (R298G; 603273.0022).
In a Dutch mother and daughter with minimal manifestations of ADULT
syndrome, including hypothelia and palmar hyperlinearity, van
Zelst-Stams and van Steensel (2009) identified heterozygosity for a
missense mutation in the C-terminal end of the proline-rich domain of
TP63 (P127L; 603273.0026). The authors stated that mutations in this
domain have primarily been reported to cause limb-mammary syndrome.
In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right
ventricular dysplasia, who did not have the skin and limb manifestations
of ADULT syndrome, Valenzise et al. (2008) identified the R298Q mutation
in the TP63 gene. The mutation was also found in his mother, who
displayed only hypodontia and athelia. Valenzise et al. (2008) noted
that their findings highlighted the clinical overlapping of TP63-related
ectodermal dysplasias and the difficulty of establishing unequivocal
genotype-phenotype correlations.
- Limb-Mammary Syndrome
In a patient with limb-mammary syndrome (603543), who had bilateral
split hand/foot malformation, isolated cleft palate, and normal hair,
skin, and teeth, but absent nipples, van Bokhoven et al. (2001)
identified a frameshift mutation in the TP63 gene (603273.0012), which
was predicted to truncate the p63-alpha protein within the SAM domain.
- Rapp-Hodgkin Syndrome
In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; 129400),
Kantaputra et al. (2003) identified heterozygosity for a missense
mutation (S545P; 603273.0019) in the TP73L gene. Kantaputra et al.
(2003) stated that this was the first genetic abnormality to be
described in RHS, and noted that this provides molecular data to support
the clinically observed overlap between EEC, AEC, and RHS.
In a mother and daughter with RHS associated with corneal dystrophy and
premature menopause, Holder-Espinasse et al. (2007) identified
heterozygosity for a 1-bp deletion in the TP73L gene (603273.0025).
In a patient who displayed an overlapping phenotype with features of
both AEC and RHS, Prontera et al. (2008) identified heterozygosity for
an 11-bp duplication in the TP63 gene (603273.0027).
- Orofacial Cleft 8
Because mutations in the TP63 gene underlie several monogenic
malformation syndromes manifesting cleft lip with or without cleft
palate, Leoyklang et al. (2006) performed mutation analysis of the 16
exons of the gene in 100 Thai patients with nonsyndromic CL/P (see
129400). In total, 21 single nucleotide changes were found, of which 6
were in the coding regions, including 3 novel nonsynonymous changes:
S90L, R313G, and D564H. The R313G change was concluded to be pathogenic
on the basis of its amino acid change, evolutionary conservation,
occurrence in a functionally important domain, predicted damaging
function, de novo occurrence, and its absence in 500 control
individuals. The finding highlighted further the wide phenotypic
spectrum of TP63 gene mutations.
- Split-Hand/Foot Malformation 6
In 12 of 13 affected members of a consanguineous Turkish family with a
recessive form of SHFM (SHFM6; 225300) caused by mutation in the WNT10B
gene (601906), Ugur and Tolun (2008) also detected homozygosity or
heterozygosity for a rare TP63 insertion polymorphism (dbSNP rs34201045)
at an alternate promoter used for transcription of an
N-terminal-truncated isotype.
- Lung Cancer Susceptibility
For discussion of a possible association between variation in the TP63
gene and lung cancer, see 614210.
- Functional Effects of p63 Mutations
Using mouse models, Lo Iacono et al. (2008) found that p63 mutations
associated with split-hand/foot malformation (e.g., K194E; 603273.0005)
and ectrodactyly-ectodermal dysplasia-cleft lip (e.g., R279H;
603273.0007), which lie within the DNA-binding domain of p63, reduced
the ability of p63 to activate DLX5 (600028) and DLX6 (600030) promoter
reporter constructs.
GENOTYPE/PHENOTYPE CORRELATIONS
Ianakiev et al. (2000) identified 4 TP63 mutations in patients with
SHFM4 and EEC3. All 4 mutations were found in exons that fall within the
DNA-binding domain of p63. The 2 amino acids mutated in the families
with SHFM appeared to be involved primarily in maintenance of the
overall structure of the domain, in contrast to the p63 mutations
responsible for EEC syndrome, which reside in amino acid residues that
directly interact with DNA.
McGrath et al. (2001) noted that p63 mutations resulting in the AEC
syndrome result in amino acid substitutions in the sterile alpha motif
(SAM) domain and are predicted to affect protein-protein interactions.
In contrast, the vast majority of the mutations found in EEC syndrome
are amino acid substitutions in the DNA-binding domain. The authors
suggested that a distinct genotype-phenotype correlation can be
recognized for EEC and AEC syndromes.
Van Bokhoven and Brunner (2002) reviewed the spectrum of p63 mutations
underlying 5 human malformation syndromes. Clustering of mutations
established a clear genotype-phenotype correlation: in the DNA binding
domain (DBD) for EEC syndrome and in the SAM domain for AEC syndrome.
Limb-mammary syndrome (LMS; 603543) differs from EEC syndrome in at
least 3 respects: (1) mammary gland and nipple hypoplasia are consistent
features of LMS but are only occasionally seen in EEC syndrome; (2)
patients with LMS do not have the hair and skin defects that are seen in
EEC syndrome; (3) whereas patients with LMS have cleft palate, those
with EEC syndrome have cleft lip/palate but never have cleft palate
only. Phenotypically, LMS is most similar to ADULT syndrome. Two
isolated patients with an LMS phenotype had, in exons 13 and 14,
frameshift mutations that resulted in truncation of the p63-alpha
protein. Therefore, the abundant p63 product in epithelial cells would
be missing the transactivation inhibitory domain (TID).
Brunner et al. (2002) reviewed p63 mutations causing developmental
syndromes. They stated that the pattern of heterozygous mutations is
distinct for each syndrome, and that consistent with this
syndrome-specific mutation pattern, the functional consequences of
mutations on the p63 proteins also vary, invoking dominant-negative and
gain-of-function mechanisms rather than a simple loss of function.
Rinne et al. (2006) reviewed the clinical features of 227 patients with
p63 mutations and detailed the variable phenotypic features associated
with 5 mutation hotspots, which are all C-T transitions at CpG islands
(see 603273.0001; 603273.0006-603273.0008; 603273.0024).
In affected members of 2 unrelated families with EEC syndrome, features
of LMS, and severe micturition difficulties, Maclean et al. (2007)
identified the R227Q mutation in the TP73L gene (603273.0024). The
authors stated that 4 of the 6 cases/families reported with EEC and the
R227Q mutation have manifested this distinct urologic abnormality (see
van Bokhoven et al., 2001), indicative of a genotype/phenotype
correlation.
ANIMAL MODEL
Yang et al. (1999) generated mice deficient in p63 by targeted
disruption. p63 -/- mice have major defects in their limb, craniofacial,
and epithelial development. p63 is expressed in the ectodermal surfaces
of the limb buds, branchial arches, and epidermal appendages, which are
all sites of reciprocal signaling that direct morphogenetic patterning
of the underlying mesoderm. The limb truncations are due to a failure to
maintain the apical ectodermal ridge (AER), which is essential for limb
development. The embryonic epidermis of p63 -/- mice undergoes an
unusual process of nonregenerative differentiation, culminating in a
striking absence of all squamous epithelia and their derivatives,
including mammary, lacrimal, and salivary glands. Yang et al. (1999)
concluded that p63 is critical for maintaining the progenitor-cell
populations that are necessary to sustain epithelial development and
morphogenesis.
Mills et al. (1999) independently generated mice deficient in p63. The
p63-deficient mice were born alive but had striking developmental
defects. Their limbs were absent or truncated, defects that were caused
by a failure of the AER to differentiate. The skin of p63-deficient mice
did not progress past an early developmental stage: it lacked
stratification and did not express differentiation markers. Structures
dependent upon epidermal-mesenchymal interactions during embryonic
development, such as hair follicles, teeth, and mammary glands, were
absent in p63-deficient mice.
Keyes et al. (2006) studied spontaneous tumorigenesis in p63 +/- mice in
both wildtype and p53-compromised backgrounds. p63 +/- mice were not
tumor prone, and mice heterozygous for both p63 and p53 had fewer tumors
than p53 +/- mice. The rare tumors that developed in mice with
compromised p63 were distinct from those of p53 +/- mice. Furthermore,
p63 +/- mice were not prone to chemically induced tumorigenesis, and p63
expression was maintained in carcinomas. Keyes et al. (2006) concluded
that p63 plays a markedly different role in tumor formation than p53.
Suzuki et al. (2008) showed that Dlx5 (600028), Dlx6 (600030), p63, and
Bmp7 (112267), a putative p63 target gene, were all expressed in
developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or
both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice.
The AER is a transitory multilayered ectoderm acting as a signaling
center essential for distal limb development and digit patterning. Lo
Iacono et al. (2008) stated that the normal stratified organization of
the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6
double-knockout limbs. They found that p63 colocalized with Dlx5 and
Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5
and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63
isoform expressed in developing limbs. Delta-N p63-alpha bound and
activated transcription of Dlx5 and Dlx6 reporter constructs. Other
delta-N isoforms were less active, and isoforms containing the
N-terminal transactivation domain showed no activity with Dlx5 and Dlx6
reporters.
Su et al. (2010) generated mice lacking TAp63. In 2.5 years of study,
both heterozygous and TAp63-null mice developed spontaneous carcinomas
and sarcomas and had a significantly shorter life span than the wildtype
cohort. Paradoxically, a larger proportion of TAp63-null mice (24%) were
tumor-free compared with TAp63 heterozygous mice (15%). Su et al. (2010)
concluded that their data suggested that TAp63 is a haploinsufficient
tumor suppressor gene. Consistent with this finding, sarcomas and
carcinomas from TAp63 heterozygous mice retained the wildtype allele of
TAp63. TAp63 heterozygous and null mice developed highly metastatic
tumors and 10% of these metastases were found in the brain, a rare
finding in spontaneous mouse tumor models.
CLDN16
| dbSNP name | rs192579160(C,T); rs3214506(G,C); rs1491994(T,C); rs1491993(T,A); rs1491992(A,G); rs1491991(T,C); rs148819735(G,A); rs3774015(T,C); rs3774014(G,A); rs60253290(A,G); rs3774013(G,A); rs3774012(T,A); rs17445040(A,G); rs16865430(T,G); rs111390130(A,G); rs138826744(C,A); rs62278699(C,T); rs6797278(T,C); rs9990186(G,A); rs9990412(A,G); rs9990189(C,G); rs13098887(A,G); rs6784836(G,A); rs111257679(C,T); rs74896531(G,T); rs62278700(T,C); rs114586001(T,C); rs56337446(C,T); rs140161445(C,T); rs55656755(G,A); rs55718103(T,G); rs17445180(G,A); rs56131966(A,T); rs17504620(G,A); rs56195821(C,T); rs13063025(G,A); rs12638207(T,C); rs1425117(G,A); rs145023817(G,A); rs9880512(T,C); rs139366782(C,T); rs187433788(G,A); rs144495861(T,C); rs11709598(A,C); rs6801387(G,A); rs3774008(C,T); rs16865437(T,G); rs7648450(C,G); rs1559651(A,G); rs1946326(G,A); rs17445474(A,T); rs115632748(T,A); rs3774007(A,G); rs3774006(T,C); rs11915813(A,G); rs73192461(T,C); rs368036460(A,G); rs17504970(G,C); rs9825448(A,G); rs9826201(A,G); rs7625694(T,A); rs9826657(A,G); rs12489000(A,G); rs150990751(C,T); rs16865441(A,G); rs11927924(G,A); rs6770981(T,C); rs115774017(A,T); rs79157522(G,A); rs77798557(G,T); rs2049673(A,G); rs146819408(C,T); rs77136700(C,T); rs151046044(T,G); rs2288234(A,G); rs74835022(T,G); rs147944406(C,A); rs114479157(C,T); rs60457733(C,T); rs7618571(C,T); rs3774005(A,C); rs3774004(G,C); rs2378569(C,A); rs141613332(C,T); rs58109815(C,T); rs141841751(C,T); rs80235219(A,G); rs7647553(A,G); rs56786355(T,G); rs116190168(A,G); rs34910816(A,G); rs35323433(T,C); rs149798349(G,A); rs189773232(A,G); rs114668081(A,T); rs112253194(G,A); rs2293532(T,C); rs116488781(A,G); rs9844654(T,A); rs115514339(A,C); rs116119310(G,A) |
| ccdsGene name | CCDS3296.1 |
| cytoBand name | 3q28 |
| EntrezGene GeneID | 10686 |
| EntrezGene Description | claudin 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN16:NM_006580:exon1:c.G166C:p.A56P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5427 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A0SDD8 |
| ExAC AF | 0.195,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Nephritis;
Membranous glomerulonephropathy
SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash;
Malar rash
HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia
IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of B cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells
LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Antiribonuclear protein positive;
Anti-SSB positive;
Anti-factor VIII positive
MISCELLANEOUS:
Onset in infancy or childhood
MOLECULAR BASIS:
Caused by mutations in the caspase 10 gene (CASP10, 601762.0001)
OMIM Title
*603959 CLAUDIN 16; CLDN16
;;PARACELLIN 1; PCLN1
OMIM Description
DESCRIPTION
CLDN16 is selectively expressed at tight junctions of renal epithelial
cells of the thick ascending limb of the Henle loop, where it plays a
central role in the reabsorption of divalent cations (Kausalya et al.,
2006).
CLONING
Simon et al. (1999) identified CLDN16, which they called paracellin-1
(PCLN1), and found that it encodes a protein of 305 amino acids with 4
transmembrane domains and intracellular N and C termini. The PCLN1
protein shows sequence and structural similarity to members of the
claudin family (see 603718), with 10 to 18% amino acid identity with
individual claudins. The highest homology between PCLN1 and the claudins
is in a segment of the first extracellular domain that is thought to
bridge the intracellular space. PCLN1 has a consensus threonine-X-valine
PDZ-binding domain at the C terminus. Unlike the other claudins, which
have an amino terminus of only 6 to 7 amino acids, PCLN1 encodes a
cytoplasmic amino terminus of 73 amino acids. This segment is highly
hydrophilic with a net positive charge. Northern blot analysis revealed
that PCLN1 is expressed as a 3.5-kb transcript that is found only in
kidney. Expression studies of PCLN1 indicated that PCLN1 mRNA is
detectable only in the thick ascending limb of Henle and in the distal
convoluted tubule. Confocal microscopy using antibodies to both PCLN1
and occludin (602876) demonstrated that both are found to colocalize,
indicating that PCLN1 is a component of the tight junction.
GENE STRUCTURE
Simon et al. (1999) determined that the CLDN16 gene consists of 5 exons,
each flanked by canonic splice donor and acceptor sequences.
GENE FUNCTION
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was CLDN16. These 37 genes included several
splicing factors for which knockdown generates mitotic spindle defects.
In addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
MOLECULAR GENETICS
- Renal Hypomagnesemia 3
Epithelia permit selective and regulated flux from apical to basolateral
surfaces by transcellular passage through cells or paracellular flux
between cells. Tight junctions constitute the barrier to paracellular
conductance. Renal magnesium ion resorption occurs predominantly through
a paracellular conductance in the thick ascending limb of Henle. In 10
kindreds with primary hypomagnesemia mapping to chromosome 3q (HOMG3;
248250), Simon et al. (1999) identified homozygosity and compound
heterozygosity for 10 different mutations in the PCLN1 gene, including
premature termination codons, splice site mutations, and missense
mutations (see, e.g., 603959.0001-603959.0009). Simon et al. (1999)
concluded that their results identified PCLN1 as a renal tight junction
protein that when mutated causes massive renal magnesium wasting with
hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and
renal failure. Simon et al. (1999) inferred that these mutations cause
loss of normal PCLN1 function and that no other genes are redundant in
function to PCLN1.
Weber et al. (2000) analyzed the PCLN1 gene in 8 families with
hypomagnesemia mapping to 3q27 and identified 8 different mutations. In
7 of 13 mutant alleles, they detected a leu151 substitution without
evidence for a founder effect: leu151 to phe (603959.0010), leu151 to
trp (603959.0011), and leu151 to pro (603959.0014). Leu151 is a residue
of the first extracellular loop of paracellin-1, the part of the protein
expected to bridge the intercellular space and to be important for
paracellular conductance. The study pointed to the predominant role of
paracellin in the paracellular reabsorption of divalent cations in the
thick ascending limb of the loop of Henle.
By transfecting mutant CLDN16 cDNAs into human and canine polarized
epithelial cells, Kausalya et al. (2006) found that 9 of 21
disease-associated mutant CLDN16 proteins were retained in the
endoplasmic reticulum, where they underwent proteasomal degradation. Of
the others, 3 accumulated in the Golgi complex, 2 were delivered to
lysosomes, and 7 localized to tight junctions. One of the 2 mutants
delivered to lysosomes was exposed on the cell surface prior to
internalization. Of the mutants delivered to the cell surface, 4 were
defective in paracellular Mg(2+) transport. Pharmacologic chaperones
rescued surface expression of several retained CLDN16 mutants.
In a 2.5-year-old Iranian boy with hypomagnesemia and nephrocalcinosis,
Muller et al. (2006) identified homozygosity for a nonsense mutation in
the CLDN16 gene (603959.0017). Studies in tissue culture cells
demonstrated that surface expression of the mutant CLDN16 was strongly
reduced and it was instead found in the endoplasmic reticulum and
lysosomes. Blocking clathrin (see 118955)-mediated endocytosis restored
cell surface expression of mutant CLDN16, suggesting a possible
therapeutic strategy for patients with this or similar CLDN16 mutations.
- Childhood Hypercalciuria, Self-Limiting
Weber et al. (2001) suggested that individuals heterozygous for CLDN16
mutations may be at increased risk of developing renal stone disease
(nephrolithiasis). Muller et al. (2003) screened a cohort of 11 families
with idiopathic hypercalciuria and identified a novel homozygous
mutation in the CLDN16 gene (T303R; 603959.0015) in 2 families. In
contrast to classic symptoms of familial hypomagenesemia with
hypercalciuria and nephrocalcinosis, patients displayed serious but
self-limiting childhood hypercalciuria (see 248250) with preserved
glomerular filtration rate. They showed that the mutation results in an
activation of a PDZ-domain binding motif, thereby disabling the
association of the tight junction scaffolding protein ZO1 (601009) with
CLDN16. In contrast to wildtype CLDN16, the mutant no longer localized
to tight junctions in kidney epithelial cells but instead accumulated in
lysosomes. Thus, mutations at different intragenic sites in the CLDN16
gene may lead to particular clinical phenotypes with a distinct
prognosis. Mutations in CLDN16 that affect interaction with ZO1 lead to
lysosomal mistargeting, providing insight into the molecular mechanism
of a disease-associated mutation in the CLDN16 gene.
ANIMAL MODEL
Ohba et al. (2000) showed that hereditary renal tubular dysplasia, an
autosomal recessive disease of Japanese black cattle, is associated with
deletion of a bovine chromosome 1 microsatellite marker. This region
includes sequences encoding bovine Cldn16. The authors suggested that
the cattle disease could be a model for human renal hypomagnesemia.
SNAR-I
| dbSNP name | rs13323015(C,T) |
| cytoBand name | 3q28 |
| EntrezGene GeneID | 100170222 |
| snpEff Gene Name | RP11-332P22.1 |
| EntrezGene Description | small ILF3/NF90-associated RNA I |
| EntrezGene Type of gene | snRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4458 |
PYDC2
| dbSNP name | rs293833(A,G) |
| cytoBand name | 3q28 |
| EntrezGene GeneID | 152138 |
| EntrezGene Description | pyrin domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PYDC2:NM_001083308:exon1:c.A242G:p.Q81R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q56P42 |
| dbNSFP Uniprot ID | PYDC2_HUMAN |
| dbNSFP KGp1 AF | 0.643772893773 |
| dbNSFP KGp1 Afr AF | 0.75406504065 |
| dbNSFP KGp1 Amr AF | 0.660220994475 |
| dbNSFP KGp1 Asn AF | 0.407342657343 |
| dbNSFP KGp1 Eur AF | 0.742744063325 |
| dbSNP GMAF | 0.3563 |
| ESP Afr MAF | 0.224756 |
| ESP All MAF | 0.245566 |
| ESP Eur/Amr MAF | 0.256018 |
| ExAC AF | 0.688 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Brownish macular and lentiginous lesions, disseminated, present on
extremities, trunk, and neck;
HISTOLOGY:;
Digitiform acanthosis of the rete ridges;
Pronounced hyperpigmentation at tips of rete ridges;
Small horn cysts;
Acanthosis, mild;
Hypergranulosis, focal
MISCELLANEOUS:
Age of onset varies between 18 years and 53 years
MOLECULAR BASIS:
Caused by mutation in the protein O-glucosyltransferase-1 gene (POGLUT1,
615618.0001)
OMIM Title
*615701 PYRIN DOMAIN-CONTAINING PROTEIN 2; PYDC2
;;PYRIN DOMAIN-ONLY PROTEIN 2; POP2
OMIM Description
DESCRIPTION
Pyrin domain (PYD) proteins are signaling molecules involved in host
defense against pathogens through activation of inflammatory mediator
pathways. PYDC2 binds to the central adaptor protein ASC (PYCARD;
606838) and to the PYD-containing pathogen recognition receptor PAN1
(NLRP2; 609364), thereby blocking formation of cryopyrin (NLRP3;
606416)- and PAN1-containing inflammasomes, activation of caspase-1
(CASP1; 147678), and processing and secretion of bioactive
interleukin-1-beta (IL1B; 147720) (Dorfleutner et al., 2007).
CLONING
By searching databases for sequences encoding cellular PYD-only proteins
(POPs), Dorfleutner et al. (2007) identified PYDC2, which they termed
POP2. The predicted 97-amino acid protein shares significant similarity
with the PYDs of various inflammasome proteins, including 61% identity
with the PYD of PAN1. RT-PCR analysis detected expression of a 294-bp
transcript in human myeloid cell lines. Confocal microscopy showed that
epitope-tagged POP2 localized primarily to nuclei and cytoplasmic
vesicular structures in transfected HEK293 cells.
Independently, Bedoya et al. (2007) also cloned and characterized POP2.
GENE FUNCTION
Using pull-down assays, coimmunoprecipitation analysis, and yeast
2-hybrid assays, Dorfleutner et al. (2007) showed that POP2 bound ASC
and PAN1 via PYD-PYD interactions. Immunofluorescence microscopy
demonstrated partial colocalization of POP2 with PAN1 and the PYD of ASC
in punctate cytoplasmic structures. Expression of POP2 with ASC and
cryopyrin or with ASC and PAN1 interfered with caspase-1 activation and
IL1B secretion. Dorfleutner et al. (2007) proposed that POP2 modulates
caspase-1 activation by specific inflammasomes.
Using transfection and luciferase analyses, Bedoya et al. (2007) showed
that POP2 inhibited TNF (191160)- and p65 (RELA; 164014)-induced NFKB
(see 164011)-dependent gene transcription via a mechanism involving
changes in NFKB nuclear import or distribution. Immunofluorescence
microscopy demonstrated that POP2 colocalized with ASC in perinuclear
specks, but POP2 also inhibited speck formation by CIAS1 (NLRP3;
606416). Bedoya et al. (2007) concluded that POP2 is a negative
regulator of NFKB activity that may influence the assembly of
PYD-dependent complexes.
GENE STRUCTURE
Dorfleutner et al. (2007) stated that the PYDC2 gene contains 1 exon.
MAPPING
Dorfleutner et al. (2007) stated that the PYDC2 gene maps to chromosome
3q28.
MGC2889
| dbSNP name | rs4687396(C,A); rs112278569(A,G); rs140122534(A,G); rs75362127(A,T); rs1814901(C,A); rs78436786(A,G); rs79731529(A,T); rs80343241(C,T) |
| ccdsGene name | CCDS3303.2 |
| cytoBand name | 3q29 |
| EntrezGene GeneID | 84789 |
| snpEff Gene Name | HRASLS |
| EntrezGene Description | uncharacterized protein MGC2889 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
DPPA2P3
| dbSNP name | rs9288760(C,T); rs6777021(G,A); rs62288198(G,A); rs62288199(G,A); rs111993093(T,C); rs6444762(A,G) |
| cytoBand name | 3q29 |
| EntrezGene GeneID | 100128023 |
| snpEff Gene Name | RP11-407B7.2 |
| EntrezGene Description | developmental pluripotency associated 2 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1396 |
FAM43A
| dbSNP name | rs1773221(A,G); rs63360263(A,C); rs1773219(A,G); rs9877161(G,A); rs1773218(A,G); rs813153(T,C); rs4677673(A,G); rs79296405(G,C) |
| cytoBand name | 3q29 |
| EntrezGene GeneID | 131583 |
| EntrezGene Description | family with sequence similarity 43, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3186 |
NCBP2-AS2
| dbSNP name | rs335824(C,T); rs3732874(G,A); rs3075(G,A) |
| cytoBand name | 3q29 |
| EntrezGene GeneID | 152217 |
| snpEff Gene Name | PIGZ |
| EntrezGene Description | NCBP2 antisense RNA 2 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4449 |
| ExAC AF | 0.267 |
LOC100129917
| dbSNP name | rs6840352(A,G); rs6811804(G,C) |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 100129917 |
| snpEff Gene Name | CPLX1 |
| EntrezGene Description | uncharacterized LOC100129917 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3039 |
IDUA
| dbSNP name | rs2045064(C,T); rs4690221(C,T); rs3822020(A,G); rs115548745(G,A); rs80086308(G,A); rs11936407(T,C); rs3822030(G,T); rs3806756(C,G); rs3806758(G,C); rs3806759(G,A); rs3806760(A,G); rs10471249(T,C); rs10471250(T,C); rs150831164(C,G); rs28504164(C,T); rs4690222(G,A); rs1799846(A,G); rs935966(G,A); rs55796339(T,C); rs3755957(C,T); rs3755955(G,A); rs3733342(G,A); rs3733341(C,G); rs6815946(T,C); rs6829789(G,C); rs6848974(C,T); rs201826605(G,C) |
| ccdsGene name | CCDS3343.1 |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 3425 |
| EntrezGene Description | iduronidase, alpha-L- |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IDUA:NM_000203:exon6:c.G701C:p.S234T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6251 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.002286 |
| ESP All MAF | 0.000772 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002791 |
OMIM Clinical Significance
Eyes:
Progressive peripheral annular corneal opacification
Neuro:
Normal intelligence
Cardiac:
Valvular heart disease
Facies:
Hurler-like facies
Limbs:
Swollen fingers
Growth:
Dwarfed stature
Joints:
Progressive joint destruction
Misc:
Pseudo-Hurler or Hurler-like variable features
Lab:
Mucopolysacchariduria (both chondroitin sulfate B and heparitin sulfate);
Alpha-iduronidase deficiency in some cases;
Fibroblast metachromasia;
Increased fibroblast mucopolysaccharide;
Normal urinary mucopolysaccharide;
Mucopolysaccharide accumulations in perichondrium, coronary arteries,
aorta, and renal glomerular epithelial cells;
Lipid accumulations in peripheral neurons but not in central neurons
Inheritance:
Autosomal recessive
OMIM Title
*252800 ALPHA-L-IDURONIDASE; IDUA
;;IDURONIDASE, ALPHA-L
OMIM Description
DESCRIPTION
Alpha-L-iduronidase (IDUA; EC 3.2.1.76), the enzyme deficient in MPS I
(see 607014, 607015, and 607016), hydrolyzes the terminal
alpha-L-iduronic acid residues of the glycosaminoglycans dermatan
sulfate and of heparan sulfate (Neufeld and Muenzer, 2001). It was
originally defined as the 'Hurler corrective factor' (Barton and
Neufeld, 1971).
CLONING
Scott et al. (1990) used amino acid sequence data from purified human
liver IDUA (Clements et al., 1989) to isolate both a genomic clone and a
cDNA clone for IDUA. Scott et al. (1991) isolated and sequenced cDNA
clones containing part of the human IDUA coding region and used PCR from
reverse-transcribed RNA to obtain the full IDUA sequence. Analysis of
the predicted 653-amino acid precursor protein showed that IDUA has a
26-amino acid signal peptide that is cleaved immediately before the
amino terminus of the 74-kD polypeptide present in human liver IDUA. The
protein sequence contains 6 potential N-glycosylation sites. Evidence of
alternatively spliced mRNA from the IDUA gene was found in fibroblasts,
liver, kidney, and placental RNA.
GENE STRUCTURE
Scott et al. (1992) demonstrated that the IDUA gene spans approximately
19 kb and contains 14 exons. The first 2 exons are separated by an
intron of 566 bp; a large intron of approximately 13 kb follows, and the
last 12 exons are clustered within 4.5 kb.
MAPPING
By in situ hybridization and Southern blot analysis of mouse-human cell
hybrids, Scott et al. (1990) determined that the IDUA gene maps to
4p16.3, not to chromosome 22 as earlier reported by Schuchman et al.
(1982, 1984). Scott et al. (1990) confirmed the presence of human IDUA
activity in human-mouse cell hybrids by using a monoclonal antibody
specific to human IDUA. Scott et al. (1992) found that the polymorphic
locus D4S111 used in the diagnosis of Huntington disease (143100) is the
consequence of an 86-bp variable number tandem repeat (VNTR) within the
IDUA gene. The gene mapped to chromosome 22 by Schuchman et al. (1982,
1984) by use of a polyclonal antibody in human-mouse cell hybrids may
have been a crossreacting protein.
Grosson et al. (1994) mapped the homologous locus in the mouse, Idua, to
chromosome 5 in a continuous linkage group that included the homolog of
the Huntington disease gene.
MOLECULAR GENETICS
Scott et al. (1990) failed to detect major deletions or gene
rearrangements in the IDUA gene in any of the 40 MPS I patients studied
by Southern blot analysis.
Scott et al. (1992) reported the presence of a common mutation
accounting for 31% of MPS I alleles in a study of 64 MPS I patients.
Chemical cleavage and then direct PCR sequencing detected the mutation.
The mutation is a single base substitution that introduces a stop codon
at position 402 (W402X; 252800.0001) of the alpha-L-iduronidase protein
and is associated with an extremely severe clinical phenotype in
homozygotes. Patients who are compound heterozygotes having one allele
carrying the W401X mutation have a wide range of clinical phenotypes.
Scott et al. (1992) identified 2 additional mutations, one that
introduces a stop codon at position 70 (Q70X; 252800.0002) and the other
that alters the proline at position 533 to an arginine (P533R;
252800.0003) in the 653 amino acid alpha-L-iduronidase protein.
Allele-specific oligonucleotides were used to detect the mutations in a
group of 73 MPS I patients and Q70X was found to account for 15% of all
MPS I alleles and P533R for 3% of MPS I alleles. Both mutations are
associated with an extremely severe clinical phenotype in homozygotes.
MPS I patients heterozygous for either mutation may have a wide range of
clinical phenotypes. Mutations W402X (Scott et al., 1992), Q70X, and
P533R accounted for 53% of MPS I alleles, which together define 28% of
MPS I genotypes.
Bunge et al. (1995) identified 13 novel and 7 previously reported
mutations of the IDUA gene, covering 88% of mutant alleles and 86% of
genotypes, in a total of 29 patients with MPS I of differing clinical
severity.
Scott et al. (1995) stated that 46 disease-producing mutations and 30
polymorphisms had been identified in the IDUA gene. In a mutation
analysis of 85 mucopolysaccharidosis families (73 Hurler, 5
Hurler/Scheie, 7 Scheie), Beesley et al. (2001) identified 165 of the
170 mutant alleles. The 85 MPS I families were screened for 9 known
mutations. W420X was the most frequent mutation in their population
(43.3%) and Q70X was the second most frequent (15.9%). In 30 families,
either one or both of the mutations were not identified, which accounted
for 25.9% of the total alleles. All 14 exons of the alpha-L-iduronidase
gene were then screened in those patients and 23 different sequence
changes were found, 17 of which were previously unknown. The novel
sequence changes included 4 deletions, 6 missense mutations, a splice
site mutation, and a rare polymorphism.
Alleles that cause the milder phenotypes, Hurler/Scheie and Scheie
syndromes, are often missense mutations. Tieu et al. (1995) reported 4
novel mutations of the IDUA gene in 1 patient with the Scheie syndrome
and in 3 patients with the Hurler/Scheie syndrome. The novel mutations,
all single base changes, encoded the substitutions R492P (252800.00011)
(Scheie) and X654G (252800.0013), P496L, and L490P (252800.0012)
(Hurler/Scheie). The L490P mutation was apparently homozygous, whereas
each of the others was found in compound heterozygosity with a Hurler
mutation. The deleterious nature of the mutations was confirmed by
absence of enzyme activity upon transfection of the corresponding
mutagenized cDNAs into COS-1 cells.
Aronovich et al. (1996) described the molecular defect underlying IDUA
pseudodeficiency. The study was prompted by a patient who appeared to
have, by biochemical study, both MPS I and MPS II. The common IDS
mutation R468W (309900.0012) was found in the proband, his mother, and
his sister, confirming transmission of Hunter syndrome. Additionally,
the proband, his sister, and his father were found to be heterozygous
for a common IDUA mutation, W402X (252800.0001). Notably, a new IDUA
mutation, A300T (252800.0016), was identified in the proband, his
sister, and his mother, accounting for reduced IDUA activity in these
individuals. The proband's sister was asymptomatic and her cells
demonstrated normal glycosaminoglycan metabolism, thus demonstrating
that the W402X/A300T compound heterozygous genotype is an IDUA
pseudodeficiency state.
POPULATION GENETICS
Bunge et al. (1994) screened 46 European patients with
mucopolysaccharidosis type I for mutations in the IDUA gene. The 2
common nonsense mutations, W402X and Q70X, were identified in 37% and
35% of mutant alleles, respectively. Considerable differences were seen
in the frequency of these 2 mutations in patients from northern Europe
(Norway and Finland) and other European countries (mainly the
Netherlands and Germany). In Scandinavia, W402X and Q70X accounted for
17% and 62% of the MPS I alleles, respectively, whereas in other
European countries W402X was about 2.5 times more frequent (48%) than
Q70X (19%).
Gatti et al. (1997) screened 27 Italian MPS I patients for IDUA
mutations. Mutations were found in 18 patients, with 28 alleles
identified. The 2 common mutations in northern Europeans (W402X and
Q70X) accounted for only 11% and 13% of the alleles, respectively. The
R89Q i(252800.0015) mutation, uncommon in Europeans, was found in 1
patient, accounting for 1 of 54 alleles (1.9%). The P533R, A327P and
G51D mutations accounted for 11%, 5.6%, and 9.3% of the total alleles,
respectively. The P533R mutation was relatively frequent in Sicily.
In a study of Israeli-Arab MPS I patients, Bach et al. (1993) identified
4 alleles, none of which had been found in Europeans. In all instances,
the probands were homozygous and the parents heterozygous for the mutant
alleles, as anticipated from the consanguinity in each family. One
allele had 2 amino acid substitutions and was identified in a family
from Gaza. The 3 single-substitution alleles were found in 7 families, 5
of them Druze, residing in a very small area of northern Israel,
suggesting a founder effect.
Yamagishi et al. (1996) studied mutations in the IDUA gene from 19
Japanese MPS I patients, including 2 pairs of sibs, with various
clinical phenotypes (Hurler, 6 cases; Hurler/Scheie, 7 cases; Scheie, 6
cases). Two common mutations accounted for 42% of the 38 alleles in
their patients: a novel 5-bp insertion (704ins5; 252800.0014), which had
not been found other populations, accounted for 18%, and an R89Q
mutation, found uncommonly in Caucasians, accounted for 24%. None of the
patients carried W402X or the Q79X mutations commonly found in
Caucasians. Homozygosity for the 704ins5 mutation was associated with a
severe phenotype, and the R89Q mutation was associated with a mild
phenotype. Compound heterozygosity for these 2 mutations produced an
intermediate phenotype. Haplotype analysis using polymorphisms linked to
the IDUA locus demonstrated that each mutation occurs on a different
specific haplotype, suggesting that individuals with each of these
common mutations derive from common founders. The data documented the
molecular heterogeneity and racial differences in mutations in MPS I.
Li et al. (2002) screened 22 unrelated MPS I patients from the United
States and identified 11 different mutations in the IDUA gene, including
4 novel ones. The Q70X mutation (252800.0002) was found in 30% of
alleles and the W402X mutation (252800.0001) was identified in 39% of
alleles.
Lee et al. (2004) performed mutation analysis of the IDUA gene in 10
unrelated Korean patients with the various clinical phenotypes of MPS I
and identified 7 different mutations, 4 of which were novel. The 704ins5
mutation (252800.0014) was found in 4 patients and the L346R mutation
(252800.0020) in 6. These 2 mutations accounted for half the mutations
found in Korean MPS I patients.
ANIMAL MODEL
Stoltzfus et al. (1992) cloned and characterized cDNA encoding the
canine alpha-L-iduronidase and demonstrated mRNA deficiency in the MPS I
dog. Menon et al. (1992) demonstrated that the canine IDUA gene has 14
exons spread over 13 kb. An unusual GC dinucleotide was found at the
donor splice site of intron 11. A transcriptional start site was
identified by primer extension 177 bp upstream of the initiator AUG
codon. The upstream region was found to be similar to the promoter
region of many housekeeping genes: it is GC rich and has 7 potential Sp1
binding sites but no TATA box or CAAT motif. The mutation in canine MPS
I was found to be a G-to-A transition in the donor splice site in intron
1. The mutation caused retention of intron 1 in the RNA and created a
premature termination codon at the exon-intron junction.
CRIPAK
| dbSNP name | rs13135515(A,T); rs35852462(T,A); rs13114537(G,C); rs13142985(A,G); rs57037487(A,G); rs34299899(A,G); rs11729037(A,G); rs75492419(C,T); rs6599308(A,G); rs116818578(C,T); rs6599309(C,G) |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 285464 |
| snpEff Gene Name | KIAA1530 |
| EntrezGene Description | cysteine-rich PAK1 inhibitor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2328 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, cortical pulverulent, juvenile-onset;
Cataracts, congenital, cerulean;
Microcornea (2 of 5 patients);
Coloboma of iris (1 of 5 patients)
MOLECULAR BASIS:
Caused by mutation in the v-Maf avian musculoaponeurotic fibrosarcoma
oncogene homolog (MAF, 177075.0001)
OMIM Title
*610203 CYSTEINE-RICH INHIBITOR OF PAK1; CRIPAK
;;FLJ34443
OMIM Description
DESCRIPTION
CRIPAK is a negative regulator of PAK1 (602590) that is upregulated by
estrogen (Talukder et al., 2006).
CLONING
By yeast 2-hybrid screening of a mammary gland cDNA expression library
to identify PAK1-interacting proteins, Talukder et al. (2006) cloned
CRIPAK. The predicted 446-amino acid protein contains an N-terminal C4
zinc finger domain, followed by 12 C3H zinc finger domains. Northern
blot analysis detected wide expression of CRIPAK, with highest levels in
trachea, prostate, and adrenal gland. RT-PCR revealed CRIPAK expression
in all cancer cell lines examined. Confocal microscopy of transfected
breast cancer cells showed that CRIPAK had a predominant cytoplasmic and
membrane localization; in some areas, CRIPAK partially colocalized with
PAK1.
GENE FUNCTION
Using GST pull-down and coimmunoprecipitation analyses, Talukder et al.
(2006) confirmed the interaction between CRIPAK and PAK1. Mutational
analysis defined the binding regions as amino acids 132 to 270 of PAK1
and amino acids 367 to 446 of CRIPAK. Kinase assays showed that CRIPAK
was not a substrate of PAK1, and CRIPAK inhibited both PAK1-mediated
protein phosphorylation and autophosphorylation in vitro and
intracellularly. Luciferase analysis revealed that CRIPAK inhibited both
PAK1-dependent and -independent activation of estrogen receptor (ESR1;
133430). Confocal microscopy showed that, in the presence of estrogen,
CRIPAK localization shifted from the cytoplasm to the nuclear
compartment, where it colocalized with ESR. During small interfering
RNA-mediated downregulation of CRIPAK, PAK1 activity increased. Talukder
et al. (2006) concluded that CRIPAK is upregulated by hormones and that
it negatively regulates PAK1 kinase activity.
GENE STRUCTURE
Talukder et al. (2006) determined that the CRIPAK gene is intronless.
MAPPING
By genomic sequence analysis, Talukder et al. (2006) mapped the CRIPAK
gene to chromosome 4p16.3.
MIR943
| dbSNP name | rs1077020(T,C) |
| ccdsGene name | CCDS3358.2 |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 100126332 |
| snpEff Gene Name | WHSC1 |
| EntrezGene Description | microRNA 943 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2608 |
| ESP Afr MAF | 0.333333 |
| ESP All MAF | 0.24854 |
| ESP Eur/Amr MAF | 0.211651 |
| ExAC AF | 0.204 |
NOP14-AS1
| dbSNP name | rs1419045(T,G); rs58279895(C,T); rs2185885(A,G); rs2798287(C,A); rs1263338(C,T) |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 317648 |
| snpEff Gene Name | NOP14 |
| EntrezGene Description | NOP14 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2631 |
ADRA2C
| dbSNP name | rs76337672(G,C) |
| cytoBand name | 4p16.3 |
| EntrezGene GeneID | 152 |
| EntrezGene Description | adrenoceptor alpha 2C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3779 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, sensorineural, especially affecting high frequencies
CARDIOVASCULAR:
[Vascular];
Hypertension
GENITOURINARY:
[Kidneys];
Glomerulonephropathy;
Hematuria, gross and microscopic;
Proteinuria;
End-stage renal failure;
Thinning of the glomerular basement membrane (early in the disease);
Thickening of the glomerular basement membrane (later in the disease);
Splitting of the glomerular basement membrane;
Diffuse lamellation of the glomerular basement membrane
LABORATORY ABNORMALITIES:
Hematuria, gross and microscopic;
Proteinuria
MISCELLANEOUS:
Progressive disorder;
Hearing loss is variable
MOLECULAR BASIS:
Caused by mutation in the collagen, type IV, alpha-3 gene (COL4A3,
120070.0009)
OMIM Title
+104250 ALPHA-2C-ADRENERGIC RECEPTOR; ADRA2C
;;ALPHA-2-ADRENERGIC RECEPTOR, RENAL TYPE
CONGESTIVE HEART FAILURE AND BETA-BLOCKER RESPONSE, MODIFIER OF, INCLUDED
OMIM Description
CLONING
Regan et al. (1988) cloned ADRA2C from a human kidney cDNA library using
the gene for the human platelet alpha-2-adrenergic receptor (ADRA2A;
104210) as a probe. The deduced amino acid sequence resembled the human
platelet alpha-2-adrenergic receptor. In this work, Regan et al. (1988)
achieved expression of the receptor in cultured cells, free of other
adrenergic receptor subtypes; this approach should help in developing
more selective alpha-adrenergic ligands for pharmaceutical purposes.
By use of RT-PCR and Northern blotting, Eason and Liggett (1993) found
that ADRAC2 is expressed in most tissues as a 2.8-kb mRNA, but is not
expressed in liver, fat, stomach, or colon. Schaak et al. (1997)
reported that the 5-prime untranslated region of the ADRA2C gene is 891
bp long and the 3-prime untranslated region 550 bp. Thus, the mRNA is
approximately 2,840 bp long.
GENE STRUCTURE
By studying cosmid clones covering the entire gene, Riess et al. (1994)
found that the ADRA2C gene is intronless.
MAPPING
Hoehe et al. (1989) found close linkage between the G8 (D4S10) marker of
Huntington disease (HD; 143100) and a RFLP of the ADRA2C gene; thus, the
ADRA2C gene is presumably in band 4p16.1.
Using 2 (GT)n repeats in close proximity to the ADRA2C gene, Riess et
al. (1994) analyzed its precise location. Linkage disequilibrium (LD)
studies of a microsatellite in HD families showed strong nonrandom
association to the HD mutation, indicating tight linkage to the HD gene.
The investigation of families carrying recombinant chromosomes,
pulsed-field analysis, and genomic walking mapped the ADRA2C gene
adjacent to D4S81, 500 kb proximal to the HD gene.
MOLECULAR GENETICS
In a study of 54 patients with congestive heart failure treated with the
beta-blocker metoprolol, Lobmeyer et al. (2007) found that the ADRB1
(109630) R389G and the del322-325 ADRA2C polymorphisms synergistically
influenced the ejection fraction response to beta-blocker therapy.
ANIMAL MODEL
Alpha-2-adrenergic receptors have a critical role in regulating
neurotransmitter release from sympathetic nerves and from adrenergic
neurons in the central nervous system. To help elucidate the individual
roles of the 3 highly homologous alpha-2-adrenergic receptors (ADRA2A;
ADRA2B, 104260; and ADRA2C) in this process, Hein et al. (1999) studied
neurotransmitter release in mice in which the genes encoding the 3
alpha-2-adrenergic receptor subtypes were disrupted. Hein et al. (1999)
demonstrated that both the ADRA2A and ADRA2C subtypes are required for
normal presynaptic control of transmitter release from sympathetic
nerves in the heart and from central noradrenergic neurons. ADRA2A
receptors inhibited transmitter release at high stimulation frequencies,
whereas the ADRA2C subtype modulated neurotransmission at lower levels
of nerve activity. Both low and high frequency regulation seemed to be
physiologically important, as mice lacking both ADRA2A and ADRA2C
receptor subtypes had elevated plasma noradrenaline concentrations and
developed cardiac hypertrophy with decreased left ventricular
contractility by 4 months of age.
WFS1
| dbSNP name | rs4689389(G,A); rs4234726(G,C); rs112734131(C,T); rs4280818(T,G); rs56737083(A,G); rs4996963(G,A); rs10002743(G,A); rs62283056(G,C); rs73795934(A,G); rs6833959(G,A); rs10937713(G,A); rs4513637(G,A); rs4558932(C,T); rs79035843(C,T); rs6824720(A,G); rs10937714(C,T); rs28420833(G,A); rs78467194(C,T); rs4689391(G,A); rs58630370(T,C); rs11727100(A,C); rs4476672(A,G); rs4328980(A,G); rs4262051(G,A); rs752854(C,T); rs1079214(T,C); rs9997552(C,T); rs1079215(A,G); rs1079216(T,C); rs3889821(C,T); rs12511160(C,A); rs12499820(A,G); rs9997824(T,C); rs148627651(C,T); rs10028718(C,T); rs10005859(G,A); rs10028875(C,T); rs142174837(T,C); rs10008312(G,A); rs78191003(C,A); rs113254625(G,A); rs10001190(A,G); rs4568307(A,G); rs4343789(C,G); rs4688985(A,G); rs4688986(C,A); rs4689392(G,A); rs4234729(T,C); rs79270851(C,T); rs9993624(C,T); rs3821940(C,A); rs182881351(C,T); rs6817447(G,T); rs3821942(A,G); rs4689393(T,C); rs4688987(C,T); rs4688988(C,T); rs12508672(G,A); rs116433160(A,G); rs4458523(T,G); rs4342257(G,C); rs56141488(C,G); rs4688989(T,C); rs71524348(G,T); rs112871383(C,T); rs4689394(C,G); rs145989135(G,A); rs139981753(T,C); rs6446479(G,C); rs4280817(G,T); rs4293850(A,C); rs11732178(G,C); rs11732208(G,C); rs5018647(A,C); rs5018648(C,G); rs71539642(G,A); rs9998519(C,T); rs10010131(A,G); rs9998835(C,G); rs10012946(T,C); rs13101355(T,C); rs13147655(A,G); rs1801213(C,G); rs7655482(T,C); rs11729672(A,G); rs11725494(C,T); rs11725500(C,G); rs4416547(G,A); rs193127193(A,G); rs4308429(A,G); rs4308430(A,G); rs4467645(C,T); rs13128674(C,T); rs13103357(A,G); rs10026334(G,A); rs13108780(A,G); rs142246306(G,A); rs13114527(T,G); rs74711425(C,T); rs12649341(G,A); rs10755148(A,G); rs10937719(C,G); rs61251604(G,A); rs6838400(C,G); rs10937720(A,G); rs6446480(C,T); rs6446482(C,G); rs28625666(A,T); rs28729642(C,T); rs73071607(C,T); rs4689395(G,A); rs4234730(A,G); rs111789569(C,T); rs113887414(T,C); rs13130845(A,C); rs77463352(G,A); rs4481292(C,T); rs4501291(C,T); rs61450979(G,A); rs113703919(C,A); rs79408528(C,T); rs4689397(G,A); rs881796(C,T); rs4234731(A,G); rs3821943(C,T); rs146638864(C,T); rs141394240(G,T); rs61706555(T,C); rs113823191(C,G); rs12642481(G,A); rs112428272(T,A); rs74889336(A,T); rs4689398(C,T); rs4688991(C,G); rs1801212(G,A); rs56072215(C,T); rs1801206(C,T); rs1801208(G,A); rs1801214(C,T); rs138232538(G,A); rs734312(G,A); rs71524375(C,T); rs140427062(C,T); rs1046316(A,G); rs1046317(T,C); rs1802453(G,A); rs1046319(C,T); rs1046320(G,A); rs1046322(G,A); rs1046325(A,G); rs111800114(C,A); rs75810305(G,C); rs9457(G,C); rs3200(C,T) |
| ccdsGene name | CCDS3386.1 |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 7466 |
| EntrezGene Description | Wolfram syndrome 1 (wolframin) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | WFS1:NM_006005:exon4:c.C325T:p.H109Y,WFS1:NM_001145853:exon4:c.C325T:p.H109Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5937 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O76024 |
| dbNSFP Uniprot ID | WFS1_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.076e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Jerky smooth pursuit
RESPIRATORY:
[Larynx];
Glottic airway narrowing caused by laryngeal abductor paralysis;
Hoarseness;
Laryngeal stridor;
Nocturnal dyspnea
MUSCLE, SOFT TISSUE:
Mild distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Progressive cerebellar ataxia;
Gait ataxia;
Dysmetria;
Limb fasciculations;
Cerebellar atrophy;
EMG shows neurogenic findings
VOICE:
Dysphonia
MISCELLANEOUS:
Onset in adulthood;
May be X-linked
OMIM Title
*606201 WFS1 GENE; WFS1
;;WOLFRAMIN
OMIM Description
CLONING
Strom et al. (1998) screened 4 candidate genes in a refined critical
linkage interval for Wolfram syndrome (222300) on chromosome 4p16. One
of these genes, WFS1, which they called 'wolframin,' codes for a
predicted 890-amino acid transmembrane protein with a calculated
molecular mass of about 100 kD. WFS1 was predicted to have 9 central
transmembrane domains, with an extracytoplasmic N terminus and an
intracytoplasmic C terminus. Human WFS1 shares 87% amino acid identity
with its mouse homolog. Northern blot analysis detected a 3.6-kb
transcript in all human tissues examined. Expression was strong in
heart, intermediate in brain, placenta, lung, and pancreas, and weak in
liver, skeletal muscle, and kidney.
Independently, Inoue et al. (1998) positionally cloned the WFS1 gene.
They obtained the full-length cDNA by screening an infant brain cDNA
library, followed by 5-prime RACE. The WFS1 hydrophobicity curve
suggested the presence of approximately 10 transmembrane segments in
WFS1. Northern blot analysis detected a major transcript of 3.7 kb in
all human tissues examined, including pancreas. Northern blot analysis
of total RNA showed high expression of WFS1 in pancreatic islets
compared with exocrine pancreas.
Hofmann et al. (2003) reported that wolframin is ubiquitously expressed,
with highest levels in brain, pancreas, heart, and insulinoma beta-cell
lines. Wolframin assembled into higher molecular weight complexes of 400
kD in the membrane, and N-glycosylation was essential for its biogenesis
and stability.
By Western blot, Berry et al. (2013) demonstrated expression of Wfs1 in
whole mouse eye at embryonic day 18.5 (E18.5) and in whole lens tissue
extract at postnatal days 3 and 21. Immunocytochemistry demonstrated
high-level expression of Wfs1 in the developing mouse lens at E18.5, but
not at E12.5.
GENE STRUCTURE
Inoue et al. (1998) found that the WFS1 gene contains 8 exons, spanning
33.4 kb of genomic DNA.
MAPPING
By genomic sequence analysis, Strom et al. (1998) mapped the WFS1 gene
to chromosome 4p16.
GENE FUNCTION
Using biochemical methods, Takeda et al. (2001) showed that the WFS1
protein is an integral, endoglycosidase H-sensitive membrane
glycoprotein that localizes primarily in the endoplasmic reticulum (ER).
Immunofluorescence staining of overexpressed WFS1 in transiently
transfected COS-7 cells showed a characteristic reticular pattern over
the cytoplasm and overlapped with ER marker staining. In rat brain, at
both the protein and mRNA level, WFS1 was present predominantly in
selected neurons in the hippocampus CA1, amygdaloid areas, olfactory
tubercle, and superficial layer of the allocortex.
Osman et al. (2003) found that human WFS1 expressed in Xenopus oocytes
localized to the ER. Planar oocyte lipid bilayers containing WFS1 showed
a large cation-selective channel activity that was blocked by Mg(2+) or
Ca(2+). Fused bilayers containing WFS1 showed an elevated slope
conductance following activation by inositol 1,4,5-triphosphate. Osman
et al. (2003) proposed that WFS1 functions as an ER calcium channel or
as a regulator of ER calcium channel activity.
Using real-time PCR, Fonseca et al. (2005) found that Wfs1 was induced
by ER stress in mouse fibroblasts and that its expression was controlled
by Ire1-alpha (ERN1; 604033) and Perk (EIF2AK3; 604032), which are
involved in the unfolded protein response. Expression of Wfs1 was
upregulated in mouse islets during glucose-induced insulin secretion,
and knockdown of Wfs1 in mouse beta cells resulted in ER stress and cell
dysfunction. Fonseca et al. (2005) hypothesized that Wolfram syndrome
involves chronic ER stress in pancreatic beta cells.
Using yeast 2-hybrid analysis, Zatyka et al. (2008) found that the
C-terminal domain of WFS1, which is positioned in the ER lumen, bound
the C-terminal domain of the ER-localized Na+/K+ ATPase beta-1 subunit
(ATP1B1; 182330). The interaction was confirmed by reciprocal
coimmunoprecipitation analysis of proteins expressed in transfected
COS-7 cells and endogenous proteins in human and mouse cell lines.
Wolfram syndrome patient fibroblasts with 2 different WFS1 mutations
showed reduced ATP1B1 levels. Conversely, knockdown of Atp1b1 expression
in a mouse insulinoma cell line led to reduced Wfs1 expression. Zatyka
et al. (2008) concluded that interaction with WFS1 may be important for
ATP1B1 maturation in the ER and that loss of this interaction may
contribute to the pathology seen in Wolfram syndrome.
MOLECULAR GENETICS
- Wolfram Syndrome 1
Strom et al. (1998) identified loss-of-function mutations in both
alleles of the WFS1 gene in patients with Wolfram syndrome-1 (WFS1;
222300). Homozygous mutations were found in 5 families; compound
heterozygosity was found in 3 other families. In a ninth family, only a
heterozygous stop mutation was found. No mutations in either allele were
detected in 3 other families. One of the families was reportedly
consanguineous but no mutations were detected in that family. Mutations
in exon 1, which was not included in the mutation screen, intronic
mutations including deletions, or mutations in the regulatory flanking
regions of the gene could be pathogenic in these families.
Hardy et al. (1999) performed direct DNA sequencing to screen the entire
coding region of the WFS1 gene in 30 patients from 19 British kindreds
with Wolfram syndrome. DNA was also screened for structural
rearrangements (deletions and duplications) and point mutations in
mtDNA. No pathogenic mtDNA mutations were found in this cohort. The
authors identified 24 mutations in the WFS1 gene: 8 nonsense mutations,
8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4
frameshift mutations. Of these, 23 were novel mutations, and most
occurred in exon 8. Most patients were compound heterozygotes for 2
mutations, and there was no common founder mutation. The data were also
analyzed for genotype-phenotype relationships. Although some interesting
cases were noted, consideration of the small sample size and frequency
of each mutation indicated no clear-cut correlations between any of the
observed mutations and disease severity. There were no obvious mutation
hotspots or clusters.
Khanim et al. (2001) stated that mutation analysis of the WFS1 gene had
identified mutations in 90% of patients with Wolfram syndrome. Most were
compound heterozygotes with private mutations distributed throughout the
gene with no obvious hotspots.
Colosimo et al. (2003) identified 19 different mutations in the WFS1
gene in a study of 19 Italian patients with Wolfram syndrome. Mutations
were found in 18 of the 19 patients (95%). All of the mutations except 1
were novel, were preferentially located in WFS1 exon 8, and included
deletions, insertions, duplications, and nonsense and missense changes.
In particular, a 16-bp deletion in WFS1 codon 454 (606201.0019) was
detected in 5 different unrelated nuclear families, being the most
prevalent alteration in these Italian patients.
In a review of the mutational spectrum of the WFS1 gene, Cryns et al.
(2003) pointed out that mutations associated with Wolfram syndrome are
spread over the entire coding region and are typically inactivating,
suggesting that a loss of function causes the disease phenotype. In
contrast, only noninactivating mutations have been found in DFNA6/14
families, and these mutations are mainly located in the C-terminal
protein domain.
In a study of 6 Spanish families with a total of 7 Wolfram syndrome
patients, Domenech et al. (2004) identified 3 previously undescribed
mutations in the WFS1 gene as well as the duplication 409dup16
(606201.0013), previously reported as 425ins16 (Gomez-Zaera et al.,
2001).
Hansen et al. (2005) identified mutations in the WFS1 gene in 8 affected
members of 7 Danish families with Wolfram syndrome. Four of the
mutations were novel. Mutations were identified in 11 of 14 disease
chromosomes; in 3 families, only 1 mutation was found.
Zalloua et al. (2008) performed family-based linkage analysis followed
by systematic screening of WFS1 exons in Lebanese juvenile-onset
insulin-dependent diabetes (222100) probands and found homozygous or
compound heterozygous WFS1 mutations in 22 (5.5%) of the 399 probands,
of whom 17 were diagnosed with WFS and 5 with nonsyndromic nonautoimmune
diabetes mellitus. Overall, 38 probands and affected family members were
homozygous or compound heterozygous for WFS1 mutations, 11 (29%) of whom
were diagnosed with nonsyndromic DM; all of the latter patients carried
a complex WFS1 mutation (606201.0024), which the authors designated
WFS1(LIB) and which resulted in the delayed onset or absence of
extrapancreatic features of WFS. In addition, there were 2 patients with
an initial diagnosis of nonsyndromic DM that was revised to WFS when
they developed optic atrophy during the course of the study; Zalloua et
al. (2008) noted that longer follow-up of the WFS1-mutated nonsyndromic
DM patients or a specific study of adult patient populations would be
needed to determine whether a subset of the WFS1(LIB) patients are
exempted from extrapancreatic manifestations during their lifetime.
- Pathophysiology of WFS1 Mutations in Wolfram Syndrome
In a patient carrying both a nonsense (frameshift) and a missense
mutation, Hofmann et al. (2003) detected mRNA levels half that of
controls; sequencing confirmed that these transcripts were exclusively
derived from the missense allele. Transfection experiments with the
missense transcript revealed a markedly reduced steady-state level of
wolframin and a strongly reduced half-life. Hofmann et al. (2003)
concluded that the pathophysiology in Wolfram syndrome in the presence
of a missense mutation is likely that of reduced protein dosage rather
than dysfunction of the mutant protein.
By analyzing WFS1 patient cells and COS-7 cells expressing 4 missense
and 2 truncating mutations in WFS1, Hofmann and Bauer (2006) found that
all mutations led to drastically reduced steady-state levels of WFS1
protein. Mutant proteins were highly unstable and were removed by
proteasomal degradation. Hofmann and Bauer (2006) concluded that WFS1
mutations cause loss of function by cellular depletion of WFS1.
- Autosomal Dominant Nonsyndromic Sensorineural Deafness
Bespalova et al. (2001) defined a subset of nonsyndromic sensorineural
hearing loss affecting low frequencies without profound deafness
(600965) in which all individuals studied had WFS1 mutations (e.g.,
606201.0015). This subset included families that had been linked to loci
designated DFNA6 and DFNA14. Bespalova et al. (2001) concluded that
mutations in the WFS1 gene are a common cause of sensorineural hearing
loss. Additionally, an autosomal dominant sensorineural hearing loss
designated DFNA38 was shown to be caused by mutation in the WFS1 gene
(606201.0014).
Cryns et al. (2002) stated that only 2 of the more than 70 loci
identified as associated with hereditary hearing impairment are
associated with an auditory phenotype that predominantly affects the low
frequencies: DFNA1 (124900) and DFNA6/14 (600965). Cryns et al. (2002)
did mutation screening of the WFS1 gene in 8 autosomal dominant families
and 12 sporadic cases in which affected persons had low-frequency
sensorineural hearing impairment. They identified 7 missense mutations
and a single amino acid deletion affecting conserved amino acids in 6
families and 1 sporadic case, indicating that mutations in WFS1 are a
major cause of inherited low-frequency hearing impairment. Among the 10
WFS1 mutations reported in low-frequency sensorineural hearing
impairment, none was expected to lead to premature protein termination,
and 9 clustered in the C-terminal protein domain. In contrast, 64% of
the Wolfram syndrome mutations are inactivating. The results indicated
that only noninactivating mutations in WFS1 are responsible for
nonsyndromic low-frequency hearing impairment.
Fukuoka et al. (2007) analyzed the WFS1 gene in 206 Japanese autosomal
dominant and 64 autosomal recessive (sporadic) nonsyndromic hearing loss
probands with varying severities of hearing loss and identified 2
different missense mutations in 3 unrelated families (see 606201.0014
and 606201.0020, respectively). All of the mutation-positive patients
had dominantly inherited low-frequency sensorineural hearing loss.
Because both mutations had previously been identified in patients of
European ancestry, Fukuoka et al. (2007) suggested that the sites are
likely to be mutation hotspots.
- Autosomal Dominant Wolfram-like Syndrome
Domenech et al. (2002) screened the WFS1 gene in 48 patients with
autosomal recessive deafness, 38 patients with type 2 diabetes mellitus
(NIDDM; 125853), and 23 patients with both deafness and NIDDM. In 3
unrelated patients who had both deafness and diabetes, they identified 3
different heterozygous missense mutations, which were located in the
intracytoplasmic domain of the protein and were not detected in 49
healthy controls. Domenech et al. (2002) stated that the lack of
knowledge about the function of WFS1 made it difficult to explain the
possible contribution of these mutations to the diseases. One of the
mutations, V871M, was also found in a patient who had only deafness and
was present in her deaf sister, but was detected in her unaffected
father. (The V871M variant had previously been detected by Young et al.,
2001 in a family with autosomal dominant deafness, but did not segregate
with disease in that family; see 606201.0014.)
In a 3-generation Danish family segregating an autosomal dominant
Wolfram-like syndrome (WFSL; 614296) in which affected individuals had
deafness, optic atrophy, and impaired glucose regulation mapping to
chromosome 4p16.3, Eiberg et al. (2006) analyzed the candidate gene WFS1
and identified a missense mutation (E864K; 606201.0020) in affected
individuals. The mutation was not found in unaffected family members or
in 2 family members who had only isolated congenital hearing impairment.
In a 60-year-old French man with congenital hearing impairment and NIDDM
and his 81-year-old mother with deafness, diabetes, and optic atrophy,
both of whom were known to be negative for the common mtDNA mutations
associated with the maternally inherited diabetes-deafness syndrome
(MIDD; 520000), Valero et al. (2008) identified heterozygosity for the
E864K mutation in the WSF1 gene.
In affected members of a Dutch family with deafness and optic neuropathy
in whom screening of the OPA1 gene (605290) and mtDNA screening for the
3 most frequent Leber optic atrophy (535000) mutations were both
negative, Hogewind et al. (2010) identified heterozygosity for a
missense mutation in the WSF1 gene (K836N; 606201.0027).
Rendtorff et al. (2011) analyzed the WSF1 gene in 15 probands with
deafness and optic atrophy who were known to be negative for mutation in
the OPA1 and TIMM8A (300356) genes, and identified heterozygosity for
the same missense mutation in the WSF1 gene (A684V; 606201.0028) in 6
probands. Two additional probands were heterozygous for 2 different WFS1
missense mutations (see, e.g., 606201.0031). In 7 of the 8
mutation-positive families, there were spouses with isolated
sensorineural hearing loss (SNHL); analysis of the GJB2 gene (121011)
revealed that 3 of the probands who were heterozygous for mutation in
WFS1 also carried a known SNHL-related mutation in the GJB2 gene
(121011.0001 or 121011.0005), inherited from a deaf parent who did not
have optic atrophy.
- Cataract 41
In an affected member of a 4-generation family of Irish descent
segregating autosomal dominant congenital nuclear cataract mapping to
chromosome 4p16.1 (CTRCT41; 116400), Berry et al. (2013) performed exome
sequencing and identified heterozygosity for a missense mutation in the
WFS1 gene (606201.0032). Direct genomic sequencing confirmed that the
mutation cosegregated completely with disease in the family. Screening
of the WFS1 gene in a panel of 50 unrelated individuals with autosomal
dominant cataract did not reveal any other mutations.
- Association with Type 2 Diabetes
Sandhu et al. (2007) conducted a gene-centric association study for type
2 diabetes in multiple large cohorts and identified 2 SNPs located in
the WFS1 gene, dbSNP rs10010131 (606201.0021) and dbSNP rs6446482
(602201.0022), that were strongly associated with diabetes risk (P = 1.4
x 10(-7) and P = 3.4 x 10(-7), respectively, in the pooled study set).
The risk allele was the major allele for both SNPs, with a frequency of
60% for both. The authors noted that both are intronic, with no obvious
evidence for biologic function.
ANIMAL MODEL
Ishihara et al. (2004) disrupted the wfs1 gene in mice. The mutant mice
developed glucose intolerance or overt diabetes due to insufficient
insulin (see 176730) secretion in vivo. Islets isolated from mutant mice
exhibited decreased insulin secretion in response to glucose. The
defective insulin secretion was accompanied by reduced cellular calcium
responses to the secretagogue. Immunohistochemical analyses demonstrated
progressive beta-cell loss in mutant mice, while alpha cells, which
barely express WFS1 protein, were preserved. Furthermore, isolated
islets from mutant mice exhibited increased apoptosis, at high
concentration of glucose or with exposure to endoplasmic reticulum
stress inducers. The authors suggested that WFS1 protein may play an
important role in both stimulus-secretion coupling for insulin
exocytosis and maintenance of beta-cell mass.
MRFAP1
| dbSNP name | rs28622928(G,A); rs28461572(C,T); rs10023643(C,T); rs113938573(G,T); rs12695(C,G); rs7660424(A,G); rs1059220(G,A) |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 93621 |
| EntrezGene Description | Morf4 family associated protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04086 |
BLOC1S4
| dbSNP name | rs3172604(G,T); rs73091227(T,C) |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 55330 |
| snpEff Gene Name | CNO |
| EntrezGene Description | biogenesis of lysosomal organelles complex-1, subunit 4, cappuccino |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4082 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Prominent supraorbital ridges;
Sloping forehead;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Hypertelorism;
Exotropia;
Progressive retinitis pigmentosa;
Cortical cataract;
Subcapsular cataract;
[Nose];
Large nose
SKELETAL:
[Spine];
Kyphoscoliosis
SKIN, NAILS, HAIR:
[Skin];
Cutis verticis gyrata (onset age 40)
NEUROLOGIC:
[Central nervous system];
Mental retardation
OMIM Title
*605695 BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 4; BLOC1S4
;;BLOC1, SUBUNIT 4; BLOS4;;
CAPPUCCINO, MOUSE, HOMOLOG OF; CNO
OMIM Description
CLONING
Gwynn et al. (2000) described a spontaneous mutation in the mouse,
designated 'cappuccino' (cno), that is a model of Hermansky-Pudlak
syndrome (HPS; 203300). Melanosomes of cno/cno mice were found to be
immature and dramatically decreased in number in the eye and skin,
resulting in severe oculocutaneous albinism. Platelet dense body
contents (adenosine triphosphate, serotonin) were markedly deficient,
leading to defective aggregation and prolonged bleeding. Lysosomal
enzyme concentrations were significantly elevated in the kidney and
liver. Genetic, immunofluorescence microscopy, and lysosomal protein
trafficking studies indicated that the AP3 complex is intact in cno/cno
mice. Gwynn et al. (2000) concluded that the cappuccino gene encodes a
product involved in an AP3-independent mechanism critical to the
biogenesis of lysosome-related organelles.
Gwynn et al. (2000) determined that the cappuccino mutation maps to
mouse chromosome 5. Ciciotte et al. (2003) reported positional cloning
of the mouse cappuccino gene. The normal gene is ubiquitously expressed
and encodes a 215-amino acid protein with a predicted molecular
molecular mass of 23.1 kD. The protein coassembles with pallidin
(604310) and the muted protein (607289) in the BLOC1 complex. In cno
mutant mice, Ciciotte et al. (2003) identified an 11-bp deletion
(nucleotides 427-437), causing a frameshift. The mutation abolished the
ability of the mutant cno protein to interact with BLOC1.
By database searching, Ciciotte et al. (2003) identified a corresponding
human cDNA (GenBank GENBANK AK002092) encoding a deduced 217-amino acid
protein. The mouse and human proteins share 77% overall sequence
identity. There are no predicted transmembrane domains, suggesting that
the protein is cytosolic. Northern blot analysis detected ubiquitous
expression of an approximately 1.35-kb CNO transcript. An additional,
high molecular mass band was detected in skeletal muscle.
GENE STRUCTURE
By sequence analysis, Ciciotte et al. (2003) determined that the entire
CNO cDNA sequence is contained within a single exon in both mouse and
human.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the human
CNO gene to chromosome 4 (TMAP SHGC-67821). By homology with the mouse
cno gene on chromosome 5, human CNO maps to 4p16-p15.
MOLECULAR GENETICS
Ciciotte et al. (2003) performed mutation screening of the human CNO
gene in 18 HPS patients with no defect in previously identified HPS
genes by amplification of genomic DNA from cultured fibroblasts and
sequencing. No defects were observed.
Ciciotte et al. (2003) noted that of a total of 142 HPS patients
screened to that time, no defect in the known BLOC1 components had been
detected, suggesting that BLOC1 function is critical in humans or,
alternatively, that BLOC1 defects in humans are exceedingly rare.
NOMENCLATURE
The mouse cappuccino gene is not related to the cappuccino (capu) gene
of Drosophila (Emmons et al., 1995).
CCDC96
| dbSNP name | rs871133(A,G); rs871134(C,T) |
| ccdsGene name | CCDS3395.1 |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 100129931 |
| EntrezGene Symbol | LOC100129931 |
| EntrezGene Description | uncharacterized LOC100129931 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | CCDC96:NM_153376:exon1:c.T309C:p.V103V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03627 |
| ESP Afr MAF | 0.066172 |
| ESP All MAF | 0.033293 |
| ESP Eur/Amr MAF | 0.018345 |
| ExAC AF | 0.966 |
MIR4798
| dbSNP name | rs114771990(C,T) |
| ccdsGene name | CCDS47008.1 |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 100616471 |
| snpEff Gene Name | SORCS2 |
| EntrezGene Description | microRNA 4798 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01837 |
| ExAC AF | 0.002268 |
PSAPL1
| dbSNP name | rs34264596(G,A); rs6854053(T,C); rs6822277(G,A); rs4302467(A,G); rs62277598(C,T); rs6854437(T,G); rs58448418(T,C); rs6822927(G,C); rs6849590(A,G); rs58274198(C,T); rs76781555(G,C); rs74563302(G,C); rs34241247(G,A); rs10030127(G,A); rs10011121(C,A); rs75278193(A,C); rs59286727(A,C); rs61318481(C,G); rs77810263(C,A); rs10033032(G,A); rs73796584(T,A); rs138981228(C,G); rs114620595(G,T); rs10023470(A,G); rs10014338(C,A); rs7439798(G,A); rs4318651(A,G); rs59409649(G,A); rs60816800(C,T); rs12498567(G,A); rs61734061(A,G); rs4689746(A,G); rs6843370(G,A); rs61738677(G,T); rs6850206(C,T); rs61740031(C,T); rs56402179(C,T); rs11548325(C,A) |
| ccdsGene name | CCDS47008.1 |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 768239 |
| snpEff Gene Name | SORCS2 |
| EntrezGene Description | prosaposin-like 1 (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4238 |
MIR548I2
| dbSNP name | rs140817192(A,G) |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 101928948 |
| EntrezGene Symbol | LOC101928948 |
| EntrezGene Description | uncharacterized LOC101928948 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
| ExAC AF | 0.001715 |
DRD5
| dbSNP name | rs6283(C,T); rs1967551(T,C); rs1967550(G,T) |
| ccdsGene name | CCDS3405.1 |
| cytoBand name | 4p16.1 |
| EntrezGene GeneID | 1816 |
| EntrezGene Description | dopamine receptor D5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DRD5:NM_000798:exon1:c.C978T:p.P326P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4082 |
| ExAC AF | 0.632 |
OMIM Clinical Significance
Hair:
Double rows of eyelashes
Cardiac:
Congenital heart defect;
Ventricular septal defect;
Patent ductus arteriosus;
Sinus bradycardia;
Stress-induced asystole;
Wandering atrial pacemaker
Limbs:
Leg edema;
Varicose veins;
Arterial disease of legs
Inheritance:
Autosomal dominant
OMIM Title
+126453 DOPAMINE RECEPTOR D5; DRD5
;;DOPAMINE RECEPTOR D1B; DRD1B
DYSTONIA, PRIMARY CERVICAL, INCLUDED
OMIM Description
CLONING
Tiberi et al. (1991) isolated and characterized a rat gene encoding a
dopamine receptor that is structurally and functionally similar to the
D1 dopamine receptor (DRD1; 126449). The gene encodes a protein of 475
amino acids with structural features that are consistent with G
protein-coupled receptors. The expressed protein binds dopaminergic
ligands and mediates stimulation of adenylyl cyclase with pharmacologic
properties similar to those of the D1 dopamine receptor. In striking
contrast to the previously cloned D1 receptor, little or no mRNA for the
receptor described here was observed in striatum, nucleus accumbens,
olfactory tubercle, and frontal cortex. High levels of mRNA for this
receptor were found in distinct layers of the hippocampus, the mamillary
nuclei, and the anterior pretectal nuclei, all brain regions that have
been shown to exhibit little or no D1 dopamine receptor binding.
Grandy et al. (1991) found that the human DRD5 protein shares 49%
sequence identity with the DRD1 protein.
By in situ hybridization studies, Polymeropoulos et al. (1991) showed
that the D5 dopamine receptor is neuron specific and that it localizes
within limbic regions of the brain.
Beischlag et al. (1995) investigated the expression of the functional
DRD5 gene by in situ hybridization of both monkey and human brains using
a 5-prime D5-specific riboprobe. They found that DRD5 mRNA was most
abundant in discrete cortical areas (layers II, IV, and VI), the dentate
gyrus, and hippocampal subfields but they detected very little message
in the striatum. Unexpectedly, D5 mRNA antisense riboprobes labeled
discrete cell bodies in the pars compacta of the substantia nigra.
- Pseudogenes
Weinshank et al. (1991) cloned and characterized the human DRD5 gene and
found a second closely related gene, GL39, which was shown to represent
a pseudogene. This was the first pseudogene to be described in the G
protein-coupled receptor superfamily. It exhibited 94% nucleotide
sequence homology to the functional gene and may have arisen from a gene
duplication event followed by a mutation approximately 8 million years
ago, before the emergence of man. This recently evolved pseudogene is
transcribed in the human brain with a tissue distribution similar to
that for the closely related functional gene. Grandy et al. (1991)
identified 2 pseudogenes which were 98% identical to each other and 95%
identical to the DRD5 sequence. Relative to the D5 sequence, both
contained insertions and deletions that resulted in several in-frame
termination codons. Premature termination of translation was the
probable explanation for the failure of these genes to produce receptors
in COS-7 and 293 cells even though their messages were transcribed.
GENE FUNCTION
Polymeropoulos et al. (1991) found that DRD5, like DRD1, stimulates
adenylate cyclase activity.
Grandy et al. (1991) determined that, compared with DRD1, DRD5 displayed
a higher affinity for dopamine and was able to stimulate a biphasic
rather than a monophasic intracellular accumulation of cAMP.
Liu et al. (2000) demonstrated that GABA-A ligand-gated channels complex
selectively with dopamine D5 receptors through the direct binding of the
D5 carboxy-terminal domain with the second intracellular loop of the
GABA-A gamma-2 (short) receptor subunit (137164). This physical
association enables mutual inhibitory functional interactions between
these receptor systems. Liu et al. (2000) concluded that the data
highlight a previously unknown signal transduction mechanism whereby
subtype-selective G protein-coupled receptors dynamically regulate
synaptic strength independently of classically defined second-messenger
systems, and suggest a possible framework in which to view these
receptor systems in the maintenance of psychomotor disease states,
particularly schizophrenia (181500).
Li et al. (2008) found that pharmacologic activation of DRD5 in human
renal proximal tubule cells and HEK cells increased degradation of the
glycosylated form of the angiotensin II type 1 receptor (AGTR1; 106165),
a prohypertensive protein, via the ubiquitin pathway.
GENE STRUCTURE
Beischlag et al. (1995) described the genomic organization of the
5-prime flanking region and promoter of the human dopamine D5 receptor
gene. The gene contains 2 exons separated by a small and variably sized
intron (of either 179 or 155 bp). The transcriptional start site lies
2,125 bp upstream from the translational initiation site. Promoter
deletion analysis indicated that the DRD5 gene promoter contains a
positive modulator from nucleotide position -199 to -182 and a negative
modulator from position -500 to -251 relative to the transcription
initiation site.
MAPPING
Using PCR, Polymeropoulos et al. (1991) studied the segregation of the
DRD5 gene in human/rodent somatic cell hybrids and showed that the gene
is located on chromosome 4. By in situ hybridization, Tiberi et al.
(1991) mapped the human DRD5 gene, which they called D1B, to chromosome
4p16.3.
Using gene-specific amplification with PCR on a panel of somatic cell
hybrids carrying different human chromosomes, Eubanks et al. (1992)
mapped the DRD5 gene to 4p. Further localization was carried out through
the isolation and analysis of yeast artificial chromosomes (YAC),
fluorescence in situ suppression hybridization to human metaphase
chromosomes, and analysis of a panel of somatic cell hybrids subdividing
human chromosome 4 into 9 regions. In this way, DRD5 was located at
4p15.33-p15.1, centromeric to the location of the Huntington disease
locus (143100).
By combining in situ hybridization results with sequence analysis of PCR
products from microdissected chromosomes, somatic cell hybrids, and
radiation hybrids, Grandy et al. (1992) assigned the DRD5 gene to 4p16.1
and the 2 pseudogenes, DRD5P1 and DRD5P2, to 2p11.2-p11.1 and 1q21.1,
respectively.
Sherrington et al. (1993) cloned the DRD5 receptor and used it to map
the DRD5 gene by linkage studies in 39 CEPH pedigrees. Combining their
data with those of others, they placed the DRD5 gene at 4p15.3.
The mouse Drd5 gene is located on chromosome 5 (Wilkie et al., 1993).
Grosson et al. (1994) mapped the murine homolog of dopamine receptor D5
to mouse chromosome 5 in a continuous linkage group with 18 human
chromosome 4 loci.
MOLECULAR GENETICS
Sherrington et al. (1993) identified a polymorphic microsatellite, which
they named DRD5 (CT/GT/GA)n, and determined that there are 12 alleles of
differing sizes.
Misbahuddin et al. (2002) performed association studies between focal
dystonia blepharospasm (606798) and 10 previously reported polymorphisms
within the dopamine transporter (DAT) gene (SLC6A3; 126455) and dopamine
receptor genes D1-5. Allele 2 of the dinucleotide repeat in the D5
receptor gene was found to have an increased frequency in blepharospasm
cases compared with controls (606798.0001). The same allele had been
found in association with another form of focal dystonia, primary
cervical dystonia (Placzek et al., 2001). Among 100 German and 121
French patients with idiopathic focal dystonia, including blepharospasm
and torticollis, Sibbing et al. (2003) found no association with allele
2 or allele 6 of the DRD5 polymorphism.
Daly et al. (1999) reported a significant association between
attention-deficit/hyperactivity disorder (ADHD; 143465) and the 148-bp
allele of a microsatellite located 18.5 kb 5-prime to the DRD5 gene.
Subsequent studies of this (CA)n repeat marker showed nonsignificant
trends toward association with the same allele. Although there was no
evidence to suggest that the D5 microsatellite is itself functional, the
association reported by Daly et al. (1999) was in the opinion of Lowe et
al. (2004) too strong to be ignored. Therefore, they hypothesized that
if the association with ADHD were true, the microsatellite may be in
linkage disequilibrium (LD) with 1 or more functional variants. To this
end, they invited all known groups with samples based on parent-proband
trios to genotype their samples for the marker and present their data
for analysis. Fourteen independent samples were analyzed individually
and, in the absence of heterogeneity, analyzed as a joint sample. The
joint analysis showed association with the DRD5 locus (P = 0.00005; odds
ratio 1.24; 95% confidence interval 1.12-1.38). This association
appeared to be confined to the predominantly inattentive and combined
clinical subtypes.
POPULATION GENETICS
By analyzing short-read mapping depth for 159 human genomes, Sudmant et
al. (2010) demonstrated accurate estimation of absolute copy number for
duplications as small as 1.9 kb pairs, ranging from 0 to 48 copies.
Sudmant et al. (2010) identified 4.1 million 'singly unique nucleotide'
positions informative in distinguishing specific copies and used them to
genotype the copy and content of specific paralogs within highly
duplicated gene families. These data identified human-specific
expansions in genes associated with brain development, such as GPRIN2
(611240) and SRGAP2 (606524), which have been implicated in neurite
outgrowth and branching. Also included were the brain-specific HYDIN2
gene (610813), associated with micro- and macrocephaly; DRD5, a dopamine
D5 receptor; and the GTF2I (601679) transcription factors, whose
deletion has been associated with visual-spatial and sociability
deficits among Williams-Beuren syndrome (194050) patients, among others.
The data of Sudmant et al. (2010) also revealed extensive population
genetic diversity, especially among the genes NPEPPS (606793), UGT2B17
(601903), and NBPF1 (610501), as well as LILRA3 (604818), which is the
most highly stratified gene by copy number in the human genome. In
addition, Sudmant et al. (2010) detected signatures consistent with gene
conversion in the human species.
ANIMAL MODEL
Li et al. (2008) found that Drd5-null mice developed hypertension
associated with increased expression of Agtr1 in renal cortical tubules.
Treatment of the mice with the AGTR1 antagonist losartan normalized
blood pressure. Activation of DRD5 in human renal proximal tubule cells
increased degradation of glycosylated AGTR1 in proteasomes via
activation of the ubiquitin pathway. Li et al. (2008) concluded that the
hypertension in Drd5-null mice was caused in part by increased Agtr1
expression resulting from the absence of the negative effect of Drd5 on
Agtr1, consistent with a novel mechanism whereby blood pressure is
regulated by the interaction of 2 counterregulatory G protein-coupled
receptors, DRD5 and AGTR1.
LINC01096
| dbSNP name | rs28378481(A,G) |
| cytoBand name | 4p15.33 |
| EntrezGene GeneID | 285548 |
| snpEff Gene Name | NKX3-2 |
| EntrezGene Description | long intergenic non-protein coding RNA 1096 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03398 |
| ExAC AF | 0.003085 |
PTTG2
| dbSNP name | rs6811863(G,C) |
| ccdsGene name | CCDS54755.1 |
| cytoBand name | 4p14 |
| EntrezGene GeneID | 23216 |
| EntrezGene Symbol | TBC1D1 |
| EntrezGene Description | TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PTTG2:NM_006607:exon1:c.G131C:p.R44P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NZH5-2 |
| dbNSFP KGp1 AF | 0.727564102564 |
| dbNSFP KGp1 Afr AF | 0.697154471545 |
| dbNSFP KGp1 Amr AF | 0.693370165746 |
| dbNSFP KGp1 Asn AF | 0.973776223776 |
| dbNSFP KGp1 Eur AF | 0.577836411609 |
| dbSNP GMAF | 0.2727 |
| ESP Afr MAF | 0.296002 |
| ESP All MAF | 0.388248 |
| ESP Eur/Amr MAF | 0.435465 |
| ExAC AF | 0.641 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataract, congenital, multiple types;
Cataract, zonular central nuclear;
Cataract, nuclear;
Cataract, lamellar;
Opacities in embryonal nuclei;
Cataract, anterior subcapsular;
Cataract, anterior polar;
Cataract, posterior polar;
Cataract, fan-shaped;
Cataract, posterior subcapsular;
Cataract, cortical;
Cataract, laminar;
Cataract, progressive (in some patients);
Cataract, total;
Cataract, presenile;
Microcornea (in some patients);
Coloboma of the iris (in some patients);
Microphthalmia (in some patients);
Decreased visual acuity;
Nystagmus;
Amblyopia;
Strabismus;
Glaucoma
MOLECULAR BASIS:
Caused by mutation in the alpha-A-crystallin gene (CRYAA, 123580.0001)
OMIM Title
*604231 PITUITARY TUMOR-TRANSFORMING GENE 2; PTTG2
OMIM Description
CLONING
During the course of studies mapping the PTTG1 (604147) gene to
chromosome 5q33, Prezant et al. (1999) found evidence for a related
gene, which they referred to as PTTG2, on chromosome 4. They stated that
PTTG1 and PTTG2 are highly conserved at both the nucleotide and amino
acid levels, including the potential SH3 binding domain. They found
low-level PTTG2 expression in normal pituitary and in some other normal
tissues, and moderately elevated expression in some pituitary tumors.
GENE STRUCTURE
The PTTG2 gene is intronless (Prezant et al., 1999).
MAPPING
By radiation hybrid mapping, Prezant et al. (1999) mapped the PTTG2 gene
to human chromosome 4p12.
DCAF4L1
| dbSNP name | rs2660320(C,T); rs2660332(A,G); rs2660334(A,G); rs149897467(G,A); rs76330961(T,C); rs2581439(A,G); rs144441211(C,T); rs2581438(G,A) |
| ccdsGene name | CCDS33978.1 |
| cytoBand name | 4p13 |
| EntrezGene GeneID | 285429 |
| EntrezGene Description | DDB1 and CUL4 associated factor 4-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DCAF4L1:NM_001029955:exon1:c.C309T:p.S103S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3085 |
| ESP Afr MAF | 0.24512 |
| ESP All MAF | 0.403429 |
| ESP Eur/Amr MAF | 0.223372 |
| ExAC AF | 0.756 |
TEC
| dbSNP name | rs3805184(A,G); rs1008277(T,C); rs1979972(C,T); rs2661529(C,A); rs2071027(T,C); rs16861035(T,C); rs77876977(C,T); rs4446283(C,T); rs28521484(C,T); rs6447616(A,G); rs73136301(C,G); rs17470892(T,C); rs111997140(A,G); rs138972385(C,G); rs17470919(T,C); rs73244489(T,A); rs6844543(T,C); rs7682890(A,T); rs996222(T,A); rs996223(G,A); rs17574371(T,C); rs2661547(T,G); rs2661548(A,G); rs77833414(T,G); rs3749503(G,A); rs16861057(G,A); rs4695338(C,T); rs2704426(C,T); rs141688093(G,A); rs2704427(T,C); rs2704428(T,C); rs17574399(A,T); rs11728070(T,C); rs1507919(A,T); rs16861065(C,A); rs16861067(T,C); rs10938522(C,T); rs2251240(T,C); rs2661535(A,C); rs7654182(A,G); rs2089508(G,A); rs147756445(T,C); rs80105690(C,T); rs73138411(C,T); rs2456928(C,T); rs4571301(G,A); rs76166149(A,T); rs10021919(G,A); rs882715(G,A); rs12502528(C,T); rs2464502(T,C); rs2704436(A,G); rs13146998(C,G); rs2704435(T,C); rs17471024(A,G); rs6817928(C,T); rs2704397(C,T); rs3792622(A,G); rs3792621(C,T); rs142459783(T,C); rs13104849(T,C); rs2704398(C,T); rs7678246(G,C); rs12649067(C,T); rs28702422(C,A); rs6845941(C,G); rs2704399(A,T); rs11730441(C,T); rs3913948(A,G); rs3805180(C,T); rs3805179(C,T); rs7689953(A,G); rs2243840(A,G); rs3792620(T,G); rs10805164(C,T); rs10805165(T,C); rs2271174(C,T); rs2271173(G,A); rs139186461(T,C); rs2256425(G,A); rs13136882(C,T); rs7684558(G,A); rs7668350(A,C); rs2704434(G,A); rs7669393(A,G); rs4695339(C,T); rs4695340(G,A); rs4695341(T,C); rs4695342(G,A); rs4695343(G,A); rs4695344(T,G); rs56401019(T,A); rs62309327(T,C); rs62309328(A,G); rs4695345(C,T); rs4695346(T,G); rs4695347(T,C); rs4695348(A,G); rs4695349(T,C); rs4695350(A,G); rs6814614(C,G); rs2704433(A,G); rs6845196(T,C); rs2661543(T,G); rs1466990(T,C); rs1466991(T,C); rs1466992(C,G); rs1466993(T,C); rs1466994(G,A); rs2089509(G,A); rs2089510(G,T); rs2089511(G,A); rs6851861(T,C); rs73138418(C,T); rs1466995(C,T); rs1466996(G,A); rs7671720(C,T); rs7654108(T,C); rs7670351(G,A); rs7695902(A,G); rs7654466(T,C); rs7696119(A,G); rs7696271(A,G); rs45598338(C,A); rs28514576(A,G); rs2661544(C,A); rs11945978(C,T); rs79739642(C,T); rs1961973(A,T); rs1961974(G,T); rs1961975(A,T); rs12512766(C,T); rs12502268(T,C); rs12512837(C,A); rs4323077(G,C); rs4504220(G,A); rs4392481(C,T); rs4392482(C,T); rs6814046(C,T); rs11727920(T,C); rs12499674(C,T); rs147701204(A,T); rs6818552(G,T); rs6845258(A,G); rs143693636(A,G); rs7692882(A,C); rs4312730(T,C); rs13146265(A,G); rs12108537(G,A); rs9715214(T,G); rs147180903(C,G); rs10938524(T,C); rs28578119(G,C); rs28740900(T,A); rs28408546(G,A); rs28538414(T,G); rs62309332(A,T); rs7693779(G,A); rs73244496(T,C); rs77890319(A,G); rs185720992(T,C); rs55869455(A,G); rs73244499(T,C); rs11732808(G,A); rs4695355(G,A); rs4694887(T,C); rs148687911(T,C); rs4695356(G,A); rs28491198(T,C); rs115970631(G,A); rs4235153(T,C); rs13146503(C,T); rs2352592(G,C); rs13136179(A,T); rs115203014(G,C); rs75568209(T,A); rs28653632(T,G); rs28496010(C,T); rs17471142(G,A); rs16861112(C,T); rs16861113(C,T); rs16861114(G,A); rs10805166(G,A); rs11725773(G,A); rs7680282(C,T); rs12500534(T,C); rs7664091(A,G); rs2352593(A,G); rs73138437(T,C); rs141105095(C,A); rs28372254(T,C); rs6829390(G,A); rs17655303(T,C); rs67807921(T,C); rs4695357(A,C); rs62309333(C,A); rs4695358(T,C); rs2704425(T,C); rs6837345(C,T); rs2457415(A,C); rs11727072(C,T); rs1509656(G,A); rs141530978(A,C); rs59192457(C,T); rs55885170(A,C); rs2457414(C,A); rs79981131(G,T); rs56363516(A,T); rs6834565(A,G); rs56196488(T,C); rs2704415(C,G); rs62309349(G,A); rs2017242(C,A); rs111585757(G,C); rs1973578(G,A); rs73138448(G,T); rs56381082(A,C); rs73244502(T,A); rs145241419(G,A); rs2664036(A,G); rs80307876(G,C); rs1912163(T,G); rs2457416(C,G); rs1912164(G,A); rs2055802(A,G); rs2055803(A,G); rs1355219(C,T); rs1355220(T,C); rs377736897(G,T); rs1509657(T,C); rs2664037(T,A); rs12511665(C,T); rs73814695(T,A); rs2704408(C,G); rs2457417(T,A); rs2664038(T,C); rs7697423(C,T); rs73814697(C,T); rs143092010(G,A); rs1396877(G,A); rs73138468(C,T); rs2704420(G,A); rs2664039(C,T); rs60145199(G,A); rs111828811(T,C); rs58948620(G,A); rs56789983(G,A); rs56156164(C,T); rs2664026(C,G); rs7687704(C,T); rs113229436(G,C); rs2704414(C,T); rs60658182(C,T); rs7692950(G,A); rs75717929(T,C); rs2352594(A,C); rs2704413(G,A); rs73814699(C,T); rs2664035(G,A); rs9684908(G,T); rs192062545(C,A); rs13108221(G,A); rs73138481(T,C); rs73138482(C,T); rs73246006(T,C); rs16851721(T,C); rs35898502(T,C); rs73138485(C,G); rs4695360(G,A); rs112802689(G,A); rs34253217(A,G); rs4695361(C,T); rs73814701(T,C); rs73138491(C,T); rs114896567(C,T); rs74478906(A,G); rs16861128(G,A); rs4456935(G,A); rs56840999(G,C); rs4695362(A,T); rs73138494(A,T); rs142252715(C,T); rs2704424(G,C); rs11947838(G,A); rs6835999(A,G); rs2704423(A,G); rs2704422(G,A); rs2704421(T,C); rs62309355(T,C); rs181266558(T,G); rs2664017(A,G); rs2664018(C,T); rs139851514(C,G); rs2664019(A,G); rs3792618(T,A); rs2464503(C,T); rs2464504(C,T); rs2464505(G,A); rs2664020(G,C); rs138183107(T,C); rs2704402(A,G); rs2704403(A,G); rs2704404(C,T); rs2704405(A,G); rs906901(G,T); rs75962184(C,A); rs2704406(A,G); rs2704407(A,G); rs2664023(T,C); rs2704409(C,A); rs2664024(T,C); rs2664025(C,T); rs62309358(G,A); rs62309359(T,C); rs78933973(C,T); rs2704412(C,T); rs2457411(T,G); rs2664028(G,T); rs150470803(G,A); rs76446980(C,T); rs4695363(G,A); rs2704389(T,C); rs2457412(G,A); rs2664029(T,G); rs2704390(C,A); rs17574833(A,C); rs1988444(A,C); rs7662355(C,T); rs1972082(G,A); rs79569057(G,A); rs373535564(G,A); rs2704391(A,G); rs4695364(G,A); rs187111040(A,G); rs2664030(A,G); rs4695365(T,A); rs2704392(A,G); rs2664031(T,C); rs2664032(T,C); rs12643804(G,A); rs2457413(T,C); rs9996158(A,G); rs149468245(G,A); rs143016036(A,G); rs55666922(T,C); rs2704393(G,C); rs2704394(A,C); rs2704395(C,T); rs191874224(A,C); rs1157532(A,G); rs1355218(A,C); rs2352595(A,G); rs13117386(C,G); rs7674061(C,T); rs10022525(G,A); rs10014883(A,G); rs7669018(T,C); rs10006371(C,A); rs35103777(C,T); rs10805167(C,T); rs36076484(T,C); rs4694891(C,G); rs13144944(G,A); rs13151613(G,T); rs36081732(T,C); rs62311477(T,C); rs10013366(T,A); rs12501146(C,T); rs12508645(G,C); rs12501247(C,G); rs2055800(T,C); rs2353295(A,G); rs28410946(G,A); rs1472971(A,G); rs1472972(C,G); rs10517214(C,G); rs1472973(T,C); rs1812667(G,A); rs181070642(G,A); rs9291321(G,C); rs55677378(T,C); rs7676110(A,G); rs7697203(G,A); rs7681182(T,G); rs12510449(A,T); rs12498600(G,C); rs12510551(A,G); rs9291322(G,C); rs144005912(C,T); rs13113745(C,T); rs13118885(G,A); rs4478160(T,G); rs11724334(G,A); rs7678145(C,A); rs76942152(A,C); rs59741528(C,T); rs6447624(C,T); rs79247526(G,A); rs76565310(C,T); rs13129386(C,T); rs6836661(C,T); rs6818382(T,C); rs1912162(T,A); rs2036766(A,G); rs2036767(A,G); rs4694892(G,T); rs2136502(G,T); rs2136503(G,C); rs4235154(C,T); rs6447625(G,A); rs7688059(A,G); rs9994779(G,A); rs10433724(G,C); rs12651507(T,C) |
| ccdsGene name | CCDS3481.1 |
| cytoBand name | 4p12 |
| EntrezGene GeneID | 7006 |
| EntrezGene Description | tec protein tyrosine kinase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TEC:NM_003215:exon5:c.A392G:p.Q131R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5986 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P42680 |
| dbNSFP Uniprot ID | TEC_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 7.321e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
RESPIRATORY:
Progressive breathing difficulty
SKELETAL:
Mild joint laxity;
Delayed bone maturation;
[Spine];
Atlanto-axial subluxation;
Lumbar lordosis;
Irregular vertebral end plates;
Os odontoideum and atlanto-axial instability;
Spondylolysis and spondylolisthesis of L5;
[Pelvis];
Flat femoral head with subluxation and sloping acetabulum;
[Limbs];
Small femoral capital epiphyses
MUSCLE, SOFT TISSUE:
Hand muscle wasting
NEUROLOGIC:
[Peripheral nervous system];
Hemiparesis;
Quadriparesis;
Limb weakness;
Brisk reflexes;
Clonus in legs;
Bulbar palsy;
Tongue fasciculations
OMIM Title
*600583 TEC PROTEIN TYROSINE KINASE; TEC
OMIM Description
DESCRIPTION
Tyrosine kinases can be classified as either membrane associated
receptors or intracellular nonreceptor molecules. The latter include BTK
(300300), ITK (186973), TXK (600058), and BMX (300101). Mouse Tec is a
non-receptor type protein-tyrosine kinase that is highly expressed in
many hematopoietic cell lines (Sato et al., 1994).
CLONING
Sato et al. (1994) found that the human TEC cDNA encodes a peptide of
631 amino acid residues and a predicted mass of 73,624 Da. Homology
between human TEC and other members of the TEC family occurs not only in
the Src homology domains (SH3 and SH2) and kinase domains, but also in
an N-terminal domain unique to this family of tyrosine kinases. Overall,
the human TEC is 60% homologous to mouse Tsk/ltk (186973) and 57%
homologous to human BTK (300300). Northern blot analysis detected 2.6-kb
and 3.6-kb mRNAs in a wide range of human hematopoietic cell lines,
including myeloid, B-, and T-cell lineages. Interestingly, high
expression of TEC was seen in each of 3 patients examined with
myelodysplastic syndrome.
MAPPING
By fluorescence in situ hybridization, Sato et al. (1994) mapped the
gene to 4p12, the same location reported for TXK.
MOLECULAR GENETICS
Hantschel et al. (2007) identified TEC kinase and BTK kinase as major
binders of the tyrosine kinase inhibitor dasatinib, which is used for
treatment of BCR/ABL (see 151410)-positive CML (608232). Dasatinib did
not bind ITK. They generated stable cell lines expressing a
thr442-to-ile (T442I) substitution in the TEC gene, which conferred
resistance to dasatinib. They suggested that, like the structurally
homologous thr315 residue in the ABL gene (see 189980.0001), the TEC
thr442 residue is the gatekeeper residue critical for dasatinib binding.
ANIMAL MODEL
Using Tec -/- Btk (300300) -/- double-knockout mice, Shinohara et al.
(2008) showed that these tyrosine kinases were crucial in Rankl
(TNFSF11; 602642)-induced osteoclastogenesis. In response to Rankl
stimulation, Btk and Tec formed a signaling complex required for
osteoclastogenesis with adaptor molecules such as Blnk (604515), which
also recruited Syk (600085), linking Rank (TNFRSF11A; 603499) and ITAM
(see 608740) signals to phosphorylate Plc-gamma (see 172420). Tec kinase
inhibition reduced osteoclastic bone resorption in models of
osteoporosis and inflammation-induced bone destruction. Shinohara et al.
(2008) concluded that their studies provided a link between
immunodeficiency and abnormal bone homeostasis owing to defects in
signaling molecules shared by B cells and osteoclasts.
UTP3
| dbSNP name | rs149552771(C,T); rs16845390(G,C); rs187936171(A,G) |
| ccdsGene name | CCDS3546.1 |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 57050 |
| EntrezGene Description | UTP3, small subunit (SSU) processome component, homolog (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UTP3:NM_020368:exon1:c.C1229T:p.A410V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.2374 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NQZ2 |
| dbNSFP Uniprot ID | SAS10_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0002684 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe to profound;
Delayed motor development;
Hypotonia;
Spastic tetraplegia;
Ataxia;
Seizures;
Lissencephaly;
Agyria (posterior-to-anterior gradient);
Pachygyria (posterior-to-anterior gradient);
Polymicrogyria;
Subcortical laminar heterotopia;
Hooked aspect of the frontal horn of the lateral ventricles due to
abnormally shaped basal ganglia;
Ventricular dilatation;
Thin corpus callosum;
Abnormal hippocampus;
Agenesis of the corpus callosum;
Absence or hypoplasia of the anterior limb of the internal capsule;
Hypoplasia of the cerebellar vermis;
Hypoplasia of the brainstem
MISCELLANEOUS:
Most cases occur de novo
MOLECULAR BASIS:
Caused by mutation in the alpha-tubulin 1A gene (TUBA1A, 602529.0001)
OMIM Title
*611614 UTP3, S. CEREVISIAE, HOMOLOG OF; UTP3
;;CHARGED AMINO ACID-RICH LEUCINE ZIPPER 1; CRL1; CRLZ1
OMIM Description
CLONING
Sakuma et al. (2001) cloned mouse Utp3, which they called Crl1. The
deduced 469-amino acid protein is rich in charged amino acids and
contains a putative leucine zipper region and a region that shares
significant homology with yeast Sas10. In situ hybridization revealed
expression in olfactory bulb and cerebral cortex in mouse embryos at
17.5 days postcoitum. Postnatally, Crl1 expression was also observed in
cerebellar cortex, with strong expression in hippocampus.
GENE FUNCTION
By yeast 2-hybrid analysis, Sakuma et al. (2001) showed that mouse Crl1
interacted specifically with Pebp2b2, which is encoded by a splice
variant of Pebp2b (CBFB; 121360).
Lim et al. (2006) showed that the CRLZ1 and IgJ (147790) genes are
adjacent but divergently transcribed in human and mouse. By chromatin
immunoprecipitation and FACS analysis of sorted mouse pre-B cells and
plasma cells, they found that IgJ was expressed in the plasma cell
stage, whereas Crlz1 was expressed in the pre-B cell stage. The
stage-specific expression of IgJ and Crlz1 was regulated by chromatin
accessibility and acetylation. DNase I hypersensitive site 1 on the IgJ
promoter was opened in plasma cells, but hypersensitive sites 9 and 10
on the Crlz1 promoter were opened in pre-B cells. H3 (see 602810) and H4
(see 602822) histones were hyperacetylated in the chromatin of Crlz1 in
pre-B cells, whereas those in the chromatin of IgJ were hyperacetylated
in plasma cells. Lim et al. (2006) concluded that the CRLZ1-IgJ locus
shows stage-specific gene expression regulation, and they proposed that
additional regulatory elements may exist between the genes to coordinate
chromatin accessibility and histone acetylation over the locus.
MAPPING
By genomic sequence analysis, Lim et al. (2006) mapped the UTP3 gene
upstream of the IGJ gene on chromosome 4q21. The UTP3 and IGJ genes are
transcribed in opposite directions, and the positioning and orientation
of the genes are conserved on mouse chromosome 5.
DCK
| dbSNP name | rs7656043(A,G); rs72552071(C,T); rs2035576(T,G); rs3775289(T,C); rs66547610(T,C); rs9993633(G,A); rs6446988(A,G); rs1580469(A,G); rs4694360(G,A); rs6446989(A,G); rs143067496(G,C); rs149292410(T,C); rs114734420(C,T); rs151338753(C,G); rs141901254(A,C); rs2171195(G,C); rs67578661(A,C); rs28715337(G,T); rs115701049(G,T); rs2171194(A,G); rs12648166(A,G); rs10805074(A,G); rs7698012(G,A); rs7684954(A,G); rs34969740(G,A); rs1552381(G,A); rs4235090(A,G); rs4490428(A,T); rs7689110(C,T); rs140629346(C,T); rs6446998(G,T); rs7439745(G,A); rs184987505(C,A); rs6819369(T,C); rs150357557(C,G); rs7699712(C,T); rs4308342(T,G); rs10518080(T,C); rs11935198(T,A); rs12501375(C,T); rs7439562(A,G); rs4021444(G,C); rs2363439(A,G); rs67437265(C,T); rs28734949(C,T); rs936869(T,C); rs936868(T,C); rs1486271(A,T); rs74938707(C,T); rs1385986(A,G); rs16845668(A,G); rs4694362(C,T); rs12513202(C,T); rs12513206(C,T); rs4643786(C,T); rs16845677(A,T) |
| ccdsGene name | CCDS3548.1 |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 1633 |
| EntrezGene Description | deoxycytidine kinase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DCK:NM_000788:exon3:c.C364T:p.P122S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6875 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P27707 |
| dbNSFP Uniprot ID | DCK_HUMAN |
| dbNSFP KGp1 AF | 0.0334249084249 |
| dbNSFP KGp1 Afr AF | 0.0589430894309 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0437062937063 |
| dbNSFP KGp1 Eur AF | 0.0131926121372 |
| dbSNP GMAF | 0.03352 |
| ESP Afr MAF | 0.047435 |
| ESP All MAF | 0.022759 |
| ESP Eur/Amr MAF | 0.010116 |
| ExAC AF | 0.019 |
OMIM Clinical Significance
Teeth:
Radicular dentin dysplasia
Skel:
Cortical sclerosis
Radiology:
Dense long bones;
Dense maxillary and mandibular alveoli;
Narrow or occluded marrow spaces and thick cortices
Inheritance:
Autosomal dominant
OMIM Title
*125450 DEOXYCYTIDINE KINASE; DCK
OMIM Description
DESCRIPTION
Deoxycytidine kinase (DCK; EC 2.7.1.74) is responsible for the
phosphorylation of several deoxyribonucleosides and their analogs. It
has broad substrate specificity for deoxyadenosine (dAdo) and
deoxyguanosine (dGuo) as well as for deoxycytidine (dCyd). It is also a
key enzyme in the phosphorylation of a variety of antineoplastic and
antiviral nucleoside analogs including cytosine arabinoside (araC) and
dideoxycytidine (ddCyd); deficiency of deoxycytidine kinase activity
mediates resistance to these drugs (summary by Chottiner et al., 1991).
CLONING
Huang et al. (1989) cloned the DCK gene. Similarities to previously
studied proteins such as the beta subunit of prolyl-4-hydroxylase
(176790) were revealed. Chottiner et al. (1991) also cloned human
deoxycytidine kinase from a T-lymphoblast DNA library. The cDNA sequence
encoded a 30.5-kD protein corresponding to the subunit molecular mass of
the purified protein. The authors of Huang et al. (1989) subsequently
discovered that the sequence they had thought to represent DCK is in
fact the human homolog of ERp72, the function of which is not yet known,
and published a correction; the gene studied by Chottiner et al. (1991)
is the true deoxycytidine kinase.
GENE STRUCTURE
By isolating genomic clones of DCK, Song et al. (1993) demonstrated that
the gene extends over more than 34 kb of DNA and that the coding region
is composed of 7 exons ranging in size from 90 to 1,544 bp. The 5-prime
flanking region is highly G+C rich and contains 4 regions that are
potential Sp1 binding sites.
MAPPING
By PCR using genomic primers flanking the third exon of the DCK gene,
Song et al. (1993) demonstrated in a human-hamster hybrid panel and in
murine-human hybrid cell lines that the DCK gene is located on human
chromosome 4. By fluorescence in situ hybridization, Stegmann et al.
(1993) assigned the DCK gene to 4q13.3-q21.1.
GENE FUNCTION
Human deoxyribonucleoside kinases are required for the pharmacologic
activity of several clinically important anticancer and antiviral
nucleoside analogs. Human deoxycytidine kinase and thymidine kinase-1
(188300) had been described as cytosolic enzymes, whereas human
deoxyguanosine kinase (601465) and thymidine kinase-2 (188250) were
believed to be located in the mitochondria. Johansson et al. (1997)
expressed 4 human deoxyribonucleoside kinases as fusion proteins with
the green fluorescent protein to study their intracellular locations in
vivo. They found that the human deoxycytidine kinase is located in the
cell nucleus, and the human deoxyguanosine kinase in mitochondria. The
fusion proteins between green fluorescent protein and thymidine kinases
1 and 2 were both predominantly located in the cytosol. Site-directed
mutagenesis of a putative nuclear targeting signal, identified in the
primary structure of deoxycytidine kinase, completely abolished nuclear
import of the protein. Reconstitution of a deoxycytidine
kinase-deficient cell line with the wildtype nuclear or the mutant
cytosolic enzymes restored sensitivity toward anticancer nucleoside
analogs.
CXCL6
| dbSNP name | rs16850073(C,T); rs1957077(T,C) |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 6372 |
| EntrezGene Description | chemokine (C-X-C motif) ligand 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2787 |
OMIM Clinical Significance
Eyes:
Blue sclerae
Facies:
Mandibular hypoplasia
Limbs:
Campomelia;
Femoral and tibial bowing;
Sloping shoulders
Radiology:
Shallow glenoid fossae;
Upward bowed clavicles;
Persistent wormian bones
Inheritance:
Autosomal dominant
OMIM Title
*138965 CHEMOKINE, CXC MOTIF, LIGAND 6; CXCL6
;;SMALL INDUCIBLE CYTOKINE SUBFAMILY B, MEMBER 6; SCYB6;;
GRANULOCYTE CHEMOTACTIC PROTEIN 2; GCP2
OMIM Description
DESCRIPTION
Chemokines are a group of small (approximately 8-14 kD), mostly basic,
structurally related molecules that regulate cell trafficking of various
types of leukocytes through interactions with a subset of
7-transmembrane, G protein-coupled receptors. Chemokines also play
fundamental roles in the development, homeostasis, and function of the
immune system, and they have effects on cells of the central nervous
system as well as on endothelial cells involved in angiogenesis or
angiostasis. Chemokines are divided into 2 major subfamilies, CXC and
CC, based on the arrangement of the first 2 of the 4 conserved cysteine
residues; the 2 cysteines are separated by a single amino acid in CXC
chemokines and are adjacent in CC chemokines. CXC chemokines are further
subdivided into ELR and non-ELR types based on the presence or absence
of a glu-leu-arg sequence adjacent and N terminal to the CXC motif
(summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
CLONING
The best characterized granulocyte chemotactic protein is interleukin-8
(IL8; 146930), also known as GCP1. Proost et al. (1993) isolated a new
human granulocyte chemotactic protein, GCP2, coproduced with IL8 by
osteosarcoma cells. They found that human and bovine GCP2 are 67%
identical at the amino acid level. Their sequences showed only weak
similarity with that of IL8, and human GCP2 did not crossreact in a
radioimmunoassay for IL8.
Rovai et al. (1997) cloned the human GCP2 gene, as well as epithelial
cell-derived neutrophil-activating peptide-78 (ENA78, or SCYB5; 600324).
Both coding and noncoding portions of the GCP2 gene share very high
nucleotide similarity to ENA78, except for the occurrence of a long
interspersed sequence 5-prime of the GCP2 gene. The GCP2 gene encodes a
propeptide of 114 amino acids. Despite 85% identity of the first 270
nucleotides 5-prime of the transcription start sites, GCP2 and the other
CXC chemokine gene ENA78 showed cell-specific differences in regulation.
Wuyts et al. (1997) synthesized and purified a human GCP2 protein of 75
amino acids. In vitro, synthetic GCP2 was an equally active
chemoattractant for neutrophilic granulocytes as was natural 75-amino
acid GCP2. Synthetic GCP2 did not stimulate eosinophil, monocyte, or
lymphocyte chemotaxis.
GENE FUNCTION
Wuyts et al. (1997) showed that GCP2 binds to the chemokine receptors
CXCR1 and CXCR2. In vivo studies in rabbit demonstrated that GCP2 is a
potent inflammatory mediator.
MAPPING
Using PCR of a radiation hybrid panel, Modi and Chen (1998) mapped the
GCP2 gene to an 1.8-cR interval on chromosome 4q. This tight cluster
contains many members of the CXC chemokine subfamily, and 2 additional
genes, IL8 and MIG (601704), are located about 6 cR distal to this
group. Modi and Chen (1998) suggested that these chemokine genes are all
derived through tandem gene duplication from an ancestral gene located
on chromosome 4, and that the position of SDF1 (600835) on chromosome 10
represents a translocation event.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999)
localized a number of CXC chemokine genes to 4q12-q21. They proposed
that the order in this region is centromere--IL8--GRO1 (155730)/PPBP
(121010)/PF4 (173460)--SCYB5/SCYB6--GRO2 (139110)/GRO3 (139111)--SCYB11
(604852)--SCYB10 (147310)--MIG--telomere. The SCYB6 gene was mapped to
4q12-q13.
PPBP
| dbSNP name | rs73824590(A,G) |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 5473 |
| EntrezGene Description | pro-platelet basic protein (chemokine (C-X-C motif) ligand 7) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01102 |
OMIM Clinical Significance
Eyes:
Cone-rod retinal dystrophy;
Initial color vision and visual acuity loss;
Night blindness;
Peripheral visual field loss;
Widespread retinal pigmentation;
Chorioretinal atrophy;
Early blindness
Inheritance:
Autosomal dominant (19q13.1-q13.2)
OMIM Title
*121010 PRO-PLATELET BASIC PROTEIN; PPBP
;;CXC CHEMOKINE LIGAND 7; CXCL7;;
SMALL INDUCIBLE CYTOKINE SUBFAMILY B, MEMBER 7; SCYB7
PLATELET BASIC PROTEIN, INCLUDED; PBP, INCLUDED;;
CONNECTIVE TISSUE-ACTIVATING PEPTIDE III, INCLUDED; CTAP3, INCLUDED;;
BETA-THROMBOGLOBULIN, INCLUDED; TGB, INCLUDED;;
THROMBOGLOBULIN, BETA-1, INCLUDED; TGB1, INCLUDED;;
NEUTROPHIL-ACTIVATING PEPTIDE 2, INCLUDED; NAP2, INCLUDED;;
THROMBOCIDIN 1, INCLUDED; TC1, INCLUDED;;
THROMBOCIDIN 2, INCLUDED; TC2, INCLUDED
OMIM Description
For background information on chemokines, see CXCL1 (155730).
DESCRIPTION
Pro-platelet basic protein (PPBP) is the precursor of the 2 platelet
alpha-granule proteins, platelet basic protein (PBP) and connective
tissue-activating peptide III (CTAP3). Upon platelet activation they are
released and further processed in plasma to beta-thromboglobulin (TGB)
and neutrophil-activating peptide-2 (NAP2).
CLONING
By purifying proteins with antibacterial activity from platelet
granules, followed by cation exchange chromatography, continuous acid
urea polyacrylamide gel electrophoresis, mass spectrometry, and
N-terminal sequencing, Krijgsveld et al. (2000) identified the
thrombocidins, TC1 and TC2, as variants of the NAP2 and CTAP3 forms of
PPBP, respectively. TC1 and TC2 differ from NAP2 and CTAP3 by a
C-terminal truncation of 2 amino acids (ala and asp) and by their
bactericidal and fungicidal properties, which apparently do not involve
pore formation.
GENE FUNCTION
CTAP3 is a platelet-derived growth factor that stimulates a variety of
specific metabolic and cellular activities including mitogenesis,
extracellular matrix synthesis, glucose metabolism, and plasminogen
activator synthesis in human fibroblast cultures (Castor et al., 1983;
Castor et al., 1985).
Using mass spectrometry, Aivado et al. (2007) generated serum proteome
profiles from 122 patients with myelodysplastic syndrome (MDS), 72
non-MDS patients with cytopenia, and 24 controls, and identified a
profile that distinguished MDS from non-MDS cytopenias. Peptide mass
fingerprinting and quadrupole SELDI-TOF mass spectrometry identified 2
differential proteins, CXCL4 (PF4) and CXCL7, both of which had
significantly decreased serum levels in MDS. The decrease was confirmed
with independent antibody assays, and subtype analyses revealed
decreased serum levels of these 2 proteins in advanced MDS. Aivado et
al. (2007) suggested that there may be a concerted disturbance of
transcription or translation of these chemokines in advanced MDS.
GENE STRUCTURE
Majumdar et al. (1991) compared beta-thromboglobulin with platelet
factor-4 (PF4; 173460). The TGB gene is 1,139 bp long and, like other
members of the small inducible gene (SIG) family, it is divided into 3
exons.
MAPPING
By PCR analysis of human/hamster somatic cell hybrids, Majumdar et al.
(1991) demonstrated that the TGB gene, like the PF4 gene, is located on
chromosome 4. Southern blot analysis of genomic DNA suggested that, as
with the PF4 gene, there are multiple copies of the TGB gene in the
human genome. Wenger et al. (1991) mapped the CTAP3 gene to chromosome
4q12-q13 by in situ hybridization.
Tunnacliffe et al. (1992) stated that all of the CXC SIGs map to
chromosome 4. By pulsed field gel electrophoresis (PFGE), Tunnacliffe et
al. (1992) demonstrated that the TGB genes (which are duplicate) are
closely linked to the duplicated PF4 genes and to other previously
mapped CXC SIGs, namely, IL8 (146930), GRO1 (155730), GRO2 (139110), and
GRO3 (139111), on a single 700-kb restriction fragment located in bands
4q12-q13. The only CXC SIG not linked to this cluster is that encoding
gamma-interferon-induced 10-kD protein (SCYB10; 147310), which is
located in band 4q21. By analysis of lambda genomic clones, Tunnacliffe
et al. (1992) demonstrated that the TGB1 and PF4 genes are separated by
less than 7 kb, and the TGB2 and PF4-alternate (PF4V1; 173461) genes by
approximately 5 kb. Within each TGB/PF4 duplication, the TGB-like gene
is upstream of its linked PF4-like gene. The genes in this closely
linked complex are expressed in a megakaryocyte-specific fashion.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999)
localized a number of CXC chemokine genes to 4q12-q21. They proposed
that the order in this region is centromere--IL8--GRO1/PPBP/PF4--SCYB5
(600324)/SCYB6 (138965)--GRO2/GRO3--SCYB11 (604852)--SCYB10--MIG
(601704)--telomere.
CXCL5
| dbSNP name | rs352047(C,G); rs3775488(T,C); rs425535(T,C) |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 6374 |
| EntrezGene Description | chemokine (C-X-C motif) ligand 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1795 |
OMIM Clinical Significance
Ears:
Profound, congenital, neurosensory, nonsyndromal deafness
Inheritance:
Autosomal recessive (17p12-q12)
OMIM Title
*600324 CHEMOKINE, CXC MOTIF, LIGAND 5; CXCL5
;;SMALL INDUCIBLE CYTOKINE SUBFAMILY B, MEMBER 5; SCYB5;;
NEUTROPHIL-ACTIVATING PEPTIDE ENA-78; ENA78;;
LIPOPOLYSACCHARIDE-INDUCED CXC CHEMOKINE; LIX
OMIM Description
CLONING
Epithelial cell-derived neutrophil-activating peptide ENA78 is an
inflammatory chemokine that is produced concomitantly with interleukin-8
(IL8; 146930) in response to stimulation with either interleukin-1
(IL1B; 147720) or tumor necrosis factor-alpha (TNFA; 191160). Chang et
al. (1994) identified a full-length ENA78 cDNA and isolated its genomic
clone.
Rovai et al. (1997) cloned the human ENA78 gene (which is also
symbolized SCYB5) as well as GCP2 (SCYB6; 138965). Both coding and
noncoding portions of the GCP2 gene share very high nucleotide
similarity to ENA78, except for the occurrence of a long interspersed
sequence 5-prime of the GCP2 gene. Despite 85% identity of the first 270
nucleotides 5-prime of the transcription start sites, GCP2 and the other
CXC chemokine gene ENA78 showed cell-specific differences in regulation.
GENE STRUCTURE
Chang et al. (1994) determined that the ENA78 gene consists of 4 exons
and 3 introns, with a structure resembling that of the IL8 gene. The
transcriptional initiation site was mapped to a position 96 bp upstream
from the translation initiation site.
GENE FAMILY
Chemokines are a group of small (approximately 8-14 kD), mostly basic,
structurally related molecules that regulate cell trafficking of various
types of leukocytes through interactions with a subset of
7-transmembrane, G protein-coupled receptors. Chemokines also play
fundamental roles in the development, homeostasis, and function of the
immune system, and they have effects on cells of the central nervous
system as well as on endothelial cells involved in angiogenesis or
angiostasis. Chemokines are divided into 2 major subfamilies, CXC and
CC, based on the arrangement of the first 2 of the 4 conserved cysteine
residues; the 2 cysteines are separated by a single amino acid in CXC
chemokines and are adjacent in CC chemokines. CXC chemokines are further
subdivided into ELR and non-ELR types based on the presence or absence
of a glu-leu-arg sequence adjacent and N terminal to the CXC motif
(summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
MAPPING
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999)
localized a number of CXC chemokine genes to chromosome 4q12-q21. They
proposed that the order in this region is centromere--IL8--GRO1
(155730)/PPBP (121010)/PF4 (173460)--SCYB5/SCYB6--GRO2 (139110)/GRO3
(139111)--SCYB11 (604852)--SCYB10 (147310)--MIG (601704)--telomere. The
SCYB5 gene was localized to 4q12-q13.
By fluorescence in situ hybridization, Chang et al. (1994) mapped the
ENA78 gene to 4q13-q21, the same region to which several other
inflammatory cytokine genes have been mapped. Chang et al. (1994) found
that even though the ENA78 and IL8 genes share great similarity in
genomic structure and chromosome location, they appear to be regulated
by different mechanisms.
PPBPP2
| dbSNP name | rs142758164(G,T); rs146945422(T,C); rs9995317(G,A); rs10032146(A,G); rs10020783(C,A); rs9997991(G,A); rs9998075(G,C); rs139470446(G,A); rs116634382(C,T) |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 10895 |
| snpEff Gene Name | PPBPL2 |
| EntrezGene Description | pro-platelet basic protein pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
CXCL2
| dbSNP name | rs9131(C,T) |
| cytoBand name | 4q13.3 |
| EntrezGene GeneID | 2920 |
| EntrezGene Description | chemokine (C-X-C motif) ligand 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4624 |
OMIM Clinical Significance
Hair:
Premature hair graying
Inheritance:
Autosomal dominant form
OMIM Title
*139110 CHEMOKINE, CXC MOTIF, LIGAND 2; CXCL2
;;GRO2 ONCOGENE; GRO2;;
SMALL INDUCIBLE CYTOKINE SUBFAMILY B, MEMBER 2; SCYB2;;
MACROPHAGE INFLAMMATORY PROTEIN 2; MIP2;;
GRO PROTEIN, BETA; GROB;;
MIP2-ALPHA; MIP2A
OMIM Description
DESCRIPTION
Chemokines are a group of small (approximately 8-14 kD), mostly basic,
structurally related molecules that regulate cell trafficking of various
types of leukocytes through interactions with a subset of
7-transmembrane, G protein-coupled receptors. Chemokines also play
fundamental roles in the development, homeostasis, and function of the
immune system, and they have effects on cells of the central nervous
system as well as on endothelial cells involved in angiogenesis or
angiostasis. Chemokines are divided into 2 major subfamilies, CXC and
CC, based on the arrangement of the first 2 of the 4 conserved cysteine
residues; the 2 cysteines are separated by a single amino acid in CXC
chemokines and are adjacent in CC chemokines. CXC chemokines are further
subdivided into ELR and non-ELR types based on the presence or absence
of a glu-leu-arg sequence adjacent and N terminal to the CXC motif
(summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
CLONING
The GRO1 gene (CXCL1; 155730) was initially identified by Anisowicz et
al. (1987) by its constitutive overexpression in spontaneously
transformed Chinese hamster fibroblasts. (The name GRO stood for
growth-related.) Subsequently, a protein with melanoma
growth-stimulating activity (MGSA) was shown to be identical. Haskill et
al. (1990) reported the identification of 2 other GRO genes, which they
called GRO-beta and GRO-gamma (GRO3, CXCL3; 139111). These 2 share 90%
and 86% identity at the deduced amino acid level with the original
GRO-alpha isolate. One amino acid substitution, proline in GRO-alpha by
leucine in GRO-beta and GRO-gamma, leads to a large predicted change in
protein conformation. Significant differences were also found in the
3-prime untranslated region, including different numbers of ATTTA
repeats associated with mRNA instability. DNA hybridization with
oligonucleotide probes and partial sequence analysis of the genomic
clones confirmed that the 3 forms are derived from related but different
genes. Expression studies revealed tissue-specific regulation as well as
regulation by specific inducing agents, including interleukin-1, tumor
necrosis factor, and lipopolysaccharide.
Wolpe et al. (1989) showed that macrophages, in response to endotoxin,
secrete a protein with a molecular mass of about 6,000 daltons and with
an affinity for heparin. They termed this protein macrophage
inflammatory protein-2 (MIP2). It is a potent chemotactic agent for
polymorphonuclear leukocytes. Subcutaneous administration caused a
localized inflammatory reaction. Partial N-terminal sequence data showed
similarity to the family of proteins of which the archetype is platelet
factor-4 (PF4; 173460). The sequence of the MIP2 gene was found to be
most closely related to that of the GRO-beta gene.
Tekamp-Olson et al. (1990) used a cDNA clone of murine Mip2 to clone
cDNAs for 2 human homologs, MIP2-alpha and MIP2-beta, which are highly
homologous to each other and to the previously isolated gene for MGSA.
Thus, the 3 GRO genes represent the human homologs of the murine Mip2
gene.
GENE STRUCTURE
Haskill et al. (1990) reported the identification of 2 other GRO The
GROB gene consists of 4 exons, 3 introns, and a 3-prime untranslated
region of about 700 bp terminating at the polyadenylation site.
MAPPING
Studies by Haskill et al. (1990) indicated that the 3 GRO genes, GRO1,
GRO2, AND GRO3, map to chromosome 4q21.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999)
localized a number of CXC chemokine genes to 4q12-q21. They proposed
that the order in this region is centromere--IL8--GRO1/PPBP
(121010)/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2/GRO3--SCYB11
(604852)--SCYB10 (147310)--MIG (601704)--telomere. The GRO2 gene was
localized to 4q12-q13.
ANIMAL MODEL
Nieuwenhuis et al. (2002) showed that clearance of intranasally applied
Pseudomonas aeruginosa is impaired in the lungs of CD1d
(188410)-deficient mice as well as in T cell-deficient mice. Failure to
clear the bacteria was associated with a markedly reduced influx of
neutrophils in the bronchoalveolar lavage fluid in the early stages of
the infection, which was thought to result from impaired production of
chemokines such as Mip2 by alveolar macrophages. Prior administration of
alpha-galactosylceramide to wildtype mice induced almost complete
eradication of P. aeruginosa from their lungs, indicating that
activation of CD1d-restricted T cells by alpha-galactosylceramide is
critical in host defense against these bacteria. Sequential radiologic,
macroscopic pathology, and histopathologic analyses confirmed early
enhanced inflammation and resolution of inflammation and bacterial
phagocytosis by alveolar macrophages in the
alpha-galactosylceramide-treated mice, whereas control mice exhibited
higher numbers of bacteria, lung hemorrhage, and swelling. Flow
cytometric analysis demonstrated that the macrophage activation in
alpha-galactosylceramide-treated mice was associated with increased
numbers of Ifng (147570)-producing NKT cells. Nieuwenhuis et al. (2002)
concluded that activation of CD1d-restricted T cells is crucial in
regulating the antimicrobial immune functions of macrophages at the lung
mucosal surface and suggested that this activity may help in preventing
colonization in diseases such as cystic fibrosis (219700) and in
patients undergoing chemotherapy.
In diseased mouse and human arteries, Zhao et al. (2004) demonstrated
that 5-lipoxygenase (5-LO; 152390)-positive macrophages localize to
areas of neoangiogenesis and that these cells constitute a main
component of aortic aneurysms induced by an atherogenic diet containing
cholate in Apoe (107741) -/- mice. 5-LO deficiency markedly attenuated
the formation of these aneurysms and was associated with reduced matrix
metalloproteinase-2 (MMP2; 120360) activity and diminished plasma
macrophage inflammatory protein-1-alpha (CCL3; 182283), but only
minimally affected the formation of lipid-rich lesions. The leukotriene
LTD4 strongly stimulated expression of CCL3 in macrophages and CXCL2 in
endothelial cells. Zhao et al. (2004) concluded that the 5-LO pathway is
linked to hyperlipidemia-dependent inflammation of the arterial wall and
to the pathogenesis of aortic aneurysms through a potential chemokine
intermediary route.
PPEF2
| dbSNP name | rs13139405(C,G); rs6824610(C,A); rs138073376(C,T); rs56024633(C,T); rs4859559(G,A); rs113024463(A,G); rs67158160(A,G); rs62321581(C,T); rs57739155(C,T); rs7681054(C,T); rs7685485(G,A); rs112371403(G,A); rs112839809(C,G); rs6844961(G,A); rs144302593(C,T); rs78305413(T,G); rs1394913(C,T); rs1394914(A,G); rs1394915(T,C); rs6817104(C,T); rs11097149(G,C); rs7654738(T,C); rs6811934(T,C); rs7697123(A,C); rs7672213(G,C); rs3817099(A,G); rs17000961(T,A); rs34155925(C,T); rs2135234(C,T); rs17000973(G,A); rs2135235(G,A); rs2047976(T,C); rs2047977(C,G); rs4621455(C,G); rs6842665(C,T); rs6531991(A,C); rs6531992(C,T); rs6531993(T,C); rs7685710(C,T); rs2047978(T,C); rs2047979(A,G); rs2047980(T,C); rs9998204(G,A); rs7669770(A,T); rs111955246(C,T); rs7669792(A,G); rs7674933(T,A); rs6531996(A,G); rs4859560(C,T); rs4859561(A,G); rs17001036(C,T); rs4859562(T,C); rs4859563(T,A); rs6845562(T,C); rs6815430(C,A); rs6816009(C,T); rs1394916(A,G); rs6858658(T,G); rs7696829(A,C); rs75653918(T,C); rs2056021(A,G); rs34097437(C,G); rs13132709(G,A); rs144745376(A,G); rs142187732(C,A); rs1546567(C,T); rs1546568(T,C); rs4324568(T,A); rs6826893(C,T); rs57659593(G,T); rs7669428(G,A); rs11934786(A,G); rs11935735(T,G); rs4288032(A,G); rs11097163(A,G); rs1972062(T,C); rs11930088(C,T); rs2174513(T,G); rs1972063(T,C); rs13130621(A,G); rs13103042(G,A); rs13131530(A,G); rs138418695(A,G); rs1983110(A,G); rs9994323(C,T); rs1021923(C,T); rs1021924(A,T); rs60011229(T,C); rs61148547(G,A); rs11097164(C,T); rs28610422(G,A); rs13116352(G,A); rs11724044(C,T); rs10518141(T,C); rs7668152(A,G); rs7668165(A,C); rs2174514(G,A); rs2174515(T,C); rs7694386(G,A); rs13124155(G,T); rs4859410(G,A); rs4859564(A,G); rs4317229(A,G); rs4590067(G,A); rs4490489(G,C); rs4397019(G,A); rs13132374(G,A); rs6532010(G,A); rs4484327(T,C); rs1973635(A,G); rs11944337(G,C); rs1973634(T,C); rs7666135(A,G); rs1976518(C,T); rs1976517(G,A); rs1566975(C,T); rs12498639(T,G); rs13123426(G,A); rs7673337(A,G); rs62318860(T,G); rs4241574(T,C); rs4241575(G,A); rs13120456(T,C); rs7691712(A,G); rs7691755(A,G); rs2280100(C,T); rs4505851(T,C); rs12054638(C,T); rs10009966(G,C); rs11938543(G,A); rs76558075(G,T); rs78910534(G,C); rs11725766(A,G); rs11721508(C,A); rs2047984(T,C); rs28436183(G,T); rs17001163(T,C); rs2047983(G,A); rs11727067(A,G); rs59427215(G,A); rs13116688(C,G); rs28406986(G,A); rs73825577(T,C); rs75418875(C,T); rs113631320(C,T); rs4859565(A,G); rs7438682(A,G); rs142665888(G,A); rs35565943(C,T); rs115208952(C,T); rs28602989(C,A); rs75873273(G,A); rs13150842(G,A); rs55738856(C,T); rs56141568(T,A); rs9993150(C,T); rs10007472(T,C); rs11731367(G,A); rs1876095(A,G); rs61446730(C,T); rs35334463(T,C); rs13147538(A,G); rs13149107(A,G); rs11942273(G,A); rs28453978(G,A); rs1847731(T,C); rs11934638(C,T); rs4859566(G,A); rs75251702(C,T); rs1505613(T,C); rs17221100(A,G) |
| ccdsGene name | CCDS34013.1 |
| cytoBand name | 4q21.1 |
| EntrezGene GeneID | 5470 |
| EntrezGene Description | protein phosphatase, EF-hand calcium binding domain 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PPEF2:NM_006239:exon17:c.G2026A:p.E676K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5243 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O14830 |
| dbNSFP Uniprot ID | PPE2_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0001626 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Short philtrum;
Frontal bossing;
[Ears];
Prominent ears;
Conductive hearing loss;
[Eyes];
Blepharophimosis;
Upslanting palpebral fissures;
[Nose];
Prominent nose;
[Mouth];
Thin lips;
Small mouth
CARDIOVASCULAR:
[Heart];
Tetralogy of Fallot
SKELETAL:
[Hands];
Long fingers;
Partial cutaneous syndactyly (2-3 fingers);
Fifth finger camptodactyly;
Fifth finger clinodactyly
SKIN, NAILS, HAIR:
[Skin];
Prominent veins (especially over scalp and limbs);
[Hair];
Sparse hair
MUSCLE, SOFT TISSUE:
Sparse subcutaneous fat
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios
OMIM Title
*602256 PROTEIN PHOSPHATASE, EF-HAND CALCIUM-BINDING DOMAIN 2; PPEF2
OMIM Description
CLONING
During random sequencing of human retina cDNAs, Sherman et al. (1997)
identified a homolog of Drosophila rdgC. Full-length cDNAs of the gene,
termed PPEF2, predicted a 753-amino acid protein that is 39% identical
to that of Drosophila rdgC and has a domain structure similar to that of
rdgC and PPEF1 (300109). Sherman et al. (1997) noted the existence of a
shorter alternatively spliced form of PPEF2, termed PPEF2(S), that uses
alternative splice acceptor sites in exons 5 and 14 and predicts a
598-amino acid protein lacking EF-hand domains. Northern blot analysis
of rat tissues revealed a 3.7-kb PPEF2 mRNA in retina. In situ
hybridization and cell fractionation experiments further revealed that
the gene is expressed exclusively in the inner segments of the
photoreceptor cells of the retina and in the pineal gland. Sherman et
al. (1997) stated that the inner segment localization implies that PPEF2
probably does not dephosphorylate rhodopsin and is probably not directly
involved in phototransduction.
GENE STRUCTURE
By genomic analysis, Sherman et al. (1997) determined that the PPEF2
gene contains at least 15 exons spanning 33 kb.
MAPPING
Sherman et al. (1997) used Southern blot hybridization and PCR of
human-rodent cell lines to map the PPEF2 gene to human chromosome 4.
ANIMAL MODEL
Ramulu et al. (2001) produced mice carrying targeted disruptions in the
Ppef1 and Ppef2 genes. By analyzing both single and double mutant mice,
they observed that rod light responses and rhodopsin dephosphorylation
kinetics were normal. Furthermore, there was no evidence of retinal
degeneration in the PPEF mutant mice. Ramulu et al. (2001) concluded
that in contrast to loss of rdgC function in Drosophila, elimination of
PPEF function does not cause retinal degeneration in vertebrates.
SOWAHB
| dbSNP name | rs2645673(A,G); rs78372520(A,G); rs2703131(T,C); rs2703130(G,T) |
| cytoBand name | 4q21.1 |
| EntrezGene GeneID | 345079 |
| snpEff Gene Name | ANKRD56 |
| EntrezGene Description | sosondowah ankyrin repeat domain family member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2796 |
GK2
| dbSNP name | rs6837906(T,C) |
| ccdsGene name | CCDS3585.1 |
| cytoBand name | 4q21.21 |
| EntrezGene GeneID | 2712 |
| EntrezGene Description | glycerol kinase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GK2:NM_033214:exon1:c.A12G:p.P4P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2553 |
| ESP Afr MAF | 0.143506 |
| ESP All MAF | 0.153107 |
| ESP Eur/Amr MAF | 0.158023 |
| ExAC AF | 0.231 |
OMIM Clinical Significance
Skin:
Pigment demarcation of upper arm and deltoid area of blacks
Inheritance:
Autosomal dominant
OMIM Title
*137028 GALACTOKINASE 2; GALK2
;;GK2
OMIM Description
CLONING
Lee et al. (1992) sought to clone a human galactokinase gene by its
ability to substitute for the enzyme in yeast. They used a method for
identifying mammalian cDNAs by complementation or other functional
activity in yeast.
Pastuszak et al. (1996) isolated an N-acetylgalactosamine (GalNAc)
kinase from pig kidney and found that partial peptide sequences of this
porcine enzyme were 90% similar to human GK2. Enzyme assays showed that
human GK2 is a highly efficient GalNAc kinase with galactokinase
activity when this sugar is present at high concentrations. Thus,
Pastuszak et al. (1996) stated that although human GK2 was identified
based on its galactokinase activity, it is actually a GalNAc kinase.
MAPPING
Lee et al. (1992) unexpectedly found that the gene which complemented a
galactokinase-deficient strain of Saccharomyces cerevisiae mapped not to
chromosome 17 (604313) but to chromosome 15, thus calling into question
which of the genes, GK1 on 17 or GK2 on 15, is the site of the mutation
in the galactokinase deficiency form of galactosemia (see 230200). The
strategy they used might be adopted for cloning various human disease
genes affecting intermediary metabolism for which yeast mutants are
known. (The mapping to chromosome 15 was done by analysis of genomic DNA
from a panel of human-rodent somatic cell hybrids using PCR.)
THAP9
| dbSNP name | rs982146(G,A); rs13130011(C,T); rs13105865(A,G); rs6535410(G,A); rs11735300(G,A); rs11731547(A,G); rs13144052(G,A); rs6824099(T,C); rs13140582(A,G); rs114882323(T,A); rs3214025(A,G); rs3214024(A,G); rs7698055(G,A); rs6822414(C,T); rs60909079(G,C); rs10022876(A,G); rs11729089(C,T); rs4693527(T,C); rs6843050(C,T); rs11723060(G,A); rs10857215(T,C); rs13119020(G,T); rs6849955(C,A); rs6826437(A,T); rs28531938(G,C); rs35895091(A,G); rs11099558(T,C); rs11099559(C,A); rs2125171(C,T); rs1026452(C,T); rs1963498(C,G); rs3940815(T,A); rs1031639(G,A); rs897945(G,T); rs141598796(C,A); rs6535411(A,G); rs35532215(G,A); rs6842476(T,C); rs1047564(G,A) |
| ccdsGene name | CCDS3598.1 |
| cytoBand name | 4q21.22 |
| EntrezGene GeneID | 79725 |
| EntrezGene Description | THAP domain containing 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | THAP9:NM_024672:exon5:c.C2009A:p.A670E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.503 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H5L6 |
| dbNSFP Uniprot ID | THAP9_HUMAN |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 1.870e-04,4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Frontal bossing;
Microcephaly;
[Face];
Coarse facies;
Dysmorphic features;
[Eyes];
Deep-set eyes;
Hypotelorism;
Upslanting palpebral fissures;
[Nose];
Depressed nasal bridge;
Anteverted nares;
[Mouth];
Cleft palate
RESPIRATORY:
[Lung];
Lung hypoplasia in those with diaphragmatic hernia
CHEST:
[Diaphragm];
Diaphragmatic hernia
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
[Feet];
Club feet
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation;
Seizures;
Holoprosencephaly
MISCELLANEOUS:
Highly variable phenotype;
Midline defects;
Contiguous gene deletion syndrome
MOLECULAR BASIS:
Caused by deletion (1.7Mb) of 1q41-q42
OMIM Title
*612537 THAP DOMAIN-CONTAINING PROTEIN 9; THAP9
OMIM Description
CLONING
By searching databases, Roussigne et al. (2003) identified several
proteins containing an N-terminal THAP domain, including THAP9. The THAP
domain of the deduced 903-amino acid THAP9 protein includes a C2CH
signature, an AVPTIF box, and several other conserved amino acids. The
THAP domain is followed by a stretch that shares similarity with the
Drosophila P element transposase.
MAPPING
Hartz (2009) mapped the THAP9 gene to chromosome 4q21.22 based on an
alignment of the THAP9 sequence (GenBank GENBANK AK026973) with the
genomic sequence (build 36.1).
GENE FUNCTION
Majumdar et al. (2013) showed that human THAP9 can mobilize Drosophila P
elements in both Drosophila and human cells. Chimeric proteins formed
between the Drosophila P element transposase N-terminal THAP DNA-binding
domain; the C-terminal regions of human THAP9 can also mobilize
Drosophila P elements. Majumdar et al. (2013) concluded that human THAP9
is an active DNA transposase that, although 'domesticated,' still
retains the catalytic activity to mobilize P transposable elements
across species.
TIGD2
| dbSNP name | rs17015025(G,A); rs17015027(A,G); rs2280099(A,G); rs8582(T,A) |
| cytoBand name | 4q22.1 |
| EntrezGene GeneID | 166815 |
| snpEff Gene Name | FAM13A |
| EntrezGene Description | tigger transposable element derived 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1538 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial weakness;
[Neck];
Neck weakness
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, restrictive;
Cardiomyopathy, hypertrophic
RESPIRATORY:
Respiratory insufficiency;
Reduced forced vital capacity
CHEST:
[Diaphragm];
Diaphragmatic paralysis
SKELETAL:
[Spine];
Scoliosis;
Rigid spine;
Stiff spine;
[Limbs];
Contractures of the knees and ankles;
Valgus ankle deformity;
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness, severe, diffuse;
Muscle atrophy, diffuse;
Easy fatigability;
Skeletal muscle biopsy shows dystrophic changes;
Necrotic fibers;
Internal nuclei;
Variation in fiber size;
Apoptotic nuclei;
Myofibrillar myopathy;
Sarcoplasmic accumulation of electron-dense granulofilamentous material;
Myopathic and neurogenic changes seen on EMG;
Z-disk streaming;
Z-disk degeneration
NEUROLOGIC:
[Central nervous system];
Toe-walking in early childhood;
Clumsy gait;
Loss of ambulation;
[Behavioral/psychiatric manifestations];
Axonal and demyelinating peripheral neuropathy;
Chronic denervation;
Distal sensory impairment;
Hyporeflexia;
Giant axonal neuropathy;
Axonal loss;
Thin myelin sheaths
VOICE:
Hypernasal speech
LABORATORY ABNORMALITIES:
Markedly increased serum creatine kinase
MISCELLANEOUS:
Onset in late childhood or early teens;
Rapidly progressive;
Early death may occur;
Most mutations occur de novo
MOLECULAR BASIS:
Caused by mutation in the BCL2-associated athanogene 3 gene (BAG3,
603883.0001)
OMIM Title
*612973 TIGGER TRANSPOSABLE ELEMENT-DERIVED GENE 2; TIGD2
OMIM Description
DESCRIPTION
DNA transposons, such as Tiggers, are repetitive elements that move in
the genome by excision and reintegration without an RNA intermediate.
TIGD2 belongs to a family of genes derived from Tiggers (Smit and Riggs,
1996; Dou et al., 2004). For further information on Tiggers, see TIGD1
(612972).
CLONING
Dou et al. (2004) reported that TIGD2 contains 525 amino acids.
MAPPING
Hartz (2009) mapped the TIGD2 gene to chromosome 4q22.1 based on an
alignment of the TIGD2 sequence (GenBank GENBANK AL833679) with the
genomic sequence (build 36.1).
PDHA2
| dbSNP name | rs11725710(G,C); rs143994593(A,G); rs200969445(A,G) |
| ccdsGene name | CCDS3644.1 |
| cytoBand name | 4q22.3 |
| EntrezGene GeneID | 5161 |
| EntrezGene Description | pyruvate dehydrogenase (lipoamide) alpha 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PDHA2:NM_005390:exon1:c.A568G:p.T190A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.604 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P29803 |
| dbNSFP Uniprot ID | ODPAT_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 3.334e-04,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Multifactorial
GROWTH:
[Other];
Failure to thrive
ABDOMEN:
[Gastrointestinal];
Infantile pyloric stenosis;
Nonbilious projectile vomiting;
Palpable pyloric "olive";
Visible gastric peristalsis
METABOLIC FEATURES:
Hypochloremic metabolic alkalosis
MISCELLANEOUS:
Most common form of bowel obstruction in infancy;
Sex ratio of 4-4.5 males to 1 female;
Incidence 8/1,000 newborns;
Onset of symptoms 2-4 weeks of age
MOLECULAR BASIS:
Susceptibility conferred by mutation in the promoter of the nitric
oxide synthase-1 gene (NOS1, 163731.0001)
OMIM Title
*179061 PYRUVATE DEHYDROGENASE, ALPHA-2; PDHA2
;;PYRUVATE DEHYDROGENASE, E1-ALPHA POLYPEPTIDE, TESTIS-SPECIFIC
OMIM Description
CLONING
The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl
CoA, an essential step in aerobic glucose metabolism. Dahl et al. (1990)
extended their previous work on the X-linked gene for the E1-alpha
subunit of this complex, PDHA1 (300502), which is expressed in somatic
tissues, and identified an autosomal gene, PDHA2. PDHA2 has 84%
nucleotide sequence similarity with the PDHA1 cDNA. Dahl et al. (1990)
found that PDHA2 was testis-specific and was expressed in postmeiotic
spermatogenic cells. They suggested that to circumvent the problems of
X-chromosome inactivation or the absence of an X chromosome in haploid
spermatogenic cells for which PDH is essential for carbohydrate
oxidation, an autosomal 'backup' gene, PDHA2, exists.
GENE STRUCTURE
Dahl et al. (1990) found that the PDHA2 gene lacks introns and has
characteristics of a functional processed gene. Protamine genes (e.g.,
182880), which are also expressed only in germ cells, are likewise
intronless. DNA sequencing of the gene showed that the transcribed
region spans only approximately 1.4 kb. In contrast, the PDHA1 gene
contains 10 introns and spans approximately 17 kb.
Pinheiro et al. (2010) identified 61 CpG sites along the human PDHA2
gene. Nineteen CpG sites were grouped in a CpG island that covered the
core promoter and extended 73 nucleotides into the coding region, and 14
CpG sites formed an additional CpG island downstream within the PDHA2
coding region. Pinheiro et al. (2010) found that all CpG sites were
heavily methylated in somatic tissues (gastric cells and lymphocytes)
and that only the second CpG island was fully demethylated in diploid
and haploid testicular germ cells. Pinheiro et al. (2010) concluded that
demethylation of the PDHA2 core promoter is not a prerequisite for
transcription initiation in germ cells.
MAPPING
Using a probe for PDHA1, Dahl et al. (1990) found significant in situ
hybridization with an autosomal locus, PDHA2, located on chromosome
4q22-q23. Mapping of the gene to chromosome 4 was also done by isolation
of the gene from a chromosome 4-specific genomic library.
Brown et al. (1990) showed by in situ hybridization that a PDH gene maps
to the mouse X chromosome, homologous to human PDHA1, whereas the
testis-specific form, Pdha2, is encoded by a gene on mouse chromosome
19.
PCNAP1
| dbSNP name | rs1540053(C,T); rs4141887(T,C) |
| cytoBand name | 4q23 |
| EntrezGene GeneID | 100507053 |
| EntrezGene Symbol | LOC100507053 |
| snpEff Gene Name | ADH4 |
| EntrezGene Description | uncharacterized LOC100507053 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1979 |
LOC256880
| dbSNP name | rs3756087(A,G); rs17029673(A,G) |
| cytoBand name | 4q23 |
| EntrezGene GeneID | 256880 |
| snpEff Gene Name | DNAJB14 |
| EntrezGene Description | uncharacterized LOC256880 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4894 |
FLJ20021
| dbSNP name | rs113561582(T,C) |
| cytoBand name | 4q24 |
| EntrezGene GeneID | 90024 |
| snpEff Gene Name | AP001816.1 |
| EntrezGene Description | uncharacterized LOC90024 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0242 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3V197 |
| dbNSFP KGp1 AF | 0.0173992673993 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.034965034965 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01745 |
| ExAC AF | 0.003958 |
CENPE
| dbSNP name | rs73837615(G,A); rs143981900(C,G); rs17215862(G,A); rs150712923(G,T); rs2720448(C,T); rs72665049(C,G); rs2623064(C,A); rs2711896(T,G); rs200749958(A,T); rs2720449(G,A); rs13114629(G,A); rs61355145(G,A); rs2720452(T,C); rs143170546(C,T); rs72665052(T,C); rs2623070(G,A); rs116628520(T,C); rs79126480(G,C); rs75153789(T,C); rs2623069(G,A); rs2711889(A,G); rs2720453(T,C); rs2623085(G,A); rs115296640(T,C); rs12505289(C,T); rs12506065(C,A); rs12506198(G,A); rs61751592(G,C); rs150282431(G,T); rs12507348(C,T); rs61034129(T,C); rs61088886(C,T); rs72665054(C,T); rs61638317(G,C); rs144262479(T,C); rs11730764(T,C); rs11730765(T,C); rs2711888(C,A); rs2623060(G,A); rs58786870(A,T); rs2954141(C,A); rs12505908(G,A); rs72665056(C,T); rs181221363(G,A); rs2720455(G,A); rs2720456(G,A); rs2720457(G,T); rs2623082(T,C); rs115374331(G,A); rs2720458(C,G); rs73837644(T,C); rs2720460(A,G); rs2623063(G,A); rs2720461(A,G); rs2720462(T,G); rs115572126(C,T); rs149725992(T,C); rs2623062(C,T); rs2720463(G,A); rs2711901(T,G); rs2711900(G,A); rs115886007(T,G); rs2243682(G,A); rs6830791(A,G); rs6836162(C,T); rs116240157(A,T); rs2866633(C,T); rs7686105(G,A); rs7664021(T,C); rs2126470(T,C); rs1381657(C,G); rs1381658(C,T); rs2711899(T,C); rs2711898(C,T); rs62327333(A,T); rs1031803(A,C); rs111517422(A,T); rs2615541(G,A); rs1031804(C,T); rs2615542(A,G); rs2169508(T,A); rs2711895(G,T); rs80269225(G,C); rs79088594(G,A); rs2711894(G,T); rs115960863(A,C); rs62327334(C,T); rs79431579(G,A); rs56256243(A,G); rs2711893(T,A); rs56981575(T,C); rs72946153(T,C); rs66869812(T,C); rs2720464(G,A); rs58648171(C,T); rs114361669(T,C); rs7684528(C,G); rs148960888(G,A); rs17216959(T,G); rs6832024(A,T); rs12512468(A,G); rs2711891(T,C); rs192448667(G,A); rs138663506(T,C); rs11729856(G,A); rs2251322(C,T); rs144716013(C,A); rs75568479(A,C); rs2711890(G,A); rs2615539(C,G); rs78117560(A,T); rs11737673(T,A); rs11725048(A,G); rs61744934(C,T); rs2251634(C,T); rs72665071(G,A); rs75104188(A,G); rs2045746(G,T); rs12511516(G,A); rs73837650(T,A); rs2720467(T,C); rs2720468(A,G); rs2720469(C,T); rs2720470(G,A); rs17283027(A,G); rs6810571(G,T); rs116550427(A,T); rs68023422(C,T); rs56378042(A,G); rs72665080(G,A); rs7672974(G,C); rs78820409(A,G); rs12506575(A,C); rs115740812(T,C); rs72665085(C,G); rs55895342(T,C); rs12505012(T,C); rs12505118(A,T); rs17283077(C,G); rs55708783(C,T); rs55777543(T,C); rs11931693(C,T); rs11932885(G,C); rs6813563(G,A); rs72665089(A,G); rs11727498(C,T); rs12504143(G,A); rs17217250(T,C); rs17283194(T,C); rs6841136(A,C); rs4698879(C,T); rs3765086(A,G); rs142988615(G,A); rs72665093(T,C); rs3974474(T,C); rs73837653(A,G); rs143981485(A,G); rs72665095(A,C); rs72665096(T,C); rs73837654(G,A); rs17283278(C,T); rs6847142(C,A); rs115383008(T,C); rs6847357(C,G); rs115495561(G,A); rs6830082(T,A); rs7662455(G,A); rs78336913(C,T); rs151113663(A,G); rs113866998(C,T); rs77059819(A,G); rs17217431(A,G); rs4699050(A,G); rs4699051(T,C); rs17217473(A,C); rs3816642(C,T); rs2290943(A,G); rs116520973(G,T); rs6837114(C,T); rs78963143(T,C) |
| ccdsGene name | CCDS34042.1 |
| cytoBand name | 4q24 |
| EntrezGene GeneID | 1062 |
| EntrezGene Description | centromere protein E, 312kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CENPE:NM_001286734:exon22:c.G2722T:p.D908Y,CENPE:NM_001813:exon23:c.G2797T:p.D933Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7901 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 3.416e-04,1.383e-04 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
NEUROLOGIC:
[Central nervous system];
Seizures, partial, unilateral;
Generalized tonic-clonic seizures, secondary;
Seizures affect the vocal cords, lips, mouth, and face;
Difficulty speaking during seizures;
Gurgling or drooling during seizures;
Nocturnal seizures;
EEG shows unilateral centrotemporal spikes
MISCELLANEOUS:
Onset 5 to 10 years of age;
Most common form of childhood idiopathic epilepsy;
Seizures usually remit in adolescence;
Boys are more often affected than girls (3:2);
Affected individuals may have learning or behavioral problems during
the period when seizures occur
OMIM Title
*117143 CENTROMERIC PROTEIN E; CENPE
;;KINESIN FAMILY MEMBER 10; KIF10
OMIM Description
DESCRIPTION
The CENPE gene encodes a large kinetochore-associated kinesin-like motor
protein required for spindle microtubule capture and attachment at the
kinetochore during cell division (summary by Mirzaa et al., 2014).
CLONING
Yen et al. (1991) identified a 250- to 300-kD human
centromere-associated protein, CENPE, by preparing monoclonal antibodies
against a fraction of HeLa chromosome scaffold proteins enriched for
centromere/kinetochore components. In cells progressing through
different parts of the cell cycle, the localization of CENPE differs
markedly from that observed for the previously identified centromere
proteins CENPA (117139), CENPB (117140), CENPC (117141), and CENPD
(117142). In contrast to these antigens, no monoclonal antibody staining
was detected during interphase, and staining first appeared at the
centromere region of chromosomes during prometaphase. Microinjection of
the monoclonal antibody 177, which demonstrated CENPE, into metaphase
cells blocked or significantly delayed progression into anaphase,
although the morphology of the spindle and the configuration of the
metaphase chromosomes appeared normal in these metaphase-arrested cells.
Thus, CENPE function is required for the transition from metaphase to
anaphase.
MAPPING
Testa et al. (1994) used CENPE cDNA to map the human gene to chromosome
4q24-q25 by fluorescence in situ hybridization.
Gross (2014) mapped the CENPE gene to chromosome 4q24 based on an
alignment of the CENPE sequence (GenBank GENBANK AB209996) with the
genomic sequence (GRCh38).
NOMENCLATURE
Lawrence et al. (2004) presented a standardized kinesin nomenclature
based on 14 family designations. Under this system, CENPE, or KIF10,
belongs to the kinesin-7 family.
GENE FUNCTION
Yen et al. (1992) identified CENPE as a kinesin-like motor protein (Mr
312,000) that accumulates in the G2 phase of the cell cycle. CENPE
associates with kinetochores during congression, relocates to the
spindle midzone at anaphase, and is quantitatively discarded at the end
of the cell division. CENPE is probably one of the motors responsible
for mammalian chromosome movement and/or spindle elongation.
Wood et al. (1997) cloned the Xenopus CENPE, which shows 74% identity
with the human homolog. This protein associates with Xenopus centromeres
in vivo and in vitro, and is required for metaphase chromosome
alignment. Addition of anti-Xenopus CENPE antibodies disrupts metaphase
chromosome alignment. Wood et al. (1997) further demonstrated that
Xenopus CENPE powers chromosome movement towards microtubule plus ends
in vitro. These data support a model in which CENPE functions in
congression to tether kinetochores to microtubule plus ends.
Yao et al. (2000) investigated the function of CENPE in attachment of
kinetochores to spindle microtubules, alignment of chromosomes, and
checkpoint signaling, using antisense oligonucleotides to suppress its
synthesis and accumulation. They showed that CENPE is essential for
stable, bioriented attachment of chromosomes to spindle microtubules,
for development of tension across aligned chromosomes, for stabilization
of spindle poles, and for satisfying the mitotic checkpoint.
Using Xenopus egg extracts, Abrieu et al. (2000) found that CENPE is
required for establishing and maintaining a checkpoint that delays
anaphase onset until all centromeres are correctly attached to the
mitotic spindle. When CENPE function was disrupted by immunodepletion or
antibody addition, extracts failed to arrest in response to spindle
damage. Mitotic arrest could be restored by addition of high levels of
soluble MAD2 (601467), demonstrating that the absence of CENPE
eliminates kinetochore-dependent signaling but not the downstream steps
in checkpoint signal transduction. Because it directly bound both to
spindle microtubules and to the kinetochore-associated checkpoint kinase
BUBR1 (602860), the authors concluded that CENPE is a central component
in the vertebrate checkpoint that modulates signaling activity in a
microtubule-dependent manner.
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was CENPE. These 37 genes included several
splicing factors for which knockdown generates mitotic spindle defects.
In addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
Spiliotis et al. (2005) showed that defects resulting from septin (see
604061) depletion correlated with the loss of the mitotic motor and
CENP-E from the kinetochores of congressing chromosomes. The authors
suggested that mammalian septins may form a mitotic scaffold for CENP-E
and other effectors to coordinate cytokinesis with chromosome
congression and segregation.
MOLECULAR GENETICS
In a brother and sister, born of unrelated parents of European descent,
with autosomal recessive primary microcephaly-13 (MCPH13; 616051),
Mirzaa et al. (2014) identified compound heterozygous missense mutations
in the CENPE gene (D933N, 117143.0001 and K1355E, 117143.0002). The
mutations, which were found by whole-exome sequencing, segregated with
the disorder in the family. Studies of patient cells as well as cells
transfected with the mutations demonstrated abnormalities in spindle
microtubule organization and mitotic progression.
ANIMAL MODEL
Putkey et al. (2002) found that Cenpe deletion in mice caused early
embryonic lethality, with embryos unable to implant or develop past
implantation. Conditional Cenpe disruption in cultured mouse embryonic
fibroblasts and in regenerating adult liver following chemical injury
led to abnormalities in chromosome alignment during cell division. Most
Cenpe-null chromosomes moved to the spindle equator in metaphase, but
their kinetochores bound only half the normal number of microtubules.
Some metaphase chromosomes were near spindle poles. Putkey et al. (2002)
concluded that CENPE is essential for the maintenance of chromosome
stability through efficient stabilization of microtubule capture at
kinetochores.
LEF1
| dbSNP name | rs4245927(A,G); rs115825108(G,A); rs142286975(G,T); rs2269834(C,A); rs57835721(G,T); rs1291492(G,T); rs10025431(T,G); rs115503552(A,G); rs4386676(T,C); rs6533343(C,G); rs7376170(T,C); rs7377757(C,T); rs739728(C,A); rs4245928(A,C); rs17038504(C,T); rs10022726(C,T); rs17038507(C,T); rs10034874(T,C); rs10023288(C,T); rs6819308(C,T); rs17038514(C,T); rs57340953(C,T); rs77800899(C,A); rs6826687(A,G); rs72894311(C,T); rs79905861(C,T); rs7681436(C,T); rs6533346(G,C); rs6840356(G,A); rs4956151(T,C); rs4956152(G,A); rs13109482(G,T); rs6847336(C,A); rs6847362(C,T); rs6852709(A,G); rs4613638(A,G); rs58754095(G,T); rs58126563(T,C); rs61605115(A,G); rs72894325(T,C); rs4956153(T,C); rs139296833(T,C); rs144335472(C,T); rs56797829(T,C); rs6851584(G,A); rs141929220(A,G); rs17038547(G,A); rs6834963(T,C); rs2107029(T,C); rs2107030(T,C); rs116303326(A,G); rs2880322(T,G); rs2276335(C,T); rs76590649(A,G); rs75434343(C,T); rs3796993(C,T); rs7696959(T,C); rs140168930(C,T); rs113710141(T,C); rs113269231(G,A); rs7672996(A,T); rs3796994(G,A); rs17439845(G,A); rs145455922(G,A); rs1291490(C,T); rs6814413(T,C); rs183616121(G,A); rs6815281(T,C); rs28544029(T,A); rs116782553(T,A); rs7664774(C,T); rs7664819(C,T); rs138119200(C,T); rs7665504(G,A); rs4956155(G,A); rs4956156(G,T); rs4956157(G,A); rs113227786(G,T); rs11730239(G,A); rs6819640(T,C); rs113428728(A,G); rs59589123(T,C); rs191413109(G,A); rs115933424(C,T); rs3796995(C,T); rs3796997(T,C); rs3819199(C,T); rs7681524(T,C); rs3796998(T,C); rs3796999(T,C); rs72894349(T,C); rs3797000(A,C); rs72894352(T,C); rs75592688(T,C); rs4403119(G,A); rs182369023(T,G); rs4391117(T,G); rs5024489(T,C); rs3797001(T,C); rs4956036(A,T); rs6826742(G,T); rs6827373(G,A); rs6853083(T,A); rs4256291(G,A); rs78806672(G,A); rs4547871(A,G); rs78836820(G,T); rs114018724(C,T); rs17038591(C,T); rs7676998(C,T); rs7677491(G,T); rs16996935(A,G); rs10856986(T,C); rs72894366(T,C); rs75074786(A,G); rs4279288(G,A); rs7673917(T,C); rs1380770(T,C); rs7655476(G,A); rs28660527(T,C); rs58333585(T,C); rs115516519(A,G); rs7686902(A,G); rs898518(C,A); rs7694643(G,A); rs115172975(T,G); rs7678072(T,A); rs4458527(G,C); rs7654054(C,T); rs76655938(G,A); rs59361220(C,T); rs6533350(A,G); rs34271707(C,T); rs73839826(A,G); rs78866112(A,G); rs6533351(A,G); rs138712738(T,C); rs7665096(C,T); rs7671583(G,T); rs744369(A,G); rs112851762(G,A); rs2003869(A,G); rs72896198(G,A); rs77655345(C,G); rs79151491(G,C); rs749414(T,G); rs75471275(G,A); rs9992390(G,C); rs371056210(C,T); rs114748567(C,T); rs139630013(C,A); rs74668181(T,C); rs77485235(A,G); rs7698317(G,T); rs371917853(A,C); rs7698367(C,T); rs11939273(T,C); rs72660421(T,A); rs56202832(T,C); rs75331420(G,C); rs62310683(G,A); rs10011173(G,A); rs10022956(T,C); rs41500451(G,C); rs74473524(T,C); rs113111240(G,A); rs10516550(C,T); rs77178783(G,A); rs116600462(G,T); rs76027781(A,C); rs183111537(C,T); rs4245929(A,T); rs4245930(G,A); rs28374811(G,A); rs6833849(G,T); rs1460405(C,T); rs200784859(G,A); rs4643888(G,A); rs4423942(C,A); rs55772027(T,C); rs141445464(T,G); rs72660430(T,G); rs75694954(G,A); rs4624731(G,A); rs6838919(G,A); rs79901457(A,G); rs2061531(C,T); rs143691561(A,G); rs17038617(T,G); rs956237(G,A); rs17038620(G,A); rs6852833(C,T); rs6835110(T,A); rs28617637(A,T); rs10025623(G,A); rs9992744(T,C); rs4956159(A,C); rs55664149(A,C); rs114497955(A,G); rs9999061(T,C); rs113819596(A,C); rs62310705(T,G); rs139899428(T,C); rs17038627(C,G); rs59757914(G,A); rs6533354(A,G); rs17038630(G,T); rs922168(C,T); rs139853310(G,A); rs9992327(C,T); rs9992763(G,T); rs183408883(T,C); rs12647780(A,G); rs12641774(C,A); rs922167(C,T); rs922166(A,G); rs76183486(C,T); rs12503104(C,T); rs75293340(G,A); rs56010250(C,T); rs924724(T,C); rs922165(G,A); rs922164(C,T); rs922163(C,T); rs7656283(A,G); rs111344984(G,A); rs72660438(T,C); rs7668764(G,T); rs72660440(T,C); rs4956037(G,A); rs6846337(A,G); rs56090219(A,G); rs78447779(C,G); rs78062294(T,A); rs17038678(T,C); rs1566746(A,G); rs17038683(A,G); rs78328567(A,C); rs17038688(C,A); rs80082245(G,A); rs77176747(C,T); rs6817603(C,A); rs2201967(G,A); rs74463214(A,C); rs72660442(G,A); rs11933238(T,A); rs60385316(G,C); rs77024134(T,C); rs60097999(T,C); rs2221339(C,T); rs72660443(T,C); rs78934491(T,C); rs62310711(T,C); rs61752607(C,T); rs56101204(A,G); rs60543822(A,G); rs73839842(C,T); rs111742123(A,C) |
| ccdsGene name | CCDS3679.1 |
| cytoBand name | 4q25 |
| EntrezGene GeneID | 51176 |
| EntrezGene Description | lymphoid enhancer-binding factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LEF1:NM_001130713:exon2:c.G253A:p.D85N,LEF1:NM_001166119:exon2:c.G49A:p.D17N,LEF1:NM_016269:exon2:c.G253A:p.D85N,LEF1:NM_001130714:exon2:c.G253A:p.D85N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8834 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PDK3 |
| dbNSFP KGp1 AF | 0.00869963369963 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0158311345646 |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.000908 |
| ESP All MAF | 0.005151 |
| ESP Eur/Amr MAF | 0.007326 |
| ExAC AF | 0.008368 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial swelling (in some patients);
[Mouth];
Cleft palate (in some patients)
SKIN, NAILS, HAIR:
[Nails];
Yellow nails (in some patients)
MUSCLE, SOFT TISSUE:
Lymphedema, predominantly in the lower limbs;
Paucity or absence of lymph nodes in the axillae and above the inguinal
ligaments seen on scintilymphangiography
MISCELLANEOUS:
Onset around puberty
OMIM Title
+153245 LYMPHOID ENHANCER-BINDING FACTOR 1; LEF1
;;TRANSCRIPTION FACTOR, T CELL-SPECIFIC, 1, ALPHA;;
TCF1-ALPHA
SEBACEOUS TUMORS, SOMATIC, INCLUDED
OMIM Description
DESCRIPTION
LEF1 is a nuclear protein that is expressed in pre-B and T cells. It
binds to a functionally important site in the T-cell receptor-alpha
(TCRA; see 186880) enhancer and confers maximal enhancer activity. LEF1
belongs to a family of regulatory proteins that share homology with high
mobility group protein-1 (HMG1; 163905) (Waterman et al., 1991; van
Genderen et al., 1994).
CLONING
By sequencing tryptic peptides of TCF1-alpha purified from Jurkat human
T-cell nuclear extracts, followed by PCR and screening a Jurkat cDNA
library, Waterman et al. (1991) cloned 2 TCF1-alpha splice variants. The
deduced full-length protein contains 399 amino acids and has a
calculated molecular mass of 44.2 kD. The C-terminal half of TCF1-alpha
contains a serine- and threonine-rich segment, a 68-amino acid domain
that shares similarity with a conserved region of HMG and nonhistone
chromosomal proteins, and a putative nuclear localization signal. The
shorter TCF1-alpha variant encodes a protein with an in-frame 28-amino
acid deletion within the serine- and threonine-rich segment. Northern
blot analysis detected an abundant 3.4-kb transcript and a minor 2.3-kb
transcript in mouse and human T-cell lines and in mouse thymus, but not
in B-cell lines, a macrophage cell line, or in other mouse tissues
examined. SDS-PAGE of purified human TCF1-alpha showed 3 distinct
protein bands, and the major TCF1-alpha protein had an apparent
molecular mass of 55 kD.
By screening a human genomic PAC library and testis, melanoma, and fetal
brain cDNA libraries, Hovanes et al. (2000) identified several LEF1
splice variants. The most common transcript encodes the 399-amino acid
protein, which contains a conserved N-terminal beta-catenin (CTNNB1;
116806)-binding domain and a C-terminal HMG-type DNA-binding/bending
domain. Another variant encodes a 413-amino acid protein that differs at
the C terminus. Use of alternatively spliced sequences in intron 3,
which the authors called exons 3a and 3b, introduces in-frame stop
codons, producing proteins of 16 and 18 kD that lack the HMG-like
DNA-binding domain and nuclear localization signal. These proteins are
predicted to be cytoplasmic and capable of interacting with
beta-catenin.
GENE FUNCTION
Using footprint, mobility-shift, and Southwestern blot experiments,
Waterman et al. (1991) showed that recombinant full-length TCF1-alpha
and its isolated HMG-like domain bound to the DNA sequence
5-prime-GGCACCCTTTGAA-3-prime in the TCRA enhancer, most likely as a
monomer. Following expression in HeLa cells, TCF1-alpha activated
expression of a reporter gene containing the TCF1-alpha-binding motif.
Zhou et al. (1995) reported that several hair keratin genes (see KRTHA1;
601077) possess consensus LEF1-binding motifs located in similar
positions relative to their TATA box. They demonstrated that LEF1 binds
to hair keratin promoters in vitro, and that LEF1 is present during skin
development in ectoderm that will express these promoters as the cells
differentiate. In addition, they showed that mouse Lef1 mRNA is present
in pluripotent ectoderm, and that it is upregulated in a highly
restricted pattern just before the formation of underlying mesenchymal
condensates and the commitment of overlying ectodermal cells to
invaginate and become hair follicles.
Hovanes et al. (2000) transfected human and other mammalian cell lines
with a reporter gene construct containing the LEF1 promoter region and
observed highest LEF1 expression in mature human T- and B-cell lines.
Since the LEF1 gene is not expressed in B lymphocytes, Hovanes et al.
(2000) proposed that expression of LEF1 is normally silenced in B cells
by elements not present in the promoter fragment tested.
Constitutive activation of the Wnt (see 164975) signaling pathway is a
root cause of many colon cancers. Activation of this pathway is caused
by genetic mutations that stabilize the beta-catenin protein (CTNNB1;
116806), allowing it to accumulate in the nucleus and form complexes
with other members of the lymphoid enhancer factor and T-cell factor
family of transcription factors (referred to collectively as LEF/TCFs;
see TCF4, 602272) to activate transcription of target genes. Hovanes et
al. (2001) reported that LEF1 is a target gene ectopically activated in
colon cancer. The pattern of this ectopic expression is unusual because
it derives from selective activation of a promoter for a full-length
LEF1 isoform that binds beta-catenin, but not a second, intronic
promoter that drives expression of a dominant-negative isoform.
Beta-catenin/TCF complexes can activate the promoter for full-length
LEF1, indicating that in cancer high levels of these complexes
misregulate transcription to favor a positive feedback loop for Wnt
signaling by inducing selective expression of full-length,
beta-catenin-sensitive forms of LEF/TCFs. The significance of the
findings was discussed by de Lau and Clevers (2001).
Merrill et al. (2001) showed that Lef1 and Tcf3 (604652) controlled
differentiation of multipotent stem cells in mouse skin. Lef1 required
Wnt signaling and stabilized beta-catenin to express hair-specific
keratins and control hair differentiation. In contrast, Tcf3 acted
independently of its beta-catenin-interacting domain to suppress
features of epidermal differentiation, in which Tcf3 was normally shut
off, and promote features of the follicle outer root sheath and
multipotent stem cells. Lef1 lacking its beta-catenin-binding domain
suppressed hair differentiation and supported sebocyte differentiation.
Yasumoto et al. (2002) found that functional cooperation between LEF1
and an MITF (156845) isoform, MITF-M, in several mammalian cell lines
resulted in synergistic transactivation of the DCT (191275) promoter, an
early melanoblast marker. Beta-catenin was required for efficient
transactivation, but was dispensable for the interaction between MITF-M
and LEF1.
The morphogenesis of organs as diverse as lungs, teeth, and hair
follicles is initiated by a downgrowth from a layer of epithelial stem
cells. During follicular morphogenesis, stem cells form this bud
structure by changing their polarity and cell-cell contact. Jamora et
al. (2003) showed that this process is achieved through simultaneous
receipt of 2 external signals: a WNT protein (WNT3A; 606359) to
stabilize beta-catenin, and a bone morphogenetic protein inhibitor
(Noggin; 602991) to produce Lef1. Beta-catenin binds to and activates
Lef1 transcription complexes that appear to act uncharacteristically by
downregulating the gene encoding E-cadherin (192090), an important
component of polarity and intercellular adhesion. When either signal is
missing, functional Lef1 complexes are not made, and E-cadherin
downregulation and follicle morphogenesis are impaired. In Drosophila,
E-cadherin can influence the plane of cell division and cytoskeletal
dynamics. Consistent with this notion, Jamora et al. (2003) showed that
forced elevation of E-cadherin levels block invagination and follicle
production. Jamora et al. (2003) concluded that their findings reveal an
intricate molecular program that links 2 extracellular signaling
pathways to the formation of a nuclear transcription factor that acts on
target genes to remodel cellular junctions and permit follicle
formation.
Hematopoietic stem cells (HSCs) have the ability to renew themselves and
to give rise to all lineages of the blood. Reya et al. (2003) showed
that the WNT signaling pathway has an important role in this process.
Overexpression of activated beta-catenin expands the pool of HSCs in
long-term cultures by both phenotype and function. Furthermore, HSCs in
their normal microenvironment activate a LEF1/TCF reporter, which
indicates that HSCs respond to WNT signaling in vivo. To demonstrate the
physiologic significance of this pathway for HSC proliferation, Reya et
al. (2003) showed that the ectopic expression of axin (603816) or a
frizzled (603408) ligand-binding domain, inhibitors of the WNT signaling
pathway, led to inhibition of HSC growth in vitro and reduced
reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs
induced increased expression of HOXB4 (142965) and NOTCH1 (190198),
genes previously implicated in self-renewal of HSCs. Reya et al. (2003)
concluded that the WNT signaling pathway is critical for normal HSC
homeostasis in vitro and in vivo, and provide insight into a potential
molecular hierarchy of regulation of HSC development.
Epithelial mesenchymal transformation (EMT) of the medial edge
epithelial seam creates palatal confluence. Nawshad and Hay (2003)
showed that Tgfb3 (190230) brought about palatal seam EMT in mice by
stimulating expression of Lef1 in medial edge epithelial cells. Tgfb3
activated Lef1 in the absence of beta-catenin via nuclear phospho-Smad2
(601366) and Smad4 (600993).
EDAR (604095) plays a key role in ectodermal differentiation via
activation of the NF-kappa-B (see 164011) pathway. Using transfected
human embryonic kidney cells and fibroblasts from mouse embryos
defective in NF-kappa-B pathway components, Shindo and Chaudhary (2004)
showed that EDAR signaling repressed LEF1-beta-catenin-dependent
transcription independent of its stimulatory effect on NF-kappa-B
activity. In addition, EDAR with an anhidrotic ectodermal dysplasia
(129490)-associated mutation exhibited defects in both NF-kappa-B
activation and LEF1/beta-catenin repression. Since LEF1/beta-catenin
controls expression of EDA (300451), the results suggested negative
feedback regulation of the EDA-EDAR axis.
Galceran et al. (2004) found that mouse Lef1 bound multiple sites in the
Dll1 (606582) promoter in vitro and in vivo, and mutation of the Lef1
sites impaired expression of a reporter transgene in the presomitic
mesoderm of embryonic mice.
Skokowa et al. (2006) found significantly decreased or absent LEF1
expression in arrested promyelocytes from patients with congenital
neutropenia (see 202700). LEF1 decrease resulted in defective expression
of downstream target genes, including CCND1 (168461), MYC (190080), and
BIRC5 (603352). Promyelocytes from healthy individuals showed highest
LEF1 expression. Reconstitution of LEF1 in early hematopoietic
progenitors from 2 individuals with congenital neutropenia resulted in
the differentiation of these progenitors into mature granulocytes.
Competitive binding and chromatin immunoprecipitation (ChIP) assays
showed that LEF1 directly bound to and regulated the transcription
factor CEBPA (116897). The findings indicated that LEF1 plays a role in
granulopoiesis.
Gattinoni et al. (2009) reported that induction of Wnt/beta-catenin
signaling by inhibitors of Gsk3b (605004) or by Wnt3a arrested mouse Cd8
(see 186910)-positive T-cell development into effector T cells capable
of cytotoxicity or Ifng (147570) production. Instead, Wnt signaling
promoted expression of Tcf7 (189908) and Lef1 and generation of
self-renewing multipotent Cd8-positive memory stem cells capable of
proliferation and antitumor activity. Gattinoni et al. (2009) concluded
that Wnt signaling has a key role in maintaining the self-renewing stem
cell-like properties of mature memory CD8-positive T cells.
Using RT-PCR and flow cytometric analysis, Zhao et al. (2010)
demonstrated that mouse Tcf7 and Lef1 were highly expressed in naive T
cells, downregulated in effector T cells, and upregulated in memory T
cells. Memory Cd8-positive T cells expressing the p45 Tcf7 isoform and
beta-catenin had enhanced Il2 (147680) production capacity and enhanced
effector capacity to clear Listeria monocytogenes. Zhao et al. (2010)
concluded that constitutive activation of the Wnt pathway favors memory
CD8 T-cell formation during immunization, resulting in enhanced immunity
upon a second encounter with the same pathogen.
Using a genetic approach, Driessens et al. (2010) found no evidence that
the beta-catenin pathway regulates T-cell memory phenotype, in contrast
with the findings of Gattinoni et al. (2009). The findings of Driessens
et al. (2010) suggested that the generation of Cd8-positive memory stem
cells observed by Gattinoni et al. (2009) with the use of Gsk3b
inhibitors was not a consequence of activation of the beta-catenin
pathway, but was rather due activation of another Gsk3b-dependent
pathway. In a reply, Gattinoni et al. (2010) noted that others,
including Zhao et al. (2010) and Jeannet et al. (2010), had also
identified Wnt and beta-catenin as crucial factors in postthymic
Cd8-positive T-cell differentiation and memory development. Using
Western blot analysis, Gattinoni et al. (2010) showed that addition of
Wnt3a or Gsk3b inhibitor stabilized beta-catenin in primed Cd8-positive
mouse T cells.
GENE STRUCTURE
Hovanes et al. (2000) determined that the LEF1 gene spans at least 52 kb
and contains 12 exons. In addition, 2 alternative exons (exons 3a and
3b) appear to be located in intron 3. The 5-prime UTR is highly GC rich
and contains 4 major alternative start sites, the first of which falls
within an initiator-like consensus sequence. The promoter region
contains no TATA box, but it has SP1 (189906)-binding sites, a GAGA
site, and an E box.
MOLECULAR GENETICS
In a genomewide analysis of leukemic cells from 242 pediatric acute
lymphocytic leukemia (ALL; 613065) patients using high resolution,
single-nucleotide polymorphism (SNP) arrays and genomic DNA sequencing,
Mullighan et al. (2007) identified mutations in genes encoding principal
regulators of B-lymphocyte development and differentiation in 40% of
B-progenitor ALL cases. Deletions were detected in LEF1, IKZF1 (603023),
IKZF3 (606221), TCF3 (147141), and EBF1 (164343). The PAX5 (167414) gene
was the most frequent target of somatic mutation, being altered in 31.7%
of cases.
BIOCHEMICAL FEATURES
Love et al. (1995) reported the solution structure for a complex of the
LEF1 HMG domain and basic region with its DNA-binding site. They found
that LEF1 binding occurs in the minor groove through its HMG domain. It
creates a sharp bend in the DNA that facilitates the binding of other
transcription factors to adjacent sequences.
MAPPING
By Southern blot analysis of DNA from panels of interspecies somatic
cell hybrids, Milatovich et al. (1991) assigned LEF1 to 4cen-q31.2. They
further refined the assignment to 4q23-q25 by in situ hybridization. The
corresponding gene was assigned to distal mouse chromosome 3 by the
study of recombinant inbred strains.
ANIMAL MODEL
Lef1 is a sequence-specific DNA-binding protein that is expressed in
pre-B and T lymphocytes of adult mice, and in the neural crest,
mesencephalon, tooth germs, whisker follicles, and other sites during
mouse embryogenesis. Van Genderen et al. (1994) generated mice carrying
a homozygous germline mutation in the Lef1 gene that eliminated Lef1
protein expression and caused postnatal lethality. The mutant mice
lacked teeth, mammary glands, whiskers, and hair, although they
developed rudimentary hair follicles. The Lef1-deficient mice also
lacked the mesencephalic nucleus of the trigeminal nerve, the only
neural crest-derived neuronal populations. The mutant mice showed no
obvious defects in lymphoid cell populations at birth. Van Genderen et
al. (1994) suggested that Lef1 plays an essential role in the formation
of several organs and structures that require inductive tissue
interactions.
To test whether LEF1 patterning might be functionally important for hair
patterning and morphogenesis, Zhou et al. (1995) used transgenic
technology to alter the patterning and timing of human LEF1 expression
over the surface ectoderm of mice. Striking abnormalities arose in the
positioning and orientation of hair follicles, leaving a marked
disruption of this normally uniform patterning. Moreover, elevated
levels of LEF1 in the lip furrow epithelium of developing transgenic
mice triggered these cells to invaginate, sometimes leading to the
inappropriate adoption of hair follicle and tooth cell fates.
Kratochwil et al. (2002) investigated LEF1 function in inductive
signaling during tooth development and concluded that FGF4 (164980) is a
direct target of Lef1 and Wnt signaling. They observed that
developmentally arrested tooth rudiments in Lef1 null mice (Van Genderen
et al., 1994) failed to express Fgf4, Shh (600725), and Bmp4 (112262).
Kratochwil et al. (2002) generated mice carrying a mutation to eliminate
the interaction of LEF1 with CTNNB1, and concluded that the role of LEF1
in tooth development is dependent on its interaction with CTNNB1 and Wnt
signaling. They showed that beads soaked with recombinant FGF4 protein
induced the delayed expression of Shh in the epithelium and could fully
overcome the developmental arrest of Lef1-deficient tooth germs. Using a
chemical inhibitor of FGF signaling, they were able to mimic the arrest
of tooth development seen in Lef1-deficient mice. Kratochwil et al.
(2002) hypothesized that the sole function of LEF1 in odontogenesis may
be to activate Fgf4 and to connect the Wnt and FGF signaling pathways at
a specific developmental step.
By inserting the bacterial beta-galactosidase gene in-frame into the
exon encoding the DNA-binding domain of Lef1, Galceran et al. (2004)
created mice expressing a truncated form of Lef1 that could interact
with beta-catenin but could not bind DNA. Homozygous mutant mice died
perinatally. The vertebral column and the rib cage were severely
malformed, suggesting that Lef1 is involved in the generation and
patterning of paraxial mesoderm. Mutant embryos showed fusion of
somites, defects in the rostrocaudal patterning of somites, and a lack
or misrouting of neural crest-derived spinal nerves. They also showed
abnormal expression of developmentally regulated transcription factors.
CFI
| dbSNP name | rs551(G,A); rs7437875(C,G); rs6821803(T,C); rs11726949(T,C); rs13104777(T,C); rs6848178(T,A); rs6822976(G,A); rs6822669(C,T); rs13136383(C,T); rs9998151(T,C); rs6836770(G,A); rs7438961(G,A); rs4698783(C,G); rs4698784(A,T); rs72674874(T,C); rs6533452(A,G); rs6533453(C,T); rs72674876(C,T); rs139522303(G,A); rs7441380(G,C); rs56970406(C,T); rs7698552(A,G); rs11098042(C,T); rs10002034(C,T); rs11098043(A,G); rs11943677(A,G); rs62324894(T,A); rs75884661(C,A); rs10049635(G,C); rs9997805(C,A); rs10020460(A,G); rs62324896(C,G); rs11098044(T,C); rs7437142(G,T); rs62324897(T,C); rs9647471(G,A); rs9647472(C,A); rs6533454(A,G); rs6533455(T,C); rs7683027(G,A); rs116750895(T,G); rs2298749(C,T); rs4382037(C,T); rs4541508(T,C); rs17610314(A,G); rs6533456(G,T); rs7356506(G,A); rs41279307(G,A); rs3822272(C,T); rs7675451(T,G); rs72888500(G,T); rs13152659(T,C); rs7439356(T,C); rs7674237(C,T); rs76014294(A,T); rs79375065(G,A); rs11098045(A,G); rs10856999(A,C); rs10857000(A,G); rs13129180(T,A); rs17040826(C,G); rs4404543(G,C); rs191615574(C,T); rs13108145(C,T); rs6533457(T,G); rs6533458(C,T); rs7439880(T,C); rs11734208(C,G); rs7435548(G,A); rs6533459(T,G); rs4469075(C,G); rs17040841(T,A); rs885448(A,T); rs71603045(A,G); rs144699530(G,A); rs12512308(G,A); rs57319600(C,A); rs11934594(T,C); rs11929767(G,A); rs180952846(G,C); rs11721403(G,A); rs12498247(C,A); rs12506605(A,G); rs80198023(A,G); rs113552407(G,A); rs11098046(C,T); rs7659870(G,A); rs75447116(C,A); rs138223394(G,A); rs144136361(T,C); rs80305536(C,G); rs139492211(G,A); rs192892434(C,T); rs147856299(A,G); rs141744270(A,G); rs182050881(C,A); rs62324931(T,C); rs62324932(G,A); rs114426252(A,T); rs112049445(G,A); rs6821213(A,G); rs6821707(G,A); rs112009111(A,T); rs12508249(T,C); rs12510639(C,A); rs4629448(A,C); rs12510718(G,A); rs12510755(G,A); rs9994307(T,C); rs112575645(A,C); rs115269619(G,A); rs35935666(T,G); rs72674889(C,A); rs62324934(T,C); rs72674890(T,G); rs62324935(T,C); rs4626205(A,C); rs4288008(G,A); rs998538(C,T); rs998539(A,G); rs34854248(T,A); rs12506161(A,G); rs4600912(G,A); rs1000954(C,T); rs6533461(A,G); rs4371619(G,T); rs72674894(A,G); rs10049804(T,C); rs10049642(G,A); rs10857001(T,C); rs191869694(C,T); rs79686659(G,A); rs62324937(C,T); rs10016598(T,C); rs10004794(G,A); rs10027082(A,C); rs72674895(C,T); rs72674896(G,C); rs10029485(A,G); rs10461144(T,G); rs143360663(T,A); rs4698785(T,C); rs114367488(C,T); rs28880991(G,T); rs9994162(C,T); rs139921728(C,G); rs28879996(A,C); rs12508074(A,T); rs11932466(C,T); rs11932539(G,A); rs11932501(C,T); rs11937379(T,C); rs11932552(C,A); rs28762207(T,C); rs10011911(T,A); rs28855226(C,T); rs10000072(C,A); rs10000458(G,A); rs28787106(C,T); rs28786383(T,A); rs28829108(T,C); rs77281977(T,C); rs9654197(C,A); rs11726234(C,T); rs28785634(G,A); rs28862613(A,C); rs28827596(A,G); rs79954953(G,A); rs4698786(A,G); rs4698787(C,T); rs4698788(T,C); rs12650933(A,G); rs7675460(C,A); rs10024583(T,A); rs6533464(G,A); rs75605785(C,T); rs72890361(C,T); rs7671905(T,C); rs180691619(T,A); rs4382036(T,C) |
| ccdsGene name | CCDS34049.1 |
| cytoBand name | 4q25 |
| EntrezGene GeneID | 3426 |
| EntrezGene Description | complement factor I |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CFI:NM_000204:exon13:c.G1642C:p.E548Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6413 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7ETH0 |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.004993 |
| ESP All MAF | 0.001692 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0007237 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Henoch-Schonlein purpura
MUSCLE, SOFT TISSUE:
Polymyositis
IMMUNOLOGY:
Autoimmune disease;
Systemic lupus erythematosus;
Sjogren syndrome;
C2 deficiency
MOLECULAR BASIS:
Caused by mutation in the complement component 2 gene (C2, 613927.0001)
OMIM Title
*217030 COMPLEMENT FACTOR I; CFI
;;COMPLEMENT COMPONENT I;;
FACTOR I; FI;;
C3b INACTIVATOR
OMIM Description
DESCRIPTION
The CFI gene encodes complement factor I ('eye'), a serine proteinase in
the complement pathway responsible for cleaving and inactivating the
activities of C4b (120820) and C3b (see 120700). Factor I is a plasma
glycoprotein composed of 2 polypeptide chains linked by disulfide bonds.
Both the light and heavy chains of factor I are encoded by the CFI gene
(Catterall et al., 1987). The light chain contains the serine protease
domain (Vyse et al., 1994).
CLONING
Catterall et al. (1987) isolated cDNA clones corresponding to the gene
encoding complement factor I from a human liver cDNA library. The
deduced 583-amino acid protein comprises both the heavy and light chains
of component I, which are sequentially coded from the N terminal. The
light chain N terminal is found at residue 322 after 4 basic residues,
providing evidence that factor I is synthesized as a single chain
polypeptide that is subsequently cleaved. Both the heavy (35.4 kD) and
light (27.6 kD) chains contain 3 potential N-glycosylation sites.
Northern blot analysis detected a 2.4-kb mRNA transcript.
Goldberger et al. (1987) also cloned the human CFI gene.
GENE STRUCTURE
Vyse et al. (1994) determined that the CFI gene spans 63 kb and contains
13 exons, the first 8 of which encode the heavy chain and the last 5 the
light chain.
MAPPING
By somatic cell hybridization, Goldberger et al. (1987) and Shiang et
al. (1987) mapped the CFI gene to chromosome 4q23-q25.
Shiang et al. (1989) mapped the CFI locus to 4q25 by use of somatic cell
hybrids, in situ hybridization, and genetic linkage with RFLP markers.
They proposed that the order of loci was as follows:
cen--GC--INP10--ADH3--EGF--IF--IL2--MNS--qter. By hybridization to
fragments generated by low-frequency cutting restriction enzymes and
pulsed field electrophoresis, Kolble et al. (1989) showed that the CFI
and EGF (131530) genes are located about 40 kb apart. The alcohol
dehydrogenase cluster (103720) appeared to be more than 550 kb proximal
to EGF, whereas CFI lies distal to EGF.
MOLECULAR GENETICS
Nakamura and Abe (1985) described 2 polymorphisms of the C3b inactivator
gene, designated FI*A and FI*B, demonstrated by electrophoretic blotting
technique. In the course of studying sera from 305 persons, Zhou and
Larsen (1989) identified a third variant, designated FI*C. Data on gene
frequencies of allelic variants were tabulated by Roychoudhury and Nei
(1988). Ding et al. (1991) provided data on polymorphisms of the CFI
gene in Chinese, Korean, and Japanese populations.
- Complement Factor I Deficiency
In 2 sibs with complement factor I deficiency (CFID; 610984), Vyse et
al. (1996) identified a homozygous mutation in the CFI gene
(217030.0001). An unrelated patient was compound heterozygous for 2
mutations in the CFI gene (217030.0001; 217030.0002).
In 2 Brazilian sisters, born of consanguineous parents, with complement
factor I deficiency, Baracho et al. (2003) identified a homozygous
mutation in the CFI gene (217030.0003). Each parent was heterozygous for
the mutation. The older sister had recurrent infections and developed
systemic lupus erythematosus (SLE; 152700) with glomerulonephritis and
the younger sister died at age 3 years of sepsis.
Servais et al. (2007) described 2 patients with factor I deficiency who
developed glomerulonephritis with isolated C3 deposits. The authors
called the disorder 'glomerulonephritis C3.' The patients were found to
have heterozygous mutations in the CFI gene (see, e.g., 217030.0007).
- Susceptibility to Atypical Hemolytic Uremic Syndrome 3
In 3 unrelated patients with atypical hemolytic uremic syndrome (AHUS3;
612923), Fremeaux-Bacchi et al. (2004) identified 3 different
heterozygous mutations in the CFI gene (217030.0003-217030.0005). In 2
cases, a nonsense mutation was associated with heterozygous factor I
deficiency. In another case, a heterozygous mutation likely led to
functional factor I deficiency. In 2 families, an asymptomatic parent
also carried the mutation, suggesting incomplete penetrance and that
heterozygous pathogenic mutations in the CFI gene confer susceptibility
to the development of aHUS.
Caprioli et al. (2006) identified 5 different CFI mutations (see, e.g.,
217030.0008-217030.0009) in 7 (4.5%) of 156 patients with AHUS. Three of
5 patients had decreased serum C3 levels. Normal renal function was
preserved in 33.3% of patients with CFI mutations. Kidney transplant was
not effective in preventing recurrence.
- Susceptibility to Age-Related Macular Degeneration 13
Van de Ven et al. (2013) identified a missense mutation in the CFI gene
(G119R; 217030.0010) in 20 of 3,567 patients with age-related macular
degeneration (ARMD13; 615439) and 1 of 3,937 controls, consistent with
G119R conferring high risk for developing ARMD (odds ratio, 22.20; p =
3.79 x 10(-6)).
Seddon et al. (2013) sequenced the exons of 681 genes within all
reported ARMD loci and related pathways in 2,493 cases. First, each gene
was tested for increased or decreased burden of rare variants in cases
compared to controls. Seddon et al. (2013) found that 7.8% of ARMD cases
compared to 2.3% of controls were carriers of rare missense CFI variants
(odds ratio = 3.6; p = 2 x 10(-8)). There was a preponderance of
dysfunctional variants in cases compared to controls. Seddon et al.
(2013) then tested individual variants for association with disease.
NEUROG2
| dbSNP name | rs901474(T,G) |
| ccdsGene name | CCDS3698.1 |
| cytoBand name | 4q25 |
| EntrezGene GeneID | 63973 |
| EntrezGene Description | neurogenin 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NEUROG2:NM_024019:exon2:c.A588C:p.G196G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.06657 |
| ESP Afr MAF | 0.023777 |
| ESP All MAF | 0.100542 |
| ESP Eur/Amr MAF | 0.139832 |
| ExAC AF | 0.891 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly (less common);
[Face];
Facial weakness
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
SKELETAL:
[Spine];
Scoliosis;
Spinal fusion;
Lordosis;
Kyphosis;
[Feet];
Achilles tendon contractures
MUSCLE, SOFT TISSUE:
Neonatal hypotonia;
Delayed motor milestones;
Generalized muscle weakness;
Proximal muscle weakness;
Proximal muscle atrophy;
Muscle hypertrophy;
EMG shows myopathic changes;
Muscle biopsy shows dystrophic changes;
Toe-walking;
Difficulty walking;
Difficulty climbing stairs;
Frequent falls;
Muscle cramps;
Myalgia;
Muscle MRI shows fatty infiltration;
Decreased glycosylation of alpha-dystroglycan
NEUROLOGIC:
[Central nervous system];
Some patients have neurologic involvement;
Mental retardation;
White matter abnormalities on MRI;
Cerebellar atrophy;
Cerebellar cysts;
Nodular heterotopia (rare);
Pachygyria (rare);
Ventricular dilatation (rare)
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Variable age of onset (range 1-40 years);
Highly variable severity;
Some patients never gain ambulation or become wheelchair-bound
MOLECULAR BASIS:
Caused by mutation in the fukutin-related protein gene (FKRP, 606596.0001)
OMIM Title
*606624 NEUROGENIN 2; NEUROG2
;;NGN2;;
ATOH4
OMIM Description
DESCRIPTION
Neurogenin-2 is a member of the neurogenin subfamily of basic
helix-loop-helix (bHLH) transcription factor genes that play an
important role in neurogenesis from migratory neural crest cells
(Simmons et al., 2001; Yan et al., 2001).
GENE STRUCTURE
Sommer et al. (1996) determined that the mouse Ngn2 gene contains a
single coding exon.
GENE FUNCTION
During mouse neurogenesis, Ngn2 and Ngn1 (NEUROG1; 601726) are expressed
in distinct progenitor populations in the central and peripheral nervous
systems (Sommer et al., 1996; Ma et al., 1996). Their expression
patterns partially overlap in some areas but are distinct in others.
Targeted mutation analyses showed that Ngn1 is essential for the
determination of neuronal precursors for proximal cranial sensory
ganglia (Ma et al., 1998) and that Ngn2 is essential for the
determination of precursors for epibranchial placode-derived sensory
neurons (Fode et al., 1998).
Yan et al. (2001) observed that in the developing chick retina, Ngn2 was
expressed in a subpopulation of proliferating progenitor cells. Ectopic
expression of Ngn2 in nonneural, retinal pigment epithelial cell culture
triggered de novo generation of cells that expressed neural-specific
markers and exhibited neuronal morphologies. Further molecular and
morphologic analyses showed that the main products of the induced
neurogenesis were cells resembling young photoreceptor cells and cells
resembling retinal ganglion cells. The generation of multiple cell types
suggested that Ngn2 induces various retinal pathways. Thus, whereas Ngn2
in the peripheral nervous system specifies one type of sensory neuron,
Ngn2 in the retina is likely to be involved in a common step leading to
different cellular pathways. The finding that Ngn2 can instruct
nonneuronal retinal pigment epithelial cells to differentiate toward
retinal neurons demonstrated one possible way to induce de novo retinal
neurogenesis.
Ma et al. (1999) presented a detailed analysis of mouse Ngn1, also
called Neurod3, and Neurog2 expression during neural crest migration and
early dorsal root gangliogenesis in wildtype and neurogenin-deficient
mouse embryos. They concluded that Neurod3 and Neurog2 control 2
distinct phases of neurogenesis that generate different classes of
sensory neurons.
Using assays in transgenic mice, Simmons et al. (2001) identified
separable regulatory elements both 5-prime and 3-prime of the mouse
Neurog2 coding region that direct Neurog2 expression to distinct but
partially overlapping neural progenitor cell populations within the
developing spinal cord. Analysis of reporter gene expression in the
transgenic mice led the authors to conclude that Neurog2 progenitor
cells in the ventral domain give rise to a subset of motor neurons,
while Neurog2 progenitor cells in the dorsal domain give rise to a
subset of interneurons that send their axons to the floor plate.
From study of reporter gene constructs in transgenic mice, Scardigli et
al. (2001) found that expression of Neurog2 in the ventral spinal cord
results from the modular activity of at least 3 enhancers that are
active in distinct progenitor domains. They observed that
Neurog2-deficient embryos displayed striking defects in ventral spinal
cord gene expression, and concluded that Neurog2 function is required
for the correct expression of Pax6 (607108) and several homeodomain
proteins normally expressed in defined neuronal populations. By
examining Neurog2 expression and enhancer activity in Pax6 mutant mice,
Scardigli et al. (2001) concluded that Pax6 regulates Neurog2 expression
in the spinal cord by controlling distinct enhancer elements that are
active at different positions along the dorsoventral axis. They
hypothesized that Neurog2 is both responsive to and a regulator of
genetic pathways that provide positional identity and specify neuronal
fates in the ventral spinal cord.
Using embryonic chicken and rodent models, Mizuguchi et al. (2001),
Novitch et al. (2001), and Zhou et al. (2001) found that Olig2 (606386)
and Ngn2 were coexpressed in motoneuron progenitors and that both were
required for motoneuron differentiation.
Lee and Pfaff (2003) showed that Neurod4 (611635) and Ngn2 actively
participated with Isl1 (600366) and Lhx3 (600577) to specify motor
neuron subtype in embryonic chicken spinal cord and in P19 mouse stem
cells.
Heng et al. (2008) demonstrated that the proneural protein Neurog2,
which controls neurogenesis in the embryonic cortex, directly induces
the expression of the small GTP-binding protein Rnd2 (601555) in newly
generated mouse cortical neurons before they initiate migration. Rnd2
silencing leads to a defect in radial migration of cortical neurons
similar to that observed when the Neurog2 gene is deleted. Remarkably,
restoring Rnd2 expression in Neurog2-mutant neurons is sufficient to
rescue their ability to migrate. Heng et al. (2008) concluded that their
results identified Rnd2 as a novel essential regulator of neuronal
migration in the cerebral cortex and demonstrated that Rnd2 is a major
effector of Neurog2 function in the promotion of migration. Thus, a
proneural protein controls the complex cellular behavior of cell
migration through a remarkably direct pathway involving the
transcriptional activation of a small GTP-binding protein.
ANK2
| dbSNP name | rs17044999(G,A); rs10026837(G,C); rs28527179(G,C); rs76753897(T,C); rs6851781(T,C); rs190957094(A,G); rs28736434(C,G); rs11728431(A,G); rs17045004(G,A); rs145381805(A,G); rs10461191(C,G); rs66577927(G,T); rs11098175(G,A); rs28707176(G,T); rs28607631(C,T); rs13109854(A,C); rs4834306(A,C); rs9759629(C,A); rs9994544(C,T); rs10516589(A,G); rs6849218(T,C); rs12499952(T,G); rs6830542(G,A); rs6830420(A,T); rs141398611(C,T); rs6831677(A,G); rs77068395(T,C); rs62317060(C,T); rs17045022(G,A); rs28477884(C,T); rs7681443(G,A); rs6844637(A,G); rs13108692(C,T); rs6829330(T,C); rs1074565(G,A); rs62317061(G,A); rs28775941(C,T); rs13129574(G,A); rs13104956(T,C); rs34887644(T,C); rs34863541(T,C); rs77288922(A,T); rs28796914(A,T); rs6822647(A,G); rs12503358(G,A); rs12510987(A,G); rs6823012(A,C); rs6823719(G,A); rs115718058(C,T); rs7667863(G,T); rs6533654(T,C); rs7672708(G,C); rs6533655(C,T); rs6856390(T,G); rs6533657(T,C); rs4834307(T,C); rs28626896(A,T); rs1550953(T,G); rs1026089(G,A); rs28602840(C,T); rs7665345(G,C); rs6533658(G,C); rs1839110(C,G); rs28793639(G,A); rs12504220(G,T); rs11736185(A,G); rs116059908(A,G); rs28798987(G,T); rs116136723(G,A); rs62317066(G,A); rs2882821(T,C); rs36016946(A,G); rs13111602(A,G); rs921184(T,C); rs10516590(C,T); rs17045043(T,A); rs2352024(T,C); rs140591196(G,A); rs62317067(T,C); rs6814192(A,C); rs11733766(C,T); rs2166867(G,C); rs10013796(C,T); rs6817867(T,G); rs6818236(T,C); rs6845908(A,G); rs2121929(A,G); rs56268780(G,A); rs11731160(G,T); rs62317068(T,A); rs7680385(T,C); rs7655551(A,G); rs11098176(A,G); rs11098177(G,C); rs7675091(G,C); rs12512624(G,T); rs12513383(C,T); rs17671955(T,C); rs11098178(G,A); rs11722815(G,A); rs28405251(T,C); rs149159097(C,T); rs1037184(G,A); rs17045059(A,G); rs17045062(G,C); rs17615706(T,C); rs17672142(T,C); rs17672170(A,G); rs1448224(A,G); rs11934475(T,C); rs141488887(G,T); rs11930795(G,C); rs78517991(A,C); rs1448221(G,T); rs9999588(G,A); rs114984946(G,T); rs11943728(A,G); rs115947133(G,C); rs17045073(T,C); rs17045076(A,G); rs17045079(T,C); rs895763(T,C); rs895762(A,G); rs17045083(A,G); rs7657978(T,C); rs35242524(C,T); rs76559001(G,T); rs11724318(G,A); rs13120334(C,T); rs115716046(G,T); rs112127337(T,C); rs17045090(C,T); rs138625390(T,C); rs115893745(T,G); rs116252490(A,G); rs6835163(A,G); rs11729125(G,T); rs11098181(G,C); rs11730064(G,T); rs78835026(C,T); rs143908796(G,A); rs11731228(G,A); rs151254118(C,G); rs141375158(A,T); rs76330897(C,T); rs78705103(T,G); rs149063988(A,G); rs113087247(A,G); rs138110881(A,G); rs60690506(A,T); rs62317087(A,C); rs184261507(C,T); rs114143461(C,T); rs9760421(A,G); rs144990878(A,G); rs17672637(G,A); rs186472199(T,G); rs11732017(A,G); rs115338965(A,G); rs7654188(G,C); rs140414202(G,T); rs183928715(A,G); rs190267104(C,A); rs13134226(A,G); rs11728353(T,C); rs7675254(T,C); rs192049068(G,A); rs2121928(G,C); rs10016365(C,A); rs7695288(C,A); rs10031906(T,C); rs7680555(G,T); rs7681372(G,A); rs115215335(T,A); rs138891394(G,A); rs139747875(C,T); rs78842575(A,G); rs12503758(T,A); rs28464633(G,A); rs184495880(C,T); rs6845832(T,C); rs6851031(T,G); rs4404544(C,A); rs6533659(C,T); rs6840202(A,G); rs6533660(A,G); rs7689257(A,G); rs72892475(T,G); rs10015915(G,A); rs12506747(C,T); rs9996317(A,G); rs78187663(C,T); rs7678728(T,G); rs72892486(T,G); rs41467946(G,C); rs72892490(A,C); rs28576606(T,C); rs6844138(G,C); rs35360943(C,T); rs72892499(C,T); rs72892500(T,C); rs10030826(G,A); rs72894406(T,A); rs6833019(T,C); rs17045162(G,C); rs59201260(T,A); rs58114681(C,T); rs6844384(T,C); rs58668059(G,A); rs6819908(C,G); rs17617571(C,T); rs6833457(G,A); rs13146876(A,C); rs6833604(A,G); rs17045191(A,G); rs11940222(G,A); rs11945062(T,A); rs11722823(A,G); rs191364914(A,G); rs56154447(A,G); rs28509773(C,T); rs28535931(C,T); rs11098182(A,G); rs12645477(G,A); rs2352221(G,A); rs72894426(A,G); rs2174559(G,A); rs11945962(T,C); rs62317105(G,A); rs6851865(A,G); rs62317106(G,A); rs17045209(C,A); rs7678761(T,A); rs62317134(G,C); rs56080855(C,A); rs11943880(C,G); rs75521963(C,T); rs11943958(C,A); rs11735361(G,A); rs7697332(T,G); rs7697334(T,C); rs59831391(A,G); rs60003296(G,A); rs7679855(G,C); rs7679866(G,A); rs7684713(G,C); rs7684575(A,T); rs7662988(T,A); rs7663240(T,C); rs7663450(T,A); rs13141212(T,C); rs11930182(T,C); rs11943596(G,A); rs7664364(A,G); rs7665021(A,T); rs66703771(C,A); rs2352223(G,C); rs2352222(T,G); rs11736256(G,A); rs12512809(G,T); rs12512769(C,T); rs6835538(C,T); rs6849022(A,G); rs111650646(G,C); rs6820222(A,G); rs72671515(G,A); rs6820742(G,A); rs147244507(C,T); rs6851602(T,C); rs114992944(A,C); rs6852844(T,C); rs12503954(A,G); rs12501268(T,C); rs6833100(A,G); rs10212850(T,C); rs10212851(T,C); rs73840981(A,G); rs6840895(G,A); rs1354680(T,C); rs1354679(T,C); rs1354678(A,G); rs199982030(T,C); rs12499424(C,T); rs12507075(A,G); rs10213287(A,T); rs114142181(A,G); rs7655703(C,T); rs7655898(A,T); rs1818253(T,A); rs143809157(G,T); rs61489606(G,A); rs7662664(C,T); rs6533662(A,G); rs61104276(A,G); rs73840986(A,G); rs6810920(T,C); rs6833846(A,G); rs6851527(A,C); rs6851571(A,G); rs6852975(C,T); rs9997195(G,C); rs12508051(A,G); rs73840988(G,A); rs12508918(A,G); rs79682981(G,T); rs13124501(G,C); rs148635370(A,G); rs2174558(C,T); rs1532878(G,A); rs7666402(C,A); rs5029416(C,T); rs57613404(A,G); rs1532877(A,G); rs1532876(G,C); rs145042011(T,C); rs10012535(G,A); rs2055656(C,G); rs2055655(C,T); rs11098183(A,G); rs142728728(C,T); rs7687726(A,G); rs17045339(C,T); rs1506065(G,A); rs7699298(A,G); rs115222477(T,C); rs17045344(G,A); rs961295(A,G); rs961294(A,T); rs17618813(C,T); rs10025489(G,C); rs17045354(G,A); rs17045357(A,G); rs1506064(A,G); rs114163103(G,A); rs146569202(A,G); rs17618891(A,G); rs2036606(T,A); rs2036605(C,T); rs116726054(C,T); rs148170304(A,G); rs150673740(G,A); rs11098184(A,G); rs7697164(A,C); rs7697387(A,C); rs17680801(C,T); rs7698083(G,T); rs74679997(C,G); rs75316869(A,C); rs1013484(A,G); rs1032913(A,G); rs4833419(T,C); rs35052270(G,C); rs6821639(A,G); rs6822320(G,A); rs41487550(A,G); rs115844198(A,T); rs2135351(T,G); rs2352182(G,A); rs9884956(C,T); rs6849033(C,G); rs6826293(T,C); rs11935371(A,G); rs1395112(T,C); rs1395111(A,G); rs10029917(C,T); rs116822737(G,A); rs1354677(T,C); rs79996714(T,C); rs1395109(A,G); rs7438369(G,T); rs72671556(A,G); rs116170925(C,T); rs9991382(G,A); rs10014072(A,G); rs13103796(A,G); rs141721247(A,G); rs72896482(G,A); rs9994849(G,A); rs115900323(T,A); rs11938726(T,C); rs2055654(G,A); rs10155397(A,G); rs17045384(C,T); rs13101601(T,C); rs13115459(T,C); rs1395114(C,T); rs11728485(C,T); rs12504906(G,T); rs1354681(C,T); rs78241134(C,T); rs2036603(A,G); rs2036604(G,T); rs62314881(G,T); rs144599640(C,T); rs12643026(C,A); rs10155204(C,T); rs62314882(G,A); rs7673390(C,T); rs56103716(C,T); rs7674202(C,T); rs10015472(G,A); rs10015551(G,T); rs9307387(G,A); rs4260545(C,G); rs10433900(C,T); rs9685098(C,T); rs114644307(C,T); rs7654153(C,T); rs1395113(C,T); rs716051(A,G); rs149556211(C,A); rs144250442(C,T); rs313941(T,C); rs7679280(G,A); rs191343591(A,C); rs9683500(A,G); rs313940(G,A); rs313939(T,C); rs313938(T,C); rs313937(C,T); rs6533663(G,C); rs6856101(G,A); rs11098185(T,C); rs17045472(A,G); rs313936(T,C); rs7657219(A,G); rs313935(T,A); rs7663732(C,T); rs1026975(T,G); rs73843305(C,T); rs72671573(C,T); rs313942(A,G); rs4834310(A,C); rs931838(G,A); rs10003890(A,G); rs35308370(C,T); rs190946414(C,A); rs10007543(A,G); rs182763090(T,C); rs313985(C,T); rs313984(C,T); rs313983(T,C); rs184801136(A,C); rs646862(G,A); rs646863(C,A); rs313982(G,A); rs313981(G,A); rs72671578(G,C); rs313980(C,A); rs141224680(A,G); rs313979(A,G); rs313978(G,T); rs145141676(A,C); rs313977(C,A); rs313976(C,A); rs113044314(A,C); rs313975(A,G); rs678035(T,C); rs677110(T,C); rs72671580(G,A); rs144245852(A,C); rs642955(A,G); rs11726017(G,A); rs7690846(T,C); rs674181(A,G); rs644851(G,T); rs145856562(A,G); rs75429792(G,A); rs674632(T,A); rs644059(A,T); rs675127(A,T); rs632895(G,A); rs144002354(T,C); rs689117(C,T); rs582050(T,C); rs35784458(T,C); rs595091(G,T); rs602125(G,T); rs62314901(T,C); rs4834311(A,G); rs2279891(T,C); rs2279892(G,A); rs2279893(A,C); rs374334206(T,G); rs2279894(C,G); rs7692578(G,C); rs17045523(C,T); rs640369(A,G); rs28504136(T,G); rs149785340(T,C); rs35711204(G,T); rs28706836(C,T); rs13149330(A,G); rs77363045(C,T); rs313964(A,T); rs11931464(A,G); rs142707059(C,T); rs313963(T,A); rs884556(T,C); rs884555(T,C); rs313962(C,G); rs666609(C,A); rs79210227(A,C); rs7694725(T,C); rs2882846(T,C); rs2171059(T,C); rs2135354(G,A); rs140808734(A,C); rs115356844(T,C); rs313974(G,A); rs35099032(G,A); rs34620563(G,A); rs79911383(G,A); rs9991647(G,A); rs313973(C,T); rs34633474(A,C); rs7676179(A,T); rs313971(C,G); rs313970(G,A); rs313969(T,A); rs313968(C,A); rs313967(T,C); rs62314903(A,T); rs313966(G,A); rs10013950(C,T); rs12645981(G,A); rs11098186(T,C); rs671411(G,A); rs11098187(A,C); rs671390(G,A); rs671344(A,G); rs17045528(A,G); rs116766123(A,G); rs670473(G,C); rs12500552(A,G); rs13118274(A,G); rs665096(G,C); rs148584102(T,A); rs1395106(A,G); rs7656666(A,G); rs76634305(A,G); rs649022(C,T); rs76065429(G,T); rs17045534(T,A); rs6819998(G,A); rs593773(G,A); rs6820287(A,G); rs6820973(G,A); rs623708(C,A); rs10029516(G,T); rs10029379(C,T); rs6826558(C,T); rs7669861(C,G); rs620520(C,T); rs6832446(C,T); rs4834312(C,T); rs4834313(C,T); rs4834314(T,C); rs17045537(G,A); rs141692094(G,T); rs7682194(A,G); rs592670(A,G); rs7682781(A,G); rs7683146(C,A); rs591261(T,C); rs7683186(A,G); rs7683536(C,T); rs7688341(C,T); rs666988(C,A); rs667448(C,T); rs10016477(A,G); rs10016484(A,G); rs12643848(T,G); rs685798(A,T); rs17045555(A,G); rs684932(C,T); rs683964(C,T); rs6533665(C,T); rs6848104(C,T); rs683065(T,C); rs6816790(C,T); rs6533666(G,C); rs2046444(C,G); rs78124503(G,A); rs626267(A,G); rs116035564(C,T); rs624979(A,G); rs17476377(G,A); rs66515247(T,C); rs11729382(A,G); rs12645686(A,G); rs6844654(C,T); rs28532593(T,A); rs62313780(G,T); rs62313781(C,G); rs6822373(T,G); rs28571834(T,C); rs28408551(A,G); rs10049545(G,A); rs6850896(A,G); rs6850936(A,G); rs9996202(C,T); rs9996300(C,G); rs6851877(G,A); rs9996681(C,T); rs11723690(G,A); rs12644569(T,C); rs313948(A,G); rs12641335(C,T); rs12644634(T,C); rs67664334(A,G); rs2101317(A,G); rs2086959(G,T); rs313950(G,A); rs313951(G,A); rs74508604(A,C); rs77649042(C,A); rs2086961(G,A); rs313952(A,G); rs2086962(G,A); rs11733187(A,G); rs2101318(C,T); rs7660069(G,T); rs10025185(A,G); rs11943828(A,G); rs11943832(A,G); rs313953(A,T); rs313954(T,C); rs313955(T,C); rs313956(A,G); rs313957(T,C); rs313958(G,A); rs12647986(T,G); rs112026223(T,A); rs111348484(C,T); rs313959(G,T); rs13114240(C,T); rs56070938(T,C); rs9759975(C,T); rs17045572(A,C); rs4834315(A,G); rs13134980(C,T); rs145839623(G,T); rs138751313(G,A); rs7690733(T,C); rs1032912(G,A); rs114520743(A,C); rs148655440(A,G); rs143401466(A,G); rs146809925(C,G); rs7673051(G,T); rs10461192(G,A); rs145875834(C,T); rs7656725(T,C); rs7679106(G,A); rs17626050(A,G); rs28635205(T,C); rs2352184(G,A); rs5018999(G,A); rs2352185(G,T); rs1506067(T,C); rs17045600(C,A); rs7699082(G,A); rs6533668(C,T); rs13148213(C,T); rs17045612(C,A); rs1506060(G,A); rs1506059(G,T); rs12511290(T,C); rs56086085(T,A); rs10022885(C,A); rs313934(T,A); rs10023704(C,A); rs11943192(C,G); rs594604(T,C); rs11945663(G,A); rs976738(C,T); rs17045629(C,G); rs78651265(G,A); rs140755186(C,T); rs13101559(A,T); rs17626532(C,T); rs12502247(A,G); rs13131795(G,C); rs1395108(G,T); rs966192(C,T); rs1395107(C,A); rs1506063(T,C); rs313961(T,G); rs35441384(T,C); rs4833420(A,G); rs4834316(A,G); rs17045646(C,T); rs13149379(T,C); rs17045653(A,C); rs313960(A,G); rs10003143(C,A); rs59674936(C,T); rs1506062(C,T); rs17683210(C,T); rs2202535(T,C); rs11731598(A,G); rs7697312(A,G); rs12501010(G,C); rs17045676(A,G); rs73841237(A,G); rs11730002(T,C); rs182778137(G,A); rs112419226(C,T); rs13135212(C,T); rs7664927(A,G); rs7664966(A,G); rs114908085(C,T); rs76299786(A,G); rs4834317(C,G); rs4833421(A,G); rs13104234(C,T); rs79788652(G,T); rs17614202(A,G); rs17676256(G,A); rs10026778(T,A); rs76827053(G,A); rs112992945(G,T); rs145158664(G,A); rs76483236(C,T); rs13435324(G,A); rs13435322(C,A); rs10020548(C,T); rs74637905(T,C); rs10021192(G,A); rs34556792(A,G); rs12500983(A,T); rs13126726(G,A); rs13126963(G,C); rs13102062(T,C); rs2352531(T,C); rs72892075(C,T); rs62313832(T,A); rs72673430(C,G); rs3112979(T,C); rs3112980(G,A); rs7689214(G,A); rs3112981(G,A); rs76713843(A,T); rs6854397(G,A); rs1351998(G,C); rs1351997(G,A); rs6812102(A,G); rs13125789(C,A); rs17482808(G,A); rs6844347(T,C); rs13132078(C,G); rs12644844(A,G); rs11937884(A,G); rs11947171(G,C); rs11929834(G,A); rs7666110(T,C); rs13109440(C,A); rs17045692(A,G); rs11943785(G,A); rs10516592(A,G); rs9307388(A,T); rs6818600(G,A); rs6823694(G,T); rs6823699(G,T); rs34699139(G,A); rs13138151(G,A); rs10028798(G,A); rs10028936(C,T); rs10029109(G,T); rs10031600(G,A); rs10031464(C,T); rs10031639(C,T); rs7674543(A,G); rs7679631(C,T); rs7658364(T,A); rs13152297(C,T); rs13101312(G,A); rs10516593(A,C); rs13134375(T,C); rs13107246(G,A); rs13107430(G,A); rs13107459(G,A); rs13107082(C,G); rs413019(G,A); rs17590551(T,A); rs17590572(T,C); rs403618(G,A); rs369617(C,G); rs2629738(G,T); rs148515060(G,T); rs395351(A,C); rs1825551(T,A); rs436855(A,G); rs17590579(G,A); rs113265364(C,T); rs17590593(A,G); rs78890567(C,T); rs4627864(G,A); rs113093146(C,A); rs78845030(A,G); rs77137327(G,T); rs75624381(A,C); rs76711917(G,A); rs75533414(G,A); rs113477458(C,A); rs117396551(G,A); rs17045700(G,C); rs400883(T,G); rs2107026(T,A); rs115261168(T,C); rs17444914(A,T); rs17444921(A,G); rs112080344(G,T); rs113658536(T,C); rs407709(A,T); rs7675829(T,C); rs7697503(C,T); rs404950(G,A); rs1485586(G,A); rs6814622(A,C); rs4833422(C,T); rs76677347(C,T); rs399754(G,A); rs41434448(C,G); rs6813737(A,C); rs28407732(T,C); rs28504410(A,G); rs113869299(C,T); rs113201457(C,T); rs28708505(G,A); rs62313179(G,T); rs1989931(C,T); rs1989930(G,C); rs112527853(G,T); rs113297341(G,C); rs78822675(A,G); rs2158199(A,G); rs28401224(G,T); rs10488906(T,G); rs113418449(T,C); rs28672777(T,G); rs34588824(T,C); rs17445053(T,C); rs72896013(G,T); rs10012958(A,C); rs62313181(G,A); rs28582963(G,A); rs28552803(C,T); rs2079120(T,A); rs2079119(G,A); rs139686225(T,A); rs11931148(C,T); rs6847102(A,G); rs6858425(T,C); rs6832486(A,T); rs6832972(G,T); rs2107024(G,C); rs2107023(C,T); rs2107022(G,A); rs113656555(T,C); rs7682245(G,A); rs7686618(A,G); rs6533671(C,A); rs141479464(G,A); rs4834321(T,C); rs10428310(A,T); rs10488905(C,G); rs13435473(G,A); rs11933707(A,G); rs10488904(A,T); rs7667099(G,A); rs1982764(A,G); rs1982765(A,T); rs12639681(G,A); rs142889074(G,A); rs33957486(C,G); rs35085115(G,A); rs17445088(A,C); rs2285711(A,G); rs2285710(C,T); rs2285709(G,A); rs2107020(A,G); rs2107018(C,G); rs967099(A,G); rs17445130(G,A); rs28639887(G,T); rs74560261(G,A); rs17529579(A,G); rs6850181(A,T); rs11942005(A,G); rs62313184(G,T); rs13120716(C,T); rs17445186(A,G); rs6533672(T,C); rs6533673(G,A); rs6533674(C,T); rs6828068(G,A); rs13118200(T,A); rs115293750(C,T); rs11943237(A,G); rs2352535(T,C); rs6819591(C,T); rs79822984(C,T); rs74488490(A,G); rs11936521(C,A); rs10019154(T,A); rs28507635(T,G); rs62313186(C,A); rs4834322(T,A); rs55999542(T,A); rs4834323(A,G); rs7682316(C,A); rs77584325(A,G); rs146517812(A,G); rs62313188(G,C); rs72898040(A,T); rs62313189(G,A); rs78759141(T,C); rs72898042(T,G); rs77976172(G,A); rs115310125(A,T); rs62313190(G,A); rs60150779(G,A); rs62313193(T,C); rs114799344(A,G); rs79243447(C,T); rs17590970(C,A); rs72673488(A,G); rs10857021(T,A); rs116297790(T,G); rs17445340(T,G); rs62313210(G,T); rs1468224(A,G); rs1468223(G,A); rs17445375(A,T); rs362492(T,C); rs362463(A,G); rs17445431(C,G); rs1159903(T,C); rs28556940(G,A); rs72898056(A,G); rs3025748(A,G); rs17529905(G,C); rs55825558(C,A); rs362469(T,A); rs114178930(A,G); rs72898060(A,G); rs4834324(C,T); rs374001441(C,T); rs10488901(G,C); rs114878611(T,C); rs56306776(C,G); rs74367714(G,A); rs4361387(T,G); rs6855296(A,G); rs62313212(G,A); rs6533675(A,T); rs75615859(G,T); rs362462(C,A); rs362461(G,A); rs78900140(G,A); rs62313213(C,A); rs147424826(T,C); rs362498(A,C); rs6533676(T,C); rs72675205(A,G); rs362503(T,G); rs362502(T,G); rs201815083(A,T); rs200591177(C,T); rs116278389(G,A); rs4834325(T,G); rs12498202(A,T); rs6533677(A,G); rs1966338(G,A); rs362497(A,T); rs75153632(A,T); rs62313214(G,A); rs362496(C,T); rs3025734(A,G); rs362495(A,G); rs185460571(G,A); rs29436(C,T); rs28456239(C,A); rs58084858(A,G); rs62313215(G,A); rs67547401(C,T); rs72898100(C,G); rs79243690(C,T); rs80244955(G,A); rs1074951(T,G); rs6814721(C,T); rs45455305(C,T); rs29336(G,A); rs29420(T,G); rs29335(A,T); rs3025732(G,T); rs76498366(A,G); rs29334(T,C); rs111399711(C,T); rs114193215(C,T); rs112555353(G,C); rs114118047(C,T); rs116447087(A,G); rs115289119(C,G); rs29409(G,T); rs34606884(T,C); rs188421168(C,G); rs145055397(G,A); rs58239914(G,A); rs11937675(C,T); rs1011263(T,C); rs29407(A,G); rs29402(T,C); rs29401(T,C); rs28148(A,G); rs28149(T,A); rs17629353(C,T); rs29399(A,G); rs29397(C,T); rs29333(C,T); rs29394(C,T); rs29332(T,C); rs29393(A,G); rs28262(C,T); rs29391(G,C); rs29387(C,T); rs29385(A,G); rs29383(G,C); rs11098190(T,C); rs29382(A,G); rs146867620(T,C); rs29330(G,A); rs29374(A,G); rs29329(A,G); rs29367(T,C); rs29328(T,C); rs6813622(T,G); rs6836518(C,T); rs67565176(C,T); rs72900032(T,G); rs29327(T,C); rs29326(T,C); rs115457606(C,A); rs17530377(G,A); rs29362(G,A); rs29361(T,C); rs29360(G,A); rs29358(C,T); rs29325(C,T); rs29357(C,T); rs29356(T,C); rs29355(T,C); rs29354(G,C); rs29353(T,G); rs3025719(G,A); rs29351(G,A); rs29324(T,G); rs29349(C,T); rs12650475(C,T); rs28567982(A,C); rs77997722(G,A); rs29348(A,G); rs7677909(G,A); rs29341(C,T); rs67331492(C,G); rs3025713(C,T); rs29321(T,C); rs29322(T,C); rs29306(G,A); rs29305(C,T); rs29320(A,G); rs29319(C,T); rs2158198(G,A); rs55685321(G,C); rs4833424(A,G); rs7684377(G,A); rs67078837(C,T); rs4834326(C,A); rs29303(C,T); rs3025711(G,T); rs17591736(G,A); rs115029780(C,T); rs10013347(T,C); rs29302(T,C); rs29301(G,A); rs29311(T,G); rs67082188(T,C); rs115977708(G,A); rs144496717(G,A); rs4833425(G,T); rs62313241(G,A); rs67411781(C,T); rs29309(C,T); rs67372598(G,A); rs3025705(G,A); rs29308(C,G); rs12502536(C,T); rs7662138(G,C); rs35705941(G,C); rs7680114(G,A); rs6837523(A,G); rs62313242(G,C); rs10018929(G,A); rs9996310(A,C); rs10030701(T,G); rs77531568(A,G); rs10023495(T,C); rs112281686(C,T); rs10516594(A,G); rs116250719(A,G); rs76370480(G,T); rs12643649(A,C); rs13118355(T,A); rs28551572(G,A); rs7684392(C,T); rs10003988(T,C); rs76456008(C,T); rs188738461(C,A); rs145876191(G,A); rs114292958(T,A); rs4501227(A,C); rs114476657(G,A); rs56098215(A,G); rs114450632(A,G); rs72675269(A,C); rs6833692(G,A); rs7676554(A,C); rs6834212(C,T); rs143580810(G,A); rs186201187(A,G); rs11940206(A,G); rs77085476(A,G); rs17045918(G,C); rs6853278(A,G); rs9307389(C,A); rs17045935(T,C); rs7686947(A,T); rs73841961(T,C); rs34770281(A,G); rs184283500(A,G); rs35336373(A,G); rs3736575(C,T); rs59906453(A,T); rs66792339(G,A); rs73841965(G,A); rs73841966(T,G); rs28433959(T,A); rs73841967(G,T); rs73841968(A,G); rs10005957(C,T); rs2091247(A,G); rs1980334(G,A); rs57906331(G,T); rs10031463(A,G); rs2272231(G,T); rs2272230(C,T); rs2272229(G,A); rs2272228(C,G); rs114617711(C,T); rs72901931(G,T); rs13435655(T,C); rs62313243(T,G); rs28621036(C,T); rs10021845(G,T); rs57734175(T,C); rs56279783(G,A); rs9968405(G,A); rs1524994(A,G); rs1524995(G,A); rs9968457(C,T); rs2272235(G,A); rs28594555(T,C); rs60602406(A,G); rs190275293(C,A); rs34316658(A,G); rs114002696(T,C); rs34846498(A,G); rs35398949(G,A); rs75838583(G,A); rs34053670(T,G); rs140992864(G,A); rs3796928(C,G); rs28377576(T,C); rs3733615(A,G); rs3733617(C,T); rs10013743(A,G); rs36210417(T,C); rs4834329(T,C); rs10516595(G,A); rs34888209(G,A); rs2177690(C,G); rs35728190(C,T); rs10212670(G,A); rs11930964(G,T); rs1524996(T,C); rs151200998(T,A); rs13124425(G,A); rs78778496(A,T); rs55966162(A,G); rs13137710(G,A); rs4834330(T,C); rs6533678(T,A); rs6533679(A,G); rs17483176(T,C); rs13115070(A,G); rs13115314(C,T); rs2293324(T,C); rs45517840(C,T); rs13141896(A,G); rs13142459(G,A); rs11946150(A,G); rs11943271(T,C); rs13133297(T,A); rs13133299(T,C); rs34938525(A,G); rs6826485(T,C); rs2352599(C,T); rs13146692(T,C); rs17483231(A,C); rs17045986(C,A); rs4834331(G,A); rs4834332(C,A); rs1054076(G,A); rs112502375(A,T); rs4834333(A,G); rs12711019(A,G); rs6853358(T,A); rs13435752(C,T); rs17614543(A,G); rs1554667(A,G); rs11550170(A,G) |
| ccdsGene name | CCDS3702.1 |
| cytoBand name | 4q26 |
| EntrezGene GeneID | 287 |
| EntrezGene Description | ankyrin 2, neuronal |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ANK2:NM_001148:exon38:c.T9854C:p.I3285T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q01484-4 |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0065963060686 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.002724 |
| ESP All MAF | 0.006843 |
| ESP Eur/Amr MAF | 0.008953 |
| ExAC AF | 0.008222 |
OMIM Clinical Significance
Spine:
Ankylosing vertebral hyperostosis
Skin:
Tylosis;
Punctate palmar and solar hyperkeratosis
Inheritance:
Autosomal dominant
OMIM Title
*106410 ANKYRIN 2; ANK2
;;ANKYRIN, NONERYTHROID;;
ANKYRIN, BRAIN;;
ANKYRIN, NEURONAL;;
ANKYRIN-B
OMIM Description
CLONING
Tse et al. (1991) studied immunoreactive isoforms of erythrocyte ankyrin
found in nonerythroid tissues. Using an erythrocyte ankyrin cDNA clone
as a hybridization probe, they isolated a clone from a human genomic
library that hybridized at low but not at high stringency. Further
studies suggested that the clone represented part of a gene for
nonerythroid ankyrin, which they designated ANK2.
Otto et al. (1991) isolated and sequenced cDNAs related to 2 brain
ankyrin isoforms and showed that they are produced through alternative
splicing of the mRNA from a single gene.
GENE STRUCTURE
The ANK2 gene contains 46 exons (Mohler et al., 2007). Exon 38 is
brain-specific.
GENE FUNCTION
The axon initial segment (AIS) is the site at which neural signals
arise, and should be the most efficient site to regulate neural
activity. Kuba et al. (2010) reported that deprivation of auditory input
in an avian brainstem auditory neuron leads to an increase in AIS
length, thus augmenting the excitability of the neuron. The length of
the AIS, defined by the distribution of voltage-gated sodium channels
and the AIS anchoring protein, ankyrin G, increased by 1.7 times in 7
days after auditory input deprivation. This was accompanied by an
increase in the whole-cell sodium current, membrane excitability, and
spontaneous firing. Kuba et al. (2010) concluded that their work
demonstrated homeostatic regulations of the AIS, which may contribute to
the maintenance of the auditory pathway after hearing loss. Furthermore,
plasticity at the spike initiation site suggests a powerful pathway for
refining neuronal computation in the face of strong sensory deprivation.
MAPPING
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization, Tse et al. (1991) assigned the ANK2 gene to 4q25-q27.
By analysis of human/rodent cell hybrids, Otto et al. (1991) assigned
the brain ankyrin gene to chromosome 4.
MOLECULAR GENETICS
Schott et al. (1995) characterized a large French kindred with long QT
syndrome associated with sinus node dysfunction and episodes of atrial
fibrillation segregating as an autosomal dominant trait. They mapped the
disorder to an 18-cM interval on 4q25-q27 (LQT4; 600919). Mohler et al.
(2003) sequenced the ANK2 gene, which maps to the same region, and
identified a glu1425-to-gly (E1425G) missense mutation (106410.0001).
Ankyrin-B appears to be the first identified protein to be implicated in
a congenital long QT syndrome that is not an ion channel or channel
subunit.
Mohler et al. (2004) identified 8 unrelated probands harboring 5
different ankyrin-B loss-of-function mutations
(106410.0001-106410.0005), 4 of which were previously undescribed, and
expanded the phenotype previously described by Schott et al. (1995).
Mohler et al. (2004) found that humans with ankyrin-B mutations display
varying degrees of cardiac dysfunction, including bradycardia, sinus
arrhythmia, idiopathic ventricular fibrillation, catecholaminergic
polymorphic ventricular tachycardia, and risk of sudden death. However,
a prolonged rate-corrected QT interval was not a consistent feature,
indicating that ankyrin-B dysfunction represents a clinical entity
distinct from classic long QT syndromes. The mutations were localized in
the ankyrin-B regulatory domain, which distinguishes function of
ankyrin-B from ankyrin-G (ANK3; 600465) in cardiomyocytes. All mutations
abolished ability of ankyrin-B to restore abnormal Ca(2+) dynamics and
abnormal localization and expression of Na/Ca exchanger, Na/K ATPase,
and InsP3 receptor in ankyrin-B +/- cardiomyocytes. This study,
considered together with the first description of ankyrin-B mutations
associated with cardiac dysfunction (Mohler et al., 2003), supported a
previously undescribed paradigm for human disease due to abnormal
coordination of multiple functionally related ion channels and
transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP3
receptor.
Mohler et al. (2007) identified 4 previously undescribed ANK2 variants
resulting in cardiac dysfunction. They presented the first description
of differences in cellular phenotypes conferred by specific ANK2
variants, and proposed that the various degrees of ankyrin-B loss of
function contribute to the range of severity of cardiac dysfunction.
They concluded that their data identified ANK2 variants as modulators of
human arrhythmias, provided the first insight into the clinical spectrum
of 'ankyrin-B syndrome,' and reinforced the role of ankyrin-B-dependent
protein interactions in regulating cardiac electrogenesis.
ANIMAL MODEL
Mohler et al. (2003) reported that mice heterozygous for a null mutation
in ankyrin-B were haploinsufficient and displayed arrhythmia similar to
humans. The mutation in ankyrin-B resulted in disruption in the cellular
organization of the sodium pump, the sodium/calcium exchanger, and
inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding proteins),
which reduced the targeting of these proteins to the transverse tubules
as well as reducing overall protein level. Ankyrin-B mutation also led
to altered calcium ion signaling in adult cardiomyocytes that resulted
in extrasystoles, and provided a rationale for the arrhythmia. Thus,
Mohler et al. (2003) identified a novel mechanism for cardiac arrhythmia
due to abnormal coordination of multiple functionally related ion
channels and transporters.
TRAM1L1
| dbSNP name | rs17049006(G,A) |
| ccdsGene name | CCDS3707.1 |
| cytoBand name | 4q26 |
| EntrezGene GeneID | 133022 |
| EntrezGene Description | translocation associated membrane protein 1-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TRAM1L1:NM_152402:exon1:c.C243T:p.A81A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0652 |
| ESP Afr MAF | 0.075125 |
| ESP All MAF | 0.047824 |
| ESP Eur/Amr MAF | 0.033837 |
| ExAC AF | 0.069 |
LINC01061
| dbSNP name | rs72918577(G,A); rs72489565(T,C) |
| cytoBand name | 4q26 |
| EntrezGene GeneID | 100131884 |
| EntrezGene Symbol | LOC100131884 |
| snpEff Gene Name | AC110373.1 |
| EntrezGene Description | capicua transcriptional repressor pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2681 |
PDE5A
| dbSNP name | rs79682490(T,G); rs76705409(C,T); rs13124532(C,T); rs11729521(T,C); rs11734241(A,G); rs17006190(C,G); rs116281224(A,G); rs116765299(T,C); rs28685688(T,C); rs76867030(A,G); rs142766571(A,T); rs115006805(T,A); rs2306455(G,A); rs75089612(T,C); rs115920291(C,T); rs10031483(T,C); rs35264119(G,A); rs113015137(A,C); rs10031665(T,C); rs77408616(C,G); rs3733519(A,G); rs3733520(C,G); rs3733523(C,T); rs12510138(G,C); rs12502423(A,C); rs151014459(G,C); rs13107334(T,G); rs2127826(A,G); rs2127827(A,G); rs4834779(G,A); rs146959528(G,T); rs3775841(A,C); rs74878216(T,C); rs7692994(C,A); rs114554681(G,A); rs3775842(G,A); rs3775843(T,C); rs3775844(G,A); rs3822190(G,A); rs3822191(A,T); rs7699064(C,T); rs13121569(A,G); rs2127822(A,G); rs10008791(A,C); rs11736416(C,T); rs3775846(C,T); rs145898633(G,C); rs1480935(T,C); rs61747388(G,A); rs1383532(T,A); rs1383533(G,A); rs2291185(C,A); rs148293337(G,C); rs57594176(T,C); rs10030660(G,A); rs13104219(G,T); rs13103899(A,G); rs145762447(G,A); rs116396619(A,G); rs10004484(C,T); rs34868248(A,G); rs75475204(G,A); rs115471072(G,C); rs10019674(T,C); rs3822192(A,C); rs3733525(A,G); rs3775847(A,C); rs3775848(C,T); rs6534139(G,A); rs1155577(C,T); rs35289699(T,C); rs10013305(G,A); rs3775849(G,C); rs3775850(G,A); rs7688802(G,A); rs7695620(G,A); rs3775851(T,C); rs145956842(C,T); rs115976413(C,T); rs3775852(A,G); rs149817212(C,T); rs115663936(A,G); rs6534140(C,T); rs55826301(T,C); rs10034450(A,G); rs2257018(T,C); rs1480939(T,C); rs1480940(T,C); rs6858592(G,A); rs6835635(T,C); rs2256645(C,T); rs13128602(A,G); rs184108102(C,A); rs58452170(A,T); rs150884942(C,G); rs7678400(G,A); rs2622498(A,T); rs1480936(C,T); rs1010739(C,T); rs2622497(A,C); rs150518724(C,T); rs11098531(G,A); rs62319606(G,C); rs17292047(G,A); rs12502531(T,G); rs12498539(C,T); rs12498599(C,T); rs58074349(A,G); rs9997631(C,G); rs10009626(T,C); rs11724055(G,A); rs2622496(A,T); rs2715018(T,C); rs76402695(G,C); rs115109544(G,C); rs3822194(A,G); rs3822195(C,T); rs3775854(C,T); rs147307386(T,C); rs2306456(C,G); rs2306457(T,A); rs13140150(A,C); rs145591844(T,A); rs201236087(C,T); rs11947234(A,G); rs6853998(C,A); rs6858777(A,G); rs1480934(T,C); rs2928991(C,A); rs11933966(G,A); rs36040693(A,G); rs2715022(G,A); rs10018280(T,G); rs2715021(A,G); rs34308924(T,C); rs12108288(A,G); rs3775856(C,T); rs114276127(T,C); rs184492775(C,T); rs2127823(G,T); rs2170276(A,C); rs3775858(A,G); rs55825515(A,G); rs149180072(A,G); rs1552092(C,T); rs145654729(T,A); rs3736115(G,A); rs17050695(G,T); rs17050700(T,C); rs59732491(G,C); rs9884402(A,G); rs183774402(G,A); rs9995026(T,A); rs11723090(T,C); rs144492086(C,A); rs11098532(C,A); rs4513554(T,C); rs62319609(A,G); rs17358524(A,G); rs28540362(G,A); rs2953292(G,A); rs2928992(A,C); rs2715020(T,C); rs13133969(A,C); rs2622499(G,A); rs2622500(G,A); rs59516282(G,A); rs112189670(G,A); rs12646525(T,C); rs12503853(C,A); rs13140391(A,G); rs13140409(A,G); rs12648182(T,A); rs12648259(T,A); rs6833334(C,T); rs6834347(C,T); rs147662846(A,C); rs55661135(G,A); rs13137618(G,A); rs149494214(A,C); rs13137511(C,T); rs9884862(A,G); rs6829903(C,T); rs79647663(G,A); rs2389863(A,G); rs10012485(C,T); rs12505618(G,A); rs149799929(C,T); rs2892867(G,A); rs66887589(T,C); rs6822275(T,C); rs28412979(G,A); rs56173225(G,A); rs12331968(T,C); rs34676199(G,T); rs13115778(G,T); rs2389864(G,A); rs111265410(T,C); rs7678973(T,C); rs7659250(C,T); rs6842674(T,C); rs4834784(A,G); rs72920701(G,A); rs11931723(T,C); rs2389865(T,C); rs2389866(C,T); rs7669520(T,C); rs74994681(T,A); rs58354482(A,C); rs2389867(A,G); rs2389868(G,A); rs140318785(G,A); rs7697823(C,G); rs10032993(T,C); rs10021460(G,C); rs9998919(A,G); rs2389869(C,T); rs17358860(T,A); rs3756154(C,T); rs35850447(T,C); rs62319647(A,C); rs7670921(G,C); rs60421281(T,G); rs35999787(A,T); rs17051261(G,A); rs1987179(T,C); rs17051262(G,A); rs143964578(A,T); rs11737395(C,G); rs2892869(T,C); rs4834786(G,A); rs4834787(T,C); rs7684899(C,T); rs2389870(T,C); rs115362416(A,G); rs10518335(C,T); rs62319649(T,C); rs10518336(G,A); rs28625289(A,T); rs28382361(C,T); rs13119104(C,G); rs4264816(T,C); rs13120581(G,T); rs13125819(A,G); rs3756155(T,A); rs28394116(T,G); rs12642735(G,A); rs3756156(G,A); rs4146266(C,T); rs3756157(A,C); rs78520912(C,G); rs28650385(C,T); rs28564258(C,T); rs7439678(G,C); rs190892668(A,C); rs78421882(C,T); rs3733526(G,A); rs13118388(A,C); rs34601943(C,A); rs10022664(A,G); rs146095381(A,G); rs113618360(T,C); rs2389884(C,T); rs4626181(C,A); rs4597811(T,C); rs10050092(T,C); rs41464847(A,G); rs57960799(T,A); rs12505735(C,A); rs7681796(G,A); rs7681980(G,A); rs35967840(G,C); rs9307480(T,C); rs192439363(C,G); rs10013852(C,T); rs6847164(C,T); rs138458101(A,T); rs28566610(A,C); rs114513627(C,T); rs12502511(G,A); rs6817975(C,A); rs4834788(A,G); rs28578366(C,T); rs6534145(A,G); rs4834789(T,G); rs4834790(T,C); rs116585222(T,G); rs4833620(C,T); rs78266833(C,T); rs6534146(G,A); rs13106925(C,T); rs59590064(T,C); rs11730798(G,T); rs11731568(C,T); rs7693919(G,A); rs10021469(C,T); rs13122502(C,G); rs62319657(G,A); rs6817317(A,G); rs13136296(C,T); rs13136462(C,T); rs6534147(C,T); rs185815707(G,A); rs4287988(A,G); rs7672519(C,T); rs6534148(T,C); rs7672961(C,A); rs6831062(C,G); rs4833621(T,C); rs62319658(G,T); rs144432761(C,T); rs115635695(A,G); rs6832740(T,C); rs6855918(C,T); rs3109370(A,G); rs75483765(C,T); rs4833622(G,A); rs2953293(T,G); rs2953294(T,A); rs2953290(A,G); rs6854072(T,G) |
| ccdsGene name | CCDS3713.1 |
| cytoBand name | 4q26 |
| EntrezGene GeneID | 8654 |
| EntrezGene Description | phosphodiesterase 5A, cGMP-specific |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PDE5A:NM_033437:exon14:c.T1766C:p.L589P,PDE5A:NM_001083:exon14:c.T1922C:p.L641P,PDE5A:NM_033430:exon14:c.T1796C:p.L599P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7322 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O76074 |
| dbNSFP Uniprot ID | PDE5A_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.013164 |
| ESP All MAF | 0.004459 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001366 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmar telangiectasias (described in 1 family)
NEUROLOGIC:
[Central nervous system];
Cerebral cavernous malformations;
Seizures;
Recurrent headaches;
Hemorrhagic stroke
MISCELLANEOUS:
Genetic heterogeneity (see 116800 for summary);
Sporadic cases often single lesions versus multiple lesions in familial
cases
MOLECULAR BASIS:
Caused by mutation in the CCM2 gene (CCM2, 607929.0001)
OMIM Title
*603310 PHOSPHODIESTERASE 5A; PDE5A
OMIM Description
DESCRIPTION
Cyclic nucleotide phosphodiesterases (PDEs; EC 3.1.4.17) are a
superfamily of enzymes that catalyze the hydrolysis of
3-prime,5-prime-cyclic nucleotides to the corresponding nucleoside
5-prime-monophosphates. The PDEs have been subdivided into several
families on the basis of sequence, substrate specificity, kinetic
properties, and regulatory features. See 171885. Members of the PDE5
family are cGMP-binding, cGMP-specific enzymes.
CLONING
By screening several human cDNA libraries with a bovine PDE5 cDNA,
Loughney et al. (1998) isolated cDNAs encoding human PDE5A. The
predicted 875-amino acid human protein is approximately 96% identical to
bovine PDE5A. Like the bovine protein, human PDE5A contains a
cGMP-binding domain in its N-terminal portion and a catalytic domain in
its C-terminal region. Recombinant PDE5A protein hydrolyzed cGMP in
vitro. Northern blot analysis revealed that PDE5A is expressed as a
7.9-kb mRNA and a less abundant 6-kb mRNA in various human tissues.
Loughney et al. (1998) isolated an alternatively spliced PDE5A mRNA,
PDE5A2, which encodes a protein with a differing N terminus.
Independently, Stacey et al. (1998) and Yanaka et al. (1998) cloned
PDE5A cDNAs.
By RACE-PCR of corpus cavernosum cDNA, Lin et al. (2002) cloned 3 PDE5A
variants, PDE5A1, PDE5A2, and PDE5A3, that use 3 alternate first exons.
The splice variants encode proteins that differ at their N termini.
Compared with PDE5A3, the shortest protein, PDE5A1 and PDE5A2 have
N-terminal extensions of 52 and 10 residues, respectively. PDE5A1 has 13
glutamines in a stretch of 18 amino acids near its N terminus.
Semiquantitative RT-PCR detected PDE5A1 and PDE5A2 expression in all
tissues examined. PDE5A3 was detected at highest levels in urinary
bladder, urethra, uterus, and heart, but little to no expression was
detected in skeletal muscle, lung, brain, kidney, and liver. PDE5A3 was
variably expressed in 5 of 8 patient corpus cavernosum samples, whereas
PDE5A1 and PDE5A2 were expressed in all 8 samples.
GENE FUNCTION
Jaumann et al. (2012) found that Prkg1 (176894)-null mice had a normal
hearing threshold, but they were more vulnerable than wildtype mice to
noise-induced hearing loss and showed markedly less recovery than
wildtype mice following acoustic trauma. Prkg1 was expressed in sensory
cells and neurons of the inner ear of wildtype mice, and its expression
partly overlapped that of Pde5. Pharmacologic inhibition of Pde5 in
wildtype mice and rats almost completely prevented noise-induced
cochlear damage and caused Prkg1-dependent upregulation of
poly(ADP-ribose) in hair cells and spiral ganglion. Jaumann et al.
(2012) concluded that the protective effect of Prkg1 involves activation
of poly(ADP-ribose) polymerase (see 173870).
BIOCHEMICAL FEATURES
Using the multiwavelength anomalous dispersion method, Sung et al.
(2003) reported the 3-dimensional crystal structures of the human PDE5A
catalytic domain (residues 537-860) complexed with 3 drug molecules:
sildenafil, tadalafil, and vardenafil.
GENE STRUCTURE
Yanaka et al. (1998) reported that the PDE5A gene contains 21 exons and
spans more than 100 kb.
Lin et al. (2002) identified 2 additional exons in the PDE5A gene,
representing 2 of 3 alternately spliced first exons arranged in the
order A1-A3-A2. Promoter activity was detected upstream from exon A1 and
in the intron preceding exon A2. The upstream promoter likely directs
expression of all 3 PDE5A isoforms, while the intronic promoter is
specific for the A2 isoform. DNase footprinting detected functional AP2
(107580)- and SP1 (189906)-binding sites in both promoter regions, and
both promoter regions were upregulated by increasing concentrations of
either cAMP or cGMP.
MAPPING
By fluorescence in situ hybridization, Yanaka et al. (1998) mapped the
PDE5A gene to 4q26. Loughney et al. (1998) mapped the PDE5A gene to
4q25-q27 by analysis of mapped YACs.
ANIMAL MODEL
Sebkhi et al. (2003) demonstrated Pde5a immunoreactivity in smooth
muscle cells of the medial layer of pulmonary arteries and veins in the
normal lung of Sprague-Dawley rats, with localization to distal
muscularized arteries after the rats underwent hypoxia-induced pulmonary
hypertension (see 178400). Sebkhi et al. (2003) observed that
pretreatment with the PDE5A-inhibitor sildenafil significantly reduced
the increase in pulmonary artery pressure in a dose-dependent manner (60
to 90% reduction). When begun after 14 days of hypoxia, sildenafil
significantly reduced pulmonary artery pressure (30% reduction) and
partially reversed pulmonary artery muscularization (approximately 40%
reduction). Sebkhi et al. (2003) concluded that PDE5A inhibition
attenuates the rise in pulmonary artery pressure and vascular remodeling
when given before chronic exposure to hypoxia and when administered as a
treatment during ongoing hypoxia-induced pulmonary hypertension.
In mice exposed to chronic cardiac pressure overload, Takimoto et al.
(2005) demonstrated that blocking the intrinsic catabolism of cGMP with
an oral PDE5A inhibitor (sildenafil) suppressed chamber and myocyte
hypertrophy and improved in vivo heart function. Sildenafil also
reversed preestablished hypertrophy induced by pressure load and
restored chamber function to normal. Pde5a inhibition deactivated
multiple hypertrophy signaling pathways triggered by pressure load
(e.g., the calcineurin (see 114105)/NFAT (see 600489),
phosphoinositide-3 kinase (see 171833)/Akt (see 164730), and ERK1
(601795)/ERK2 (176948) pathways), but did not suppress hypertrophy
induced by overexpression of calcineurin in vitro or Akt in vivo,
suggesting upstream targeting of these pathways.
PP12613
| dbSNP name | rs10025131(T,C); rs9993206(A,G); rs77005784(G,A); rs4833772(G,C); rs28515183(G,A) |
| cytoBand name | 4q27 |
| EntrezGene GeneID | 100192379 |
| snpEff Gene Name | TMEM155 |
| EntrezGene Description | uncharacterized LOC100192379 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03857 |
SPATA5
| dbSNP name | rs79940431(G,C); rs12502829(G,C); rs75339138(A,T); rs6820411(C,A); rs11944526(A,G); rs11944529(A,G); rs10518408(G,A); rs958872(A,G); rs74564963(T,C); rs11098678(A,T); rs113651922(C,G); rs78856673(A,C); rs73844966(T,A); rs28437586(C,T); rs79652896(T,C); rs58669578(G,A); rs72919893(A,T); rs959567(C,A); rs111309989(C,T); rs17006332(A,C); rs73844968(C,T); rs113598918(C,T); rs72674964(T,C); rs17006333(A,C); rs2125450(C,G); rs1542436(G,T); rs10222773(A,C); rs2390397(C,T); rs76195983(A,C); rs1563706(T,C); rs11733198(G,A); rs72921704(G,A); rs375038301(A,G); rs77917118(T,G); rs11098679(G,A); rs61460425(T,C); rs6824053(A,T); rs6850504(T,C); rs79844573(C,T); rs7668548(C,G); rs13128461(T,C); rs191900961(G,T); rs56347837(C,T); rs140482759(G,A); rs56404645(G,C); rs55747868(G,A); rs17006351(G,A); rs6534368(A,G); rs11098682(G,T); rs6534369(C,T); rs6815568(G,A); rs193289859(T,A); rs28665564(T,C); rs28590148(A,G); rs13136087(C,T); rs144446522(C,A); rs112162521(C,T); rs56051027(C,T); rs73844971(C,T); rs56032107(A,G); rs60079348(G,A); rs72921727(A,G); rs6843763(G,A); rs6849378(G,A); rs79347160(T,G); rs28809291(T,C); rs12507568(G,T); rs75636052(T,C); rs6849917(C,T); rs6819246(A,G); rs62323559(G,A); rs72921733(T,G); rs76050849(A,G); rs62324460(A,G); rs2125451(A,C); rs72921739(T,C); rs73844974(G,T); rs75123170(G,A); rs73844975(C,T); rs6534370(C,T); rs6841279(G,C); rs112234594(C,T); rs60307903(C,A); rs60148848(G,A); rs78511033(T,C); rs9685004(C,A); rs9685166(C,T); rs11941763(G,C); rs78935967(A,G); rs73844977(G,A); rs906832(A,G); rs76380729(T,C); rs906833(C,T); rs6819383(A,G); rs11930927(T,C); rs6819925(C,A); rs1567380(C,A); rs1567381(C,T); rs1976584(A,C); rs112826135(G,A); rs147279336(C,T); rs7669574(C,T); rs12500306(T,C); rs73844978(A,C); rs113057977(C,T); rs58873737(C,T); rs1458756(A,G); rs57820745(C,T); rs80066757(A,G); rs7673580(T,C); rs72674985(A,C); rs41324754(C,T); rs73844980(A,T); rs73844981(T,G); rs58844024(T,C); rs7686314(T,C); rs6534371(T,C); rs7686510(T,A); rs6824939(G,A); rs7668400(C,T); rs78872040(A,G); rs58548393(C,A); rs78422579(C,T); rs4833849(C,T); rs1467052(T,C); rs1467994(C,A); rs144600219(C,G); rs6845135(G,C); rs77977175(C,T); rs77653269(A,G); rs80049802(G,A); rs1509491(A,G); rs2136425(C,G); rs6843767(T,G); rs4833850(C,T); rs75909847(T,G); rs138657389(G,A); rs4833851(T,A); rs60653156(C,G); rs9996342(G,A); rs74750441(T,G); rs73844983(G,A); rs73844984(C,T); rs9999412(C,T); rs9999551(G,C); rs115909719(G,A); rs114940584(G,A); rs116394888(C,T); rs78929981(C,G); rs9790459(C,A); rs79069550(A,G); rs6828008(A,G); rs11098683(A,G); rs79431029(T,A); rs77791284(C,G); rs6829821(G,A); rs76892807(C,T); rs60798115(G,A); rs75295805(G,A); rs62324121(G,A); rs138782958(A,G); rs7677728(C,T); rs55840673(G,A); rs7678678(C,T); rs12645413(C,A); rs60257753(T,C); rs7662778(T,G); rs76219548(A,G); rs7662961(T,G); rs113026594(C,G); rs2390448(G,A); rs116577906(T,C); rs78286637(A,G); rs115719359(T,A); rs114055156(T,C); rs79526119(A,G); rs146829312(A,G); rs10003337(T,A); rs9991815(G,A); rs4833852(A,C); rs4833258(T,C); rs116567435(T,C); rs116056438(A,G); rs7690544(G,A); rs180864824(C,A); rs62324123(A,G); rs12503830(T,C); rs112684538(C,T); rs73844985(C,A); rs75934988(A,G); rs4833853(C,T); rs80269801(A,G); rs75873355(T,G); rs73844986(G,A); rs115182815(C,G); rs74974679(G,C); rs2390462(T,A); rs1113562(C,T); rs1018216(A,G); rs4833854(A,C); rs56299539(A,G); rs10020032(T,G); rs28731123(C,T); rs114583559(T,C); rs4833260(T,C); rs77338865(G,A); rs4833855(G,A); rs112158908(C,A); rs4343743(A,G); rs11931493(A,G); rs4288022(T,C); rs4833856(G,T); rs74746070(G,A); rs4833857(G,A); rs12649970(A,G); rs143001377(T,C); rs139782593(G,C); rs140581978(T,G); rs2390450(G,T); rs114206864(A,T); rs78240780(C,T); rs138368620(C,T); rs6845113(C,G); rs77414650(T,C); rs148671215(A,G); rs13114321(G,A); rs77859982(C,G); rs11098688(A,T); rs116021612(G,T); rs6534372(C,T); rs75701960(A,G); rs7658477(C,T); rs76224023(C,A); rs80156863(G,A); rs76449710(T,C); rs6816823(C,T); rs150597650(C,G); rs75378429(C,T); rs4358418(C,T); rs77086511(C,T); rs73844989(T,C); rs4833261(G,A); rs61572782(T,A); rs78609886(C,T); rs6843303(G,A); rs78827317(C,T); rs6534373(A,G); rs6534374(A,C); rs6849695(G,A); rs58960515(C,T); rs115273305(A,G); rs189228903(G,A); rs10434040(C,T); rs4833858(G,C); rs73844990(C,T); rs4833859(C,T); rs192441805(C,T); rs4833262(C,T); rs75165150(G,A); rs11935287(C,T); rs72677125(G,A); rs56259295(A,G); rs1912111(G,T); rs1912110(C,T); rs73844991(C,T); rs115211518(A,T); rs78047379(C,T); rs6534376(T,C); rs11729798(C,A); rs111353229(C,T); rs73844992(C,T); rs73844993(G,C); rs73844994(G,A); rs10006274(C,T); rs116177334(A,G); rs111794176(C,T); rs6534377(T,C); rs73844995(G,T); rs6534378(A,C); rs141134537(A,G); rs74804576(A,C); rs4240268(A,T); rs74371729(G,A); rs7665828(T,C); rs35343500(G,C); rs1472949(G,A); rs73844996(T,C); rs7694331(A,G); rs73844997(G,A); rs7672998(T,C); rs62325778(G,A); rs4833862(T,C); rs7660751(C,T); rs4833863(C,T); rs114417265(C,T); rs7667362(G,A); rs6534379(A,C); rs28741994(A,G); rs9762613(C,T); rs62325780(T,G); rs76279737(T,G); rs140142646(A,T); rs10009744(A,G); rs11945742(T,A); rs77458038(A,G); rs4264846(G,A); rs79375541(G,A); rs181726955(C,T); rs4470648(A,G); rs182988753(A,C); rs13135008(A,T); rs141992708(T,C); rs977670(G,A); rs7666511(C,T); rs77523406(G,A); rs9998489(T,C); rs139311019(G,A); rs75384149(G,A); rs114052871(G,C); rs147652660(T,C); rs78948106(A,T); rs60845082(T,C); rs77723493(C,T); rs58144366(T,G); rs78478792(C,T); rs149042931(T,G); rs139017689(C,T); rs142101394(G,T); rs145812463(C,T); rs116734093(G,A); rs11732615(A,G); rs115824245(C,T); rs78086240(G,A); rs78537478(G,C); rs116071170(A,G); rs59917868(G,A); rs60436719(A,T); rs75134348(A,G); rs115339879(G,A); rs142556484(A,G); rs1112618(A,G); rs1112617(G,A); rs1112616(T,G); rs76466805(C,T); rs2136426(T,G); rs2136427(A,G); rs2390463(T,G); rs78127075(A,G); rs7683800(G,A); rs28862721(T,G); rs7683891(C,G); rs183996099(G,A); rs4833864(T,C); rs4833865(C,T); rs80292818(A,C); rs10212729(C,T); rs4833866(T,A); rs78901551(A,G); rs78798931(C,G); rs4833867(T,C); rs76106786(T,C); rs1848694(G,A); rs1605856(A,G); rs116006006(G,A); rs141671756(T,C); rs75037875(G,C); rs4833868(A,G); rs115461940(G,A); rs79513354(G,A); rs6534381(G,A); rs76651500(C,G); rs7440687(G,T); rs185982472(C,T); rs2063294(T,C); rs2893027(G,C); rs6848318(C,T); rs78581334(G,C); rs76421926(T,C); rs62322467(C,T); rs76536358(G,A); rs116706973(T,A); rs76924127(T,C); rs62322468(T,A); rs17411291(T,C); rs62322469(A,C); rs75662953(T,C); rs2063293(C,T); rs59975405(T,C); rs141703720(A,G); rs114203957(G,A); rs114451655(C,T); rs56068700(C,T); rs147713800(C,T); rs6823893(A,T); rs56818068(C,T); rs11098690(T,C); rs78616588(T,C); rs114996042(T,C); rs72677165(G,A); rs138465433(C,T); rs11946849(G,A); rs10032263(C,T); rs2390451(A,G); rs9995772(A,G); rs75821028(T,C); rs78459265(C,T); rs9307518(C,G); rs56677645(A,G); rs6815609(C,T); rs1912109(A,G); rs76591610(A,G); rs4833870(C,T); rs114823807(C,G); rs4833871(A,G); rs137897806(A,G); rs150680935(A,G); rs114021040(T,G); rs12650496(C,G); rs11098691(G,C); rs12650569(G,A); rs36119595(A,G); rs148567791(C,G); rs4240269(G,A); rs28362076(T,C); rs6534382(G,T); rs55719340(G,A); rs6842497(C,A); rs114880842(G,T); rs79143230(A,G); rs62322472(G,A); rs116641763(C,T); rs74985307(G,C); rs73845002(T,C); rs7657682(A,G); rs115167584(T,C); rs115317900(T,C); rs6814557(A,C); rs6814701(A,G); rs149342637(A,G); rs74996532(T,A); rs1567383(C,T); rs10223027(G,A); rs76646042(C,T); rs62322474(A,G); rs77607196(A,G); rs6534384(C,T); rs6841083(C,T); rs6841097(C,A); rs11721909(G,A); rs111347742(G,A); rs142918195(T,C); rs199542399(A,C); rs9307520(A,G); rs72677179(A,T); rs12508176(A,G); rs78067417(A,C); rs17006460(C,T); rs140544159(C,T); rs190696390(C,T); rs112029027(A,G); rs116542008(G,T); rs79537916(T,C); rs113421733(A,G); rs17006466(C,T); rs10013375(T,C); rs1509488(A,G); rs116620333(T,G); rs141402569(G,A); rs149416397(C,G); rs76573749(G,A); rs62322475(C,T); rs7677578(G,C); rs76372254(A,G); rs9918042(T,C); rs6823951(T,C); rs115751472(T,C); rs79136782(G,A); rs11937566(A,G); rs532886(C,T); rs200950298(G,A); rs115894523(A,G); rs405194(C,T); rs72677190(A,T); rs79114941(C,A); rs72677191(C,T); rs76899030(C,T); rs375826(G,C); rs433220(C,T); rs12500537(C,T); rs448662(G,A); rs383025(A,T); rs415352(T,G); rs377185(G,C); rs379082(G,A); rs12646318(T,C); rs72677195(C,T); rs74653718(T,C); rs425344(G,A); rs1428271(G,A); rs199626476(T,C); rs2115151(A,T); rs2893028(T,C); rs72925630(A,G); rs449105(C,A); rs11946896(A,G); rs11947806(A,G); rs74859689(T,G); rs451666(G,A); rs11947938(A,G); rs55840184(A,G); rs58035564(T,C); rs74991849(A,T); rs382219(G,T); rs73848605(G,T); rs72678907(C,G); rs412925(A,G); rs433022(T,C); rs116328847(C,T); rs76136588(T,C); rs78844089(G,A); rs2561150(G,A); rs307021(A,C); rs307022(G,C); rs145407911(G,A); rs307023(G,A); rs172594(T,G); rs10518410(A,G); rs307024(G,C); rs56037508(A,G); rs59160662(G,T); rs2663712(A,T); rs307025(A,G); rs72678912(C,T); rs307026(G,A); rs307027(G,T); rs373549(T,G); rs417366(G,T); rs307028(A,G); rs307029(C,T); rs307030(A,G); rs307031(G,C); rs373371166(G,A); rs78820937(T,C); rs307032(A,G); rs150689740(G,A); rs2561147(A,G); rs11098692(A,G); rs147921666(G,A); rs412493(T,C); rs424272(C,T); rs374612(A,G); rs72678923(C,T); rs114167326(G,T); rs11098693(A,G); rs12507443(G,A); rs6849385(A,G); rs6855054(G,A); rs7675748(T,C); rs307064(T,C); rs307063(C,G); rs307062(C,T); rs113355713(G,A); rs364413(C,G); rs374451(A,G); rs72678927(G,A); rs307061(G,C); rs307060(A,G); rs62322492(G,A); rs76852366(C,T); rs62322493(G,A); rs28424219(G,A); rs76624555(G,T); rs307058(G,A); rs72678933(A,T); rs56048437(T,C); rs146770224(A,G); rs307057(G,A); rs72925661(T,C); rs148001070(T,C); rs72678934(T,A); rs306015(C,T); rs76783597(A,T); rs60083175(T,G); rs4833872(C,A); rs55705925(G,A); rs72678937(G,A); rs113421275(A,G); rs55805143(A,G); rs7697284(C,A); rs306013(T,C); rs28439225(C,T); rs114431475(G,T); rs28453165(C,T); rs306012(T,C); rs306011(T,C); rs13146450(G,A); rs7675273(C,T); rs80026757(C,G); rs189536545(G,A); rs72678941(A,T); rs306010(T,C); rs116601926(C,A); rs306008(A,G); rs112434001(C,A); rs3853108(T,A); rs306007(T,A); rs17006514(G,A); rs62322501(G,A); rs73845005(A,T); rs201449478(A,T); rs199860645(T,A); rs17006517(C,T); rs114438276(A,G); rs306003(T,C); rs148720367(C,T); rs306002(C,T); rs62322502(G,A); rs72678953(G,A); rs10031660(A,G); rs77473497(T,A); rs77734041(A,G); rs113774986(A,G); rs61110894(T,A); rs11721376(A,C); rs75480763(T,C); rs77302371(C,T); rs80239175(C,T); rs146961551(G,A); rs72678960(A,G); rs10025084(A,C); rs430224(A,G); rs75419965(A,G); rs1428267(A,G); rs72678964(A,G); rs28754542(G,C); rs446392(G,A); rs2561148(T,C); rs307038(A,G); rs79430306(A,G); rs307037(C,G); rs62322506(C,G); rs141403891(T,G); rs72678969(C,T); rs9999118(A,G); rs62322507(G,C); rs62322508(C,A); rs56958921(C,A); rs56997888(A,G); rs6842253(T,G); rs148644930(C,T); rs6847671(T,C); rs11098695(C,T); rs60018439(T,C); rs13137124(G,A); rs79604898(C,T); rs111318965(C,T); rs13142857(G,A); rs56262366(G,A); rs4833265(C,T); rs115653717(T,G); rs72678975(G,A); rs418166(A,C); rs436593(G,A); rs7674347(T,C); rs7696223(A,G); rs7675113(T,G); rs76390404(T,C); rs80020468(G,A); rs11943399(G,A); rs307044(G,A); rs11934360(A,T); rs78696106(G,A); rs307043(C,G); rs307042(G,T); rs10050306(C,G); rs307041(A,G); rs12645822(A,G); rs307040(A,T); rs307039(G,A); rs79515614(G,A); rs1319221(A,T); rs150428236(G,A); rs78823690(G,A); rs13126167(G,A); rs62322513(A,G); rs1346502(C,T); rs142479867(C,A); rs1703833(A,G); rs62322514(C,T); rs375540(A,G); rs10013234(A,C); rs425661(G,A); rs303084(G,A); rs303083(C,T); rs6534387(A,T); rs41469749(C,T); rs116061456(C,T); rs10518413(G,C); rs303082(G,C); rs149292658(G,C); rs303081(C,T); rs7655348(A,G); rs113760440(G,A); rs304624(G,A); rs62322536(A,G); rs304621(C,G); rs141061088(G,A); rs149239285(G,T); rs303090(T,G); rs303089(T,C); rs170000(T,C); rs142323094(A,G); rs112661264(G,T); rs304617(T,C); rs177516(C,A); rs303088(A,C); rs56280121(A,G); rs72678992(C,T); rs4833874(A,G); rs4833875(G,A); rs304615(T,C); rs10857094(G,A); rs303086(G,A); rs28465022(T,C); rs6830898(G,A); rs12648547(T,G); rs10023993(T,G); rs7679580(A,G); rs6534388(T,C); rs13107109(G,C); rs6820876(T,G); rs116251955(A,G); rs72679002(C,T); rs13140938(T,C); rs451780(G,A); rs75599173(A,G); rs304653(C,T); rs114403027(A,C); rs115186119(G,C); rs9685277(C,T); rs304652(G,A); rs216102(T,C); rs184252618(T,C); rs75131146(T,G); rs3866205(A,T); rs7676303(A,G); rs114121568(T,C); rs79476642(G,A); rs28579706(C,T); rs182143988(G,A); rs304640(G,A); rs28435873(C,T); rs28418915(T,C); rs115685402(C,T); rs4479721(C,T); rs56242870(A,T); rs6534390(T,A); rs115789495(G,A); rs6845318(A,G); rs114635717(C,T); rs386798(C,G); rs442065(C,T); rs6852810(A,G); rs10515502(C,G); rs416938(C,T); rs7700245(G,A); rs7699963(A,G); rs427208(G,T); rs451205(C,T); rs402998(C,T); rs17006613(C,T); rs10003186(G,A); rs447419(T,C); rs138958957(G,A); rs415413(G,A); rs303125(A,G); rs7674410(C,T); rs303127(C,G); rs7680456(C,G); rs7681309(A,T); rs112949411(C,T); rs72680822(C,T); rs303128(A,G); rs303129(G,T); rs76195519(A,G); rs17006622(A,G); rs303130(T,C); rs115823061(T,C); rs304657(T,C); rs304658(G,A); rs11932158(G,A); rs10010823(T,C); rs303117(G,A); rs215491(G,C); rs72680832(T,A); rs368830006(G,T); rs303118(C,T); rs303119(T,G); rs303121(G,A); rs17419716(T,C); rs6849700(T,C); rs79846367(C,T); rs303122(G,A); rs303123(C,T); rs369941888(T,G); rs4538492(A,G); rs79714749(C,G); rs10518411(C,T); rs13133626(T,G); rs13135224(T,C); rs6534391(G,A); rs371686478(T,C); rs374918633(T,A); rs304665(C,A); rs303111(A,T); rs7694671(T,C); rs303112(C,A); rs303113(A,T); rs303114(A,T); rs303115(C,G); rs149802310(A,G); rs303116(A,G); rs150114630(C,T); rs10014276(G,T); rs4240270(C,T); rs77944149(C,T); rs11944380(T,C); rs17006641(A,G); rs12646888(G,C); rs115757710(T,A); rs186241(G,A); rs371773591(A,G); rs304654(T,C); rs75152000(A,G); rs2561146(A,G); rs78546607(C,T); rs373971753(A,G); rs11098697(C,T); rs408436(C,T); rs11727519(A,T); rs4833877(T,G); rs303092(T,G); rs148526886(G,A); rs373214608(A,T); rs366557(C,T); rs394456(T,C); rs11736350(T,C); rs303093(A,G); rs11736544(T,A); rs303094(T,C); rs28540268(G,A); rs447000(C,T); rs150598970(G,A); rs303096(G,A); rs303097(A,G); rs7661216(A,G); rs12643962(A,T); rs375608873(C,A); rs371496263(C,T); rs4833879(T,G); rs183307925(A,C); rs159989(A,G); rs3899083(T,C); rs303099(G,A); rs12639743(C,T); rs13108144(C,T); rs13108348(C,T); rs4446330(C,T); rs4619905(A,G); rs303100(T,C); rs28432673(A,G); rs303101(G,T); rs28492927(T,G); rs303102(C,G); rs9996924(G,A); rs371610434(G,A); rs17006653(A,T); rs304634(G,T); rs369872147(G,A); rs304635(C,T); rs304637(A,G); rs167353(T,C); rs376750906(A,G); rs373467039(C,T); rs160056(C,G); rs10000771(G,C); rs4833880(C,G); rs159990(T,G); rs115960718(T,C); rs4833881(T,G); rs116537704(G,A); rs216100(A,G); rs80233658(G,A); rs149240(G,A); rs73845047(A,G); rs72680852(G,A); rs72680854(G,A); rs303104(T,A); rs303105(C,G); rs62324561(A,G); rs115557805(A,C); rs445176(G,A); rs28375064(C,T); rs2561151(C,A); rs58531879(G,A); rs10005627(G,T); rs146851793(G,A); rs143711318(T,C); rs7356282(C,T); rs11946394(A,G); rs304672(A,G); rs304673(A,G); rs74330756(G,A); rs304676(T,G); rs11944115(T,C); rs11939366(G,T); rs115504686(A,G); rs303135(G,A); rs303136(A,G); rs303137(A,G); rs73845050(C,T); rs72680859(T,C); rs77488168(C,T); rs11732505(C,G); rs160058(A,G); rs140358117(G,T); rs7681254(T,C); rs7657654(C,T); rs303138(C,G); rs160059(T,A); rs73845051(G,A); rs160060(G,A); rs4479722(A,G); rs303142(T,G); rs115898682(G,A); rs143245114(C,G); rs76259472(A,T); rs147516634(A,G); rs78187741(A,G); rs302518(C,A); rs302519(G,T); rs302520(T,A); rs302521(A,G); rs302522(A,G); rs79724756(A,G); rs304696(A,T); rs140085048(G,A); rs114543395(G,A); rs11946773(C,A); rs145734628(C,T); rs141805535(C,T); rs147125834(C,T); rs146288959(C,T); rs184544255(G,T); rs149924389(T,C); rs145011014(G,C); rs7695079(C,A); rs11946212(C,T); rs302529(C,T); rs302530(T,C); rs61144116(C,T); rs302531(G,T); rs302533(A,C); rs28622988(T,A); rs17006701(T,A); rs28482022(G,T); rs302512(T,C); rs72680868(G,T); rs7692997(C,G); rs302511(T,C); rs4336244(C,G); rs75684369(A,C); rs302509(G,A); rs116009090(A,G); rs302508(A,G); rs77121911(A,G); rs75635024(A,G); rs78799953(A,G); rs302507(G,A); rs2120516(C,T); rs182554475(C,T); rs2166027(C,T); rs11940736(T,C); rs11098699(C,G); rs72680873(G,A); rs7678219(A,G); rs16997745(A,G); rs991183(G,A); rs111551457(C,G); rs112689654(A,G); rs2221171(T,C); rs4833883(A,G); rs76937921(A,G); rs6839115(T,G); rs4833884(G,A); rs4833268(C,A); rs7663175(G,T); rs7662711(A,T); rs11944698(A,G); rs35206443(G,T); rs73845064(A,C); rs2201997(G,T); rs12108584(T,C); rs149274337(C,A); rs6534392(T,C); rs115498535(T,G); rs76843533(C,T); rs115963921(C,T); rs302534(A,T); rs72680892(A,G); rs78239964(C,G); rs7669991(G,A); rs7670452(C,T); rs57716228(T,C); rs145432515(G,A); rs11735364(T,C); rs79497103(C,G); rs116168765(C,T); rs67815781(G,A); rs11945343(G,A); rs67773307(G,A); rs67547538(G,A); rs76018596(G,C); rs75066165(G,C); rs59922378(T,C); rs78877826(C,A); rs2028717(G,T); rs114806116(C,A); rs72682705(G,A); rs114773802(C,T); rs1031135(C,T); rs11098700(G,C); rs1031134(G,A); rs302517(G,T); rs144722390(C,T); rs1031133(G,C); rs17744570(C,A); rs72914052(A,G); rs302516(G,A); rs116757893(A,G); rs112042792(C,T); rs114009189(G,A); rs6857271(G,A); rs13120866(A,G); rs11942230(A,G); rs79963326(T,G); rs4645220(C,T); rs115662143(A,G); rs77920014(G,A); rs7665617(G,C); rs7665722(A,G); rs931708(G,A); rs931707(G,A); rs931706(T,G); rs6835053(A,G); rs6812920(T,G); rs72682720(G,T); rs79133823(A,T); rs114309270(G,C); rs1562063(G,A); rs76655102(T,C); rs931705(C,T); rs302543(G,C); rs11947137(C,G); rs13148385(A,G); rs17006770(C,T); rs4833886(A,C); rs141991954(A,G); rs11939262(A,G); rs11935129(T,A); rs7684146(C,A); rs7684799(C,T); rs4833887(T,C); rs4833888(T,G); rs11941747(A,G); rs78880429(T,C); rs13109534(T,C); rs302537(C,A); rs11734868(A,G); rs28608043(C,T); rs140426842(G,A); rs148995406(T,C); rs13141181(G,A); rs13116874(T,C); rs74885537(A,G); rs77035223(A,G); rs2099955(C,T); rs2083935(A,C); rs28478182(T,A); rs17006775(G,A); rs6812009(A,G); rs11098701(C,G); rs77408554(G,A); rs72682732(G,T); rs11945458(A,G); rs11936355(C,T); rs13114886(T,A); rs373911740(A,G); rs4833890(G,C); rs11098703(C,G); rs302540(T,C); rs6832852(A,G); rs6833383(G,T); rs6833050(A,G); rs74340512(G,A); rs302541(A,G); rs1500122(A,C); rs13110588(G,A); rs78635238(A,G); rs11731898(C,A); rs80281381(T,G); rs147180936(G,A); rs138877448(A,G); rs6811630(G,A); rs302535(G,T); rs6811839(G,A); rs79329203(A,T); rs115105971(A,G); rs114156840(G,C); rs79620219(A,G); rs74915014(C,T); rs904712(T,C); rs6851102(A,G); rs60122285(A,G); rs11098704(A,G); rs66848469(G,T); rs13136692(G,A); rs11726870(A,G); rs112740272(C,T); rs11098705(C,T); rs11098706(A,G); rs113086206(G,A); rs12500715(T,C); rs6830258(G,A); rs6830451(G,A); rs138515990(T,C); rs6835952(A,C); rs6835971(A,G); rs72915845(G,A); rs4833891(T,C); rs17006799(A,G); rs2047585(A,G); rs2047584(A,T); rs2047583(C,T); rs2047582(C,A); rs151281956(G,A); rs112601155(A,G); rs2047202(C,G); rs114542642(G,A); rs169950(T,C); rs2047201(C,T); rs73845079(G,T); rs72682747(C,T); rs4833892(A,G); rs11930165(C,G); rs72915872(A,G); rs6534393(T,C); rs7674700(T,C); rs143039469(G,A); rs6832894(T,C); rs74724396(C,T); rs1048476(A,G); rs114141981(T,A); rs147279670(T,C); rs2132078(G,A) |
| ccdsGene name | CCDS3730.1 |
| cytoBand name | 4q28.1 |
| EntrezGene GeneID | 166378 |
| EntrezGene Description | spermatogenesis associated 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SPATA5:NM_145207:exon15:c.G2485T:p.D829Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.638 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0034965034965 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.001816 |
| ESP All MAF | 0.004229 |
| ESP Eur/Amr MAF | 0.005465 |
| ExAC AF | 0.01 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Multifactorial
NEUROLOGIC:
[Central nervous system];
Walking during slow-wave sleep (sleepwalking);
Sudden arousal from slow-wave sleep with screaming, autonomic, and
behavioral manifestations of intense fear (sleep terrors)
MISCELLANEOUS:
Onset of sleepwalking between 4 and 8 years old;
Sleepwalking usually remits in adolescence;
Prevalence of sleepwalking up to 26% in childhood;
Prevalence of sleepwalking about 3% in adults;
Sleepwalking triggered by alcohol, sleep deprivation, stress;
Onset of sleep terrors between age 4 and 12 years old;
Sleep terrors usually remit during adolescence;
Prevalence of sleep terrors about 3% in children;
Prevalence of sleep terrors less than 1% in adults;
Affected individuals have amnesia for events
OMIM Title
*613940 SPERMATOGENESIS-ASSOCIATED PROTEIN 5; SPATA5
;;SPERMATOGENESIS-ASSOCIATED FACTOR; SPAF
OMIM Description
CLONING
Liu et al. (2000) cloned mouse Spata5, which they called Spaf. The
deduced 892-amino acid protein contains a putative mitochondrial
localization signal and 2 ATPase modules typical of AAA family proteins
(see 601681). Northern blot analysis of mouse tissues detected high
expression of a 3-kb Spaf transcript in testis, with much weaker
expression in spleen and little to no expression in other tissues
examined. Spaf was also highly expressed as 3- and 1.7-kb transcripts in
mouse 03RAT cells, which were derived from a poorly differentiated
squamous cell carcinoma. Immunohistochemical analysis detected Spaf in
prepubertal and adult mouse testis, where it was expressed in
spermatogonia and early spermatocytes up to the zygotene stage. Spaf was
not detected in somatic cells of testis. Spaf distributed diffusely
throughout the cytoplasm of germ cells and also localized to
mitochondria. Western blot analysis detected endogenous and in
vitro-translated Spaf at an apparent molecular mass of 97 kD.
MAPPING
Hartz (2011) mapped the SPATA5 gene to chromosome 4q28.1 based on an
alignment of the SPATA5 sequence (GenBank GENBANK AF361489) with the
genomic sequence (GRCh37).
TNRC18P1
| dbSNP name | rs35060427(G,T); rs116174196(A,G); rs10033976(C,A); rs59742217(C,T); rs12642653(A,G); rs59439529(A,G); rs6537003(T,G) |
| ccdsGene name | CCDS47136.1 |
| cytoBand name | 4q31.21 |
| EntrezGene GeneID | 644962 |
| snpEff Gene Name | TBC1D9 |
| EntrezGene Description | TNRC18P1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4073 |
SMARCA5-AS1
| dbSNP name | rs1510882(A,G) |
| ccdsGene name | CCDS3761.1 |
| cytoBand name | 4q31.21 |
| EntrezGene GeneID | 100128055 |
| snpEff Gene Name | SMARCA5 |
| EntrezGene Description | SMARCA5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1777 |
GUSBP5
| dbSNP name | rs17017911(G,A); rs375420078(C,A); rs77865740(A,G); rs1055373(C,A) |
| cytoBand name | 4q31.21 |
| EntrezGene GeneID | 441046 |
| snpEff Gene Name | SMARCA5 |
| EntrezGene Description | glucuronidase, beta pseudogene 5 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3219 |
POU4F2
| dbSNP name | rs3827594(C,G); rs61733420(G,T); rs6825713(G,A) |
| ccdsGene name | CCDS34074.1 |
| cytoBand name | 4q31.22 |
| EntrezGene GeneID | 5458 |
| EntrezGene Description | POU class 4 homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POU4F2:NM_004575:exon2:c.C924G:p.S308S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09963 |
| ESP Afr MAF | 0.157059 |
| ESP All MAF | 0.108181 |
| ESP Eur/Amr MAF | 0.08314 |
| ExAC AF | 0.081 |
MAB21L2
| dbSNP name | rs4696537(G,C); rs72959811(C,T); rs13105060(T,A) |
| ccdsGene name | CCDS3773.1 |
| cytoBand name | 4q31.3 |
| EntrezGene GeneID | 10586 |
| snpEff Gene Name | LRBA |
| EntrezGene Description | mab-21-like 2 (C. elegans) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1961 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Seizures, generalized, associated with fever;
Generalized tonic-clonic seizures;
Hypertonic seizures;
Hypotonic seizures;
Seizures occur in absence of intracranial infection or defined pathologic
or traumatic cause;
Seizures usually last less than 15 minutes;
Seizures recur in 33% of patients;
Patients show normal psychomotor development;
Between 2 and 7% of children will develop afebrile seizure disorders
later in life
MISCELLANEOUS:
Onset 3 months of age up to 5 years;
Seizures remit by age 5 years;
Genetic heterogeneity (see FEB1 121210);
Mutation in the MASS1 gene has been identified in 1 of 48 families
with familial febrile seizures linked to 5q14
MOLECULAR BASIS:
Caused by mutation in the homolog of the mouse monogenic, audiogenic
seizure susceptibility 1 gene (MASS1, 602851.0001)
OMIM Title
*604357 MAB21, C. ELEGANS, HOMOLOG-LIKE 2; MAB21L2
OMIM Description
CLONING
The C. elegans mab21 cell fate specification gene participates in the
formation of sensory organs in the male nematode tail and is essential
for other developmental functions elsewhere in the C. elegans embryo.
MAB21L1 (601280), a human homolog of the C. elegans mab21 gene, has been
cloned and partially characterized. Mariani et al. (1999) cloned and
characterized the human MAB21L2 gene and the murine Mab21l1 and Mab21l2
genes, all of which are homologs of the C. elegans mab21 gene. The 2
mammalian genes, which encode 41-kD nuclear basic proteins of 359 amino
acids, are expressed in partially overlapping territories in the
embryonic brain, eye, and limbs, as well as in neural crest derivatives.
Based on genetic data implicating mab21 as a downstream target of
transforming growth factor-beta (TGFB1; 190180) signaling, together with
the distribution of Mab21 transcripts in the mouse embryo, Mariani et
al. (1999) proposed that these novel genes are relevant factors in
various aspects of vertebrate neural development.
Using optical projection tomography in addition to bright-field imaging,
Rainger et al. (2014) examined expression of Mab21l2 in mouse embryos at
10.5 days postcoitum and observed strong expression in the rostral and
distal regions of the developing neural retina, with no expression
immediately adjacent to the closing optic fissure. Expression was also
observed in the dorsal and ventral aspects of the developing forelimb
bud and in the developing pharyngeal arches, as well as in the midbrain.
MAPPING
By PCR screening of a YAC library and by FISH, Mariani et al. (1999)
mapped the MAB21L2 gene to chromosome 4q31. They mapped the murine
Mab21l2 gene to chromosome 3, in a region showing homology of synteny
with human 4q31, by haplotype and linkage analysis of a backcross DNA
panel.
MOLECULAR GENETICS
In 3 independent exome-sequencing projects, Rainger et al. (2014)
identified 4 different missense mutations in the MAB21L2 gene in 8
patients from 5 unrelated families with bilateral clinical anophthalmia
or microphthalmia and coloboma, with or without rhizomelic skeletal
dysplasia (MCOPS14; 615877). The mutations segregated with the disease
in each family and were not found in public databases, including those
of the 1000 Genomes Project and the NHLBI Exome Variant Server. In 4 of
the families, the mutations were heterozygous and located near each
other, involving R51 in 3 families (R51H, 604357.0001; R51C,
604357.0002) and E49 (E49K; 604357.0003) in 1 family; however, 2
brothers born of consanguineous parents were homozygous for an R247Q
mutation (604257.0004) for which their unaffected parents were both
heterozygous. Rainger et al. (2014) stated that the restricted
repertoire of mutations in the monoallelic cases strongly suggested an
unusual genetic mechanism beyond simple loss of function; they further
noted that the 2 patients with homozygous mutations were the least
severely affected. All 4 mutations resulted in complete loss of the
single-stranded RNA (ssRNA)-binding activity observed with wildtype
MAB21L2, and the 3 heterozygous mutations showed significant
stabilization of the protein compared to wildtype or the R247Q mutant.
On immunoblot analysis, induction of wildtype MAB21L2 consistently
resulted in an approximately 1.5-fold increase in phospho-ERK1 (MAPK3;
601795), and a similar level of induction was observed with the R51H
substitution; the combination of protein stabilization and phospho-ERK1
induction suggested that the monoallelic MAB21L2 mutations might be
activating mutations.
DKFZP434I0714
| dbSNP name | rs1351902(A,T); rs28716085(A,G) |
| cytoBand name | 4q31.3 |
| EntrezGene GeneID | 54553 |
| snpEff Gene Name | FBXW7 |
| EntrezGene Description | uncharacterized protein DKFZP434I0714 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4059 |
TKTL2
| dbSNP name | rs11735477(T,A); rs114733407(A,G) |
| ccdsGene name | CCDS3805.1 |
| CosmicCodingMuts gene | TKTL2 |
| cytoBand name | 4q32.2 |
| EntrezGene GeneID | 84076 |
| EntrezGene Description | transketolase-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TKTL2:NM_032136:exon1:c.A1770T:p.Q590H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H0I9 |
| dbNSFP Uniprot ID | TKTL2_HUMAN |
| dbNSFP KGp1 AF | 0.192307692308 |
| dbNSFP KGp1 Afr AF | 0.144308943089 |
| dbNSFP KGp1 Amr AF | 0.0883977900552 |
| dbNSFP KGp1 Asn AF | 0.284965034965 |
| dbNSFP KGp1 Eur AF | 0.203166226913 |
| dbSNP GMAF | 0.1919 |
| ESP Afr MAF | 0.160009 |
| ESP All MAF | 0.176303 |
| ESP Eur/Amr MAF | 0.184651 |
| ExAC AF | 0.167 |
ANP32C
| dbSNP name | rs2288675(C,T); rs2288674(G,A) |
| cytoBand name | 4q32.3 |
| EntrezGene GeneID | 55016 |
| EntrezGene Symbol | MARCH1 |
| snpEff Gene Name | MARCH1 |
| EntrezGene Description | membrane-associated ring finger (C3HC4) 1, E3 ubiquitin protein ligase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ANP32C:NM_012403:exon1:c.G212A:p.R71K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.281 |
| ESP Afr MAF | 0.162052 |
| ESP All MAF | 0.381593 |
| ESP Eur/Amr MAF | 0.49407 |
| ExAC AF | 0.424 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Dysconjugate gaze;
Esotropia;
Nystagmus;
Strabismus;
Exotropia
MUSCLE, SOFT TISSUE:
Increased muscle tone
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Psychomotor delay;
Mental retardation, moderate to severe;
Increased muscle tone;
Hyperreflexia;
Extensor plantar responses;
Ankle clonus;
Seizures;
Cerebellar signs;
Pyramidal signs;
Wide-based gait;
Truncal ataxia;
Finger dysmetria;
Polymicrogyria, most severe in the frontoparietal regions;
Polymicrogyria, anterior to posterior gradient;
Areas of dysmyelination on MRI;
Brainstem hypoplasia;
Cerebellar hypoplasia
MOLECULAR BASIS:
Caused by mutation in the G protein-coupled receptor 56 gene (GPR56,
604110.0001)
OMIM Title
*606877 ACIDIC LEUCINE-RICH NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER C; ANP32C
;;PP32R1
OMIM Description
CLONING
Kadkol et al. (1999) identified and cloned ANP32C and ANP32D (606878),
which they called PP32R1 and PP32R2, respectively, by RT-PCR of
prostatic adenocarcinoma amplified with primers for PP32 (600832).
ANP32C, ANP32D, and PP32 share approximately 90% amino acid sequence
identity.
GENE FUNCTION
Kadkol et al. (1999) determined that, whereas PP32 is a tumor
suppressor, both ANP32C and ANP32D are tumorigenic. ANP32C and ANO32D
were able to stimulate transformed focus formation when cotransfected
into NIH 3T3 cells along with tumor promoters. NIH 3T3 cells transformed
with ANP32C and ANP32D were also tumorigenic in nude mice. Kadkol et al.
(1999) suggested that the alternative use of the PP32, ANP32C, and
ANP32D genes may modulate the oncogenic potential of human prostate
cancer.
Brody et al. (1999) determined that the region of PP32 spanning amino
acids 150 to 174 is responsible for its tumor suppressor activity, and
that this is a region of divergence between PP32 and ANP32C.
GENE STRUCTURE
Kadkol et al. (1999) stated that the ANP32C gene is intronless.
MAPPING
By PCR analysis of a monochromosomal panel followed by sequence
confirmation, Kadkol et al. (1999) mapped the ANP32C gene to chromosome
4.
MOLECULAR GENETICS
Kochevar et al. (2004) found that PP32R1 expression levels vary among
human tumor cell lines, with the highest levels found in prostatic
adenocarcinoma cell lines. It also appears to be polymorphic at
nucleotides 4520 and 4664 in human tobacco-associated oral mucosal
lesions, human fibroblast cell lines, and several carcinoma cell lines.
PC3 human prostatic adenocarcinoma cells likewise appeared to be
polymorphic at these loci, but additionally contained a 4870T-C
transversion, resulting in a tyr140-to-his (Y140H) substitution. The
Y140H substitution lies in a functionally important region of the
molecule. In the PC3 prostate cancer line, Kochevar et al. (2004) found
that the Y140H substitution was either homozygous or hemizygous and
accompanied by loss of heterozygosity. ACHN cells stably transfected
with PP32R1 containing the Y140H substitution showed a markedly
increased rate of growth. Kochevar et al. (2004) concluded that the
Y140H substitution could thus be causally associated with the neoplastic
growth properties of PC3.
MIR6082
| dbSNP name | rs28570267(C,T); rs28393763(C,A) |
| cytoBand name | 4q34.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03352 |
| ExAC AF | 0.012 |
HAND2
| dbSNP name | rs76525259(A,C) |
| cytoBand name | 4q34.1 |
| EntrezGene GeneID | 9464 |
| EntrezGene Description | heart and neural crest derivatives expressed 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0427 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Teeth];
Misshapen teeth;
Large teeth;
Irregular teeth;
Missing teeth
SKIN, NAILS, HAIR:
[Skin];
Normal sweating;
[Nails];
Dystrophic fingernails;
Dystrophic toenails;
Thin, flat fingernail plates;
[Hair];
Thin body hair;
Fine scalp hair;
Thin scalp hair;
Sparse scalp hair (in some patients);
Hairs can be painlessly plucked with little force;
Sparse or absent eyebrows;
Sparse or absent eyelashes
MISCELLANEOUS:
One Pakistani family reported (last curated November 2012)
OMIM Title
*602407 HEART- AND NEURAL CREST DERIVATIVES-EXPRESSED 2; HAND2
;;HLH TRANSCRIPTION FACTOR HAND2;;
DECIDUUM, HEART, AUTONOMIC NERVOUS SYSTEM, NEURAL CREST-DERIVED; DHAND2;;
DHAND
OMIM Description
DESCRIPTION
The HAND2 gene encodes a basic helix-loop-helix (bHLH) transcription
factor that is expressed in heart (Russell et al., 1998).
CLONING
Using murine Hand1 (602406) as query in a genomic database screen,
followed by PCR and conventional hybridization, Russell et al. (1998)
cloned HAND2 from a fetal cardiac cDNA library. The deduced protein
contains 217 amino acids. HAND2 has a conserved N-terminal polyalanine
tract and several potential phosphorylation sites. It shares 100% amino
acid identity with a partial rat Hand2 protein. HAND2 also shares 92%
and 97% identity with chicken and mouse Hand2, with 100% amino acid
identity within the bHLH region. Northern blot analysis of several human
tissues detected robust expression of a 2.3-kb transcript in heart.
GENE FUNCTION
Srivastava et al. (1997) demonstrated that Hand2 is required for
formation of the right ventricle of the heart and the aortic arch
arteries in mouse.
Using mammalian 1-hybrid analysis, Dai and Cserjesi (2002) demonstrated
that mouse Hand2 contains a strong transcriptional activation domain in
the N-terminal third of the protein. Recombinant and in vitro translated
Hand2 could form homodimers under some conditions, and it
heterodimerized with E12 (TCF3; 147141). Electrophoretic mobility shift
assay indicated that the Hand2-E12 heterodimer bound several E-box DNA
sequences, while neither transcription factor alone bound DNA.
Dai et al. (2002) provided evidence that mammalian Hand2 interacts with
GATA4 (600576) and p300 (602700) to activate expression via
cardiac-specific promoters. Mutation analysis revealed that the bHLH
domain of Hand2 physically interacted with the C-terminal zinc finger
domain of GATA4. The bHLH domain of Hand2 also interacted with the CH3
domain of p300. Transcriptional synergy between Hand2 and Gata4 required
p300 recruitment.
Using an algorithm for microRNA target identification that incorporates
features of RNA structure and target accessibility, Zhao et al. (2005)
showed that HAND2, a transcription factor that promotes ventricular
cardiomyocyte expansion, is a target of microRNA-1 (miR-1; 609326). The
work of Zhao et al. (2005) suggested that miR-1 genes titrate the
effects of critical cardiac regulatory proteins to control the balance
between differentiation and proliferation during cardiogenesis.
Li et al. (2011) demonstrated that progesterone-induced expression of
the basic helix-loop-helix transcription factor Hand2 in the uterine
stroma suppresses the production of several fibroblast growth factors
(FGFs) that act as paracrine mediators of mitogenic effects of estrogen
on the epithelium. In mouse uteri lacking Hand2, continued induction of
these FGFs in the stroma maintained epithelial proliferation and
stimulated estrogen-induced pathways, resulting in impaired
implantation. Thus, Li et al. (2011) concluded that HAND2 is a critical
regulator of the uterine stromal-epithelial communication that directs
proper steroid regulation conducive for the establishment of pregnancy.
MAPPING
By radiation hybrid analysis, Russell et al. (1998) mapped the HAND2
gene to chromosome 4q33.
ANIMAL MODEL
Reciprocal interactions between vascular endothelial cells and vascular
mesenchymal cells are essential for angiogenesis. Yamagishi et al.
(2000) showed that Hand2 is expressed in the developing vascular
mesenchyme and its derivative, vascular smooth muscle cells (VSMCs).
Targeted deletion of the Hand2 gene in mice revealed severe defects of
embryonic and yolk sac vascular development by embryonic day 9.5.
Vascular endothelial cells expressed most markers of differentiation.
Vascular mesenchymal cells migrated appropriately but failed to make
contact with vascular endothelial cells and did not differentiate into
VSMCs. In a screen for genes whose expression was dependent upon Hand2
(using subtractive hybridization comparing wildtype and Hand2-null
hearts), neuropilin-1 (NRP1; 602069), the receptor for the 165-amino
acid form of vascular endothelial growth factor (VEGF; 192240), was
found to be downregulated in Hand2 mutants. These results suggested that
HAND2 is required for vascular development and regulates angiogenesis,
possibly through a VEGF signaling pathway.
Charite et al. (2001) stated that Hand2 is essential for craniofacial
development in mouse and that deletion of Hand2 causes early embryonic
lethality. They found that expression of a Hand2 reporter was completely
absent in branchial arches 1 and 2 of mouse embryos lacking endothelin
receptor A (EDNRA; 131243), although Hand2 expression in other areas,
including heart, was unaffected in Ednra -/- embryos. Charite et al.
(2001) identified a conserved functional ATTA motif within the 5-prime
UTR of the Hand2 upstream region that was bound by Dlx6 (600030), but
not Dlx5 (600028) or Dlx2 (126255), in an Ednra-dependent manner. In
addition, Dlx6 expression was undetectable in the first branchial arch
in Ednra -/- embryos, whereas Dlx6 expression in more proximal regions
appeared independent of Ednra signaling. Charite et al. (2001) concluded
that Dlx6, Hand2, and Ednra signaling is involved in a complex
regulatory program for craniofacial development in mouse.
Villanueva et al. (2002) found that expression of nebulette (605491)
decreased about 4-fold in the hearts of Hand2-null mice.
Ruest et al. (2004) presented evidence that residual Hand2 expression
detected in the distal mandibular arch region in Ednra -/- and Dlx5 -/-
Dlx6 -/- mouse embryos contributes to lower incisor formation
independent of Ednra and Dlx5/Dlx6 expression.
In mice with conditional deletion of Gata4 early in cardiac
morphogenesis, Zeisberg et al. (2005) observed hearts with striking
myocardial thinning, absence of mesenchymal cells within the endocardial
cushions, and selective hypoplasia of the right ventricle, highly
reminiscent of the phenotype of Hand2-null embryos. In situ
hybridization studies revealed that Hand2 transcripts were decreased
compared to those in controls. Zeisberg et al. (2005) concluded that
normal expression of HAND2 requires GATA4.
FAM92A1P2
| dbSNP name | rs6834900(C,T); rs2016910(T,G); rs1075695(C,G); rs1075694(A,T); rs2603345(G,T); rs2603344(T,G); rs17275540(G,A) |
| cytoBand name | 4q35.1 |
| EntrezGene GeneID | 403315 |
| snpEff Gene Name | FAM92A3 |
| EntrezGene Description | family with sequence similarity 92, member A3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01148 |
CLDN22
| dbSNP name | rs4862156(T,G) |
| cytoBand name | 4q35.1 |
| EntrezGene GeneID | 80014 |
| EntrezGene Symbol | WWC2 |
| snpEff Gene Name | CLDN24 |
| EntrezGene Description | WW and C2 domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01791 |
CLDN24
| dbSNP name | rs6839940(C,G); rs7688467(G,A) |
| ccdsGene name | CCDS54824.1 |
| cytoBand name | 4q35.1 |
| EntrezGene GeneID | 100132463 |
| EntrezGene Description | claudin 24 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN24:NM_001185149:exon1:c.G621C:p.Q207H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.22206959707 |
| dbNSFP KGp1 Afr AF | 0.19512195122 |
| dbNSFP KGp1 Amr AF | 0.157458563536 |
| dbNSFP KGp1 Asn AF | 0.229020979021 |
| dbNSFP KGp1 Eur AF | 0.265171503958 |
| dbSNP GMAF | 0.2227 |
| ExAC AF | 0.147 |
CDKN2AIP
| dbSNP name | rs73870525(A,G); rs73870526(A,G); rs73870527(G,A); rs73870528(G,A); rs3187025(G,A) |
| ccdsGene name | CCDS34110.1 |
| cytoBand name | 4q35.1 |
| EntrezGene GeneID | 55602 |
| EntrezGene Description | CDKN2A interacting protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CDKN2AIP:NM_017632:exon3:c.A774G:p.Q258Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0101 |
| ESP Afr MAF | 0.045166 |
| ESP All MAF | 0.015301 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.004245 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Sensorineural deafness (in some patients);
[Eyes];
Ptosis (uncommon)
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Proximal muscle weakness (in some patients);
Ragged red fibers seen on biopsy;
Cytochrome c oxidase deficiency;
Lipid and glycogen accumulation;
Mitochondrial DNA deletions;
Abnormal mitochondria morphology;
Fragmented mitochondrial network;
Paracrystalline inclusions;
Combined mitochondrial respiratory chain deficiency (in most patients)
NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia;
Dysarthria;
Bulbar weakness;
Frontal lobe dementia;
Motor neuron disease;
Extensor plantar responses;
Parkinsonism (less common);
Cortical atrophy (in some patients);
[Peripheral nervous system];
Hyporeflexia;
Areflexia
MISCELLANEOUS:
Two unrelated families have been reported (last curated July 2014);
Late-adult onset (usually after age 50 years);
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the coiled-coil-helix-coiled-coil helix domain-containing
protein 10 gene (CHCHD10, 615903.0001)
OMIM Title
*615914 CYCLIN-DEPENDENT KINASE INHIBITOR 2A-INTERACTING PROTEIN; CDKN2AIP
;;CDKN2A-INTERACTING PROTEIN;;
COLLABORATOR OF ARF; CARF
OMIM Description
DESCRIPTION
CDKN2AIP plays a central role in DNA damage response and influences a
number of signaling pathways involved in cell proliferation, apoptosis,
and senescence (Cheung et al., 2014).
CLONING
Using p19(ARF) (CDKN2A; 600160) as bait in a yeast 2-hybrid screen of a
human testis cDNA library, Hasan et al. (2002) cloned CDKN2AIP, which
they designated CARF. The deduced 580-amino acid protein is serine rich
(21%) and has a calculated molecular mass of 61 kD. In human, mouse, and
monkey cells, CARF localized to the nucleoplasm and appeared to be
excluded from the core of the nucleolus. SDS-PAGE detected CARF at an
apparent molecular mass near 84 kD.
GENE FUNCTION
Using coimmunoprecipitation and protein pull-down assays, Hasan et al.
(2002) confirmed interaction between CARF and p14(ARF), whether the
proteins were epitope-tagged or endogenous. CARF and p14(ARF)
colocalized predominantly at the periphery of the nucleolus in several
mammalian cell lines. Overexpression and knockdown studies revealed that
ARF and CARF stabilize each other. In addition, knockdown of CARF
reduced p14(ARF)-mediated increases in p53 (TP53; 191170) and p21
(CDKN1A; 116899). Coexpression of CARF and/or p14(ARF) reduced colony
number in U2OS cells in an additive manner. Hasan et al. (2002)
concluded that CARF is a novel regulator of the p19(ARF)-MDM2
(164785)-p53 senescence pathway.
Cheung et al. (2014) reported that CARF can bind p53 directly as well as
regulate it to induce cellular senescence and apoptosis independent of
p19(ARF). They also stated that suppression of CARF can lead to
aneuploidy, DNA damage, mitotic catastrophe, and apoptosis through the
ATR (601215)-CHK1 (CHEK1; 603078) pathway. Using overexpressing and
superexpressing human cell lines, Cheung et al. (2014) found that
moderate CARF overexpression induced senescence, whereas very high
expression increased cell proliferation. A critical level of CARF was
required to maintain genomic integrity, and deregulation of CARF led to
loss of DNA damage response through the ATM (607585)-CHK1-CHK2 (CHEK2;
604373), p53, and ERK (see 601795) pathways, causing either mitotic
catastrophe and apoptosis, or enhanced proliferation and malignant
transformation.
MAPPING
Hasan et al. (2002) reported that the CDKN2AIP gene maps to chromosome
4.
Hartz (2014) mapped the CDKN2AIP gene to chromosome 4q35.1 based on an
alignment of the CDKN2AIP sequence (GenBank GENBANK AK000043) with the
genomic sequence (GRCh38).
FLJ38576
| dbSNP name | rs1877319(G,A); rs7696703(G,A); rs34233508(A,T); rs4862660(G,A); rs184461082(C,T); rs4862661(A,G); rs35575344(C,T); rs35168015(A,G); rs28465054(A,C); rs28545770(G,A); rs10001084(C,G); rs6813815(C,T); rs6813694(A,C); rs35641294(G,A) |
| cytoBand name | 4q35.2 |
| EntrezGene GeneID | 651430 |
| snpEff Gene Name | CYP4V2 |
| EntrezGene Description | uncharacterized LOC651430 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.472 |
C5orf55
| dbSNP name | rs2672776(T,C); rs2671892(A,G); rs10035612(G,C) |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 116349 |
| snpEff Gene Name | AHRR |
| EntrezGene Description | chromosome 5 open reading frame 55 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4417 |
PP7080
| dbSNP name | rs1053299(G,A); rs890973(T,C) |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 25845 |
| snpEff Gene Name | CTD-2228K2.5 |
| EntrezGene Description | uncharacterized LOC25845 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2176 |
SLC12A7
| dbSNP name | rs1058508(T,C); rs3810853(G,A); rs3810854(C,T); rs150136345(C,T); rs2241601(G,C); rs10063723(G,A); rs2241602(A,G); rs2241603(C,G); rs4975572(C,T); rs73026788(C,T); rs140336994(C,T); rs142697615(T,C); rs73026791(G,A); rs2115283(C,T); rs2115284(G,A); rs185798132(C,A); rs4365871(T,G); rs73026795(G,A); rs28524573(A,G); rs2241604(C,T); rs140304822(C,T); rs2241605(G,A); rs2241606(A,G); rs60281693(G,A); rs56128821(G,A); rs35791340(C,T); rs11133608(C,T); rs10056336(A,G); rs10058105(T,C); rs34036146(G,C); rs6859798(C,T); rs73028810(T,G); rs4505991(C,T); rs4275011(G,C); rs4291057(T,A); rs13152999(G,A); rs4571515(A,G); rs4308515(G,A); rs113686383(T,G); rs4975699(C,G); rs35661060(G,A); rs4975568(G,A); rs4246750(C,T); rs4246749(G,A); rs2241608(G,A); rs4975567(G,A); rs113303019(T,A); rs78533651(T,A); rs11956454(G,A); rs10056989(C,T); rs2334955(G,A); rs13170649(C,G); rs6863419(T,C); rs12657777(G,A); rs78129596(C,T); rs737154(C,T); rs56078134(A,C); rs13186367(C,T); rs7737804(G,A); rs4975566(C,G); rs4975695(G,A); rs12515500(C,A); rs3789198(A,C); rs3789199(A,G); rs4975694(A,C); rs3789202(C,T); rs3789203(G,A); rs182512144(G,C); rs73731151(C,A); rs10780095(C,T); rs12523242(A,C); rs41280366(C,T); rs7714914(G,A); rs11133613(A,G); rs115389597(G,A); rs6866735(T,C); rs11952124(G,T); rs74673540(C,T); rs4975685(C,G); rs6879334(G,A); rs6865765(A,G); rs4526148(C,T); rs75852888(A,G); rs4999131(T,C); rs10474882(G,A); rs114013202(C,T); rs7722436(A,G); rs7727079(T,C); rs7709347(C,T); rs77314253(G,A); rs4975669(A,G); rs6869234(A,G); rs10054219(A,G); rs4073269(T,C); rs75090992(T,G); rs140769727(C,T); rs73028879(G,A); rs79689524(C,T); rs4975663(A,G); rs6864667(G,A); rs78626155(G,A); rs149435304(C,T); rs6866158(C,T); rs57559281(G,A); rs4975658(A,G); rs6554595(C,T); rs7721352(G,A); rs6883411(C,G); rs6883412(C,T); rs4975550(T,C); rs4975549(C,T); rs146192391(G,A); rs57354118(C,T); rs78812676(T,C); rs59946080(A,G); rs111301377(G,A); rs73028891(C,T); rs73028895(G,A); rs6871378(T,C); rs67037922(A,G); rs6867513(A,G); rs28676483(C,T); rs4975652(C,A); rs4975651(G,A); rs4975650(C,T); rs35832527(T,C); rs6879835(A,C); rs6862111(G,C); rs57803195(C,G); rs58030542(C,T); rs10067280(C,T); rs4502870(C,T); rs6894574(T,C); rs55950426(C,T); rs146612790(G,A); rs7715723(C,T); rs35188965(C,T); rs10044441(C,A); rs7708161(A,G); rs4535497(C,A); rs4975643(G,A); rs76310640(C,T); rs4565255(T,C); rs4639275(C,G); rs73031117(C,T); rs6874041(C,T); rs75473167(C,T); rs6864465(T,C) |
| ccdsGene name | CCDS34129.1 |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 10723 |
| EntrezGene Description | solute carrier family 12 (potassium/chloride transporter), member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC12A7:NM_006598:exon4:c.G350A:p.R117H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5454 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y666 |
| dbNSFP Uniprot ID | S12A7_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 8.143e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
*604879 SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER
7; SLC12A7
;;POTASSIUM-CHLORIDE COTRANSPORTER 4; KCC4
OMIM Description
Cation chloride cotransporters, including the potassium-chloride
cotransporters (KCCs), are involved in the electroneutral movement of
ions across the plasma membrane. Under most physiologic conditions, KCCs
function as efflux pathways (Mount et al., 1999).
CLONING
By searching EST databases, Mount et al. (1999) identified a cDNA
encoding SLC12A7, which they initially termed KCC3 but later renamed
KCC4. The deduced 1,083-amino acid SLC12A7 protein contains 12
membrane-spanning segments, 8 phosphorylation sites, 7 of which are in
the C terminus, and 4 potential N-glycosylation sites. SLC12A7 shares
65% amino acid identity with SLC12A4 (604119) and 66% identity with
SLC12A6 (604878). Northern blot analysis detected a 5.3-kb SLC12A7
transcript in most tissues tested, with highest expression in heart and
kidney and little or no expression in adult brain. Functional analysis
confirmed that SLC12A7 is a KCC.
MAPPING
By radiation hybrid and somatic cell hybrid analyses, Mount et al.
(1999) mapped the SLC12A7 gene, which contains marker D5S110, to 5p15.3.
ANIMAL MODEL
Boettger et al. (2002) generated mice constitutively lacking KCC4, which
is predominantly expressed in kidney, heart, lung, and liver. Kcc4 -/-
mice were born at the expected mendelian ratio. They were viable and
fertile; however, their body weight was roughly 90% that of their
littermates. Mice had normal hearing loss at postnatal day 14, indicated
by normal auditory brainstem responses. Hearing deteriorated quickly
during the following week, after which mice were nearly deaf, with a
hearing loss of 70 to 80 decibels. Histologic analysis revealed that the
inner ear developed normally and could not be distinguished from those
of wildtype animals at postnatal day 14. At postnatal day 21, however,
outer hair cells of basal turns of the cochlea were almost totally
absent, whereas inner hair cells were still present. The degeneration
proceeded from basal to apical turns. In adult knockout mice, the organ
of Corti was lost completely in basal turns. In apical turns, some hair
cells survived, accounting for the residual hearing ability in adult
mice. Even in adult mice, there was no collapse of the Reissner
membrane, which separates the scala media from the scala vestibuli,
suggesting that Kcc4 is not essential for endolymph production. Outer
hair cells of Kcc4 -/- mice degenerated before Deiters cells were lost,
although Deiters cells and not outer hair cells normally express Kcc4 at
this stage. This is consistent with a disturbance of extracellular
homeostasis due to impaired salt uptake by Deiters cells, and may lead
to death of outer hair cells by osmotic stress or membrane
depolarization. Deafness in Kcc4 -/- mice was associated with renal
tubular acidosis. The urine of knockout mice was more alkaline than that
of wildtype littermates, whereas concentrations of sodium, potassium,
and chloride were not changed. Blood gas analysis indicated a
compensated metabolic acidosis with significantly decreased base excess.
Immunofluorescence revealed that Kcc4 is expressed in basolateral
membranes of several nephron segments. Intracellular chloride
concentration was increased in proximal tubules and particularly in
alpha-intercalated cells of knockout mice. Considering the prominent
chloride/bicarbonate exchange activity in alpha-intercalated cells, the
rise in intracellular chloride predicts a more alkaline intracellular pH
in the knockout mice. This will decrease apical proton secretion by
increasing the electrochemical gradient against which pumping has to
occur. Thus, KCC4 joins the hydrogen ATPase (192132) and AE1 anion
exchanger (109270) as the third transport protein of alpha-intercalated
cells whose mutation entails renal tubular acidosis. Boettger et al.
(2002) concluded that KCC4 is important for potassium recycling by
siphoning potassium ions after their exit from outer hair cells into
supporting Deiters cells, where potassium enters the gap junction
pathway.
MIR4277
| dbSNP name | rs12523324(G,A) |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 100422966 |
| EntrezGene Description | microRNA 4277 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3411 |
| ExAC AF | 0.485 |
LOC101929034
| dbSNP name | rs260394(C,T); rs260393(C,T) |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 101929034 |
| snpEff Gene Name | CTD-2194D22.1 |
| EntrezGene Description | uncharacterized LOC101929034 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2443 |
IRX2
| dbSNP name | rs189879032(C,T); rs11432(A,G); rs201221127(T,A); rs11960311(T,A) |
| cytoBand name | 5p15.33 |
| EntrezGene GeneID | 153572 |
| EntrezGene Description | iroquois homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Jerky smooth pursuit
RESPIRATORY:
[Larynx];
Glottic airway narrowing caused by laryngeal abductor paralysis;
Hoarseness;
Laryngeal stridor;
Nocturnal dyspnea
MUSCLE, SOFT TISSUE:
Mild distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Progressive cerebellar ataxia;
Gait ataxia;
Dysmetria;
Limb fasciculations;
Cerebellar atrophy;
EMG shows neurogenic findings
VOICE:
Dysphonia
MISCELLANEOUS:
Onset in adulthood;
May be X-linked
OMIM Title
*606198 IROQUOIS HOMEOBOX PROTEIN 2; IRX2
;;IRXA2
OMIM Description
DESCRIPTION
IRX2 is a member of the Iroquois homeobox gene family. Members of this
family appear to play multiple roles during pattern formation of
vertebrate embryos.
CLONING
Members of the Iroquois complex in Drosophila, including the highly
homologous homeobox genes caupolican, araucan, and mirror, act as
prepattern molecules in neurogenesis. Bosse et al. (1997) identified 3
members of the Iroquois homeobox gene family in mouse and showed that
they are involved in several embryonic developmental processes including
anterior/posterior and dorsal/ventral patterning of specific regions of
the central nervous system, and regionalization of the otic vesicle,
branchial epithelium, and limbs.
Lewis et al. (1999) determined that the homeodomains of human Iroquois
homeobox proteins are about 90% identical to the homeodomains of the
Drosophila Iroquois complex proteins and about 93% identical to each
other. Each of the IRX proteins contains a hexapeptide-like motif. By
screening of a human genomic library with chicken IRX2 cDNA and EST
database searching, Ogura et al. (2001) cloned 4 human IRX genes,
including IRX2, which encodes a deduced protein that is highly
homologous to mouse Irx2.
MAPPING
By fluorescence in situ hybridization, Ogura et al. (2001) mapped the
IRX2 and IRX1 (606197) genes to chromosome 5p15.3 and the IRX5 (606195)
and IRX7 (606196) genes to chromosome 16q11.2-q13.
LOC101929153
| dbSNP name | rs10074533(G,A) |
| cytoBand name | 5p15.32 |
| EntrezGene GeneID | 101929153 |
| snpEff Gene Name | CTD-2161F6.2 |
| EntrezGene Description | uncharacterized LOC101929153 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1492 |
MIR4636
| dbSNP name | rs257095(C,T) |
| ccdsGene name | CCDS3875.1 |
| cytoBand name | 5p15.31 |
| EntrezGene GeneID | 100616326 |
| snpEff Gene Name | SEMA5A |
| EntrezGene Description | microRNA 4636 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09366 |
| ExAC AF | 0.718 |
TAS2R1
| dbSNP name | rs2234235(A,G); rs41469(C,T) |
| ccdsGene name | CCDS3876.1 |
| cytoBand name | 5p15.31 |
| EntrezGene GeneID | 50834 |
| EntrezGene Description | taste receptor, type 2, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R1:NM_019599:exon1:c.T850C:p.L284L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.02755 |
| ESP Afr MAF | 0.020654 |
| ESP All MAF | 0.031063 |
| ESP Eur/Amr MAF | 0.036395 |
| ExAC AF | 0.031 |
ROPN1L-AS1
| dbSNP name | rs114411846(C,T) |
| cytoBand name | 5p15.2 |
| EntrezGene GeneID | 100505845 |
| snpEff Gene Name | ROPN1L |
| EntrezGene Description | ROPN1L antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04408 |
LSP1P3
| dbSNP name | rs434405(A,G); rs411622(C,A); rs73747105(C,T); rs654983(C,T); rs573961(G,A) |
| cytoBand name | 5p13.3 |
| EntrezGene GeneID | 729862 |
| EntrezGene Description | lymphocyte-specific protein 1 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4945 |
RXFP3
| dbSNP name | rs9292519(G,A); rs171631(C,A) |
| cytoBand name | 5p13.2 |
| EntrezGene GeneID | 51289 |
| EntrezGene Description | relaxin/insulin-like family peptide receptor 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3039 |
GDNF-AS1
| dbSNP name | rs2975100(G,A); rs78670708(G,A); rs115458972(G,C); rs368101215(A,C); rs12514589(T,A); rs78047098(A,G); rs2973123(A,C); rs58599734(A,C); rs114485991(G,A); rs143805094(C,T); rs371482306(C,T); rs1981844(G,C); rs7708085(T,C); rs2910696(T,C); rs17327388(A,G); rs2910695(G,C); rs74843650(C,T); rs2910694(T,C); rs2973121(C,T); rs113712237(T,C); rs1423429(T,A); rs2973120(C,T); rs2910693(T,C); rs115374705(G,A); rs2910692(T,C); rs2366621(C,T); rs1862573(G,A); rs1862572(A,G); rs143104428(G,T); rs2973119(G,A); rs77210937(C,G); rs10051467(T,C); rs7719899(C,G); rs2910762(T,C); rs182247650(C,T); rs2973118(G,A); rs1423451(G,C); rs114633636(A,G); rs73750384(C,G); rs4869553(T,G); rs367916698(A,G); rs2910761(A,G); rs2973117(T,C); rs80198467(T,C); rs62360376(A,T); rs2973116(G,A); rs189065848(C,G); rs78251725(G,A); rs13356512(T,C); rs57493077(T,C); rs2910759(G,A); rs115137337(T,G); rs1862585(C,A); rs11745806(A,T); rs10036409(C,A); rs75210866(G,T); rs2973114(T,C); rs10473072(T,G); rs74293537(G,A); rs9292676(C,T); rs78622063(C,T); rs2910757(G,A); rs78566175(C,T); rs2973113(C,T); rs10472293(G,A); rs2973112(G,A); rs2910756(A,C); rs75220215(G,T); rs77061238(C,G); rs62360378(G,C); rs9292677(A,G); rs72747322(T,G); rs77797047(C,A); rs1363927(G,A); rs2910755(C,T); rs149333842(C,T); rs2910754(T,C); rs2973111(G,T); rs371055280(A,G); rs372388666(G,A); rs11740052(C,T); rs2910753(C,G); rs2973110(G,A); rs77047478(T,C); rs2910752(T,G); rs139876674(T,C); rs1423450(C,G); rs74626636(A,G); rs5007332(G,A); rs2973109(T,C); rs1862584(G,A); rs113269706(A,C); rs1862583(C,G); rs3112464(A,G); rs3112463(A,G); rs3096144(G,C); rs71619887(C,T); rs11749351(A,G); rs4869555(T,C); rs145532561(C,T); rs1423449(G,A); rs74619471(T,C); rs10063653(C,A); rs6860082(G,A); rs191651686(G,T); rs6864288(C,A); rs2910750(T,C); rs16903763(C,G); rs16903764(G,T); rs1423448(G,A); rs1833866(C,T); rs1423447(A,G); rs59519939(G,A); rs34243637(T,C); rs11740708(G,A); rs12653508(G,A); rs76145402(C,G); rs2112999(T,G); rs2910749(C,T); rs2973106(C,G); rs140177500(G,A); rs2910748(A,T); rs2910747(A,T); rs147745512(G,A); rs148758795(C,T); rs17328268(A,T); rs115234103(T,C); rs1423446(G,A); rs375147530(C,T); rs182183049(A,G); rs12517785(C,G); rs34104370(C,T); rs12523613(A,G); rs10073345(T,C); rs148002324(C,T); rs12518583(C,T); rs115509020(C,G); rs10067271(C,T); rs142701913(C,A); rs61537857(C,T); rs57153969(A,C); rs12519276(C,T); rs140007512(T,C); rs115718567(G,C); rs368403198(T,C); rs28733167(C,T); rs10079283(T,C); rs79184697(G,A); rs6879269(T,A) |
| cytoBand name | 5p13.2 |
| EntrezGene GeneID | 100861519 |
| snpEff Gene Name | GDNF |
| EntrezGene Description | GDNF antisense RNA 1 (head to head) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intergenic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1331 |
LOC100506548
| dbSNP name | rs7725810(T,C); rs389737(T,C) |
| cytoBand name | 5p13.1 |
| EntrezGene GeneID | 100506548 |
| snpEff Gene Name | RPL37 |
| EntrezGene Description | uncharacterized LOC100506548 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3489 |
OXCT1-AS1
| dbSNP name | rs1876654(T,C); rs193197823(C,G); rs76243675(C,T); rs183673542(G,A) |
| cytoBand name | 5p13.1 |
| EntrezGene GeneID | 5019 |
| EntrezGene Symbol | OXCT1 |
| snpEff Gene Name | OXCT1 |
| EntrezGene Description | 3-oxoacid CoA transferase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1878 |
ANXA2R
| dbSNP name | rs1054428(T,C) |
| ccdsGene name | CCDS34153.1 |
| cytoBand name | 5p12 |
| EntrezGene GeneID | 389289 |
| snpEff Gene Name | C5orf39 |
| EntrezGene Description | annexin A2 receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ANXA2R:NM_001014279:exon1:c.A356G:p.Q119R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3ZCQ2 |
| dbNSFP Uniprot ID | AX2R_HUMAN |
| dbNSFP KGp1 AF | 0.198717948718 |
| dbNSFP KGp1 Afr AF | 0.107723577236 |
| dbNSFP KGp1 Amr AF | 0.364640883978 |
| dbNSFP KGp1 Asn AF | 0.00874125874126 |
| dbNSFP KGp1 Eur AF | 0.321899736148 |
| dbSNP GMAF | 0.1983 |
| ESP Afr MAF | 0.149796 |
| ESP All MAF | 0.266954 |
| ESP Eur/Amr MAF | 0.326977 |
| ExAC AF | 0.267,8.133e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Focal dystonia, upper limb;
Writer's cramp;
Musician's cramp
MISCELLANEOUS:
Onset in third or fourth decade;
May be progressive;
May be triggered by increased practice
OMIM Title
*611296 CHROMOSOME 5 OPEN READING FRAME 39; C5ORF39
;;ANNEXIN II RECEPTOR; AX2R;;
AXIIR
OMIM Description
CLONING
Lu et al. (2006) identified a receptor for annexin II (AXII), a
heterotetrameric protein, composed of 2 11-kD subunits (S100A10/ANX2L;
114085) and 2 36-kD subunits (ANXA2; 151740), that stimulates osteoclast
formation. Using radiolabeled annexin II, Lu et al. (2006) identified a
crosslinked 55-kD protein complex which was shown to be composed of the
11-kD subunit of the annexin II tetramer along with the receptor. Pools
from a human marrow cDNA library were transfected into NIH3T3 cells and
screened for any that bound radiolabeled annexin II tetramer. The
receptor clone, AX2R, was isolated and further characterized. The
deduced AX2R protein is a type I transmembrane protein with 1
transmembrane domain. It contains 193-amino acids, only 4 of which are
in the cytoplasmic tail, and has a molecular mass of 26 kD; thus, the
55-kD complex first identified may include 2 p11 subunits.
GENE FUNCTION
By expression studies, Lu et al. (2006) showed that AX2R was transcribed
in most tissues examined, except heart, brain, and skeletal muscle. Its
expression level was comparable in CD4(+)- and CD8(+)-expressing T cells
but decreased in activated CD8+ T cells. An antibody to the AX2R protein
blocked the effects of annexin II on human osteoclast formation in a
dose-dependent manner.
MAPPING
Using a somatic cell hybrid panel, Lu et al. (2006) mapped the AX2R gene
to chromosome 5p12.
NNT
| dbSNP name | rs10065689(T,C); rs142839934(A,G); rs10065863(T,C); rs79231838(G,A); rs375196601(G,A); rs374757717(A,T); rs12187908(T,C); rs10057103(C,T); rs112380038(G,A); rs78539141(G,A); rs1072745(T,C); rs1072746(G,C); rs67261887(T,A); rs4991951(A,G); rs10074229(G,A); rs79866958(G,A); rs13161838(A,C); rs28582463(C,T); rs7720818(C,T); rs13356232(A,C); rs114924835(C,T); rs10058080(T,C); rs73751786(A,G); rs114633201(A,T); rs6451719(T,C); rs6896932(C,T); rs145278679(A,G); rs371686665(A,C); rs138593206(T,C); rs377048341(G,A); rs145159980(G,C); rs7713458(G,A); rs73751789(T,C); rs114397622(G,A); rs10473316(T,C); rs7713749(T,C); rs6898436(C,T); rs16873432(T,C); rs16873435(T,C); rs73751792(A,C); rs3805722(T,C); rs16873438(A,G); rs73751797(G,A); rs6862487(T,G); rs115185963(C,T); rs374334770(A,G); rs10051937(A,T); rs72760478(T,C); rs72760479(G,A); rs112540127(A,G); rs376886353(A,T); rs10461744(A,C); rs78621428(C,T); rs62367650(G,A); rs6860092(G,A); rs115539696(A,G); rs57983993(G,A); rs34361740(A,G); rs139827320(G,A); rs6875118(T,C); rs768357(C,T); rs73751800(C,T); rs6893250(A,G); rs72760481(C,T); rs76751262(C,T); rs55912106(A,G); rs6863699(C,T); rs10066806(C,T); rs10051788(A,G); rs148899440(A,G); rs13165656(A,C); rs116602813(A,G); rs71629192(G,C); rs76322641(G,A); rs149371069(C,T); rs13177579(G,T); rs7708386(G,C); rs2330326(C,A); rs10059613(T,C); rs79032419(A,G); rs2303733(A,C); rs78818665(A,G); rs34132518(T,C); rs12332274(T,C); rs369902524(A,G); rs9292890(T,C); rs3828696(G,A); rs73753604(C,T) |
| ccdsGene name | CCDS3949.1 |
| cytoBand name | 5p12 |
| EntrezGene GeneID | 23530 |
| EntrezGene Description | nicotinamide nucleotide transhydrogenase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NNT:NM_012343:exon20:c.A2977G:p.I993V,NNT:NM_182977:exon20:c.A2977G:p.I993V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6821 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q13423 |
| dbNSFP Uniprot ID | NNTM_HUMAN |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0244755244755 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.002951 |
| ESP All MAF | 0.004306 |
| ESP Eur/Amr MAF | 0.005 |
| ExAC AF | 0.009124 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Eyelid twitching
NEUROLOGIC:
Involuntary rhythmic myoclonic movements ('tremor') of the distal
extremities, usually fingers;
Movements ('tremors') characterized by 8 to 10-Hz discharges;
Eyelid twitching;
Myoclonus;
Generalized tonic-clonic seizures (GTCS), infrequent;
Mental retardation has been reported;
EEG shows generalized and focal spike and wave complexes;
Photoparoxysmal response on EEG;
Electrophysiologic studies indicate cortical origin;
Giant somatosensory evoked potentials (SEPs);
Enhancement of the C-reflex;
Jerk-locked premyoclonus spikes
MISCELLANEOUS:
Adult onset (range 12 to 59 years);
Nonprogressive course;
Tremor may be elicited by movement or postural maintenance;
Clinically resembles essential tremor, but not responsive to beta-adrenergic
blockers;
Anticonvulsants are effective (phenobarbital, valproic acid, benzodiazepines);
Genetic heterogeneity (see BAFME1, 601068)
OMIM Title
*607878 NICOTINAMIDE NUCLEOTIDE TRANSHYDROGENASE; NNT
OMIM Description
DESCRIPTION
NNT is a pyridine nucleotide transhydrogenase (EC 1.6.1.1). These
integral inner mitochondrial membrane proteins are part of the
energy-transfer system of the respiratory chain and catalyze the
transfer of a hydride ion between nicotinamide adenine dinucleotide,
NAD(H), and oxidized nicotinamide dinucleotide phosphate, NADP(H)
(summary by Zieger and Ware, 1997).
CLONING
Using bovine Nnt as probe, Arkblad et al. (1996) cloned NNT from a heart
cDNA library, and they cloned mouse Nnt from a mouse liver cDNA library.
The deduced 1,086-amino acid NNT protein has a 43-amino acid
presequence, 10 membrane-spanning alpha helices, and substrate-binding
sites for NAD(H) and NADP(H). It shares 97% amino acid identity with
bovine Nnt and 94% identity with mouse Nnt. A hypervariable region is
located in the first transmembrane helix, and the presequences are less
conserved.
Zieger and Ware (1997) cloned NNT from a cell line established from a
solid tumor in a patient with megakaryoblastic leukemia.
Meimaridou et al. (2012) found wide expression of NNT in humans, with
expression most readily detectable in adrenal, heart, kidney, thyroid,
and adipose tissues.
MAPPING
By FISH, Arkblad et al. (1997) mapped the NNT gene to chromosome
5p13.1-cen. They mapped the mouse Nnt gene to chromosome 13D2.
GENE FUNCTION
Meimaridou et al. (2012) studied the adrenal glands from Nnt-deficient
mice and observed slightly disorganized zonae fasciculatae with higher
levels of apoptosis than wildtype mice. There were no observable
differences in the levels of the steroidogenic enzymes CYP11A1 (118485)
and CYP11B1 (610613) between wildtype and mutant mice; however, the
mutant mice did have lower basal and stimulated levels of corticosterone
than their wildtype counterparts. Knockdown of NNT in the human
adrenocortical H295R cell line by short hairpin RNA not only increased
the levels of mitochondrial reactive oxygen species and apoptosis but
also lowered the glutathione (GSH; see 601002)/glutathione disulfide
(GSSG) ratio, implying that these cells also have impaired redox
potential.
MOLECULAR GENETICS
In 3 kindreds with glucocorticoid deficiency mapping to chromosome
5p13-q12 (GCCD4; 614736), Meimaridou et al. (2012) identified
homozygosity for 3 different mutations in the NNT gene
(607878.0001-607878.0003) that segregated with disease in each family
and were not found in controls. Subsequent analysis of the NNT gene in
100 individuals with GCCD of unknown etiology revealed homozygosity or
compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g.,
607878.0004-607878.0006). The mutations were spread throughout the NNT
gene and included a mutation that destroyed the translation-initiating
methionine, 2 additional splice site mutations, and many missense and
nonsense changes.
LOC100287592
| dbSNP name | rs250234(C,T); rs250236(C,T) |
| cytoBand name | 5q11.1 |
| EntrezGene GeneID | 100287592 |
| snpEff Gene Name | CTD-2089N3.2 |
| EntrezGene Description | uncharacterized LOC100287592 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.466 |
HSPB3
| dbSNP name | rs7699(G,A); rs7823(T,C) |
| ccdsGene name | CCDS3961.1 |
| cytoBand name | 5q11.2 |
| EntrezGene GeneID | 8988 |
| EntrezGene Description | heat shock 27kDa protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HSPB3:NM_006308:exon1:c.G282A:p.L94L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4977 |
| ESP Afr MAF | 0.459828 |
| ESP All MAF | 0.445256 |
| ESP Eur/Amr MAF | 0.396628 |
| ExAC AF | 0.554,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604624 HEAT-SHOCK 27-KD PROTEIN 3; HSPB3
;;HEAT-SHOCK PROTEIN 27-LIKE PROTEIN; HSPL27
OMIM Description
DESCRIPTION
The HSPB3 gene encodes a small heat-shock protein. Small heat-shock
proteins are characterized by a conserved sequence of 80 to 100 amino
acids, often called the alpha-crystallin (see CRYAA, 123580) domain, and
range in size from 12 to 43 kD in the monomeric state; as multimeric
complexes, they range from 150 to 800 kD (Lam et al., 1996).
CLONING
By partial sequencing of cDNA clones and sequence database searching,
Lam et al. (1996) isolated an adult heart cDNA that encodes a novel
small heat-shock protein of 241 amino acids. Because of its high
sequence homology with hsp27 (see HSPB1, 602195), they termed the
protein heat-shock protein 27-like protein (HSPL27).
The sequence of HSPL27 was corrected by Boelens et al. (1998), who
determined that the cDNA isolated by Lam et al. (1996) in fact included
a part of PIK4CB (602758). The HSPL27 protein, called HSPB3 by Boelens
et al. (1998), contains 150 amino acids, has a molecular mass of
approximately 17 kD, and a pI of 5.95. It contains casein kinase II but
not MAP kinase recognition sites. Northern blot analysis revealed
expression of a 0.9-kb transcript in smooth muscle only.
GENE STRUCTURE
The HSPB3 gene contains 1 coding exon (Boelens et al., 1998).
MAPPING
By FISH analysis, Lam et al. (1996) mapped the HSPB3 gene to chromosome
5q11.2.
MOLECULAR GENETICS
By candidate gene analysis of 2 sisters with adult-onset distal
hereditary motor neuropathy 2C (HMN2C; 613376), Kolb et al. (2010)
identified a heterozygous mutation in the HSPB3 gene (R7S; 604624.0001).
The authors noted that mutations in the heat-shock proteins HSPB1
(602195) and HSPB8 (608014) both result in distal HMN with minimal
sensory involvement (HMN2B, 608634 and HMN2A, 158590, respectively).
MIR449B
| dbSNP name | rs10061133(A,G) |
| ccdsGene name | CCDS3966.1 |
| cytoBand name | 5q11.2 |
| EntrezGene GeneID | 693123 |
| snpEff Gene Name | GPX8 |
| EntrezGene Description | microRNA 449b |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1267 |
| ESP Afr MAF | 0.041135 |
| ESP All MAF | 0.085146 |
| ESP Eur/Amr MAF | 0.104411 |
| ExAC AF | 0.109 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Anteriorly displaced ears;
[Nose];
Upturned nose
RESPIRATORY:
[Lung];
Pulmonary hypoplasia
CHEST:
[External features];
Small chest
GENITOURINARY:
[Internal genitalia, male];
Absence of germ cells;
[Internal genitalia, female];
Absence of germ cells
SKELETAL:
[Limbs];
Short arms;
Slight ankle varus deformity;
Frog-leg positioning of the legs;
Bilateral humeral fractures;
Gracile bones
MUSCLE, SOFT TISSUE:
Edema at birth
ENDOCRINE FEATURES:
Hypoplastic adrenal glands
PRENATAL MANIFESTATIONS:
Hydrops fetalis;
[Movement];
Normal or near normal fetal movements;
[Amniotic fluid];
Polyhydramnios
MISCELLANEOUS:
Based on report of 2 sibs in 2008
OMIM Title
*613132 MICRO RNA 449B; MIR449B
;;miRNA449B;;
MIRN449B
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene
expression by inhibiting mRNA translation or inducing mRNA degradation.
The miRNAs MIR449A (613131) and MIR449B are located within intron 1 of
the CDC20B gene, and they share a common promoter with CDC20B (Yang et
al., 2009).
CLONING
Using miRNA profiling to identify E2F1 (189971) target genes in a human
osteosarcoma cell line, Yang et al. (2009) identified MIR449A and
MIR449B. Both miRNAs have the same seed sequence,
5-prime-GGCAGUG-3-prime.
GENE FUNCTION
Using quantitative real-time PCR, Yang et al. (2009) confirmed that E2F1
induced strong MIR449A and MIR449B expression in a number of human cell
lines. Expression of these miRNAs correlated well with endogenous E2F1
activation during the cell cycle. E2F1 also induced expression of the
MIR449A and MIR449B host gene, CDC20B. Chromatin immunoprecipitation
analysis coupled with quantitative PCR and reporter gene assays
confirmed that E2F1 bound and activated a common MIR449A-MIR449B-CDC20B
promoter. Yang et al. (2009) identified MIR449-binding sites in the
3-prime UTRs of CDK6 (603368) and CDC25A (116947), and using several
techniques, they demonstrated downregulation of CDK6 and CDC25A by
MIR449A. Transfection of an MIR449A mimic induced cell cycle arrest at
G1 phase in several human cancer cell lines through inhibition of the
RB1 (614041)-E2F1 pathway, which includes CDK6 and CDC25A. Expression of
MIR449A and MIR449B was downregulated in a panel of cancer cell lines
compared with a normal epithelial cell line, and this downregulation
appeared to occur epigenetically through histone methylation of the
MIR449A-MIR449B-CDC20B promoter.
The Mir34/Mir449 family consists of 6 homologous miRNAs at 3 genomic
loci: Mir34a (611172), Mir34b (611374), Mir34c (611375), Mir449a,
Mir449b, and Mir449c. Song et al. (2014) reported that mice deficient
for all Mir34/Mir449 family miRNAs exhibited postnatal mortality
infertility, and strong respiratory dysfunction caused by defective
mucociliary clearance. In both mouse and Xenopus, Mir34/Mir449-deficient
multiciliated cells exhibited a significant decrease in cilia length and
number, due to defective basal body maturation and apical docking. The
effect of Mir34/Mir449 on ciliogenesis was mediated, at least in part,
by posttranscriptional repression of Cp110 (609544), a centriolar
protein suppressing cilia assembly. Consistent with this, Cp110
knockdown in Mir34/Mir449-deficient multiciliated cells restored
ciliogenesis by rescuing basal body maturation and docking. Song et al.
(2014) concluded that their findings elucidated conserved cellular and
molecular mechanisms through which Mir34/Mir449 regulate motile
ciliogenesis.
GENE STRUCTURE
Yang et al. (2009) identified 2 functional E2F1-binding sites in the
common promoter region of MIR449A, MIR449B, and their host gene, CDC20B.
MAPPING
By genomic sequence analysis, Yang et al. (2009) mapped the MIR449A and
MIR449B genes within intron 1 of the CDC20B gene on chromosome 5q11.2.
RNF138P1
| dbSNP name | rs4865953(A,C); rs12513672(C,G); rs192730554(C,G); rs6878401(C,T); rs148626671(T,C); rs2292282(T,C); rs2292281(T,G); rs2292280(T,G) |
| ccdsGene name | CCDS34159.1 |
| cytoBand name | 5q11.2 |
| EntrezGene GeneID | 379013 |
| snpEff Gene Name | PPAP2A |
| EntrezGene Description | ring finger protein 138, E3 ubiquitin protein ligase pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1901 |
ACTBL2
| dbSNP name | rs13159014(A,G); rs11950494(T,G); rs16886992(G,A); rs146468598(C,T); rs61737336(A,G) |
| ccdsGene name | CCDS34163.1 |
| cytoBand name | 5q11.2 |
| EntrezGene GeneID | 345651 |
| EntrezGene Description | actin, beta-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTBL2:NM_001017992:exon1:c.G620A:p.R207Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8058 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q562R1 |
| dbNSFP Uniprot ID | ACTBL_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.001922 |
| ESP Eur/Amr MAF | 0.002674 |
| ExAC AF | 0.001813 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, mild
HEAD AND NECK:
[Head];
Microcephaly, mild (-2 SD)
ABDOMEN:
Situs solitus
GENITOURINARY:
[Kidneys];
Decreased kidney volume (1 patient)
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate to severe;
Lack of speech or poor speech;
Dysarthria;
Seizures;
Pyramidal signs (in some);
Spasticity (in some);
Abnormal EEG;
Polymicrogyria, diffuse, asymmetric;
Abnormal corpus callosum;
Cerebellar atrophy, mild (1 patient)
MISCELLANEOUS:
Two unrelated families have been reported (last curated September
2012)
MOLECULAR BASIS:
Caused by mutation in the rotatin gene (RTTN, 610436.0001)
OMIM Title
*614835 ACTIN, BETA-LIKE, 2; ACTBL2
OMIM Description
CLONING
Using RT-PCR to amplify actin-like transcripts from hepatocellular
carcinomas, Chang et al. (2006) obtained a partial cDNA for ACTBL2.
MAPPING
Hartz (2012) mapped the ACTBL2 gene to chromosome 5q11.2 based on an
alignment of the ACTBL2 sequence (GenBank GENBANK AY970384) with the
genomic sequence (GRCh37).
HTR1A
| dbSNP name | rs878567(A,G); rs6449693(G,A); rs34118353(G,A); rs6294(C,T) |
| cytoBand name | 5q12.3 |
| EntrezGene GeneID | 3350 |
| EntrezGene Description | 5-hydroxytryptamine (serotonin) receptor 1A, G protein-coupled |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3834 |
OMIM Clinical Significance
Nose:
Bifid nose
Eyes:
No hypertelorism;
Ptosis
Skel:
Soliosis
GU:
Cryptorchidism
Inheritance:
Autosomal dominant form;
? also a recessive form (210400)
OMIM Title
*109760 5-@HYDROXYTRYPTAMINE RECEPTOR 1A; HTR1A
;;SEROTONIN 5-HT-1A RECEPTOR;;
BETA-2-ADRENERGIC RECEPTOR-LIKE PROTEIN G-21
OMIM Description
CLONING
Kobilka et al. (1987) cloned and sequenced a DNA fragment in the human
genome which cross-hybridizes with a full-length beta-2-adrenergic
receptor at reduced stringency. Like the beta-2-adrenergic receptor
(109690), this gene appears to be intronless, containing an
uninterrupted long open reading frame which encodes a putative protein
with all the expected structural features of a G protein-coupled
receptor. Although the G-21 clone was found to map to the same location
as that for the glucocorticoid receptor (138040) (see later), Kobilka et
al. (1987) thought it unlikely that G-21 represents a pseudogene for the
beta-2-adrenergic receptor or some other gene for several reasons. Most
pseudogenes do not contain uninterrupted coding blocks because of the
lack of selected pressure in preventing termination mutations. For the
same reason one would not expect to find well-conserved regions of
homology such as those observed between the G-21 and the G
protein-coupled receptors. Finally, the G-21 gene is expressed in
several tissues as revealed by Northern blot analysis. The tissue
distribution of the mRNA is unique, being highest in lymphoid tissues.
MAPPING
Kobilka et al. (1987) determined the chromosomal localization of the
G-21 clone (the designation for the DNA segment) by Southern blot
analysis of DNA from 12 hamster and human somatic cell hybrids and by in
situ hybridization. By these methods it was found to be located at
5q11.2-q13. Melmer et al. (1991) showed close linkage of HTR1A to highly
polymorphic microsatellite markers on chromosome 5. Oakey et al. (1991)
mapped the Htra1 gene to distal mouse chromosome 13.
GENE FUNCTION
Fargin et al. (1988) reported that the protein product of the genomic
clone G21, transiently expressed in monkey kidney cells, has all the
typical ligand-binding characteristics of the 5-hydroxytryptamine
(5-HT-1A) receptor. At least 6 subtypes of 5-HT receptors (1A, 1B, 1C,
1D, 2, and 3) have been characterized extensively by pharmacologic and
physiologic methods. See review by El Mestikawy et al. (1991).
Various chronic antidepressant treatments increase adult hippocampal
neurogenesis. Santarelli et al. (2003) used genetic and radiologic
methods to show that disrupting antidepressant-induced neurogenesis
blocks behavioral responses to antidepressants. Serotonin 1A
receptor-null mice were insensitive to the neurogenic and behavioral
effects of fluoxetine, a serotonin-selective reuptake inhibitor.
X-irradiation of a restricted region of mouse brain containing the
hippocampus prevented the neurogenic and behavioral effects of 2 classes
of antidepressants, SSRIs and tricyclics. Santarelli et al. (2003)
concluded that their findings suggested that the behavioral effects of
chronic antidepressants may be mediated by the stimulation of
neurogenesis in the hippocampus.
Using a selective molecular probe and PET scan, Kepe et al. (2006) found
decreased density of 5-HT-1A receptors in the hippocampus of 8 patients
with Alzheimer disease (AD; 104300) and 6 patients with mild cognitive
impairment compared to 5 normal controls. The decreases in 5-HT-1A
receptor densities correlated with decreased glucose utilization as
measured by PET scan.
MOLECULAR GENETICS
In a 33-year-old Taiwanese woman with menstrual cycle-dependent periodic
fevers (614674) that were successfully treated with a serotonin receptor
antagonist, Jiang et al. (2012) identified a 1-bp deletion in the
upstream promoter (109760.0001). Functional analysis demonstrated that
the mutant promoter has increased interaction with a negative regulator
of HTR1A expression, PARP1 (173870), and causes additional reduction in
transcription.
ANIMAL MODEL
Brain serotonin has been implicated in a number of physiologic processes
and pathologic conditions. These effects are mediated by at least 14
different 5-HT receptors. Parks et al. (1998) inactivated the gene
encoding the 5-HT-1A receptor in mice and found that receptor-deficient
animals had an increased tendency to avoid a novel and fearful
environment and to escape a stressful situation, behaviors consistent
with an increased anxiety and stress response. Based on the role of the
5-HT-1A receptor and the feedback regulation of the 5-HT system, Parks
et al. (1998) hypothesized that an increased serotonergic
neurotransmission is responsible for the anxiety-like behavior of
receptor-deficient animals. This view is consistent with earlier studies
showing that pharmacologic activation of the 5-HT system is anxiogenic
in animal models and also in humans.
To investigate the contribution of individual serotonin receptors to
mood control, homologous recombination to generate mice lacking specific
serotonergic receptor subtypes has been used. Ramboz et al. (1998)
demonstrated that mice without 5-HT-1A receptors displayed decreased
exploratory activity and increased fear of aversive environments (open
or elevated spaces). 5-HT-1A knockout mice also exhibited a decreased
immobility in the forced swim test, an effect commonly associated with
antidepressant treatment. Although 5-HT-1A receptors are involved in
controlling the activity of serotonergic neurons, these knockout mice
had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly
because of an upregulation of 5-HT-1B autoreceptors. Heterozygous
5-HT-1A mutants expressed approximately one-half of wildtype receptor
density and displayed intermediate phenotypes in most behavioral tests.
These results demonstrated that 5-HT-1A receptors are involved in the
modulation of exploratory and fear-related behaviors and suggested that
reductions in 5-HT-1A receptor density due to genetic defects are
environmental stressors that may result in heightened anxiety.
Heisler et al. (1998) used a gene-targeting technology to generate mice
deficient in 5-HT-1A receptors. Homozygous mutants displayed a
consistent pattern of responses indicative of elevated anxiety levels in
open-field, elevated-zero maze, and novel-object assays. Moreover, they
exhibited antidepressant-like responses in a tail-suspension assay.
These results were interpreted as indicating that the targeted
disruption of the serotonin receptor gene leads to heritable
perturbations in the serotonergic regulation of emotional state.
Although some of the behavioral assays differed in design and the mouse
lines used differed in their genetic backgrounds, the results of Ramboz
et al. (1998) and Heisler et al. (1998) led to essentially the same
conclusions. In each case, homozygous mutant mice showed less
exploratory behavior than wildtype mice. Whatever the mechanism, these
studies provided another example of how a single gene mutation can alter
behavior. Julius (1998) suggested that 'the most significant question
may be whether behavioral changes in these mice will be good predictors
of anxiolytic drug activity in humans. If so, then 5-HT-1A receptor
knockout mice may earn their keep as sentinels for new therapeutic
compounds.'
Gross et al. (2002) used a tissue-specific, conditional rescue strategy
to show that expression of the serotonin-1A receptor primarily in the
hippocampus and cortex, but not in the raphe nuclei, is sufficient to
rescue the behavioral phenotype of knockout mice. Furthermore, using the
conditional nature of the transgenic mice, Gross et al. (2002) suggested
that receptor expression during the early postnatal period, but not in
the adult, is necessary for this behavioral rescue. Gross et al. (2002)
concluded that postnatal developmental processes help to establish adult
anxiety-like behavior. In addition, the normal role of the serotonin-1A
receptor during development may be different from its function when this
receptor is activated by therapeutic intervention in adulthood.
Audero et al. (2008) investigated the consequences of altering the
autoinhibitory capacity of serotonin neurons with the reversible
overexpression of serotonin-1A autoreceptors in transgenic mice.
Overexpressing mice exhibited sporadic bradycardia and hypothermia that
occurred during a limited developmental period and frequently progressed
to death. Moreover, overexpressing mice failed to activate autonomic
target organs in response to environmental challenges. Audero et al.
(2008) concluded that their findings showed that excessive serotonin
autoinhibition is a risk factor for catastrophic autonomic dysregulation
and provided a mechanism for a role of altered serotonin homeostasis in
sudden infant death syndrome (SIDS; 272120).
Richardson-Jones et al. (2010) generated transgenic mice with decreased
levels of serotonin-1A autoreceptors in the raphe nuclei but no change
in serotonin-1A heteroreceptors. Mice with low 5HT1A autoreceptor levels
had increased spontaneous activity of serotonergic neurons compared to
mice with high 5HT1A levels, consistent with decreased autoinhibition in
the former group. Compared to mice with high 5HT1A autoreceptor levels,
mice with low 5HT1A autoreceptor levels had an increased physiologic
response to acute stress, decreased behavioral despair, and better
behavioral response to the antidepressant fluoxetine. After 8 days of
fluoxetine treatment, low 5HT1A mice had increased serotonin levels in
the hippocampus compared to high 5HT1A mice, although levels in both
mice increased and were normalized by 26 days. A reduction in 5HT1A
autoreceptor levels prior to antidepressant treatment resulted in better
response to treatment, suggesting that decreased autoreceptor function
may allow an earlier response to treatment. The findings were consistent
with the hypothesis that feedback inhibition by 5HT1A autoreceptors
delays onset of response by limiting the initial increase in serotonin.
Although 5HT1A autoreceptors desensitized after chronic treatment with
fluoxetine, desensitization alone was not sufficient to explain the
response to fluoxetine. Serotonergic tone, governed by intrinsic
autoreceptor levels, prior to the onset of treatment appeared to be
critical for establishing responsiveness. The results established a
causal relationship between 5HT1A autoreceptor levels, resilience under
stress, and response to antidepressants.
MIR4803
| dbSNP name | rs3112399(T,A) |
| ccdsGene name | CCDS4012.1 |
| cytoBand name | 5q13.2 |
| EntrezGene GeneID | 100616377 |
| snpEff Gene Name | MAP1B |
| EntrezGene Description | microRNA 4803 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.36 |
| ExAC AF | 0.199 |
TMEM174
| dbSNP name | rs16903311(C,G); rs1104891(G,A); rs4302564(T,A) |
| cytoBand name | 5q13.2 |
| EntrezGene GeneID | 134288 |
| EntrezGene Description | transmembrane protein 174 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Deafness, stable bilateral symmetric prelingual;
Moderate-to-severe in all frequencies, but slightly more pronounced
in mid-frequencies;
Normal static compliance on tympanometry;
Normal middle ear pressures on tympanometry
MISCELLANEOUS:
Patients have a distinctive shallow U-shaped audiogram
MOLECULAR BASIS:
Caused by mutation in the calcium-binding protein 2 gene (CABP2, 607314.0001)
OMIM Title
*614909 TRANSMEMBRANE PROTEIN 174; TMEM174
OMIM Description
CLONING
By PCR of a human kidney cDNA library, Wang et al. (2010) cloned
TMEM174. The deduced 243-amino acid protein has 2 transmembrane domains
and a calculated molecular mass of 26 kD. Database analysis revealed a
possible splice variant that was predicted to encode the same protein.
RT-PCR detected TMEM174 expression in kidney and Raji B-lymphoma cells,
with little to no expression in other human tissues or cell lines
examined. Microarray and EST database analysis confirmed predominant
TMEM174 expression in human and mouse kidney. Fluorescence-tagged
TMEM174 colocalized with a marker of the endoplasmic reticulum (ER).
Database analysis detected TMEM174 orthologs in several vertebrates, and
chimpanzee and human TMEM174 share 99% amino acid identity.
GENE FUNCTION
Wang et al. (2010) found that overexpression of TMEM174 increased cell
proliferation in 293T and HeLa cells. TMEM174 induced activator
protein-1 (AP1) reporter genes, with more efficient activation of JUN
(165160) than FOS (164810). TMEM174-mediated FOS induction was
accompanied by enhanced ERK (see 601795) phosphorylation and ELK1
(311040) activity. Mutation analysis revealed that the 2 transmembrane
domains of TMEM174 were required for its ER localization and
transcriptional activity.
GENE STRUCTURE
Wang et al. (2010) determined that the TMEM174 gene contains 3 exons.
MAPPING
By genomic sequence analysis, Wang et al. (2010) mapped the TMEM174 gene
to chromosome 5q13.2.
GCNT4
| dbSNP name | rs9293639(C,T); rs56682994(A,G); rs3811986(G,A); rs3811987(G,A); rs4704166(C,T); rs74826834(T,G); rs76385772(T,C) |
| cytoBand name | 5q13.3 |
| EntrezGene GeneID | 51301 |
| EntrezGene Description | glucosaminyl (N-acetyl) transferase 4, core 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05923 |
IQGAP2
| dbSNP name | rs9293683(C,T); rs112909162(A,G); rs55995866(A,G); rs79568940(A,C); rs114658658(T,A); rs4479826(G,A); rs10462539(T,C); rs10462540(G,A); rs28386181(T,C); rs3886043(G,A); rs3886042(G,A); rs4314381(A,G); rs9293684(A,G); rs11747990(T,C); rs11744637(C,T); rs116395790(A,G); rs72775764(A,G); rs4254886(T,C); rs190108084(T,G); rs7706926(C,G); rs115998215(C,T); rs7707426(C,G); rs7731240(T,C); rs7718641(T,G); rs6453217(C,T); rs150225576(C,T); rs10065322(G,A); rs4501323(T,C); rs56181354(G,C); rs148776274(C,T); rs115564194(C,T); rs4501324(T,C); rs4296785(C,T); rs56950047(C,A); rs4704310(T,G); rs6892302(A,T); rs59851723(C,A); rs6453218(C,T); rs10942770(C,G); rs56015344(T,A); rs13175420(C,T); rs13157262(A,G); rs184947308(G,A); rs6887962(C,T); rs72775766(G,A); rs6453219(C,T); rs58768211(A,G); rs6878741(T,G); rs7732016(G,A); rs6879280(T,G); rs62363252(G,A); rs12523532(G,A); rs10073382(A,G); rs115417159(C,T); rs10073448(A,G); rs4382145(G,C); rs79857509(G,A); rs73116027(G,A); rs11747835(G,A); rs6865628(T,A); rs10068074(T,C); rs10073228(G,A); rs10073282(G,T); rs6453220(C,T); rs74352689(C,T); rs59428516(C,A); rs60570368(A,G); rs10044351(G,A); rs10044370(G,A); rs10044373(G,A); rs10043040(T,C); rs10070688(A,G); rs10072221(T,C); rs10077372(G,A); rs10079393(G,A); rs4615280(G,A); rs4563602(G,A); rs11749318(T,C); rs1122058(A,G); rs7715388(C,G); rs80189433(G,A); rs11741153(G,T); rs77452337(T,A); rs7717110(T,C); rs13183341(G,A); rs184920727(A,G); rs7731045(T,C); rs10068404(C,G); rs6887687(A,G); rs59640448(G,C); rs7732454(T,C); rs13165962(C,G); rs56373165(A,G); rs10474472(A,G); rs34483409(G,C); rs35997496(G,T); rs57915897(C,T); rs59094350(T,C); rs61567151(A,G); rs10035823(T,C); rs202102996(C,T); rs56218844(A,G); rs56057159(T,C); rs7710677(T,G); rs79293540(T,G); rs6880514(T,C); rs6876318(A,T); rs10063932(G,A); rs35450692(C,A); rs10474473(T,G); rs10058784(T,G); rs35985253(C,T); rs34637558(A,C); rs4469181(C,T); rs112042956(C,T); rs4566772(C,G); rs60846807(A,G); rs184941587(A,T); rs148584932(T,C); rs28489619(G,A); rs7718320(T,A); rs10213849(T,C); rs149113565(A,T); rs11950587(A,T); rs11743541(G,A); rs150825486(C,T); rs7700783(C,T); rs76045075(C,T); rs57446989(T,G); rs4130148(G,A); rs7706078(C,T); rs7730891(A,G); rs146214088(C,T); rs147845780(G,T); rs112179910(C,T); rs58151471(A,G); rs4704313(G,T); rs10068651(T,C); rs150849576(A,G); rs35145043(A,C); rs6453223(C,A); rs35893266(G,T); rs6859929(C,A); rs34590851(G,T); rs6880993(A,G); rs111768278(T,C); rs114147688(C,T); rs10067617(C,A); rs10076920(T,A); rs9765093(G,A); rs9763690(C,G); rs71630923(C,G); rs35875364(C,G); rs10474474(G,T); rs6896727(G,A); rs4704315(G,T); rs6898214(C,T); rs10942781(T,C); rs12697851(G,A); rs10474475(C,A); rs10473982(C,T); rs10474476(G,T); rs10473983(C,T); rs11739424(G,A); rs11739486(G,A); rs11739493(G,A); rs11747022(C,T); rs13153156(T,A); rs34650005(A,G); rs13166671(G,A); rs13153602(T,C); rs62363257(T,G); rs34791684(A,G); rs56022338(A,G); rs10039356(G,A); rs10056768(T,A); rs10045155(C,T); rs10077518(T,C); rs10077639(T,C); rs57315995(A,T); rs4529172(T,C); rs4267853(A,G); rs10035095(A,G); rs4452539(T,C); rs10050545(A,G); rs6863995(T,A); rs6877961(G,A); rs10038378(G,A); rs10054147(T,C); rs10036503(T,A); rs13158578(A,G); rs35862107(A,G); rs7706384(A,G); rs7727651(G,A); rs188673066(A,T); rs6890308(C,G); rs4333298(C,T); rs35801602(C,T); rs10058628(T,C); rs11745552(G,A); rs4703707(T,G); rs12109439(T,C); rs1129691(T,C); rs6877133(G,T); rs6899112(A,G); rs11744445(A,T); rs28662810(C,T); rs72775777(C,G); rs72775779(T,A); rs13184383(G,C); rs13184703(G,A); rs10474477(A,G); rs13168171(A,G); rs10038589(T,C); rs6859984(C,T); rs5009957(G,A); rs6862109(T,A); rs11742542(C,T); rs59205567(G,A); rs4703708(G,A); rs6453224(G,T); rs3925034(G,A); rs4326119(C,A); rs4074256(A,G); rs2068434(A,G); rs4704317(C,T); rs4704318(T,C); rs4703709(G,T); rs13187591(G,C); rs10942782(T,C); rs62364799(G,A); rs78973453(A,G); rs10942783(A,C); rs10045331(T,A); rs4703710(T,C); rs13153728(A,C); rs13172341(C,T); rs13154264(A,G); rs13158404(T,C); rs10035371(A,G); rs10035441(A,G); rs6884352(G,C); rs7711417(T,C); rs75751487(C,T); rs4516832(G,A); rs6891303(G,A); rs6877305(T,G); rs7707762(C,G); rs76431346(G,A); rs62361960(A,G); rs13185509(A,G); rs6453225(A,C); rs6453226(A,C); rs7727095(A,G); rs6892634(A,G); rs11743558(A,C); rs10059685(T,C); rs188973090(T,C); rs142796418(C,T); rs66732343(C,A); rs7710225(G,A); rs10064273(T,G); rs7711045(G,A); rs116289500(A,G); rs10066611(A,G); rs72775785(A,G); rs10066800(A,G); rs10073517(G,A); rs7722628(C,T); rs7722629(C,T); rs7721561(G,A); rs6868542(A,G); rs78809842(C,T); rs77456191(T,G); rs66809740(A,G); rs6453227(G,A); rs75589359(T,A); rs12697853(C,T); rs35259902(C,T); rs13181156(T,A); rs6863053(G,A); rs4544808(A,C); rs35854488(T,G); rs6878408(T,C); rs10079855(C,A); rs4704320(T,G); rs72775791(T,C); rs62361963(G,A); rs7737478(C,T); rs12332250(A,G); rs10057926(A,G); rs10080194(C,T); rs36184107(T,C); rs4516825(T,G); rs62361964(G,C); rs62361965(G,A); rs9293686(A,G); rs7711193(T,C); rs4704321(C,T); rs36041872(G,A); rs62361967(A,G); rs4703711(C,T); rs4585424(C,T); rs7737274(C,T); rs113568003(C,T); rs6453229(C,T); rs62361968(C,T); rs28528159(G,A); rs6453230(G,A); rs2359198(A,G); rs62361970(G,T); rs6872396(C,T); rs4145111(A,C); rs4704324(G,A); rs12522582(C,A); rs16873459(A,T); rs6886903(A,C); rs10035948(G,C); rs2884654(G,A); rs4235700(A,G); rs80233413(C,T); rs10043064(C,T); rs2047731(A,G); rs7707801(T,C); rs115352191(A,T); rs17748061(C,T); rs7713954(T,C); rs4704326(A,G); rs138627507(G,A); rs116069612(A,G); rs16873461(T,C); rs4704327(A,G); rs9686939(A,G); rs9687487(G,A); rs75476743(T,C); rs2202113(T,A); rs2202114(T,C); rs13355881(C,T); rs7731027(C,T); rs10462543(A,G); rs9293687(A,G); rs9293688(C,T); rs4703712(A,C); rs10064543(G,A); rs111878060(C,T); rs16873476(T,C); rs12513951(C,T); rs72775801(A,G); rs75291218(T,C); rs4704328(C,T); rs58542602(A,G); rs6893849(T,C); rs4704329(C,A); rs4704330(A,G); rs4704331(C,G); rs10065424(T,C); rs4704332(A,C); rs4704333(C,T); rs62361989(G,A); rs6875519(C,A); rs114821105(C,T); rs879017(A,G); rs873787(G,A); rs141128819(T,C); rs115302538(A,G); rs72777503(A,G); rs3885957(T,C); rs12518675(A,T); rs12521026(G,C); rs10474480(A,G); rs10474481(T,G); rs12519329(A,G); rs10041515(A,T); rs12519473(A,G); rs10044688(G,A); rs12657065(A,C); rs4704334(A,C); rs75531184(G,T); rs62361993(T,G); rs116663180(G,A); rs62361994(A,T); rs4704335(A,C); rs62361995(G,A); rs76365530(G,T); rs12513594(G,A); rs77234863(C,G); rs75225145(G,C); rs3912001(C,G); rs111790429(G,A); rs10942784(C,A); rs10055118(G,T); rs74442978(T,A); rs142513059(C,T); rs74462895(C,T); rs10072548(C,T); rs10080190(A,G); rs140088773(A,T); rs3913473(A,T); rs3913474(C,T); rs3913475(C,T); rs6453231(T,G); rs7710523(T,A); rs115418253(T,C); rs17680732(C,A); rs114719298(G,A); rs58087114(C,T); rs115865393(C,A); rs79537528(A,G); rs6869692(G,A); rs1566(A,G); rs72777511(C,T); rs1501690(A,G); rs869733(T,C); rs17680756(G,A); rs6453232(A,G); rs115779460(G,A); rs10078127(C,T); rs61233297(G,A); rs4704336(A,G); rs12523647(C,T); rs12513400(C,T); rs10474482(C,T); rs34567739(G,A); rs74405149(C,A); rs142831157(G,A); rs7735089(G,C); rs7735600(G,A); rs115113615(C,T); rs4704337(G,A); rs186787270(C,T); rs55699952(G,A); rs4704338(G,A); rs4704339(A,G); rs16873483(A,G); rs3797373(T,C); rs3082639(T,G); rs3797376(A,G); rs77841122(G,A); rs3776768(C,T); rs12109754(A,G); rs114156959(T,A); rs17748322(T,C); rs145441996(A,C); rs73121895(G,A); rs115053642(T,A); rs78114638(A,G); rs116575996(C,T); rs62362011(T,C); rs62362012(T,C); rs115836959(T,C); rs145440036(C,T); rs905162(G,A); rs74602434(G,A); rs905163(A,G); rs905164(A,G); rs2840106(T,G); rs138520013(C,T); rs2134190(A,G); rs62362013(G,T); rs10073592(T,C); rs62362014(G,A); rs62362015(C,T); rs115928024(G,A); rs62362016(G,C); rs116284097(G,A); rs2173926(T,C); rs3822528(A,G); rs1131232(G,A); rs4704340(A,G); rs2270908(T,C); rs2270907(A,G); rs112878151(G,C); rs9654416(T,G); rs144240270(G,C); rs115658394(T,G); rs3797378(T,C); rs62362017(C,T); rs3736395(T,G); rs3736394(G,A); rs72777520(A,G); rs3797380(C,G); rs10079178(T,A); rs3797382(C,T); rs4704341(T,A); rs116365861(T,C); rs1501788(C,T); rs1501787(G,A); rs4397115(A,G); rs9293689(G,A); rs2005247(T,C); rs2011213(T,A); rs9293690(A,C); rs144078732(G,A); rs146002643(T,C); rs115002864(G,A); rs7722452(C,T); rs75808626(T,C); rs139013851(T,C); rs147580181(C,G); rs6888854(C,T); rs141398992(T,A); rs78115482(T,A); rs76216551(G,A); rs62362018(T,C); rs11948140(C,T); rs77491266(C,T); rs11948805(C,T); rs11952193(A,G); rs11952962(T,C); rs62362019(T,A); rs62362020(G,A); rs56110610(G,A); rs112911797(A,C); rs4704342(T,C); rs4704343(T,A); rs147563888(G,A); rs72777522(C,T); rs78062727(G,A); rs10056943(C,A); rs79907392(G,A); rs10077289(C,T); rs17652394(C,T); rs4704344(T,C); rs4558967(C,T); rs16873519(C,T); rs3797385(A,T); rs6898614(C,T); rs6883527(T,A); rs11951829(A,C); rs3797387(C,T); rs6889168(T,C); rs62362022(A,C); rs76400829(G,A); rs55689909(C,T); rs1393098(G,A); rs1501689(G,A); rs114740183(T,C); rs10056433(C,T); rs62362035(A,G); rs112180703(A,G); rs7706945(A,G); rs62362036(C,T); rs3797388(C,T); rs3797389(G,A); rs62362037(G,A); rs3822529(C,G); rs112603271(A,T); rs62362038(C,A); rs62362039(C,T); rs62362040(T,G); rs116089155(A,G); rs77028445(C,T); rs3797390(A,G); rs9293691(C,T); rs10462357(C,T); rs114713484(C,T); rs62362044(C,T); rs4704345(A,G); rs4704346(C,T); rs7716863(A,G); rs7735320(C,T); rs13173701(T,A); rs12697854(C,T); rs12697855(G,A); rs12697856(G,T); rs6453233(G,C); rs6882084(T,C); rs6882116(T,G); rs6453234(C,A); rs6453235(C,T); rs6453236(G,A); rs62362045(C,T); rs1047530(T,C); rs1047529(A,C); rs2069693(G,T); rs1047494(T,C); rs2069689(A,G); rs961536(A,G); rs2069685(T,C); rs2069681(A,G); rs2069680(T,A); rs2069678(G,A); rs1875503(A,G); rs1910004(G,C); rs950643(C,G); rs2069664(G,A); rs2069663(A,G); rs2069662(G,A); rs2069698(C,T); rs2069658(A,T); rs2069657(C,T); rs2069656(A,G); rs2069655(G,A); rs924592(C,T); rs2069646(G,A); rs2069641(C,T); rs457717(A,G); rs2431349(C,A); rs3756521(C,T); rs2431350(C,G); rs442721(T,C); rs382705(G,C); rs416451(C,G); rs1697845(C,T); rs2455219(A,G); rs2455220(T,C); rs6881371(A,G); rs2455221(G,A); rs2431351(C,T); rs2431352(T,G); rs2909888(A,G); rs2431353(T,C); rs2455222(G,A); rs2431354(C,T); rs2455223(G,A); rs10805905(A,G); rs2455224(T,C); rs10077302(T,C); rs2431356(G,A); rs6453237(T,A); rs10045033(A,T); rs6453238(T,A); rs73123717(C,G); rs3822541(G,T); rs2455225(A,G); rs2431358(C,T); rs2455226(A,T); rs2431359(C,T); rs2909889(A,G); rs2910822(T,C); rs17567779(G,A); rs463815(A,G); rs463272(C,T); rs390086(C,T); rs3797400(G,A); rs457233(G,A); rs465959(G,A); rs406217(G,A); rs3797405(A,G); rs410262(C,T); rs428121(T,G); rs372390(T,C); rs429071(A,G); rs431160(C,G); rs3797409(C,T); rs3797410(G,A); rs73123736(C,T); rs441157(A,T); rs3797412(A,G); rs113517708(T,C); rs7728450(T,C); rs12513912(G,C); rs402804(T,C); rs2909890(A,G); rs2909891(A,G); rs395661(T,C); rs2909892(G,A); rs1697844(A,G); rs2432192(A,G); rs2455227(G,A); rs10035308(T,C); rs10042932(C,T); rs10037254(G,A); rs17652611(A,G); rs6860675(T,G); rs2455228(G,A); rs2431360(A,T); rs2432180(A,G); rs73123746(T,A); rs13173162(C,T); rs113097343(C,T); rs6453239(C,T); rs6453240(A,G); rs6867296(A,G); rs2455229(G,A); rs2910819(C,T); rs2455230(G,C); rs2937415(C,T); rs2516272(A,C); rs2455231(T,C); rs2432181(G,A); rs2432182(A,G); rs2431357(A,G); rs2431355(G,T); rs2432183(G,A); rs10474483(T,G); rs16873541(A,C); rs2455232(G,A); rs2455233(G,A); rs3797418(G,T); rs2432184(A,T); rs56149215(A,G); rs2432185(C,T); rs439170(T,A); rs190582089(C,T); rs462322(G,T); rs462315(G,A); rs455249(C,G); rs457821(G,A); rs590674(A,T); rs388058(T,G); rs114677303(G,T); rs371806(C,G); rs75922924(G,A); rs79320830(C,T); rs2455234(A,G); rs2431347(G,A); rs2431348(C,A); rs2937414(T,A); rs2909886(A,G); rs2937413(C,T); rs2910820(A,G); rs2937412(T,G); rs460617(A,G); rs2909887(G,A); rs456114(G,A); rs13170396(A,G); rs458426(A,G); rs466101(G,A); rs466170(G,A); rs385385(A,G); rs421226(A,G); rs2455235(A,T); rs421666(G,T); rs10066333(G,C); rs2194254(G,A); rs138270471(G,A); rs2059219(T,A); rs2059221(A,G); rs2455236(A,G); rs79280348(G,A); rs427380(C,T); rs420138(G,A); rs457999(G,T); rs463016(C,G); rs186286911(T,C); rs458059(G,A); rs7717164(G,A); rs460562(G,T); rs2059222(G,A); rs456801(T,C); rs458661(C,T); rs456918(T,A); rs458142(T,C); rs463079(G,A); rs429703(A,G); rs460374(A,T); rs465988(G,T); rs460482(C,T); rs462587(A,G); rs460294(G,A); rs615951(G,A); rs2455213(A,G); rs2432186(T,G); rs2431366(T,A); rs2455214(G,A); rs2431364(T,G); rs186190186(C,G); rs142103523(G,A); rs1423605(G,C); rs460431(T,C); rs461273(A,G); rs430389(A,G); rs457182(G,A); rs62362962(A,G); rs457054(A,G); rs456708(A,G); rs461475(A,G); rs456572(A,T); rs77432821(A,G); rs12697857(G,A); rs458573(T,A); rs463147(T,G); rs461187(A,G); rs149236008(A,G); rs463973(A,G); rs2252231(T,C); rs2431363(A,G); rs2431362(G,A); rs2455215(T,C); rs2432188(G,C); rs2431361(C,A); rs458581(T,C); rs457745(T,A); rs457127(C,A); rs466393(T,C); rs462307(A,G); rs3815774(T,G); rs462219(A,G); rs458994(A,C); rs113700636(G,A); rs465731(G,A); rs459846(G,A); rs455933(G,A); rs411588(T,C); rs419660(C,G); rs444783(C,A); rs144645144(T,A); rs138601146(G,A); rs382669(T,G); rs2937411(G,A); rs144338768(C,T); rs1862244(G,A); rs192399236(G,T); rs2161218(T,C); rs13189844(G,A); rs1862243(C,G); rs2455217(C,A); rs2432189(G,A); rs664494(C,T); rs32947(T,C); rs3797435(A,G); rs9293692(C,G); rs2287930(G,A); rs2287931(T,C); rs4704347(C,T); rs4704348(A,G); rs4704349(T,A); rs6896971(A,G); rs6876309(G,A); rs36001422(A,G); rs6862238(A,G); rs3797437(C,A); rs3797438(T,G); rs3822546(T,G); rs3797441(A,C); rs6886902(G,A); rs2161589(C,G); rs1038919(T,G); rs10942788(G,C); rs1038920(G,A); rs3797442(G,A); rs3797443(A,G); rs3797444(T,C); rs253089(T,G); rs3797446(G,A); rs253090(C,T); rs6869755(C,T); rs6869765(C,T); rs6890835(A,G); rs6873558(G,A); rs7734540(A,G); rs253091(G,A); rs253093(T,C); rs253094(A,G); rs145998117(C,G); rs253095(G,C); rs4704350(G,A); rs253096(A,G); rs73125588(G,A); rs73764706(G,A); rs17568154(T,C); rs4235701(A,G); rs34950321(C,T); rs3764935(G,A); rs3797450(A,T); rs3776771(A,G); rs193013079(C,T); rs3776772(A,G); rs13181696(A,G); rs3776773(G,A); rs4704351(A,G); rs57811893(G,A); rs7734335(A,G); rs35787934(G,A); rs35919076(A,G); rs111422822(C,T); rs17652917(C,T); rs4704352(G,A); rs56832798(A,T); rs41271836(A,G); rs73125590(G,A); rs73125592(T,C); rs10063153(T,G); rs6453244(T,C); rs141750292(C,G); rs2303162(C,T); rs115894903(C,T); rs11741978(C,T); rs112506424(G,T); rs111338176(C,T); rs80194933(T,C); rs111783543(C,A); rs112500780(G,C); rs253165(A,G); rs383644(T,C); rs112535938(G,A); rs7709577(A,T); rs13170865(T,A); rs114123629(C,T); rs77720536(A,G); rs56215827(G,C); rs146224808(T,G); rs10447162(G,C); rs10805907(T,C); rs142170858(T,C); rs78591028(G,T); rs7725717(A,G); rs7706686(C,T); rs80329490(G,A); rs144227274(C,T); rs73764708(A,T); rs11951337(G,A); rs61128079(T,A); rs7708326(T,G); rs979862(T,C); rs11749139(T,G); rs6883768(A,G); rs72761032(T,G); rs6884442(A,C); rs59277133(C,T); rs10514070(G,A); rs1472215(C,T); rs116817624(T,C); rs73127567(G,A); rs56347914(C,A); rs10036196(A,G); rs10036832(T,C); rs7712485(T,C); rs4703715(T,C); rs7731047(C,T); rs4704354(G,T); rs4704355(G,A); rs4704356(C,A); rs10514071(G,A); rs11951708(T,C); rs13188539(G,A); rs13188565(G,A); rs13175585(T,C); rs13154881(G,A); rs13154915(G,A); rs11952627(T,C); rs10213703(C,T); rs10214128(G,A); rs10213750(C,T); rs10214133(G,A); rs10214134(G,A); rs10213957(A,G); rs12054935(A,G); rs10942789(C,T); rs468648(A,G); rs10063791(A,G); rs113695873(G,A); rs28609562(A,T); rs13168057(C,T); rs11956898(G,T); rs13181615(C,T); rs11950408(T,C); rs2307122(A,G); rs34954(C,G); rs3816909(T,G); rs10942790(G,A); rs111692848(G,A); rs10063755(G,A); rs10063832(G,A); rs71630933(G,T); rs3822547(A,G); rs3822548(T,C); rs60285761(C,T); rs3797451(T,C); rs3797452(T,C); rs12697858(T,C); rs10060848(A,G); rs10062454(T,G); rs10053089(C,T); rs62363009(G,A); rs4704357(T,A); rs1689771(T,A); rs13188750(T,C); rs113440882(A,G); rs11953613(A,T); rs10055683(C,T); rs7717826(C,T); rs463188(A,T); rs464494(C,T); rs12735(A,G) |
| ccdsGene name | CCDS34188.1 |
| cytoBand name | 5q13.3 |
| EntrezGene GeneID | 10788 |
| EntrezGene Description | IQ motif containing GTPase activating protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IQGAP2:NM_006633:exon23:c.C2681T:p.T894I,IQGAP2:NM_001285460:exon22:c.C2531T:p.T844I,IQGAP2:NM_001285462:exon11:c.C1169T:p.T390I,IQGAP2:NM_001285461:exon11:c.C1169T:p.T390I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6695 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00824175824176 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0224274406332 |
| dbSNP GMAF | 0.008264 |
| ESP Afr MAF | 0.002497 |
| ESP All MAF | 0.015317 |
| ESP Eur/Amr MAF | 0.021896 |
| ExAC AF | 0.017 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Horizontal nystagmus
NEUROLOGIC:
[Central nervous system];
Ataxia;
Delayed motor development;
Dysarthria;
Dysdiadochokinesis;
Broad-based gait;
Cerebellar atrophy
MISCELLANEOUS:
Onset in infancy
OMIM Title
*605401 IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 2; IQGAP2
OMIM Description
CLONING
GTPase-activating proteins (GAPs) accelerate the intrinsic GTPase
activity of Ras proteins, resulting in conversion of these GTPases from
their active GTP-bound form to the inactive GDP-bound form (see 139150).
IQ motif-containing GAP1 (IQGAP1; 603379) was identified based on its
homology to a RasGAP homolog from S. pombe, Sar1. Brill et al. (1996)
identified IQGAP2 by screening a mouse brain cDNA library with a human
IQGAP1 probe at low stringency. Human IQGAP2 cDNA clones were then
isolated from liver cDNA libraries. The assembled full-length sequence
encodes a 1,575-amino acid protein that is 62% identical to IQGAP1 and
contains all domains previously identified in IQGAP1. These domains
include a calponin homology (CH) domain, which is present in several
actin-binding proteins; an IQGAP repeat domain containing 5 copies of a
novel 50- to 55-amino acid repeat; a WW putative protein interaction
domain; and 4 IQ motifs implicated in calmodulin (CALM1; 114180)
binding. Like IQGAP1, IQGAP2 has several segments that have a high
probability of forming coiled-coil structures similar to those in myosin
heavy chains and intermediate filament proteins. IQGAP1 and IQGAP2 also
share 25% amino acid identity with Sar1 over a 700-amino acid region.
Northern blot analysis detected expression of an IQGAP2 transcript in
mouse liver and of a shorter transcript in mouse testis. IQGAP2
expression was also detected in human hepatoblastoma and hepatocellular
carcinoma cell lines, suggesting that IQGAP2 is expressed within
hepatocytes in the liver.
GENE FUNCTION
By transfection and coprecipitation experiments, Brill et al. (1996)
demonstrated that IQGAP2 bound CALM1 and that this binding required the
IQ motifs of IQGAP2. IQGAP2 also bound the GTPases CDC42 (116952) and
RAC1 (602048) through its C terminus, but it showed no evidence of GAP
activity toward them.
MAPPING
By Southern blot analysis of somatic cell hybrid DNA, Brill et al.
(1996) mapped the IQGAP2 gene to chromosome 5q11-q13.
NCRUPAR
| dbSNP name | rs6887764(G,A); rs12517193(G,A) |
| cytoBand name | 5q13.3 |
| EntrezGene GeneID | 100302746 |
| snpEff Gene Name | IQGAP2 |
| EntrezGene Description | non-protein coding RNA, upstream of F2R/PAR1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.259 |
LOC728769
| dbSNP name | rs141178499(T,A); rs4704506(G,T) |
| cytoBand name | 5q14.1 |
| EntrezGene GeneID | 728769 |
| snpEff Gene Name | CTD-2037K23.2 |
| EntrezGene Description | uncharacterized LOC728769 |
| EntrezGene Type of gene | unknown |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
CTD-2201I18.1
| dbSNP name | rs77595215(G,A); rs9293800(G,A); rs2241824(T,C); rs12659471(A,C); rs4703797(A,G); rs1465853(A,G); rs256439(T,C); rs256438(T,G); rs256437(T,C); rs12110039(A,G); rs3749685(G,T); rs17878747(C,A); rs394947(C,T); rs6897999(A,G); rs384941(C,T); rs2229396(G,A); rs75841921(G,C); rs2288394(C,T); rs17885983(T,C); rs2288395(G,C); rs10514175(G,A); rs2434301(A,G); rs6891246(A,T); rs17880343(A,G); rs2913544(G,T); rs2918422(C,G); rs2434300(A,G); rs140954796(G,C) |
| ccdsGene name | CCDS4049.1 |
| CosmicCodingMuts gene | THBS4 |
| cytoBand name | 5q14.1 |
| EntrezGene GeneID | 101929215 |
| EntrezGene Symbol | LOC101929215 |
| snpEff Gene Name | THBS4 |
| EntrezGene Description | uncharacterized LOC101929215 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | THBS4:NM_003248:exon22:c.G2862C:p.Q954H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7706 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P35443 |
| dbNSFP Uniprot ID | TSP4_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.001307 |
| ESP Eur/Amr MAF | 0.001977 |
| ExAC AF | 0.001553 |
LOC644936
| dbSNP name | rs4703807(G,A); rs11741016(G,A); rs115436468(C,T); rs11738835(T,C); rs11747861(C,T); rs35486429(C,T) |
| cytoBand name | 5q14.1 |
| EntrezGene GeneID | 644936 |
| snpEff Gene Name | CTC-512J14.7 |
| EntrezGene Description | actin, beta pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4394 |
SPZ1
| dbSNP name | rs1862136(G,C); rs2047589(G,A); rs35337118(A,C); rs16876315(T,C); rs1052345(A,T) |
| ccdsGene name | CCDS43336.1 |
| cytoBand name | 5q14.1 |
| EntrezGene GeneID | 84654 |
| EntrezGene Description | spermatogenic leucine zipper 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SPZ1:NM_032567:exon1:c.G49C:p.V17L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BXG8 |
| dbNSFP Uniprot ID | SPZ1_HUMAN |
| dbNSFP KGp1 AF | 0.776098901099 |
| dbNSFP KGp1 Afr AF | 0.849593495935 |
| dbNSFP KGp1 Amr AF | 0.682320441989 |
| dbNSFP KGp1 Asn AF | 0.949300699301 |
| dbNSFP KGp1 Eur AF | 0.642480211082 |
| dbSNP GMAF | 0.2231 |
| ESP Afr MAF | 0.174215 |
| ESP All MAF | 0.277623 |
| ESP Eur/Amr MAF | 0.326061 |
| ExAC AF | 0.715,4.085e-05 |
CRSP8P
| dbSNP name | rs13177210(A,C); rs116822866(T,C) |
| cytoBand name | 5q14.1 |
| EntrezGene GeneID | 441089 |
| snpEff Gene Name | CTC-512J14.5 |
| EntrezGene Description | mediator complex subunit 27 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1387 |
LOC100289230
| dbSNP name | rs34495(G,T); rs149968041(T,C) |
| cytoBand name | 5q21.1 |
| EntrezGene GeneID | 100289230 |
| snpEff Gene Name | CHD1 |
| EntrezGene Description | uncharacterized LOC100289230 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2815 |
RAB9BP1
| dbSNP name | rs188741095(G,A); rs4571441(T,C) |
| cytoBand name | 5q21.2 |
| EntrezGene GeneID | 9366 |
| snpEff Gene Name | CTD-2374C24.1 |
| EntrezGene Description | RAB9B, member RAS oncogene family pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
LINC01023
| dbSNP name | rs10066173(A,G) |
| cytoBand name | 5q21.3 |
| EntrezGene GeneID | 100652853 |
| snpEff Gene Name | AC034207.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 1023 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2075 |
SNORA13
| dbSNP name | rs17266115(T,G) |
| cytoBand name | 5q22.1 |
| EntrezGene GeneID | 654322 |
| snpEff Gene Name | EPB41L4A |
| EntrezGene Description | small nucleolar RNA, H/ACA box 13 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08448 |
| ESP Afr MAF | 0.103881 |
| ESP All MAF | 0.136379 |
| ESP Eur/Amr MAF | 0.150678 |
| ExAC AF | 0.126 |
EPB41L4A-AS2
| dbSNP name | rs2900063(C,T) |
| cytoBand name | 5q22.2 |
| EntrezGene GeneID | 54508 |
| snpEff Gene Name | EPB41L4A |
| EntrezGene Description | EPB41L4A antisense RNA 2 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1143 |
TSSK1B
| dbSNP name | rs77802290(G,C); rs7730801(T,A); rs17135618(A,G); rs11241209(G,T); rs56081130(G,A); rs11953401(G,A); rs34936289(C,T); rs35724644(G,T); rs78102202(G,A) |
| ccdsGene name | CCDS43351.1 |
| cytoBand name | 5q22.2 |
| EntrezGene GeneID | 83942 |
| snpEff Gene Name | MCC |
| EntrezGene Description | testis-specific serine kinase 1B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04959 |
SOWAHA
| dbSNP name | rs40470(T,G); rs10051188(A,T); rs10075719(T,G) |
| ccdsGene name | CCDS43361.1 |
| cytoBand name | 5q31.1 |
| EntrezGene GeneID | 134548 |
| snpEff Gene Name | ANKRD43 |
| EntrezGene Description | sosondowah ankyrin repeat domain family member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SOWAHA:NM_175873:exon1:c.T1635G:p.F545L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2M3V2 |
| dbNSFP Uniprot ID | ANR43_HUMAN |
| dbNSFP KGp1 AF | 1.0 |
| dbNSFP KGp1 Afr AF | 1.0 |
| dbNSFP KGp1 Amr AF | 1.0 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.0 |
| ExAC AF | 1.0 |
C5orf66-AS1
| dbSNP name | rs1643538(G,C); rs1700488(G,A) |
| cytoBand name | 5q31.1 |
| EntrezGene GeneID | 101927953 |
| EntrezGene Symbol | LOC101927953 |
| snpEff Gene Name | CTC-203F4.1 |
| EntrezGene Description | uncharacterized LOC101927953 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1593 |
C5orf20
| dbSNP name | rs12654326(G,T); rs4976256(T,C); rs17733025(C,A); rs10074641(A,C); rs10059928(G,C); rs4976298(T,C); rs17168353(A,G); rs73789361(G,A); rs10061623(G,A); rs79805596(G,A); rs744247(C,T); rs17168355(G,A); rs17168357(G,A); rs67187482(T,A); rs12518053(G,T); rs12520799(T,A); rs12520809(T,C); rs1031844(T,G) |
| cytoBand name | 5q31.1 |
| EntrezGene GeneID | 140947 |
| EntrezGene Description | chromosome 5 open reading frame 20 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1024 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Normal kidneys
SKELETAL:
[Limbs];
Osteolysis of patellae (bone loss of posterior patella);
[Hands];
Osteolysis of scaphoids (bone loss and fragmentation of scaphoid);
Short fourth metacarpals;
[Feet];
Osteolysis of tali (bone loss and fragmentation of posterior talus)
MISCELLANEOUS:
Onset 13-15 years
OMIM Title
*609710 DENDRITIC CELL NUCLEAR PROTEIN 1
;;DCNP1;;
C5ORF20
OMIM Description
CLONING
Masuda et al. (2002) used PCR-based cDNA subtraction in conjunction with
differential screening to isolate genes specifically expressed in human
hematopoietic stem cell-derived dendritic cells (DCs) but not in
monocytes. They identified a novel gene, DCNP1 (dendritic cell nuclear
protein-1), encoding a deduced 244-amino acid protein with a predicted
molecular mass of approximately 27 kD. Northern blot analysis detected
expression of DCNP1 in DCs but not in monocytes or B cells, and at a
much higher level in mature than in immature DCs, indicating an
upregulation of transcription during the differentiation and maturation
processes of DCs. Northern blot analysis on multiple human tissues
detected expression of DCNP1 in brain and skeletal muscle.
Immunofluorescence analysis revealed that DCNP1 resides mainly in the
nucleus, particularly on the periphery. Using immunohistochemical
analysis, Masuda et al. (2002) compared the expression of DCNP1 and CD68
(153634), a marker for DCs and macrophages, in spleen, lymph node,
liver, and brain. DCNP1-positive and CD68-positive cells showed a
similar localization in these tissues, but there were fewer
DCNP1-positive than CD68-positive cells.
MAPPING
By sequence analysis, Masuda et al. (2002) mapped the DCNP1 gene to
chromosome 5.
GENE STRUCTURE
Masuda et al. (2002) determined that the DCNP1 gene contains 1 exon.
NEUROG1
| dbSNP name | rs192260351(T,C); rs8192558(A,C) |
| cytoBand name | 5q31.1 |
| EntrezGene GeneID | 4762 |
| EntrezGene Description | neurogenin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEMATOLOGY:
Moderate-severe bleeding tendencies (epistaxis, menorrhagia, hemarthrosis,
easy bruisability);
Thrombocytopenia, mild;
Mildly decreased to low-normal platelet count (80-150 x 10(9)/L);
Bleeding time normal to mildly prolonged;
Increased platelet content of PLAU;
Degraded platelet alpha-granule proteins;
Reduced platelet aggregation response to adenosine 5'-diphosphate
(ADP);
Absent platelet aggregation response to epinephrine;
Normal platelet aggregation response to ristocetin and arachidonic
acid (AA);
Normal platelet fibrinogen;
Normal von Willebrand factor;
Normal thrombospondin;
Normal beta-thromboglobulin;
Normal platelet morphology;
Decreased multimerin
MISCELLANEOUS:
Bleeding is usually delayed-onset after challenge;
Good response to fibrinolytic inhibitors;
Prevalence of 1 in 300,000 in Quebec
MOLECULAR BASIS:
Caused by tandem duplication of the urinary plasminogen activator
gene (PLAU, 191840.0002)
OMIM Title
*601726 NEUROGENIN 1; NEUROG1
;;NGN1;;
NEUROGENIC DIFFERENTIATION 3; NEUROD3
OMIM Description
Basic helix-loop-helix (bHLH) proteins are transcription factors
involved in determining cell type during development. Lee et al. (1995)
described a bHLH protein, which they termed NeuroD (neurogenic
differentiation), that functions during neurogenesis. McCormick et al.
(1996) described the cloning and characterization of 2 additional NEUROD
genes, NEUROD2 (601725) and NEUROD3. The latter gene has also been
designated NEUROG1 and NGN1. Sequences for the mouse and human homologs
were presented. NEUROD2 shows a high degree of homology to the bHLH
region of NEUROD, whereas NEUROD3 is more distantly related. McCormick
et al. (1996) found that mouse NeuroD3 is expressed transiently during
embryonic development, with the highest level of expression between days
10 and 12.
GENE FUNCTION
Sun et al. (2001) found that in addition to inducing neurogenesis, NGN1
inhibits the differentiation of neural stem cells into astrocytes. While
NGN1 promotes neurogenesis by functioning as a transcriptional
activator, NGN1 inhibits astrocyte differentiation by sequestering the
CREB-binding protein (CBP; 600140)/SMAD1 (601595) transcription complex
away from astrocyte differentiation genes and by inhibiting the
activation of STAT transcription factors (600555) necessary for
gliogenesis. Thus, 2 distinct mechanisms are involved in the activation
and suppression of gene expression during cell-fate specification by
NGN1.
Ma et al. (1999) presented a detailed analysis of Neurod3 and Neurog2
(606624) expression during neural crest migration and early dorsal root
gangliogenesis in wildtype and various neurogenin mutant mouse embryos.
They concluded that Neurod3 and Neurog2 control 2 distinct phases of
neurogenesis that generate different classes of sensory neurons.
MAPPING
Tamimi et al. (1997) mapped the NEUROD3 gene to chromosome 5q23-q31 by
fluorescence in situ hybridization. They mapped the mouse homolog to
chromosome 13.
ANIMAL MODEL
Ma et al. (1998) generated Ngn1-deficient mice that failed to generate
the proximal subset of cranial sensory neurons. They concluded that Ngn1
is required for the activation of a cascade of downstream bHLH factors
and functions in the determination of neuronal precursors.
Using immunocytochemistry, nerve tract tracing, and electron microscopy,
Ma et al. (2000) characterized an abnormal inner ear phenotype in the
Ngn1-null mutants generated by Ma et al. (1998). In summary, Ngn1-null
mutants lack differentiated inner ear sensory neurons. Ma et al. (2000)
hypothesized that efferent and autonomic nerve fibers are lost
secondarily to the absence of afferent nerve fibers. The Ngn1 mutant
ears develop smaller sensory epithelia with hair cells that are
morphologically normal but disorganized and reduced in number. Ma et al.
(2000) concluded that Ngn1 is essential for development of the inner ear
sensory neurons.
Using in situ hybridization and immunofluorescence, Gowan et al. (2001)
compared the embryonic expression of Mash1 (ASCL1; 100790), Math1
(ATOH1; 601461), and Ngn1 in mouse and concluded that they define 3
distinct, nonoverlapping populations of neural progenitor cells in the
dorsal neural tube. They used reporter gene constructs in transgenic
mice to identify a neural-specific enhancer sequence 5-prime of the Ngn1
coding region that directs gene expression to a subset of the normal
Ngn1 expression domain. Combining their expression data with loss- and
gain-of-function experiments in mouse and chick, Gowan et al. (2001)
hypothesized that Atoh1 and the neurogenin factors repress each other's
expression, resulting in progenitors expressing only one bHLH factor.
Ngn1 progenitors give rise to a subset of dorsal cells that coexpress
Lim1/2 (LHX1, 601999; LHX2, 603759) and Brn3a (POU4F1; 601632). Either
Ngn1 or Neurog2 is required for these cells to form. Gowan et al. (2001)
concluded that although Ngn1, Neurog2, and Atoh1 appear to have
redundant functions in inducing neurogenesis, they have distinct roles
in specifying neuronal cell subtype in the dorsal neural tube.
LOC389332
| dbSNP name | rs13172407(G,C); rs2287961(C,T); rs2287962(C,A); rs2287963(A,G) |
| cytoBand name | 5q31.1 |
| EntrezGene GeneID | 389332 |
| EntrezGene Description | uncharacterized LOC389332 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1552 |
HNRNPA0
| dbSNP name | rs7875(T,C) |
| cytoBand name | 5q31.2 |
| EntrezGene GeneID | 26249 |
| EntrezGene Symbol | KLHL3 |
| EntrezGene Description | kelch-like family member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1396 |
PROB1
| dbSNP name | rs141056757(G,T) |
| ccdsGene name | CCDS54909.1 |
| cytoBand name | 5q31.2 |
| EntrezGene GeneID | 389333 |
| snpEff Gene Name | AC135457.1 |
| EntrezGene Description | proline-rich basic protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PROB1:NM_001161546:exon1:c.C1507A:p.P503T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0231 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EW31 |
| dbNSFP Uniprot ID | CE065_HUMAN |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.027457 |
| ESP All MAF | 0.008541 |
| ESP Eur/Amr MAF | 0.000314 |
| ExAC AF | 0.00195 |
LINC01024
| dbSNP name | rs77649854(G,T); rs193014130(T,C); rs191502085(C,A); rs183902066(G,A) |
| cytoBand name | 5q31.2 |
| EntrezGene GeneID | 100505636 |
| snpEff Gene Name | PURA |
| EntrezGene Description | long intergenic non-protein coding RNA 1024 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.124 |
PURA
| dbSNP name | rs2013169(T,A) |
| cytoBand name | 5q31.2 |
| EntrezGene GeneID | 5813 |
| EntrezGene Description | purine-rich element binding protein A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.185 |
OMIM Clinical Significance
Metabolic:
Malignant hyperthermia;
Acidosis;
Hypoxia
Misc:
Triggered by certain anesthetics, such as halothane or succinylcholine;
Rapid body temperature rise
Muscle:
Masseter or generalized muscle contracture;
Rhabdomyolysis
Inheritance:
Autosomal dominant (3q13.1)
OMIM Title
*600473 PURINE-RICH ELEMENT-BINDING PROTEIN A; PURA
;;PUR-ALPHA
OMIM Description
CLONING
Bergemann and Johnson (1992) characterized an approximately 28-kD
protein from HeLa cell nuclear extracts that bound specifically to a
purine-rich repeat element located at a site of DNA binding upstream of
the human c-myc gene, and at origins of replication and transcription
initiation sites in a variety of eukaryotes. Bergemann et al. (1992)
cloned and sequenced the cDNA encoding this protein, designated PURA,
from a human fetal liver cDNA library. The deduced 322-amino acid
protein contains an N-terminal glycine-rich region, 3 repeats of a
23-amino acid class I motif, 2 repeats of a 26-amino acid class II
motif, an amphipathic helix, and a C-terminal glutamine-glutamate-rich
domain. Northern blot analysis of human fetal liver, HeLa cells, lung
tumor cells, and hepatoma cells showed expression of 4 transcripts, from
2.0 to 5.0 kb, that are either multiple PURA transcripts or homologous
mRNAs. RACE-PCR suggested the presence of 3 PURA transcripts of 1.6 to
2.1 kb.
Kelm et al. (1997) cloned mouse Pura (p46) and Purb (p44) and identified
them as the 2 components of the previously designated vascular actin
single-stranded DNA-binding factor-2, which specifically bound to
purine-rich regions within an enhancer and an exon of vascular actin
(Kelm et al., 1996).
GENE FUNCTION
Bergemann et al. (1992) used gel shift assays to show that PURA binds
preferentially to single-stranded DNA containing the purine-rich
element.
Pur-alpha is a single-stranded DNA-binding protein with specific
affinity for a purine-rich element of the configuration (GGN)n present
in several initiation zones of eukaryotic DNA replication. It interacts
with large T-antigen and cellular protein YB-1 (154030) to activate JC
viral DNA transcription in human cells (Chen et al., 1995). The
functional activities of Pur-alpha, together with its evolutionary
conservation, suggested that it may represent an important link between
DNA replication and differential gene expression.
Gallia et al. (2000) reviewed the structure and function of PURA. The
central repeat region of PURA mediates binding to its single-stranded
DNA target sequence as well as to regulatory proteins, both of which are
modulated by RNA. In its C-terminal half, PURA contains an amphipathic
alpha-helix with limited homology to the large tumor antigen of several
polyomaviruses with a PSYC, or 'psycho,' motif. It also contains an
N-terminal glycine-rich region. PURA is implicated in the
transcriptional control of a number of cellular genes, including MBP
(159430), FE65 (APBB1; 602709), and neuronal ACHR (e.g., CHRNB2;
118507), as well as viral promoters for JCV and HIV-1, which replicate
in the central nervous system. PURA is also involved in the control of
cell growth and interacts with the hypophosphorylated form of RB1
(614041).
Fragile X-associated tremor/ataxia syndrome (FXTAS; 300623) is a
neurodegenerative disorder caused by FMR1 premutation alleles containing
55 to 200 repeats of the trinucleotide CGG (309550.0004). Using
gel-shift assays with mouse and fly brain lysates, followed by protein
purification and mass spectroscopy, Jin et al. (2007) showed that
Pur-alpha bound (CGG)105. Pur-alpha bound CGG repeats in a
sequence-specific manner, and overexpression of Pur-alpha in a
Drosophila model of FXTAS suppressed CGG repeat-mediated
neurodegeneration in a dose-dependent manner. Furthermore,
immunohistochemical analysis showed that Pur-alpha was ubiquitously
expressed in wildtype fly eyes, but it was sequestered in inclusions in
fly eyes expressing (CGG)105. Human PURA was present in
ubiquitin-positive inclusions in postmortem FXTAS brain tissues. Jin et
al. (2007) hypothesized that PURA is sequestered from its normal
function by binding premutation CGG repeats, leading to pathologic
changes in FXTAS.
MAPPING
Using a 16-kb genomic probe together with hybridization of a cDNA probe
to blots of DNA from human/hamster cell lines, Ma et al. (1995) mapped
the PURA gene to 5q31. This region is frequently deleted in myelogenous
leukemias in hematologic malignancies and other cancers. Sequences with
homology to the PURA gene were also present at 6q14.
ANIMAL MODEL
Khalili et al. (2003) found that Pura -/- mice appeared normal at birth,
but at 2 weeks of age, they developed neurologic problems characterized
by severe tremor and spontaneous seizures, and they died by 4 weeks.
Regions of the hippocampus and cerebellum of Pura -/- mice showed
severely lower numbers of neurons compared with wildtype littermates,
and lamination of these regions was aberrant at time of death.
Immunohistochemical analysis of Mcm7 (600592), a marker for DNA
replication, revealed lack of proliferation of precursor cells in these
regions in Pura -/- mice. Proliferation was also low or absent in
several other tissues of Pura -/- mice, including those of myeloid
lineage, whereas those of Pura +/- mice were intermediate. Evaluation of
brain sections indicated reduced myelination and pathologic development
of oligodendrocytes and astrocytes. At postnatal day 5, a critical time
for cerebellar development, Pura and Cdk5 (123831) were both at peak
levels in bodies and dendrites of Purkinje cells of wildtype mice, but
both proteins were absent in dendrites of Pura -/- mice.
Immunohistochemical analysis revealed dramatic reduction in both
phosphorylated and nonphosphorylated neurofilaments in dendrites of the
Purkinje cell layer and of synapse formation in the hippocampus. Khalili
et al. (2003) concluded that PURA has a role in developmentally timed
DNA replication in specific cell types.
CD14
| dbSNP name | rs2563298(C,A); rs5744456(A,T); rs4914(C,G); rs147594602(C,T); rs2569190(A,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 929 |
| EntrezGene Description | CD14 molecule |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2117 |
OMIM Clinical Significance
Limbs:
Monophalangy of great toe
Inheritance:
Autosomal dominant
OMIM Title
*158120 MONOCYTE DIFFERENTIATION ANTIGEN CD14; CD14
;;MYELOID CELL-SPECIFIC LEUCINE-RICH GLYCOPROTEIN
OMIM Description
DESCRIPTION
CD14 is a single-copy gene encoding 2 protein forms: a 50- to 55-kD
glycosylphosphatidylinositol-anchored membrane protein (mCD14) and a
monocyte or liver-derived soluble serum protein (sCD14) that lacks the
anchor. Both molecules are critical for lipopolysaccharide
(LPS)-dependent signal transduction, and sCD14 confers LPS sensitivity
to cells lacking mCD14. Increased sCD14 levels are associated with
inflammatory infectious diseases and high mortality in gram-negative
shock (LeVan et al., 2001).
CLONING
Differentiation of myelomonocytic cells from pluripotent stem cells to
mature functioning monocytes/macrophages and granulocytes is accompanied
by a variety of changes, including the expression of new cell surface
antigens. One of these antigens, CD14, a 55-kD glycoprotein, is
preferentially expressed on the surface of mature cells of the monocytic
lineage. Goyert et al. (1988) isolated a cDNA clone encoding CD14 and
isolated the CD14 gene.
Ferrero et al. (1990) demonstrated that, as in man, the expression of
murine CD14 is limited to the myeloid lineage. In both mouse and man,
the CD14 protein contains leucine-rich motif that is repeated 10 times.
BIOCHEMICAL FEATURES
Kelley et al. (2013) determined the crystal structure of human CD14 at
4-angstrom resolution. The structure revealed a bent solenoid typical of
leucine-rich repeat proteins with an N-terminal pocket that likely binds
acylated ligands, such as LPS. The structures of human and mouse CD14
are similar, except that human CD14 contains an expanded pocket and
alternative rim residues that are probably important for LPS binding and
cell activation.
GENE FUNCTION
The expression profile of CD14, as well as its inclusion in the family
of leucine-rich proteins and the chromosomal location of other receptor
genes, supports the hypothesis that CD14 functions as a receptor. Its
receptor function was indeed demonstrated by Wright (1990) who showed
that it is a receptor for the lipopolysaccharide-binding
protein:lipopolysaccharide complex (LBP; 151990:LPS); also see Wright et
al. (1990). Gupta et al. (1996) transfected mouse 70Z/3 cells with human
CD14 and showed that these cells were responsive to peptidoglycan (PGN),
a polymer of alternating GlcNAc and MurNAc cross-linked by short
peptides, that is present in the cell walls of all bacteria, but is
particularly abundant in gram-positive bacteria. They concluded that
CD14 serves as a cell-activating receptor not only for LPS but also for
PGN.
Cells undergoing programmed cell death (apoptosis) are cleared rapidly
in vivo by phagocytes without inducing inflammation. Devitt et al.
(1998) showed that the glycoprotein CD14 on the surface of human
macrophages is important for the recognition and clearance of apoptotic
cells. CD14 can also act as a receptor that binds bacterial LPS,
triggering inflammatory responses. Overstimulation of CD14 by LPS can
cause the often fatal toxic-shock syndrome. Devitt et al. (1998) showed
that apoptotic cells interact with CD14, triggering phagocytosis of the
apoptotic cells. This interaction depends on a region of CD14 that is
identical to, or at least closely associated with, a region known to
bind LPS. However, apoptotic cells, unlike LPS, do not provoke the
release of proinflammatory cytokines from macrophages. These results
indicated that clearance of apoptotic cells is mediated by a receptor
whose interactions with 'nonself' components (LPS) and 'self' components
(apoptotic cells) produce distinct macrophage responses.
Savill (1998) summarized understanding of how ced-5 (see DOCK1; 601403)
and CD14 together with other molecules function in the engulfment of
cell corpses by macrophages in the process of programmed cell death. The
model incorporated the newly proposed functions of ced-5 and CD14.
LPS interacts with LBP and CD14 to present LPS to TLR4 (603030), which
activates inflammatory gene expression through NF-kappa-B (see 164011)
and MAPK signaling. Bochkov et al. (2002) demonstrated that oxidized
phospholipids inhibit LPS-induced but not TNF-alpha (191160)-induced or
interleukin-1-beta (147720)-induced NF-kappa-B-mediated upregulation of
inflammatory genes, by blocking the interaction of LPS with LBP and
CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited
inflammation and protected mice from lethal endotoxin shock. Thus, in
severe gram-negative bacterial infection, endogenously formed oxidized
phospholipids may function as a negative feedback to blunt innate immune
responses. Furthermore, Bochkov et al. (2002) identified chemical
structures capable of inhibiting the effects of endotoxins such as LPS
that could be used for the development of new drugs for treatment of
sepsis.
Children of farmers are at decreased risk of developing allergies.
Results of epidemiologic studies suggested that increased exposure to
microbial compounds might be responsible for this reduced risk.
Alterations in adaptive immune response were thought to be the
underlying mechanism. Lauener et al. (2002) measured the expression of
receptors for microbial compounds known to trigger the innate immune
response. They showed that blood cells from farmers' children expressed
significantly higher amounts of CD14 and Toll-like receptor-2 (TLR2;
603028) than those from non-farmers' children. They proposed that the
innate immune system responds to the microbial burden in the environment
and modulates the development of allergic disease.
Zanoni et al. (2009) found that stimulation of murine bone
marrow-derived dendritic cells (DCs) with LPS induced Src (190090)
kinase and Plcg2 (600220) activation, Ca(2+) influx, and calcineurin
(see 114105)-dependent nuclear Nfat (see 600490) translocation.
Induction of this pathway was Tlr4 independent and entirely dependent on
Cd14. Nfat activation was necessary for apoptotic death of terminally
differentiated DCs, allowing for maintenance of self-tolerance and
prevention of autoimmunity. Blocking this pathway in vivo resulted in
prolonged DC survival and an increase in T-cell priming capability.
Zanoni et al. (2009) concluded that CD14 is involved, through NFAT
activation, in regulation of the DC life cycle.
By coimmunoprecipitation and confocal microscopic analysis, Baumann et
al. (2010) showed that CD14 interacted with TLR7 (300365) and TLR9
(605474) in mouse and human cells and was required for TLR7- and
TLR9-dependent induction of proinflammatory cytokines. Cd14 was required
for Tlr9-dependent immune responses in mice and for optimal nucleic acid
uptake in mouse macrophages. Cd14 was dispensable for viral uptake in
mice, but it was required for triggering of TLR-dependent cytokine
responses. Baumann et al. (2010) concluded that CD14 has a dual role in
nucleic acid-mediated TLR activation by promoting selective uptake of
nucleic acids and acting as a coreceptor for endosomal TLR activation.
Using flow cytometry and confocal microscopy in mouse cells, Zanoni et
al. (2011) demonstrated that Cd14 chaperoned LPS to Tlr4, leading to Syk
(600085)-dependent internalization of Tlr4 and signaling through Trif
(607601). Zanoni et al. (2011) concluded that pathogen recognition
receptors induce both membrane transport and signal transduction.
Shirey et al. (2013) reported that CD14 and TLR2 are required for
protection against influenza-induced lethality in mice mediated by
Eritoran (also known as E5564), a potent, well-tolerated, synthetic TLR4
antagonist. Therapeutic administration of Eritoran blocked
influenza-induced lethality in mice, as well as lung pathology, clinical
symptoms, cytokine and oxidized phospholipid expression, and decreased
viral titers. CD14 directly binds Eritoran and inhibits ligand binding
to MD2 (605243). Shirey et al. (2013) concluded that Eritoran blockade
of TLR signaling represents a novel therapeutic approach for
inflammation associated with influenza, and possibly other infections.
MAPPING
Goyert et al. (1988) demonstrated by in situ hybridization and study of
somatic cell hybrid DNA that the gene is located at bands 5q23-q31.
Thus, CD14 is located in a region of chromosome 5 that contains a
cluster of genes that encode several myeloid-specific growth factors
(IL3; 147740) and granulocyte-macrophage colony-stimulating factor
(CSF2; 138960) or growth factor receptors (FMS receptor for CFS1;
164770), as well as other growth factor and receptor genes
(platelet-derived growth factor receptor, 173410, beta-2-adrenergic
receptor, 109690, and endothelial cell growth factor, 131220). This is a
region that is deleted in patients with certain forms of myeloid
leukemia.
Ferrero et al. (1990) mapped the CD14 gene to mouse chromosome 18.
By fluorescence in situ hybridization studies of deleted chromosome 5
homologs in a series of 135 patients with malignant myeloid diseases, Le
Beau et al. (1993) mapped the CD14 gene and neighboring genes to 5q31.
MOLECULAR GENETICS
Baldini et al. (1999) identified a single nucleotide polymorphism (SNP)
in the proximal CD14 promoter at position -159 from the transcription
start site, resulting in a C-to-T transition. TT homozygotes had
significantly higher levels of sCD14 than did either CC or CT genotype
carriers, and they also had lower levels of IgE. Unkelbach et al.
(1999), Hubacek et al. (1999), and Shimada et al. (2000) reported an
increased risk of myocardial infarction in individuals carrying the T
allele. (Shimada et al. (2000) and Hubacek et al. (1999) reported the
C/T polymorphism as occurring at position -260 from the translation
start site.)
Some patients with Kawasaki disease (KD), an acute febrile vasculitis of
childhood, develop coronary artery lesions after the acute phase.
Nishimura et al. (2003) found no difference in genomic and allele
frequencies of the T allele at the CD14/-159 promoter region in 67
patients with KD compared to controls. However, the KD patients with TT
genotypes had more coronary artery complications than those with CT or
CC genotypes, and the frequency of the T allele was significantly higher
than that of the C allele in KD patients. Nishimura et al. (2003)
concluded that the T allele and the TT genotype are risk factors for the
coronary artery complications in patients with KD, implicating a
possible relationship to the magnitude of the CD14 toll-like receptor
response.
Using EMSA analysis, LeVan et al. (2001) showed that the T allele at
position -159 in the proximal CD14 promoter has a decreased affinity for
DNA/protein interactions at a GC box containing a binding site for SP1
(189906), SP2 (601801), and SP3 (601804) transcription factors. Reporter
analysis demonstrated that monocytic cells with low levels of SP3, which
inhibits activating by SP1 and SP2, have increased transcriptional
activity of the T allele. In contrast, both the C and T alleles are
transcribed equivalently in SP3-rich hepatocytes. LeVan et al. (2001)
proposed that the interplay between CD14 promoter affinity and the
SP3:SP1-plus-SP2 ratio plays a critical mechanistic role in regulating
CD14 transcription and in determining the differential activity of the 2
variants of the CD14 promoter.
In a study of 216 Korean patients with IgA nephropathy (161950) who were
followed for 86 months, Yoon et al. (2003) found that an excess of the
-159C genotype occurred in patients with progressive disease (p = 0.03)
and the risk of disease progression increased as the number of C alleles
increased (p for trend = 0.002). The hazard ratio for progression in
patients with the CC genotype was 3.2 (p = 0.025) compared to patients
with the TT genotype. After lipopolysaccharide stimulation, soluble CD14
was released more abundantly from the peripheral blood mononuclear cells
of TT patients than from those of CC patients (p = 0.006), although
there was no difference in membrane-bound CD14 expression. TT patients
released less IL6 (147620) than CC patients after stimulation (p =
0.0003). Yoon et al. (2003) suggested that the CD14 -159 polymorphism is
an important marker for the progression of IgA nephropathy and may
modulate the level of the inflammatory response.
ANIMAL MODEL
Haziot et al. (1996) reported that Cd14-deficient mice were resistant to
LPS-induced shock.
Kurt-Jones et al. (2000) determined that proinflammatory cytokine
responses to respiratory syncytial virus (RSV) F protein were absent or
diminished in mice with deletions of either Cd14 or Tlr4 (603030),
respectively. Importantly, Tlr4 -/- mice had higher levels of infectious
virus in their lungs and were either unable to clear the virus or
cleared the virus several days later than wildtype mice. The authors
concluded that TLR4 and CD14 appear to be important not only in
recognizing bacterial structures such as lipopolysaccharide, but are
important in innate immune responses to viruses as well.
VTRNA1-2
| dbSNP name | rs144771304(A,G); rs12188417(T,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56663 |
| EntrezGene Description | vault RNA 1-2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | misc_RNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Sinusitis, chronic;
[Ears];
Otitis media, recurrent;
[Eyes];
Conjunctivitis, recurrent
RESPIRATORY:
Respiratory infections, recurrent;
[Airways];
Bronchitis, recurrent;
[Lungs];
Pneumonia, recurrent
ABDOMEN:
[Gastrointestinal];
Diarrhea;
Enteritis
IMMUNOLOGY:
Recurrent bacterial infections;
Absent or severely reduced numbers of B cells;
Decreased or absent pre-B cells;
Block at the pro-B to pre-B stage of differentiation;
Inability to mount antibody response to antigen;
Normal numbers and function of T cells;
Hypogammaglobulinemia, profound;
Agammaglobulinemia
MISCELLANEOUS:
Onset in first year of life;
Two patients have been reported (as of August 2010)
MOLECULAR BASIS:
Caused by mutation in the CD79B antigen gene (CD79B, 147245.0001)
OMIM Title
*612696 VAULT RNA 1-2; VTRNA1-2
;;HVG2;;
VAULT RNA COMPONENT 2; VAULTRC2
OMIM Description
CLONING
Vaults are large cytoplasmic ribonucleoproteins composed largely of MVP
(605088) and a nontranslated vault RNA component. By PCR of a human
genomic DNA library, Kickhoefer et al. (1998) cloned 3 vault RNA genes,
HVG1 (VTRNA1-1; 612695), HVG2 (VTRNA1-2), and HVG3 (VTRNA1-3; 612697).
Both HVG2 and HVG3 contain 86 bases and have an internal RNA polymerase
III (see 606007)-type promoter element and a typical polymerase III
termination signal. They both have an internal 10-base deletion compared
with HVG1.
Kickhoefer et al. (1999) found that only HVG1 was expressed in all human
cell lines examined. When expressed, HVG2 and HVG3 were often associated
with the supernatant fraction rather than microsomal pellets containing
vaults.
Nandy et al. (2009) described the structure of VTRNA1-2. The
88-nucleotide RNA forms an extended stem-loop structure with asymmetric
internal bulges. It contains characteristic internal polymerase III
A-box and B-box promoter elements and a downstream B2-box motif. Size
exclusion chromatography of fractionated HeLa cells, followed by
Northern and Western blot analyses, detected about 5% of the VTRNA1-1
and VTRNA1-2 content eluting with MVP, while 95% remained in the
supernatant.
GENE FUNCTION
Kickhoefer et al. (1998) found that HVG1, but not HVG2 or HVG3,
associated with vaults in human cell lines.
Nandy et al. (2009) found that expression of VTRNA1-1, VTRNA1-2,
VTRNA1-3, and CBL3 (VTRNA2-1; 614938) was upregulated in cord blood
lymphocytes infected with Epstein-Barr virus (EBV). Upregulation was
highest for VTRNA1-1 (about 1,100-fold) and lowest for CBL3 (about
3-fold). Expression of VTRNA1-1, VTRNA1-2, and CBL3 was also upregulated
by the EBV-related Kaposi sarcoma virus, but not by members of other
virus families.
GENE STRUCTURE
Kickhoefer et al. (2003) determined that the upstream region of the
VTRNA1-2 gene contains a TATA-like element, a consensus proximal
sequence, and a cAMP response element.
MAPPING
Kickhoefer et al. (2003) stated that the VTRNA1-1, VTRNA1-2, and
VTRNA1-3 genes map to a 16-kb region of chromosome 5.
Nandy et al. (2009) stated that the VTRNA1-2 gene is located near the
PCDHA gene cluster (604966), which Wu and Maniatis (1999) mapped to
chromosome 5q31.
PCDHB2
| dbSNP name | rs31853(G,A); rs3776103(A,G); rs3776102(A,G); rs3776101(A,G) |
| ccdsGene name | CCDS4244.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56133 |
| EntrezGene Description | protocadherin beta 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB2:NM_018936:exon1:c.G382A:p.V128I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5E7 |
| dbNSFP Uniprot ID | PCDB2_HUMAN |
| dbNSFP KGp1 AF | 0.0824175824176 |
| dbNSFP KGp1 Afr AF | 0.126016260163 |
| dbNSFP KGp1 Amr AF | 0.0441988950276 |
| dbNSFP KGp1 Asn AF | 0.0839160839161 |
| dbNSFP KGp1 Eur AF | 0.0712401055409 |
| dbSNP GMAF | 0.08264 |
| ESP Afr MAF | 0.132834 |
| ESP All MAF | 0.095125 |
| ESP Eur/Amr MAF | 0.075814 |
| ExAC AF | 0.084 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606328 PROTOCADHERIN-BETA 2; PCDHB2
;;PCDH-BETA-2
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB2 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB2.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB2 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB3
| dbSNP name | rs1055411(G,C); rs1055410(T,G); rs31849(A,G); rs17844387(A,G); rs12515688(G,A); rs3733699(A,T); rs17844392(T,C); rs31847(T,C); rs7722330(T,G); rs10463345(T,C) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56116 |
| EntrezGene Symbol | PCDHB@ |
| snpEff Gene Name | PCDHB2 |
| EntrezGene Description | protocadherin beta cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05418 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606329 PROTOCADHERIN-BETA 3; PCDHB3
;;PCDH-BETA-3
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB3 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB3.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB3 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB4
| dbSNP name | rs3776100(G,A); rs3733698(C,T); rs3733697(C,T); rs3776099(G,A); rs3088331(A,C); rs3822339(A,C); rs34501263(A,C) |
| ccdsGene name | CCDS4246.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56131 |
| EntrezGene Description | protocadherin beta 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB4:NM_018938:exon1:c.G597A:p.L199L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2383 |
| ESP Afr MAF | 0.041988 |
| ESP All MAF | 0.16577 |
| ESP Eur/Amr MAF | 0.229186 |
| ExAC AF | 0.254 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606330 PROTOCADHERIN-BETA 4; PCDHB4
;;PCDH-BETA-4
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB4 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB4.
Wu et al. (2001) determined that human PCDHB4 is paralogous to 3 mouse
PCDHBs, Pcdhb5, Pcdhb7, and Ppcdhb9.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB4 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB5
| dbSNP name | rs246725(T,C); rs79503440(C,A) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56116 |
| EntrezGene Symbol | PCDHB@ |
| EntrezGene Description | protocadherin beta cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09183 |
| ESP Afr MAF | 0.128445 |
| ESP All MAF | 0.102478 |
| ESP Eur/Amr MAF | 0.089474 |
| ExAC AF | 0.09 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606331 PROTOCADHERIN-BETA 5; PCDHB5
;;PCDH-BETA-5
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB5 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB5.
Wu et al. (2001) determined that human PCDHB5 is most paralogous to 6
mouse PCDHB genes, Pcdhb4, Pcdhb6, Pcdhb8, Pcdhb10, Pcdhb11, and
Pcdhb12.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB5 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB6
| dbSNP name | rs3776096(G,A); rs35620136(G,T); rs246708(G,C); rs17844444(G,A); rs116181422(T,C); rs17629216(G,A); rs10074197(A,T) |
| ccdsGene name | CCDS4248.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56130 |
| EntrezGene Description | protocadherin beta 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB6:NM_018939:exon1:c.G691A:p.V231I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5E3 |
| dbNSFP Uniprot ID | PCDB6_HUMAN |
| dbNSFP KGp1 AF | 0.263278388278 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.254143646409 |
| dbNSFP KGp1 Asn AF | 0.526223776224 |
| dbNSFP KGp1 Eur AF | 0.230870712401 |
| dbSNP GMAF | 0.264 |
| ESP Afr MAF | 0.042896 |
| ESP All MAF | 0.167384 |
| ESP Eur/Amr MAF | 0.231163 |
| ExAC AF | 0.264 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606332 PROTOCADHERIN-BETA 6; PCDHB6
;;PCDH-BETA-6
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB6 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB6.
Vanhalst et al. (2001) determined that unlike most PCDHB proteins,
PCDHB6 has not 1 but 2 PXXP motifs, putative SH3 protein-binding sites,
at the end of the conserved region of its cytoplasmic domains.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB6 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB17
| dbSNP name | rs246698(G,T); rs246695(C,T) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56116 |
| EntrezGene Symbol | PCDHB@ |
| snpEff Gene Name | AC005754.1 |
| EntrezGene Description | protocadherin beta cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96T98 |
| dbNSFP KGp1 AF | 0.0842490842491 |
| dbNSFP KGp1 Afr AF | 0.292682926829 |
| dbNSFP KGp1 Amr AF | 0.0745856353591 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0171503957784 |
| dbSNP GMAF | 0.08402 |
| ExAC AF | 0.019 |
PCDHB7
| dbSNP name | rs17096945(T,C); rs28470552(G,C); rs17286891(G,A); rs17096946(G,A); rs2910313(G,C); rs3733695(G,A); rs7702701(C,T); rs2907330(G,A); rs2907329(C,G); rs1811237(G,T); rs11741863(T,C); rs6892507(T,A); rs77126668(A,T) |
| ccdsGene name | CCDS4249.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56129 |
| EntrezGene Description | protocadherin beta 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB7:NM_018940:exon1:c.T142C:p.L48L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1175 |
| ESP Afr MAF | 0.112574 |
| ESP All MAF | 0.14724 |
| ESP Eur/Amr MAF | 0.165 |
| ExAC AF | 0.136,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606333 PROTOCADHERIN-BETA 7; PCDHB7
;;PCDH-BETA-7
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB7 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB7.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB7 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB8
| dbSNP name | rs2910317(T,C); rs2950844(G,C); rs7700833(C,T); rs17096961(G,A); rs2740583(T,C) |
| ccdsGene name | CCDS4250.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56128 |
| EntrezGene Description | protocadherin beta 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB8:NM_019120:exon1:c.T711C:p.N237N, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4109 |
| ESP Afr MAF | 0.441897 |
| ESP All MAF | 0.338896 |
| ESP Eur/Amr MAF | 0.286113 |
| ExAC AF | 0.261 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606334 PROTOCADHERIN-BETA 8; PCDHB8
;;PCDH-BETA-8
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB8 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB8.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB8 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB16
| dbSNP name | rs2740584(C,T); rs2204704(A,G); rs4151695(A,C); rs28664170(G,T); rs10060104(C,T); rs10069559(T,C); rs73273626(T,A); rs2980409(C,T); rs2950846(T,C); rs2338529(C,T); rs2338530(A,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 57717 |
| snpEff Gene Name | PCDHB8 |
| EntrezGene Description | protocadherin beta 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3228 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606345 PROTOCADHERIN-BETA 16; PCDHB16
;;PCDH-BETA-16;;
PCDHB8A;;
KIAA1621
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules that
mediate neural cell-cell interactions. Protocadherins constitute a
subfamily of nonclassic cadherins. PCDHB16 is a member of the beta
cluster of protocadherin genes on 5q31. For specific information on the
PCDHB genes, see 604967.
CLONING
Using PCR with degenerate primers to screen melanoma cell lines,
Matsuyoshi et al. (1997) obtained a cDNA fragment encoding part of
PCDHB16, which they termed ME1. RT-PCR analysis detected expression of
ME1 in melanoma cell lines and normal fibroblast cell lines, but not in
a squamous carcinoma cell lines or normal melanocytes, suggesting that
ME1 may play a role in the strong cell-cell adhesiveness of melanoma
cells.
By screening brain cDNA libraries for sequences with the potential to
encode large proteins, Nagase et al. (2000) isolated a cDNA encoding
PCDHB16, which they designated KIAA1621. Sequence analysis predicted
that the 787-amino acid KIAA1621 protein, which is 79% identical to
PCDH13, has features of proteins involved in cell signaling and
communication. RT-PCR analysis detected wide but moderate expression
that was lowest in liver and spleen.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the PCDHB16
gene to chromosome 5. By genomic sequence analysis, Wu et al. (2001)
mapped the PCDHB16 gene to 5q31. They localized the mouse PCDHB genes to
chromosome 18c.
PCDHB9
| dbSNP name | rs998794(A,G); rs998793(C,T); rs2740588(G,T); rs11167742(T,C); rs11167743(C,T); rs10037554(C,A); rs10040383(A,G); rs2697530(T,A); rs3733691(G,A); rs3733690(G,C); rs2907326(T,C); rs10069112(A,G); rs2910324(A,G); rs2907325(C,T); rs7735365(G,C); rs4912740(G,A); rs12654953(C,T); rs12657056(A,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 57717 |
| EntrezGene Symbol | PCDHB16 |
| snpEff Gene Name | PCDHB16 |
| EntrezGene Description | protocadherin beta 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1198 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606335 PROTOCADHERIN-BETA 9; PCDHB9
;;PCDH-BETA-9
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB9 is
1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB9.
Vanhalst et al. (2001) determined that unlike most PCDHB proteins,
PCDHB9 has not 1 but 2 PXXP motifs, putative SH3 protein-binding sites,
at the end of the conserved region of its cytoplasmic domain.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB9 gene to
chromosome 5q31. They localized the mouse PCDHB genes to chromosome 18c.
PCDHB10
| dbSNP name | rs2907323(C,G); rs75788551(T,C) |
| ccdsGene name | CCDS4252.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56126 |
| EntrezGene Description | protocadherin beta 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB10:NM_018930:exon1:c.C638G:p.T213R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UN67 |
| dbNSFP Uniprot ID | PCDBA_HUMAN |
| dbNSFP KGp1 AF | 0.101648351648 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.110497237569 |
| dbNSFP KGp1 Asn AF | 0.0926573426573 |
| dbNSFP KGp1 Eur AF | 0.154353562005 |
| dbSNP GMAF | 0.1019 |
| ESP Afr MAF | 0.048343 |
| ESP All MAF | 0.124404 |
| ESP Eur/Amr MAF | 0.163372 |
| ExAC AF | 0.14 |
PCDHB11
| dbSNP name | rs3756323(A,G); rs917535(G,A); rs139793689(G,A); rs61743184(G,A); rs57445845(G,A); rs145587367(A,G); rs186865320(C,T); rs61474131(C,A); rs592195(C,A) |
| ccdsGene name | CCDS4253.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56125 |
| EntrezGene Description | protocadherin beta 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB11:NM_018931:exon1:c.A11G:p.Q4R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5F2 |
| dbNSFP Uniprot ID | PCDBB_HUMAN |
| dbNSFP KGp1 AF | 0.152472527473 |
| dbNSFP KGp1 Afr AF | 0.247967479675 |
| dbNSFP KGp1 Amr AF | 0.174033149171 |
| dbNSFP KGp1 Asn AF | 0.0454545454545 |
| dbNSFP KGp1 Eur AF | 0.160949868074 |
| dbSNP GMAF | 0.1529 |
| ESP Afr MAF | 0.236723 |
| ESP All MAF | 0.193449 |
| ESP Eur/Amr MAF | 0.171279 |
| ExAC AF | 0.153 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606337 PROTOCADHERIN-BETA 11; PCDHB11
;;PCDH-BETA-11
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB11
is 1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
Using PCR with degenerate primers to screen melanoma cell lines,
Matsuyoshi et al. (1997) obtained a cDNA fragment encoding part of
PCDHB11, which they termed ME2. RT-PCR analysis detected expression of
ME2 in melanoma, squamous carcinoma, and normal fibroblast cell lines,
but not in normal melanocytes, suggesting that ME2 may play a role in
the strong cell-cell adhesiveness of melanoma cells.
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB11.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB11 gene
to chromosome 5q31. They localized the mouse PCDHB genes to chromosome
18c.
PCDHB12
| dbSNP name | rs2910326(C,T); rs2910327(C,T); rs2910006(A,G); rs12374500(T,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56124 |
| EntrezGene Description | protocadherin beta 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3742 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606338 PROTOCADHERIN-BETA 12; PCDHB12
;;PCDH-BETA-12
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB12
is 1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB12.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB12 gene
to chromosome 5q31. They localized the mouse PCDHB genes to chromosome
18c.
PCDHB13
| dbSNP name | rs17844617(C,T); rs2910332(C,T); rs2910333(A,G) |
| ccdsGene name | CCDS4255.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56123 |
| EntrezGene Description | protocadherin beta 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB13:NM_018933:exon1:c.C2061T:p.T687T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1226 |
| ESP Afr MAF | 0.116651 |
| ESP All MAF | 0.147993 |
| ESP Eur/Amr MAF | 0.16405 |
| ExAC AF | 0.141 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606339 PROTOCADHERIN-BETA 13; PCDHB13
;;PCDH-BETA-13
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB13
is 1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB13.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB13 gene
to chromosome 5q31. They localized the mouse PCDHB genes to chromosome
18c.
PCDHB14
| dbSNP name | rs2910004(A,G); rs2910003(C,A); rs73275709(A,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56116 |
| EntrezGene Symbol | PCDHB@ |
| EntrezGene Description | protocadherin beta cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3802 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606340 PROTOCADHERIN-BETA 14; PCDHB14
;;PCDH-BETA-14
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB14
is 1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB14.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB14 gene
to chromosome 5q31. They localized the mouse PCDHB genes to chromosome
18c.
PCDHB18
| dbSNP name | rs2907310(A,C); rs2907309(G,A); rs73281222(C,T); rs2910001(T,C); rs2907308(G,A); rs2910000(C,T); rs2907307(A,G); rs3733683(C,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56116 |
| EntrezGene Symbol | PCDHB@ |
| EntrezGene Description | protocadherin beta cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2112 |
PCDHB19P
| dbSNP name | rs2910335(A,G); rs9687052(G,C); rs631696(A,G); rs2109038(G,T); rs2907302(G,A); rs6877134(C,T); rs2907301(G,A); rs587342(T,C); rs660082(G,A) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 84054 |
| snpEff Gene Name | PCDHB18 |
| EntrezGene Description | protocadherin beta 19 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2222 |
PCDHB15
| dbSNP name | rs35154204(C,T); rs618096(G,A) |
| ccdsGene name | CCDS4257.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 56121 |
| EntrezGene Description | protocadherin beta 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PCDHB15:NM_018935:exon1:c.C61T:p.L21L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.009183 |
| ESP Afr MAF | 0.004539 |
| ESP All MAF | 0.017223 |
| ESP Eur/Amr MAF | 0.023721 |
| ExAC AF | 0.03 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm may occur
NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms
MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially
MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)
OMIM Title
*606341 PROTOCADHERIN-BETA 15; PCDHB15
;;PCDH-BETA-15
OMIM Description
DESCRIPTION
Cadherins are calcium-dependent cell-cell adhesion molecules, and
protocadherins constitute a subfamily of nonclassic cadherins. PCDHB15
is 1 of 16 tandemly arranged genes in the PCDHB gene cluster (604967) on
chromosome 5q31. Unlike the PCDHA (see 604966) and PCDHG (see 604968)
genes, which function as 'variable' exons that are spliced to downstream
constant region exons to produce mRNAs, the PCDHB genes do not use
constant region exons to produce mRNAs. Thus, each single-exon PCDHB
gene encodes the extracellular, transmembrane, and short cytoplasmic
domains of the protein (Wu et al., 2001). For further information on the
PCDHB genes, see 604967.
CLONING
By PCR of a brain cDNA library, Wu and Maniatis (1999) cloned
full-length PCDHB15.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the PCDHB15 gene
to chromosome 5q31. They localized the mouse PCDHB genes to chromosome
18c.
SLC25A2
| dbSNP name | rs11952797(G,A) |
| ccdsGene name | CCDS4258.1 |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 83884 |
| EntrezGene Description | solute carrier family 25 (mitochondrial carrier |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC25A2:NM_031947:exon1:c.C168T:p.A56A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4679 |
| ESP Afr MAF | 0.351112 |
| ESP All MAF | 0.475473 |
| ESP Eur/Amr MAF | 0.386628 |
| ExAC AF | 0.58 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Isolated cases
HEAD AND NECK:
[Head];
Microcephaly, acquired;
[Face];
Mask-like facies;
Expressionless facial appearance;
Bitemporal narrowing;
Frontal bossing, mild;
Prominent glabella;
Maxillary hypoplasia;
Retrognathia;
Long, smooth philtrum;
[Ears];
Abnormal ear configuration;
Triangular-shaped ears;
Prominent antihelices;
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Short palpebral fissures;
Blepharophimosis;
Hypertelorism;
Sparse eyelashes;
Sparse eyebrows;
[Nose];
Flat, broad nasal bridge;
Short nose;
Large, anteverted nasal tip;
[Mouth];
Small mouth;
Long, everted upper lip;
Thin upper lip;
High-arched palate;
[Teeth];
Abnormal dentition;
Curved incisors;
[Neck];
Short neck;
Broad neck
CHEST:
[External features];
Laterally displaced nipples;
Hypoplastic nipples
GENITOURINARY:
[External genitalia, male];
Small penis;
[Internal genitalia, male];
Cryptorchidism;
[External genitalia, female];
Hypoplastic labia
SKELETAL:
Joint contractures;
[Skull];
Asymmetric skull;
Craniosynostosis;
[Hands];
Camptodactyly;
Clinodactyly;
Tapering fingers
SKIN, NAILS, HAIR:
[Skin];
Tight, glistening facial skin;
[Hair];
Upswept frontal hair pattern;
Low anterior hairline;
Sparse hair;
Unruly hair;
Sparse eyebrows;
High-arched eyebrows;
Misaligned eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Developmental delay;
[Behavioral/psychiatric manifestations];
Happy demeanor
OMIM Title
*608157 SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ORNITHINE TRANSPORTER),
MEMBER 2; SLC25A2
;;ORNITHINE TRANSPORTER, MITOCHONDRIAL, 2; ORNT2
OMIM Description
DESCRIPTION
The ORNT2 gene encodes a mitochondrial ornithine transporter that is 88%
identical to that encoded by ORNT1 (603861).
CLONING
Using sequences of a region conserved among mammalian and fungal
mitochondrial ornithine and carnitine transporters, Camacho et al.
(2003) screened an EST database for additional transporters belonging to
the ORNT family. They identified a novel intronless gene, ORNT2, which
encodes a protein 88% identical to ORNT1. Northern blot analysis and PCR
demonstrated highest ORNT2 expression in liver, with less significant
expression in pancreas and minimal expression in kidney.
Immunofluorescence analysis of transiently transfected fibroblasts from
control and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
(HHH; 238970) patients demonstrated that ORNT2 is localized to
mitochondria. The ORNT2 cDNA is 1,412 bp, with a 186-bp 5-prime
untranslated region, a 903-bp open reading frame, and a 323-bp 3-prime
untranslated region. It contains a variant polyadenylation signal
(CATAA) 18 bases before the terminal poly(A). Camacho et al. (2003)
found that Ornt2 is nonfunctional in mouse because it is not translated.
Yeast have no ortholog of Ornt2.
GENE STRUCTURE
Camacho et al. (2003) confirmed the intronless nature of ORNT2 using
PCR. They suggested that ORNT2 arose by a retrotranspositional event
from ORNT1 mediated either by a retroviral infection or endogenous
reverse transcriptase activity.
GENE FUNCTION
Patients with completely dysfunctional ORNT1 are mildly affected
compared with patients with other urea cycle disorders. Camacho et al.
(2003) found that when ORNT2 is overexpressed transiently in cultured
fibroblasts from HHH patients, it rescues the deficient ornithine
metabolism in those cells. Camacho et al. (2003) proposed that ORNT2 may
be responsible for the milder phenotype in HHH patients secondary to a
gene redundancy effect.
MAPPING
Camacho et al. (2003) used a radiation hybrid panel to map the ORNT2
gene to the 5q31 region (D5S500-D5S402).
TAF7
| dbSNP name | rs2429349(T,C); rs7730(A,G); rs10310(T,C); rs17602721(T,C); rs11547633(T,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 6879 |
| EntrezGene Description | TAF7 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 55kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
RESPIRATORY:
Progressive breathing difficulty
SKELETAL:
Mild joint laxity;
Delayed bone maturation;
[Spine];
Atlanto-axial subluxation;
Lumbar lordosis;
Irregular vertebral end plates;
Os odontoideum and atlanto-axial instability;
Spondylolysis and spondylolisthesis of L5;
[Pelvis];
Flat femoral head with subluxation and sloping acetabulum;
[Limbs];
Small femoral capital epiphyses
MUSCLE, SOFT TISSUE:
Hand muscle wasting
NEUROLOGIC:
[Peripheral nervous system];
Hemiparesis;
Quadriparesis;
Limb weakness;
Brisk reflexes;
Clonus in legs;
Bulbar palsy;
Tongue fasciculations
OMIM Title
*600573 TAF7 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR,
55-KD; TAF7
;;TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR 2F; TAF2F;;
TBP-ASSOCIATED FACTOR, RNA POLYMERASE II, 55-KD; TAFII55
OMIM Description
CLONING
Chiang and Roeder (1995) reported the cloning of a subunit of the TFIID
protein complex (see 313650), which is required for transcription by
promoters targeted by RNA polymerase II. The TFIID complex binds to the
TATA box in class II promoters and then recruits other factors as well
as RNA polymerase II. TFIID is composed of the TATA-binding protein
(TBP; 600075) and multiple TBP-associated factors (TAFs), one of which
has a predicted size of 55 kD from SDS gel electrophoresis. The human
TFIID subunit TAF2F (also referred to as TAFII55) was isolated from a
cell line that expresses an epitope-tagged TBP allowing for the
immunoprecipitation of the TFIID complex and associated factors. Based
on partial peptide sequence of 1 TAF, Chiang and Roeder (1995) designed
degenerate PCR primers and used them to produce a probe which was, in
turn, hybridized to a human placenta cDNA library. The predicted protein
is 349 amino acids (40 kD) and contains 40% charged residues, which may
account for its larger than expected electrophoretic mobility. The mRNA
was expressed in all tissues examined. The authors showed that TAFII55
interacts with TAFII230, the largest subunit of TFIID, and with multiple
transcription activators, including Sp1 (189906), YY1 (600013), USF
(191523), CTF (600729; discussed also in 164005), and adenoviral E1A
(discussed in 607102).
GENE FUNCTION
Gegonne et al. (2006) stated that TAF7 binds to TAF1 (313650) and
inhibits its acetyltransferase activity, resulting in transcriptional
repression. They found that TAF7 bound to TAF1 and associated with TFIID
during formation of the preinitiation complex and dissociated from the
preinitiation complex upon transcriptional initiation. Addition of
polymerase II to the assembling preinitiation complex was associated
with TAF1 and TAF7 phosphorylation and the release of TAF7. Gegonne et
al. (2006) proposed that TAF7 is a checkpoint regulator suppressing
premature transcription initiation until assembly of the preinitiation
complex is complete.
GENE STRUCTURE
By genomic sequence analysis, Wu et al. (2001) determined that the mouse
and human TAF2F genes contain a single exon.
MAPPING
By genomic sequence analysis, Wu et al. (2001) mapped the TAF7 (TAF2F)
gene to 5q31 on the opposite strand between the PCDHB (604967) and PCDHG
(604968) gene clusters. They mapped the mouse Taf2f gene and PCDH gene
clusters to chromosome 18c.
LOC729080
| dbSNP name | rs6892015(A,G) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 729080 |
| snpEff Gene Name | AC005740.3 |
| EntrezGene Description | glycine cleavage system protein H (aminomethyl carrier) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.354 |
MIR5197
| dbSNP name | rs2042253(T,C) |
| cytoBand name | 5q31.3 |
| EntrezGene GeneID | 100846991 |
| snpEff Gene Name | CTB-57H20.1 |
| EntrezGene Description | microRNA 5197 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.298 |
| ExAC AF | 0.112 |
GPR151
| dbSNP name | rs17104742(G,A) |
| ccdsGene name | CCDS34266.1 |
| cytoBand name | 5q32 |
| EntrezGene GeneID | 134391 |
| EntrezGene Description | G protein-coupled receptor 151 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR151:NM_194251:exon1:c.C119T:p.P40L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0127 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8TDV0 |
| dbNSFP Uniprot ID | GP151_HUMAN |
| dbNSFP KGp1 AF | 0.0444139194139 |
| dbNSFP KGp1 Afr AF | 0.0406504065041 |
| dbNSFP KGp1 Amr AF | 0.0690607734807 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0686015831135 |
| dbSNP GMAF | 0.04454 |
| ESP Afr MAF | 0.041761 |
| ESP All MAF | 0.064201 |
| ESP Eur/Amr MAF | 0.075698 |
| ExAC AF | 0.069 |
ADRB2
| dbSNP name | rs1801704(C,T); rs1042713(G,A); rs1042714(G,C); rs1042717(G,A); rs1042718(C,A); rs1042719(G,C); rs1042720(G,A) |
| cytoBand name | 5q32 |
| EntrezGene GeneID | 154 |
| EntrezGene Description | adrenoceptor beta 2, surface |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2429 |
| ESP Afr MAF | 0.18384 |
| ESP All MAF | 0.340203 |
| ESP Eur/Amr MAF | 0.42033 |
| ExAC AF | 0.679 |
OMIM Clinical Significance
Mouth:
Mouth ulcerations
GU:
Genital ulcerations;
Epididymitis
Skin:
Erythema nodosum-like eruptions;
Superficial thrombophlebitis;
Pustular skin lesions;
Hyperirritability;
Raynaud phenomenon
Hair:
Alopecia areata
Neuro:
Brainstem syndrome;
Meningoencephalomyelitic syndrome;
Organic confusional state;
Schizoaffective disorder
Joints:
Arthritis
Eyes:
Uveitis;
Hypopyon;
Iritis;
Iridocyclitis;
Choreoretinitis
Inheritance:
Familial cases reported, but probably not Mendelian
OMIM Title
+109690 BETA-2-ADRENERGIC RECEPTOR; ADRB2
;;BETA-ADRENERGIC RECEPTOR; ADRBR;;
BETA-2-ADRENOCEPTOR; BAR; B2AR;;
ADRB2R
BETA-2-ADRENORECEPTOR AGONIST, REDUCED RESPONSE TO, INCLUDED
OMIM Description
CLONING
Kobilka et al. (1987) reported the cloning and complete nucleotide
sequence of the cDNA for human beta-2-adrenergic receptor. The deduced
amino acid sequence (413 residues) encodes a protein containing 7
clusters of hydrophobic amino acids suggestive of membrane-spanning
domains. While the protein shows 87% identity overall with the
previously cloned hamster beta-2-adrenergic receptor, the most highly
conserved regions are the putative transmembrane helices (95% identical)
and cytoplasmic loops (93% identical), suggesting that these regions of
the molecule harbor important functional domains.
GENE STRUCTURE
Whereas the rhodopsin gene (180380) consists of 5 exons interrupted by 4
introns, the beta-adrenergic receptor genes contain no introns in either
their coding or untranslated sequences (Kobilka et al., 1987).
Emorine et al. (1987) characterized the promoter region of the gene.
MAPPING
Because of a lack of beta-adrenergic receptors, Chinese hamster
fibroblasts do not respond to the beta-adrenergic agonist with an
increase in cellular cAMP. Thus, by study of hamster-human somatic cell
hybrids, Sheppard et al. (1983) could assign to human chromosome 5 the
structural gene for the beta-2-adrenergic receptor.
By studies in somatic cell hybrids and by in situ hybridization, Kobilka
et al. (1987) localized the gene to 5q31-q32. This position is the same
as that for the gene coding for platelet-derived growth factor receptor
(173410) and is adjacent to the site of the FMS oncogene (164770), the
receptor for CSF1 (120420). By in situ hybridization, Yang-Feng et al.
(1990) regionalized the assignment to 5q32-q34. By analysis of
interspecific backcrosses, Oakey et al. (1991) mapped the corresponding
mouse gene, symbolized Adrb2, to the proximal portion of chromosome 18.
BIOCHEMICAL FEATURES
- Crystal Structure
Cherezov et al. (2007) reported the crystal structure of a human beta-2
adrenergic receptor-T4 lysozyme fusion protein bound to the partial
inverse agonist carazolol at 2.4-angstrom resolution. The structure
provides a high-resolution view of a human G protein-coupled receptor
bound to a diffusible ligand. Ligand-binding site accessibility is
enabled by the second extracellular loop, which is held out of the
binding cavity by a pair of closely spaced disulfide bridges and a short
helical segment within the loop. Cholesterol, a necessary component for
crystallization, mediates an intriguing parallel association of receptor
molecules in the crystal lattice. Although the location of carazolol in
the beta-2-adrenergic receptor is very similar to that of retinal in
rhodopsin (180380), structural differences in the ligand-binding site
and other regions highlight the challenges in using rhodopsin as a
template model for this large receptor family.
Rosenbaum et al. (2007) reported that to overcome the structural
flexibility of the beta-2-adrenergic receptor and to facilitate its
crystallization, they engineered a beta-2-adrenergic receptor fusion
protein in which T4 lysozyme replaces most of the third intracellular
loop of the G protein-coupled receptor and showed that this protein
retains near-native pharmacologic properties. Analysis of adrenergic
receptor ligand-binding mutants within the context of the reported
high-resolution structure of the fusion protein provided insights into
inverse-agonist binding and the structural changes required to
accommodate catecholamine agonists. Amino acids known to regulate
receptor function are linked through packing interactions and a network
of hydrogen bonds, suggesting a conformational pathway from the
ligand-binding pocket to regions that interact with G proteins.
Rasmussen et al. (2007) reported a structure of the human beta-2
adrenoceptor (beta-2-AR), which was crystallized in a lipid environment
when bound to an inverse agonist and in complex with a Fab that binds to
the third intracellular loop. Diffraction data were obtained by
high-brilliance microcrystallography and the structure determined at
3.4-angstrom/3.7-angstrom resolution. The cytoplasmic ends of the
beta-2-AR transmembrane segments and the connecting loops are well
resolved, whereas the extracellular regions of the beta-2-AR are not
seen. The beta-2-AR structure differs from rhodopsin in having weaker
interactions between the cytoplasmic ends of transmembrane domains 3 and
6, involving the conserved E/DRY sequences. Rasmussen et al. (2007)
concluded that these differences may be responsible for the relatively
high basal activity and structural instability of the beta-2-AR, and
contribute to the challenges of obtaining diffraction-quality crystals
of non-rhodopsin G protein-coupled receptors.
Rasmussen et al. (2011) generated a camelid antibody fragment, which
they called a nanobody, to the beta-2-AR that exhibits G protein-like
behavior, and obtained an agonist-bound, active-state crystal structure
of the receptor-nanobody complex. Comparison with the inactive beta-2-AR
structure revealed subtle changes in the binding pocket; however, these
small changes were associated with an 11-angstrom outward movement of
the cytoplasmic end of transmembrane segment 6, and rearrangements of
transmembrane segments 5 and 7 that were remarkably similar to those
observed in opsin, an active form of rhodopsin.
Rosenbaum et al. (2011) used the inactive structure of the human
beta-2-AR as a guide to design a beta-2-AR agonist that can be
covalently tethered to a specific site on the receptor through a
disulfide bond. The covalent beta-2-AR-agonist complex formed
efficiently, and was capable of activating a heterotrimeric G protein.
Rosenbaum et al. (2011) crystallized a covalent agonist-bound
beta-2-AR-T4L fusion protein in lipid bilayers through the use of
lipidic mesophase method, and determined its structure at 3.5-angstrom
resolution. A comparison to the inactive structure and an
antibody-stabilized active structure showed how binding events at both
the extracellular and intracellular surfaces are required to stabilize
an active conformation of the receptor. The structures were in agreement
with long-timescale (up to 30 microseconds) molecular dynamics
stimulations showing that an agonist-bound active conformation
spontaneously relaxes to an inactive-like conformation in the absence of
a G protein or stabilizing antibody.
Rasmussen et al. (2011) presented the crystal structure of the active
state ternary complex composed of agonist-occupied monomeric beta-2-AR
and nucleotide-free Gs (139320) heterotrimer. The principal interactions
between the beta-2-AR and Gs involve the amino- and carboxy-terminal
alpha-helices of Gs, with conformational changes propagating to the
nucleotide-binding pocket. The largest conformational changes in the
beta-2-AR include a 14-angstrom outward movement at the cytoplasmic end
of transmembrane segment 6 and an alpha-helical extension of the
cytoplasmic end of transmembrane segment 5. The most surprising
observation is a major displacement of the alpha-helical domain of
G-alpha-s relative to the Ras-like GTPase domain.
Chung et al. (2011) applied peptide amide hydrogen-deuterium exchange
mass spectrometry to probe changes in the structure of the
heterotrimeric bovine G protein, Gs, on formation of a complex with
agonist-bound human beta-2-AR. They reported structural links between
the receptor-binding surface and the nucleotide-binding pocket of Gs
that undergo higher levels of hydrogen-deuterium exchange than would be
predicted from the crystal structure of the beta-2-AR-Gs complex.
Together with x-ray crystallographic and electron microscopic data of
the beta-2-AR-Gs complex, Chung et al. (2011) provided a rationale for a
mechanism of nucleotide exchange, whereby the receptor perturbs the
structure of the amino-terminal region of the alpha-subunit of Gs and
consequently alters the 'P-loop' that binds the beta-phosphate in GDP.
GENE FUNCTION
Using oligonucleotide directed site-specific mutagenesis, Fraser et al.
(1988) accomplished point mutation at nucleotide 388 of the BAR gene.
The mutation resulted in a guanine-to-adenine substitution, exchanging
an asparagine for a highly conserved aspartic acid at residue 130 of the
human beta-adrenergic receptor. The mutant beta-adrenergic receptor
appeared capable of interacting with the stimulatory guanine
nucleotide-binding regulatory protein, but the ability of guanine
nucleotides to alter agonist affinity was attenuated.
Luttrell et al. (1999) demonstrated that activated beta-2-adrenergic
receptor binds beta-arrestin-1 (ARRB1; 107940), which then binds c-src
(190090) at its amino terminus. This interaction targets the complex to
clathrin-coated pits and allows for beta-2-adrenergic activation of the
MAP kinases ERK1 (601795) and ERK2 (176948).
Patients with nocturnal asthma represent a subset of asthmatics who
experience a marked worsening of airway obstruction and symptoms while
asleep. Nocturnal asthmatics display greater bronchial hyperreactivity
than do nonnocturnal asthmatics. Several studies had suggested that
autonomic function may be different in nocturnal asthma as compared to
nonnocturnal asthma. Szefler et al. (1991) found that circulating
neutrophil and lymphocyte beta-2-adrenergic receptors, which are
potential markers for ADRB2s of bronchial smooth muscle and other lung
cells, decrease at 4:00 a.m. as compared to 4:00 p.m. in patients with
nocturnal asthma. No such downregulation of ADRB2 was found in
nonnocturnal asthmatics or normal subjects.
Davare et al. (2001) found that the beta-2 adrenergic receptor is
directly associated with one of its ultimate effectors, the class C
L-type calcium channel Ca(V)1.2 (114206). This complex also contains a G
protein, an adenylyl cyclase (see 103070), cAMP-dependent kinase (see
601639), and the counterbalancing phosphatase PP2A (see 605997). Davare
et al. (2001) used electrophysiologic recordings from hippocampal
neurons to demonstrate highly localized signal transduction from the
receptor to the channel. The assembly of this signaling complex provides
a mechanism that ensures specific and rapid signaling by a G
protein-coupled receptor.
Although trafficking and degradation of several membrane proteins are
regulated by ubiquitination catalyzed by E3 ubiquitin ligases, the
connection of ubiquitination with regulation of mammalian G
protein-coupled receptor function has been unclear. Shenoy et al. (2001)
demonstrated that agonist stimulation of endogenous or transfected
beta-2 adrenergic receptors led to rapid ubiquitination of both the
receptors and the receptor regulatory protein, beta-arrestin (ARRB2;
107941). Moreover, proteasome inhibitors reduced receptor
internalization and degradation, thus implicating a role for the
ubiquitination machinery in the trafficking of the beta-2 adrenergic
receptor. Receptor ubiquitination required beta-arrestin, which bound
the E3 ubiquitin ligase MDM2 (164785). Abrogation of beta-arrestin
ubiquitination, either by expression in MDM2-null cells or by
dominant-negative forms of MDM2 lacking E3 ligase activity, inhibited
receptor internalization with marginal effects on receptor degradation.
However, an ADRB2 mutant lacking lysine residues, which was not
ubiquitinated, was internalized normally but was degraded ineffectively.
Shenoy et al. (2001) concluded that their results delineated an adaptor
role of beta-arrestin in mediating the ubiquitination of the beta-2
adrenergic receptor and indicated that ubiquitination of the receptor
and of beta-arrestin have distinct and obligatory roles in the
trafficking and degradation of this prototypic G protein-coupled
receptor.
Harrison et al. (2003) demonstrated that signaling via the erythrocyte
beta-2 adrenergic receptor and heterotrimeric guanine nucleotide-binding
protein (GNAS; 139320) regulated the entry of the human malaria parasite
Plasmodium falciparum. Agonists that stimulate cAMP production led to an
increase in malarial infection that could be blocked by specific
receptor antagonists. Moreover, peptides designed to inhibit GNAS
protein function reduced parasitemia in P. falciparum cultures in vitro,
and beta-antagonists reduced parasitemia of P. berghei infections in an
in vivo mouse model. Harrison et al. (2003) suggested that signaling via
the erythrocyte beta-2-adrenergic receptor and GNAS may regulate
malarial infection across parasite species.
By analyzing Adrb2-deficient mice, Elefteriou et al. (2005) demonstrated
that the sympathetic nervous system favors bone resorption by increasing
expression in osteoblast progenitor cells of the osteoclast
differentiation factor Rankl (602642). This sympathetic function
requires phosphorylation by protein kinase A (PKA; see 176911) of ATF4
(604064), a cell-specific CREB (123810)-related transcription factor
essential for osteoblast differentiation and function. That bone
resorption cannot increase in gonadectomized Adrb2-deficient mice
highlights the biologic importance of this regulation, but also
contrasts sharply with the increase in bone resorption characterizing
another hypogonadic mouse with low sympathetic tone, the ob/ob mouse.
This discrepancy is explained, in part, by the fact that CART (602606),
a neuropeptide whose expression is controlled by leptin and nearly
abolished in ob/ob mice, inhibits bone resorption by modulating Rankl
expression. Elefteriou et al. (2005) concluded that their study
established that leptin-regulated neural pathways control both aspects
of bone remodeling, and demonstrated that integrity of sympathetic
signaling is necessary for the increase in bone resorption caused by
gonadal failure.
In HEK293 cells in vitro, Ni et al. (2006) found that activation of
ADRB2 receptors stimulated gamma-secretase activity and beta-amyloid
(APP; 104760) production. Stimulation involved the association of ADRB2
with PSEN1 (104311) and required agonist-induced endocytosis of ADRB2.
Similar effects were observed after activation of the opioid receptor
OPRD1 (165195). In mouse models of Alzheimer disease (AD; 104300),
chronic treatment with ADRB2 agonists increased cerebral amyloid
plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid
plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2
receptors may contribute to beta-amyloid accumulation in AD.
Using nanoscale live-cell scanning ion conductance and fluorescence
resonance energy transfer microscopy in cardiomyocytes from healthy
adult rats and mice, Nikolaev et al. (2010) found that spatially
confined beta-2 adrenergic receptor-induced cAMP signals were localized
exclusively to the deep transverse tubules, whereas functional beta-1
adrenergic receptors (ADRB1; 109630) were distributed across the entire
cell surface.
Using immunofluorescence microscopy, Coureuil et al. (2010) demonstrated
that Neisseria meningitidis (Nm) colonies at the cell surface of human
brain endothelial cells promoted translocation of ARRB1 and ARRB2 to the
inner surface of the plasma membrane, facing the bacteria. ARRBs
translocated under the colonies served as a scaffolding platform for
signaling events elicited by Nm. ADRB2 was the only G protein-coupled
receptor expressed in the cell line that played a permissive role in the
formation of cortical plaques under colonies and in bacterial crossing
of cell monolayers. Coureuil et al. (2010) concluded that the ADRB2/ARRB
signaling pathway is required for Nm to promote stable adhesion to brain
endothelial cells and subsequent crossing of the blood-brain barrier.
MOLECULAR GENETICS
Reihsaus et al. (1993) found 6 different polymorphic forms of ADRB2.
These polymorphisms consisted of amino acid substitutions. When they
were mimicked by site-directed mutagenesis of the cloned human ADRB2
cDNA and expressed in Chinese hamster fibroblasts, some were found to
display different pharmacologic properties. Specifically, they found
that glycine at position 16 (R16G; 109690.0001), rather than arginine,
imparted enhanced agonist-promoted downregulation. This prompted them to
determine ADRB2 phenotypes of 2 well-defined asthmatic cohorts: 23
nocturnal asthmatics with 34% nocturnal depression of peak expiratory
flow rates and 22 nonnocturnal asthmatics with virtually no such
depression (2.3%). The frequency of the gly16 allele was 80.4% in the
nocturnal group as compared to 52.2% in the nonnocturnal group, while
the arg16 allele was present in 19.6% of the nocturnal group and 47.8%
of the nonnocturnal group. Turki et al. (1995) hypothesized that gly16
may be overrepresented in nocturnal asthma. This overrepresentation of
the gly16 allele in nocturnal asthma was significant at P = 0.007, with
a 3.8 odds ratio for having both nocturnal asthma and the gly16
polymorphism. Comparisons of the 2 cohorts as to homozygosity for gly16,
homozygosity for arg16, or heterozygosity were also consistent with
segregation of gly16 with nocturnal asthma. There was no difference in
the frequency of the gln27-to-glu (Q27E; 190690.0002) and thr164-to-ile
(T164I; 109690.0003) polymorphisms between the 2 groups.
The beta-2-adrenergic receptor agonists are the most widely used agents
in the treatment of asthma, but the genetic determinants of
responsiveness to these agents are unknown. It had been reported that
gly16 (see 109690.0001) is associated with increased agonist-promoted
downregulation of ADRB2 as compared with arg16. A form of the receptor
with glu27 (Q27E; 109690.0002) had been shown to be resistant to
downregulation when compared with gln27, but only when coexpressed with
arg16. In a group of 269 children in a longitudinal study of asthma,
Martinez et al. (1997) performed spirometry before and after
administration of albuterol and correlated the findings with the
genotypes of these 2 polymorphisms. Two polymorphisms showed marked
linkage disequilibrium, with 97.8% of all chromosomes that carried arg16
also carrying gln27. When compared to homozygotes for gly16, homozygotes
for arg16 were 5.3 times and heterozygotes for the polymorphism arg16 to
gly were 2.3 times more likely to respond to albuterol, respectively.
Similar trends were observed for asthmatic and nonasthmatic children,
and results were independent of baseline lung function, ethnic origin,
and previous use of antiasthma medication. No association was found
between glu27 and response to albuterol.
In a study of 190 asthmatics, Israel et al. (2001) found that the
homozygous arg16 genotype of the ADRB2 gene was positively associated
with an acute response to treatment, but was also associated with a
significant decrease in response after regular use of beta-agonists,
whereas the gly-gly genotype showed no change with regular use.
In a discussion of genetic polymorphism of drug targets, one aspect of
pharmacogenomics, Evans and McLeod (2003) discussed genetic
polymorphisms of the ADRB2 gene that alter the process of signal
transduction by the beta-2-adrenergic receptor. They stated that the
R16G (109690.0001) and (Q27E; 109690.0002) substitutions are relatively
common, with allele frequencies of 0.4 to 0.6. They noted that Drysdale
et al. (2000) had identified 13 distinct SNPs in ADRB2, which were
organized into 12 haplotypes and that this finding led to evaluation of
the importance of haplotype structure as compared with individual SNPs
in determining receptor function and pharmacologic response.
In a study of 65 healthy and drug-free subjects, Lonnqvist et al. (1992)
demonstrated that some individuals have resistance to the lipolytic
effects of catecholamines and that this is the result of decreased ADRB2
expression in fat cells. The resistance was studied in vivo and in
isolated abdominal subcutaneous adipocytes. Some of the plotted data
demonstrated bimodality consistent with a relatively simple genetic
basis for the difference. Whether the genetic difference is located at
the ADRB2 locus or at another site was unclear. The clinical consequence
of catecholamine resistance in apparently healthy subjects was also not
clear.
It is well established that obesity is under strong genetic influence,
with up to 40% of the variation in body fat content being attributed to
genetic factors. Genes that are involved in the regulation of
catecholamine function may be of particular importance for human obesity
because of the central role catecholamines play in energy expenditure,
both as hormones and as neurotransmitters. This regulation is in part
affected by stimulating lipid mobilization through lipolysis in fat
cells. The beta-2 adrenoceptor is a major lipolytic receptor in human
fat cells. Large et al. (1997) investigated whether the common
polymorphisms arg16 to gly and gln27 to glu are related to obesity. They
found that gln27 to glu was indeed markedly associated with obesity with
a relative risk for obesity of approximately 7 and an odds ratio of
approximately 10. Homozygotes for glu27 had an average fat mass excess
of 20 kg and approximately 50% larger fat cells than controls. However,
no significant association with changes in ADRB2 function was observed.
The polymorphism arg16gly was associated with altered ADRB2 function,
with gly16 carriers showing a 5-fold increased agonist sensitivity
without any change in ADRB2 expression. However, it was not
significantly linked with obesity. The findings of Large et al. (1997)
suggested that genetic variation in the ADRB2 gene may be of major
importance for obesity, energy expenditure, and lipolytic ADRB2 function
in adipose tissue, at least in women.
By PCR-direct sequencing, Yamada et al. (1999) screened the 5-prime
untranslated region of the ADRB2 gene from 40 obese subjects. They
identified 2 polymorphic sites: a T-to-C transition at -47 and a T-to-C
transition at -20. By PCR and restriction digestion, they further
analyzed the association of these polymorphisms with obesity in 574
subjects. The -47T-C substitution was in tight linkage disequilibrium
with the -20T-C substitution. These polymorphisms were also in linkage
disequilibrium with codon 16 and codon 27 polymorphisms. Subjects
carrying the -47C/-20C allele had greater body mass index (25.5 +/- 4.5
vs 24.4 +/- 4.1 kg/m2; p = 0.007) and higher serum triglyceride levels
(166 +/- 160 vs 139 +/- 95 mg/dl; p = 0.015) than -47T/-20T homozygotes.
The variant allele frequency was significantly higher in obese subjects
than in nonobese subjects (0.18 vs 0.11; p = 0.0026). Furthermore, an
increased frequency of the variant allele was shown in diabetic patients
compared with nondiabetic subjects (0.19 vs 0.11; p = 0.0005). The
authors pointed out that the association may be attributable to the
greater proportion of diabetic patients in the obese group. They
suggested that the exchange at -47 may alter the expression level of the
ADRB2 gene, because the nucleotide substitution at -47 results in a
cys-to-arg exchange at the C terminal of the leader peptide.
The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic
receptors, ADRB2 and ADRA1B (104220), and the dopamine receptor type 1A
gene (DRD1A; 126449). Krushkal et al. (1998) used an efficient
discordant sib-pair ascertainment scheme to investigate the impact of
this region of the genome on variation in systolic blood pressure in
young Caucasians. They measured 8 highly polymorphic markers spanning
this positional candidate gene-rich region in 427 individuals from 55
3-generation pedigrees containing 69 discordant sib pairs, and
calculated multipoint identity by descent probabilities. The results of
genetic linkage and association tests indicated that the region between
markers D5S2093 and D5S462 was significantly linked to 1 or more
polymorphic genes influencing interindividual variation in systolic
blood pressure levels. Since the ADRA1B and DRD1A genes are located
close to these markers, the data suggested that genetic variation in 1
or both of these G protein-coupled receptors, which participate in the
control of vascular tone, plays an important role in influencing
interindividual variation in systolic blood pressure levels.
In a metaanalysis of 28 published studies, Contopoulos-Ioannidis et al.
(2005) confirmed the association between the gly16 polymorphism and
nocturnal asthma, but found no association between the R16G or Q27E
variants and asthma susceptibility overall or bronchial
hyperresponsiveness.
Dallongeville et al. (2003) studied the association between the G16R
(109690.0001) and Q27E (109690.0002) polymorphisms of the ADRB2 receptor
and metabolic syndrome (605552) in 276 male and female patients with
metabolic syndrome and 872 controls. Metabolic syndrome was defined
according to National Cholesterol Education Program Adult Treatment
Panel III guidelines. The G16R (P less than 0.005) and Q27E (P less than
0.04) polymorphisms were associated with metabolic syndrome in men, but
not in women. Because both variants were in linkage disequilibrium, a
haplotype analysis was performed. There was no evidence of any
statistically significant association between ADRB2 haplotypes and
metabolic syndrome.
EVOLUTION
Cagliani et al. (2009) analyzed the recent evolutionary history of the
ADRB genes in humans, with particular concern to selective patterns.
Although their data suggested neutral selection for the ADRB1 gene, most
tests rejected neutral evolution for the ADRB2 and ADRB3 genes.
Selection of specific ADRB2 alleles was found particularly in European,
African, and Asian samples. The inferred ADRB2 haplotypes partitioned
into 3 major clades with a coalescence time of 1 to 1.5 million years,
suggesting that the ADRB2 gene is either subject to balanced selection
or undergoing a selective sweep. Haplotype analysis also revealed
ethnicity-specific differences. There was significant deviations from
Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct
European cohorts; HWE deviation depended on sex (females were in
disequilibrium), and genotypes displaying maximum and minimum relative
fitness differed across population samples, suggesting a complex
situation possibly involving epistasis or maternal selection.
Wilson et al. (2010) noted errors in the chimpanzee Adrb sequence used
by Cagliani et al. (2009) to estimate the node for appearance of the
human most recent common ancestor (MRCA). The correction suggested a
significantly more ancient MRCA for this gene. Wilson et al. (2010) also
reviewed haplotypes at the 3-prime end of the ADRB2 gene that were not
addressed by Cagliani et al. (2009). In a response from the Cagliani
group, Fumagalli et al. (2010) noted the data correction and
recalculated the time to MRCA as 1.9 million years. They proposed that
this increased depth provides further support that ADRB2 has been
evolving under a balancing-selection regime.
ANIMAL MODEL
Rohrer et al. (1999) found that mice lacking both Adrb1 and Adrb2 had
normal basal heart rate, blood pressure, and metabolic rate. However,
stimulation with beta-receptor agonists or exercise revealed significant
impairment in chronotropic range, vascular reactivity, and metabolic
rate; maximal exercise capacity was not affected. Beta-receptor
stimulation of cardiac inotropy and chronotropy was mediated almost
exclusively by Adrb1, whereas vascular relaxation and metabolic rate
were controlled by all 3 beta receptors. Compensatory alterations in
cardiac muscarinic receptor density and vascular Adrb3 responsiveness
were also observed in Adrb1/Adrb2 double-knockout mice.
Maurice et al. (1999) tested the hypothesis that genetic manipulation of
the myocardial beta-adrenergic receptor system, which is impaired in
heart failure, can enhance cardiac function. They delivered adenoviral
transgenes, including human B2AR, to the myocardium of rabbits using an
intracoronary approach. Catheter-mediated delivery of Adeno-B2AR
produced diffuse multichamber myocardial expression, peaking 1 week
after gene transfer. The delivery of the transgene reproducibly produced
5- to 10-fold B2AR overexpression in the heart, which, at 7 and 21 days
after delivery, resulted in increased in vivo hemodynamic function,
compared with control rabbits that received an empty adenovirus.
To determine whether the sympathetic nervous system is the efferent arm
of diet-induced thermogenesis, Bachman et al. (2002) created mice that
lacked the beta-adrenergic receptors ADRB1, ADRB2, and ADRB3. Beta-less
mice on a chow diet had a reduced metabolic rate and were slightly
obese. On a high-fat diet, beta-less mice, in contrast to wildtype mice,
developed massive obesity that was due entirely to a failure of
diet-induced thermogenesis. Bachman et al. (2002) concluded that the
beta-adrenergic receptors are necessary for diet-induced thermogenesis
and that this efferent pathway plays a critical role in the body's
defense against diet-induced obesity.
Odley et al. (2004) developed transgenic mice expressing constitutively
active (GTPase-deficient) or dominant-inhibitory (non-GTP-binding) Rab4
(179511) mutants. Expression of constitutively active Rab4 had no effect
on cardiac structure or function, but the dominant-inhibitory Rab4
mutant impaired the responsiveness of Adrb2 to endogenous and exogenous
catecholamines. These defects were accompanied by bizarre vesicular
structures and abnormal accumulation of Adrb2 in the sarcoplasm and
subsarcolemma. Odley et al. (2004) presented further evidence that Rab4
is involved in bidirectional sarcolemmal-vesicular Adrb2 trafficking,
which occurs continuously in healthy hearts and is necessary for normal
baseline adrenergic responsiveness and resensitization after
catecholamine exposure.
LOC644762
| dbSNP name | rs1991804(T,A); rs1991805(G,C) |
| ccdsGene name | CCDS4299.1 |
| cytoBand name | 5q32 |
| EntrezGene GeneID | 644762 |
| snpEff Gene Name | PDE6A |
| EntrezGene Description | mitochondrial fission factor pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1694 |
KIF4B
| dbSNP name | rs137888317(G,A); rs6580126(G,T); rs17116710(G,A); rs10056252(A,G); rs60928118(G,A) |
| ccdsGene name | CCDS47324.1 |
| cytoBand name | 5q33.2 |
| EntrezGene GeneID | 285643 |
| EntrezGene Description | kinesin family member 4B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KIF4B:NM_001099293:exon1:c.G334A:p.V112I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.215 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2VIQ3 |
| dbNSFP Uniprot ID | KIF4B_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 3.253e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Ears];
Conductive hearing loss;
Sensorineural hearing loss;
Mixed hearing loss;
Preauricular pits;
Preauricular tags;
External auditory canal atresia;
Malformed ossicles;
Internal auditory canal hypoplasia;
[Eyes];
Strabismus;
[Mouth];
Submucosal cleft palate;
Trismus;
[Neck];
Branchial cleft cysts;
Branchial cleft fistulae
SKELETAL:
[Hands];
Short distal phalanx (5th finger);
Pointed phalanx (5th finger);
Bony erosions (5th finger);
[Feet];
Short distal phalanges (toes 2-4)
OMIM Title
*609184 KINESIN FAMILY MEMBER 4B; KIF4B
OMIM Description
CLONING
By searching databases for sequences similar to mouse Kif4 (KIF4A;
300521), followed by PCR and screening a HeLa cell cDNA library, Oh et
al. (2000) cloned KIF4B.
GENE STRUCTURE
Oh et al. (2000) determined that KIF4B is an intronless gene, and they
suggested that it may be a processed pseudogene of KIF4A.
MAPPING
By FISH, Ha et al. (2000) mapped the KIF4B gene to chromosome 5q33.1.
NIPAL4
| dbSNP name | rs1105282(A,G); rs10071997(C,G); rs951958(C,A); rs951959(C,T); rs951957(T,C); rs889033(C,A); rs57064749(C,T); rs114432814(T,C); rs77011229(G,T); rs112023831(G,A); rs4704864(C,G); rs4704742(T,C); rs56259240(G,A); rs11745505(T,C); rs11745566(T,C); rs77955342(C,T); rs10066571(A,G); rs4704865(G,A); rs55635824(G,A); rs10063083(C,G); rs75772565(G,A); rs115502782(C,T); rs76367243(G,T); rs6878502(A,T); rs4704866(G,A); rs372087764(C,T); rs78563550(T,C); rs10076407(T,C); rs59237026(T,C); rs145704043(G,A); rs114312788(C,T); rs4704867(G,T); rs4704868(T,C); rs6860175(A,G); rs6878792(G,C); rs6860507(A,G); rs10476050(C,A); rs4704869(G,A); rs6879450(G,A); rs9313606(A,C); rs9313607(T,C); rs4704870(T,C); rs61743233(C,T); rs9313608(C,T); rs10476052(C,A); rs3734029(T,C); rs3822692(A,T); rs74580303(G,T); rs78888263(C,T); rs6556051(T,C); rs11749762(T,C) |
| ccdsGene name | CCDS47328.1 |
| cytoBand name | 5q33.3 |
| EntrezGene GeneID | 348938 |
| EntrezGene Description | NIPA-like domain containing 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NIPAL4:NM_001172292:exon3:c.C536T:p.A179V,NIPAL4:NM_001099287:exon4:c.C593T:p.A198V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7884 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q0D2K0-2 |
| ESP Afr MAF | 0.000251 |
| ESP All MAF | 8.1e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 1.633e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Bilateral nuclear cataract, congenital
MISCELLANEOUS:
Cataracts present at birth or develop in infancy
OMIM Title
*609383 NIPA-LIKE DOMAIN-CONTAINING 4; NIPAL4
;;ICHTHYIN; ICHYN
OMIM Description
CLONING
By in silico analyses, Lefevre et al. (2004) cloned NIPAL4, which they
called ichthyin. The deduced 404-amino acid protein has a calculated
molecular mass of 44 kD. The protein has several putative transmembrane
domains and shares approximately 75% sequence identity with the mouse
and rat orthologs. It is predicted to localize in the plasma membrane,
but does not possess a signal sequence. RT-PCR detected expression of
ichthyin at high levels in brain, lung, stomach, skin, and leukocytes,
and in all other tissues tested except liver, thyroid, and fetal brain,
in which no expression was detectable. Strong expression was observed in
cultured keratinocytes from normal skin biopsies; expression was weaker
in cultured fibroblasts from the same skin biopsies, in placenta and in
lymphocytes.
GENE STRUCTURE
Lefevre et al. (2004) determined that the NIPAL4 gene contains 6 exons.
MAPPING
By in silico and sequence analyses, Lefevre et al. (2004) mapped the
NIPAL4 gene to chromosome 5q33.
MOLECULAR GENETICS
In 23 patients from 14 consanguineous families with nonsyndromic
autosomal recessive congenital ichthyosis (ARCI6; 612281), Lefevre et
al. (2004) identified 6 homozygous mutations in the NIPAL4 gene (see,
e.g., 609383.0001-609383.0002).
Dahlqvist et al. (2007) studied 27 patients from 18 ARCI families with
the specific ultrastructural features of the epidermis that characterize
electron microscopy-analyzed ichthyosis designated type III (EM type
III). Mutation screening of NIPAL4 revealed 4 different missense or
splice site mutations (see, e.g., 609383.0003-609383.0004) in affected
members from 16 of 18 (89%) families with these characteristics of ARCI
EM type III.
MIR146A
| dbSNP name | rs2910164(C,G) |
| cytoBand name | 5q34 |
| EntrezGene GeneID | 406938 |
| snpEff Gene Name | CTC-231O11.1 |
| EntrezGene Description | microRNA 146a |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3815 |
| ESP Afr MAF | 0.384885 |
| ESP All MAF | 0.279709 |
| ESP Eur/Amr MAF | 0.233668 |
| ExAC AF | 0.713 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial weakness;
[Eyes];
Ptosis (less common);
Absence of ophthalmoparesis;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory muscle weakness may occur
MUSCLE, SOFT TISSUE:
Muscle biopsy shows 60-80-nm tubular aggregates arranged in hexagonal
arrays in type 2 fibers
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor milestones (in some);
Proximal muscle weakness due to defect at the neuromuscular junction;
Proximal muscle atrophy;
Distal muscle weakness may also occur;
Easy fatigability;
Muscle cramps;
Gowers sign;
Waddling gait;
Decremental compound motor action potential (CMAP) response to repetitive
nerve stimulation seen on EMG;
Increased jitter seen on single fiber EMG
IMMUNOLOGY:
Absence of acetylcholine receptor (AChR) autoantibodies
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Onset in first decade;
Favorable response to acetylcholinesterase inhibitors;
Distinct disorder from acquired limb-girdle myasthenia (159400)
and congenital limb-girdle myasthenia (254300)
MOLECULAR BASIS:
Caused by mutation in the glutamine:fructose-6-phosphate aminotransferase
1 gene (GFPT1, 138292.0001)
OMIM Title
*610566 MICRO RNA 146A; MIR146A
;;miRNA146A;;
MIRN146A
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs), such as MIRN146A, are an evolutionarily conserved
class of endogenous 22-nucleotide noncoding RNAs involved in
posttranscriptional gene repression. In animals, miRNAs are processed
from long primary transcripts through a 60-bp hairpin precursor step
into mature forms by sequential cutting with 2 RNase III enzymes, Drosha
(RNASEN; 608828) and Dicer (606241). Mature miRNAs are then loaded onto
the ribonucleoprotein complex dubbed RISC (RNA-induced silencing
complex), where they guide recognition and translational repression or
degradation of target mRNAs (summary by Taganov et al., 2006).
CLONING
Taganov et al. (2006) stated that the human genome contains 2 miRNA146
genes, MIRN146A and MIRN146B (610567), on chromosomes 5 and 10,
respectively. They determined that MIRN146A is located within exon 2 of
the LOC285628 gene. The primary LOC285628 transcript contains no
significant ORF, suggesting it belongs to a class of noncoding RNAs.
Using RACE, Taganov et al. (2006) found that the MIRN146A primary
transcript contains 2,337 bp. The mature products of MIRN146A and
MIRN146B differ by only 2 nucleotides in the 3-prime region.
Using quantitative real-time PCR, Sonkoly et al. (2007) found ubiquitous
but variable miR146A expression in human tissues. In skin, miR146A was
preferentially expressed in immune cells, with highest level in CD4
(186940)-positive/CD25 (IL2RA; 147730)-positive T cells, but was absent
from keratinocytes and dermal fibroblasts.
GENE FUNCTION
By expression profiling, Taganov et al. (2006) found that the mature
forms of MIRN132 (610016), MIRN155 (609337), MIRN146A, and MIRN146B were
induced in a monocyte cell line following exposure to lipopolysaccharide
(LPS). Promoter analysis of MIRN146A revealed that transcription
following LPS, TNF (191160), or IL1B (147720) exposure was dependent on
NFKB (see 164011). Luciferase reporter analysis suggested that sequences
in the 3-prime UTRs of TRAF6 (602355) and IRAK1 (300283) may basepair
with MIRN146A and MIRN146B. Taganov et al. (2006) proposed that MIRN146A
and MIRN146B may function as negative regulators of Toll-like receptors
and cytokine signaling by downregulating IRAK1 and TRAF6 protein levels.
Using microarray analysis and quantitative real-time PCR, Sonkoly et al.
(2007) found that expression of miR146A was upregulated in psoriasis
(see 177900), but not in atopic eczema (see 603165), compared with
normal human skin.
Using microarray and Northern blot analysis, Chang et al. (2008) showed
that MIRN146A was among several miRNAs downregulated by MYC (190080) in
mouse and human B-cell lymphoma cell lines. MYC bound the MIRN146A
upstream region.
Using DNA arrays and Northern blot analysis, Lukiw et al. (2008) found
that the expression of MIR146A was significantly upregulated in
Alzheimer disease (AD; 104300) neocortex and hippocampus compared with
normal control tissue. They identified a putative MIR146A-binding site
in the 3-prime UTR of CFH (134370), and confirmed that the expression of
CFH was downregulated in AD brain compared with controls. Upregulation
of MIR146A and downregulation of CFH was also found in stressed primary
human neuronal/glial cell cocultures, which is a model of AD. They
further found that MIR146A was upregulated by NF-kappa-B (see 164011)
and concluded that NF-kappa-B-sensitive MIR146A modulates the expression
of CFH as part of the inflammatory response in AD brain.
One of the most common subtypes of myelodysplastic syndrome (MDS), 5q-
syndrome (153550), is characterized by an isolated interstitial deletion
of chromosome 5q, severe anemia, variable neutropenia, and normal or
high platelet counts with dysplastic megakaryocytes. Starczynowski et
al. (2010) postulated that loss of miRNAs encoded within the common
deleted region in 5q- syndrome may result in haploinsufficiency due to
loss of inhibition of their targets. They found that expression of
MIR145 (611795) and MIR146A was reduced in MDS patients with deletion of
chromosome 5q. Loss of both MIR145 and MIR146A resulted in activation of
innate immune signaling due to elevated expression of their respective
targets, TIRAP (606252) and TRAF6. Knockdown of both Mir145 and Mir146a
or overexpression of Traf6 in mouse hematopoietic stem/progenitor cells
(HSPCs) recapitulated several features of 5q- syndrome, including
thrombocytosis, mild neutropenia, and megakaryocytic dysplasia.
Starczynowski et al. (2010) concluded that inappropriate activation of
innate immune signals in HSPCs due to loss of miRNA-mediated inhibition
is involved in several features of 5q- syndrome.
Using RT-PCR analysis, Curtale et al. (2010) found that expression of
MIR146A was low in human naive T cells, but that it was abundant in
memory T cells, with induction initiated by T-cell receptor (TCR; see
186880) stimulation. Binding sites for NF-kappa-B and ETS (see 164720)
in the MIR146A promoter were required for induction of MIR146A
transcription upon TCR engagement. MIR146A modulated activation-induced
cell death by acting as an antiapoptotic factor, and it targeted FADD
(602457). AP1 (165160) activity and IL2 (147680) production were
impaired by MIR146A expression. Curtale et al. (2010) concluded that
several signaling pathways other than inflammation are influenced by
MIR146A.
Using mice lacking Tlr4 (603030) or the essential TLR signaling molecule
Irak1, Chassin et al. (2010) demonstrated that Mir146a mediated
translational repression and proteolytic degradation of Irak1, which was
sufficient to induce intestinal epithelial innate immune tolerance and
provide protection from bacteria-induced epithelial damage in neonates.
Intraepithelial endotoxin persistence during the neonatal period
maintained tolerance through sustained Mir146a expression and
additionally facilitated transcription of a distinct set of genes
involved in cell survival, differentiation, and homeostasis. Chassin et
al. (2010) concluded that neonatal intestinal epithelial innate immune
tolerance is an example of restriction of signaling to prevent
bacteria-induced intestinal epithelial damage during the transition
between fetal, neonatal, and adult life.
MAPPING
Taganov et al. (2006) stated that the MIRN146A gene maps to chromosome
5.
MOLECULAR GENETICS
Jazdzewski et al. (2008) found that the rarer C allele of a common G/C
SNP (dbSNP rs2910164) within the pre-miR-146a sequence reduced the
amount of pre- and mature miR146A 1.9- and 1.8-fold, respectively,
compared with the G allele. The SNP is located on the passenger strand
of pre-miR146A, at position +60 relative to the first nucleotide, and
the C allele is predicted to cause mispairing within the hairpin. EMSA
experiments showed that the C allele interfered with binding of HeLa
cell nuclear proteins to pre-miR146a, and it also caused inefficient
inhibition of the miR146a target genes TRAF6 and IRAK1, as well as of
PTC1 (CCDC6; 601985), in reporter gene assays. Jazdzewski et al. (2008)
genotyped 608 patients with papillary thyroid carcinoma (PTC; 188550)
and 901 controls and found that GC heterozygosity was associated with
increased risk of acquiring PTC, whereas both homozygous states were
protective. They concluded that the G/C SNP alters pre-miR146a
processing and contributes to predisposition to PTC by altering
expression of miR146a target genes in the Toll-like receptor and
cytokine signaling pathway.
TENM2
| dbSNP name | rs17068248(G,C); rs73803141(G,T); rs6863083(C,G); rs6884481(T,C); rs4869027(G,A); rs10043619(C,T); rs79786345(G,A); rs11739327(T,G); rs7730469(C,T); rs7731005(C,T); rs112021736(G,A); rs113636873(G,A); rs192217273(C,T); rs147806095(G,T); rs113755797(C,T); rs10462891(C,T); rs10475839(C,A); rs4075224(C,A); rs4349736(G,A); rs13355217(T,C); rs72645738(T,G); rs189283964(C,T); rs150478377(T,C); rs138842223(G,A); rs116329261(A,G); rs56857681(C,A); rs148083232(A,G); rs150588845(T,G); rs149027113(G,T); rs146633052(G,A); rs73803148(A,G); rs6865179(A,G); rs73363414(C,T); rs7341056(C,T); rs76904045(A,T); rs73363417(C,T); rs369966412(C,T); rs72645740(G,A); rs116665728(T,G); rs78963759(C,T); rs72645742(T,C); rs9687521(C,A); rs76473847(A,G); rs1030191(C,A); rs183583272(G,A); rs4242220(T,G); rs1024987(C,G); rs115416111(A,T); rs1559110(C,T); rs73363425(A,G); rs72645744(G,T); rs13178466(C,T); rs4869028(A,T); rs115011593(A,T); rs4868789(C,A); rs4868790(C,A); rs57736136(A,T); rs13183992(A,G); rs17068271(A,G); rs1946230(A,G); rs1946229(C,T); rs76623727(C,T); rs977156(C,T); rs1422535(T,C); rs1543824(C,G); rs1541658(A,G); rs1541657(G,T); rs10043375(C,T); rs73363435(T,C); rs144782578(G,T); rs12152864(T,C); rs1895267(G,A); rs1895266(G,A); rs73363445(G,A); rs13187898(C,T); rs112133585(A,G); rs6882979(T,C); rs13155681(C,T); rs114823271(C,T); rs35441103(C,G); rs4868791(G,A); rs4869029(G,A); rs116634751(C,G); rs4868792(A,G); rs73367432(A,C); rs4868793(A,G); rs6881538(T,A); rs11134453(A,G); rs11134454(T,C); rs80209671(C,T); rs11134455(A,T); rs4868794(T,C); rs6886887(T,A); rs114089343(G,A); rs114772809(A,C); rs1422534(T,C); rs13165082(G,A); rs115360612(G,C); rs79788980(C,A); rs35472878(T,A); rs114547547(C,T); rs33916372(G,A); rs77071440(G,T); rs17068337(A,G); rs73367443(C,T); rs4869030(A,G); rs75143066(G,A); rs76669883(T,C); rs17498388(A,G); rs10077097(T,C); rs888913(A,C); rs115591277(G,T); rs115436727(G,A); rs201994929(T,C); rs143743986(G,A); rs190677624(A,G); rs200068864(T,A); rs4869031(C,T); rs4869032(T,G); rs6890961(C,T); rs12520270(G,T); rs80063754(G,A); rs78990355(A,C); rs13166175(C,A); rs13186421(T,A); rs200918832(C,A); rs73367458(G,A); rs10078722(G,A); rs11134457(G,A); rs6555742(C,A); rs10051468(G,C); rs7702966(C,A); rs11742583(T,C); rs1422533(G,A); rs1422532(C,G); rs13164798(A,G); rs11134458(T,C); rs79029223(A,G); rs2862038(A,G); rs2112583(T,C); rs17414058(T,C); rs11957484(A,G); rs190099364(C,T); rs6883599(A,G); rs4869034(C,T); rs58489073(A,C); rs184497212(T,G); rs73367478(A,G); rs2902120(A,G); rs73367481(C,T); rs9284973(G,A); rs1422531(C,T); rs1422530(G,A); rs1422529(T,G); rs73367490(T,C); rs73367492(C,T); rs10045539(G,A); rs17414317(T,A); rs73369704(T,C); rs6859502(C,T); rs17068395(G,A); rs36085460(A,T); rs10036733(G,A); rs11739983(G,A); rs10070112(A,G); rs13169226(G,A); rs13355851(C,G); rs73369714(A,G); rs112165341(A,G); rs34287204(C,T); rs13177293(T,G); rs13157095(A,C); rs73803153(A,G); rs11739827(G,T); rs4509046(T,C); rs6874782(G,T); rs57104133(G,C); rs61175961(T,A); rs57699167(G,C); rs10064569(T,G); rs7715979(C,T); rs79867368(A,T); rs1422528(T,C); rs7726117(A,C); rs11749740(A,G); rs11749791(A,C); rs4869035(C,T); rs4869036(G,C); rs10475517(A,C); rs35874839(A,G); rs76521859(G,A); rs10475840(A,G); rs2862266(C,A); rs7737147(A,T); rs1422526(T,C); rs58116562(C,G); rs1422525(A,C); rs58724977(A,C); rs9313374(T,A); rs9313375(T,C); rs10069563(G,A); rs13176584(C,A); rs7724360(A,G); rs7724361(A,G); rs10076695(A,G); rs10076753(A,G); rs74648754(T,C); rs72829329(G,C); rs2112582(A,G); rs10068472(G,T); rs11959347(T,C); rs71603830(C,T); rs10078588(T,A); rs10055654(A,G); rs66870020(A,C); rs28555227(A,G); rs1422524(T,C); rs1422523(G,A); rs28503554(G,A); rs12654350(A,C); rs114562093(A,G); rs150586695(G,A); rs12654913(A,C); rs10054691(T,C); rs12522584(C,T); rs1422522(A,G); rs1422521(T,C); rs62388804(C,T); rs62388805(G,A); rs11749953(T,C); rs1582486(G,T); rs1582485(G,T); rs1363490(A,C); rs1363489(T,G); rs4869040(A,G); rs9313377(A,C); rs6555743(A,C); rs7727820(G,T); rs11749309(G,T); rs190907472(G,A); rs11750022(C,T); rs973621(T,A); rs4868795(A,C); rs7700957(G,A); rs1895265(A,C); rs10085006(C,G); rs1158821(A,C); rs1158822(T,C); rs9313378(C,T); rs34731725(G,A); rs7704394(T,C); rs73801207(G,A); rs11750777(G,A); rs11750839(G,A); rs11741259(T,C); rs6863407(C,T); rs6863935(C,A); rs11742145(T,C); rs11745240(A,G); rs73363536(T,C); rs73363539(A,T); rs13182244(T,C); rs66716755(G,A); rs62388807(C,T); rs13162461(C,G); rs4509045(T,C); rs78953766(C,T); rs55786063(G,T); rs73363545(A,C); rs4242221(C,T); rs13355678(C,A); rs59730067(C,T); rs2068650(A,C); rs4242222(A,G); rs4317341(A,G); rs10039718(C,T); rs10043275(T,G); rs4280897(G,C); rs7704674(A,G); rs79605586(C,T); rs10475842(A,G); rs9313379(G,A); rs10067798(T,A); rs10060218(G,T); rs10062352(G,C); rs28478711(A,G); rs10072266(T,A); rs10072329(T,C); rs73801210(C,T); rs73371335(T,C); rs6867603(A,C); rs10044739(T,C); rs62388811(T,G); rs189417871(G,A); rs6899302(T,C); rs1073193(T,C); rs148745334(C,T); rs10072836(C,G); rs6879403(C,T); rs57335634(C,T); rs73801211(T,C); rs115735903(T,C); rs73801213(T,C); rs9313380(T,C); rs10475843(G,C); rs10475844(A,G); rs4437397(C,T); rs73373217(C,T); rs116018027(C,T); rs73801214(A,G); rs59414410(G,A); rs116699552(G,C); rs6892920(T,C); rs146721030(T,A); rs6871562(A,G); rs79837103(C,T); rs6555744(A,C); rs112168886(C,T); rs6555745(G,A); rs79493081(C,G); rs13170051(A,G); rs67258610(G,T); rs73801216(G,A); rs10076216(G,A); rs6889487(G,T); rs6893810(G,A); rs13186467(G,A); rs191741128(C,T); rs6895048(C,A); rs72829350(C,T); rs7701318(C,T); rs72829351(C,T); rs34626167(A,T); rs33998648(G,A); rs35879280(G,T); rs35615477(A,T); rs35828091(A,T); rs34755583(C,A); rs34558216(G,A); rs13156620(A,G); rs28393956(C,T); rs28463574(C,T); rs7710345(A,G); rs62388814(G,C); rs13355529(C,T); rs13355567(G,A); rs34515992(C,T); rs10037354(C,T); rs112380552(G,A); rs71603832(C,T); rs10058279(C,G); rs6880579(C,T); rs72829353(G,T); rs4323254(T,C); rs4543291(T,C); rs62388829(C,T); rs115848723(G,A); rs116223929(C,T); rs6887290(G,T); rs62388830(T,C); rs6887079(C,T); rs13183290(A,G); rs13165913(T,C); rs75998988(G,A); rs59098493(A,G); rs4562064(G,A); rs4518425(G,C); rs4549550(G,A); rs4392647(A,C); rs4257797(T,G); rs7724862(T,C); rs6884191(A,C); rs6884816(G,C); rs6884689(C,G); rs7707070(T,C); rs74956288(A,G); rs12153692(A,T); rs67460411(G,A); rs10475845(A,G); rs371108791(G,C); rs77631446(C,T); rs9284974(C,T); rs111929858(T,G); rs4538630(T,G); rs7707198(A,T); rs4495205(G,A); rs114714600(C,T); rs193235319(C,T); rs1030668(C,T); rs11134459(T,C); rs11134460(C,T); rs11134461(G,A); rs184352244(G,A); rs79269909(A,C); rs80003210(T,C); rs13175808(C,T); rs12658474(C,A); rs12658534(G,A); rs12652339(T,C); rs11742767(A,G); rs114626336(G,A); rs13181278(C,G); rs143221491(T,C); rs11952900(A,G); rs11959428(C,T); rs35549373(T,A); rs10063642(A,T); rs114555132(G,A); rs1030669(T,C); rs1864978(T,G); rs1864977(A,G); rs6555746(T,C); rs1864976(A,G); rs116524323(A,G); rs12654709(A,G); rs12652718(T,C); rs17068499(G,A); rs13185245(A,G); rs6555747(C,A); rs6880489(T,G); rs79822896(A,G); rs73363817(C,A); rs191716553(A,G); rs116219203(A,G); rs138809795(G,A); rs1864975(T,C); rs76121955(C,T); rs4868797(A,C); rs6898161(T,C); rs6876770(A,G); rs4868798(G,A); rs78897068(A,G); rs12522574(T,C); rs12519893(C,A); rs17499927(C,T); rs17499941(T,G); rs17499962(C,T); rs7716047(C,T); rs1963409(G,A); rs138202007(C,T); rs1025482(C,T); rs7725953(G,C); rs17500137(T,G); rs2053061(C,T); rs2053060(C,T); rs6420072(G,A); rs10866611(A,C); rs200899931(C,T); rs72829377(G,A); rs141289203(A,G); rs6555748(G,T); rs10058318(G,T); rs11957887(A,G); rs73801228(A,G); rs12515748(T,G); rs77431082(T,C); rs13154921(C,T); rs11738397(C,T); rs7378751(G,T); rs10866612(A,G); rs11134463(G,T); rs11739491(C,A); rs11745971(A,G); rs78652691(G,A); rs180951778(A,G); rs73801230(T,C); rs6555750(T,G); rs7719534(G,A); rs7719299(A,G); rs6555751(G,A); rs73801235(G,A); rs72829381(C,A); rs2077837(T,C); rs7723006(T,C); rs12519007(C,T); rs6889293(T,C); rs74452601(T,G); rs1864979(C,T); rs12516554(C,T); rs1432886(G,C); rs6555752(T,C); rs6555753(G,T); rs150009523(C,A); rs6555754(A,T); rs7445522(T,G); rs6555755(A,G); rs6555756(A,G); rs59226163(T,C); rs10069806(C,T); rs6555757(T,C); rs34036339(C,T); rs62383310(C,G); rs6863544(T,C); rs13175181(G,A); rs7443457(T,C); rs145260783(C,A); rs12652771(T,C); rs12655294(A,G); rs77348130(A,G); rs12659544(G,A); rs7448661(G,C); rs6555758(G,C); rs60006712(A,G); rs12519979(G,T); rs11134464(G,C); rs200313136(T,A); rs58980212(T,C); rs140280442(C,T); rs11748124(C,T); rs7448195(G,A); rs6555759(A,C); rs1025481(A,G); rs144753868(C,A); rs1025480(A,T); rs189600980(C,G); rs57418568(G,C); rs201425760(A,G); rs76372288(G,A); rs1025483(A,C); rs1025484(G,A); rs74606057(G,C); rs13173259(C,T); rs144225522(A,C); rs35144300(C,T); rs78887390(T,C); rs1432880(A,C); rs1432881(T,C); rs1432882(G,C); rs9791043(A,T); rs35512038(C,T); rs79874336(A,G); rs141716115(C,T); rs74496535(T,G); rs180941360(G,A); rs146259935(T,C); rs139424221(T,C); rs62383319(T,A); rs4869050(A,G); rs111683573(A,G); rs35888866(G,A); rs4869051(A,G); rs12659637(A,G); rs10214221(T,C); rs55813449(T,C); rs67720183(A,G); rs55710701(T,C); rs1529695(G,C); rs78026641(A,G); rs999624(A,T); rs57178789(T,A); rs10076223(A,G); rs13181123(A,C); rs13181260(A,G); rs62383323(A,G); rs12657574(T,C); rs10050723(A,G); rs114015789(T,A); rs74631863(T,A); rs146395133(C,A); rs67594515(G,A); rs148738192(C,G); rs74580202(G,A); rs10462892(C,G); rs114046848(A,G); rs75018194(T,A); rs891951(C,T); rs891952(C,T); rs1560659(A,G); rs1560660(G,A); rs1432884(C,A); rs145762704(G,A); rs4869052(T,C); rs4309994(A,G); rs4242224(C,T); rs79636915(C,G); rs10055311(T,C); rs180680023(G,A); rs56349163(A,G); rs56336890(A,G); rs67641748(G,A); rs7737557(C,T); rs77898885(A,G); rs68179237(G,T); rs12654476(T,A); rs12656403(A,C); rs12654925(T,C); rs1030670(C,T); rs80193549(A,G); rs2053059(C,T); rs7715415(A,G); rs6555763(C,T); rs6881662(G,C); rs58447180(G,C); rs13154542(A,G); rs13174736(T,C); rs79548771(A,G); rs147503767(T,G); rs143907824(T,C); rs147274129(C,T); rs1529694(G,A); rs75649688(A,G); rs73367214(A,G); rs4869053(C,T); rs75227745(C,T); rs117911426(A,C); rs117501264(A,T); rs2112626(A,T); rs74505929(A,C); rs6890751(G,A); rs55941714(A,G); rs13359666(T,G); rs56194981(A,G); rs143391570(T,C); rs10043795(T,C); rs1368378(C,T); rs1432885(C,A); rs12514409(A,G); rs6867921(G,A); rs10059004(C,T); rs2052509(G,T); rs2052510(A,G); rs1035419(T,G); rs77863025(C,T); rs1035418(C,G); rs79223001(A,C); rs9687011(C,A); rs6859661(A,T); rs112964125(C,T); rs115833126(G,A); rs114373661(G,A); rs888978(T,A); rs888977(C,T); rs1972645(C,T); rs5024074(A,G); rs114918500(C,T); rs7709569(T,C); rs7709731(T,G); rs114329017(T,A); rs4869054(A,G); rs115645637(C,G); rs4869055(A,G); rs1808380(T,C); rs75055792(C,A); rs111703856(T,A); rs77278414(G,A); rs6886928(G,A); rs4868800(G,T); rs6898357(A,G); rs10051918(G,A); rs9313384(C,T); rs13157086(G,A); rs883322(G,T); rs883323(C,T); rs888976(A,G); rs79408697(T,C); rs13357319(T,G); rs888975(C,T); rs1862347(T,C); rs888974(G,T); rs10071347(A,G); rs4044321(A,G); rs2336893(A,G); rs2336894(T,G); rs2336895(G,A); rs149997518(G,T); rs2080974(T,G); rs2080975(T,G); rs2080976(T,C); rs2098651(C,G); rs13186288(T,C); rs77430230(C,T); rs4869056(G,A); rs4869057(A,G); rs4869058(T,A); rs11747772(C,T); rs11738110(T,G); rs986391(G,A); rs12188010(A,T); rs1549212(C,T); rs1549213(G,C); rs1549214(T,C); rs11948504(G,T); rs78458955(C,G); rs59577747(T,C); rs12188278(A,G); rs10039321(T,C); rs114274794(C,T); rs10042499(A,G); rs62382791(A,G); rs10475852(T,C); rs13153563(T,C); rs115598145(G,A); rs7734360(A,G); rs10065886(A,C); rs10035359(C,T); rs181747066(A,G); rs13160227(G,A); rs10475853(G,T); rs34561169(G,A); rs10040492(T,C); rs1024993(C,T); rs1024994(T,C); rs9313385(A,G); rs12173126(G,A); rs1993612(A,G); rs6881950(G,C); rs3095948(T,C); rs6882026(C,A); rs13174305(A,G); rs6863316(T,G); rs11742457(G,A); rs11742502(C,T); rs278012(T,A); rs175874(C,T); rs278013(A,C); rs11749653(T,C); rs113259494(T,C); rs278014(T,A); rs2248716(A,G); rs990201(C,A); rs278016(A,G); rs7707806(C,G); rs6879246(C,T); rs73382905(C,G); rs1903110(C,A); rs113406271(C,T); rs116327241(A,G); rs11750548(G,A); rs142734892(G,C); rs78939696(C,T); rs13159986(A,G); rs11744500(T,G); rs78646014(C,T); rs4869061(C,T); rs4868803(G,A); rs278008(G,A); rs28538319(G,A); rs278007(G,A); rs172137(G,A); rs11738133(C,T); rs4869062(T,C); rs4868804(A,G); rs10053050(C,T); rs1459071(A,G); rs898171(G,A); rs732711(A,C); rs278006(C,T); rs3101178(G,C); rs3101179(T,G); rs10475856(A,G); rs981898(A,T); rs6893866(A,C); rs11134465(G,A); rs73382930(G,A); rs11134466(T,C); rs11738927(A,G); rs74912115(C,T); rs11743417(G,A); rs72819683(C,G); rs12716235(A,G); rs1459066(C,T); rs115108152(C,T); rs10052061(A,C); rs278010(A,C); rs73382941(G,T); rs75166987(G,C); rs7730427(A,G); rs10045114(C,A); rs2336897(C,T); rs962065(T,C); rs1966924(C,A); rs11739021(T,C); rs2336898(A,G); rs115699484(A,G); rs57629844(T,G); rs59710284(G,A); rs116607018(G,A); rs4472280(C,A); rs6867945(A,G); rs2219498(C,T); rs279393(G,A); rs279392(C,T); rs145375609(C,G); rs73382951(T,C); rs113947680(T,C); rs62382816(C,T); rs112112765(C,T); rs279390(A,G); rs10516034(T,G); rs73803914(G,T); rs279389(A,C); rs10071710(A,G); rs151077695(C,A); rs279388(A,C); rs73803916(A,C); rs10066983(T,C); rs10046048(A,G); rs34313662(T,C); rs140939676(C,T); rs203308(A,G); rs7443768(G,C); rs279399(T,C); rs185763(C,T); rs6881298(G,A); rs279397(A,C); rs57302052(A,G); rs4398654(A,G); rs56921614(G,C); rs17068890(A,G); rs61567681(T,C); rs279395(A,G); rs72819700(A,G); rs17068894(A,G); rs279394(T,C); rs73803920(C,A); rs203307(C,T); rs56791471(C,T); rs73801312(T,C); rs28540685(C,T); rs17068913(A,G); rs73801313(C,T); rs2061446(C,T); rs56340626(A,C); rs57724524(C,T); rs73801314(G,A); rs17068914(G,A); rs6878759(C,T); rs10072830(G,T); rs57372018(C,A); rs73801318(C,T); rs73801319(T,C); rs10223130(A,T); rs2125576(G,T); rs2243779(C,G); rs72821808(G,A); rs17068919(A,C); rs17068921(C,G); rs17068924(G,T); rs10516035(G,T); rs60639149(G,A); rs2609854(A,G); rs279385(T,A); rs73801320(C,T); rs17068925(C,T); rs279386(G,T); rs60855331(C,T); rs56107821(C,T); rs73801322(C,G); rs7718412(G,A); rs12522388(C,A); rs73801323(G,T); rs4546405(C,A); rs4463193(T,A); rs4463194(T,A); rs4351166(T,C); rs1459076(T,C); rs4432913(T,C); rs1459075(T,C); rs1459074(A,T); rs11950863(C,T); rs17068955(T,A); rs4431367(G,C); rs1459073(T,C); rs73801348(A,C); rs11134467(G,A); rs17068972(T,A); rs56842294(G,C); rs59834824(C,T); rs6885478(T,C); rs2168988(C,T); rs4587095(T,A); rs4587096(T,C); rs138623614(G,A); rs898173(G,C); rs73801349(C,T); rs1563729(T,C); rs6555764(A,G); rs4993463(G,A); rs4993462(A,C); rs4993461(A,C); rs4993460(G,A); rs7704071(C,T); rs7704469(G,A); rs7704222(C,G); rs7724248(T,C); rs4582299(G,A); rs6863828(A,G); rs6885086(T,C); rs6885448(T,G); rs6555765(C,T); rs2546988(G,A); rs56950359(T,A); rs12521170(A,G); rs73801354(T,C); rs7725107(A,G); rs6890602(G,A); rs41378648(A,T); rs67528580(A,G); rs10516036(C,T); rs56116300(A,T); rs7723247(T,C); rs113675742(A,G); rs10035233(T,C); rs368187664(G,A); rs6860687(T,C); rs279408(A,G); rs279409(A,C); rs279410(A,G); rs75678085(G,A); rs898172(G,A); rs279412(T,C); rs279413(C,T); rs7728582(C,T); rs78370857(A,G); rs279414(T,C); rs78728902(G,A); rs203309(G,A); rs73384971(G,A); rs279415(C,T); rs139005713(G,A); rs73386406(T,A); rs279416(C,A); rs10057249(G,A); rs146107091(G,A); rs151163008(A,G); rs73386413(C,G); rs279407(T,C); rs279406(A,T); rs10065273(A,G); rs78040966(C,T); rs116409713(A,G); rs147444977(G,A); rs77690538(A,C); rs279405(G,A); rs279404(G,T); rs56322524(G,A); rs279403(T,C); rs73801358(G,C); rs1459072(A,G); rs79116903(C,T); rs78264383(T,G); rs6555766(A,G); rs10516040(G,T); rs114291767(G,A); rs76051987(C,T); rs77707798(C,G); rs114613251(G,A); rs76356463(A,C); rs67298145(G,A); rs115176706(C,T); rs10057680(A,G); rs10050810(T,C); rs77234331(T,A); rs7719478(A,G); rs115380265(T,C); rs74411493(C,T); rs2337015(T,C); rs875208(G,C); rs150358473(A,G); rs2337016(T,G); rs4869066(C,T); rs6897962(T,C); rs4869067(C,T); rs145890607(G,A); rs150306814(C,T); rs6555767(G,A); rs2337019(G,A); rs142831750(G,T); rs2244456(A,T); rs72830091(A,G); rs2337020(A,G); rs2337021(C,T); rs140074463(G,A); rs7717495(A,G); rs4401595(T,A); rs142631005(G,A); rs6869167(G,A); rs7715344(G,C); rs4583906(A,G); rs113481914(G,A); rs148975996(G,A); rs35366185(C,T); rs7703401(T,C); rs34725756(A,G); rs6555768(T,C); rs35325704(C,G); rs77741835(A,G); rs115002578(C,T); rs77611961(C,T); rs67767662(T,G); rs61165988(G,T); rs10064701(C,T); rs10072896(T,C); rs10065043(C,T); rs6862936(G,A); rs116318925(A,C); rs17432815(G,A); rs77751109(C,T); rs13436455(T,C); rs13436693(A,C); rs4624810(A,G); rs79067689(A,G); rs6891311(G,A); rs76046887(C,T); rs9313387(G,A); rs6895940(G,A); rs9313388(A,C); rs10064302(G,A); rs4479863(T,G); rs76440658(G,A); rs115077379(G,A); rs115325851(G,C); rs12187148(A,G); rs4868805(C,T); rs12188727(G,C); rs6879227(G,A); rs114782257(C,T); rs74794871(T,C); rs1834118(G,A); rs4242225(G,A); rs1862875(G,A); rs7721878(C,A); rs13174776(C,G); rs6869161(T,A); rs148594194(G,T); rs11750131(C,T); rs79092875(A,T); rs11738000(C,T); rs116171842(G,C); rs12651802(G,C); rs144217756(G,T); rs4869071(G,C); rs2018599(T,C); rs146513090(T,C); rs149123064(G,T); rs143106620(C,T); rs116076987(G,A); rs140159815(A,T); rs2337000(C,G); rs111476197(C,A); rs7711527(G,A); rs114733127(C,T); rs10516038(T,C); rs4242227(T,C); rs115890356(A,G); rs79213262(G,A); rs73801389(A,C); rs6873862(G,A); rs115419309(C,T); rs7719922(G,A); rs141079697(G,A); rs4434400(C,T); rs6880746(A,G); rs4637571(G,A); rs148722311(C,T); rs116357847(T,C); rs9313389(G,T); rs10440702(T,C); rs12657288(T,G); rs1364370(T,C); rs1023629(G,A); rs116819929(G,A); rs73801392(C,T); rs13358694(C,T); rs77967474(A,G); rs10042653(C,T); rs2973668(G,A); rs1364369(A,C); rs142181586(C,G); rs2336972(T,A); rs139116474(C,T); rs2973667(C,T); rs2973666(T,A); rs2973665(A,C); rs143362854(G,T); rs138311218(A,C); rs2911502(C,A); rs115020798(A,G); rs57533222(A,G); rs79032928(G,T); rs2911501(A,G); rs2973664(C,T); rs80300596(C,T); rs2911500(A,G); rs2973663(T,C); rs2973662(A,G); rs2911499(G,A); rs146277993(A,G); rs2973661(C,A); rs13361271(C,A); rs13361323(G,A); rs66851511(A,C); rs6898256(A,C); rs112744575(C,T); rs76012891(G,A); rs113604703(C,T); rs1364368(G,A); rs1424290(C,A); rs139387641(C,T); rs114634183(A,G); rs6863601(A,G); rs145754927(G,A); rs13166995(G,A); rs76764423(A,T); rs72832022(G,A); rs963184(T,A); rs150878118(A,G); rs113060475(C,T); rs10462970(C,G); rs7708656(G,A); rs111350568(C,T); rs183519039(T,C); rs10045595(T,G); rs7714651(C,A); rs78440179(G,A); rs144987073(T,A); rs111345375(G,A); rs112841190(T,C); rs116774501(T,A); rs75529495(C,T); rs68057166(G,A); rs7707689(G,A); rs11749188(T,G); rs150585861(G,C); rs11749935(T,C); rs10780110(A,C); rs79616101(G,C); rs75393760(C,A); rs4869072(G,A); rs139639760(T,C); rs10454960(A,G); rs10454966(A,C); rs10043694(G,A); rs114972252(G,T); rs77430387(A,G); rs13361383(C,T); rs76762275(G,A); rs7737681(G,A); rs188396797(G,A); rs6555770(C,G); rs151136246(G,A); rs111301367(T,G); rs13435968(C,T); rs10060371(T,C); rs148333567(C,A); rs113079519(G,C); rs141034991(A,G); rs11134472(A,C); rs10036294(G,A); rs111906962(C,T); rs115245607(C,T); rs116315310(G,C); rs11950268(C,T); rs10056158(C,T); rs7447131(G,A); rs6555771(A,G); rs73388353(G,A); rs73388354(C,G); rs7448951(C,A); rs4869074(G,A); rs4868808(A,T); rs6883993(T,C); rs1421989(C,T); rs4869075(A,G); rs4869076(T,C); rs4869077(A,G); rs10866613(G,A); rs2052466(G,A); rs2909794(T,C); rs73388370(C,T); rs2973660(G,T); rs10066325(G,A); rs35949741(C,T); rs2909802(A,G); rs140166806(C,T); rs191773673(A,G); rs6889047(G,T); rs60519985(C,T); rs11738127(G,A); rs17434346(C,A); rs11134473(G,A); rs12109973(G,T); rs13354770(T,C); rs12716236(A,G); rs74459937(A,T); rs13361359(G,A); rs114027429(T,A); rs73370917(T,G); rs10061026(A,G); rs58820246(G,A); rs12522225(C,A); rs73370922(A,C); rs73370924(G,A); rs6555772(G,A); rs1421983(A,C); rs4869078(C,A); rs4869079(A,G); rs4869080(A,G); rs7700480(C,T); rs7704178(A,G); rs17069307(G,A); rs6555773(A,G); rs55767954(C,T); rs2909797(A,G); rs10035896(G,A); rs7725644(T,G); rs7729681(T,C); rs6869111(A,G); rs2909803(C,G); rs11739852(C,T); rs2909796(G,A); rs1421978(T,C); rs73370952(G,A); rs1421979(T,C); rs76277748(C,A); rs114893842(G,C); rs4868810(C,G); rs2909795(A,C); rs62382859(G,T); rs7727245(G,A); rs2973656(G,A); rs2052467(C,T); rs2973657(A,G); rs6555774(A,G); rs13181047(T,G); rs2973658(C,T); rs2973659(A,T); rs59859592(A,T); rs13165876(A,C); rs2973670(C,A); rs10064131(T,G); rs28580528(T,C); rs76875573(A,G); rs1477284(C,T); rs116399029(G,C); rs62384363(C,T); rs1024971(A,G); rs1024970(A,G); rs139067792(G,A); rs56236411(G,A); rs1963355(G,C); rs7727154(T,A); rs17512980(C,A); rs6555775(G,C); rs75904225(T,A); rs142364418(C,T); rs17525725(A,G); rs2909799(C,G); rs72835627(G,A); rs116799233(A,G); rs7723890(G,A); rs10061595(C,T); rs143122265(A,G); rs191110355(G,A); rs2112309(A,G); rs13354056(A,G); rs66804094(A,C); rs67007847(A,C); rs7727799(C,T); rs12189098(A,T); rs183549184(T,A); rs56221163(C,A); rs183220602(A,G); rs75681774(C,T); rs142276227(T,C); rs1862198(G,A); rs2193981(C,A); rs1421988(C,A); rs1421987(C,T); rs7443761(G,A); rs36055428(A,C); rs72835637(A,G); rs80112998(C,T); rs28547994(C,A); rs74548364(G,A); rs10063203(A,G); rs11954345(A,G); rs79947379(A,G); rs1421985(T,C); rs7379592(G,C); rs11738159(T,C); rs13172139(G,T); rs7379874(A,G); rs7378687(T,C); rs112327777(T,G); rs1363205(G,A); rs11953311(A,G); rs11134476(C,T); rs11134477(G,A); rs11134478(G,T); rs11134479(C,A); rs72835641(C,T); rs7449290(G,A); rs187547103(T,A); rs11741952(T,C); rs10866614(C,T); rs192588984(T,C); rs10866615(C,T); rs7708803(A,G); rs13182072(T,C); rs1421981(C,T); rs1421982(T,C); rs7719650(G,A); rs6880465(A,G); rs1363203(A,G); rs74960537(G,C); rs78159819(T,C); rs114964983(T,C); rs144578380(G,A); rs114725471(T,C); rs149879240(G,A); rs114148586(A,G); rs145758039(G,A); rs10054737(A,T); rs11746548(C,G); rs6887945(G,A); rs7727661(A,G); rs7710122(T,C); rs73372716(G,C); rs11744503(C,T); rs73372718(C,T); rs10067507(C,T); rs9313391(A,G); rs11951480(A,G); rs11948513(T,C); rs73803272(T,C); rs10074148(G,A); rs12109229(A,G); rs17069346(G,C); rs7732654(C,G); rs7714662(A,G); rs11134480(T,C); rs7719459(C,T); rs10866616(T,C); rs150780085(C,T); rs7708105(T,C); rs58144271(A,C); rs32403(T,C); rs32402(A,C); rs32401(T,C); rs11952894(T,C); rs32400(A,G); rs139331284(C,T); rs32399(T,C); rs11958744(A,T); rs190452341(G,A); rs42412(T,C); rs39950(A,G); rs248143(A,G); rs248142(T,C); rs248141(G,A); rs248140(T,A); rs248139(G,A); rs248138(A,G); rs11740181(G,A); rs248137(G,A); rs11740138(C,T); rs248136(A,C); rs248135(T,G); rs192203(C,T); rs190327(G,A); rs60838429(T,A); rs62384402(G,A); rs823323(T,C); rs111338788(C,T); rs2194157(A,G); rs864789(C,G); rs865403(T,G); rs11959037(T,C); rs10075943(T,G); rs139600442(C,T); rs56738437(G,A); rs32422(C,T); rs190712560(A,T); rs61159476(T,C); rs32421(A,T); rs9942389(T,C); rs145099139(G,T); rs32420(C,T); rs10065576(C,T); rs32419(C,G); rs145403623(A,G); rs32418(C,T); rs17436436(A,G); rs35278978(T,G); rs112460288(A,G); rs62384407(C,T); rs40583(G,A); rs10475524(G,T); rs10475862(A,C); rs6882229(C,T); rs6886222(A,G); rs76822241(A,G); rs32417(C,T); rs6893479(G,A); rs32416(C,T); rs32415(C,T); rs74691366(T,A); rs32414(C,T); rs32413(G,A); rs7735238(T,A); rs32412(C,T); rs32411(T,C); rs17069417(A,G); rs32410(G,C); rs10038819(A,G); rs187550440(G,C); rs32409(G,A); rs7730283(G,C); rs2617978(G,A); rs60646204(T,C); rs32408(T,G); rs143196841(A,G); rs39951(G,T); rs79354762(C,T); rs32407(T,C); rs112534623(A,T); rs2545245(A,G); rs32406(T,C); rs864788(T,C); rs32405(T,C); rs140108111(G,C); rs76459383(G,A); rs9284975(C,T); rs77090653(A,G); rs111677561(A,T); rs148822801(T,G); rs3101754(G,C); rs111865608(T,C); rs111409432(C,G); rs181362181(A,G); rs149346962(C,T); rs183613504(C,T); rs187230750(T,C); rs146519210(A,G); rs184368682(T,G); rs146669971(G,A); rs139231986(A,T); rs115727007(G,A); rs116806729(A,G); rs114796281(C,T); rs147573803(T,C); rs189058300(A,T); rs2431733(G,T); rs138873097(C,T); rs115104886(A,G); rs143683688(G,A); rs142754507(A,G); rs1833763(C,T); rs112634396(C,T); rs9313392(A,T); rs75515423(C,T); rs10069922(C,A); rs2249289(A,G); rs918526(A,G); rs1862417(C,A); rs78429876(C,T); rs11954577(A,G); rs2337032(A,T); rs2337033(A,G); rs77675248(T,C); rs1123570(C,A); rs7716012(G,C); rs1422935(A,G); rs17069454(C,G); rs79847800(C,A); rs1422934(T,C); rs9313393(C,T); rs140441796(A,G); rs7709317(T,C); rs2546934(C,T); rs113700407(G,C); rs36064369(G,C); rs76584564(T,A); rs113785497(C,T); rs1345734(G,C); rs1422933(A,G); rs1422932(A,G); rs9313394(C,T); rs75920169(C,T); rs994890(C,A); rs13171977(T,C); rs1422931(C,T); rs1422930(C,T); rs78041840(T,C); rs994889(A,C); rs12521197(T,C); rs113419440(G,A); rs59637382(G,C); rs994888(C,G); rs10866618(A,G); rs80259472(T,C); rs113891890(C,G); rs2546932(A,G); rs71603845(G,A); rs62384411(G,A); rs190734526(C,T); rs114370021(G,A); rs11745279(G,C); rs17069484(T,G); rs112286096(T,C); rs116452202(C,T); rs11958655(A,C); rs2546930(A,G); rs75921427(A,G); rs11955678(T,C); rs78300591(G,A); rs11134482(A,T); rs13359764(T,A); rs79831573(T,C); rs2617984(A,G); rs2546929(C,T); rs2546960(G,A); rs2617983(G,A); rs11948431(A,T); rs2546959(T,G); rs6890434(T,A); rs12515305(A,G); rs77609307(C,T); rs150481478(G,T); rs2617981(C,A); rs889069(A,G); rs889068(A,G); rs76543967(T,G); rs751206(A,G); rs142836207(G,A); rs75903975(C,A); rs66943039(T,C); rs115801738(A,G); rs148160470(G,C); rs12523097(T,C); rs12520988(G,A); rs73801478(G,A); rs12521680(C,A); rs2546957(A,G); rs74835835(C,T); rs148826070(G,A); rs188108881(A,G); rs1345735(T,C); rs200897344(G,T); rs2617956(A,G); rs10516039(T,C); rs115498265(G,A); rs17069520(G,A); rs143289543(A,C); rs183640166(C,A); rs17069526(T,A); rs11955430(T,G); rs148436615(G,T); rs113031206(C,T); rs79684284(C,T); rs58485045(A,G); rs10475863(C,G); rs730256(A,G); rs17069538(T,C); rs7711388(A,G); rs17069541(C,T); rs1422946(A,G); rs12522181(A,G); rs116608460(A,T); rs17069547(T,A); rs11134483(C,T); rs10039736(C,G); rs150764353(G,A); rs56379512(C,T); rs200663178(C,T); rs73375658(C,T); rs2161422(C,T); rs75437447(A,G); rs67727213(A,T); rs10042104(G,T); rs2052523(T,G); rs2617958(A,G); rs3909404(G,A); rs3909403(A,G); rs3909402(C,G); rs58243181(G,A); rs2546951(A,G); rs142359469(G,C); rs189567194(C,A); rs181521232(C,T); rs754925(C,G); rs62383377(T,A); rs7733844(T,G); rs17069574(G,A); rs17069578(A,G); rs17069579(A,G); rs12153623(G,A); rs17069585(T,A); rs114337186(G,A); rs2617963(G,C); rs10064267(A,C); rs2011893(A,G); rs2019072(A,G); rs992047(A,C); rs1821254(A,G); rs11950941(A,T); rs79491112(G,A); rs144669971(G,A); rs11134485(A,G); rs985650(G,A); rs985649(A,G); rs10076491(C,T); rs61027918(A,G); rs17069614(C,G); rs17069617(A,G); rs62383379(C,T); rs17069620(A,G); rs2569047(T,C); rs10065915(A,G); rs10052830(C,T); rs73803833(G,A); rs17069629(C,T); rs62383380(A,T); rs17069633(A,G); rs6863895(T,C); rs80262838(C,T); rs76264128(A,G); rs2546945(A,G); rs11947994(G,A); rs79078287(T,C); rs1862419(A,C); rs192758680(G,A); rs76971884(A,G); rs76758788(A,T); rs75053845(A,G); rs17069646(T,C); rs143505078(C,A); rs116217804(G,A); rs9764066(T,G); rs35439597(T,C); rs2546944(T,C); rs76603748(C,T); rs2546943(A,G); rs6882264(G,C); rs10068776(T,G); rs62383381(T,C); rs889067(C,A); rs74773770(A,G); rs77771262(G,C); rs79718105(T,C); rs72824974(G,C); rs889066(G,A); rs62383382(T,C); rs62383383(A,G); rs62383384(A,G); rs13158058(G,T); rs77502237(T,C); rs150555087(G,A); rs55859018(G,C); rs17438932(T,C); rs115219124(G,A); rs190219543(G,A); rs201133879(C,T); rs79177976(C,T); rs77735252(G,T); rs6896795(A,G); rs73803849(T,C); rs6897051(C,T); rs6897683(G,C); rs77602169(T,A); rs247990(T,G); rs247992(A,G); rs247993(A,G); rs247994(A,G); rs67926229(T,C); rs73803854(T,C); rs57705150(C,T); rs7714553(C,T); rs1368360(T,C); rs143952469(G,C); rs11952245(A,G); rs115861046(C,T); rs1862418(A,T); rs1432820(G,C); rs17069703(G,C); rs112490474(G,A); rs17069705(T,G); rs60572841(A,G); rs10516041(G,A); rs10516042(A,G); rs10052693(T,G); rs114898031(A,G); rs142403993(G,C); rs247995(G,A); rs918527(C,T); rs73803862(C,T); rs17069720(T,C); rs116249627(C,T); rs11741090(G,A); rs116548948(A,G); rs17069724(T,A); rs11750851(C,T); rs79822290(T,C); rs750732(A,G); rs3860782(A,C); rs3860783(A,G); rs12657034(A,G); rs146651093(T,C); rs4588609(T,C); rs148385141(A,T); rs116217896(A,G); rs10866620(G,A); rs10866621(A,T); rs11134486(T,C); rs2337118(T,C); rs55755459(T,G); rs1347135(A,G); rs1347136(T,C); rs11747996(A,G); rs247996(G,A); rs67610852(G,A); rs247997(G,A); rs247998(G,A); rs247999(G,A); rs73803864(A,G); rs10516043(C,T); rs248000(T,A); rs35613923(A,G); rs72824985(G,A); rs7732210(G,A); rs11749990(A,G); rs248001(C,G); rs6555782(G,A); rs73803868(A,G); rs72824988(A,T); rs17069767(A,G); rs17051818(C,G); rs73803871(C,G); rs34118922(G,A); rs17440127(A,C); rs2033464(C,T); rs248003(A,G); rs12055092(T,C); rs56911760(G,A); rs1422942(A,T); rs248004(T,C); rs6897880(G,A); rs35102735(A,G); rs12188085(C,T); rs12188092(C,T); rs9313395(G,A); rs10053703(A,G); rs9313396(G,T); rs13358864(T,A); rs17069798(G,A); rs17051821(G,T); rs247988(T,C); rs191949434(C,T); rs78956363(A,G); rs56114918(A,G); rs114937562(C,A); rs247987(A,G); rs56133446(C,T); rs247986(A,G); rs247985(T,A); rs56780921(A,T); rs57002229(T,C); rs3101762(C,A); rs3097826(T,G); rs3097825(G,T); rs3097824(C,A); rs10076072(T,A); rs57617749(T,G); rs7380815(T,A); rs6859094(T,C); rs4976568(G,C); rs114987391(G,A); rs142270456(A,T); rs2617989(C,T); rs2617988(C,A); rs2617987(A,G); rs17069810(G,A); rs62383401(C,T); rs115855008(A,C); rs80018365(C,T); rs66885574(C,T); rs17069814(G,A); rs6859101(G,A); rs2053048(G,C); rs2878892(C,T); rs2053049(C,G); rs58279035(C,T); rs17531616(A,C); rs58209338(G,A); rs75530783(G,A); rs17069822(T,C); rs79794097(A,G); rs182055053(A,G); rs11738706(C,T); rs2116763(G,A); rs4976569(G,C); rs2617968(C,T); rs59563471(A,G); rs115381341(C,T); rs2569036(T,A); rs189704432(C,T); rs1964376(C,T); rs7708643(C,T); rs11955988(G,A); rs36001918(G,A); rs34000130(C,T); rs2617969(G,A); rs2617970(G,A); rs78559078(G,A); rs112281938(A,G); rs13155210(C,T); rs10067987(C,T); rs35832334(A,G); rs6866450(A,G); rs6867056(G,T); rs7712718(C,T); rs72824998(C,G); rs72824999(G,A); rs62383404(A,T); rs3101758(G,A); rs62383405(G,A); rs2337119(G,C); rs10043193(G,A); rs116742800(G,A); rs10043220(G,C); rs891931(T,C); rs750851(T,C); rs750850(A,G); rs750849(T,C); rs750848(A,G); rs147981815(A,G); rs68186230(C,T); rs187282861(T,G); rs2569040(C,T); rs7706234(T,C); rs2337120(C,T); rs10036661(T,C); rs147826039(G,C); rs2244626(G,T); rs1036192(C,A); rs10079060(G,A); rs7730804(T,C); rs2163764(T,C); rs12153437(G,A); rs2617971(G,A); rs6876251(G,A); rs6555783(A,G); rs150862240(G,A); rs180887100(G,A); rs11741507(A,G); rs10073793(G,A); rs11134488(A,G); rs11741618(A,G); rs11748226(C,T); rs111598609(T,C); rs7722031(A,G); rs114201378(C,T); rs12188893(G,A); rs12186523(T,G); rs12187313(A,C); rs968547(G,A); rs12186726(T,C); rs12186727(T,C); rs12187477(A,G); rs34454819(G,A); rs2617972(A,C); rs77806782(A,G); rs2569049(C,T); rs1077046(G,A); rs1077047(A,G); rs984228(G,C); rs76358692(A,G); rs2617974(G,A); rs2569052(A,G); rs148472412(G,A); rs919737(G,T); rs11747227(A,G); rs2569053(T,C); rs11747283(A,G); rs57005148(C,T); rs73387348(C,G); rs149871307(C,A); rs68176346(A,G); rs111637334(A,G); rs4976571(G,A); rs3101759(C,T); rs4976572(G,A); rs72833198(A,G); rs150391891(A,G); rs114752953(T,G); rs919738(A,G); rs77719428(A,G); rs139165158(G,C); rs6863691(A,G); rs1897558(A,C); rs80205076(C,A); rs74855881(C,T); rs4404700(C,T); rs1529681(G,A); rs1529682(G,C); rs1529683(G,A); rs1529684(A,G); rs10055910(C,T); rs1560650(G,A); rs10040185(T,C); rs116533120(C,T); rs11951377(G,C); rs6885364(C,T); rs1469678(G,T); rs3748(C,A); rs4976573(A,C); rs4976574(T,C); rs4246812(G,C); rs17631810(G,A); rs138005929(C,T); rs6555784(T,A); rs6862251(C,T); rs4976575(C,T); rs919739(C,T); rs74556701(G,A); rs62383426(C,T); rs1432821(C,T); rs116153756(C,T); rs111269520(A,C); rs1006807(G,C); rs41386247(A,G); rs1432822(T,A); rs4976536(C,T); rs4976537(C,T); rs7723815(A,G); rs73387374(G,A); rs4368756(G,C); rs17069944(T,C); rs141887298(G,A); rs10077866(G,C); rs77293598(G,A); rs2337129(G,A); rs2337130(A,G); rs4507512(T,C); rs7719852(T,A); rs10040521(A,T); rs10040595(A,T); rs149621930(T,G); rs143353540(A,C); rs76367642(C,T); rs1347134(A,C); rs1816402(A,G); rs1862350(C,A); rs141109388(C,A); rs188954462(A,C); rs112170411(C,T); rs7709145(G,A); rs4580796(A,G); rs62383436(G,A); rs1835941(A,G); rs73389248(G,T); rs113106770(G,A); rs4976576(G,A); rs7736194(C,T); rs12521672(T,C); rs12519010(C,G); rs66830482(G,A); rs74381891(G,A); rs76764770(G,A); rs9637846(G,A); rs1560649(G,C); rs4976538(C,T); rs891933(C,T); rs891932(C,T); rs4311439(C,T); rs61686441(G,A); rs9632432(A,T); rs11745853(A,C); rs7712496(C,T); rs11134489(A,G); rs1036193(A,G); rs1013017(C,T); rs1560654(G,A); rs7718516(C,G); rs10072561(A,C); rs7724079(C,A); rs13176788(C,T); rs7724483(A,T); rs7728598(C,T); rs918495(C,T); rs7711412(T,G); rs9313397(T,C); rs140084479(C,T); rs7733899(C,A); rs1560653(C,T); rs113959591(T,G); rs7716939(T,C); rs75194345(T,C); rs1560651(G,A); rs12518736(C,A); rs7707033(C,T); rs7707882(C,A); rs6555785(C,T); rs6555786(G,A); rs78889305(C,T); rs10045434(A,G); rs9313398(G,A); rs76367430(T,C); rs72835020(C,T); rs79385125(G,A); rs4976577(T,C); rs13153393(A,G); rs10516044(G,C); rs147826611(G,A); rs4373298(C,A); rs4976578(T,C); rs114834615(C,T); rs34962507(A,G); rs4246813(T,C); rs35982759(T,C); rs35359043(G,A); rs66482664(G,A); rs10214212(C,T); rs10213694(T,G); rs4976579(G,T); rs11134490(C,A); rs4976581(T,C); rs10063149(A,G); rs10078128(G,A); rs12522921(C,A); rs78727388(G,A); rs7709334(C,T); rs10447202(A,C); rs115920573(A,T); rs151141678(G,A); rs9313399(A,T); rs10069488(C,T); rs2132545(T,C); rs4976582(G,A); rs11742154(A,G); rs79043881(A,G); rs11134491(T,C); rs2173019(T,A); rs1472357(C,T); rs116196834(C,T); rs74709618(A,G); rs11134492(G,A); rs11134493(G,A); rs13161927(A,G); rs57355184(G,T); rs903851(G,A); rs78632218(C,G); rs10072804(A,T); rs903850(G,A); rs7702720(T,G); rs12658120(A,G); rs4976583(G,A); rs12659719(C,T); rs1874462(G,C); rs1874461(A,G); rs12659776(G,T); rs1472356(A,G); rs77120541(C,T); rs1472355(G,T); rs10516045(T,C); rs60353035(C,A); rs17731087(C,T); rs139944473(T,A); rs144964995(T,A); rs34608084(G,A); rs17069979(A,G); rs2173018(A,G); rs58151545(A,G); rs57141803(G,A); rs61098277(A,G); rs111293251(C,G); rs34571245(C,A); rs34187866(G,C); rs1874460(G,C); rs147544549(C,T); rs2291784(G,A); rs3797719(A,G); rs72835050(A,G); rs10041718(G,C); rs6887745(A,G); rs1496398(A,G); rs77723635(A,G); rs6898935(A,C); rs7700672(A,C); rs6892072(T,A); rs6897788(T,C); rs6876382(C,G); rs4976539(A,G); rs77415347(A,C); rs9918152(A,G); rs17731147(T,C); rs57386019(T,A); rs11740385(T,G); rs6875022(T,G); rs7709161(C,G); rs75158439(C,A); rs17070005(A,G); rs111461041(G,T); rs9986122(T,G); rs6879767(A,T); rs6880386(G,C); rs6885116(A,G); rs6885774(G,A); rs370482080(C,T); rs7708354(T,G); rs3756603(T,C); rs73385778(C,T); rs1363560(T,C); rs10069012(A,C); rs112636179(A,G); rs7714057(C,T); rs61392317(G,A); rs7735069(T,A); rs4976584(A,C); rs4976585(C,T); rs115045421(A,G); rs116745085(A,G); rs13356441(T,A); rs73385790(G,C); rs3733985(T,C); rs3733986(A,G); rs74454753(T,C); rs28584680(A,G); rs2161301(T,C); rs2161300(G,T); rs138767919(C,T); rs4976586(C,T); rs77537094(G,A); rs150021651(G,A); rs12514168(A,G); rs12519946(C,G); rs55972503(C,G); rs10079495(T,A); rs74387103(C,T); rs11959012(C,T); rs11959062(G,A); rs73391714(G,A); rs6887837(C,T); rs6888483(G,A); rs60646276(T,A); rs60118636(T,C); rs62385562(T,C); rs12514624(A,T); rs1960425(T,C); rs111795565(T,G); rs3733988(C,T); rs12189266(C,T); rs2112554(A,G); rs2112553(T,C); rs11134497(T,C); rs17070027(C,T); rs17070030(G,T); rs139635233(A,C); rs2337158(T,C); rs6868169(G,A); rs6889555(T,C); rs6868534(G,A); rs10447194(C,T); rs10447203(A,G); rs73801862(T,A); rs11747056(A,G); rs62385563(T,C); rs112465595(G,A); rs35960642(A,G); rs6876197(T,C); rs11743769(A,G); rs11743857(A,G); rs11743859(A,G); rs112897621(A,G); rs62385591(A,G); rs6882883(T,C); rs35888677(A,G); rs13164502(C,T); rs11740056(G,A); rs35639841(A,G); rs4292464(T,C); rs6888941(C,G); rs6889331(A,G); rs1862299(T,C); rs142399665(C,T); rs2173017(C,T); rs11747472(T,G); rs17632540(C,T); rs3733989(A,G) |
| cytoBand name | 5q34 |
| EntrezGene GeneID | 57451 |
| snpEff Gene Name | ODZ2 |
| EntrezGene Description | teneurin transmembrane protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TENM2:NM_001122679:exon22:c.C4105T:p.R1369W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8855 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 8e-05 |
| ESP Eur/Amr MAF | 0.000119 |
| ExAC AF | 8.162e-06 |
FBLL1
| dbSNP name | rs3733977(G,A) |
| cytoBand name | 5q34 |
| EntrezGene GeneID | 345630 |
| EntrezGene Description | fibrillarin-like 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2456 |
| ESP Afr MAF | 0.193143 |
| ESP All MAF | 0.171678 |
| ESP Eur/Amr MAF | 0.162217 |
| ExAC AF | 0.192 |
MIR4634
| dbSNP name | rs7709117(G,A) |
| cytoBand name | 5q35.2 |
| EntrezGene GeneID | 100616202 |
| snpEff Gene Name | CTD-2532K18.1 |
| EntrezGene Description | microRNA 4634 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4844 |
| ExAC AF | 0.221 |
DRD1
| dbSNP name | rs4867798(T,C); rs686(G,A); rs182759154(G,A); rs155417(T,C); rs74414188(G,T); rs4532(C,T); rs5326(C,T); rs265981(A,G) |
| cytoBand name | 5q35.2 |
| EntrezGene GeneID | 1812 |
| EntrezGene Description | dopamine receptor D1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3421 |
OMIM Clinical Significance
Hair:
Double rows of eyelashes
Cardiac:
Congenital heart defect;
Ventricular septal defect;
Patent ductus arteriosus;
Sinus bradycardia;
Stress-induced asystole;
Wandering atrial pacemaker
Limbs:
Leg edema;
Varicose veins;
Arterial disease of legs
Inheritance:
Autosomal dominant
OMIM Title
*126449 DOPAMINE RECEPTOR D1; DRD1
;;DOPAMINE RECEPTOR D1A; DRD1A
OMIM Description
DESCRIPTION
The diverse physiologic actions of dopamine are mediated by its
interaction with 2 types of G protein-coupled receptor, D1 and D2
(126450), which stimulate and inhibit, respectively, the enzyme adenylyl
cyclase.
CLONING
Three groups reported the cloning of the D1 dopamine receptor gene
(Dearry et al., 1990; Zhou et al., 1990; Sunahara et al., 1990). The
gene encodes a protein of 446 amino acids having a predicted relative
molecular mass of 49,300 and a transmembrane topology similar to that of
other G protein-coupled receptors. Northern blot analysis and in situ
hybridization showed that the mRNA for this receptor is most abundant in
caudate, nucleus accumbens, and olfactory tubercle, with little or no
mRNA detectable in substantia nigra, liver, kidney, or heart (Dearry et
al., 1990).
GENE FUNCTION
The activator region-1 (AR1) in the upstream promoter of the D1A gene
contains partially overlapping binding sites for SP1 (189906) and AP2
(see TFAP2A; 107580) on opposite strands. Using gel mobility shift and
reporter gene assays, Yang et al. (2000) found that human ZIC2 (603073)
bound the AR1 sequence and repressed its expression. ZIC2 also
significantly decreased expression of endogenous D1a in a mouse
neuroblastoma cell line. ZIC2 efficiently blocked SP1 and SP3 (601804)
binding to an AR1 probe and inhibited SP1- and SP3-mediated AR1 promoter
activity. ZIC2 also displaced SP1 and SP2 binding to AR1 over time,
leading to complete suppression of D1A promoter activity.
A critical step in transport of membrane proteins from the endoplasmic
reticulum (ER) to the cell surface involves bulk flow mechanisms or the
presence of specific ER-export sequences. Bermak et al. (2001) noted the
presence of a conserved 4-amino acid spacing of hydrophobic residues,
FxxxFxxxF, within the proximal C terminus of GPCRs, including DRD1.
Fluorescence microscopy analysis of rat Drd1 with its C-terminal phe
residues mutated to ala demonstrated that the phe residues are critical
to cell surface localization. Functional analysis showed reduced ligand
binding and ablated cAMP production in response to dopamine in cells
expressing the mutant Drd1 protein. Expression of a wildtype C-terminal
Drd1/N-terminal CD8 (186910) chimeric protein, but not of a phe-mutant
Drd1 protein, conferred cell surface expression. Bermak et al. (2001)
concluded that the FxxxFxxxF motif and all of its phe residues are
essential for normal receptor transport.
Using a yeast 2-hybrid screen, Bermak et al. (2001) identified DRIP78
(606092) as a protein that interacts with DRD1. Binding analysis showed
that the hydrophobic sequence of rat Drd1 is critical for its
interaction with Drip78, and that residues 488 to 673 of rat Drip78
contain 2 potential zinc-finger domains that are crucial for its
association with Drd1. Coexpression of Drd1 and Drip78 resulted in
inhibition of Drd1 surface expression and intracellular trapping. Bermak
et al. (2001) concluded that DRIP78, like calnexin (CANX; 114217) and
GRP78 (HSPA5; 138120), is an ER-resident protein that prevents premature
transport of protein cargo to the Golgi by masking the FxxxFxxxF motif
of DRD1.
By immunohistochemical analysis, Mayerhofer et al. (1999) showed that
DRD1 is expressed in human ovarian tissue within granulosa cells of
large follicles and in luteal cells of the corpus luteum. In granulosa
luteal cells, DRD1 immunoreactivity was associated with the cell
membrane and/or with the cytoplasm of most cells. DRD1 in granulosa cell
(GC) cultures was biologically active. Treatment of human luteinized GC
cultures with SKF38393, a selective dopamine receptor agonist, increased
cAMP levels 2- to 3-fold within 3 to 6 hours. SKF38393 treatment also
significantly increased the threonine phosphorylation of DARPP32
(604399).
Lee et al. (2002) reported that dopamine D1 receptors modulate NMDA
glutamate receptor-mediated functions through direct protein-protein
interactions. Two regions in the D1 receptor carboxyl tail could
directly and selectively couple to NMDA glutamate receptor subunits
NR1-1A (138249) and NR2A (138253). While one interaction was involved in
the inhibition of NMDA receptor-gated currents, the other was implicated
in the attenuation of NMDA receptor-mediated excitotoxicity through a
phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Stipanovich et al. (2008) demonstrated that drugs of abuse, as well as
food reinforcement learning, promote the nuclear accumulation of 32-kD
dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399). This
accumulation is mediated through a signaling cascade involving dopamine
D1 receptors, cAMP-dependent activation of protein phosphatase-2A (see
176915), and dephosphorylation of DARPP32 at ser97 and inhibition of its
nuclear export. The nuclear accumulation of DARPP32, a potent inhibitor
of protein phosphatase-1 (see 176875), increased the phosphorylation of
histone H3 (see 602810), an important component of nucleosomal response.
Mutation of ser97 profoundly altered behavioral effects of drugs of
abuse and decreased motivation for food, underlining the functional
importance of this signaling cascade.
Working memory is a key function for human cognition, dependent on
adequate dopamine neurotransmission. McNab et al. (2009) showed that the
training of working memory, which improves working memory capacity, is
associated with changes in the density of cortical dopamine D1
receptors. Fourteen hours of training over 5 weeks in 13 volunteers,
healthy males aged 20 to 28 years, was associated with changes in both
prefrontal and parietal D1 binding potential, as determined by positron
emission tomography while the participants were resting before and after
training. McNab et al. (2009) concluded that this plasticity of the
dopamine D1 receptor system demonstrates a reciprocal interplay between
mental activity and brain biochemistry in vivo.
Lim et al. (2012) showed that chronic stress in mice decreases the
strength of excitatory synapses on D1 dopamine receptor-expressing
nucleus accumbens medium spiny neurons owing to activation of the
melanocortin-4 receptor (MC4R; 155541). Stress-elicited increases in
behavioral measurements of anhedonia, but not increases in measurements
of behavioral despair, are prevented by blocking these melanocortin-4
receptor-mediated synaptic changes in vivo. Lim et al. (2012) concluded
that stress-elicited anhedonia requires a neuropeptide-triggered, cell
type-specific synaptic adaptation in the nucleus accumbens and that
distinct circuit adaptations mediate other major symptoms of
stress-elicited depression.
GENE STRUCTURE
Sunahara et al. (1990) reported that the DRD1 gene is intronless.
MAPPING
By Southern blot hybridization to DNAs from a hybrid cell panel,
Sunahara et al. (1990) mapped the DRD1 gene to chromosome 5. Family
linkage studies confirmed this assignment and suggested that it is in
the same general region as the gene for glucocorticoid receptor (138040)
and D5S22, a marker about 12 cM from GRL. This places it in the 5q31-q34
region near the structurally homologous genes for beta-2-adrenergic
receptor (109690) and alpha-1-adrenergic receptor (104220). Using pulsed
field gel electrophoresis and a range of different restriction enzyme
digests, Boultwood et al. (1991) established that GRL and DRD1 are on
the same 300-kb genomic DNA fragment. Grandy et al. (1990) used the
recently cloned DRD1 gene to map the locus to chromosome 5 in
rodent-human somatic cell hybrids. Fluorescence in situ hybridization
refined the localization to 5q35.1. A 2-allele EcoRI RFLP associated
with DRD1 allowed confirmation of the localization by linkage analysis
in CEPH families. The homologous gene in the mouse is located on
chromosome 13 (Wilkie et al., 1993).
MOLECULAR GENETICS
- Association with Systolic Blood Pressure Levels
The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic
receptors, ADRB2 (109690) and ADRA1B (104220), and the dopamine receptor
type 1A gene. Krushkal et al. (1998) used an efficient discordant
sib-pair ascertainment scheme to investigate the impact of this region
of the genome on variation in systolic blood pressure in young
Caucasians. They measured 8 highly polymorphic markers spanning this
positional candidate gene-rich region in 427 individuals from 55
3-generation pedigrees containing 69 discordant sib pairs, and
calculated multipoint identity by descent probabilities. The results of
genetic linkage and association tests indicated that the region between
markers D5S2093 and D5S462 was significantly linked to one or more
polymorphic genes influencing interindividual variation in systolic
blood pressure levels. Since the ADRA1B and DRD1A genes are located
close to these markers, the data suggested that genetic variation in one
or both of these G protein-coupled receptors, which participate in the
control of vascular tone, plays an important role in influencing
interindividual variation in systolic blood pressure levels.
- Association with Nicotine Dependence
Huang et al. (2008) found a significant association between nicotine
dependence (188890) and a SNP (dbSNP rs686) in the DRD1 gene among 1,366
African Americans. In a pooled sample of 1,366 African Americans and 671
European Americans, dbSNP rs686 and dbSNP rs4532 were both significantly
associated with nicotine dependence. Several haplotypes related to these
SNPs also suggested an association. In vitro functional expression
studies indicated that dbSNP rs686, which is located in the 3-prime
untranslated region, is functionally involved in the regulation of DRD1
expression.
- Association with Schizophrenia
Allen et al. (2008) performed a metaanalysis comparing 725 patients with
schizophrenia (see 181500) with 1,075 controls and found that the DRD1
-48A-G allele (dbSNP rs4532) was associated with susceptibility to
schizophrenia (odds ratio, 1.18; 95% CI, 1.01-1.38; p = 0.037).
According to the Venice guidelines for the assessment of cumulative
evidence in genetic association studies (Ioannidis et al., 2008), the
DRD1 association showed a 'strong' degree of epidemiologic credibility.
ANIMAL MODEL
The brain dopaminergic system is a critical modulator of basal ganglion
function and plasticity. To investigate the contribution of the dopamine
D1 receptor to this modulation, Xu et al. (1994) used gene targeting
technology to generate D1 receptor mutant mice. Although histologic
analyses suggested no major changes in the anatomy of mutant mouse
brains, the expression of dynorphin (131340) was greatly reduced in the
striatum and related regions of the basal ganglia. The mutant mice did
not respond to the stimulant and suppressive effects of D1 receptor
agonists and antagonists, respectively, and they exhibited locomotor
hyperactivity.
Since dopamine produced by the kidney is an intrarenal regulator of
sodium transport, Albrecht et al. (1996) investigated the possibility
that an abnormality of the dopaminergic system may be important in the
pathogenesis of hypertension. In the spontaneously hypertensive rat
(SHR), in spite of normal renal production of dopamine and normal
receptor density, there is defective transduction of the D1 receptor
signal in renal proximal tubules, resulting in decreased inhibition of
sodium transport by dopamine. Two D1-like receptor genes have been
cloned in mammals, DRD1A and DRD1B (126453). Although both receptor
genes are expressed in the kidney, DRD1A is more abundant than DRD1B in
renal proximal tubules. Therefore, Albrecht et al. (1996) studied the
effect of deletion of D1A receptors in mice generated by homologous
recombination. They found that systolic blood pressure was greater in
homozygous and heterozygous mice than in normal sex-matched litter mate
controls; moreover, mice lacking 1 or both Drd1a alleles developed
diastolic hypertension.
Chronic blockade of dopamine D2 receptors, a common mechanism of action
for antipsychotic drugs, downregulates D1 receptors in the prefrontal
cortex and, as shown by Castner et al. (2000), produces severe
impairments in working memory. These deficits were reversed in monkeys
by short-term coadministration of a D1 agonist, ABT431, and this
improvement was sustained for more than a year after cessation of D1
treatment. Castner et al. (2000) concluded that pharmacologic modulation
of the D1 signaling pathway can produce long-lasting changes in
functional circuits underlying working memory. Resetting this pathway by
brief exposure to the agonist may provide a valuable strategy for
therapeutic intervention in schizophrenia and other
dopamine-dysfunctional states.
GMCL1P1
| dbSNP name | rs9329136(G,A); rs9647596(A,G); rs4976745(T,A); rs7379857(T,A); rs9286053(A,G); rs78956869(G,A); rs7380658(G,T); rs7719717(T,G); rs12657143(G,A); rs7715462(A,G); rs7715618(A,C); rs138663781(C,A); rs13169133(G,A); rs10479619(T,C); rs13184406(C,T); rs13184677(C,T); rs2961663(C,T); rs2961664(C,T); rs3812083(T,C); rs11960863(C,G) |
| cytoBand name | 5q35.3 |
| EntrezGene GeneID | 64396 |
| snpEff Gene Name | AC136940.3 |
| EntrezGene Description | germ cell-less, spermatogenesis associated 1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1804 |
OR2Y1
| dbSNP name | rs9329115(C,T); rs10464105(C,G); rs11954074(C,T); rs11960429(G,A) |
| ccdsGene name | CCDS34323.1 |
| CosmicCodingMuts gene | OR2Y1 |
| cytoBand name | 5q35.3 |
| EntrezGene GeneID | 134083 |
| EntrezGene Description | olfactory receptor, family 2, subfamily Y, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2Y1:NM_001001657:exon1:c.G918A:p.R306R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.08586 |
| ESP Afr MAF | 0.234453 |
| ESP All MAF | 0.090958 |
| ESP Eur/Amr MAF | 0.017442 |
| ExAC AF | 0.045 |
HEIH
| dbSNP name | rs78251062(A,G); rs61686884(G,A); rs61321448(T,C) |
| cytoBand name | 5q35.3 |
| EntrezGene GeneID | 100859930 |
| snpEff Gene Name | AC022413.1 |
| EntrezGene Description | hepatocellular carcinoma up-regulated EZH2-associated long non-coding RNA |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05693 |
OR2V1
| dbSNP name | rs10073017(C,T) |
| ccdsGene name | CCDS58992.1 |
| cytoBand name | 5q35.3 |
| EntrezGene GeneID | 26693 |
| EntrezGene Description | olfactory receptor, family 2, subfamily V, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2V1:NM_001258283:exon1:c.G368A:p.R123H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.112179487179 |
| dbNSFP KGp1 Afr AF | 0.341463414634 |
| dbNSFP KGp1 Amr AF | 0.0801104972376 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0633245382586 |
| dbSNP GMAF | 0.112 |
| ExAC AF | 0.071 |
OR2V2
| dbSNP name | rs2546423(A,G) |
| ccdsGene name | CCDS4461.1 |
| cytoBand name | 5q35.3 |
| EntrezGene GeneID | 285659 |
| EntrezGene Description | olfactory receptor, family 2, subfamily V, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2V2:NM_206880:exon1:c.A662G:p.H221R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96R30 |
| dbNSFP Uniprot ID | OR2V2_HUMAN |
| dbNSFP KGp1 AF | 0.637820512821 |
| dbNSFP KGp1 Afr AF | 0.802845528455 |
| dbNSFP KGp1 Amr AF | 0.698895027624 |
| dbNSFP KGp1 Asn AF | 0.597902097902 |
| dbNSFP KGp1 Eur AF | 0.531662269129 |
| dbSNP GMAF | 0.3627 |
| ESP Afr MAF | 0.221289 |
| ESP All MAF | 0.383438 |
| ESP Eur/Amr MAF | 0.466512 |
| ExAC AF | 0.592 |
LOC102577426
| dbSNP name | rs192351763(T,C); rs1149251(C,G); rs77721124(C,A); rs1149252(C,T) |
| cytoBand name | 5q35.3 |
| snpEff Gene Name | TRIM7 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
HUS1B
| dbSNP name | rs1211554(C,A); rs1766848(G,T) |
| ccdsGene name | CCDS4470.1 |
| cytoBand name | 6p25.3 |
| EntrezGene GeneID | 135458 |
| EntrezGene Description | HUS1 checkpoint homolog b (S. pombe) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HUS1B:NM_148959:exon1:c.G802T:p.D268Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0122 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHY5 |
| dbNSFP Uniprot ID | HUS1B_HUMAN |
| dbNSFP KGp1 AF | 0.777014652015 |
| dbNSFP KGp1 Afr AF | 0.428861788618 |
| dbNSFP KGp1 Amr AF | 0.867403314917 |
| dbNSFP KGp1 Asn AF | 0.842657342657 |
| dbNSFP KGp1 Eur AF | 0.910290237467 |
| dbSNP GMAF | 0.2227 |
| ESP Afr MAF | 0.486155 |
| ESP All MAF | 0.238659 |
| ESP Eur/Amr MAF | 0.097674 |
| ExAC AF | 0.849 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Normal kidneys
SKELETAL:
[Limbs];
Osteolysis of patellae (bone loss of posterior patella);
[Hands];
Osteolysis of scaphoids (bone loss and fragmentation of scaphoid);
Short fourth metacarpals;
[Feet];
Osteolysis of tali (bone loss and fragmentation of posterior talus)
MISCELLANEOUS:
Onset 13-15 years
OMIM Title
*609713 HYDROXYUREA-SENSITIVE 1, S. POMBE, HOMOLOG OF, B; HUS1B
OMIM Description
CLONING
By database searching, Hang et al. (2002) identified HUS1B, a novel
paralog of the human cell cycle checkpoint gene HUS1 (603760). HUS1B
encodes a 278-amino acid protein that is 48% identical to the HUS1
protein. Hang et al. (2002) also identified mouse and rat orthologs of
HUS1B. Northern blot analysis showed that expression of HUS1B in human
tissues parallels that of HUS1. A 1.4-kb HUS1B transcript was observed
in all tissues tested and an additional 1-kb band was observed in testis
and prostate. Total HUS1B expression was highest in testis.
GENE FUNCTION
A HUS1-RAD1 (603153)-RAD9 (603761) protein complex is thought to form a
proliferating cell nuclear antigen (PCNA; 176740)-like structure that is
important for cell cycle checkpoint function. Using a yeast 2-hybrid
analysis, Hang et al. (2002) showed that whereas HUS1 can bind RAD1,
RAD9, and another molecule of HUS1, HUS1B directly interacts with RAD1
but not with RAD9 or HUS1, suggesting that HUS1B cannot simply
substitute for HUS1 in the protein complex. Overexpression of HUS1B but
not HUS1 in human 293T cells led to clonogenic cell death. Hang et al.
(2002) suggested that HUS1B and HUS1 have distinct but related roles in
regulating cell cycle checkpoints and genomic integrity.
GENE STRUCTURE
Hang et al. (2002) determined that the HUS1B gene is intronless.
MAPPING
By sequence analysis, Hang et al. (2002) mapped the HUS1B gene to
chromosome 6p25.3-p25.1.
FOXC1
| dbSNP name | rs984253(A,T); rs2745599(A,G) |
| cytoBand name | 6p25.3 |
| EntrezGene GeneID | 2296 |
| EntrezGene Description | forkhead box C1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2548 |
OMIM Clinical Significance
Eyes:
Congenital cataracts
Ears:
Sensorineural deafness
Facies:
Appearance suggestive of Down syndrome;
Long, broad, and smooth philtrum;
Flat face
Neuro:
Mental retardation
Skel:
Radioulnar synostosis
Joints:
Idiopathic chondrolysis
Growth:
Pstnatal short stature
Lab:
Normal high-resolution karyotype
Inheritance:
Unknown
OMIM Title
*601090 FORKHEAD BOX C1; FOXC1
;;FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 7; FKHL7;;
FORKHEAD-RELATED ACTIVATOR 3; FREAC3
OMIM Description
CLONING
Forkhead transcription factors are distinguished by a characteristic
100-amino acid DNA-binding motif originally identified as a region of
homology between Drosophila forkhead and rat Hnf3 (see 602294). Pierrou
et al. (1994) identified 7 human genes containing forkhead domains,
including FOXC1, which they called FREAC3. Northern blot analysis
revealed that FOXC1 was expressed nearly ubiquitously as a 3.9-kb mRNA.
Smaller mRNAs were detected in fetal colon and kidney and in leukocytes.
GENE FUNCTION
Pierrou et al. (1994) determined the DNA binding specificity of FOXC1
through selection of high-affinity binding sites from random sequence
oligonucleotides.
Using an inducible FOXC1 construct, Berry et al. (2008) found that
expression of several hundred genes was altered by FOXC1 in human
nonpigmented ciliary epithelial cells. Northern blot analysis estimated
that FOXC1 induced the expression of the stress response gene HSPA6
(140555) about 37-fold and the apoptosis regulator FOXO1A (136533) about
13-fold. The promoter regions of zebrafish and human FOXO1A contain
consensus FOXC1 binding sites; chromatin immunoprecipitation and
reporter gene assays confirmed that FOXC1 bound these sites and
activated the FOXO1A promoter. Knockdown of FOXC1 in human trabecular
meshwork cells reduced FOXO1A expression and increased cell death in
response to oxidative stress. Morpholino-mediated knockdown of Foxo1a in
zebrafish embryos resulted in increased cell death in the developing
eye.
Omatsu et al. (2014) found that the transcription factor Foxc1 is
preferentially expressed in the adipo-osteogenic progenitor Cxcl12
(600835)-abundant reticular (CAR) cells essential for hematopoietic stem
and progenitor cell maintenance in vivo in the developing and adult bone
marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR
cells, from embryogenesis onward, osteoblasts appeared normal, but
hematopoietic stem and progenitor cells were markedly reduced and marrow
cavities were occupied by adipocytes (yellow adipose marrow) with
reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted
hematopoietic stem and progenitor cells and reduced Cxcl12 and stem cell
factor (SCF; 184745) expression in CAR cells, but did not induce a
change in yellow marrow. Omatsu et al. (2014) concluded that their data
suggested a role for FOXC1 in inhibiting adipogenic processes in CAR
progenitors. FOXC1 might also promote CAR cell development, upregulating
CXCL12 and stem cell factor expression.
Using bioinformatic analysis, Pan et al. (2014) identified a long
noncoding RNA (lncRNA) gene, FOXCUT (615976), upstream of the FOXC1 gene
promoter region. By real-time quantitative PCR analysis of 82 esophageal
squamous cell carcinomas (ESCCs; see 133239), they found that expression
of FOXCUT and FOXC1 were significantly upregulated in ESCCs compared
with adjacent noncancerous tissues. Upregulation of FOXCUT and FOXC1
correlated with poor differentiation, advanced lymph node
classification, metastasis, and poor prognosis. Knockdown of FOXCUT via
small interfering RNA reduced expression of both FOXCUT and FOXC1,
whereas knockdown of FOXC1 had no effect on FOXCUT expression. Knockdown
of either FOXC1 or FOXCUT inhibited ESCC cell proliferation, colony
formation, migration, and invasive potential. Pan et al. (2014)
concluded that FOXCUT and FOXC1 may constitute a functional lncRNA-mRNA
gene pair.
MAPPING
Larsson et al. (1995) mapped the FOXC1 gene to chromosome 6p25 by
fluorescence in situ hybridization and somatic cell hybrid analysis.
MOLECULAR GENETICS
In a patient with primary congenital glaucoma (see 601631) who had a
balanced translocation between 6p25 and 13q22, Nishimura et al. (1998)
cloned the chromosomal breakpoints and identified 2 candidate genes, 1
of which was the FKHL7 (FOXC1) gene. In a second primary congenital
glaucoma patient with partial 6p monosomy, the FOXC1 gene was found to
be deleted. A group of dominant disorders involving changes in the
anterior segment of the eye had previously been mapped to 6p25; see
Axenfeld-Rieger syndrome type 3 (RIEG3; 602482) and iridogoniodysgenesis
type 1 (IRID1; 601631). Nishimura et al. (1998) demonstrated that
patients with Rieger and/or Axenfeld anomalies and iris hypoplasia
harbored mutations in the FOXC1 gene (601090.0001-601090.0003,
respectively). The findings demonstrated that mutations in FOXC1 cause a
spectrum of glaucoma phenotypes.
By DNA sequencing of FOXC1 in 5 families and 16 sporadic patients with
anterior segment defects, Mears et al. (1998) found 3 mutations: a 10-bp
deletion predicted to cause a frameshift and premature protein
truncation prior to the FOXC1 forkhead DNA-binding domain, as well as 2
missense mutations of conserved amino acids within the FOXC1 forkhead
domain (601090.0008 and 601090.0009). However, mutation screening and
genetic linkage analyses excluded FOXC1 from underlying the anterior
segment disorders in 2 of the families with linkage to 6p25. The
findings demonstrated that although mutations of FOXC1 result in
anterior segment defects and glaucoma in some patients, it is probable
that at least one more locus involved in the regulation of eye
development is also located at 6p25.
Nishimura et al. (2001) analyzed the coding region of the FOXC1 gene in
70 probands with congenital anterior chamber defects and detected 9
mutations, 8 of which were novel (see, e.g., 601090.0005-601090.0007).
Affected members from 2 families, one with iris hypoplasia and the other
with Peters anomaly (604229), had 2 different partial duplications of
6p25, respectively, both encompassing the FOXC1 gene (see 601090.0006).
These data suggested that both FOXC1 haploinsufficiency and increased
gene dosage may cause anterior-chamber defects of the eye.
Saleem et al. (2001) investigated 5 missense mutations of the FOXC1
transcription factor found in patients with Axenfeld-Rieger
malformations to determine their effects on FOXC1 structure and
function. Molecular modeling of the FOXC1 forkhead domain predicted that
the missense mutations did not alter FOXC1 structure. Biochemical
analyses indicated that whereas all mutant proteins correctly localized
to the cell nucleus, the I87M (601090.0009) mutation reduced FOXC1
protein levels. DNA-binding experiments revealed that although the S82T
(601090.0008) and S131L (601090.0002) mutations decreased DNA binding,
the F112S (601090.0004) and I126M (601090.0003) mutations did not.
However, the F112S and I126M mutations decreased the transactivation
ability of FOXC1. All the FOXC1 mutations had the net effect of reducing
FOXC1 transactivation ability. These results indicated that the FOXC1
forkhead domain contains separable DNA-binding and transactivation
functions. In addition, these findings demonstrated that reduced
stability, DNA binding, or transactivation, all causing a decrease in
the ability of FOXC1 to transactivate genes, can underlie
Axenfeld-Rieger malformations. Saleem et al. (2003) studied an
additional 5 missense mutations in the FOXC1 gene. Biologic analyses
indicated that all missense mutations studied caused various FOXC1
perturbations, including nuclear localization defects, reduced or
abolished DNA binding capacity, and a reduction in the transactivation
capacity of FOXC1.
Lines et al. (2002) reviewed the molecular genetics of Axenfeld-Rieger
malformations, including the roles of PITX2 (601542) and FOXC1 in human
disease and mouse models.
Using genotyping and FISH to investigate a 9-generation Scottish family
segregating autosomal dominant iridogoniodysgenesis, originally reported
by Zorab (1932), Lehmann et al. (2002) demonstrated an interstitial
duplication of chromosome 6p25 encompassing the FOXC1 gene
(601090.0006).
In 5 affected members of a 4-generation family segregating autosomal
dominant anterior segment defects, including a patient who also had
Peters anomaly, Honkanen et al. (2003) identified the F112S mutation
(601090.0004) in the FOXC1 gene. Extraocular features were present in 4
of the 5 patients.
Maclean et al. (2005) stated that 12 cases had been reported of a
distinctive clinical phenotype associated with deletion of distal
chromosome 6p (612582), the features of which included Axenfeld-Rieger
malformation, hearing loss, congenital heart disease, dental anomalies,
developmental delay, and a characteristic facial appearance. They
reported the case of a child in whom recognition of the specific ocular
and facial phenotype led to identification of a 6p microdeletion arising
from a de novo 6;18 translocation. Detailed analysis confirmed deletion
of the FOXC1, FOXF2 (603250), FOXQ1 (612788) forkhead gene cluster at
6p25. CNS anomalies included hydrocephalus and hypoplasia of the
cerebellum, brainstem, and corpus callosum with mild to moderate
developmental delay. Unlike previous reports, hearing was normal.
Berry et al. (2006) demonstrated that FOXC1 and the PITX2A isoform of
PITX2 physically interact and that the interaction requires crucial
functional domains on both proteins, e.g., the C-terminal activation
domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence studies
revealed colocalization of FOXC1 and PITX2A within a common nuclear
subcompartment, and transcription assay studies showed that PITX2A can
function as a negative regulator of FOXC1 transactivity. The authors
suggested that this negative regulation offers an explanation as to why
increased FOXC1 gene dosage produces a phenotype resembling that of
PITX2 deletions and mutations, and they concluded that functional
interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1
gene dosage in Axenfeld-Rieger syndrome and related anterior segment
dysgeneses.
In a mother and son with Axenfeld-Rieger syndrome, Ito et al. (2007)
analyzed the FOXC1 gene and identified a missense mutation (601090.0010)
that was de novo in the mother.
In 5 affected members of a 3-generation family with Axenfeld-Rieger
syndrome, who displayed a substantial degree of intrafamilial phenotypic
variability including Peters anomaly in 1 patient, Weisschuh et al.
(2008) identified heterozygosity for a nonsense mutation in the FOXC1
gene (601090.0011). The authors also screened the PITX2 (601542) and
CYP1B1 (601771) genes in this family and identified no disease-causing
mutations, although they did find that 2 known functional polymorphisms
in CYP1B1, V432L and N453S, were carried in heterozygosity by all
affected individuals except for the proband, who was homozygous for the
common N453 allele, and her brother, who was homozygous for the minor
L432 allele.
Aldinger et al. (2009) analyzed brain imaging studies in 18 individuals
with chromosome 6p25 copy number variation involving the FOXC1 gene and
3 patients with intragenic mutations of FOXC1, all of whom had been
previously reported (Pearce et al., 1982, 1983; Gould et al., 1997;
Mears et al., 1998; Nishimura et al., 1998; Lehmann et al., 2000;
DeScipio et al., 2005; Lin et al., 2005; Maclean et al., 2005; Chanda et
al., 2008) with phenotypes of glaucoma, Axenfeld-Rieger anomaly or
syndrome type 3, cardiac malformations, and/or brain anomalies,
particularly Dandy-Walker malformation. All of the patients had
abnormalities on MRI, showing classic or mild Dandy-Walker malformation
(DWM), mega cisterna magna (MCM), or cerebellar vermis hypoplasia (CVH).
The combined genotype and phenotype data showed consistently more severe
phenotypes among individuals with large compared to small deletions,
suggesting contributions from more than 1 causative gene in the region;
in addition, all 12 deletions involved the FOXC1 gene plus at least 2
exons of the GMDS gene (602884), implicating 1 or both of these genes as
having a previously unrecognized role in cerebellar development. In 3
patients from 2 families with missense mutations in FOXC1 resulting in
Axenfeld anomaly (601090.0003) and Axenfeld-Rieger syndrome type 3
(601090.0008), respectively, Aldinger et al. (2009) observed mild CVH
and an abnormal white matter signal corresponding to prominent
perivascular spaces. Aldinger et al. (2009) concluded that alteration of
FOXC1 function alone can cause CVH and contributes to MCM and DWM.
In 2 unrelated patients with iridogoniodysgenesis, Fetterman et al.
(2009) identified heterozygosity for a FOXC1 missense mutation in the
inhibitory domain (601090.0012) and stated that this was the first
missense mutation to be reported outside of the forkhead domain. Noting
that the iridogoniodysgenesis phenotype is more commonly associated with
FOXC1 duplications than mutations, Fetterman et al. (2009) suggested
that FOXC1 duplications and mutations that disrupt the inhibitory domain
may lead to disease through similar mechanisms and thus have more
similar phenotypes when compared to disease caused by missense mutations
with reduced protein function.
ANIMAL MODEL
The mouse gene Mf1, which encodes a forkhead/winged helix transcription
factor expressed in many embryonic tissues, including prechondrogenic
mesenchyme, periocular mesenchyme, meninges, endothelial cells, and
kidney, is the mouse homolog of FOXC1. Homozygous null Mf1-lacZ mice die
at birth with hydrocephalus, eye defects, and multiple skeletal
abnormalities identical to those of the classic mutant, congenital
hydrocephalus. Kume et al. (1998) showed that congenital hydrocephalus
involves a point mutation in Mf1, generating a truncated protein lacking
the DNA-binding domain. Mesenchyme cells from Mf1-lacZ embryos
differentiated poorly into cartilage in micromass culture and did not
respond to added BMP2 and TGF-beta-1. The differentiation of arachnoid
cells in the mutant meninges was also abnormal.
The autosomal recessive mouse mutation congenital hydrocephalus (ch) is
characterized by congenital, lethal hydrocephalus in association with
multiple developmental defects, notably skeletal defects, in tissues
derived from the cephalic neural crest. Hong et al. (1999) used
positional cloning methods to map ch in the vicinity of D13Mit294 and
confirmed that the ch phenotype is caused by homozygosity for a nonsense
mutation in the Mf1 gene. They found that ch heterozygotes have the
glaucoma-related distinct phenotype of multiple anterior segment defects
resembling Axenfeld-Rieger anomaly. They also localized a second member
of this gene family (Hfh1), a candidate for other developmental defects,
approximately 470 kb proximal to Mf1.
Smith et al. (2000) reported that Mf1 +/- mice have anterior segment
abnormalities similar to those reported in humans: small or absent canal
of Schlemm, aberrantly developed trabecular meshwork, iris hypoplasia,
severely eccentric pupils, and displaced Schwalbe line, but with normal
intraocular pressure. The penetrance of clinically obvious abnormalities
varied with genetic background. In some affected eyes, collagen bundles
were half normal diameter, or collagen and elastic tissue were very
sparse, suggesting that abnormalities in extracellular matrix synthesis
or organization may contribute to development of the ocular phenotypes.
Similar abnormalities were found in Mfh1 +/- mice (FOXC2; 602402), but
no disease-associated mutations were identified in the human homolog
FOXC2 in 32 ARA patients.
Kume et al. (2001) found that Foxc1 -/- Foxc2 -/- compound homozygous
mice died earlier with much more severe defects than single homozygotes
alone. Compound homozygous mice had profound abnormalities in the first
and second branchial arches and in early remodeling of blood vessels.
They showed complete absence of segmented paraxial mesoderm, including
anterior somites. In situ hybridization showed that both Foxc1 and Foxc2
were required for transcription in the anterior presomitic mesoderm of
paraxis (TCF15; 601010), Mesp1 (608689), Mesp2 (605195), Hes5 (607348),
and Notch1 (190198) and for formation of sharp boundaries of Dll1
(606582), Lfng (602576), and ephrin B2 (EFNB2; 600527) expression. Kume
et al. (2001) proposed that FOXC1 and FOXC2 interact with the Notch
signaling pathway and are required for prepatterning of anterior and
posterior domains in the presumptive somites through a putative
Notch/Delta/Mesp regulatory loop.
Libby et al. (2003) demonstrated that Tyr (606933) activity modifies the
phenotype in Foxc1 +/- mice and also in mice deficient in Cyp1b1
(601771), which have ocular drainage structure abnormalities resembling
those reported in human primary congenital glaucoma patients. The severe
dysgenesis in eyes lacking both Cyp1b1 and Tyr was alleviated by
administration of the tyrosinase product dihydroxyphenylalanine
(L-DOPA). The authors concluded that their studies raised the
possibility that a tyrosinase/L-DOPA pathway modifies human primary
congenital glaucoma.
Using N-ethyl-N-nitrosourea mutagenesis, Zarbalis et al. (2007) produced
'hole-in-the-head' (hith) mice, which had cortical and skull defects but
survived to adulthood. These mice had a phe107-to-leu mutation in Foxc1
that destabilized the protein without substantially altering
transcriptional activity. Embryonic and postnatal histologic analysis
showed that diminished Foxc1 expression in all 3 layers of meningeal
cells in Foxc1(hith/hith) mice contributed to cortical and skull defects
and that the prominent phenotypes appeared as the meninges
differentiated into pia, arachnoid, and dura. Analysis of cortical
phenotypes showed that Foxc1(hith/hith) mice displayed detachment of
radial glial endfeet, marginal zone heterotopias, and cortical
dyslamination. Zarbalis et al. (2007) concluded that the meninges
regulate development of the skull and cerebral cortex by controlling
aspects of the formation of these neighboring structures and that
defects in meningeal differentiation can lead to severe cortical
dysplasia.
Aldinger et al. (2009) generated Foxc1-null mice and observed embryonic
abnormalities of the cerebellar rhombic lip due to loss of
mesenchyme-secreted signaling molecules with subsequent loss of Atoh1
(601461) expression in the vermis. Foxc1 homozygous hypomorphs had
cerebellar vermis hypoplasia with medial fusion and foliation defects.
LINC01011
| dbSNP name | rs56101234(C,A); rs2326106(T,G); rs6920013(C,T); rs6920145(C,T); rs13191403(G,A); rs1054132(G,T); rs1054133(T,C); rs8583(C,T); rs2002(T,C); rs11201(C,T) |
| cytoBand name | 6p25.2 |
| EntrezGene GeneID | 401232 |
| snpEff Gene Name | NQO2 |
| EntrezGene Description | long intergenic non-protein coding RNA 1011 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2484 |
HTATSF1P2
| dbSNP name | rs6942303(A,G); rs6919992(C,G); rs6903839(T,C); rs6920375(C,T); rs6919219(G,A); rs6919232(G,A); rs9285966(C,T); rs6920900(C,G); rs6924045(G,T); rs4959753(G,A); rs6905363(A,G); rs11966750(C,G); rs10223660(C,T); rs13198902(G,A); rs6931684(C,T); rs4959754(T,C); rs1963161(T,C); rs376470361(C,T); rs4959756(T,C); rs9942449(G,A); rs13193229(T,A); rs6938396(C,G); rs74756259(C,T); rs6596930(A,G); rs927340(G,A); rs1040861(C,A); rs12192697(T,C); rs4269412(C,T) |
| cytoBand name | 6p25.2 |
| EntrezGene GeneID | 401233 |
| snpEff Gene Name | NQO2 |
| EntrezGene Description | HIV-1 Tat specific factor 1 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4729 |
PPP1R3G
| dbSNP name | rs7762427(C,G); rs397654(A,G); rs1065500(G,T) |
| cytoBand name | 6p25.1 |
| EntrezGene GeneID | 648791 |
| EntrezGene Description | protein phosphatase 1, regulatory subunit 3G |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05785 |
| ExAC AF | 0.026 |
PIP5K1P1
| dbSNP name | rs169077(G,C); rs197128(A,G); rs197129(G,A); rs6597293(G,C); rs197130(T,C); rs11754300(T,C); rs2163455(C,A); rs7744601(T,C); rs77949614(C,T) |
| cytoBand name | 6p24.3 |
| EntrezGene GeneID | 100526836 |
| EntrezGene Symbol | BLOC1S5-TXNDC5 |
| snpEff Gene Name | TXNDC5 |
| EntrezGene Description | BLOC1S5-TXNDC5 readthrough (NMD candidate) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4803 |
MIR5689
| dbSNP name | rs9295535(T,C) |
| cytoBand name | 6p24.3 |
| EntrezGene GeneID | 100846998 |
| snpEff Gene Name | RP1-290I10.7 |
| EntrezGene Description | microRNA 5689 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.208 |
| ExAC AF | 0.068 |
NHLRC1
| dbSNP name | rs146342540(C,T); rs10949481(A,T); rs10949482(C,T); rs10949483(G,A); rs115931931(A,G) |
| ccdsGene name | CCDS4542.1 |
| cytoBand name | 6p22.3 |
| EntrezGene GeneID | 378884 |
| EntrezGene Description | NHL repeat containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NHLRC1:NM_198586:exon1:c.C332T:p.P111L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7695 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6VVB1 |
| dbNSFP Uniprot ID | NHLC1_HUMAN |
| dbNSFP KGp1 AF | 0.368131868132 |
| dbNSFP KGp1 Afr AF | 0.19918699187 |
| dbNSFP KGp1 Amr AF | 0.444751381215 |
| dbNSFP KGp1 Asn AF | 0.409090909091 |
| dbNSFP KGp1 Eur AF | 0.410290237467 |
| dbSNP GMAF | 0.3687 |
| ESP Afr MAF | 0.243062 |
| ESP All MAF | 0.337009 |
| ESP Eur/Amr MAF | 0.385015 |
| ExAC AF | 0.385 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Bilateral macular retinal pigment epithelial mottling;
Bilateral macular retinal pigment epithelial atrophy;
Bilateral red-speckled retinal pigment epithelium;
Ring of moderately increased perifoveal autofluorescence;
Dyschromatopsia;
Gradual progressive loss of central visual acuity;
Central scotomata;
Electro-oculogram (EOG), flash electroretinogram (ERG) and pattern
ERG (PERG) initially normal;
Greatly reduced light-adapted scotopic and photopic ERG by 7th decade;
Unrecordable PERG by 7th decade
MOLECULAR BASIS:
Caused by mutation in the prominin 1 gene (PROM1, 604365.0003)
OMIM Title
*608072 NHL REPEAT-CONTAINING 1 GENE; NHLRC1
;;EPM2B GENE; EPM2B;;
MALIN
OMIM Description
DESCRIPTION
The NHLRC1 gene encodes malin, a single subunit E3 ubiquitin (UBB;
191339) ligase, which contains a RING-HC-type zinc finger and 6 NHL
domains and is subclassified as a member of the RING-HCa family (Gentry
et al., 2005).
CLONING
Within an 840-kb region on chromosome 6p22.3 in which the putative EPM2B
locus for Lafora disease (254780) was mapped, Chan et al. (2003)
identified a single-exon gene, termed NHLRC1. The gene is predicted to
encode a 395-amino acid protein, termed malin ('mal' for seizure in
French), containing a zinc finger of the RING type and 6 NHL-repeat
protein-protein interaction domains. The presence of the RING finger
predicts an E3 ubiquitin ligase function. Northern blot analysis
indicated 2 transcripts of 1.5 kb and 2.4 kb in all tissues examined,
including multiple subregions of the brain. In cultured cells, malin was
localized at the endoplasmic reticulum and, to a lesser extent, in the
nucleus. These results were similar to those observed for laforin
(EPM2A; 607566).
MAPPING
Chan et al. (2003) identified the NHLRC1 gene between markers D6S1688
and D6S1567 on chromosome 6p22.3.
GENE FUNCTION
By yeast 2-hybrid screen of a human brain cDNA library, Gentry et al.
(2005) found that malin directly bound and interacted with laforin in
HEK293T cells in vivo. Laforin is polyubiquitinated in a malin-dependent
manner, which leads to laforin degradation. Ubiquitination depended on
malin's RING domain but not on its NHL domains, whereas the NHL domains
functioned as a substrate-interacting motif to bind laforin. Mutations
in the NHLRC1 gene abolished both laforin polyubiquitination and
degradation. Gentry et al. (2005) concluded that malin is a
single-subunit E3 ligase, that laforin is a malin substrate, and that
malin regulates laforin protein concentration. They further suggested
that mutations in the NHLRC1 gene resulting in loss of the E3 ligase
activity of malin underlie the onset of Lafora disease.
Lohi et al. (2005) showed that laforin is a GSK3B (605004) ser9
phosphatase, and therefore capable of inactivating glycogen synthase
(GYS1; 138570) through GSK3. Laforin also interacted with malin, which
has been shown to bind GYS1. The authors proposed that laforin, in
response to appearance of polyglucosans, directs 2 negative feedback
pathways: polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity and
polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal
degradation.
Cori disease (232400) is a glycogen storage disease characterized by
deficiency of the glycogen debranching enzyme AGL (610860). Cheng et al.
(2007) showed that malin interacted with mouse Agl and promoted its
ubiquitination. Transfection studies in HepG2 cells showed that Agl was
cytoplasmic, whereas malin was predominantly nuclear. However, after
depletion of glycogen stores, about 90% of transfected cells exhibited
partial nuclear Agl staining. Elevation of cAMP increased malin levels
and malin/Agl complex formation. Cheng et al. (2007) concluded that
ubiquitination of AGL may play a role in the pathophysiology of both
Lafora disease and Cori disease.
Mittal et al. (2007) showed that laforin and malin were recruited to
aggresomes upon proteasomal blockade, possibly to clear misfolded
proteins through the ubiquitin-proteasome system (UPS). Garyali et al.
(2009) tested this possibility using a variety of cytotoxic misfolded
proteins, including the expanded polyglutamine protein, as potential
substrates. Laforin and malin, together with Hsp70 (HSPA1A; 140550) as a
functional complex, suppressed the cellular toxicity of misfolded
proteins; all 3 members of the complex were required for this function.
Laforin and malin interacted with misfolded proteins and promoted their
degradation through the UPS, and they were recruited to the
polyglutamine aggregates and reduced the frequency of aggregate-positive
cells. Garyali et al. (2009) suggested that the malin-laforin complex is
a novel player in the neuronal response to misfolded proteins.
MOLECULAR GENETICS
In 34 probands with Lafora disease, Chan et al. (2003) identified 17
different mutations in the NHLRC1 gene in 26 families, including 8
deletions, 1 insertion, 7 missense changes, and 1 nonsense change (see,
e.g., 608072.0001). Eighteen families were homozygous and 8 were
compound heterozygous for the mutations.
Gomez-Abad et al. (2005) identified 18 mutations, including 12 novel
mutations, in the malin gene (see, e.g., 608072.0005-608072.0007) in 23
of 25 patients with Lafora disease who did not have mutations in the
laforin gene. P69A (608072.0002) was the predominant mutation,
identified in 14 chromosomes from 9 unrelated patients; haplotype
analysis suggested a founder effect for only 2 of these families.
Singh et al. (2005) identified 6 different mutations in the NHLRC1 gene
in 5 of 8 Japanese families with Lafora disease. Another Japanese family
had a mutation in the EPM2A gene, and 2 Japanese families did not have
mutations in either gene. Singh et al. (2005) concluded that mutations
in the NHLRC1 gene are a common cause of Lafora disease in Japan.
Singh et al. (2006) identified 7 different mutations, including 2 novel
mutations, in the NHLRC1 gene in affected members of 8 families with
Lafora disease. The authors stated that 39 different mutations had been
identified in the NHLRC1 gene.
Ianzano et al. (2005) reported the creation of a Lafora progressive
myoclonus epilepsy mutation database.
ANIMAL MODEL
More than 5% of purebred miniature wirehaired dachshunds (MWHDs) in the
United Kingdom suffer an autosomal recessive progressive myoclonic
epilepsy (PME), which Lohi et al. (2005) showed to be Lafora disease
(254780). Using homozygosity and linkage analysis, they mapped the MWHD
disease locus to canine chromosome 35, which is syntenic in its entirety
to human 6p25-p21. They then cloned canine Epm2b (NHLRC1). PCR
identified a repeat region in affected dogs and revealed biallelic
expansion of the dodecamer repeat with 19 to 26 copies of the D
sequence. Comparing the amount of Epm2b mRNA in skeletal muscle from 3
affected dogs and 2 controls with quantitative RT-PCR showed that
affected mRNA levels were more than 900 times reduced. To determine
whether the extra D sequence is specific to MWHDs, Lohi et al. (2005)
sequenced Epm2b from 2 normal unrelated dogs from each of 128 breeds.
Sixty percent of their chromosomes had 3 repeats (2 Ds and 1 T) and 40%,
2 repeats (1 D and 1 T). Almost all breeds had examples of both variants
in homozygous or heterozygous state. They tested the next non-MWHD PME
case to present to the clinic, a basset hound, and found a homozygous
14-copy expansion of the repeat. Lohi et al. (2005) devised a test to
detect and counteract the mutant allele through controlled breeding.
ID4
| dbSNP name | rs9465545(A,G); rs1047033(A,G); rs59812764(T,G); rs7765893(T,C); rs1047014(T,C); rs11545617(C,T) |
| cytoBand name | 6p22.3 |
| EntrezGene GeneID | 3400 |
| EntrezGene Description | inhibitor of DNA binding 4, dominant negative helix-loop-helix protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2098 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
RESPIRATORY:
Progressive breathing difficulty
SKELETAL:
Mild joint laxity;
Delayed bone maturation;
[Spine];
Atlanto-axial subluxation;
Lumbar lordosis;
Irregular vertebral end plates;
Os odontoideum and atlanto-axial instability;
Spondylolysis and spondylolisthesis of L5;
[Pelvis];
Flat femoral head with subluxation and sloping acetabulum;
[Limbs];
Small femoral capital epiphyses
MUSCLE, SOFT TISSUE:
Hand muscle wasting
NEUROLOGIC:
[Peripheral nervous system];
Hemiparesis;
Quadriparesis;
Limb weakness;
Brisk reflexes;
Clonus in legs;
Bulbar palsy;
Tongue fasciculations
OMIM Title
*600581 INHIBITOR OF DNA BINDING 4; ID4
;;IDB4
OMIM Description
DESCRIPTION
Transcription factors containing a basic helix-loop-helix (bHLH) motif
regulate expression of tissue-specific genes in a number of mammalian
and insect systems. DNA-binding activity of the bHLH proteins is
dependent on formation of homo- and/or heterodimers. Dominant-negative
HLH proteins encoded by Id-related genes, such as ID4, also contain the
HLH-dimerization domain but lack the DNA-binding basic domain.
Consequently, Id proteins inhibit binding to DNA and transcriptional
transactivation by heterodimerization with bHLH proteins (Pagliuca et
al., 1995).
CLONING
Pagliuca et al. (1995) reported the cDNA sequence of a novel human HLH
gene, ID4, which lacks the basic domain. ID4 is differentially expressed
in adult organs as 4 mRNA molecules that are presumably the result of
differential splicing and/or alternative polyadenylation sites.
GENE FUNCTION
Transfection experiments by Pagliuca et al. (1995) indicated that
enforced expression of the ID4 protein inhibits the transactivation of
the muscle creatine kinase (CKM; 123310) E-box enhancer by MyoD (MYOD1;
159970).
Yu et al. (2005) found aberrant Id4 methylation in a mouse model of
T-lymphoblastic leukemia following leukemic transformation, but not in
the benign preleukemic phase. ID4 was silenced by promoter methylation
in the majority of human leukemias examined, but not in normal bone
marrow, normal lymphocytes, or other tumor types. Transfection of mouse
Id4 into a mouse lymphoid tumor inhibited cell growth in vitro and in
SCID mice in vivo. Yu et al. (2005) concluded that ID4 is a putative
tumor suppressor.
MAPPING
By fluorescence in situ hybridization (FISH), Pagliuca et al. (1995)
mapped the ID4 gene to 6p22-p21.3. By the same method, Rigolet et al.
(1998) mapped the gene to 6p23-p22.3.
KAAG1
| dbSNP name | rs144752285(G,T); rs9379657(G,A); rs1277349(G,C) |
| ccdsGene name | CCDS4550.1 |
| cytoBand name | 6p22.3 |
| EntrezGene GeneID | 353219 |
| snpEff Gene Name | DCDC2 |
| EntrezGene Description | kidney associated antigen 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.022469 |
| ESP All MAF | 0.008228 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 0.002638 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
ABDOMEN:
Recurrent abdominal pain since childhood;
[Pancreas];
Chronic pancreatitis;
Pancreatic calcifications;
Intraductal calculi, especially in the caput;
Increased risk of pancreatic cancer
ENDOCRINE FEATURES:
Increased incidence of fibrocalculus pancreatic diabetes (FCPD);
Insulin-dependent but ketosis-resistant diabetes
NEOPLASIA:
Increased risk of pancreatic cancer
MISCELLANEOUS:
Median age at onset is 21 years;
Occurs most often in developing countries in tropical regions;
No phenotypic difference between patients who are homozygous or heterozygous
for mutations in the SPINK1 gene
MOLECULAR BASIS:
Caused by mutation in the serine protease inhibitor, kazal-type-1
gene (SPINK1, 167790.0001)
OMIM Title
*608211 KIDNEY-ASSOCIATED ANTIGEN 1; KAAG1
;;RU2, ANTISENSE; RU2AS
OMIM Description
CLONING
By stimulating blood lymphocytes from a renal cell carcinoma patient in
vitro with the autologous tumor cells, van den Eynde et al. (1999)
obtained cytolytic T lymphocyte (CTL) clones that killed several
autologous and allogeneic HLA-B7 renal carcinoma cell lines. They
identified the target antigen of the CTLs by screening COS cells
transfected with HLA-B7 cDNA and with a cDNA library prepared with RNA
from the tumor cells. The antigenic peptide was encoded by an antisense
transcript of the RU2 gene (605755), KAAG1, which they designated RU2AS.
The deduced KAAG1 protein contains 84 amino acids. Northern blot
analysis detected expression in normal kidney, bladder, liver, and
testis, and RT-PCR analysis detected KAAG1 expression in normal proximal
tubule epithelial cell lines. KAAG1 was expressed by a high proportion
of tumors of various histologic origin, including some derived from
tissues that did not express KAAG1, such as melanomas, sarcomas, and
colorectal carcinomas. Van den Eynde et al. (1999) determined that KAAG1
and the overlapping RU2 gene are transcribed independently.
MAPPING
Using FISH, van den Eynde et al. (1999) mapped the KAAG1 gene to
chromosome 6p22.1. KAAG1 lies in the antisense orientation and overlaps
intron 1 and the promoter region of RU2.
C6orf229
| dbSNP name | rs2251702(A,G); rs3813682(A,T) |
| cytoBand name | 6p22.3 |
| EntrezGene GeneID | 101928603 |
| EntrezGene Symbol | LOC101928603 |
| EntrezGene Description | uncharacterized LOC101928603 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C6orf229:NM_001282492:exon2:c.T684C:p.H228H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4761 |
| ExAC AF | 0.317 |
HIST1H2AA
| dbSNP name | rs6940348(C,T); rs9467583(C,T); rs9358871(G,A); rs150563946(G,A); rs4711095(A,C) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 221613 |
| snpEff Gene Name | HIST1H2BA |
| EntrezGene Description | histone cluster 1, H2aa |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04729 |
| ESP Afr MAF | 0.122106 |
| ESP All MAF | 0.048362 |
| ESP Eur/Amr MAF | 0.010581 |
| ExAC AF | 0.97 |
HIST1H2BA
| dbSNP name | rs4712960(C,T); rs4712961(C,T); rs61744293(C,T); rs9358872(G,A); rs17320558(T,A) |
| ccdsGene name | CCDS4563.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 255626 |
| EntrezGene Description | histone cluster 1, H2ba |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BA:NM_170610:exon1:c.C129T:p.I43I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.382 |
| ESP Afr MAF | 0.137313 |
| ESP All MAF | 0.230355 |
| ESP Eur/Amr MAF | 0.278023 |
| ExAC AF | 0.327 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, severe to profound
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the TRIO- and F-actin-binding protein (TRIOBP,
609761.0001)
OMIM Title
*609904 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER A; HIST1H2BA
;;HISTONE GENE CLUSTER 1, H2BA;;
HIST1 CLUSTER, H2BA;;
H2B HISTONE FAMILY, MEMBER U; H2BFU;;
TESTIS-SPECIFIC HISTONE H2B; TSH2B
OMIM Description
DESCRIPTION
The nucleosome is the basic repeat unit of eukaryotic chromatin. The
nucleosome core particle consists of an octamer formed by 2 each of the
core histones H2A (see 613499), H2B, H3 (see 602810), and H4 (see
602822), around which DNA is wrapped. A fifth histone, histone H1 (see
142709), is bound to the linker DNA between nucleosomes and is important
for the higher order structure of chromatin. HIST1H2BA is a core histone
H2B (summary by Marzluff et al. (2002) and Foster and Downs (2005)).
For additional background information on histones, histone gene
clusters, and the H2B histone family, see GENE FAMILY below.
GENE FAMILY
All core histones contain a histone fold domain, which is central to the
nucleosome core structure, and a flexible N-terminal domain that
protrudes from the nucleosome core particle. H2A and H2B histones are
unique in that they also have significant sequence on the C-terminal
side of the histone fold. The H2B C-terminal domain forms an alpha helix
and lies along the nucleosome. Like other histones, H2B histones can be
subgrouped according to their temporal expression. Replication-dependent
histones, such as HIST1H2BA through HIST1H2BO (602808), HIST2H2BE
(601831), and HIST3H2BB, are mainly expressed during S phase. In
contrast, replication-independent histones, or replacement variant
histones, can be expressed throughout the cell cycle. Most
replication-dependent H2B histone genes, as well as other core histone
genes, are located within histone gene cluster-1 (HIST1) on chromosome
6p22-p21. Two other histone gene clusters, HIST2 and HIST3, are located
on chromosomes 1q21 and 1q42, respectively, and each contains at least 1
replication-dependent H2B histone gene. In mouse, the Hist1, Hist2, and
Hist3 gene clusters are located on chromosomes 13A2-A3, 3F1-F2, and
11B2, respectively. All replication-dependent histone genes are
intronless, and they encode mRNAs that lack a poly(A) tail, ending
instead in a conserved stem-loop sequence. Unlike replication-dependent
histone genes, replication-independent histone genes are solitary genes
that are located on chromosomes apart from any other H1 or core histone
genes. Some replication-independent histone genes contain introns and
encode mRNAs with poly(A) tails (summary by Marzluff et al. (2002) and
Foster and Downs (2005)).
CLONING
By sequencing histones purified from human sperm, followed by database
analysis, Zalensky et al. (2002) identified HIST1H2BA, which they called
TSH2B. The deduced 127-amino acid protein shares 85% identity with
somatic H2B.1 (see 602803), but it has more potential phosphorylation
and myristoylation sites. TSH2B shares 95% and 93% amino acid identity
with mouse and rat Tsh2b, respectively. RT-PCR detected TSH2B expression
exclusively in testis. Using several extraction procedures, Zalensky et
al. (2002) found that TSH2B was relatively tightly bound to sperm
chromatin. Immunolocalization detected TSH2B in a punctate localization
in mature sperm, but it was not part of the telomere-binding complex.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H2BA genes. They noted that the HIST1H2BA protein
in both mouse and human diverges from the H2B consensus sequence more
significantly than other H2B family members.
MAPPING
By genomic sequence analysis, Zalensky et al. (2002) mapped the
HIST1H2BA gene to chromosome 6.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes,
including 15 H2B genes. The HIST1H2BA gene is the most telomeric H2B
gene within the HIST1 cluster. The HIST1 cluster spans over 2 Mb and
includes 2 large gaps (over 250 kb each) where there are no histone
genes, but many other genes. The organization of histone genes in the
mouse Hist1 cluster on chromosome 13A2-A3 is essentially identical to
that in human HIST1. The HIST2 cluster on chromosome 1q21 contains 6
histone genes, including 1 H2B gene (HIST2H2BE; 601831), and the HIST3
cluster on chromosome 1q42 contains 3 histone genes, including 1 H2B
gene (HIST3H2BB). Hist2 and Hist3 are located on mouse chromosomes
3F1-F2 and 11B2, respectively. Marzluff et al. (2002) noted that all 3
histone clusters in human and mouse contain pairs of H2A and H2B genes.
These paired H2A and H2B genes are transcribed from opposite strands,
with their 5-prime ends separated by an intergenic region of less than
300 nucleotides. A similar organization of H2a and H2b genes is found in
yeast, Drosophila, C. elegans, and sea urchin.
GENE FUNCTION
- H2B Histone Family
The Ran GTPase (601179) controls nucleocytoplasmic transport, mitotic
spindle formation, and nuclear envelope assembly. These functions rely
on the association of the Ran-specific exchange factor, RCC1 (179710),
with chromatin. Nemergut et al. (2001) found that RCC1 binds directly to
mononucleosomes and to histones H2A and H2B. RCC1 utilizes these
histones to bind Xenopus sperm chromatin, and the binding of RCC1 to
nucleosomes or histones stimulates the catalytic activity of RCC1.
Nemergut et al. (2001) proposed that the docking of RCC1 to H2A/H2B
establishes the polarity of the Ran-GTP gradient that drives nuclear
envelope assembly, nuclear transport, and other nuclear events.
Dorigo et al. (2004) analyzed compacted nucleosome arrays stabilized by
introduction of disulfide crosslinks and showed that the chromatin fiber
comprises 2 stacks of nucleosomes in accord with a 2-start model.
Kaposi sarcoma-associated herpesvirus (KSHV) latency-associated nuclear
antigen (LANA) mediates viral genome attachment to mitotic chromosomes.
Barbera et al. (2006) found that N-terminal LANA docks onto chromosomes
by binding nucleosomes through the folded region of histones H2A-H2B.
The same LANA residues were required for both H2A-H2B binding and
chromosome association. Further, LANA did not bind Xenopus sperm
chromatin, which is deficient in H2A-H2B; chromatin binding was rescued
after assembly of nucleosomes containing H2A-H2B. Barbera et al. (2006)
also described a 2.9-angstrom crystal structure of a nucleosome
complexed with the first 23 LANA amino acids. The LANA peptide forms a
hairpin that interacts exclusively with an acidic H2A-H2B region that is
implicated in the formation of higher order chromatin structure. Barbera
et al. (2006) concluded that their findings presented a paradigm for how
nucleosomes may serve as binding platforms for viral and cellular
proteins and revealed a previously unknown mechanism for KSHV latency.
Using a reconstituted chromatin-transcription system, Pavri et al.
(2006) showed that elongation by RNA polymerase II (see 180660) through
the nucleosomal barrier was minimally dependent on FACT (see 604328),
PAF (see 610506), and monoubiquitination of H2B at lys120.
Bungard et al. (2010) found that AMPK (see 602739) activates
transcription through direct association with chromatin and
phosphorylation of histone H2B at ser36. AMPK recruitment and H2B ser36
phosphorylation colocalized within genes activated by AMPK-dependent
pathways, both in promoters and in transcribed regions. Ectopic
expression of H2B in which ser36 was substituted by alanine reduced
transcription and RNA polymerase II association to AMPK-dependent genes,
and lowered cell survival in response to stress. Bungard et al. (2010)
concluded that their results placed AMPK-dependent H2B serine-36
phosphorylation in a direct transcriptional and chromatin regulatory
pathway leading to cellular adaptation to stress.
Fujiki et al. (2011) reported that histone H2B is acylated by O-linked
N-acetylglucosamine (GlcNAcylated) at residue S112 by O-GlcNAc
transferase (OGT; 300255) in vitro and in living cells. Histone
GlcNAcylation fluctuated in response to extracellular glucose through
the hexosamine biosynthesis pathway. H2B S112 GlcNAcylation promotes
K120 monoubiquitination, in which the GlcNAc moiety can serve as an
anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized
to euchromatic areas on fly polytene chromosomes. In a genomewide
analysis, H2B S112 GlcNAcylation sites were observed widely distributed
over chromosomes including transcribed gene loci, with some sites
colocalizing with H2B K120 monoubiquitination. Fujiki et al. (2011)
concluded that H2B S112 GlcNAcylation is a histone modification that
facilitates H2BK120 monoubiquitination, presumably for transcriptional
activation.
- Reviews
Wyrick and Parra (2009) reviewed the role of H2A and H2B
posttranslational modifications in transcription.
NOMENCLATURE
Marzluff et al. (2002) provided a nomenclature for replication-dependent
histone genes located within the HIST1, HIST2, and HIST3 clusters. The
symbols for these genes all begin with HIST1, HIST2, or HIST3 according
to which cluster they are located in. The H2A, H2B, H3, and H4 genes
were named systematically according to their location within the HIST1,
HIST2, and HIST3 clusters. For example, HIST1H2BA is the most telomeric
H2B gene within HIST1, and HIST1H2BO (602808) is the most centromeric.
In contrast, the H1 genes, all of which are located within HIST1, were
named according to their mouse homologs. Thus, HIST1H1A (142709) is
homologous to mouse H1a, HIST1H1B (142711) is homologous to mouse H1b,
and so on.
HISTORY
Maile et al. (2004) reported that serine-33 of histone H2B (H2B-S33) is
a physiologic substrate for the TAF1 (313650) C-terminal kinase domain
(CTK) and that H2B-S33 phosphorylation is essential for transcriptional
activation events that promote cell cycle progression and development.
Because of image manipulation that rendered the data, results, and
conclusions not reliable, the journal Science retracted the paper of
Maile et al. (2004) at the request of the University of California,
Riverside and Dr. Frank Sauer.
HIST1H2APS1
| dbSNP name | rs12190612(G,T); rs12203927(A,G); rs189991193(G,A); rs12192077(G,A) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 387319 |
| EntrezGene Description | histone cluster 1, H2a, pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3838 |
HIST1H1A
| dbSNP name | rs16891235(T,C); rs201609154(G,A) |
| ccdsGene name | CCDS4569.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 3024 |
| EntrezGene Description | histone cluster 1, H1a |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H1A:NM_005325:exon1:c.A419G:p.K140R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0087 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q02539 |
| dbNSFP Uniprot ID | H11_HUMAN |
| dbNSFP KGp1 AF | 0.0760073260073 |
| dbNSFP KGp1 Afr AF | 0.105691056911 |
| dbNSFP KGp1 Amr AF | 0.0745856353591 |
| dbNSFP KGp1 Asn AF | 0.0174825174825 |
| dbNSFP KGp1 Eur AF | 0.101583113456 |
| dbSNP GMAF | 0.07622 |
| ESP Afr MAF | 0.117794 |
| ESP All MAF | 0.108181 |
| ESP Eur/Amr MAF | 0.103256 |
| ExAC AF | 0.08 |
OMIM Clinical Significance
INHERITANCE:
Multifactorial
SKELETAL:
[Pelvis];
Congenital hip dislocation;
Positive Ortolani sign
MISCELLANEOUS:
Preponderance of affected females (80%) to males;
Positive family history in 12-33% patients;
Incidence 1-1.5/1,000 live births
OMIM Title
*142709 HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, MEMBER A; HIST1H1A
;;HISTONE GENE CLUSTER 1, H1A;;
HIST1 CLUSTER, H1A;;
H1A;;
H1.1;;
H1 HISTONE FAMILY, MEMBER 1, FORMERLY; H1F1, FORMERLY
OMIM Description
DESCRIPTION
The nucleosome is the fundamental repeat unit of eukaryotic chromatin.
The nucleosome core particle consists of an octamer formed by 2 each of
the core histones H2A (see 613499), H2B (see 609904), H3 (see 602810),
and H4 (see 602822), around which DNA is wrapped. A fifth histone, the
linker H1 histone, completes the nucleosome by interacting with DNA
entering and exiting the nucleosome core particle. H1 histones, such as
HIST1H1A, are involved in the formation of higher order chromatin
structures, and they modulate the accessibility of regulatory proteins,
chromatin-remodeling factors, and histone modification enzymes to their
target sites (reviewed by Izzo et al. (2008) and Happel and Doenecke
(2009)).
For additional background information on histones, histone gene
clusters, and the H1 histone family, see GENE FAMILY below.
GENE FAMILY
The H1 histone family is the most divergent class of histones, with at
least 11 different H1 histones present in humans. H1 histones have a
tripartite structure that consists of a short N-terminal domain enriched
in basic amino acids, a central conserved globular domain involved in
DNA binding, and a long C-terminal tail enriched in lysine, serine, and
proline. Like other histones, H1 histones can be subgrouped according to
their temporal expression. Replication-dependent histones, such as H1.1
through H1.5 (HIST1HB; 142711) and H1T (HIST1H1T; 142712), are mainly
expressed during S phase. In contrast, replication-independent histones,
or replacement histones, such as H1.0 (H1F0; 142708), H1T2 (H1FNT), H1OO
(H1FOO), H1X (H1FX; 602785), and HILS1 (608101), are expressed
throughout the cell cycle. All replication-dependent H1 histone genes,
as well as other core histone genes, are located within histone gene
cluster-1 (HIST1) on chromosome 6p22-p21. Two other histone gene
clusters, HIST2 and HIST3, are located on chromosomes 1q21 and 1q42,
respectively, but they are devoid of H1 genes. In mouse, the Hist1,
Hist2, and Hist3 gene clusters are located on chromosomes 13A2-A3,
3F1-F2, and 11B2, respectively. All replication-dependent histone genes
are intronless, and they encode mRNAs that lack a poly(A) tail, ending
instead in a conserved stem-loop sequence. Unlike replication-dependent
histone genes, replication-independent histone genes are solitary genes
that are located on chromosomes apart from any other H1 or core histone
genes. Some replication-independent histone genes contain introns and
encode mRNAs with poly(A) tails. H1 histones, as well as core histones,
can also be subgrouped based on their spatial expression. Somatic H1
histones (H1.1 through H1.5 and H1X) are expressed ubiquitously, whereas
other H1 histones are expressed mainly in terminally differentiated
cells (H1.0) or in germ cells (H1T, H1T2, H1OO, and HILS1) (summary by
Marzluff et al. (2002), Izzo et al. (2008), and Happel and Doenecke
(2009)).
CLONING
Eick et al. (1989) cloned the genes encoding H1.1 and H1.2 (HIST1H1C;
142710).
Using Northern blot analysis, Burfeind et al. (1994) found that the H1.1
gene was expressed in testis and thymus, but not in other human tissues.
In testis, it was restricted to early round spermatids that belonged to
the fraction of postmeiotic sperm cells. Burfeind et al. (1994) found
that the H1.1 gene is highly conserved in higher primates, whereas no
cross-hybridization could be detected with DNA from other mammalian
species, such as mouse, rat, hamster, and bull.
GENE FUNCTION
Histone H1 functions in the compaction of chromatin into higher order
structures derived from the repeating 'beads-on-a-string' nucleosome
polymer. Modulation of H1 binding activity is thought to be an important
step in the potentiation/depotentiation of chromatin structure for
transcription. It is generally accepted that H1 binds less tightly than
other histones to DNA in chromatin and can readily exchange in living
cells. Fusion proteins of histone H1 and green fluorescent protein (GFP)
have been shown to associate with chromatin in an apparently identical
fashion to native histone H1, providing a means by which to study
histone H1-chromatin interactions in living cells. Lever et al. (2000)
used human cells with a stably integrated H1.1-GFP fusion protein to
monitor histone H1 movement directly by fluorescence recovery after
photobleaching in living cells. They found that exchange is rapid in
both condensed and decondensed chromatin, occurs throughout the cell
cycle, and does not require fiber-fiber interactions. Treatment with
drugs that alter protein phosphorylation significantly reduced exchange
rates. Lever et al. (2000) concluded that histone H1 exchange in vivo is
rapid, occurs through a soluble intermediate, and is modulated by the
phosphorylation of a protein or proteins as yet to be determined.
Using techniques similar to those of Lever et al. (2000), Misteli et al.
(2000) showed that almost the entire population of H1-GFP is bound to
chromatin at any 1 time; however, H1-GFP is exchanged continuously
between chromatin regions. The residence time of H1-GFP on chromatin
between exchange events is several minutes in both euchromatin and
heterochromatin. In addition to the mobile fraction, Misteli et al.
(2000) detected a kinetically distinct, less mobile fraction. After
hyperacetylation of core histones, the residence time of H1-GFP was
reduced, suggesting a higher rate of exchange upon chromatin remodeling.
Misteli et al. (2000) concluded that their results support a model in
which linker histones bind dynamically to chromatin in a stop-and-go
mode.
Hizume et al. (2005) noted that addition of histone H1 to reconstituted
nucleosomes represses transcriptional activity and prevents sliding of
core histones along DNA. They used nucleosome core particles and histone
H1 purified from HeLa cells for in vitro nucleosome reconstitution
assays. Under optimal salt concentrations, nucleosome core particles
alone formed beads-on-a-string chromatin fibers on plasmid DNA. However,
addition of purified histone H1 induced higher order folding in a
concentration-dependent manner. Hizume et al. (2005) proposed a model of
chromatin fiber formation where fiber compaction is dependent on both
the local salt environment and histone H1 availability.
Krishnakumar et al. (2008) used genomic and gene-specific approaches to
show that 2 factors, histone H1 and PARP1 (173870), exhibit a reciprocal
pattern of chromatin binding at many RNA polymerase II-transcribed
promoters. PARP1 was enriched and H1 was depleted at these promoters.
This pattern of binding was associated with actively transcribed genes.
Furthermore, Krishnakumar et al. (2008) showed that PARP1 acts to
exclude H1 from a subset of PARP1-stimulated promoters, suggesting a
functional interplay between PARP1 and H1 at the level of nucleosome
binding. Krishnakumar et al. (2008) concluded that although H1 and PARP1
have similar nucleosome-binding properties and effects on chromatin
structure in vitro, they have distinct roles in determining gene
expression in vivo.
- Reviews
Doenecke et al. (1994) reviewed the organization and expression of H1
histone and H1 replacement histone genes.
Izzo et al. (2008) reviewed the H1 histone family and discussed specific
roles of H1 proteins that challenged the concept of H1 being a mere
structural component of chromatin and a general repressor of
transcription.
Happel and Doenecke (2009) reviewed the structural and functional
aspects of H1 histones, with an emphasis on the structural role and
impact of H1 histones on the functional state of chromatin.
MAPPING
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic
cell hybrids, Albig et al. (1993) found that 5 human H1 histone genes,
H1.1 through H1.5, and the gene encoding the testis-specific H1T subtype
are located on chromosome 6. They found that the H1.0 subtype, which is
not neighbored by core histone genes, maps to chromosome 22. By
fluorescence in situ hybridization with human metaphase chromosomes and
PCR analysis of somatic cell hybrid DNAs carrying only fragments of
chromosome 6, they demonstrated that the histone genes are clustered in
the 6p22.2-p21.1 region.
By PCR analysis of human/rodent cell hybrid DNAs, Burfeind et al. (1994)
confirmed the localization of histone H1.1 to chromosome 6 and by
radioactive in situ hybridization regionalized the locus to 6p21.3.
Through detailed localization of the H1 histone genes with radiation
hybrids and long range pulsed field gel electrophoresis, Volz et al.
(1997) found that the histone genes on the short arm of chromosome 6 are
organized into 2 clusters. The major cluster at 6p22-p21.3 contains 32
histone genes, including the H1 genes H1.1, H1.2, H1.3 (HIST1H1D;
142210), H1.4 (HIST1H1E; 142220), and H1T, numerous core histone genes,
and the HFE gene (613609).
By analysis of a YAC contig, Albig et al. (1997) mapped the H1.1 gene to
chromosome 6p21.3 within a cluster of 35 histone genes, including H1.1
to H1.4 and H1T. They found that the H1.5 gene is located in a second
cluster on 6p about 2 Mb centromeric of the major cluster. In a contig
of the histone gene-containing cosmids from this second cluster on
chromosome 6p, Albig and Doenecke (1997) found 1 H1 gene (H1.5), 5 H2A
genes, 4 H2B genes, 1 H2B pseudogene, 3 H3 genes, 3 H4 genes, and 1 H4
pseudogene. The cluster extends about 80 kb with a nonordered
arrangement of the histone genes. The dinucleotide repeat polymorphic
marker D6S105 was localized at the telomeric end of this histone gene
cluster. Almost all human histone genes isolated to that time had been
localized within the 2 clusters on 6p or in a small group of histone
genes on chromosome 1.
Albig and Doenecke (1997) reviewed the organization of histone genes in
mouse. Both the human and mouse histone gene clusters are found on 2
chromosomes and have nearly the same composition and number of genes.
The 2 histone gene clusters on human chromosome 6p correspond to 2
clusters located on mouse chromosome 13. The relative localization of
the histone H1 and H3 genes appears to be highly conserved. The 2
clusters are 0.6 Mb apart in mouse and 2 Mb apart in human. A third
cluster of mouse histone genes on chromosome 3 corresponds to the group
of human genes located on chromosome 1. The authors stated that, to that
time, a total of 55 clustered histone genes had been identified in
mouse. Albig and Doenecke (1997) gave a pictorial representation of the
mapping of the other histone genes as well as a tabular summary of human
histone gene sequences deposited in the EMBL nucleotide sequence
database.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes,
including all 6 replication-dependent H1 genes. The HIST1 cluster spans
over 2 Mb and includes 2 large gaps (over 250 kb each) where there are
no histone genes, but many other genes. The organization of histone
genes in the mouse Hist1 cluster on chromosome 13A2-A3 is essentially
identical to that in human HIST1. The HIST2 cluster on chromosome 1q21
contains 6 histone genes, and the HIST3 cluster on chromosome 1q42
contains 3 histone genes. Hist2 and Hist3 are located on mouse
chromosomes 3F1-F2 and 11B2, respectively.
NOMENCLATURE
Marzluff et al. (2002) provided a nomenclature for replication-dependent
histone genes located within the HIST1, HIST2, and HIST3 clusters. The
symbols for these genes all begin with HIST1, HIST2, or HIST3 according
to which cluster they are located in. The H1 genes, all of which are
located within HIST1, were named according to their mouse homologs.
Thus, HIST1H1A is homologous to mouse H1a, HIST1H1B is homologous to
mouse H1b, and so on. In contrast, the H2A, H2B, H3, and H4 genes were
named systematically according to their location within the HIST1,
HIST2, and HIST3 clusters. For example, HIST1H4A (602822) is the most
telomeric H4 gene within HIST1, and HIST1H4L (602831) is the most
centromeric.
HIST1H4A
| dbSNP name | rs3734528(A,G) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8359 |
| snpEff Gene Name | HIST1H3A |
| EntrezGene Description | histone cluster 1, H4a |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07576 |
| ESP Afr MAF | 0.118021 |
| ESP All MAF | 0.108642 |
| ESP Eur/Amr MAF | 0.103837 |
| ExAC AF | 0.078,8.180e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602822 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER A; HIST1H4A
;;HISTONE GENE CLUSTER 1, H4A;;
HIST1 CLUSTER, H4A;;
H4 HISTONE FAMILY, MEMBER A; H4FA;;
H4/A
OMIM Description
DESCRIPTION
The nucleosome is the basic repeat unit of eukaryotic chromatin. The
nucleosome core particle consists of an octamer formed by 2 each of the
core histones H2A (see 613499), H2B (see 609904), H3 (see 602810), and
H4, around which DNA is wrapped. A fifth histone, histone H1 (see
142709), is bound to the linker DNA between nucleosomes and is important
for the higher order structure of chromatin. HIST1H4A is a core histone
H4 (summary by Marzluff et al. (2002) and Foster and Downs (2005)).
GENE FAMILY
All core histones, including H4 histones, contain a histone fold domain,
which is central to the nucleosome core structure, and a flexible
N-terminal domain that protrudes from the nucleosome core particle. Like
other histones, H4 histones can be subgrouped according to their
temporal expression. Replication-dependent histones, such as HIST1H4A
through HIST1H4L (602831) and HIST2H4A (142750) are mainly expressed
during S phase. In contrast, replication-independent histones, or
replacement variant histones, can be expressed throughout the cell
cycle. Most replication-dependent H4 histone genes, as well as other
core histone genes, are located within histone gene cluster-1 (HIST1) on
chromosome 6p22-p21. Two other histone gene clusters, HIST2 and HIST3,
are located on chromosomes 1q21 and 1q42, respectively. HIST2 contains 1
replication-dependent H4 gene, HIST2H4A, and there are no H4 genes in
HIST3. An additional H4 gene, HIST4H4 (615069), is located on chromosome
12p13.1. In mouse, the Hist1, Hist2, and Hist3 gene clusters are located
on chromosomes 13A2-A3, 3F1-F2, and 11B2, respectively. All
replication-dependent histone genes are intronless, and they encode
mRNAs that lack a poly(A) tail, ending instead in a conserved stem-loop
sequence. Unlike replication-dependent histone genes,
replication-independent histone genes are solitary genes that are
located on chromosomes apart from any other H1 or core histone genes.
Some replication-independent histone genes contain introns and encode
mRNAs with poly(A) tails. All human and mouse H4 histone genes encode
the same protein (summary by Marzluff et al. (2002) and Foster and Downs
(2005)).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4A genes. All mouse and human H4 genes, including
HIST1H4A, encode the same protein.
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/a.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes,
including 12 H4 genes. The HIST1H4A gene is the most telomeric H4 gene
within the HIST1 cluster. The HIST1 cluster spans over 2 Mb and includes
2 large gaps (over 250 kb each) where there are no histone genes, but
many other genes. The organization of histone genes in the mouse Hist1
cluster on chromosome 13A2-A3 is essentially identical to that in human
HIST1. The HIST2 cluster on chromosome 1q21 contains 6 histone genes,
including 1 H4 gene (HIST2H4A; 142750), and the HIST3 cluster on
chromosome 1q42 contains 3 histone genes, but no H4 genes. Hist2 and
Hist3 are located on mouse chromosomes 3F1-F2 and 11B2, respectively. An
additional H4 gene, HIST4H4 (615069), is located on human chromosome
12p13.1 and mouse chromosome 6G1.
GENE FUNCTION
- H4 Histone Family
As reviewed by Felsenfeld (1992), detailed biochemical definition of the
protein complexes that regulate gene transcription led to reemergence of
questions concerning the role of histones. He reviewed evidence
suggesting that transcriptional activation requires that transcription
factors successfully compete with histones for binding to promoters.
CpG island hypermethylation and global genomic hypomethylation are
common epigenetic features of cancer cells. Fraga et al. (2005)
characterized posttranslational modifications to histone H4 in a
comprehensive panel of normal tissues, cancer cell lines, and primary
tumors. They found that cancer cells had a loss of monoacetylated and
trimethylated forms of histone H4. These changes appeared early and
accumulated during the tumorigenic process, as they showed in a mouse
model of multistage skin carcinogenesis. The losses occurred
predominantly at the acetylated lys16 and trimethylated lys20 residues
of histone H4 and were associated with the hypomethylation of DNA
repetitive sequences, a well-known characteristic of cancer cells. Fraga
et al. (2005) suggested that the global loss of monoacetylation and
trimethylation of histone H4 is a common hallmark of human tumor cells.
Wang et al. (2001) reported the purification, molecular identification,
and functional characterization of a histone H4-specific
methyltransferase, PRMT1 (602950), a protein arginine methyltransferase.
PRMT1 specifically methylates arginine-3 of histone H4 in vitro and in
vivo. Methylation of arg3 by PRMT1 facilitates subsequent acetylation of
H4 tails by p300 (602700). However, acetylation of H4 inhibits its
methylation by PRMT1. Most important, a mutation in the
S-adenosyl-L-methionine-binding site of PRMT1 substantially crippled its
nuclear receptor coactivator activity. Wang et al. (2001) concluded that
their findings reveal arg3 of H4 as a novel methylation site by PRMT1
and indicate that arg3 methylation plays an important role in
transcriptional regulation.
Agalioti et al. (2002) found that only a small subset of lysines in
histones H3 (see 602810) and H4 are acetylated in vivo by the GCN5
acetyltransferase (see 602301) during activation of the interferon-beta
gene (IFNB; 147640). Reconstitution of recombinant nucleosomes bearing
mutations in these lysine residues revealed the cascade of gene
activation via a point-by-point interpretation of the histone code
through the ordered recruitment of bromodomain-containing transcription
complexes. Acetylation of histone H4 lys8 mediates recruitment of the
SWI/SNF complex (see 603111), whereas acetylation of lys9 and lys14 in
histone H3 is critical for the recruitment of TFIID (see 313650). Thus,
the information contained in the DNA address of the enhancer is
transferred to the histone N termini by generating novel adhesive
surfaces required for the recruitment of transcription complexes.
Using deuterium exchange/mass spectrometry coupled with hydrodynamic
measures, Black et al. (2004) demonstrated that CENPA (117139) and
histone H4 form subnucleosomal tetramers that are more compact and
conformationally more rigid than the corresponding tetramers of histones
H3 and H4. Substitution into histone H3 of the domain of CENPA
responsible for compaction was sufficient to direct it to centromeres.
Thus, Black et al. (2004) concluded that the centromere-targeting domain
of CENPA confers a unique structural rigidity to the nucleosomes into
which it assembles, and is likely to have a role in maintaining
centromere identity.
Acetylation of histone H4 on lysine-16 (H4-K16Ac) is a prevalent and
reversible posttranslational chromatin modification in eukaryotes. To
characterize the structural and functional role of this mark,
Shogren-Knaak et al. (2006) used a native chemical ligation strategy to
generate histone H4 that was homogeneously acetylated at K16. The
incorporation of this modified histone into nucleosomal arrays inhibited
the formation of compact 30-nanometer-like fibers and impeded the
ability of chromatin to form cross-fiber interactions. H4-K16Ac also
inhibited the ability of the adenosine triphosphate-utilizing chromatin
assembly and remodeling enzyme ACF to mobilize a mononucleosome,
indicating that this single histone modification modulates both higher
order chromatin structure and functional interactions between a
nonhistone protein and the chromatin fiber.
In a screen for endogenous tumor-associated T-cell responses in a
primary mouse model of prostatic adenocarcinoma, Savage et al. (2008)
identified a naturally arising CD8+ T cell response that is reactive to
a peptide derived from histone H4. Despite the ubiquitous nature of
histones, T cell recognition of histone H4 peptide was specifically
associated with the presence of prostate cancer in these mice. Thus,
Savage et al. (2008) concluded that the repertoire of antigens
recognized by tumor-infiltrating T cells is broader than previously
thought and includes peptides derived from ubiquitous self antigens that
are normally sequestered from immune detection.
Dang et al. (2009) reported an age-associated decrease in yeast Sir2
(see SIRT1, 604479) protein abundance accompanied by an increase in
histone H4 lysine-16 acetylation and loss of histones at specific
subtelomeric regions in replicatively old yeast cells, which results in
compromised transcriptional silencing at these loci. Antagonizing
activities of Sir2 and Sas2, a histone acetyltransferase, regulate the
replicative life span through histone H4 lys16 at subtelomeric regions.
Dang et al. (2009) concluded that this pathway, distinct from existing
aging models for yeast, may represent an evolutionarily conserved
function of sirtuins in regulation of replicative aging by maintenance
of intact telomeric chromatin.
Xu et al. (2010) reported that significant amounts of histone H3.3 (see
601128)-H4 tetramers split in vivo, whereas most H3.1 (see 602810)-H4
tetramers remain intact during mitotic division. Inhibiting DNA
replication-dependent deposition greatly reduced the level of splitting
events, which suggested that (i) the replication-independent H3.3
deposition pathway proceeds largely by cooperatively incorporating 2 new
H3.3-H4 dimers, and (ii) the majority of splitting events occurred
during replication-dependent deposition. Xu et al. (2010) concluded that
'silent' histone modifications within large heterochromatic regions are
maintained by copying modifications from neighboring preexisting
histones without the need for H3-H4 splitting events.
Qi et al. (2010) provided multiple lines of evidence establishing PHF8
(300560) as the first monomethyl histone H4 lysine-20 (H4K20me1)
demethylase, with additional activities towards histone H3K9me1 and me2.
PHF8 is located around the transcriptional start sites of approximately
7,000 RefSeq genes and in gene bodies and intergenic regions. PHF8
depletion resulted in upregulation of H4K20me1 and H3K9me1 at the
transcriptional start site and H3K9me2 in the nontranscriptional start
sites, respectively, demonstrating differential substrate specificities
at different target locations. PHF8 positively regulates gene
expression, which is dependent on its H3K4me3-binding PHD and catalytic
domains. Importantly, patient mutations significantly compromised PHF8
catalytic function. PHF8 regulates cell survival in the zebrafish brain
and jaw development, thus providing a potentially relevant biologic
context for understanding the clinical symptoms associated with PHF8
patients. Lastly, genetic and molecular evidence supported a model
whereby PHF8 regulates zebrafish neuronal cell survival and jaw
development in part by directly regulating the expression of the
homeodomain transcription factor MSX1/MSXB (605558), which functions
downstream of multiple signaling and developmental pathways.
Liu et al. (2010) reported that PHF8, while using multiple substrates,
including H3K9me1/2 and H3K27me2, also functions as an H4K20me1
demethylase. PHF8 is recruited to promoters by its PHD domain based on
interaction with H3K4me2/3 and controls G1-S transition in conjunction
with E2F1, HCF1 (300019), and SET1A (611052), at least in part, by
removing the repressive H4K20me1 mark from a subset of E2F1-regulated
gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin
in prophase is apparently required for the accumulation of H4K20me1
during early mitosis, which might represent a component of the condensin
II loading process. Accordingly, the HEAT repeat clusters in 2
non-structural maintenance of chromosomes (SMC) condensin II subunits,
NCAPD3 (609276) and NCAPG2 (608532), are capable of recognizing
H4K20me1, and ChIP-Seq analysis demonstrated a significant overlap of
condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, Liu et al.
(2010) concluded that the identification and characterization of an
H4K20me1 demethylase, PHF8, has revealed an intimate link between this
enzyme and 2 distinct events in cell cycle progression.
Fullgrabe et al. (2013) reported that induction of autophagy is coupled
to reduction of histone H4 lysine-16 acetylation (H4K16ac) through
downregulation of the histone acetyltransferase MOF (MYST1; 609912), and
demonstrated that this histone modification regulates the outcome of
autophagy. At a genomewide level, Fullgrabe et al. (2013) found that
H4K16 deactylation is associated predominantly with the downregulation
of autophagy-related genes. Antagonizing H4K16ac downregulation upon
autophagy induction results in the promotion of cell death. Fullgrabe et
al. (2013) concluded that their findings established that alteration in
a specific histone posttranslational modification during autophagy
affects the transcriptional regulation of autophagy-related genes and
initiates a regulatory feedback loop, which serves as a key determinant
of survival versus death responses upon autophagy induction.
BIOCHEMICAL FEATURES
- Crystal Structure
Sekulic et al. (2010) reported the crystal structure of a subnucleosomal
heterotetramer, (CENP-A-H4)2 (CENP-A, 117139, in complex with histone
H4), that reveals 3 distinguishing properties encoded by the residues
that comprise the CENP-A targeting domain (CATD): (1) a CENP-A-CENP-A
interface that is substantially rotated relative to the H3-H3 interface;
(2) a protruding loop L1 of the opposite charge as that on H3; and (3)
strong hydrophobic contacts that rigidify the CENP-A-H4 interface.
Residues involved in the CENP-A-CENP-A rotation are required for
efficient incorporation into centromeric chromatin, indicating
specificity for an unconventional nucleosome shape. DNA topologic
analysis indicated that CENP-A-containing nucleosomes are octameric with
conventional left-handed DNA wrapping. Sekulic et al. (2010) concluded
that CENP-A marks centromere location by restructuring the nucleosome
from within its folded histone core.
Elsasser et al. (2012) reported the crystal structures of the DAXX
(603186) histone-binding domain with a histone H3.3-H4 dimer, including
mutants within DAXX and H3.3, together with in vitro and in vivo
functional studies that elucidated the principles underlying H3.3
recognition specificity. Occupying 40% of the histone surface-accessible
area, DAXX wraps around the H3.3-H4 dimer, with complex formation
accompanied by structural transitions in the H3.3-H4 histone fold. DAXX
uses an extended alpha-helical conformation to compete with major
interhistone, DNA, and ASF1 interaction sites. Elsasser et al. (2012)
concluded that their structural studies identified recognition elements
that read out H3.3-specific residues, and functional studies addressed
the contribution of gly90 in H3.3 and glu225 in DAXX to
chaperone-mediated H3.3 variant recognition specificity.
EVOLUTION
Histone IV genes are highly conserved across evolution. Delange and
Smith (1971) noted that, in their 110 amino acids, histone IV genes of
cattle and garden peas differ by only 2 residues.
Heintz et al. (1981) concluded that the human histone genes are
clustered in the genome but are not arranged into recognizable repeating
units. The lack of organization of the human histone genes (as
contrasted with those of invertebrates or of Xenopus laevis) may reflect
the diminished requirement for rapid synthesis of large quantities of
histone proteins during early mammalian development.
Kedes and Maxson (1981) found that the histone genes in man, mouse,
chicken, and toad show a dispersed topology; they are scattered and
separated by long stretches of nonhistone DNA. In an article subtitled
'Paradigm Lost,' the authors referred to 'this newly discovered
diaspora.'
NOMENCLATURE
Marzluff et al. (2002) provided a nomenclature for replication-dependent
histone genes located within the HIST1, HIST2, and HIST3 clusters. The
symbols for these genes all begin with HIST1, HIST2, or HIST3 according
to which cluster they are located in. The H2A, H2B, H3, and H4 genes
were named systematically according to their location within the HIST1,
HIST2, and HIST3 clusters. For example, HIST1H4A is the most telomeric
H4 gene within HIST1, and HIST1H4L (602831) is the most centromeric. In
contrast, the H1 genes, all of which are located within HIST1, were
named according to their mouse homologs. Thus, HIST1H1A (142709) is
homologous to mouse H1a, HIST1H1B (142711) is homologous to mouse H1b,
and so on.
HISTORY
Szabo et al. (1978) presented nucleic acid hybridization data indicating
that chromosome 7 carries gene(s) coding for histone H4 protein.
Steffensen (1979) presented evidence that all 5 histone genes in man are
clustered at 7q2. Yunis and Chandler (1979) located the histone genes to
bands 7q32-36 and the homologous chromosome segments in chimpanzee,
gorilla, and orangutan.
A clone containing a human histone gene cluster in the order
H3-H4-H1-H2A-H2B was isolated by Clark et al. (1981), as cited by
Hentschel and Birnstiel (1981). Sierra et al. (1982) likewise found an
arrangement of the histone genes different from that in the sea urchin
and Drosophila.
Carozzi et al. (1984) isolated an H1 histone gene from a 15-kb human DNA
genomic sequence. The presence of H2A, H2B, H3 and H4 genes in this same
15-kb fragment demonstrated that these genes are clustered.
By study of mouse-human cell hybrids and by in situ hybridization, Green
et al. (1984) showed that H3 and H4 histone genes are on 1q, probably
1q21. From in situ hybridization, Tripputi et al. (1986) concluded that
histone genes map to at least 3 different chromosomes: 1, 6, and 12.
Some may be nonexpressed pseudogenes. They commented that the number of
histone genes is between 100 and 200. The histones have the distinction
of being the only proteins coded by repetitive DNA. Tanguay et al.
(1987) reported in situ hybridization data corroborating those of
Tripputi et al. (1986), using a heterologous probe containing the 5
histone genes of Drosophila. They found that the main concentrations of
grains were at 6p12-q21, 12q11-q22, and 1cen-q25. Allen et al. (1989)
reported the conflicting assignment of histones 3 and 4 to human
chromosome 6.
HIST1H4B
| dbSNP name | rs3752420(G,A); rs3752419(G,A) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8366 |
| snpEff Gene Name | HIST1H3B |
| EntrezGene Description | histone cluster 1, H4b |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4229 |
| ESP Afr MAF | 0.191557 |
| ESP All MAF | 0.33177 |
| ESP Eur/Amr MAF | 0.403605 |
| ExAC AF | 0.395 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602829 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER B; HIST1H4B
;;HISTONE GENE CLUSTER 1, H4B;;
HIST1 CLUSTER, H4B;;
H4 HISTONE FAMILY, MEMBER I; H4FI;;
H4/I
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4B genes. All mouse and human H4 genes, including
HIST1H4B, encode the same protein.
MAPPING
By analysis of a YAC contig from 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/i.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4B.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H3B
| dbSNP name | rs2213284(G,A) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8358 |
| snpEff Gene Name | HIST1H2AB |
| EntrezGene Description | histone cluster 1, H3b |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2089 |
| ESP Afr MAF | 0.096686 |
| ESP All MAF | 0.239428 |
| ESP Eur/Amr MAF | 0.312558 |
| ExAC AF | 0.704 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602819 HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER B; HIST1H3B
;;HISTONE GENE CLUSTER 1, H3B;;
HIST1 CLUSTER, H3B;;
H3 HISTONE FAMILY, MEMBER L; H3FL;;
H3/L
OMIM Description
For background information on histones, histone gene clusters, and the
H3 histone family, see HIST1H3A (602810).
CLONING
Zhong et al. (1983) identified a gene encoding a member of the H3 class
of histones. Albig and Doenecke (1997) designated this gene H3/l.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H3B genes. They noted that all H3 genes in histone
gene cluster-1 (HIST1), including HIST1H3B, encode the same protein,
designated H3.1. H3.1 differs from H3.2, which is encoded by HIST2H3C
(142780), at only 1 residue, and from histone H3.3, which is encoded by
both H3F3A (601128) and H3F3B (601058), at a few residues.
MAPPING
By analysis of a YAC contig, Albig et al. (1997) mapped the H3/l gene to
6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called HIST1,
contains 55 histone genes, including HIST1H3B.
GENE FUNCTION
See HIST1H3A (602810) for functional information on H3.1 and the H3
histone family.
MOLECULAR GENETICS
Wu et al. (2012) reported that a K27M mutation occurring in either H3F3A
or HIST1H3B was observed in 78% of diffuse intrinsic pontine gliomas
(DIPGs) and 22% of non-brain-stem gliomas.
Lewis et al. (2013) reported that human (DIPGs) containing the K27M
mutation in either histone H3.3 (H3F3A) or H3.1 (HIST1H3B) display
significantly lower overall amounts of H3 with trimethylated lysine-27
(H3K27me3) and that histone H3K27M transgenes are sufficient to reduce
the amounts of H3K27me3 in vitro and in vivo. Lewis et al. (2013) found
that H3K27M inhibits the enzymatic activity of the Polycomb repressive
complex-2 (PRC2) through interaction with the EZH2 (601573) subunit. In
addition, transgenes containing lysine-to-methionine substitutions at
other known methylated lysines (H3K9 and H3K36) are sufficient to cause
specific reduction in methylation through inhibition of SET domain
enzymes. Lewis et al. (2013) proposed that K-to-M substitutions may
represent a mechanism to alter epigenetic states in a variety of
pathologies.
HIST1H2AB
| dbSNP name | rs111714517(C,G); rs2230655(G,A) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8335 |
| snpEff Gene Name | HIST1H4A |
| EntrezGene Description | histone cluster 1, H2ab |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
| ESP Afr MAF | 0.014078 |
| ESP All MAF | 0.009459 |
| ESP Eur/Amr MAF | 0.007093 |
| ExAC AF | 0.011 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602795 HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER B; HIST1H2AB
;;HISTONE GENE CLUSTER 1, H2AB;;
HIST1 CLUSTER, H2AB;;
H2A HISTONE FAMILY, MEMBER M; H2AFM;;
H2A/M
OMIM Description
For background information on histones, histone gene clusters, and the
H2A histone family, see HIST1H2AA (613499).
CLONING
Zhong et al. (1983) identified a gene encoding a member of the H2A class
of histones. Albig and Doenecke (1997) designated this gene H2A/m.
MAPPING
By analysis of a YAC contig, Albig et al. (1997) mapped the H2A/m gene
to chromosome 6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2AB.
GENE FUNCTION
See HIST1H2AA (613499) for functional information on H2A histones.
HIST1H3C
| dbSNP name | rs3752417(G,C); rs3752416(T,C) |
| ccdsGene name | CCDS4576.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8352 |
| EntrezGene Description | histone cluster 1, H3c |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H3C:NM_003531:exon1:c.G267C:p.A89A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.07668 |
| ESP Afr MAF | 0.110531 |
| ESP All MAF | 0.10203 |
| ESP Eur/Amr MAF | 0.097674 |
| ExAC AF | 0.073 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602812 HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER C; HIST1H3C
;;HISTONE GENE CLUSTER 1, H3C;;
HIST1 CLUSTER, H3C;;
H3 HISTONE FAMILY, MEMBER C; H3FC;;
H3/C
OMIM Description
For background information on histones, histone gene clusters, and the
H3 histone family, see HIST1H3A (602810).
CLONING
Kardalinou et al. (1993) identified a gene encoding a member of the H3
class of histones and designated it H3.1. Albig and Doenecke (1997)
designated this gene H3/c.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H3C genes. They noted that all H3 genes in histone
gene cluster-1 (HIST1), including HIST1H3C, encode the same protein,
designated H3.1. H3.1 differs from H3.2, which is encoded by HIST2H3C
(142780), at only 1 residue, and from histone H3.3, which is encoded by
both H3F3A (601128) and H3F3B (601058), at a few residues.
MAPPING
By analysis of a YAC contig, Albig et al. (1997) mapped the H3/c gene to
chromosome 6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called HIST1,
contains 55 histone genes, including HIST1H3C.
GENE FUNCTION
See HIST1H3A (602810) for functional information on H3.1 and the H3
histone family.
HIST1H1C
| dbSNP name | rs144669348(C,T); rs8384(G,C); rs61748580(G,A); rs10425(A,G) |
| ccdsGene name | CCDS4577.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 3006 |
| EntrezGene Description | histone cluster 1, H1c |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H1C:NM_005319:exon1:c.G612A:p.K204K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.000908 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002602 |
OMIM Clinical Significance
INHERITANCE:
Multifactorial
SKELETAL:
[Pelvis];
Congenital hip dislocation;
Positive Ortolani sign
MISCELLANEOUS:
Preponderance of affected females (80%) to males;
Positive family history in 12-33% patients;
Incidence 1-1.5/1,000 live births
OMIM Title
*142710 HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, MEMBER C; HIST1H1C
;;HISTONE GENE CLUSTER 1, H1C;;
HIST1 CLUSTER, H1C;;
H1C;;
H1.2;;
H1 HISTONE FAMILY, MEMBER 2, FORMERLY; H1F2; FORMERLY
OMIM Description
For background information on histones, histone gene clusters, and the
H1 histone family, see HIST1H1A (142709).
CLONING
Eick et al. (1989) cloned the genes encoding H1.2 and H1.1 (HIST1H1A;
142709).
GENE FUNCTION
Several reports described an activity that modifies
nitrotyrosine-containing proteins and their immunoreactivity to
antibodies against nitrotyrosine (e.g., Kamisaki et al., 1998). Without
knowing the product of the reaction, this activity has been called a
'denitrase.' These studies used some nonspecific proteins that have
multiple tyrosine residues, e.g., albumin, as substrate to study the
mechanism of the reaction. Irie et al. (2003) developed an assay
strategy for determining the substrate for denitrase combining 2D-gel
electrophoresis and an on-blot enzyme assay. They found that histone
H1.2, an isoform protein of linker histone, was one such substrate. H1.2
has only 1 tyrosine residue in the entire molecule, which ensured the
exact position of the substrate to be involved. It had been reported
that histones are the most prominent nitrated proteins in cancer
tissues. It was also demonstrated that tyrosine nitration of histone H1
occurs in vivo. Conceiving that H1.2 might be an intrinsic substrate for
denitrase, they performed further experiments demonstrating that the
denitrase activity behaves as an enzymatic activity because the reaction
was time-dependent and was destroyed by heat or trypsin treatment. The
activity was shown to be specific for histone H1.2, to differ from
proteasome activity, and to require no additional cofactors.
Konishi et al. (2003) found that histone H1.2 was a cytochrome
c-releasing factor that appeared in the cytoplasm after exposure of
cells to x-ray irradiation. While all nuclear histone H1 forms were
released into the cytoplasm in a p53 (TP53; 191170)-dependent manner
after irradiation, only H1.2 induced cytochrome c release from isolated
mitochondria in a BAK (BAK1; 600516)-dependent manner. Reducing H1.2
expression enhanced cellular resistance to apoptosis induced by x-ray
irradiation or etoposide, but not that induced by other apoptotic
stimuli. Thymocytes and small intestines of H1.2-deficient mice
exhibited increased cellular resistance to x-ray-induced apoptosis.
Konishi et al. (2003) concluded that histone H1.2 has a role in
transmitting apoptotic signals from the nucleus to the mitochondria
following DNA double-strand breaks.
See HIST1H1A (142709) for additional functional information on H1
histones.
MAPPING
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic
cell hybrids and by fluorescence in situ hybridization, Albig et al.
(1993) demonstrated that 6 human histone H1 genes, including H1.2, are
located on chromosome 6p22.2-p21.1. By analysis of a YAC contig, Albig
et al. (1997) mapped the H1.2 gene to chromosome 6p21.3 within a cluster
of 35 histone genes, including H1.1 to H1.4 (HIST1H1E; 142220) and H1T
(HIST1H1T; 142712). The H1.5 gene (HIST1H1B; 142711) is part of a
separate subcluster within the same chromosomal region.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H1C.
HFE
| dbSNP name | rs2794719(T,G); rs61472021(T,C); rs62625330(A,G); rs34555420(G,C); rs13196986(T,C); rs1799945(C,G); rs2071303(T,C); rs2032451(G,T); rs140080192(G,A); rs2858996(G,T); rs1572982(G,A) |
| ccdsGene name | CCDS4578.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 3077 |
| EntrezGene Description | hemochromatosis |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3077&%3Brs=1799945|http://www.ncbi.nlm.nih.gov/omim/235200,235200|http://omim.org/entry/613609#0002|http://omim.org/entry/235200#0002|http://www.ncbi.nlm.nih.gov/pubmed?term=21208937,21909115 |
| Annovar Function | HFE:NM_000410:exon2:c.C187G:p.H63D,HFE:NM_139006:exon2:c.C187G:p.H63D,HFE:NM_139003:exon2:c.C187G:p.H63D,HFE:NM_139009:exon2:c.C118G:p.H40D,HFE:NM_139004:exon2:c.C187G:p.H63D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6308 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6B0J5 |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3077&%3Brs=1799945|http://www.ncbi.nlm.nih.gov/omim/235200,235200|http://omim.org/entry/613609#0002|http://omim.org/entry/235200#0002|http://www.ncbi.nlm.nih.gov/pubmed?term=21208937,21909115 |
| dbNSFP KGp1 AF | 0.0837912087912 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.121546961326 |
| dbNSFP KGp1 Asn AF | 0.0244755244755 |
| dbNSFP KGp1 Eur AF | 0.153034300792 |
| dbSNP GMAF | 0.08356 |
| ESP Afr MAF | 0.031548 |
| ESP All MAF | 0.110718 |
| ESP Eur/Amr MAF | 0.151279 |
| ExAC AF | 0.107 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Involuntary rhythmic myoclonic movements ('tremor') of the distal
extremities, usually fingers;
Movements ('tremors') characterized by 8 to 10-Hz discharges;
Generalized tonic-clonic seizures (GTCS);
Partial seizures;
Walking impairment due to myoclonus late in disease;
Generalized and focal spike and wave complexes seen on EEG;
Photoparoxysmal response on EEG;
Electrophysiologic studies indicate cortical origin;
Giant cortical somatosensory evoked potentials (SEPs);
Enhancement of the C-reflex;
Jerk-locked premyoclonus spikes
MISCELLANEOUS:
Adult onset;
Childhood onset has been reported;
Nonprogressive course;
Tremor may be elicited by movement or postural maintenance;
Tremor is aggravated by low glucose or light;
Anticonvulsants are effective (phenobarbital, valproic acid, benzodiazepines)
OMIM Title
*613609 HFE GENE; HFE
;;HLAH
OMIM Description
CLONING
El Kahloun et al. (1993) used a yeast artificial chromosome with a
320-kb insert of genomic DNA that included the major histocompatibility
complex class I HLA-A gene (142800) to screen a human duodenal mucosa
cDNA library. They isolated 7 cDNA clones that corresponded to 7 new
non-class I structural genes. Since these genes were located within the
hemochromatosis (HFE1; 235200) candidate gene region, they referred to
the genes as HCG (hemochromatosis candidate gene) I-VII. El Kahloun et
al. (1993) concluded that HCG I, III, V, and VI are probably single-copy
genes situated 180, 155, 140, and 230 kb, respectively, centromeric to
HLA-A. There were several copies of the other 3 genes. Each of the genes
was associated with a CpG/HTF island.
Using cDNA hybridization selection with a 320-kb YAC containing the
HLA-A gene to screen a human duodenal cDNA library, Goei et al. (1994)
isolated and characterized 10 novel gene fragments. Also in search of
the HFE gene, Yaouang et al. (1994) identified a zone of linkage
disequilibrium which suggested that the HFE gene may reside within a
400-kb expanse of DNA between the locus they referred to as i97 and
HLA-F (143110). Totaro et al. (1996) generated a detailed 1.2-Mb
physical and transcription map of 6p spanning the HLA class I region
from HLA-E to approximately 500 kb telomeric of HLA-F. The localization
of known genes was refined, and a new gene from the RNA helicase
superfamily was identified. Overall, 14 transcription units in addition
to the HLA genes were detected and integrated into the map. Thirteen
cDNA fragments showed no similarity with known sequences, and could be
candidates for hemochromatosis.
By linkage disequilibrium and full haplotype analysis of hereditary
hemochromotosis patients, Feder et al. (1996) identified a 250-kb region
more than 3 Mb telomeric of the MHC on chromosome 6 that is identical by
descent in 85% of patient chromosomes. Within this region, they
identified a gene, which they termed HLA-H, that encodes a predicted
343-amino acid protein related to the MHC class I gene family. The
protein comprises a signal sequence, peptide-binding regions (alpha-1
and alpha-2 domains), a transmembrane region, and a small cytoplasmic
portion. One of the most conserved structural features of MHC class I
molecules in HLA-H are the 4 cysteine residues that form disulfide
bridges in the alpha-2 and alpha-3 domains. Northern blot analysis
detected a 4-kb major mRNA transcript in all tissues tested, except
brain.
Searching for new human MHC class I related genes, Hashimoto et al.
(1995) identified MHC-related protein-1 (MR1; 600764) and a second gene,
MR2. The HLA-H gene (HFE) reported by Feder et al. (1996) as a candidate
gene for hereditary hemochromatosis turned out to be identical to the
MR2 gene of Hashimoto et al. (1995). Hashimoto et al. (1997) isolated
the murine homolog of this gene. It was found to be similar to its human
counterpart with an overall predicted amino acid sequence similarity of
approximately 66% and expression in various tissues as in human. An
extra 8 amino acid residues between the alpha-1 and the alpha-2 domains
in the mouse molecule compared to the human counterpart could be
explained by the creation of the additional coding sequence from the
intron.
Thenie et al. (2001) isolated an antisense transcript originating from
the HFE gene locus. The RNA spans exon 1, exon 2, part of intron 1 of
the HFE gene, and 1 kb upstream of it. The antisense transcript is
polyadenylated, but displays no open reading frame, and appears to be
expressed at low levels in all tissues and cell lines tested. In vitro
coupled transcription-translation experiments revealed that HFE
expression is decreased by this antisense RNA, suggesting that it may
play a role in the regulation of HFE gene expression.
NOMENCLATURE
Mercier et al. (1997) urged strongly that the symbol HFE be used for the
hemochromatosis gene rather than 'HLA-H' as used by Feder et al. (1996).
The designation HLA-H was used also for a presumed pseudogene in the HLA
class I region; see 142800. Similarly, Bodmer et al. (1997) argued that
'HLA-H' is an undesirable designation and pointed to the accepted
authority of the WHO Nomenclature Committee for Factors of the HLA
System in determining symbols of genes in this region.
BIOCHEMICAL FEATURES
- Crystal Structure
Lebron et al. (1998) determined the 2.6-angstrom crystal structure of
the HFE protein.
GENE STRUCTURE
Feder et al. (1996) determined that the HFE gene contains 7 exons
spanning 12 kb.
MAPPING
By fluorescence in situ hybridization analysis, Hashimoto et al. (1995)
mapped the HFE gene to chromosome 6p22.
The HFE gene maps within the MHC region on chromosome 6p21.3 (Feder et
al., 1996).
Hashimoto et al. (1997) showed that whereas the human gene is located
telomeric to the MHC region on 6p, the mouse homolog was translocated
from the site telomeric to MHC on chromosome 17 to chromosome 13 along
with other genes.
GENE FUNCTION
Parkkila et al. (1997) generated an antibody to a C-terminal peptide and
used it for immunolocalization of the HLA-H protein in the
gastrointestinal tract of Finnish and American subjects presumed not to
have hereditary hemochromatosis. Although staining for the HLA-H protein
was seen in some epithelial cells in every segment of the alimentary
canal, its cellular and subcellular expression in the small intestine
was distinct from that in other segments. In contrast to the stomach and
colon, where staining is polarized and restricted to the basal lateral
surfaces, and in contrast to the epithelial cells of the esophagus and
submucosal leukocytes, which showed nonpolarized staining around the
entire plasma membrane, the staining in the small intestine was mainly
intracellular and perinuclear, limited to cells in deep crypts. Parkkila
et al. (1997) concluded that the unique subcellular localization in the
crypts of the small intestine in proximity to the presumed sites of iron
absorption supported the implication of this protein in the molecular
basis of hemochromatosis.
By immunohistochemistry, Parkkila et al. (1997) demonstrated that the
HFE protein is expressed in human placenta in the apical plasma membrane
of the syncytiotrophoblasts, where the transferrin-bound iron is
normally transported to the fetus via receptor-mediated endocytosis.
Western blot analyses showed that the HFE protein is associated with
beta-2-microglobulin (B2M; 109700) in placental membranes. Unexpectedly,
the transferrin receptor (TFR; 190010) was also found to be associated
with the HFE protein/B2M complex. These studies placed the normal HFE
protein at the site of contact with the maternal circulation where its
association with transferrin receptor raised the possibility that the
HFE protein plays some role in determining maternal/fetal iron
homeostasis.
Feder et al. (1998) demonstrated that the HFE protein forms stable
complexes with the transferrin receptor. Studies on cell-associated
transferrin at 37 degrees C suggested that overexpression of HFE protein
decreases the affinity of TFR for transferrin. Feder et al. (1998)
demonstrated that the mutant H63D (613609.0002) HFE protein found in
patients with hemochromatosis formed stable complexes with TFR, but that
overexpression of H63D did not decrease the affinity of TFR for
transferrin. In contrast, the mutant C282Y (613609.0001) HFE protein
only associated with TFR to a small degree. The results established a
molecular link between the HFE protein and the transferrin receptor,
raising the possibility that alterations in this regulatory mechanism of
iron transport may play a role in the pathogenesis of hereditary
hemochromatosis.
By analyzing the crystal structure of the HFE protein, Lebron et al.
(1998) identified a patch of histidines that could be involved in
pH-dependent interactions. Soluble TFR and HFE bound tightly at the
basic pH of the cell surface, but not at the acidic pH of intracellular
vesicles. TFR:HFE stoichiometry (2:1) differed from TFR:transferrin
stoichiometry (2:2), implying a different mode of binding for HFE and
transferrin to TFR, consistent with the demonstration that HFE,
transferrin, and TFR form a ternary complex. Lebron et al. (1998) used
the crystal structure to reveal the locations of hemochromatosis
mutations.
At the cell surface, HFE complexes with TFRC, increasing the
dissociation constant of transferrin (TF) for its receptor 10-fold. HFE
does not remain at the cell surface, but traffics with TFRC to
transferrin-positive internal compartments. Using a HeLa cell line in
which the expression of HFE is controlled by tetracycline, Roy et al.
(1999) showed that the expression of HFE reduced uptake of radioactive
iron from TF by 33%, but did not affect the endocytic or exocytic rates
of TFRC cycling. Therefore, HFE appears to reduce cellular acquisition
of iron from TF within endocytic compartments. HFE specifically reduces
iron uptake from TF, as non-TF-mediated iron uptake from
Fe-nitrilotriacetic acid was not altered. These results explained the
decreased ferritin levels seen in the HeLa cell system, and demonstrated
the specific control of HFE over the TF-mediated pathway of iron uptake.
These results also have implications for the understanding of cellular
iron homeostasis in organs such as the liver, pancreas, heart, and
spleen that are iron loaded in persons with hereditary hemochromatosis
lacking functional HFE.
The HFE protein normally binds to TFR in competition with transferrin
and, in vitro, reduces cellular iron by reducing iron uptake. However,
in vivo, HFE is strongly expressed by liver macrophages and intestinal
crypt cells, which behave as though they are relatively iron-deficient
in HH. These observations suggest, paradoxically, that expression of
wildtype HFE may lead to iron accumulation in these specialized cell
types. Drakesmith et al. (2002) showed that wildtype HFE protein raises
cellular iron by inhibiting iron efflux from the monocyte/macrophage
cell line, and extended these results to macrophages derived from
healthy individuals and HH patients. They found that the HH-associated
mutant H63D (H41D of the mature protein) lost the ability to inhibit
iron release despite binding to TFR as well as wildtype HFE. They also
showed that the ability of HFE to block iron release is not
competitively inhibited by transferrin. They concluded that HFE has 2
mutually exclusive functions: binding to TFR in competition with
transferrin and inhibition of iron release.
Zoller et al. (2003) studied the mRNA and protein expression and
activity of cytochrome b reductase-1 (CYBRD1; 605745) in duodenal
biopsies of patients with iron deficiency anemia, hereditary
hemochromatosis, and controls. They found that CYBRD1 activity in iron
deficiency is stimulated via enhanced protein expression, whereas in
hemochromatosis due to mutations in the HFE gene it is upregulated
posttranslationally. Hemochromatosis patients with no mutations in HFE
did not have increased CYBRD1 activity. Zoller et al. (2003) concluded
that there are different kinetics of intestinal iron uptake between iron
deficiency and hemochromatosis due to mutations in HFE, and that
duodenal iron accumulation in hereditary hemochromatosis due to
mutations in HFE and hereditary hemochromatosis due to mutations in
other genes is pathophysiologically different.
Drakesmith et al. (2005) found that the Nef protein of human
immunodeficiency virus-1 (HIV-1) downregulated macrophage-expressed HFE.
Iron and ferritin accumulation were increased in HIV-1-infected ex vivo
macrophages expressing wildtype HFE. The effect was lost with
Nef-deleted HIV-1 or with infected macrophages from hemochromatosis
patients expressing mutant HFE. Iron accumulation in HIV-1-infected
wildtype macrophages was paralleled by increased cellular HIV-1 Gag
protein expression.
Like classic class Ia MHC molecules, HFE has a peptide-binding groove,
but the HFE groove has no ligand. Rohrlich et al. (2005) studied the
interactions of human and mouse HFE with T lymphocytes and found that
the mouse alpha/beta TCR recognized human HFE, leading to Zap70 (176947)
phosphorylation. Cytotoxic T lymphocytes from mice lacking Hfe were able
to recognize murine Hfe. Rohrlich et al. (2005) proposed that the immune
system may be involved in control of iron metabolism.
MOLECULAR GENETICS
In patients with hereditary hemochromatosis (HFE1; 235200), Feder et al.
(1996) identified 2 mutations in the HFE gene (C282Y, 613609.0001 and
H63D, 613609.0002). The C282Y mutation was detected in 85% of all HFE
chromosomes, indicating that in their population 83% of hemochromatosis
cases are related to C282Y homozygosity.
By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2,
4, and 5 of the HFE gene, Barton et al. (1999) identified novel
mutations in 4 of 20 hemochromatosis probands who lacked C282Y
homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity.
Probands 1 and 2 were heterozygous for the previously undescribed
mutations ile105-to-thr (I105T; 613609.0009) and gly93-to-arg (G93R;
613609.0010). Probands 3 and 4 were heterozygous for the previously
described but uncommon HFE mutation ser65-to-cys (S65C; 613609.0003).
Proband 3 was also heterozygous for C282Y and had porphyria cutanea
tarda (see 176100), and proband 4 had hereditary stomatocytosis
(185000). Each of these 4 probands had iron overload. In each proband
with an uncommon HFE coding region mutation, I105T, G93R, and S65C
occurred on separate chromosomes from those with the C282Y or H63D
mutations. Neither I105T, G93R, nor S65C occurred as spontaneous
mutations in these probands. In 176 normal control subjects, 2 were
heterozygous for S65C, but I105T and G93R were not detected.
ANIMAL MODEL
To test the hypothesis that the HFE gene is involved in regulation of
iron homeostasis, Zhou et al. (1998) studied the effects of a targeted
disruption of the murine homolog of the HFE gene. The HFE-deficient mice
showed profound differences in parameters of iron homeostasis. Even on a
standard diet, by 10 weeks of age, fasting transferrin saturation was
significantly elevated compared with normal littermates, and hepatic
iron concentration was 8-fold higher than that of wildtype littermates.
Stainable hepatic iron in the HFE mutant mice was predominantly in
hepatocytes in a periportal distribution. Iron concentrations in spleen,
heart, and kidney were not significantly different from that in
littermates. Erythroid parameters were normal, indicating that the
anemia did not contribute to the increased iron storage. The study
showed that HFE protein is involved in the regulation of iron
homeostasis and that mutations in the gene are responsible for
hereditary hemochromatosis. Beutler (1998) emphasized the pathologic and
clinical importance of the knockout mouse model for hemochromatosis.
The puzzling linkage between genetic hemochromatosis and the
histocompatibility loci became even more puzzling when the gene
involved, HFE, was identified. Indeed, within the well-defined, mainly
peptide-binding, MHC-class I family of molecules, HFE seems to perform
an unusual but essential function. Understanding of HFE function in iron
homeostasis was only partial; an even more open question was its
possible role in the immune system. To advance knowledge in both of
these areas, Bahram et al. (1999) studied deletion of the HFE alpha-1
and alpha-2 putative ligand-binding domains in vivo. HFE-deficient mice
were analyzed for a comprehensive set of metabolic and immune
parameters. Faithfully mimicking human hemochromatosis, mice homozygous
for this deletion developed iron overload, characterized by a higher
plasma iron content and a raised transferrin saturation as well as an
elevated hepatic iron load. The primary defect could, indeed, be traced
to an augmented duodenal iron absorption. In parallel, measurement of
the gut mucosal iron content as well as iron regulatory proteins allowed
a more informed evaluation of various hypotheses regarding the precise
role of HFE in iron homeostasis. However, extensive phenotyping of
primary and secondary lymphoid organs including the gut provided no
compelling evidence for an obvious immune-linked function for HFE.
Inflammation influences iron balance in the whole organism. A common
clinical manifestation of these changes is anemia of chronic disease
(ACD; also called anemia of inflammation). Inflammation reduces duodenal
iron absorption and increases macrophage iron retention, resulting in
low serum iron concentrations (hyposideremia). Despite the protection
hyposideremia provides against proliferating microorganisms, this 'iron
withholding' reduces the iron available to maturing red blood cells and
eventually contributes to the development of anemia. Hepcidin
antimicrobial peptide (HAMP; 606464) is a hepatic defensin-like peptide
hormone that inhibits duodenal iron absorption and macrophage iron
release. HAMP is part of the type II acute phase response and is thought
to have a crucial regulatory role in sequestering iron in the context of
ACD. Roy et al. (2004) reported that mice with deficiencies in the
hemochromatosis gene product, Hfe, mounted a general inflammatory
response after injection of lipopolysaccharide but lacked appropriate
Hamp expression and did not develop hyposideremia. These data suggested
a previously unidentified role for Hfe in innate immunity and ACD.
Nairz et al. (2009) found that mice lacking 1 or both Hfe alleles were
protected from Salmonella typhimurium septicemia, displaying reduced
bacterial replication and prolonged host survival. Increased resistance
was associated with enhanced production of the enterochelin-binding
protein Lcn2 (600181), which reduced iron availability for Salmonella.
Macrophages lacking both Hfe and Lcn2 were unable to efficiently control
S. typhimurium or to withhold iron from the bacterium. Salmonella
lacking enterochelin overcame protection in Hfe -/- mice, as did
wildtype bacteria in Hfe -/- Lcn2 -/- double-knockout mice. Nairz et al.
(2009) concluded that loss of HFE confers host resistance to systemic
Salmonella infection by inducing the iron-capturing peptide LCN2,
thereby providing an evolutionary advantage that may account for the
high prevalence of genetic hemochromatosis.
HIST1H4C
| dbSNP name | rs2229768(T,C); rs198852(A,G); rs138617314(C,T) |
| ccdsGene name | CCDS4583.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8364 |
| EntrezGene Description | histone cluster 1, H4c |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H4C:NM_003542:exon1:c.T105C:p.I35I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.18 |
| ESP Afr MAF | 0.243985 |
| ESP All MAF | 0.226972 |
| ESP Eur/Amr MAF | 0.218256 |
| ExAC AF | 0.184 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602827 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER C; HIST1H4C
;;HISTONE GENE CLUSTER 1, H4C;;
HIST1 CLUSTER, H4C;;
H4 HISTONE FAMILY, MEMBER G; H4FG;;
H4/G
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4C genes. All mouse and human H4 genes, including
HIST1H4C, encode the same protein.
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/g.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4C.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H1T
| dbSNP name | rs198845(G,T); rs198844(C,G) |
| ccdsGene name | CCDS34349.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 3010 |
| EntrezGene Description | histone cluster 1, H1t |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H1T:NM_005323:exon1:c.C532A:p.Q178K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0032 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P22492 |
| dbNSFP Uniprot ID | H1T_HUMAN |
| dbNSFP KGp1 AF | 0.237179487179 |
| dbNSFP KGp1 Afr AF | 0.115853658537 |
| dbNSFP KGp1 Amr AF | 0.306629834254 |
| dbNSFP KGp1 Asn AF | 0.0996503496503 |
| dbNSFP KGp1 Eur AF | 0.38654353562 |
| dbSNP GMAF | 0.2369 |
| ESP Afr MAF | 0.164321 |
| ESP All MAF | 0.301322 |
| ESP Eur/Amr MAF | 0.371512 |
| ExAC AF | 0.331 |
OMIM Clinical Significance
INHERITANCE:
Multifactorial
SKELETAL:
[Pelvis];
Congenital hip dislocation;
Positive Ortolani sign
MISCELLANEOUS:
Preponderance of affected females (80%) to males;
Positive family history in 12-33% patients;
Incidence 1-1.5/1,000 live births
OMIM Title
*142712 HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, MEMBER T; HIST1H1T
;;HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, TESTIS-SPECIFIC MEMBER;;
HISTONE GENE CLUSTER 1, H1T;;
HIST1 CLUSTER, H1T;;
H1T;;
H1.T;;
H1 HISTONE, TESTIS-SPECIFIC;;
H1 HISTONE FAMILY, MEMBER T, FORMERLY; H1FT, FORMERLY
OMIM Description
For background information on histones, histone gene clusters, and the
H1 histone family, see HIST1H1A (142709).
CLONING
Drabent et al. (1991) studied the structure and expression of H1T, the
gene for testis-specific histone H1.
GENE FUNCTION
Deng et al. (1994) found that the rat H1t locus cosegregated with blood
pressure in an F2 population derived from a cross of the Dahl
salt-sensitive strain and the Lewis strain. Thus, H1t in rat is a
quantitative trait locus for blood pressure.
See HIST1H1A (142709) for additional functional information on H1
histones.
MAPPING
By study of somatic cell hybrids and by in situ hybridization, Albig et
al. (1993) demonstrated that the H1T gene is located in a cluster with 5
other H1 histone genes on chromosome 6p22.2-p21.1. By analysis of a YAC
contig, Albig et al. (1997) mapped the H1FT gene to chromosome 6p21.3
within a cluster of 35 histone genes, including H1.1 (HIST1H1A; 142709)
to H1.4 (HIST1H1E; 142220). The H1.5 gene (HIST1H1B; 142711) is part of
a separate subcluster within the same chromosomal region.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H1T.
Deng et al. (1994) reported that the rat testis-specific H1 histone gene
maps to chromosome 17,
HIST1H2BC
| dbSNP name | rs61742483(C,T) |
| ccdsGene name | CCDS4584.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8347 |
| EntrezGene Description | histone cluster 1, H2bc |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BC:NM_003526:exon1:c.G144A:p.Q48Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000681 |
| ESP All MAF | 0.000538 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.0005204 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602847 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER C; HIST1H2BC
;;HISTONE GENE CLUSTER 1, H2BC;;
HIST1 CLUSTER, H2BC;;
H2B HISTONE FAMILY, MEMBER L; H2BFL;;
H2B/L
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H2B/l.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BC.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H2AC
| dbSNP name | rs198819(C,T) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8334 |
| EntrezGene Description | histone cluster 1, H2ac |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3898 |
| ESP Afr MAF | 0.342488 |
| ESP All MAF | 0.468092 |
| ESP Eur/Amr MAF | 0.467558 |
| ExAC AF | 0.475 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602794 HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER C; HIST1H2AC
;;HISTONE GENE CLUSTER 1, H2AC;;
HIST1 CLUSTER, H2AC;;
H2A HISTONE FAMILY, MEMBER L; H2AFL;;
H2A/L
OMIM Description
For background information on histones, histone gene clusters, and the
H2A histone family, see HIST1H2AA (613499).
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes that included H2A/l.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2AC.
GENE FUNCTION
See HIST1H2AA (613499) for functional information on H2A histones.
HIST1H2BE
| dbSNP name | rs16891375(A,G); rs61978632(C,G); rs7766641(G,A) |
| ccdsGene name | CCDS4588.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8344 |
| EntrezGene Description | histone cluster 1, H2be |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BE:NM_003523:exon1:c.A18G:p.K6K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.05739 |
| ESP Afr MAF | 0.018611 |
| ESP All MAF | 0.065662 |
| ESP Eur/Amr MAF | 0.089767 |
| ExAC AF | 0.084 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602805 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER E; HIST1H2BE
;;HISTONE GENE CLUSTER 1, H2BE;;
HIST1 CLUSTER, H2BE;;
H2B HISTONE FAMILY, MEMBER H; H2BFH;;
H2B/H
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes that included H2B/h.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BE.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H2BF
| dbSNP name | rs41266807(A,G); rs1059486(A,G) |
| ccdsGene name | CCDS4592.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8343 |
| EntrezGene Description | histone cluster 1, H2bf |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BF:NM_003522:exon1:c.A36G:p.K12K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1492 |
| ESP Afr MAF | 0.197458 |
| ESP All MAF | 0.15885 |
| ESP Eur/Amr MAF | 0.13907 |
| ExAC AF | 0.157 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602804 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER F; HIST1H2BF
;;HISTONE GENE CLUSTER 1, H2BF;;
HIST1 CLUSTER, H2BF;;
H2B HISTONE FAMILY, MEMBER G; H2BFG;;
H2B/G
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes that included H2B/g.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BF.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H4E
| dbSNP name | rs143252055(G,A) |
| ccdsGene name | CCDS4593.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8367 |
| EntrezGene Description | histone cluster 1, H4e |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H4E:NM_003545:exon1:c.G273A:p.L91L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 1.627e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602830 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER E; HIST1H4E
;;HISTONE GENE CLUSTER 1, H4E;;
HIST1 CLUSTER, H4E;;
H4 HISTONE FAMILY, MEMBER J; H4FJ; H4/J
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
human HIST1H4E gene. All H4 genes, including HIST1H4E, encode the same
protein.
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/j.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4E.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H2BG
| dbSNP name | rs41266811(T,C) |
| ccdsGene name | CCDS4594.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8339 |
| EntrezGene Description | histone cluster 1, H2bg |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BG:NM_003518:exon1:c.A216G:p.E72E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.08448 |
| ESP Afr MAF | 0.126645 |
| ESP All MAF | 0.099493 |
| ESP Eur/Amr MAF | 0.085581 |
| ExAC AF | 0.094,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602798 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER G; HIST1H2BG
;;HISTONE GENE CLUSTER 1, H2BG;;
HIST1 CLUSTER, H2BG;;
H2B HISTONE FAMILY, MEMBER A; H2BFA;;
H2B/A;;
H2B.1A
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
CLONING
Albig et al. (1991) identified a gene encoding a member of the H2B class
of histones and designated it H2B.1A. Albig and Doenecke (1997)
designated this gene H2B/a.
MAPPING
By analysis of a YAC contig, Albig et al. (1997) mapped the H2B/a gene
to chromosome 6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BG.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H1D
| dbSNP name | rs16891458(A,C); rs149087080(G,C); rs2050950(A,G); rs200372842(G,A) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 3007 |
| EntrezGene Description | histone cluster 1, H1d |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05831 |
| ESP Afr MAF | 0.061584 |
| ESP All MAF | 0.050401 |
| ESP Eur/Amr MAF | 0.044714 |
| ExAC AF | 0.057 |
OMIM Clinical Significance
Heme:
Beta polypeptide hemoglobin chain;
Anemia;
Microcytosis;
Hypochromia;
Congenital dyserythropoietic anemia (Irish type);
Mild hemolytic anemia (e.g. Hb Extremadura 141900.0074);
Hemolytic microcytic anemia in compound heterozygosity with Hb C (e.g.
Hb Korle-bu 141900.0153);
Macrocytic hemolytic disease (e.g. Hb Redondo 141900.0404);
Erythrocytosis (e.g. Hb Brigham 141900.0028);
Congenital Heinz body anemia (e.g. Hb Bruxelles 141900.0033);
Sickle cell anemia (homozygous Hb SS 141900.0243);
Painful crises;
Aplastic crises;
Acute splenic sequestration;
Splenomegaly;
Dactylitis;
Ischemia;
Avascular necrosis;
Leg ulcers;
Cholelithiasis;
Priapism;
Osteonecrosis;
Osteomyelitis;
Drug-induced hemolysis (e.g. Hb Zurich 141900.0310) Methemoglobinemia
(e.g., HbM Saskatoon 141900.0165) Erythremia (e.g., Hb Osler 141900.0211)
Skin:
Jaundice;
Cyanosis (e.g. Hb M Saskatoon 141900.0165)
GI:
Cholelithiasis;
Splenomegaly (e.g. Hb Jacksonville 141900.0401);
Splenic syndrome (e.g. Hb S 141900.0243)
GU:
Hematuria (e.g. Hb Sarrebourg 141900.0435);
Urine concentrating defect (e.g. Hb S 141900.0243)
Misc:
Resistance to falciparum malaria (e.g. Hb S. 141900.0243);
Beta-delta fusion variant (e.g. Hb Lincoln Park 141900.0157);
Lab:
Abnormal red cell morphology;
Bone marrow erythroid hyperplasia;
Increased numbers of multinucleate red cell precursors;
Inclusion bodies in normoblasts;
Altered hemoglobin A(2) levels;
Altered hemoglobin F levels;
Unstable hemoglobin (e.g. Hb Koln 141900.0151);
Diminished oxygen affinity (e.g. Hb Chico 141900.0048);
Increased oxygen affinity (e.g. Hb Heathrow 141900.0102);
Increased N-terminal glycation (e.g. Hb Himeji 141900.0107);
Discrepant Hb A1c measurement (e.g. Hb Marseille 141900.0171);
Unusually low Hb A(1c) level (e.g. Hb Kodaira 141900.0409);
Red cell inclusion bodies (e.g. Hb Matera 141900.0173);
Red cell sickling (e.g. Hb S 141900.0243);
Non-Hb S red cell sickling (e.g. Hb C (Georgetown) 141900.0039);
Electrophoretic migration as Hb S (e.g. Hb Muskegon 141900.0432);
Increased red cell sickling tendency (e.g. Hb S (OMAN) 141900.0245)
Inheritance:
Autosomal dominant for some such as methemoglobinemia, polycythemia,
and Heinz body hemolytic anemia;
Autosomal recessive for others such as sickle cell disease and thalassemia
major
OMIM Title
*142210 HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, MEMBER D; HIST1H1D
;;HISTONE GENE CLUSTER 1, H1D;;
HIST1 ClUSTER, H1D;;
H1D;;
H1.3;;
H1 HISTONE FAMILY, MEMBER 3, FORMERLY; H1F3, FORMERLY
OMIM Description
For background information on histones, histone gene clusters, and the
H1 histone family, see HIST1H1A (142709).
CLONING
Albig et al. (1991) identified a gene encoding a member of the H1 class
of histones and designated it H1.3.
GENE FUNCTION
See HIST1H1A (142709) for functional information on H1 histones.
MAPPING
By in situ hybridization, Tanguay et al. (1987) mapped the histone H1.3
gene to chromosome 6p12-q21.
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic
cell hybrids and by fluorescence in situ hybridization, Albig et al.
(1993) demonstrated that 6 human H1 histone genes, including H1.3, are
located on chromosome 6p22.2-p21.1. By analysis of a YAC contig, Albig
et al. (1997) mapped the H1.3 gene to chromosome 6p21.3 within a cluster
of 35 histone genes, including H1.1 (HIST1H1A; 142709) to H1.4
(HIST1H1E; 142220) and H1T (HIST1H1T; 142712). The H1.5 gene (HIST1H1B;
142711) is part of a separate subcluster within the same chromosomal
region.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H1D.
HIST1H4F
| dbSNP name | rs16891477(C,T) |
| ccdsGene name | CCDS4598.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8361 |
| EntrezGene Description | histone cluster 1, H4f |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H4F:NM_003540:exon1:c.C99T:p.P33P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.05647 |
| ESP Afr MAF | 0.060372 |
| ESP All MAF | 0.049977 |
| ESP Eur/Amr MAF | 0.044651 |
| ExAC AF | 0.053 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602824 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER F; HIST1H4F
;;HISTONE GENE CLUSTER 1, H4F;;
HIST1 CLUSTER, H4F;;
H4 HISTONE FAMILY, MEMBER C; H4FC;;
H4/C
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
Albig et al. (1991) identified a gene encoding a member of the H4 class
of histones. Albig and Doenecke (1997) designated this gene H4/c.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4F genes. All mouse and human H4 genes, including
HIST1H4F, encode the same protein.
MAPPING
By analysis of a YAC contig, Albig et al. (1997) mapped the H4/c gene to
chromosome 6p21.3, within a cluster of 35 histone genes.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4F.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H4G
| dbSNP name | rs41266821(A,G) |
| ccdsGene name | CCDS4599.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8369 |
| EntrezGene Description | histone cluster 1, H4g |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H4G:NM_003547:exon1:c.T8C:p.V3A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0642 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q99525 |
| dbNSFP Uniprot ID | H4G_HUMAN |
| dbNSFP KGp1 AF | 0.081043956044 |
| dbNSFP KGp1 Afr AF | 0.0264227642276 |
| dbNSFP KGp1 Amr AF | 0.118784530387 |
| dbNSFP KGp1 Asn AF | 0.0262237762238 |
| dbNSFP KGp1 Eur AF | 0.139841688654 |
| dbSNP GMAF | 0.08127 |
| ESP Afr MAF | 0.049251 |
| ESP All MAF | 0.102799 |
| ESP Eur/Amr MAF | 0.130233 |
| ExAC AF | 0.114 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602832 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER G; HIST1H4G
;;HISTONE GENE CLUSTER 1, H4G;;
HIST1 CLUSTER, H4G;;
H4 HISTONE FAMILY, MEMBER L; H4FL;;
H4/L
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
human HIST1H4G gene. All H4 genes, including HIST1H4G, encode the same
protein.
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/l.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4G.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H2BH
| dbSNP name | rs139273319(G,C); rs374188201(C,T); rs61746493(C,T) |
| ccdsGene name | CCDS4601.1 |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8345 |
| EntrezGene Description | histone cluster 1, H2bh |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BH:NM_003524:exon1:c.G54C:p.A18A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.004993 |
| ESP All MAF | 0.001845 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 5.611e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602806 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER H; HIST1H2BH
;;HISTONE GENE CLUSTER 1, H2BH;;
HIST1 CLUSTER, H2BH;;
H2B HISTONE FAMILY, MEMBER J; H2BFJ;;
H2B/J
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes that included H2B/j.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BH.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H4H
| dbSNP name | rs41266829(C,T); rs2393592(A,G); rs2393593(T,C) |
| ccdsGene name | CCDS4604.1 |
| CosmicCodingMuts gene | HIST1H4H |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 8365 |
| EntrezGene Description | histone cluster 1, H4h |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H4H:NM_003543:exon1:c.G225A:p.E75E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1107 |
| ESP Afr MAF | 0.106219 |
| ESP All MAF | 0.135707 |
| ESP Eur/Amr MAF | 0.150814 |
| ExAC AF | 0.125 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602828 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER H; HIST1H4H
;;HISTONE GENE CLUSTER 1, H4H;;
HIST1 CLUSTER, H4H;;
H4 HISTONE FAMILY, MEMBER H; H4FH;;
H4/H
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4H genes. All mouse and human H4 genes, including
HIST1H4H, encode the same protein.
MAPPING
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997)
characterized a cluster of 35 histone genes, including H4/h.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4H.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HCG11
| dbSNP name | rs115643361(A,G); rs144425402(C,T); rs11962165(C,A); rs6910930(G,A); rs6911330(G,A); rs6910899(A,G); rs9461267(T,G); rs11963559(C,T); rs35355150(G,A); rs41267935(G,C); rs11754138(G,C); rs1056347(G,C) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 493812 |
| snpEff Gene Name | CTA-14H9.3 |
| EntrezGene Description | HLA complex group 11 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01745 |
LOC100270746
| dbSNP name | rs72838245(A,C); rs7751878(T,G); rs9379952(A,T) |
| cytoBand name | 6p22.2 |
| EntrezGene GeneID | 100270746 |
| snpEff Gene Name | NCRNA00240 |
| EntrezGene Description | uncharacterized LOC100270746 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09917 |
POM121L2
| dbSNP name | rs61736079(T,C); rs41269255(C,T); rs6456773(C,T); rs61736082(A,T); rs16897515(C,A); rs16897553(A,T); rs11965377(T,C) |
| ccdsGene name | CCDS59497.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 94026 |
| EntrezGene Description | POM121 transmembrane nucleoporin-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POM121L2:NM_033482:exon1:c.A3089G:p.H1030R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0289 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | C9J1I7 |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0447154471545 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.01194 |
| ExAC AF | 0.002503 |
VN1R10P
| dbSNP name | rs17739298(C,G) |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 387316 |
| EntrezGene Description | vomeronasal 1 receptor 10 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08219 |
| ESP Afr MAF | 0.034593 |
| ESP All MAF | 0.082804 |
| ESP Eur/Amr MAF | 0.104904 |
| ExAC AF | 0.105,1.635e-05 |
HIST1H3H
| dbSNP name | rs2021835(C,T) |
| ccdsGene name | CCDS4627.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 8357 |
| EntrezGene Description | histone cluster 1, H3h |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H3H:NM_003536:exon1:c.C246T:p.D82D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04775 |
| ESP Afr MAF | 0.070359 |
| ESP All MAF | 0.053975 |
| ESP Eur/Amr MAF | 0.045581 |
| ExAC AF | 0.042 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602818 HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER H; HIST1H3H
;;HISTONE GENE CLUSTER 1, H3H;;
HIST1 CLUSTER, H3H;;
H3 HISTONE FAMILY, MEMBER K; H3FK;;
H3/K
OMIM Description
For background information on histones, histone gene clusters, and the
H3 histone family, see HIST1H3A (602810).
CLONING
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H3H genes. They noted that all H3 genes in histone
gene cluster-1 (HIST1), including HIST1H3H, encode the same protein,
designated H3.1. H3.1 differs from H3.2, which is encoded by HIST2H3C
(142780), at only 1 residue, and from histone H3.3, which is encoded by
both H3F3A (601128) and H3F3B (601058), at a few residues.
MAPPING
By analysis of a YAC contig from chromosome 6p22-p21.3, Albig and
Doenecke (1997) characterized a second cluster of 16 histone genes,
including H3/k, located 2 Mb centromeric to the major histone gene
cluster.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called HIST1,
contains 55 histone genes, including HIST1H3H.
GENE FUNCTION
See HIST1H3A (602810) for functional information on H3.1 and the H3
histone family.
HIST1H2BM
| dbSNP name | rs148565959(G,A) |
| ccdsGene name | CCDS4629.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 8342 |
| EntrezGene Description | histone cluster 1, H2bm |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2BM:NM_003521:exon1:c.G141A:p.K47K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.001153 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.000244 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602802 HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER M; HIST1H2BM
;;HISTONE GENE CLUSTER 1, H2BM;;
HIST1 CLUSTER, H2BM;;
H2B HISTONE FAMILY, MEMBER E; H2BFE;;
H2B/E
OMIM Description
For background information on histones, histone gene clusters, and the
H2B histone family, see HIST1H2BA (609904).
MAPPING
By analysis of a YAC contig from chromosome 6p22-p21.3, Albig and
Doenecke (1997) characterized a second cluster of 16 histone genes,
including H2B/e, located 2 Mb centromeric to the major histone gene
cluster.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2BM.
GENE FUNCTION
See HIST1H2BA (609904) for functional information on H2B histones.
HIST1H4J
| dbSNP name | rs200499(C,T); rs200498(T,C) |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 8363 |
| EntrezGene Description | histone cluster 1, H4j |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06749 |
| ExAC AF | 0.936 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602826 HISTONE GENE CLUSTER 1, H4 HISTONE FAMILY, MEMBER J; HIST1H4J
;;HISTONE GENE CLUSTER 1, H4J;;
HIST1 CLUSTER, H4J;;
H4 HISTONE FAMILY, MEMBER E; H4FE;;
H4/E
OMIM Description
For background information on histones, histone gene clusters, and the
H4 histone family, see HIST1H4A (602822).
CLONING
Heintz et al. (1981) cloned a gene, called H4/e, encoding an H4 histone.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H4J genes. All mouse and human H4 genes, including
HIST1H4J, encode the same protein.
MAPPING
By analysis of a YAC contig from 6p22-p21.3, Albig and Doenecke (1997)
characterized a second cluster of 16 histone genes, including H4/e,
located 2 Mb centromeric to the major histone gene cluster.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4J.
GENE FUNCTION
See HIST1H4A (602822) for functional information on H4 histones.
HIST1H2AL
| dbSNP name | rs200981(A,G); rs11966705(C,T) |
| ccdsGene name | CCDS4634.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 8332 |
| EntrezGene Description | histone cluster 1, H2al |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H2AL:NM_003511:exon1:c.A42G:p.K14K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1194 |
| ESP Afr MAF | 0.188153 |
| ESP All MAF | 0.13686 |
| ESP Eur/Amr MAF | 0.110581 |
| ExAC AF | 0.104 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602793 HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER L; HIST1H2AL
;;HISTONE GENE CLUSTER 1, H2AL;;
HIST1 CLUSTER, H2AL;;
H2A HISTONE FAMILY, MEMBER I; H2AFI;;
H2A/I
OMIM Description
For background information on histones, histone gene clusters, and the
H2A histone family, see HIST1H2AA (613499).
CLONING
Albig et al. (1997) identified a gene encoding a member of the H2A class
of histones and designated it H2A/i.
MAPPING
By analysis of a YAC contig from chromosome 6p22-p21.3, Albig and
Doenecke (1997) characterized a second cluster of 16 histone genes,
including H2A/i, located 2 Mb centromeric to the major histone gene
cluster.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H2AL.
GENE FUNCTION
See HIST1H2AA (613499) for functional information on H2A histones.
HIST1H1B
| dbSNP name | rs11970638(T,C) |
| ccdsGene name | CCDS4635.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 3009 |
| EntrezGene Description | histone cluster 1, H1b |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H1B:NM_005322:exon1:c.A431G:p.K144R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0495 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P16401 |
| dbNSFP Uniprot ID | H15_HUMAN |
| dbNSFP KGp1 AF | 0.0279304029304 |
| dbNSFP KGp1 Afr AF | 0.0813008130081 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.00699300699301 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.02755 |
| ESP Afr MAF | 0.086246 |
| ESP All MAF | 0.033144 |
| ESP Eur/Amr MAF | 0.005932 |
| ExAC AF | 0.014 |
OMIM Clinical Significance
INHERITANCE:
Multifactorial
SKELETAL:
[Pelvis];
Congenital hip dislocation;
Positive Ortolani sign
MISCELLANEOUS:
Preponderance of affected females (80%) to males;
Positive family history in 12-33% patients;
Incidence 1-1.5/1,000 live births
OMIM Title
*142711 HISTONE GENE CLUSTER 1, H1 HISTONE FAMILY, MEMBER B; HIST1H1B
;;HISTONE GENE CLUSTER 1, H1B;;
HIST1 CLUSTER, H1B;;
H1B;;
H1.5;;
H1 HISTONE FAMILY, MEMBER 5, FORMERLY; H1F5, FORMERLY
OMIM Description
For background information on histones, histone gene clusters, and the
H1 histone family, see HIST1H1A (142709).
CLONING
Albig et al. (1997) isolated the gene for H1.5 histone.
GENE FUNCTION
By investigating MSX1 (142983) function in repression of myogenic gene
expression, Lee et al. (2004) identified a physical interaction between
MSX1 and H1B. Lee et al. (2004) found that MSX1 and H1B bind to a key
regulatory element of MYOD (159970), a central regulator of skeletal
muscle differentiation, where they induce repressed chromatin. Moreover,
MSX1 and H1B cooperated to inhibit muscle differentiation in cell
culture and in Xenopus animal caps. Lee et al. (2004) concluded that
their findings defined a theretofore unknown function for linker
histones in gene-specific transcriptional regulation.
See HIST1H1A (142709) for additional functional information on H1
histones.
MAPPING
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic
cell hybrids, Albig et al. (1993) found that 6 human H1 histone genes,
including H1.5, are located on chromosome 6. By fluorescence in situ
hybridization with human metaphase chromosomes and PCR analysis of
somatic cell hybrid DNAs carrying only fragments of chromosome 6, they
demonstrated that the histone genes are clustered in the 6p22.2-p21.1
region.
Albig et al. (1997) showed that there are 2 clusters of histone genes on
chromosome 6p. The H1.5 gene is located in the second cluster, about 2
Mb centromeric of the major cluster. In a contig of the histone
gene-containing cosmids from this region, Albig and Doenecke (1997)
found 1 H1 gene (H1.5), 5 H2A genes, 4 H2B genes, 1 H2B pseudogene, 3 H3
genes, 3 H4 genes, and 1 H4 pseudogene. The cluster extends about 80 kb
with a nonordered arrangement of the histone genes. The dinucleotide
repeat polymorphic marker D6S105 was localized at the telomeric end of
this histone gene cluster. Almost all human histone genes isolated to
that time had been localized within the 2 clusters on 6p or in a small
group of histone genes on chromosome 1.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called histone
gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H1B.
HIST1H3I
| dbSNP name | rs200956(T,C); rs148997555(G,A) |
| ccdsGene name | CCDS4636.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 8354 |
| EntrezGene Description | histone cluster 1, H3i |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HIST1H3I:NM_003533:exon1:c.A348G:p.K116K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2365 |
| ESP Afr MAF | 0.421244 |
| ESP All MAF | 0.250038 |
| ESP Eur/Amr MAF | 0.162326 |
| ExAC AF | 0.178 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Submandibular lymphadenopathy;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Histiocytic deposits in eyelids;
Eyelid infiltrates;
Orbital mass due to histiocytosis;
Exophthalmos;
Episcleritis;
[Nose];
Nasal mass due to histiocytosis;
[Mouth];
Retropharyngeal lymphadenopathy;
[Neck];
Cervical lymphadenopathy
CARDIOVASCULAR:
[Heart];
Atrial septal defect (rare);
Ventricular septal defect (rare);
Septal thickening (rare);
Mitral valve prolapse (rare);
Cardiomegaly (rare);
Bicommissural aortic valve (rare)
ABDOMEN:
[External features];
Inguinal lymphadenopathy, bilateral, extending across suprapubic area;
[Liver];
Hepatomegaly;
[Pancreas];
Diabetes mellitus, insulin-dependent;
Pancreatic exocrine deficiency;
Pancreatomegaly (rare);
Pancreatic hypoplasia, mild (rare);
[Spleen];
Splenomegaly
SKELETAL:
Intrauterine fractures of long bones and clavicles;
[Limbs];
Contractures of elbows;
[Hands];
Contractures of fingers;
Camptodactyly;
Clinodactyly;
[Feet];
Contractures of toes;
Hallux valgus
MUSCLE, SOFT TISSUE:
Retroperitoneal fibrosis (rare)
METABOLIC FEATURES:
Fever
ENDOCRINE FEATURES:
Diabetes mellitus, insulin-dependent;
Hypergonadotropic hypogonadism;
Hypogonadotropic hypogonadism (rare);
Growth hormone deficiency
HEMATOLOGY:
Nonclonal myeloproliferation
IMMUNOLOGY:
Hyperglobulinemia, polyclonal (in some patients);
Lymphadenopathy, generalized (in some patients)
LABORATORY ABNORMALITIES:
Elevated inflammatory markers
MISCELLANEOUS:
Very variable phenotype, with some patients having many features and
others only a few
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 29 (nucleoside transporter),
member 3 gene (SLC29A3, 612373.0001)
OMIM Title
*602814 HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER I; HIST1H3I
;;HISTONE GENE CLUSTER 1, H3I;;
HIST1 CLUSTER, H3I;;
H3 HISTONE FAMILY, MEMBER F; H3FF;;
H3/F
OMIM Description
For background information on histones, histone gene clusters, and the
H3 histone family, see HIST1H3A (602810).
CLONING
Albig et al. (1997) identified a gene, designated H3/f, encoding a
member of the H3 class of histones.
By genomic sequence analysis, Marzluff et al. (2002) identified the
mouse and human HIST1H3I genes. They noted that all H3 genes in histone
gene cluster-1 (HIST1), including HIST1H3I, encode the same protein,
designated H3.1. H3.1 differs from H3.2, which is encoded by HIST2H3C
(142780), at only 1 residue, and from histone H3.3, which is encoded by
both H3F3A (601128) and H3F3B (601058), at a few residues.
MAPPING
By analysis of a YAC contig from chromosome 6p22-p21.3, Albig and
Doenecke (1997) characterized a second cluster of 16 histone genes,
including H3/f, located 2 Mb centromeric to the major histone gene
cluster.
By genomic sequence analysis, Marzluff et al. (2002) determined that the
histone gene cluster on chromosome 6p22-p21, which they called HIST1,
contains 55 histone genes, including HIST1H3I.
GENE FUNCTION
See HIST1H3A (602810) for functional information on H3.1 and the H3
histone family.
OR2B2
| dbSNP name | rs73392698(G,A); rs9368537(C,G) |
| ccdsGene name | CCDS4641.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 81697 |
| EntrezGene Description | olfactory receptor, family 2, subfamily B, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2B2:NM_033057:exon1:c.C1005T:p.S335S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01561 |
| ESP Afr MAF | 0.051294 |
| ESP All MAF | 0.017761 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 0.005766 |
OR2B6
| dbSNP name | rs7767176(G,A); rs904142(T,C); rs9380030(A,G) |
| ccdsGene name | CCDS4642.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 26212 |
| EntrezGene Description | olfactory receptor, family 2, subfamily B, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2B6:NM_012367:exon1:c.G349A:p.V117I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0084 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P58173 |
| dbNSFP Uniprot ID | OR2B6_HUMAN |
| dbNSFP KGp1 AF | 0.0874542124542 |
| dbNSFP KGp1 Afr AF | 0.19918699187 |
| dbNSFP KGp1 Amr AF | 0.0966850828729 |
| dbNSFP KGp1 Asn AF | 0.013986013986 |
| dbNSFP KGp1 Eur AF | 0.065963060686 |
| dbSNP GMAF | 0.0877 |
| ESP Afr MAF | 0.158874 |
| ESP All MAF | 0.106583 |
| ESP Eur/Amr MAF | 0.079786 |
| ExAC AF | 0.08 |
TOB2P1
| dbSNP name | rs1150701(A,C); rs1150702(A,T); rs1150703(G,T); rs73400575(G,C); rs1150704(T,G); rs73400579(T,C); rs1233664(C,T); rs1736894(C,A) |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 222699 |
| EntrezGene Description | transducer of ERBB2, 2 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1465 |
NKAPL
| dbSNP name | rs61737338(C,T); rs12000(A,G); rs1635(C,A); rs3734564(G,A); rs1679709(A,G) |
| ccdsGene name | CCDS34353.1 |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 222698 |
| EntrezGene Description | NFKB activating protein-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NKAPL:NM_001007531:exon1:c.C68T:p.S23F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0228 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5M9Q1 |
| dbNSFP Uniprot ID | NKAPL_HUMAN |
| dbNSFP KGp1 AF | 0.0206043956044 |
| dbNSFP KGp1 Afr AF | 0.0792682926829 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.02066 |
| ESP Afr MAF | 0.063096 |
| ESP All MAF | 0.026065 |
| ESP Eur/Amr MAF | 0.007093 |
| ExAC AF | 0.011 |
ZSCAN12
| dbSNP name | rs7774788(T,C); rs7774981(T,C); rs7754960(G,C); rs7775132(T,C); rs141431207(T,C); rs73742555(C,T); rs1052215(T,G); rs2072318(A,G); rs16894038(T,C); rs2072319(T,C); rs2531825(C,T); rs3734563(A,G); rs3734562(A,G); rs1556957(A,G); rs2232440(G,T); rs2232439(C,G); rs2232438(A,C); rs1591913(C,T); rs3799500(C,G); rs7759191(A,C); rs2531826(C,A); rs3799499(G,T); rs7764722(C,T); rs17314224(T,C); rs74525464(C,T); rs77082598(G,T); rs9468364(T,A); rs9461458(C,T); rs9468365(A,T); rs2859379(C,T); rs1361385(A,G); rs1416918(G,C); rs2232434(T,C); rs2232432(A,G); rs2859348(A,G); rs2232428(C,T); rs2232427(T,G); rs9468366(T,C); rs9468367(C,A); rs73742558(T,G); rs17392982(C,T); rs77145427(A,C); rs145978013(A,G); rs9461459(T,C); rs56295386(C,T); rs28360638(C,T); rs16894060(T,C); rs57071502(G,A); rs2859359(A,G); rs111669150(C,T); rs75879046(C,T); rs79125776(C,T); rs17393066(A,G); rs9468368(G,A); rs2041230(T,C); rs2232422(G,A); rs1005125(G,A) |
| cytoBand name | 6p22.1 |
| EntrezGene GeneID | 9753 |
| EntrezGene Description | zinc finger and SCAN domain containing 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZSCAN12:NM_001163391:exon4:c.T994C:p.C332R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7901 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A8K187 |
| dbNSFP KGp1 AF | 0.00732600732601 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.010838 |
| ESP All MAF | 0.008541 |
| ESP Eur/Amr MAF | 0.007542 |
| ExAC AF | 0.003972 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Nephritis;
Membranous glomerulonephropathy
SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash;
Malar rash
HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia
IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of B cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells
LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Antiribonuclear protein positive;
Anti-SSB positive;
Anti-factor VIII positive
MISCELLANEOUS:
Onset in infancy or childhood
MOLECULAR BASIS:
Caused by mutations in the caspase 10 gene (CASP10, 601762.0001)
OMIM Title
*603978 ZINC FINGER- AND SCAN DOMAIN-CONTAINING PROTEIN 12; ZSCAN12
;;ZINC FINGER PROTEIN 96; ZFP96; ZNF96;;
KIAA0426
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Ishikawa et al. (1997) cloned ZSCAN12, which they called
KIAA0426. The transcript has an Alu repeat in its 3-prime UTR. The
deduced 604-amino acid protein shares significant homology with mouse
Zfp96. In vitro-translated ZSCAN12 had an apparent molecular mass of 81
kD by SDS-PAGE. RT-PCR detected low ZCAN12 expression in lung, thymus,
prostate, testis, and ovary, with little to no expression in all other
tissues examined.
MAPPING
By radiation hybrid analysis, Ishikawa et al. (1997) mapped the ZSCAN12
gene to chromosome 6.
NOMENCLATURE
ZSCAN12 has been referred to as ZFP96 or ZNF96 due to its homology with
mouse Zfp96; however, it is distinct from the ZNF96 gene on chromosome
19 reported by Bellefroid et al. (1993).
SCUBE3
| dbSNP name | rs1888822(T,G); rs3800388(C,T); rs57229653(C,T); rs3800387(G,A); rs1987673(G,A); rs3800386(G,A); rs138239764(G,A); rs9394282(G,C); rs144858965(G,A); rs9394283(A,T); rs1034450(C,T); rs79651640(C,T); rs3800385(G,T); rs1041528(T,A); rs7763946(G,A); rs9469964(G,A); rs763155(A,C); rs73407660(A,G); rs4713842(G,A); rs4711409(T,A); rs9469966(C,T); rs6938138(G,A); rs75378151(G,A); rs3800383(T,C); rs73407664(G,A); rs142191332(T,A); rs1929848(G,T); rs1013907(T,C); rs114716259(G,A); rs2395614(C,T); rs13214290(T,G); rs4713843(T,C); rs78199774(A,G); rs9469967(A,G); rs1929849(T,C); rs734538(G,A); rs144485993(C,A); rs73407670(C,A); rs9469969(T,C); rs35847323(C,G); rs73407675(G,A); rs3800382(T,A); rs9469972(C,T); rs58925593(T,G); rs16868695(C,T); rs2018373(G,C); rs16868699(G,C); rs4711411(A,G); rs9366882(A,T); rs2071920(C,T); rs191575296(T,C); rs182801333(G,T); rs41270062(C,T) |
| ccdsGene name | CCDS4800.1 |
| cytoBand name | 6p21.31 |
| EntrezGene GeneID | 222663 |
| EntrezGene Description | signal peptide, CUB domain, EGF-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SCUBE3:NM_152753:exon8:c.C949G:p.Q317E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5705 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IX30-2 |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.014072 |
| ESP All MAF | 0.005228 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.001927 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial muscle weakness;
[Ears];
Hearing loss, sensorineural;
Absent brainstem auditory-evoked responses;
[Eyes];
Absent pupillary reflex;
Optic atrophy;
Nystagmus;
Visual loss;
[Mouth];
Tongue fasciculations;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory insufficiency;
Sleep hypoventilation (rare)
ABDOMEN:
[Gastrointestinal];
Dysphagia (in some patients)
SKELETAL:
[Spine];
Scoliosis (in some patients);
Kyphoscoliosis (in some patients);
[Hands];
Claw hands
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal, distal, and axial, severe;
Upper limb muscle weakness may be more severe than lower limb weakness;
Hypotonia;
Muscle atrophy, diffuse, severe;
Neurogenic changes seen on EMG;
Fibrillations
NEUROLOGIC:
[Central nervous system];
Cranial nerve palsies;
Bulbar palsy;
Ataxia;
Loss of independent ambulation;
Decreased spontaneous movements;
Inability to hold head up;
Clumsiness;
Cognition is preserved;
[Peripheral nervous system];
Areflexia;
Axonal sensorimotor neuropathy;
Sural nerve biopsy shows loss of large myelinated fibers;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients)
LABORATORY ABNORMALITIES:
Abnormal acylcarnitine profiles;
Organic aciduria
MISCELLANEOUS:
Onset in first few years of life;
Progressive disorder;
Variable severity;
Early death from respiratory failure may occur;
Some patients show significant clinical improvement with riboflavin
supplementation
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 52 (riboflavin transporter),
member 2 gene (SLC52A2, 607882.0001)
OMIM Title
*614708 SIGNAL PEPTIDE-, CUB DOMAIN-, AND EGF-LIKE DOMAINS-CONTAINING PROTEIN
3; SCUBE3
OMIM Description
DESCRIPTION
Members of the SCUBE family, such as SCUBE3, are secreted, cell surface
glycoproteins with a characteristic structure that includes an
N-terminal signal peptide followed by multiple EGF (131530)-like repeats
and a C-terminal CUB domain. SCUBE3 is highly expressed in primary
osteoblasts and bone (Wu et al., 2004).
CLONING
By searching databases for sequences similar to SCUBE1 (611746) and
SCUBE2 (611747), followed by PCR of primary human osteoblasts, Wu et al.
(2004) cloned SCUBE3. The deduced 993-amino acid protein has an
N-terminal signal sequence, followed by 9 putative calcium-binding
EGF-like repeats, a spacer region, and a C-terminal CUB domain. The
spacer region contains 5 potential N-glycosylation sites. SCUBE3 was
predicted to be secreted as a mature 971-amino acid protein with a
calculated molecular mass of 107 kD. Wu et al. (2004) also identified
mouse Scube3, which shares over 96% amino acid identity with human
SCUBE3. Northern blot analysis detected an 8-kb SCUBE3 transcript that
was highly expressed in primary human osteoblasts. Lower expression of a
4-kb transcript was detected in umbilical vein endothelial cells, and
the 4-kb transcript was also weakly expressed in adult heart. SCUBE3 was
not detected in other adult human tissues. SCUBE3 was secreted from
transfected HEK293T cells. The secreted protein had an apparent
molecular mass of 130 kD, which was reduced to about 110 kD following
inhibition of N-glycosylation.
Wu et al. (2011) noted the presence of several cysteine-rich motifs
within the spacer region of SCUBE3 just prior to the CUB domain.
GENE FUNCTION
Using immunoprecipitation and Western blot analysis, Wu et al. (2004)
found that epitope-tagged SCUBE3 could form homooligomers and
heterooligomers with SCUBE1 following overexpression in HEK293T cells.
SCUBE3 also appeared to undergo limited proteolysis following secretion.
The processed protein had an apparent molecular mass of about 65 kD.
This form appeared to result from cleavage at a furin (FUR; 136950)-like
cleavage site in the spacer region of SCUBE3.
By EST database analysis, Wu et al. (2011) found that SCUBE3 was
overexpressed in lung tumors compared with normal lung. RT-PCR analysis
and histologic examination of lung tumors and adjacent normal tissues
confirmed the observation. In lung cancer cell lines, the degree of
SCUBE3 expression correlated positively with cell line invasiveness. The
C-terminal CUB domain of SCUBE3, which could be released from
full-length SCUBE3 by MMP2 (120360) and MMP9 (120361) in vitro, bound to
TGF type II receptor (TGFBR2; 190182), activated TGF-beta-1 (TGFB1;
190180)-like signaling, induced SMAD2 (601366)/SMAD3 (603109)
phosphorylation and transcriptional activity, and caused
epithelial-mesenchymal transition in transfected cells. Cotreatment with
TGF-beta-1 and the SCUBE3 CUB domain enhanced expression of a
SMAD2/SMAD3 reporter, suggesting that SCUBE3 and TGF-beta-1 do not
compete for receptor binding. Knockdown of SCUBE3 expression suppressed
cancer cell migration and invasiveness in lung tumor cell lines in
culture and suppressed tumorigenesis and cancer metastasis following
injection into nude mice.
MAPPING
By genomic sequence analysis, Wu et al. (2004) mapped the SCUBE3 gene to
chromosome 6p21.3. They mapped the mouse Scube3 gene to a region of
chromosome 17B that shares homology of synteny with human chromosome
6p21.3.
KCTD20
| dbSNP name | rs11757842(T,C); rs16888552(C,T); rs12209346(A,G); rs6457918(A,T); rs6917981(T,C); rs9462185(C,T); rs9462186(C,T); rs9368932(T,C); rs12663476(G,A); rs143457009(A,G); rs4711452(C,T); rs78373049(C,A); rs79133352(G,A); rs6905573(T,C); rs73411054(T,C); rs73411055(G,A); rs6926522(A,G); rs6899421(C,T); rs58093537(G,A); rs7744363(A,C); rs114588005(C,G); rs9357214(A,G); rs76019396(A,G); rs142796878(C,T); rs9470285(C,T); rs9767778(T,C); rs9767243(G,T); rs6923993(C,T); rs6930496(G,A); rs7752714(T,A); rs7771028(A,G); rs6936942(A,G); rs9348997(A,G); rs6457920(A,G); rs6905347(G,C); rs6905686(C,A); rs77660021(A,G); rs10947607(A,T); rs10947608(A,G); rs12214285(C,T); rs1570368(C,G); rs78422813(C,T); rs1003250(T,C); rs1003249(A,T); rs941973(G,T); rs4711453(A,G); rs6457921(G,C); rs6457922(T,C); rs9296184(T,C); rs2239808(G,C); rs2239807(A,G); rs853881(G,C); rs6902473(G,T); rs3756912(C,T); rs3756911(T,A); rs6913693(A,G); rs853882(T,C); rs853883(T,C); rs6899631(T,C); rs9470291(G,A); rs56086408(C,T); rs138823036(T,G); rs57389119(T,C); rs662384(A,G); rs2071811(A,T); rs2071810(A,G); rs41272166(C,T); rs584196(G,C); rs2146333(C,A); rs1191(C,T); rs1061632(T,C); rs146829680(G,A); rs113707520(A,G); rs1137628(C,T); rs138941886(G,C) |
| ccdsGene name | CCDS4821.1 |
| cytoBand name | 6p21.31 |
| EntrezGene GeneID | 222658 |
| EntrezGene Description | potassium channel tetramerization domain containing 20 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCTD20:NM_173562:exon4:c.G512C:p.S171T,KCTD20:NM_001286580:exon3:c.G77C:p.S26T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9043 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7Z5Y7 |
| dbNSFP Uniprot ID | KCD20_HUMAN |
| dbNSFP KGp1 AF | 0.317765567766 |
| dbNSFP KGp1 Afr AF | 0.489837398374 |
| dbNSFP KGp1 Amr AF | 0.185082872928 |
| dbNSFP KGp1 Asn AF | 0.388111888112 |
| dbNSFP KGp1 Eur AF | 0.21635883905 |
| dbSNP GMAF | 0.3182 |
| ESP Afr MAF | 0.411257 |
| ESP All MAF | 0.266569 |
| ESP Eur/Amr MAF | 0.192442 |
| ExAC AF | 0.237 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Poor linear growth
HEAD AND NECK:
[Head];
Microcephaly, postnatal (up to -6.4 SD);
[Face];
Prominent forehead;
Well-grooved philtrum;
Retrognathia;
[Eyes];
Deep-set eyes;
Blindness, postretinal
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux
GENITOURINARY:
[External genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis;
Vesicoureteral reflux;
[Bladder];
Neurogenic bladder
SKELETAL:
[Pelvis];
Hip dislocation
NEUROLOGIC:
[Central nervous system];
Global developmental delay, severe;
Seizures;
Spasticity;
Abnormal hypothalamo-pituitary axis;
Absent posterior pituitary bright spot;
Thin pituitary stalk;
Hypoplastic anterior pituitary gland;
Thin corpus callosum;
Frontotemporal hypoplasia;
Delayed myelination
ENDOCRINE FEATURES:
Pituitary insufficiency;
Hypothalamic insufficiency;
Growth hormone deficiency;
Adrenocorticotropin deficiency;
Cortisol insufficiency;
Thyroid stimulating hormone deficiency;
Hypernatremia;
Diabetes insipidus;
Hypothyroidism, central
LABORATORY ABNORMALITIES:
Hypernatremia
MISCELLANEOUS:
Onset soon after birth;
One consanguineous Saudi Arabian family has been reported (last curated
August 2014)
MOLECULAR BASIS:
Caused by mutation in the aryl hydrocarbon receptor nuclear translocator-2
gene (ARNT2, 606036.0001)
OMIM Title
*615932 POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 20; KCTD20
OMIM Description
DESCRIPTION
KCTD20 is predicted to promote cell survival (Nawa and Matsuoka, 2013).
CLONING
Using PCR, Nawa and Matsuoka (2013) cloned KCTD20 from a testis cDNA
library. The deduced 419-amino acid protein shares 81.4% and 94%
similarity with human BTBD10 (615933) and mouse Kctd20, respectively.
Western blot analysis detected mouse Kctd20 in all tissues examined
except spleen. Immunohistochemical analysis of COS-7 cells detected
Kctd20 and Btbd10 colocalized in filamentous structures.
GENE FUNCTION
AKT1 (164730), AKT2 (164731), and AKT3 (611223) promote cell survival.
BTBD10 activates AKT by binding to AKT and the catalytic subunit of PP2A
(PPP2CA; 176915), inhibiting PP2A-mediated AKT dephosphorylation. Nawa
and Matsuoka (2013) found that, like BTBD10, KCTD20 coprecipitated with
epitope-tagged AKT1, AKT2, and AKT3 from transfected COS-7 cells. KCTD20
also coprecipitated with the catalytic subunits of PP1A (PPM1A; 606108)
and PP2A. Overexpression of either BTBD10 or KCTD20 in NSC34 mouse motor
neuronal cells increased threonine phosphorylation of AKT.
MAPPING
Nawa and Matsuoka (2013) reported that the KCTD20 gene maps to
chromosome 6.
Hartz (2014) mapped the KCTD20 gene to chromosome 6p21.31 based on an
alignment of the KCTD20 sequence (GenBank GENBANK BC023525) with the
genomic sequence (GRCh38).
PANDAR
| dbSNP name | rs12199346(C,A); rs73412212(T,C); rs1977172(A,C); rs1010424(C,T); rs1010423(G,C); rs4711458(T,C); rs4711459(T,C); rs4711460(C,A); rs4711461(C,T); rs4711462(A,G); rs4714003(C,T); rs10947622(C,T); rs12214686(A,G); rs10947623(G,A) |
| cytoBand name | 6p21.2 |
| EntrezGene GeneID | 389386 |
| EntrezGene Symbol | LAP3P2 |
| snpEff Gene Name | PI16 |
| EntrezGene Description | leucine aminopeptidase 3 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1901 |
TBCC
| dbSNP name | rs116223301(G,A); rs150901240(C,G) |
| cytoBand name | 6p21.1 |
| EntrezGene GeneID | 6903 |
| EntrezGene Description | tubulin folding cofactor C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
CRIP3
| dbSNP name | rs2242416(A,G) |
| ccdsGene name | CCDS4894.2 |
| cytoBand name | 6p21.1 |
| EntrezGene GeneID | 401262 |
| EntrezGene Description | cysteine-rich protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CRIP3:NM_206922:exon8:c.T563C:p.I188T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.4277 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6Q6R5-3 |
| dbNSFP KGp1 AF | 0.457875457875 |
| dbNSFP KGp1 Afr AF | 0.0609756097561 |
| dbNSFP KGp1 Amr AF | 0.433701657459 |
| dbNSFP KGp1 Asn AF | 0.648601398601 |
| dbNSFP KGp1 Eur AF | 0.583113456464 |
| dbSNP GMAF | 0.4573 |
| ESP Afr MAF | 0.160592 |
| ESP All MAF | 0.441911 |
| ESP Eur/Amr MAF | 0.414319 |
| ExAC AF | 0.532 |
MIR4642
| dbSNP name | rs67182313(A,G) |
| ccdsGene name | CCDS4912.1 |
| cytoBand name | 6p21.1 |
| EntrezGene GeneID | 100616352 |
| snpEff Gene Name | CDC5L |
| EntrezGene Description | microRNA 4642 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4302 |
| ExAC AF | 0.077 |
MUT
| dbSNP name | rs9381784(C,T); rs11757098(T,C); rs9367355(G,A); rs79527231(C,G); rs62411929(T,C); rs76821511(T,C); rs9463480(G,T); rs79114016(T,A); rs12214609(T,C); rs150626922(A,G); rs180952069(A,G); rs6941276(T,A); rs4458686(T,C); rs9463483(T,A); rs7744595(G,C); rs6458690(A,G); rs74987455(G,A); rs76804522(G,T); rs9381786(T,G); rs1141321(C,T); rs57912929(A,G); rs9296616(T,G); rs4715129(C,T); rs2229385(C,T); rs13194103(C,A); rs4715130(T,C); rs12190697(T,C); rs142031291(G,A); rs6908203(T,C); rs6458692(C,T); rs6909128(T,G); rs6458693(T,G); rs7769646(G,A); rs192976390(T,A); rs9369901(G,A); rs77005759(G,T); rs9473559(T,A); rs72855809(T,C); rs12202075(A,G); rs9473560(A,G); rs9296617(G,C); rs75916297(T,G); rs9473561(G,A); rs4715131(C,T); rs34272273(C,T); rs7750918(C,G) |
| ccdsGene name | CCDS4924.1 |
| cytoBand name | 6p12.3 |
| EntrezGene GeneID | 4594 |
| EntrezGene Description | methylmalonyl CoA mutase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MUT:NM_000255:exon9:c.G1595A:p.R532H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8614 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P22033 |
| dbNSFP Uniprot ID | MUTA_HUMAN |
| dbNSFP KGp1 AF | 0.262362637363 |
| dbNSFP KGp1 Afr AF | 0.191056910569 |
| dbNSFP KGp1 Amr AF | 0.229281767956 |
| dbNSFP KGp1 Asn AF | 0.195804195804 |
| dbNSFP KGp1 Eur AF | 0.374670184697 |
| dbSNP GMAF | 0.2622 |
| ESP Afr MAF | 0.210849 |
| ESP All MAF | 0.313471 |
| ESP Eur/Amr MAF | 0.366047 |
| ExAC AF | 0.322 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly (in some patients);
[Ears];
Deafness (in some patients);
[Eyes];
Optic atrophy;
Loss of vision;
Decreased eye contact;
Eye deviation;
Cortical visual impairment
ABDOMEN:
[Gastrointestinal];
Poor feeding;
Vomiting
SKIN, NAILS, HAIR:
[Skin];
Dyspigmentation;
Hyperpigmented 2 to 5-mm macules mainly on the extremities;
De- or hypo-pigmented macules (less common)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Seizures (may be difficult to control);
Generalized clonic-tonic seizures;
Status epilepticus;
Tonic spasms;
Startle myoclonus;
Multifocal epileptiform discharges on diffuse slow background;
Developmental stagnation at onset of seizures;
Developmental regression;
Hypotonia;
Inability to sit unsupported;
Inability to reach;
No speech or language development;
Non-purposeful arm movements, choreoathetoid-like;
Diffuse brain atrophy;
[Peripheral nervous system];
Hyporeflexia in the upper limbs;
Hyperreflexia in the lower limbs;
[Behavioral/psychiatric manifestations];
Irritability
MISCELLANEOUS:
Onset in early infancy, between 2 weeks and 3 months;
Old Order Amish, African American, and French patients have been described;
Hyperpigmented skin macules appear after age 3 years and increase
in frequency with age
MOLECULAR BASIS:
Caused by mutation in the sialyltransferase-9 gene (SIAT9, 604402.0001)
OMIM Title
*609058 METHYLMALONYL-CoA MUTASE; MUT
;;MCM;;
METHYLMALONYL-CoA ISOMERASE
OMIM Description
DESCRIPTION
Methylmalonyl-CoA mutase (MUT) (EC 5.4.99.2) is a mitochondrial enzyme
that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA.
MUT activity requires 5-prime-deoxyadenosylcobalamin (AdoCbl), a
coenzyme form of vitamin B12.
CLONING
By screening human placenta and liver cDNA libraries with an anti-MCM
antibody, Ledley et al. (1988) isolated a partial MUT cDNA.
Jansen et al. (1989) isolated a full-length cDNA corresponding to the
MUT gene from a human liver cDNA library. The deduced 742-amino acid
protein has a molecular mass of 82.2 kD; the mature protein is 78.5 kD.
The mitochondrial leader sequence comprises 32 amino acids.
GENE STRUCTURE
Nham et al. (1990) determined that the MUT gene contains 13 exons
spanning more than 35 kb.
MAPPING
Ledley et al. (1987) assigned the methylmalonyl-CoA mutase locus to
chromosome 6p by use of a full-length MCM cDNA clone from a human liver
cDNA library. By Southern blot analysis of DNA from human-hamster
somatic cell hybrid cell lines, Ledley et al. (1988) assigned the MUT
locus to 6p23-q12. By in situ hybridization, the locus was further
localized to 6p21.2-p12. A highly informative RFLP was identified at the
MCM gene locus.
By deletion mapping in cell lines with 6p deletions, Zoghbi et al.
(1988) demonstrated that the MUT gene is located on 6p, proximal to GLO1
(138750). By use of a HindIII polymorphism identified by the MUT cDNA,
they demonstrated the linkage relationships to HLA in reference CEPH
families; the maximum lod score for MUT versus HLA was 3.04 at a
recombination fraction of 0.28. Blanche et al. (1991) presented a
genetic map of 6p which included RFLP mapping of the MUT locus.
By a study of recombinant inbred and congenic strains, Sertic et al.
(1990) demonstrated that the mouse equivalent of the MUT gene is located
on chromosome 17. Threadgill et al. (1990) assigned the gene to mouse
chromosome 17 by in situ hybridization.
MOLECULAR GENETICS
Ledley et al. (1990) could demonstrate no gross abnormalities of the MCM
gene by Southern blot analysis in cell lines from patients with
methylmalonic acidemia (MMA; see 251000). By other methods, however,
they concluded that there are several independent alleles giving
different levels of mRNA expression and biochemical phenotype of the
cultured cells. The studies provided a molecular explanation for the
wide phenotypic spectrum observed in the disorder.
In a patient with MMA mut(0), defined as having no residual enzyme
activity, Jansen and Ledley (1990) identified compound heterozygosity
for 2 mutations in the MUT gene (609058.0001 and 609058.0002).
In a patient with MMA mut(-), defined as having some residual enzyme
activity, who had been reported by Ledley et al. (1990), Crane et al.
(1992) identified a homozygous mutation in the MUT gene (609058.0005).
Crane and Ledley (1994) identified 4 novel mutations clustered near the
C terminus of the MUT protein in patients with MMA. Three of the
patients responded to cobalamin therapy. Each mutation showed
interallelic complementation in cotransfection assays with clones
bearing an R93H mutation (609058.0004). The findings suggested that the
C-terminal region of the protein represents a cobalamin-binding domain.
The location of this domain, as well as a pattern of sequence
preservation between the homologous human and Propionobacterium
shermanii enzymes, suggested a mechanism for interallelic
complementation in which the cobalamin-binding defect is complemented in
trans from the heterologous subunits of the dimer.
Drennan et al. (1996) made deductions concerning the molecular basis for
dysfunction of some mutant forms of MCM by aligning the sequence of this
gene with that of other B12-dependent enzymes, including the C-terminal
portion of the cobalamin-binding region of methionine synthase (156570)
from E. coli, the structure of which had been determined by x-ray
crystallography. Previously identified mutants such as gly623-to-arg
(609058.0008) were predicted to interfere with the structure and/or
stability of the loop that carries histidine-627, the presumed lower
axial ligand to the cobalt of adenosylcobalamin. A mutant such as
gly703-to-arg (609058.0009), which maps to the binding site for the
dimethylbenzimidazole nucleotide substituent of adenosylcobalamin, was
predicted to block the binding of adenosylcobalamin because of the
substitution of a large amino acid side chain for glycine.
Janata et al. (1997) identified 6 missense mutations producing amino
acid changes in MUT cDNA from patients with mut(-) MMA. Two of the
mutations had been reported in other patients. In 1 cell line, which the
authors referred to as doubly heterozygous (compound heterozygous is the
correct description), expression studies indicated that neither of the
constituent mutant enzymes had a Km corresponding to the lower of the 2
estimated from the extract data. The finding was thought to reflect the
natural occurrence of interallelic complementation in vivo in this cell
line.
Adjalla et al. (1998) identified 7 novel mutations in mut methylmalonic
aciduria and noted that 23 mutations had previously been identified.
Acquaviva et al. (2001) reported a novel MUT missense mutation, asn219
to tyr (N219Y; 609058.0010), in 5 unrelated families of French and
Turkish descent from a population of 19 patients with MCM apoenzyme
deficiency. All the patients exhibited a severe mut(0) methylmalonic
acidemia phenotype, and 3 of them were homozygous for the N219Y
mutation. The findings represented the first frequent MUT mutation
reported in the Caucasian population.
Acquaviva et al. (2005) analyzed a cohort of 40 MCM-deficient patients
with MMA affected by either the mut(0) or mut(-) form of the disease. By
direct sequencing of cDNA and genomic DNA of the MUT gene, they detected
42 mutations, 29 of which were novel. These included 5 frameshift
mutations (insertion, deletion, or duplication of a single nucleotide),
5 sequence modifications in consensus splice sites, 6 nonsense and 12
missense mutations, and a large genomic deletion including exon 12. They
explored how the 12 novel missense mutations might cause the observed
phenotype by mapping them onto a 3-dimensional model of the human MCM
generated by homology with the enzyme in P. shermanii. Acquaviva et al.
(2005) increased the number of mutations in the MUT gene to 84 and
discussed their prevalence and distribution throughout the coding
sequence in relation to enzyme structure. The authors noted that most of
the mutations in the MUT gene are private, with no demonstrated
hotspots. Prior to their study only 2 recurrent mutations had been
described: glu 117 to ter (E117X; 609058.0006) and N219Y, which had high
frequencies in Japanese and Caucasian populations, respectively.
Acquaviva et al. (2005) confirmed a high frequency of N219Y in
Caucasians: 12 of their 40 patients carried the mutation in a
heterozygous or homozygous state, which represented 19% of the alleles
tested.
Worgan et al. (2006) sequenced the MUT gene in 160 patients with mut
MMA. Mutations were identified in 96% of disease alleles. Mutations were
distributed through all coding exons, but predominantly in exons 2, 3,
6, and 11. A total of 116 different mutations, 68 of which were novel,
were identified; 53% were missense mutations, 22% deletions,
duplications or insertions, 16% were nonsense mutations, and 9% were
splice site mutations. Sixty-one of the mutations were identified in
only 1 family. A novel mutation in exon 2, R108C (609058.0011), was
identified in 16 of 27 Hispanic patients. SNP genotyping data
demonstrated that Hispanic patients with this mutation shared a common
haplotype. Three other mutations were seen exclusively in Hispanic
patients. Seven mutations were seen almost exclusively in black
patients, including the G717V mutation (609058.0005), which was
identified in 12 of 29 black patients. Two mutations were seen only in
Asian patients. Some frequently identified mutations were not
population-specific and were identified in patients of various ethnic
backgrounds. Some of these mutations were found in mutation clusters in
exons 2, 3, 6, and 11, suggesting that they represented recurrent
mutations.
Rincon et al. (2007) described 3 genomic alterations--1 in the MUT gene,
1 in the PCCA gene (232000), and 1 in the PCCB gene (232050)--that were
responsible for aberrant insertion of intronic sequences in patients'
mRNA. The authors targeted the aberrant intronic pseudoexons with
antisense morpholino oligonucleotides (AMOs) that prevented aberrant
splicing, thus generating normal mRNA which was translated into
functional protein, achieving therapeutic correction of the defect in
methylmalonic acidemia (251000) or propionic acidemia (606054). No
effect on MCM activity was obtained after AMO treatment in cell lines
bearing different mutations and exhibiting some levels of intronic MUT
insertions. Rincon et al. (2007) suggested that this therapeutic
strategy would be potentially applicable to a large number of cases with
deep intronic changes that remained undetected by standard
mutation-detection techniques at that time. The major issues facing
clinical applications of morpholino analogs of oligonucleotides
concerned safe delivery and optimal dose determination for each tissue
involved. Efficient and nontoxic delivery of AMO to the liver, which
would be the target tissue in this disorder, was one major challenge to
be overcome before the practical use of AMO in patients with
methylmalonic acidemia could be envisaged. In Duchenne muscular
dystrophy (310200), antisense oligonucleotides have been administered
intravenously, achieving splicing modulation to restore the coding frame
for dystrophin (Takeshima et al., 2006). The efficacy of antisense
therapeutics for splicing correction must be determined in each disease
model and for each deleterious splicing event.
C6orf141
| dbSNP name | rs6919674(C,G); rs142958452(A,C) |
| ccdsGene name | CCDS55018.1 |
| cytoBand name | 6p12.3 |
| EntrezGene GeneID | 135398 |
| EntrezGene Description | chromosome 6 open reading frame 141 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C6orf141:NM_001145652:exon1:c.C409G:p.Q137E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0051 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5SZD1 |
| dbNSFP Uniprot ID | CF141_HUMAN |
| dbNSFP KGp1 AF | 0.984432234432 |
| dbNSFP KGp1 Afr AF | 0.934959349593 |
| dbNSFP KGp1 Amr AF | 0.994475138122 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.01561 |
| ESP Afr MAF | 0.052023 |
| ESP All MAF | 0.016207 |
| ESP Eur/Amr MAF | 0.000629 |
| ExAC AF | 0.991 |
PGK2
| dbSNP name | rs28372930(G,C) |
| cytoBand name | 6p12.3 |
| EntrezGene GeneID | 5232 |
| EntrezGene Description | phosphoglycerate kinase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2287 |
OMIM Clinical Significance
Heme:
Hemolytic anemia
Misc:
Interaction of 6PGL deficiency with G6PD variant
Lab:
6-Phosphogluconolactonase deficiency
Inheritance:
Autosomal dominant
OMIM Title
*172270 PHOSPHOGLYCERATE KINASE 2; PGK2
;;PHOSPHOGLYCERATE KINASE OF SPERMATOZOA; PGKB;;
PGK, TESTICULAR
OMIM Description
DESCRIPTION
The PGK2 gene encodes a testis-specific form of phosphoglycerate kinase
(EC 2.7.2.3), which catalyzes the reversible conversion of
1,3-diphosphoglycerate to 3-phosphoglycerate during glycolysis,
generating one molecule of ATP.
See also PGK1 (311800), which is ubiquitously expressed in all somatic
tissues and maps to chromosome Xq13.
CLONING
Chen et al. (1976) identified a form of phosphoglycerate kinase unique
to spermatozoa, PGK2, which was immunologically and electrophoretically
distinct from erythrocyte PGK1.
McCarrey and Thomas (1987) isolated a cDNA clone corresponding to the
human testis-specific PGK gene. The deduced 417-residue protein showed
87% amino acid identity to PGK1.
GENE STRUCTURE
McCarrey and Thomas (1987) found that the PGK2 gene lacks introns and
contains characteristics of a processed gene, or 'retroposon,' including
the remnants of a poly(A) tail and bounding direct repeats. The
structural features were consistent with the notion that this locus
arose by reverse transcriptase-mediated processing of a tailored mRNA
transcript originally produced by the PGK1 gene. McCarrey and Thomas
(1987) concluded that the unusual conservation of function in this
processed PGK2 gene and its tissue-specific expression in
spermatogenesis may be best explained as a compensatory response to the
inactivation of the X-linked PGK1 gene in spermatogenic cells before
meiosis.
McCarrey (1990) studied further the evolution of the functional,
intronless PGK2 gene as well as the intronless PGK1 pseudogene, both of
which are retroposons of the intron-containing PGK1 gene.
MAPPING
Szabo et al. (1984) used a human cDNA probe of PGK1 (Singer-Sam et al.,
1983) to isolate a sequence subclone of the autosomal locus for PGK.
Somatic cell hybridization studies mapped the PGK2 gene to chromosome
6p23-q12. The authors concluded that this gene, located in the same
chromosome segment as HLA, was the human homolog of mouse Pgk2.
Michelson et al. (1985) mapped the human PGK2 gene to 6p21.1-p12,
proximal to the major histocompatibility complex (MHC), by use of a
panel of human-rodent somatic cell hybrids and by chromosomal in situ
hybridization.
In the mouse, testicular PGK is autosomal (VandeBerg et al., 1973).
Eicher et al. (1978) found that testis-specific mouse Pgk was closely
linked to the MHC on chromosome 17. They termed the locus Pgk2. The
kangaroo and the owl monkey show location of PGK2 on the chromosome
homologous to human chromosome 6 (Michelson et al., 1985).
HISTORY
Several early reports indicated that the functional testis-specific PGK2
gene was located on chromosome 19 and that the locus on chromosome 6 was
a pseudogene (Tani et al., 1985; Gartler et al., 1985, 1986; Willard et
al., 1985); it was later determined, however, that the functional PGK2
gene is in fact on chromosome 6p (Szabo et al., 1984). A PGK pseudogene
(PGK1P2, see 311800) maps to chromosome 19.
ANIMAL MODEL
Silver et al. (1983) showed that, in the mouse, allelic variants of the
T complex protein TCP2 (products of the Pgk2 locus) are distributed
nonrandomly among a series of T haplotypes.
GSTA7P
| dbSNP name | rs2144694(T,C); rs75087143(A,G); rs2180313(T,C); rs2224198(A,G); rs2207948(A,G); rs76329797(G,T); rs73742651(C,T); rs73742652(G,A); rs114455352(A,C); rs7739288(A,T); rs75249378(A,G); rs2608615(C,T); rs7751564(G,A); rs2748998(T,C) |
| cytoBand name | 6p12.2 |
| EntrezGene GeneID | 730152 |
| EntrezGene Description | glutathione S-transferase alpha 7, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2126 |
MTRNR2L9
| dbSNP name | rs2344448(C,T); rs6928630(T,G); rs6915206(C,T); rs6929218(T,C) |
| cytoBand name | 6q11.1 |
| EntrezGene GeneID | 100463487 |
| EntrezGene Description | MT-RNR2-like 9 (pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1804 |
SLC25A51P1
| dbSNP name | rs181524637(A,C) |
| cytoBand name | 6q12 |
| EntrezGene GeneID | 442229 |
| snpEff Gene Name | RP11-707M13.1 |
| EntrezGene Description | solute carrier family 25, member 51 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
COL19A1
| dbSNP name | rs6935768(T,C); rs2298017(G,A); rs73749313(A,C); rs202071917(G,A); rs75370197(A,C); rs1572898(C,T); rs60306811(A,G); rs2487432(A,G); rs34791579(A,C); rs75221174(G,C); rs78590943(G,A); rs13219994(T,G); rs6914372(C,T); rs2487433(A,G); rs2487434(T,G); rs34516452(A,G); rs73749317(C,T); rs2153606(G,A); rs34347922(G,A); rs77272118(C,T); rs2487435(A,G); rs80179037(A,G); rs2487436(G,A); rs190062732(C,G); rs142396545(G,C); rs62420119(G,A); rs11752293(A,G); rs7766395(G,A); rs4492160(T,A); rs113713450(G,A); rs2248317(G,A); rs2251206(C,T); rs2487437(A,C); rs13217925(G,T); rs10498870(G,A); rs1934897(T,C); rs2487438(G,T); rs2502552(C,T); rs2502551(A,C); rs12208896(G,T); rs146627676(A,G); rs2502550(T,A); rs6919210(G,C); rs13194248(T,A); rs2487439(A,G); rs12201139(G,A); rs146988472(C,T); rs73749319(A,G); rs12189777(C,T); rs1340975(A,T); rs7750029(C,A); rs13200171(C,T); rs58323230(G,C); rs2502562(G,A); rs117913500(G,A); rs2502561(T,A); rs2502560(A,C); rs58145130(T,A); rs3805956(A,C); rs7756266(T,A); rs7757078(T,C); rs7770597(G,A); rs10755538(C,T); rs2502549(T,C); rs2502545(G,A); rs60433653(T,A); rs2487440(C,T); rs12191461(G,A); rs6905176(G,A); rs113737055(A,T); rs115209673(C,T); rs2096058(A,T); rs145031731(A,C); rs60536675(T,C); rs9454908(G,A); rs57751776(C,T); rs9454909(G,A); rs113004335(T,C); rs2096059(A,G); rs2096060(G,A); rs2096061(G,A); rs2096062(T,A); rs9446168(G,A); rs10428870(C,G); rs7751448(A,T); rs9454910(C,T); rs79129886(A,G); rs80142272(G,A); rs17689265(C,T); rs6455351(A,G); rs9454912(T,C); rs77045716(T,A); rs144469345(C,G); rs56163905(A,G); rs9446169(G,A); rs142523386(A,G); rs7747604(T,C); rs73746810(C,G); rs9346362(A,C); rs114419113(C,T); rs9446170(C,T); rs9454914(G,A); rs9294855(C,A); rs17745952(A,T); rs112239227(G,A); rs1417577(A,G); rs61303512(T,C); rs9446171(A,G); rs56978419(C,T); rs1891015(C,T); rs9446172(T,C); rs79339547(T,A); rs17689448(T,C); rs1361518(G,T); rs79099652(A,T); rs6901568(T,C); rs73746815(T,C); rs16868360(C,T); rs73746816(T,C); rs149549135(C,T); rs4036075(A,G); rs61408646(A,G); rs116272879(G,T); rs113844554(C,T); rs6938495(G,C); rs183256707(A,G); rs114937269(T,C); rs146679963(C,A); rs73746817(C,T); rs7761968(A,G); rs58229763(T,G); rs57358062(T,A); rs58987459(A,C); rs6938320(A,G); rs77009897(A,T); rs78730050(G,A); rs144384309(G,A); rs74883689(G,A); rs6455352(A,T); rs3805959(A,G); rs2345783(C,T); rs138747712(G,C); rs73480069(A,T); rs2024903(T,C); rs76684688(T,G); rs73480070(A,G); rs145645084(G,C); rs77229915(G,A); rs60011987(A,G); rs9454918(T,C); rs3805962(T,A); rs78209458(G,T); rs190445652(A,G); rs190315454(A,G); rs111505094(A,G); rs9454919(T,C); rs73746821(T,A); rs73746823(T,A); rs58850476(A,C); rs9454920(T,C); rs9454921(C,T); rs73746825(T,A); rs76962455(A,G); rs3805965(A,G); rs9446176(G,A); rs73746827(G,A); rs79443238(C,T); rs1208521(A,T); rs140667842(C,A); rs10485244(A,G); rs3805967(A,G); rs1934902(G,T); rs75767729(C,T); rs115926717(G,A); rs80114627(C,T); rs17709736(A,G); rs73746829(T,A); rs6928154(C,T); rs75952104(A,G); rs114411555(T,A); rs146447880(A,G); rs6903421(T,A); rs73746834(T,C); rs7742627(A,G); rs7761144(C,T); rs74896886(A,G); rs79038868(C,G); rs6918585(G,A); rs6918763(G,A); rs74642537(T,C); rs3793031(A,G); rs3793032(G,T); rs3793033(C,G); rs17766479(G,A); rs56059453(A,G); rs79643713(G,C); rs116183546(C,T); rs78251699(A,G); rs16868408(T,G); rs144466238(C,T); rs73746840(C,A); rs76524957(T,C); rs16868411(A,G); rs112418701(G,A); rs73746841(T,G); rs73746842(C,T); rs59707679(C,A); rs56293172(C,A); rs59501442(G,A); rs59599861(A,G); rs75187070(C,A); rs149139256(G,A); rs138566702(C,T); rs60134810(T,A); rs112922152(T,G); rs3805977(C,A); rs79479192(T,G); rs80123087(A,G); rs78501511(G,A); rs113710602(G,T); rs58371414(G,C); rs115275760(G,A); rs58134065(T,C); rs114307115(G,A); rs12110870(T,A); rs74731333(A,C); rs3793035(A,G); rs3793036(T,G); rs60984333(A,G); rs182146438(G,A); rs76578357(A,G); rs9454930(G,C); rs9446178(G,A); rs3805978(T,C); rs77865179(C,T); rs16868415(G,T); rs73746845(T,G); rs9454932(G,A); rs74541013(T,A); rs2345744(C,A); rs4599586(C,T); rs144478257(A,C); rs6926567(A,C); rs181200941(A,C); rs1934904(A,G); rs6918912(G,A); rs7756062(G,C); rs6455353(G,A); rs143437551(G,A); rs76205204(A,C); rs6912321(A,T); rs76703508(G,A); rs113484159(A,G); rs6935585(T,G); rs79962441(C,T); rs9454935(C,A); rs78089952(G,C); rs78580643(A,T); rs75626659(G,A); rs73484256(A,G); rs113922331(C,T); rs78169463(A,T); rs2144955(G,A); rs147739941(T,G); rs9454937(A,G); rs6910162(A,C); rs113054770(T,C); rs113947741(G,A); rs7757327(T,C); rs7771757(C,G); rs116613599(C,T); rs148023381(G,A); rs141736558(C,T); rs150158093(G,A); rs112256476(G,A); rs142410909(T,G); rs115015588(G,A); rs144017242(C,G); rs144955549(T,C); rs62420127(A,G); rs77554293(G,A); rs144810096(G,A); rs75515009(G,A); rs75322589(A,C); rs111865181(A,G); rs80317475(A,G); rs76074382(T,G); rs61292877(A,G); rs74645477(G,A); rs112328161(A,T); rs74469211(T,C); rs78833342(C,A); rs115986845(T,A); rs77070657(A,G); rs9351779(T,C); rs111456517(G,A); rs116369848(T,A); rs79112306(T,C); rs141489378(A,G); rs2273426(C,G); rs56831384(G,A); rs12173285(G,A); rs113218707(T,G); rs16868440(G,C); rs59870841(C,G); rs7770758(A,G); rs111723011(A,C); rs76151229(G,A); rs9346369(G,C); rs9454944(G,A); rs78770762(G,T); rs3828766(T,C); rs16868442(A,G); rs1156404(C,T); rs9342782(C,T); rs9446182(A,T); rs3793039(A,G); rs75055166(T,C); rs150410188(C,T); rs3793040(A,C); rs80039519(G,A); rs114260961(C,A); rs3805989(C,G); rs3828767(G,A); rs12198558(G,C); rs7764390(G,C); rs7764576(G,T); rs80204713(T,C); rs180938909(G,A); rs3828768(T,C); rs3805991(T,A); rs77180007(T,C); rs10945192(T,C); rs16868458(A,G); rs11965784(G,A); rs7767087(T,C); rs150462835(G,A); rs7763419(A,G); rs74433103(A,G); rs6939166(T,C); rs6939371(T,G); rs115992162(G,A); rs6920252(A,T); rs76396168(A,T); rs12198026(A,G); rs6936017(T,C); rs6909759(C,T); rs7767510(A,G); rs7767650(A,G); rs6937838(A,G); rs6900009(T,A); rs28830576(C,T); rs151130472(C,T); rs10945193(G,C); rs6921039(G,T); rs2024902(G,A); rs10945194(C,A); rs58086655(C,T); rs12212536(T,C); rs12204286(T,C); rs7747377(T,G); rs35524860(T,G); rs78257235(C,G); rs34270967(T,G); rs12206806(A,G); rs12190028(G,T); rs12190080(G,A); rs6940306(T,C); rs6913378(C,G); rs3805994(A,C); rs3805996(A,G); rs12193977(G,A); rs79012355(A,G); rs3805997(A,G); rs3805998(T,G); rs3806000(A,G); rs3806002(C,T); rs12199349(G,A); rs10945195(G,A); rs3793043(C,T); rs58207835(A,G); rs73486359(G,A); rs117240964(G,A); rs13195745(C,A); rs10945196(G,T); rs7748885(C,T); rs3793044(G,C); rs73486368(C,A); rs10455227(T,A); rs150220705(C,T); rs9454955(G,A); rs138474370(A,C); rs138999968(C,T); rs149466387(C,A); rs12110922(G,A); rs12110927(G,T); rs11753925(A,G); rs181386858(C,T); rs7742508(G,A); rs73486377(C,G); rs7349861(G,A); rs2224513(G,C); rs2224514(C,T); rs76294071(C,T); rs80302829(G,A); rs6455354(G,A); rs58860000(A,T); rs6903796(G,A); rs3806003(C,A); rs116459890(T,C); rs3793045(G,A); rs12206771(C,T); rs3806004(C,T); rs73486380(C,A); rs6901226(A,G); rs187089201(A,C); rs3806005(C,A); rs59506144(A,T); rs59313485(T,C); rs113925047(C,T); rs9454960(C,A); rs3793046(C,A); rs75362801(G,A); rs73486385(G,A); rs16868517(A,T); rs3793048(G,T); rs2025107(G,A); rs58106918(G,A); rs2025108(C,T); rs17711463(C,A); rs9454961(A,G); rs9454962(A,C); rs80281228(T,A); rs9446187(G,A); rs2025109(T,C); rs12204245(G,C); rs9454963(T,A); rs28429162(G,A); rs3793051(A,G); rs74476646(T,A); rs73486387(T,C); rs3806009(C,T); rs12193795(A,T); rs3806010(C,T); rs1885338(C,T); rs77630567(A,T); rs34532535(C,T); rs6928969(T,C); rs111961715(T,G); rs12203835(G,A); rs9446188(C,G); rs12199202(A,C); rs12200700(T,A); rs3806013(C,T); rs12194223(C,T); rs1983761(C,T); rs75564151(C,T); rs80161137(A,T); rs6918625(G,C); rs75706963(C,G); rs79739613(A,G); rs3806014(C,T); rs3806015(G,A); rs3806017(A,G); rs4637602(A,T); rs76040750(A,C); rs76982939(C,A); rs4707626(G,A); rs3806018(C,A); rs62420148(A,G); rs3806019(C,A); rs77851740(C,G); rs12530055(G,A); rs9446190(C,T); rs12189656(G,A); rs3806020(G,A); rs716410(A,G); rs9454964(A,G); rs9454965(A,G); rs78451737(G,A); rs7754796(C,T); rs7754828(C,A); rs7740457(T,C); rs36123295(A,G); rs73486393(T,A); rs79699180(A,G); rs4707628(G,C); rs9454966(G,T); rs6903986(A,G); rs74670801(G,A); rs2068499(A,G); rs1885339(G,A); rs3729610(A,G); rs3806021(G,A); rs9454967(A,G); rs55927183(T,A); rs2208608(A,G); rs3806022(G,A); rs76075891(G,A); rs1535390(G,A); rs3828769(A,G); rs3806024(G,T); rs9454968(G,A); rs80337795(T,C); rs1535391(C,T); rs35665588(G,A); rs9446195(T,C); rs3793053(T,C); rs77049969(G,A); rs3806025(G,A); rs79514868(C,T); rs12190708(A,G); rs12190849(A,T); rs9446196(C,T); rs78133550(G,A); rs3806026(A,T); rs191699173(C,T); rs149622901(T,C); rs3806027(A,G); rs1535392(A,G); rs1535393(G,A); rs1535394(A,T); rs59622341(C,T); rs7772672(A,G); rs11759810(A,G); rs113841854(C,A); rs6920290(G,C); rs10945197(A,G); rs6912011(T,A); rs6907532(A,G); rs75722046(T,G); rs116456574(G,A); rs72916705(C,T); rs3806028(T,C); rs7755777(T,A); rs185222269(A,G); rs77043406(G,A); rs3793055(A,G); rs60319887(C,A); rs17712342(A,G); rs10945198(G,C); rs57448088(T,A); rs72916716(T,C); rs75209831(T,C); rs3793057(G,A); rs10485243(T,A); rs77666373(G,C); rs941862(A,C); rs3828770(T,G); rs72916722(A,C); rs3806029(G,A); rs3806030(T,C); rs193230300(C,A); rs147170492(A,G); rs76607599(G,C); rs2208609(A,G); rs78423529(T,C); rs6908849(C,T); rs6940436(T,C); rs7751501(C,T); rs60676452(T,A); rs17712597(A,G); rs3828771(T,A); rs3828772(C,A); rs3806031(C,G); rs3806032(G,A); rs73469831(C,T); rs16868569(C,G); rs3806033(T,C); rs78919829(T,C); rs75266176(T,C); rs3806034(G,C); rs79909579(T,A); rs74513856(C,T); rs6455355(A,G); rs144162366(G,A); rs76255725(T,C); rs80231644(C,A); rs79163073(T,C); rs2093374(A,G); rs941860(T,C); rs71559574(G,A); rs79378243(G,T); rs6911486(C,T); rs737331(A,G); rs737330(T,C); rs10945199(A,G); rs76239956(G,A); rs56179051(G,T); rs55959115(A,T); rs9454982(A,C); rs79121649(G,A); rs2145904(A,G); rs2145905(G,A); rs2181011(A,G); rs57248525(A,T); rs3763247(T,A); rs73746870(G,A); rs57452964(T,A); rs3806037(C,T); rs56149206(C,G); rs9454984(C,T); rs2093375(C,T); rs2093376(G,A); rs77577855(T,C); rs6938971(A,G); rs76415498(A,C); rs13210726(C,G); rs72916747(A,T); rs11964071(G,A); rs72916750(T,C); rs76802003(G,A); rs75272812(A,C); rs147325040(C,T); rs72916752(G,A); rs7773157(G,A); rs9446206(C,T); rs73746871(C,A); rs73746872(A,C); rs73746873(G,C); rs60828785(G,C); rs79063536(C,T); rs9342783(A,G); rs2296013(A,T); rs79291426(A,G); rs11754354(A,G); rs6935524(T,C); rs9364074(A,G); rs6903592(T,A); rs6919535(G,A); rs149731564(T,A); rs9454992(A,G); rs55872722(T,G); rs7762409(C,T); rs10214833(G,T); rs73746875(G,T); rs6933023(C,T); rs9454993(A,G); rs139690279(C,G); rs2025286(A,C); rs2025285(G,A); rs62420159(C,T); rs2025284(T,C); rs148942193(G,C); rs2025283(T,C); rs73746876(T,G); rs2346211(A,T); rs61190430(G,T); rs56034411(A,T); rs3806040(A,G); rs3806041(C,A); rs3818327(T,G); rs12204438(A,G); rs112141952(G,A); rs77595251(C,T); rs6928201(G,C); rs77770509(A,T); rs6928404(G,T); rs56855480(C,T); rs73746878(A,C); rs74811261(T,A); rs188747512(A,T); rs9364075(A,C); rs148995154(C,T); rs9294858(C,A); rs115884457(A,C); rs9294859(A,G); rs60172937(A,G); rs9354906(G,A); rs73746879(C,T); rs73746880(A,G); rs79869054(C,T); rs3736843(T,C); rs75660673(A,T); rs2229799(C,T); rs73746881(C,T); rs3793059(A,T); rs16880723(G,T); rs3806042(G,A); rs9354907(G,A); rs73746883(T,C); rs1998453(G,A); rs9454994(A,G); rs12204439(C,T); rs74934728(A,G); rs141072197(C,T); rs2676613(A,T); rs7756657(G,A); rs61743753(C,G); rs2296010(G,A); rs802172(A,G); rs142639439(T,C); rs79357195(G,C); rs76431522(A,G); rs802173(T,C); rs802174(T,G); rs802175(T,C); rs802176(G,T); rs117948538(G,A); rs810562(T,A); rs802177(C,T); rs76326226(C,A); rs116299788(G,A); rs1464159(G,A); rs62421668(A,G); rs77858958(T,C); rs809074(T,C); rs2296007(T,C); rs802178(A,C); rs12201626(A,G); rs12210719(A,G); rs802180(G,A); rs802181(A,G); rs77900722(G,A); rs45486305(G,A); rs802184(G,T); rs78532481(T,C); rs74942728(G,A); rs55990353(A,C); rs113274984(G,A); rs802183(G,A); rs3806051(T,A); rs3806052(A,C); rs75625971(C,T); rs12192237(C,A); rs78429925(C,A); rs12192464(C,T); rs802182(A,G); rs3793064(T,A); rs116611295(G,A); rs141582098(G,A); rs6930479(C,T); rs114126513(C,T); rs113255130(C,T); rs115225750(T,C); rs10945200(G,A); rs9454995(G,A); rs9354908(A,T); rs34437604(G,A); rs76936130(G,T); rs4544872(G,A); rs112327742(C,T); rs802185(C,A); rs12191702(C,T); rs3806053(C,G); rs802186(G,A); rs3806055(C,A); rs1517044(C,G); rs1517045(G,A); rs2296006(C,A); rs2296005(A,T); rs802187(G,A); rs802188(T,C); rs62421670(T,A); rs802189(C,T); rs6908735(T,G); rs34147000(G,T); rs692799(G,A); rs6909913(A,G); rs636192(A,C); rs58701153(A,T); rs3749913(A,G); rs3828775(G,A); rs16868632(A,C); rs9364077(A,G); rs77242997(A,T); rs1753258(G,A); rs1616745(T,G); rs3806058(C,T); rs146607731(T,C); rs10945202(G,A); rs12663063(T,A); rs540152(C,T); rs609454(G,A); rs515597(G,A); rs514586(G,A); rs75690338(C,A); rs595957(T,C); rs58673424(G,A); rs58042167(G,A); rs1474044(A,G); rs592836(A,T); rs16868641(G,A); rs75795914(T,A); rs1753251(G,C); rs12211880(G,A); rs117457807(A,G); rs671910(A,G); rs556270(A,G); rs531627(C,G); rs1200562(T,C); rs577010(C,T); rs16868648(T,G); rs6920170(A,G); rs75758881(C,T); rs513631(G,A); rs628028(A,G); rs627540(A,T); rs114752967(G,T); rs9360412(T,G); rs9360413(T,C); rs9360414(C,T); rs17690121(T,A); rs1212491(A,G); rs1517042(T,A); rs79402185(G,A); rs151303075(C,T); rs79744162(T,A); rs658805(G,A); rs118000302(T,A); rs78798811(T,C); rs3806064(T,C); rs3806065(T,C); rs583618(C,T); rs583619(C,T); rs550152(A,G); rs16868655(G,A); rs111591207(A,G); rs599793(T,C); rs6909142(C,T); rs610473(G,A); rs612668(G,A); rs613109(C,A); rs10498871(C,T); rs640392(C,G); rs12192985(T,G); rs2346212(C,T); rs2176355(C,T); rs17747228(T,C); rs1517041(A,C); rs4707687(T,C); rs77025838(T,A); rs78546554(G,A); rs36043258(G,A); rs78708214(T,C); rs1200576(A,C); rs1736(G,A); rs113178987(G,A); rs1200575(A,G); rs1201814(T,A); rs1200574(C,T); rs79130291(G,A); rs652776(G,A); rs80133191(G,A); rs552628(A,G); rs16868705(A,G); rs529805(C,T); rs9346371(C,T); rs78792977(C,T); rs637054(C,T); rs624243(T,C); rs622918(A,G); rs622566(A,G); rs997953(G,A); rs6937501(C,T); rs607716(C,T) |
| ccdsGene name | CCDS4970.1 |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 1310 |
| EntrezGene Description | collagen, type XIX, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL19A1:NM_001858:exon36:c.C2377G:p.P793A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7577 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14993 |
| dbNSFP Uniprot ID | COJA1_HUMAN |
| dbNSFP KGp1 AF | 0.0141941391941 |
| dbNSFP KGp1 Afr AF | 0.0589430894309 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01423 |
| ESP Afr MAF | 0.036541 |
| ESP All MAF | 0.013225 |
| ESP Eur/Amr MAF | 0.001279 |
| ExAC AF | 0.004158 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Conjunctivitis
GENITOURINARY:
[Kidneys];
Renal amyloidosis, late-onset (uncommon)
SKELETAL:
Arthralgia, episodic
SKIN, NAILS, HAIR:
[Skin];
Maculopapular rash, episodic;
Rash may or may not be pruritic
MUSCLE, SOFT TISSUE:
Myalgia, episodic;
Swelling of the extremities, episodic
NEUROLOGIC:
[Central nervous system];
Headache, episodic
METABOLIC FEATURES:
Fever, episodic
LABORATORY ABNORMALITIES:
Polymorphonuclear leukocytosis, episodic;
Increased serum C-reactive protein, episodic
MISCELLANEOUS:
Onset in infancy or early childhood;
Episodes occur 30 minutes to 3 hours after exposure to cold;
Episodes usually last 1 to 2 days;
See also Muckle-Wells syndrome (191900), an allelic disorder with
overlapping features
MOLECULAR BASIS:
Caused by mutation in the NLR family, pyrin-domain containing 3 gene
(NLRP3, 606416.0001)
OMIM Title
*120165 COLLAGEN, TYPE XIX, ALPHA-1; COL19A1
;;COLLAGEN, TYPE IX-LIKE; COL9A1L
OMIM Description
DESCRIPTION
The collagens are a large superfamily of genes that include a number of
subgroups. One such group is composed of fibrillar-associated collagens
with interrupted triple helices (FACIT) and includes collagen types IX
(e.g., 120210), XII (e.g., 120320), XIV (e.g., 120324), and XVI (e.g.,
120326). This group, of which COL19A1 is a member, has common structural
features, including short stretches of collagenous domains interrupted
by non-collagenous regions. These, in turn, form functional units that
serve to produce adhesion to the fibrils, provide a rigid arm that
projects from the fibril, and provide a point of interaction with other
matrix components (summary by Inoguchi et al., 1995).
CLONING
By cross-hybridization using a chicken type V collagen probe, Yoshioka
et al. (1992) isolated from a human rhabdomyosarcoma cell line a 1.8-kb
cDNA encoding a portion of a novel collagen chain with a structure
similar to that of the FACIT class of macromolecules. The novel collagen
chain was arbitrarily termed alpha-1(Y) and assigned the D segment
number D6S228E.
Myers et al. (1993) isolated cDNA clones from a library representing
transcripts synthesized by an established rhabdomyosarcoma cell line
(RH). One clone with a 4-kb insert showed an open reading frame of 2,154
nucleotides. The deduced amino acid sequence began with a 186-amino acid
noncollagenous region containing 7 cysteines. Several of the cysteines
and surrounding amino acid residues could be aligned with those in
collagen types IX, XII, and XVI. The protein terminated with an 8-amino
acid noncollagenous peptide, including an unusual single cysteine, which
would be expected to form an interchain disulfide bond. Results of
Northern blot hybridization suggested that the new collagen chain may be
uncommonly large, since the clone identified a low-abundance RNA of at
least 12.4 kb.
Inoguchi et al. (1995) also isolated a cDNA for a FACIT collagen, which
they called alpha-1(XIX) collagen. The deduced protein contains 1,142
amino acids and has a 23-residue signal peptide and 5 collagenous
domains interspersed with 6 noncollagenous regions. The mRNA has a
3-prime untranslated region of over 5 kb. Northern blot analysis
demonstrated an mRNA greater than 10 kb in the rhabdomyosarcoma cell
line CCL136, with a variety of smaller mRNAs that arose through
differential splicing.
GENE STRUCTURE
Khaleduzzaman et al. (1997) described the complete exon/intron
organization of the human COL19A1 gene and showed that it contains 51
exons, spanning more than 250 kb of genomic DNA.
MAPPING
Yoshioka et al. (1992) mapped the COL19A1 gene to 6q12-q14, where the
COL9A1 gene (120210) has been mapped. Myers et al. (1993) mapped the
COL19A1 gene to chromosome 6 by analysis of a panel of somatic cell
hybrids. By FISH, Gerecke et al. (1997) mapped the COL19A1 gene to
6q12-q13.
Khaleduzzaman et al. (1997) showed that the mouse Col19a1 gene is
located on chromosome 1A3, where Col9a1 had also been mapped. They
suggested that COL19A1 and COL9A1, and their murine counterparts, were
duplicated from the same ancestral gene of the FACIT family.
COL9A1
| dbSNP name | rs1064250(A,G); rs2459555(A,G); rs1200569(G,A); rs2881343(G,C); rs77849671(T,A); rs662828(G,C); rs661521(G,A); rs1200568(T,A); rs142404885(T,C); rs476863(T,A); rs12201251(C,T); rs16868762(T,C); rs491690(T,C); rs9346372(A,G); rs487928(C,A); rs35022420(C,T); rs572716(A,G); rs58885304(G,C); rs1200567(G,T); rs28694097(A,G); rs16868775(C,T); rs540654(T,C); rs7739562(A,C); rs79979095(G,A); rs1200566(A,G); rs7744579(T,C); rs3806066(C,G); rs1210977(A,C); rs9360416(A,C); rs1200565(G,A); rs1200564(A,G); rs78737155(T,A); rs4707705(A,T); rs4707706(G,A); rs12209467(A,C); rs7761044(T,A); rs7741471(C,G); rs7765390(T,C); rs115513529(G,A); rs2182998(A,T); rs12192538(G,A); rs117207028(T,C); rs13201224(G,A); rs13201233(G,C); rs80164481(T,C); rs75737649(A,T); rs7743980(T,A); rs3806070(G,A); rs76946863(A,G); rs1517043(G,T); rs35796471(A,T); rs538588(G,A); rs2025996(G,C); rs4342384(G,A); rs10498872(C,T); rs80039247(T,C); rs12212518(T,G); rs78739591(T,A); rs12190357(G,A); rs544179(T,C); rs2037225(T,C); rs568980(T,C); rs77054705(G,T); rs35005937(T,C); rs657572(A,G); rs74699744(G,A); rs34119578(G,T); rs642635(T,G); rs516166(C,T); rs12154117(C,T); rs59322080(T,C); rs12189752(A,G); rs6919444(G,A); rs12195968(G,A); rs12209857(C,T); rs12197487(G,C); rs12191701(A,G); rs12153902(T,C); rs12153874(A,G); rs144531999(C,T); rs12213613(C,T); rs2182999(G,A); rs1023034(A,G); rs149189932(T,C); rs116013267(A,C); rs78100299(T,C); rs7759109(T,C); rs7759110(T,C); rs6922941(T,C); rs12153933(T,C); rs6923114(T,G); rs3828777(G,A); rs17692231(A,G); rs74630657(T,C); rs78486679(C,T); rs9446213(A,G); rs13216129(A,G); rs1200579(A,C); rs12194189(C,T); rs1200580(A,G); rs9446214(T,A); rs9455012(C,T); rs12194415(C,T); rs73749919(T,C); rs13202029(A,G); rs75139444(G,A); rs73749921(C,A); rs73749922(C,A); rs6455357(G,A); rs75350484(A,G); rs1040655(A,G); rs56733295(C,A); rs73749923(G,A); rs193025853(T,G); rs16868806(C,G); rs9455015(G,A); rs79725953(A,G); rs73747127(A,T); rs74690583(G,A); rs6923695(G,T); rs35970582(A,G); rs73747128(T,C); rs701693(C,T); rs75712164(A,T); rs535308(A,G); rs6455358(G,C); rs77349995(C,T); rs12203351(C,T); rs373129626(G,A); rs500457(T,C); rs546628(T,A); rs117835644(T,A); rs28399919(T,C); rs2274586(A,G); rs1135056(T,C); rs2274584(C,T); rs519068(A,G); rs9446215(T,C); rs9455017(C,T); rs1321059(G,A); rs2138659(G,T); rs9364078(G,A); rs9346373(A,C); rs701690(T,G); rs701689(A,G); rs701688(T,C); rs701686(G,T); rs7755873(T,C); rs13219431(G,T); rs633762(A,C); rs13212724(T,A); rs534258(A,G); rs510423(G,A); rs507676(G,A); rs506908(A,G); rs10945208(A,G); rs13201660(C,T); rs1753208(T,C); rs34506690(G,A); rs590656(G,C); rs558181(A,G); rs555663(T,G); rs9354910(T,C); rs113979(C,T); rs528080(A,G); rs113677659(A,G); rs2024730(C,T); rs3806089(T,C); rs10081090(T,C); rs2025995(T,A); rs12194091(G,A); rs12197540(G,T); rs9455019(T,C); rs138301363(A,G); rs558485(C,T); rs604896(G,T); rs2076816(C,T); rs883708(A,G); rs74917222(A,T); rs883707(G,T); rs150774969(T,G); rs116227194(T,G); rs551470(A,G); rs550675(C,T); rs6935778(A,G); rs79863473(G,A); rs2296930(A,G); rs16868852(A,G); rs518558(G,A); rs518347(T,C); rs16868858(C,T); rs79048956(A,G); rs77290250(T,G); rs607156(A,G); rs77357454(G,T); rs12530229(T,G); rs12529859(A,G); rs117318207(A,T); rs3806093(G,A); rs701684(T,C); rs6455359(A,T); rs7754619(G,A); rs111601555(T,C); rs592121(A,G); rs603304(T,C); rs2274583(G,A); rs603410(G,T); rs621347(G,A); rs495558(G,T); rs3793073(A,C); rs3806095(G,A); rs75629309(A,G); rs1406843(G,A); rs616621(C,T); rs616642(T,C); rs617985(C,T); rs13199337(C,T); rs545211(G,A); rs543575(A,C); rs3806099(A,G); rs7764042(C,G); rs6455360(A,T); rs7764822(C,T); rs41303785(G,A); rs6928611(G,C); rs677152(C,T); rs62420260(A,C); rs701682(C,T); rs9455020(T,C); rs17649310(C,T); rs62420261(G,T); rs11757411(G,A); rs111730714(T,C); rs671148(T,G); rs495823(G,A); rs1406844(C,T); rs1406845(C,A); rs9446217(C,T); rs1321061(A,G); rs77071829(A,T); rs9455023(C,T); rs9455024(G,A); rs9455025(G,A); rs9446218(C,G); rs3806104(G,A); rs3828782(T,C); rs9294862(C,A); rs9455026(C,T); rs16868971(C,T); rs3793075(A,G); rs9455027(A,T); rs377496832(G,A); rs9455029(G,A); rs9455030(T,C); rs16868975(C,T); rs544433(C,T); rs16868977(T,C); rs515975(G,T); rs9455031(T,C); rs3806105(G,A); rs3806106(G,A); rs657815(C,T); rs9455033(A,G); rs9455034(C,T); rs72927399(C,T); rs564031(G,A); rs960816(C,T); rs67434938(A,G); rs9446219(C,T); rs9455035(A,T); rs9455036(C,A); rs2242589(C,T); rs199556602(T,C); rs2242588(T,C) |
| ccdsGene name | CCDS4971.1 |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 1297 |
| EntrezGene Description | collagen, type IX, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL9A1:NM_001851:exon36:c.C2470A:p.P824T,COL9A1:NM_078485:exon30:c.C1741A:p.P581T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.947 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P20849 |
| dbNSFP Uniprot ID | CO9A1_HUMAN |
| dbNSFP KGp1 AF | 0.0155677655678 |
| dbNSFP KGp1 Afr AF | 0.0670731707317 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01561 |
| ESP Afr MAF | 0.063096 |
| ESP All MAF | 0.021375 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.005579 |
OMIM Clinical Significance
Eyes:
Coloboma of iris, choroid and retina
Inheritance:
Autosomal dominant
OMIM Title
*120210 COLLAGEN, TYPE IX, ALPHA-1; COL9A1
;;COLLAGEN, CARTILAGE-SPECIFIC SHORT;;
ALPHA-1(IX) COLLAGEN CHAIN;;
CARTILAGE-SPECIFIC SHORT COLLAGEN
OMIM Description
CLONING
Type II collagen (120140) represents about 85% of the collagen of
hyaline cartilage. In addition to it, there are several minor collagens.
Using a cDNA library made from chick embryo sternal cartilage mRNA,
Ninomiya and Olsen (1984) isolated and characterized a cDNA that codes
for one of these collagens. The unusual qualities of the molecule for
which it codes included a length of only about half that of pro-alpha-1
chains and the presence of short, noncollagenous peptides containing
cysteinyl residues separating its 3 collagenous domains. The
cartilage-specific collagen was enumerated as type IX. Its function was
unknown (Mayne et al., 1985). The triple helix of type IX collagen is
composed of 3 genetically distinct polypeptide subunits--alpha-1(IX),
alpha-2(IX), and alpha-3(IX). These are the products of genes whose exon
structure is different from that of fibrillar collagens. Type IX
collagen is also a proteoglycan. Chondroitin sulfate and dermatan
sulfate chains are covalently linked to the alpha-2(IX) chain (120260).
McCormick et al. (1987) described the structure of the glycosaminoglycan
attachment site of alpha-1(IX) collagen. By a combination of cDNA and
peptide sequencing, they showed that the attachment region contains the
sequence gly-ser-ala-asp, located within the noncollagenous domain of
the alpha-2(IX) chain. The exon coding for the attachment site in the
alpha-2 gene is 48 bp long, whereas the homologous alpha-1 exon is 33 bp
long. The extra sequence in the alpha-2 molecule provides an explanation
for the kink observed at that site in type IX molecules when examined by
electron microscopy. The inserted block of amino acid residues also
provides the alpha-2 chain with a serine residue, not present in alpha-1
chains, that serves as attachment site for a glycosaminoglycan side
chain. Eyre et al. (1987) concluded that type IX collagen molecules are
covalently crosslinked in cartilage to molecules of type II collagen.
GENE FUNCTION
COMP (600310) is a pentameric glycoprotein found in the extracellular
matrix of cartilage, tendons, and ligaments. Using rotary shadowing
electron microscopy and immobilized proteins, Holden et al. (2001)
characterized the interaction between purified chick sternal cartilage
type IX collagen and purified fetal bovine Comp or the isolated human
COMP C-terminal domain. They identified a collagen-binding site between
residues 579 and 595 of the C-terminal domain of COMP that bound each of
4 noncollagenous domains in collagen IX.
MAPPING
Kimura et al. (1989) described the primary structure of type IX collagen
of rat and human based on cloning and sequencing of cDNA from cDNA
libraries. By in situ hybridization, they demonstrated that the COL9A1
gene is located in the proximal portion of the long arm of chromosome 6
(6q12-q14), probably at 6q13. By analysis of a panel of somatic cell
hybrids containing various parts of chromosome 6, Boyle et al. (1992)
confirmed the assignment to 6q12-q14. Muragaki et al. (1990)
demonstrated that mouse and human RNAs contain 2 types of COL9A1
transcripts based on the presence of 2 translation start codons located
within 2 alternative exons. Warman et al. (1993) confirmed the mapping
of COL9A1 to 6q12-q13 by fluorescence in situ hybridization and, using
an interspecific backcross panel, mapped murine Col9a1 to mouse
chromosome 1.
MOLECULAR GENETICS
- Multiple Epiphyseal Dysplasia 6
Czarny-Ratajczak et al. (2001) identified a mutation in the COL9A1 gene
(120210.0001) in affected members of a family with multiple epiphyseal
dysplasia-6 (EDM6; 614135).
- Stickler Syndrome Type IV
Van Camp et al. (2006) reported an autosomal recessive form of Stickler
syndrome (STL4; 614134) caused by mutation in the COL9A1 gene. They
described a family of Moroccan origin in which 4 children, offspring of
consanguineous parents (5th degree relatives), had features of Stickler
syndrome, including moderate to severe sensorineural hearing loss,
moderate to high myopia with vitreoretinopathy, and epiphyseal
dysplasia. Van Camp et al. (2006) considered the COL9A1 gene to be a
candidate gene on the basis of structural association with collagen
types II (120140) and IX (see 120210) and because of its high expression
in the human inner ear indicated by cDNA microarray. Mutation analysis
of the coding region of the COL9A1 gene showed a homozygous
arg295-to-stop mutation (R295X; 120210.0002) in the 4 affected children.
- Other Associations
Loughlin et al. (2002) performed finer linkage mapping of a primary hip
osteoarthritis susceptibility locus (165720) on chromosome 6 in affected
sib pair families and defined an 11.4 cM female-specific interval
flanked by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM
from the 6p telomere at 6p12.3-q13. As the COL9A1 gene maps within this
interval, it was considered a logical candidate gene for osteoarthritis
susceptibility. Loughlin et al. (2002) identified and genotyped 20
common single-nucleotide polymorphisms (SNPs) from within COL9A1 in 146
probands from the female sib pair families and in 215 age-matched
unrelated female controls. None of the SNP alleles or genotypes were
associated with osteoarthritis and there was no significant difference
in the frequency of common SNP haplotypes between the probands and the
controls. This comprehensive association analysis did not produce any
evidence supporting COL9A1 as the primary osteoarthritis susceptibility
locus mapped to chromosome 6.
ANIMAL MODEL
Nakata et al. (1993) generated transgenic mice expressing a truncated
alpha-1(IX) chain, which was expected to interfere with stable triple
helix formation and act as a trans-dominant mutation. Mice heterozygous
for the transgene developed osteoarthritis in the articular cartilage of
knee joints, while mice homozygous for the mutation developed mild
chondrodysplasia as well. The phenotypic severity correlated well with
the level of transgene expression. Jacenko et al. (1994) interpreted
these findings in mice with a dominant-negative mutation in Col9a1, as
well as the observation that mice with a homozygous null mutation in the
gene have an unexpectedly mild phenotype, as indicating that type IX
collagen is not essential for the assembly of the cartilage
extracellular matrix, although it may be important in the maintenance of
structural integrity.
Fassler et al. (1994) found that mice with 'knockout' of the Col9a1 gene
did not produce alpha-1(IX) mRNA or polypeptides and were born with no
conspicuous skeletal abnormalities but postnatally developed early-onset
osteoarthritis. Hagg et al. (1997) found that deficiency of the alpha-1
chain led to a functional knockout of all polypeptides of collagen IX,
even though the Col9a2 and the Col9a3 genes were normally transcribed.
Therefore, they concluded that synthesis of alpha-1(IX) polypeptides is
essential for the assembly of heterotrimeric collagen IX molecules.
Surprisingly, cartilage fibrils of all shapes and banding patterns found
in normal newborn, adolescent, or adult mice were formed in transgenic
animals, although they lacked collagen IX. Hagg et al. (1997) concluded
that collagen IX is not essential, and may be functionally redundant,
for fibrillogenesis in cartilage in vivo. The protein is required,
however, for long-term tissue stability, presumably by mediating
interactions between fibrillar and extrafibrillar macromolecules.
KCNQ5
| dbSNP name | rs11758568(A,G); rs7768673(A,G); rs7772714(A,G); rs10943042(T,G); rs6453591(A,T); rs1543621(C,G); rs6453592(A,T); rs6453593(A,T); rs73531872(T,C); rs12528674(T,C); rs6453594(G,A); rs9360570(T,C); rs17692055(T,G); rs10943043(G,A); rs17692121(G,A); rs12175038(G,A); rs10805964(T,C); rs55633371(C,T); rs56086224(A,G); rs58816739(G,A); rs9360571(C,G); rs6937158(T,C); rs6937341(T,G); rs150227641(G,A); rs73533641(T,C); rs12214894(A,T); rs10943044(T,C); rs9360572(G,A); rs10943045(G,T); rs12190091(A,G); rs9360573(T,A); rs56316829(G,A); rs6913237(A,G); rs6917707(A,T); rs35761287(G,A); rs17748888(G,A); rs112904854(G,A); rs13212962(G,A); rs13213217(G,A); rs6931363(A,G); rs9360580(G,A); rs76421591(C,T); rs73533649(C,T); rs17748966(G,T); rs6922044(T,C); rs6899573(C,T); rs6900054(G,A); rs6900100(C,G); rs6900103(C,A); rs12203288(A,G); rs12189933(C,T); rs12190092(G,A); rs75388924(G,A); rs10943046(T,C); rs12196826(A,G); rs4707978(G,C); rs17692606(C,A); rs192148118(T,A); rs62411982(A,T); rs12212562(G,T); rs12200468(A,G); rs12214096(G,A); rs57838719(A,T); rs9342960(T,C); rs17692655(G,A); rs80203373(T,C); rs112162457(A,G); rs73533661(C,G); rs28716878(C,A); rs12193274(G,T); rs17692715(A,G); rs9342961(C,T); rs9342962(A,G); rs182667741(A,G); rs1328857(G,A); rs1410764(C,T); rs9442830(G,A); rs6928073(A,C); rs17749408(G,A); rs17749420(G,C); rs9350467(C,T); rs112428488(G,A); rs7746067(C,T); rs62411984(G,A); rs9442831(G,A); rs55826353(A,G); rs17692874(T,C); rs17692898(T,G); rs76838516(G,A); rs4707980(T,A); rs113235414(T,C); rs112819455(G,A); rs113747080(T,A); rs62411985(G,T); rs4707981(C,T); rs10943048(A,G); rs12208907(T,C); rs12204139(G,C); rs75763951(T,C); rs1928153(T,A); rs73533670(G,A); rs12111265(C,T); rs9360584(A,G); rs12374631(G,T); rs12374630(C,G); rs57822223(C,A); rs58599475(G,T); rs9442832(T,C); rs12191848(A,G); rs12212419(T,C); rs56897294(T,C); rs114323688(C,T); rs7769363(T,G); rs7749594(G,T); rs7451091(A,T); rs143589496(G,A); rs9293893(C,T); rs10943050(C,T); rs10943051(G,A); rs9293894(T,A); rs13208048(G,A); rs12191039(T,G); rs113475402(C,A); rs75842556(A,C); rs6924417(C,T); rs113568643(G,A); rs12212818(G,A); rs78115542(G,T); rs12199549(A,C); rs12194741(T,C); rs113567389(C,G); rs12214895(G,A); rs12201380(A,G); rs4311478(A,G); rs12195259(T,A); rs113839099(G,T); rs3936157(A,G); rs4403240(A,G); rs6935174(C,T); rs7742742(G,C); rs112943727(C,T); rs73533685(A,G); rs1884090(G,A); rs7768117(T,G); rs7748594(A,G); rs60620751(G,A); rs7748934(A,C); rs7749079(A,T); rs7749264(A,T); rs62411986(G,A); rs62411987(G,A); rs12210850(G,A); rs9446734(C,T); rs769133(A,C); rs768790(C,T); rs111827220(A,G); rs12191216(C,A); rs73535764(A,C); rs151025138(A,G); rs6926943(C,T); rs72935423(A,G); rs113658733(A,G); rs73535765(C,G); rs79047153(G,C); rs189489424(A,C); rs115741489(C,T); rs11759937(G,A); rs111940815(T,C); rs73535768(A,C); rs73535770(T,A); rs4707983(C,T); rs73535771(G,A); rs139203677(C,T); rs75541452(G,A); rs76471658(C,T); rs78789588(C,T); rs9442834(A,C); rs6938189(T,C); rs6915647(C,T); rs9360587(T,C); rs141109213(C,A); rs60412240(T,C); rs111498671(A,G); rs9446735(A,G); rs9360588(A,G); rs10943055(C,G); rs112094298(A,G); rs10080760(T,G); rs75153379(G,A); rs73535789(G,A); rs7760979(A,G); rs4707984(G,C); rs7758797(T,C); rs9442835(T,C); rs113356890(G,C); rs6934995(T,C); rs9293896(G,A); rs116273037(C,T); rs115231331(C,A); rs16882711(T,C); rs9293897(G,T); rs77343543(G,T); rs7776102(G,T); rs10484913(A,C); rs12204989(C,T); rs6453597(A,G); rs73756018(T,C); rs78784467(A,T); rs16882712(G,A); rs6903328(T,C); rs75441019(A,G); rs16882715(C,T); rs7764621(C,T); rs58412450(A,G); rs113813394(T,C); rs17796704(T,C); rs73537767(A,T); rs74992990(G,A); rs9446739(T,G); rs115475489(C,A); rs73537770(A,G); rs6926720(T,C); rs55681253(C,T); rs6904964(G,A); rs75673421(G,A); rs113015069(A,G); rs78969846(A,G); rs62411990(G,A); rs111302244(C,T); rs56307817(A,C); rs55791694(G,A); rs75761182(G,C); rs111685356(G,A); rs55982853(C,T); rs79215724(G,A); rs111305382(C,T); rs16882726(G,A); rs79117867(G,C); rs78827753(G,A); rs111232109(C,A); rs113572243(A,G); rs12215865(G,T); rs74976508(T,G); rs111600783(T,C); rs73537775(C,T); rs75298955(G,A); rs78764796(G,A); rs77217482(T,C); rs76226699(T,C); rs76951078(A,G); rs56379143(T,C); rs12197962(T,C); rs4706510(A,G); rs77912034(T,C); rs112997141(G,C); rs113727718(G,A); rs111893880(C,T); rs77661114(A,G); rs9293898(C,G); rs78229582(C,T); rs73537781(A,C); rs111815762(T,C); rs76263435(T,G); rs76695427(G,A); rs112283958(T,C); rs78174450(C,T); rs76083337(T,C); rs138172514(A,G); rs75672660(T,C); rs75745103(T,G); rs2207264(G,A); rs78908562(T,C); rs112928813(C,G); rs76441442(G,A); rs6906977(G,A); rs116757550(G,C); rs9293899(A,G); rs78107065(T,C); rs115627896(A,G); rs719830(A,G); rs6918661(A,G); rs112745735(A,G); rs77097785(A,C); rs77678417(C,A); rs115286228(A,G); rs143765098(C,A); rs6924191(C,G); rs2207265(G,A); rs74516342(A,G); rs9446740(G,A); rs10943057(T,C); rs6931918(G,T); rs73537796(G,A); rs112655732(T,C); rs4707985(A,G); rs7772197(A,G); rs7772876(G,C); rs7772481(A,T); rs7738588(C,A); rs7738589(C,A); rs73537799(A,G); rs12205374(G,A); rs9360593(G,A); rs1997914(G,A); rs9342967(A,C); rs9442837(A,G); rs993314(T,C); rs9293900(C,T); rs9293901(G,C); rs150741226(G,C); rs2223939(A,G); rs145987226(G,A); rs12200908(C,A); rs2207266(A,G); rs2207267(G,A); rs6453598(A,T); rs2179952(A,T); rs6453599(G,C); rs6453600(C,T); rs9341386(G,A); rs73539714(C,T); rs12211580(T,C); rs9351938(A,G); rs73539715(C,T); rs111597711(C,T); rs76615404(C,T); rs112461894(C,T); rs79586764(G,A); rs6910780(C,T); rs9293902(T,C); rs7754096(C,A); rs80026115(G,A); rs77216269(G,A); rs62410660(G,T); rs6922479(C,T); rs6922327(A,T); rs6922837(C,T); rs6923028(C,A); rs150792064(C,T); rs9293904(G,A); rs12192751(T,G); rs9293906(G,A); rs116718231(G,A); rs9360594(C,G); rs4706511(A,G); rs66811027(C,G); rs3005766(A,G); rs2982748(G,A); rs3005765(A,T); rs16882786(T,C); rs4235869(G,T); rs6453601(C,G); rs377699332(A,C); rs7741534(G,T); rs16882798(G,A); rs9446743(C,T); rs2840791(T,C); rs12110561(G,C); rs16882804(C,T); rs116411248(C,A); rs9293907(T,C); rs2840793(T,C); rs73753893(T,A); rs9446744(C,T); rs187353989(C,T); rs2179953(T,C); rs2179954(A,G); rs7749632(T,C); rs2840794(A,G); rs2144088(T,A); rs2144089(A,G); rs6906492(C,A); rs9442843(A,G); rs6453602(C,T); rs9293908(A,G); rs9442844(A,G); rs7756180(A,G); rs2207270(G,A); rs77687724(A,T); rs7743377(T,C); rs7743692(T,C); rs7765507(C,T); rs6931185(G,T); rs73753900(G,A); rs73753901(G,A); rs6899716(C,A); rs74474165(A,G); rs144378708(A,T); rs114092251(G,A); rs73756504(A,G); rs7743912(C,T); rs75297226(C,T); rs78822287(T,G); rs79541230(C,T); rs7749542(A,G); rs2223940(C,T); rs9442846(G,A); rs2982749(G,C); rs9293911(T,C); rs9293912(C,A); rs2982750(C,T); rs2982751(T,C); rs2982752(G,A); rs186226900(C,A); rs10046418(T,C); rs59811652(C,G); rs73756510(A,T); rs12213677(T,C); rs73756512(T,C); rs12193344(A,G); rs75956027(C,G); rs113408658(A,G); rs7758723(C,T); rs76063795(T,A); rs62410662(A,T); rs9918453(C,T); rs10943059(G,A); rs10805965(A,G); rs10805966(T,C); rs7751090(T,C); rs7770272(G,A); rs7752076(T,C); rs9293913(A,G); rs9342973(G,A); rs7775641(C,T); rs6904110(C,G); rs6904313(C,T); rs12213639(A,G); rs4707987(C,T); rs6940084(G,A); rs74953834(T,G); rs62410663(G,T); rs4706512(C,T); rs4706513(A,G); rs75132367(C,T); rs6453603(T,C); rs78263070(A,G); rs9359006(T,C); rs9351942(A,C); rs9341387(C,T); rs9359007(G,C); rs7746825(C,T); rs11759755(T,G); rs139416348(G,A); rs9446752(G,T); rs9446753(T,C); rs9442847(G,A); rs6906378(T,A); rs6926416(C,T); rs6926423(A,G); rs4499888(A,G); rs9360597(G,A); rs16882869(G,C); rs12529830(C,A); rs58043271(A,T); rs7740337(A,G); rs7740606(C,A); rs4707988(G,A); rs9360598(A,G); rs4707989(G,A); rs16882872(A,C); rs11960994(T,G); rs10943061(T,C); rs60690955(G,A); rs4706514(T,C); rs60563419(C,T); rs59068902(C,A); rs4421163(A,G); rs76740054(G,A); rs77319187(C,T); rs62410664(C,T); rs6453604(T,A); rs4707990(C,T); rs190075716(C,T); rs4707991(T,C); rs7744990(C,T); rs7744865(A,G); rs78480650(T,G); rs9360599(A,G); rs6919026(C,T); rs9446754(A,G); rs59542180(G,C); rs4707992(G,T); rs4707993(C,A); rs6930400(A,C); rs6453605(C,G); rs75934643(C,T); rs9350471(A,G); rs4235870(G,A); rs79852652(G,A); rs76819274(A,G); rs75344986(C,T); rs4293967(T,C); rs9442849(T,C); rs9442850(C,A); rs62412463(T,G); rs11967126(G,A); rs7741592(G,A); rs4707994(G,C); rs6453606(G,A); rs9442851(T,C); rs9442852(C,T); rs4610523(C,T); rs9360601(C,T); rs74528013(T,C); rs13209945(G,A); rs9446758(A,G); rs3924067(C,A); rs77574559(G,A); rs16882900(A,G); rs117753267(G,A); rs73756525(C,T); rs76369079(A,G); rs9293914(G,A); rs9446760(T,C); rs79397952(A,G); rs4235871(G,T); rs10943065(G,A); rs4583938(C,T); rs10943066(C,T); rs9351945(C,G); rs9351946(C,T); rs9351947(C,T); rs4707995(A,G); rs6912655(A,G); rs9446761(G,T); rs116566483(G,T); rs9442854(G,A); rs7760479(G,A); rs4707996(G,A); rs9360602(C,A); rs6930202(A,G); rs4615346(C,G); rs2840799(A,G); rs10498884(A,G); rs75193128(G,A); rs9360603(A,C); rs17742423(G,A); rs10943068(T,G); rs2185766(A,G); rs3005768(A,G); rs1891397(C,T); rs6928101(A,G); rs2796009(C,G); rs9446762(A,G); rs2840800(T,C); rs9446763(A,G); rs73756530(C,A); rs9442857(A,G); rs2840801(G,C); rs2840802(T,C); rs73543817(T,G); rs2796008(C,A); rs2840803(G,A); rs1935515(T,C); rs9442858(T,C); rs12216112(A,G); rs73543821(T,G); rs73543825(A,G); rs73543827(A,G); rs73543828(A,C); rs62412469(A,T); rs73543830(C,T); rs3005767(A,G); rs75903302(G,A); rs1935520(G,C); rs1935523(G,A); rs4389734(C,T); rs75242268(T,C); rs59147032(C,A); rs60738138(A,G); rs144875208(A,T); rs12193189(A,C); rs9446764(C,G); rs56222185(A,G); rs16882930(G,A); rs73543839(C,T); rs12207421(T,C); rs112253106(A,T); rs12202168(G,A); rs12209384(T,A); rs7740411(A,G); rs2995342(T,A); rs2226132(G,C); rs76971743(G,A); rs116675500(T,C); rs76934284(A,C); rs12663608(C,A); rs12207705(G,A); rs149862338(G,C); rs6915355(G,A); rs2796007(A,T); rs4708000(G,A); rs12660537(T,C); rs62412471(G,C); rs6907502(T,G); rs6927484(A,G); rs6453608(A,C); rs149597516(C,T); rs148362685(T,G); rs139766110(G,C); rs78874855(A,T); rs1935508(G,A); rs57840734(C,T); rs16882934(C,G); rs35772553(G,A); rs79311091(G,T); rs76378087(G,A); rs114519936(G,A); rs141634929(G,A); rs147833044(A,G); rs2796006(A,G); rs4618485(A,G); rs55931355(T,G); rs114196851(A,G); rs61096548(G,C); rs55878925(T,C); rs2226136(A,T); rs78389299(C,T); rs60052894(G,A); rs148928809(A,G); rs58571865(T,C); rs9446769(T,C); rs76756692(A,G); rs9342975(C,A); rs77654605(T,C); rs9360605(A,G); rs2995343(C,T); rs7764400(C,T); rs3005764(T,C); rs2350089(T,C); rs1935525(T,C); rs1935524(G,A); rs75771633(C,G); rs2840798(G,C); rs2796005(C,T); rs2796004(G,A); rs2995344(C,A); rs2840797(G,A); rs2840796(A,C); rs138010003(C,T); rs78482201(G,A); rs1125083(G,T); rs1316976(A,C); rs9351948(A,G); rs191902904(C,A); rs2226135(T,C); rs2796003(A,G); rs1935521(A,G); rs1935518(C,T); rs2796002(T,C); rs9446773(A,G); rs2840795(A,G); rs9342979(A,G); rs12197861(A,T); rs2995345(T,C); rs2995346(A,G); rs1935517(C,T); rs2995347(A,C); rs3005769(C,A); rs2096182(C,G); rs72943319(C,A); rs867262(A,G); rs142967663(C,G); rs4706515(G,A); rs4566854(A,G); rs1891398(T,A); rs2211390(C,A); rs12526205(C,T); rs78752823(G,A); rs9360607(C,T); rs9446777(A,G); rs7754230(T,C); rs3763159(C,T); rs147519911(G,A); rs368678939(T,A); rs9351949(A,G); rs9351950(G,A); rs9351951(G,A); rs1891396(C,T); rs1935509(A,G); rs9442860(T,A); rs140291171(G,A); rs79355720(C,T); rs77914691(A,G); rs12664704(G,A); rs12211380(C,T); rs186176286(C,T); rs370120216(T,A); rs4591808(A,C); rs9342980(T,G); rs113623955(A,G); rs111549718(C,T); rs112348907(A,G); rs16882996(A,G); rs62412473(G,A); rs9442861(G,A); rs9442862(G,A); rs9350473(G,A); rs9442863(T,G); rs9342981(A,G); rs10943070(C,A); rs9360608(A,G); rs10805969(C,A); rs142286170(A,T); rs9986400(A,G); rs6903864(T,C); rs6924175(C,T); rs9986437(A,T); rs6908756(T,A); rs6909241(T,A); rs6909572(T,G); rs6930157(C,T); rs117537335(A,G); rs7770776(G,A); rs7770802(G,A); rs7771181(C,A); rs9342983(T,A); rs7758801(T,C); rs11756197(A,G); rs9351953(G,A); rs3920868(A,G); rs9283796(T,C); rs9360610(T,C); rs149953332(C,A); rs9350475(T,G); rs9342984(C,T); rs9360611(T,C); rs17800259(T,C); rs9360612(T,A); rs12211841(A,G); rs139516288(T,C); rs75815770(T,G); rs7775087(G,T); rs117440298(A,G); rs6909225(G,A); rs6909147(A,G); rs6915633(C,T); rs71573567(C,T); rs7739065(G,A); rs145569558(T,C); rs6453610(A,G); rs116164473(T,G); rs6913925(G,A); rs7755521(G,A); rs78561858(T,C); rs9446786(G,A); rs77682541(G,A); rs9360616(C,A); rs9442868(A,T); rs9351954(T,C); rs9360617(A,G); rs12208622(G,A); rs76197152(G,T); rs12197188(A,G); rs10498886(A,C); rs4388257(T,G); rs9446788(A,G); rs9446789(C,T); rs9293917(A,G); rs951762(A,C); rs9342986(C,T); rs368211127(C,T); rs9446790(T,G); rs9360618(G,A); rs6929515(C,T); rs6929347(A,G); rs117419568(A,T); rs9351955(G,T); rs61127549(C,T); rs9342987(T,C); rs59842658(A,C); rs9351956(G,A); rs16883037(T,C); rs79700621(T,C); rs113957493(A,G); rs2226137(A,G); rs80220717(C,T); rs73753206(A,C); rs58117677(T,G); rs57297293(A,G); rs1316784(C,T); rs9341390(G,T); rs77106808(T,G); rs1342337(A,G); rs111467388(G,A); rs73753207(A,G); rs7740837(G,A); rs140094293(G,C); rs6453611(T,C); rs56201874(G,A); rs4552693(T,C); rs4374796(C,A); rs73753208(A,G); rs9351957(A,G); rs1935527(T,G); rs59988460(A,C); rs2882328(G,T); rs1935526(A,T); rs73753209(C,T); rs116587527(G,T); rs73753211(G,A); rs6924280(T,C); rs73753213(C,G); rs7744813(C,A); rs55892007(A,G); rs56388218(C,T); rs73753214(C,T); rs4304128(A,G); rs73753215(C,G); rs16883059(A,G); rs6916116(T,C); rs6936302(A,G); rs73753217(G,A); rs9446792(G,A); rs9442871(C,T); rs12526735(A,T); rs1317537(T,C); rs1317538(G,A); rs1317539(C,T); rs1891394(C,T); rs369786715(T,C); rs80123310(C,T); rs2153830(A,C); rs150186352(A,T); rs11758798(C,T); rs6453613(C,T); rs12202465(A,G); rs79706505(T,C); rs9360621(A,G); rs12195276(C,T); rs16883089(T,C); rs9341391(A,G); rs6902737(T,A); rs6902903(T,C); rs9342990(G,A); rs10943073(T,G); rs12664923(A,T); rs885247(T,C); rs1891395(T,C); rs9351958(G,C); rs2153831(G,C); rs13206617(G,T); rs13206405(C,A); rs149744124(C,G); rs4708007(A,G); rs138764428(G,A); rs139497326(A,C); rs118002975(C,G); rs77635480(G,A); rs9351960(T,A); rs9446793(A,C); rs9446795(C,T); rs59154326(T,G); rs79009800(A,G); rs118171326(G,A); rs6924279(G,A); rs6903848(T,C); rs6924579(A,G); rs4706518(T,G); rs75974559(A,C); rs147415448(G,A); rs114793984(T,G); rs118010484(C,G); rs79627446(A,G); rs1935513(G,A); rs78705449(A,G); rs9351961(C,A); rs12190059(G,A); rs2226133(A,G); rs9360623(G,A); rs140591664(G,C); rs150096929(C,T); rs1935511(T,C); rs116535855(A,G); rs16883117(G,A); rs117543593(A,G); rs9342991(G,A); rs76812441(C,G); rs7774630(T,A); rs12210749(G,A); rs16883127(C,T); rs7764554(A,G); rs7747839(T,C); rs7758173(T,C); rs7738305(C,T); rs138587870(G,A); rs140095271(G,C); rs2211389(A,G); rs2211388(A,G); rs7753405(C,A); rs6921584(G,T); rs61566833(C,T); rs373535872(G,A); rs9342993(G,A); rs2153833(C,T); rs113050395(G,A); rs9446803(C,T); rs9360626(G,A); rs191203750(A,G); rs7741001(A,G); rs111624178(A,G); rs9446804(G,A); rs114570188(G,C); rs9446806(G,C); rs2000203(G,A); rs4708009(C,G); rs60061207(G,C); rs9446807(A,G); rs9446808(C,T); rs146439878(A,C); rs9359011(C,T); rs9446811(G,A); rs9446812(A,G); rs2350748(C,A); rs75123705(C,T); rs1539348(A,G); rs142352260(G,A); rs1574007(G,C); rs9446814(T,C); rs17745021(T,C); rs17806955(A,G); rs116433916(C,A); rs58410601(C,T); rs6453615(G,A); rs2211387(C,T); rs57053969(G,A); rs7747368(T,C); rs1342336(G,A); rs190810505(G,A); rs142761566(C,T); rs10943075(A,G); rs143435786(C,G); rs142784268(C,T); rs139738017(A,T); rs149992379(A,G); rs142346979(G,A); rs2153832(A,G); rs6928147(A,G); rs78246542(C,T); rs6453616(G,T); rs76557692(A,C); rs142817117(T,A); rs73753223(A,G); rs16883160(A,G); rs9446819(A,T); rs78635998(A,G); rs10943076(G,A); rs192029350(G,A); rs6920341(C,T); rs4706520(C,A); rs117460007(C,T); rs4706522(A,G); rs145877834(C,A); rs4397191(G,C); rs6918396(A,G); rs6919016(G,T); rs11963228(G,A); rs9442877(A,T); rs6453617(A,T); rs4706523(T,C); rs7767727(G,A); rs16883186(C,T); rs9446824(A,G); rs76535776(T,C); rs16883192(A,T); rs947612(G,A); rs9342995(G,A); rs9342996(A,G); rs147331484(A,T); rs6453618(T,C); rs16883205(C,T); rs7765606(C,T); rs10498887(G,A); rs16883209(A,G); rs7776021(G,A); rs6921182(T,C); rs6921533(T,C); rs16883215(A,G); rs6453619(C,A); rs10498888(T,G); rs1891405(G,C); rs6453620(C,T); rs9446825(T,A); rs7773521(T,G); rs113662184(C,A); rs7774687(T,G); rs146483502(C,T); rs9446827(C,A); rs76025043(A,G); rs74787748(A,G); rs7764774(G,A); rs76135294(G,A); rs77559144(C,T); rs74197654(G,A); rs76394157(A,G); rs7752262(T,G); rs7770061(A,G); rs116412700(T,G); rs78576960(A,G); rs75659165(A,C); rs113242003(C,A); rs4708011(G,A); rs4708012(T,C); rs4708013(A,T); rs112250407(A,G); rs77150253(T,C); rs77333761(C,T); rs16883236(A,G); rs2185770(G,A); rs9341396(G,A); rs77380880(T,C); rs4708015(G,A); rs116846875(G,A); rs3798465(T,C); rs12213933(G,A); rs2153840(G,C); rs76049502(T,C); rs78714417(A,G); rs117189064(C,T); rs9351964(G,A); rs76192998(C,T); rs112549001(G,A); rs9342997(T,C); rs9351965(G,A); rs10455090(C,G); rs145347587(G,A); rs78798773(A,G); rs77406600(G,A); rs9350480(A,G); rs112436741(G,A); rs76109833(C,T); rs4706525(G,A); rs375481479(G,A); rs4428468(A,C); rs75672676(C,A); rs4566855(A,G); rs4349773(A,G); rs4566856(A,G); rs9350482(A,G); rs113847322(G,A); rs4708016(G,A); rs9341397(G,T); rs1935541(C,G); rs114887904(C,A); rs9341398(A,G); rs57873383(G,A); rs4706526(T,C); rs4401620(C,G); rs6907158(G,T); rs9442878(T,A); rs4708019(T,A); rs75053922(C,T); rs9350483(A,G); rs4533951(C,G); rs76510575(C,T); rs9341399(T,C); rs7748770(G,T); rs76940443(C,T); rs116819597(A,T); rs79612389(T,C); rs9446830(G,A); rs7760183(G,A); rs144174056(G,A); rs115696517(T,C); rs34096074(G,A); rs78283110(A,G); rs9341400(C,T); rs9351966(T,A); rs3934400(T,C); rs2066369(G,A); rs9359012(G,A); rs9341401(A,G); rs77385907(A,C); rs9293918(C,T); rs6453625(T,C); rs78336317(A,G); rs2882399(A,G); rs2350369(C,G); rs7741782(A,T); rs7742112(A,T); rs56195807(A,G); rs148088554(A,G); rs6453626(A,C); rs2350370(A,G); rs7752205(A,G); rs6921049(G,A); rs9446833(T,C); rs9360631(C,T); rs7774477(C,T); rs7756518(T,C); rs9341402(C,G); rs17751765(T,C); rs9343000(C,T); rs6941990(T,C); rs9446834(C,T); rs112671778(T,G); rs9351968(T,A); rs112153980(C,T); rs9359013(G,A); rs74655312(C,T); rs7767020(G,A); rs68119906(A,G); rs4708020(A,C); rs4708021(T,C); rs12111515(G,A); rs6939209(G,T); rs6900769(G,C); rs76679028(C,T); rs7739433(C,A); rs112571272(T,C); rs16883262(C,T); rs9446835(A,G); rs144030158(C,T); rs76666800(C,T); rs1361721(T,C); rs9343001(C,A); rs35618610(A,G); rs12195583(C,T); rs1539346(T,C); rs2882398(C,T); rs149289524(C,A); rs2350364(T,G); rs2350365(A,C); rs7761599(A,G); rs4398688(T,C); rs4292489(A,G); rs6905395(G,T); rs142825183(C,T); rs6905309(A,G); rs4404742(T,G); rs4418154(G,T); rs4613780(A,G); rs9442884(G,T); rs2185771(A,G); rs2185772(C,G); rs2350366(G,A); rs1819732(A,G); rs2350367(T,A); rs2350368(C,A); rs2185773(T,C); rs6453628(A,G); rs10805970(G,C); rs4351213(C,T); rs4288171(T,C); rs4323278(G,A); rs4579314(C,A); rs1935531(C,G); rs7764195(A,C); rs114871386(C,T); rs1935532(G,A); rs114001556(T,C); rs115147858(A,T); rs2153841(A,G); rs9446840(C,A); rs9442886(G,A); rs58445745(G,T); rs4708027(C,G); rs151143603(A,G); rs146961692(A,T); rs4706527(A,G); rs1935535(G,T); rs1935536(A,C); rs7776143(A,C); rs7776435(C,T); rs1578674(A,C); rs6904597(G,A); rs6927120(T,C); rs4708029(T,G); rs4706528(C,A); rs150876959(G,A); rs4706529(T,C); rs7743399(A,G); rs7743974(G,A); rs7743780(A,G); rs79118151(T,C); rs77046031(A,G); rs73452859(G,A); rs9360636(G,C); rs9341404(A,G); rs73452861(A,G); rs6907117(T,C); rs6927134(A,G); rs6927759(G,A); rs6927779(G,T); rs6933361(G,A); rs6933440(C,A); rs6933648(A,C); rs75102173(A,T); rs11967588(T,C); rs60764744(G,A); rs9360638(T,G); rs9343005(G,T); rs9350488(C,T); rs11965567(G,A); rs9341407(T,G); rs9343006(G,A); rs9442887(T,C); rs9350489(C,T); rs9341408(C,A); rs9341409(C,A); rs191465293(A,T); rs2051025(T,C); rs1418414(C,T); rs947613(C,T); rs2051023(T,C); rs6453633(C,T); rs2051022(A,G); rs2051021(T,C); rs6921424(G,C); rs2051020(T,C); rs2066368(G,A); rs7762723(C,T); rs7763151(G,A); rs4708030(C,A); rs4708031(G,A); rs4708032(A,G); rs4708033(G,A); rs4708034(A,G); rs146468478(C,T); rs9293919(A,G); rs9293920(T,A); rs6453634(A,C); rs6453635(A,G); rs6453636(G,A); rs4235873(C,G); rs2350749(A,G); rs7751395(C,A); rs1935538(T,C); rs1935537(A,T); rs2000205(T,C); rs142465555(G,A); rs113487091(T,C); rs6453640(C,T); rs9446844(T,G); rs1935542(A,G); rs1935543(C,T); rs1342343(A,G); rs6917652(T,G); rs7739692(G,C); rs2350750(T,G); rs6453641(C,T); rs4379253(C,G); rs9360640(T,C); rs2350390(G,A); rs9343009(A,G); rs4708035(C,T); rs1891404(A,G); rs1111877(C,T); rs1935530(A,G); rs4084853(T,G); rs6453642(T,C); rs55704237(C,T); rs4706530(G,T); rs9359017(A,T); rs9360641(T,A); rs1935533(T,C); rs1935534(T,A); rs4635988(T,C); rs4142649(G,C); rs7748968(G,A); rs9446845(A,G); rs9293921(T,C); rs6453643(G,A); rs191046953(G,C); rs9442891(C,T); rs9442892(C,G); rs9442893(A,G); rs9446848(T,C); rs7772526(T,C); rs2796051(G,A); rs1418411(A,T); rs2796049(A,G); rs2796047(T,C); rs2796046(A,G); rs77727607(G,A); rs73454732(A,G); rs7768173(A,C); rs947611(T,C); rs180700273(T,C); rs78033930(C,T); rs73454734(G,A); rs6919630(A,G); rs79034941(A,G); rs6911409(T,A); rs9446851(A,G); rs9446852(A,G); rs9446853(G,A); rs9446854(A,G); rs7744354(G,T); rs7764373(T,C); rs7744386(C,T); rs7744394(C,G); rs7764571(T,A); rs112629319(G,A); rs6906616(A,G); rs6906825(A,G); rs6930212(T,C); rs6907569(A,T); rs6912022(C,T); rs9446856(C,A); rs9442895(A,G); rs112881562(G,A); rs11962533(C,G); rs1573057(C,G); rs61589891(G,A); rs2002125(A,G); rs947746(T,C); rs79442723(G,A); rs72951081(C,A); rs4235874(T,C); rs7748250(C,T); rs35291526(T,C); rs9343011(C,T); rs9343012(C,T); rs12208815(A,G); rs2350389(A,G); rs13207257(C,T); rs1974369(A,G); rs6453644(T,C); rs55756640(G,A); rs7765352(A,G); rs34000107(G,A); rs9446858(T,G); rs2027544(G,A); rs16883423(C,T); rs9360644(G,A); rs884957(G,A); rs72951099(G,A); rs7762949(T,G); rs6909792(C,T); rs7748040(A,G); rs7748418(A,G); rs12200591(G,C); rs952880(C,A); rs6939559(C,T); rs6939575(A,G); rs9360646(T,C); rs6940584(G,C); rs9341412(C,A); rs9293923(C,A); rs9359018(T,C); rs6931707(T,C); rs12206282(G,A); rs7747411(C,T); rs7751361(A,G); rs878523(A,G); rs947748(G,A); rs1815729(T,G); rs10428833(G,A); rs947747(T,C); rs1815728(A,G); rs112693001(C,T); rs1815727(A,G); rs1815726(C,T); rs2882406(G,A); rs2350388(C,T); rs2350387(G,A); rs7763514(C,T); rs6453650(G,A); rs12200306(A,G); rs72953123(C,T); rs75485693(G,T); rs2027545(G,A); rs74931273(G,T); rs3799278(A,G); rs9351979(T,C); rs12199673(C,A); rs1970547(G,T); rs75101658(T,C); rs58694306(A,G); rs3823118(G,A); rs1970548(G,A); rs72948806(A,G); rs1970549(G,A); rs6907229(C,T); rs9446860(C,T); rs9351980(T,A); rs7756501(G,A); rs9343015(C,T); rs2350386(G,C); rs9350490(C,T); rs2882405(A,G); rs2882404(C,T); rs3799280(C,T); rs6937240(C,T); rs6937253(C,G); rs9446861(T,C); rs2350385(T,C); rs150657380(G,A); rs10498891(T,C); rs3778268(T,C); rs3757105(G,A); rs2069085(A,G); rs16883476(A,G); rs118096221(T,C); rs3799286(A,G); rs144300640(C,T); rs9293925(A,G); rs17522390(G,A); rs9343016(G,A); rs6453651(A,G); rs9341413(A,G); rs75178700(A,G); rs61743058(C,T); rs17810318(G,A); rs35522191(A,G); rs10943078(A,T); rs16883494(C,T); rs10455270(T,C); rs10943079(A,C); rs74933502(G,A); rs12215980(A,G) |
| ccdsGene name | CCDS4976.1 |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 56479 |
| EntrezGene Description | potassium voltage-gated channel, KQT-like subfamily, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.8613 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0211081794195 |
| dbSNP GMAF | 0.01194 |
| ExAC AF | 0.013 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Gaze-evoked horizontal nystagmus;
Saccadic pursuits
ABDOMEN:
[Gastrointestinal];
Dysphagia
NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia;
Gait ataxia;
Truncal ataxia;
Limb ataxia;
Hyporeflexia;
Hyperreflexia (in some patients);
Dysarthria;
Postural tremor, slow, irregular (in some patients);
Cogwheel rigidity (in some patients);
Cerebellar atrophy;
Myoclonus (in a subset of patients);
Cognitive impairment (in some patients);
[Peripheral nervous system];
Impaired vibration sense at the ankles (in some patients)
MISCELLANEOUS:
Variable age at onset (range teens to late adult);
Slowly progressive
MOLECULAR BASIS:
Caused by mutation in the potassium voltage-gated channel, SHAL-related
subfamily, member 3 gene (KCND3, 605411.0001)
OMIM Title
*607357 POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 5; KCNQ5
;;POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY Q, MEMBER 5
OMIM Description
DESCRIPTION
Voltage-dependent potassium channels are key regulators of the resting
membrane potential and modulate the excitability of electrically active
cells. The channels are usually tetrameric and can interact with
auxiliary subunits that enhance or modify currents mediated by the
pore-forming subunits.
CLONING
Using homology with the KCNQ potassium channel family to identify
candidate ESTs, followed by screening a brain cDNA library, Lerche et
al. (2000) obtained a full-length KCNQ5 cDNA. The deduced 932-amino acid
protein has a calculated molecular mass of about 102 kD. KCNQ5 contains
6 transmembrane domains, with a pore domain between transmembrane
segments S5 and S6. It has several potential sites for protein kinase C
(see 176960) phosphorylation, but lacks the N-terminal site for
cAMP-dependent phosphorylation that is present in KCNQ1 (607542) and
KCNQ2 (602235). KCNQ5 shares 65% amino acid identity with KCNQ4
(603537), 50% identity with KCNQ3 (602232) and KCNQ2, and 40% identity
with KCNQ1, with greatest homology in the membrane-spanning region and
the pore region. Northern blot analysis revealed a major 7.5-kb
transcript in adult skeletal muscle and brain. Within brain, KCNQ5
showed strongest expression in cerebral cortex, occipital pole, frontal
lobe, and temporal lobe. In contrast to KCNQ2, KCNQ5 expression was
reduced or absent in cerebellum.
Schroeder et al. (2000) cloned KCNQ5 from a thalamus cDNA library and by
5-prime and 3-prime RACE of a brain cDNA library. They identified
several splice variants that differ in their cytoplasmic C-terminal
tails. One variant was isolated from brain, while another was isolated
from skeletal muscle. In situ hybridization of rat brain sections
confirmed widespread expression of Kcnq5 in brain and in superior
cervical ganglia. There was also a faint signal in rat cerebellum, in
contrast to Northern blot analysis of human brain regions that showed no
expression in cerebellum.
GENE FUNCTION
Lerche et al. (2000) found that, upon expression in Xenopus oocytes,
KCNQ5 generated voltage-dependent, slowly activating K(+)-selective
currents that showed inward rectification at positive membrane voltages.
The currents were insensitive to the K(+) channel blocker
tetraethylammonium, but were strongly inhibited by the selective
M-current blocker linopirdine. Coexpression of KCNQ5 with KCNQ3 resulted
in currents that showed significantly increased amplitude and slower
activation kinetics.
Schroeder et al. (2000) found that currents generated by KCNQ5 expressed
in Xenopus oocytes were also inhibited by M1 muscarinic receptor
(118510) activation and were activated by niflumic acid. A KCNQ5 splice
variant identified in skeletal muscle displayed altered gating kinetics,
notably a lack of current relaxations after hyperpolarizing voltage
steps.
By recording channel currents produced in cRNA-injected Xenopus oocytes,
Zhang et al. (2003) found that phosphatidylinositol (4,5)-bisphosphate
activated all members of the KCNQ channel family analyzed, including
KCNQ5.
MAPPING
By FISH, Lerche et al. (2000) and Schroeder et al. (2000) mapped the
KCNQ5 gene to chromosome 6q14.
DPPA5
| dbSNP name | rs76770796(C,T); rs73754622(G,C) |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 340168 |
| EntrezGene Description | developmental pluripotency associated 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0202 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus
SKELETAL:
Joint contractures (with age)
MUSCLE, SOFT TISSUE:
Muscle atrophy;
Muscle weakness
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Ataxia;
Tremor;
Spasticity;
Extensor plantar responses;
Hyperreflexia;
Cognitive deficits (less common);
Dysarthria (less common);
Leukoencephalopathy in the periventricular and deep white matter and
brainstem, cerebellum, and spinal cord tracts;
Lesions are symmetrical;
Magnetic resonance spectroscopy shows increased lactate in white matter;
[Peripheral nervous system];
Peripheral axonal neuropathy;
Hyporeflexia;
Decreased proprioception and vibration sense
MISCELLANEOUS:
Variable severity;
Onset between age 2 and 15 years;
Slowly progressive;
One patient with episodic ataxia and later onset has been reported
(as of June 2010)
MOLECULAR BASIS:
Caused by mutation in the aspartyl-tRNA synthetase 2 gene (DARS2,
610956.0001)
OMIM Title
*611111 DEVELOPMENTAL PLURIPOTENCY-ASSOCIATED GENE 5; DPPA5
;;EMBRYONAL STEM CELL-SPECIFIC GENE 1; ESG1
OMIM Description
CLONING
Using subtractive cDNA hybridization, Kim et al. (2005) identified mouse
developmental pluripotency-associated gene-5 (Dppa5), which is
differentially expressed in mouse primordial germ cells and gonocytes.
Using a bioinformatics approach, Kim et al. (2005) identified human
DPPA5. Northern blot analysis detected strong expression of mouse Dppa5
only in primordial germ cells, with rapid downregulation in gonocytes
and developing germ cells. Mouse Dppa5 was also expressed in embryonic
stem cells and embryonic carcinoma cells. RT-PCR detected expression of
human DPPA5 in primordial and embryonic germ cells and in embryonic stem
cells, but not in embryonic carcinoma cells. DPPA5 expression was
downregulated in differentiated human embryonic stem cells compared with
strong expression in undifferentiated human embryonic stem cells. No
expression of DPPA5 was detected in human somatic tissues by RT-PCR or
Northern blot analysis.
By searching for genes similar to the 3 mouse Khdc1 genes, Pierre et al.
(2007) identified a family of related genes in eutharian mammals. In
human, this family includes KHDC1 (611688), DPPA5, OOEP (611689), and
ECAT1 (611687). The proteins encoded by these genes contain an atypical
KH domain with amino acid changes at critical sites, suggesting that it
may not bind RNA like canonical KH domains.
MAPPING
By genomic sequence analysis, Pierre et al. (2007) mapped the DPPA5 gene
to chromosome 6q13. In mouse, the Dppa5 genes maps to chromosome 9E1.
EVOLUTION
Pierre et al. (2007) identified a family of KHDC1-related genes,
including DPPA5, in eutherian mammals, but not in fish, bird, or
opossum. These genes map to a single syntenic region in human,
chimpanzee, macaque, dog, and bovine, but a paracentric inversion
separated the genes in mouse and rat.
OOEP
| dbSNP name | rs496530(A,G); rs497243(A,C) |
| ccdsGene name | CCDS47451.1 |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 441161 |
| EntrezGene Description | oocyte expressed protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OOEP:NM_001080507:exon2:c.T275C:p.V92A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0036 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F2Z364 |
| dbNSFP KGp1 AF | 0.513736263736 |
| dbNSFP KGp1 Afr AF | 0.315040650407 |
| dbNSFP KGp1 Amr AF | 0.488950276243 |
| dbNSFP KGp1 Asn AF | 0.590909090909 |
| dbNSFP KGp1 Eur AF | 0.596306068602 |
| dbSNP GMAF | 0.4858 |
| ESP Afr MAF | 0.367243 |
| ESP All MAF | 0.488045 |
| ESP Eur/Amr MAF | 0.454589 |
| ExAC AF | 0.531 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Microphthalmia, bilateral;
Coloboma of iris;
Coloboma, choreoretinal;
Coloboma, uveoretinal
MISCELLANEOUS:
Reduced penetrance
MOLECULAR BASIS:
Caused by mutation in the sonic hedgehog gene (SHH, 600725.0016)
OMIM Title
*611689 OOCYTE-EXPRESSED PROTEIN, DOG, HOMOLOG OF; OOEP
;;KH HOMOLOGY DOMAIN-CONTAINING PROTEIN 2; KHDC2;;
FLOPED, MOUSE, HOMOLOG OF; FLOPED
OMIM Description
CLONING
By searching for genes similar to the 3 mouse Khdc1 genes, Pierre et al.
(2007) identified a family of related genes in eutharian mammals. In
human, this family includes KHDC1 (611688), DPPA5 (611111), OOEP, and
ECAT1 (611687). The proteins encoded by these genes contain an atypical
KH domain with amino acid changes at critical sites, suggesting that it
may not bind RNA like canonical KH domains.
GENE FUNCTION
Li et al. (2008) identified a subcortical maternal complex (SCMC) in
mouse that assembled during oocyte growth and was essential for zygotes
to progress beyond the first embryonic cell division. Within this large
complex, Floped, Mater (NRLP5; 609658), and Tle6 interacted with each
other, and Filia independently bound Mater. Although the transcripts
encoding these proteins were degraded during meiotic maturation and
ovulation, the SCMC persisted in the early embryo. The SCMC, which was
located in the subcortex of the egg, was excluded from regions of
cell-cell contact in the cleavage-stage embryo and segregated to the
outer cells of the morulae and blastocyst. Oocytes lacking Floped and/or
Mater were fertilized, but the embryos did not progress beyond the
cleavage stage of development, and female mice lacking Floped and/or
Mater were sterile.
MAPPING
By genomic sequence analysis, Pierre et al. (2007) mapped the OOEP gene
to chromosome 6q13. In mouse, the Ooep gene maps to chromosome 9E1.
EVOLUTION
Pierre et al. (2007) identified a family of KHDC1-related genes,
including OOEP, in eutherian mammals, but not in fish, bird, or opossum.
These genes map to a single syntenic region in human, chimpanzee,
macaque, dog, and bovine, but a paracentric inversion separated the
genes in mouse and rat.
COL12A1
| dbSNP name | rs560250(T,C); rs581649(A,T); rs970547(C,T); rs672648(C,A); rs516533(G,A); rs10755329(T,A); rs473777(C,T); rs860569(T,C); rs544419(T,C); rs515103(C,T); rs626497(G,A); rs146714320(T,G); rs556674(G,A); rs864983(G,C); rs1332021(C,A); rs370932323(G,A); rs600493(G,T); rs17186509(T,C); rs662965(A,T); rs636917(T,C); rs636885(G,T); rs636444(G,T); rs635567(C,A); rs17790499(T,A); rs620619(C,G); rs620129(G,T); rs499018(G,C); rs619607(C,T); rs240722(C,A); rs51630(T,C); rs6453815(A,G); rs1412710(T,C); rs240723(A,C); rs183552058(G,A); rs9443157(A,T); rs594013(T,C); rs11966644(A,C); rs556846(G,C); rs78654791(C,G); rs1412709(G,A); rs594012(A,T); rs4708174(A,C); rs240727(G,A); rs1332778(T,C); rs240730(C,A); rs1332020(C,T); rs1332019(C,A); rs2239643(T,C); rs240731(T,C); rs240732(A,G); rs240733(A,G); rs240734(G,A); rs240735(C,T); rs240736(A,G); rs240737(C,T); rs240738(G,A); rs240724(A,G); rs11753997(C,T); rs240725(A,G); rs185449009(A,G); rs184766(C,T); rs240741(T,C); rs76277336(T,C); rs7774649(C,T); rs114142785(G,C); rs147224848(A,G); rs4706592(T,C); rs17710795(A,G); rs17783615(C,T); rs9447453(C,A); rs35116474(T,C); rs114908543(C,T); rs240721(A,G); rs73747435(G,A); rs3777505(C,A); rs9360895(A,G); rs10484915(T,C); rs73747437(T,C); rs3777506(G,A); rs16886237(G,A); rs3777507(A,G); rs3777508(A,G); rs74406061(G,A); rs12198145(C,T); rs3777509(C,A); rs73463812(C,A); rs12215389(A,G); rs16886240(C,T); rs240412(T,G); rs240413(A,G); rs192448534(G,A); rs240414(G,A); rs240415(G,A); rs240416(A,C); rs240417(G,A); rs171264(G,A); rs9293997(T,C); rs743004(C,T); rs743005(C,G); rs145880018(A,T); rs1407734(C,G); rs743003(C,T); rs7768671(T,C); rs56131181(A,G); rs3777510(T,C); rs12176508(T,A); rs115285483(G,A); rs114204065(C,A); rs240433(A,T); rs1474847(C,T); rs588691(T,C); rs1998454(G,C); rs601846(A,G); rs4276458(A,G); rs1967709(A,T); rs1407733(A,T); rs9443160(C,T); rs910523(T,C); rs240363(T,A); rs240365(T,C); rs3756791(G,A); rs240366(C,T) |
| ccdsGene name | CCDS43481.1 |
| CosmicCodingMuts gene | COL12A1 |
| cytoBand name | 6q13 |
| EntrezGene GeneID | 1303 |
| EntrezGene Description | collagen, type XII, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL12A1:NM_080645:exon50:c.G5680A:p.G1894S,COL12A1:NM_004370:exon65:c.G9172A:p.G3058S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7553 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q99715-2 |
| dbNSFP KGp1 AF | 0.72206959707 |
| dbNSFP KGp1 Afr AF | 0.64837398374 |
| dbNSFP KGp1 Amr AF | 0.792817679558 |
| dbNSFP KGp1 Asn AF | 0.676573426573 |
| dbNSFP KGp1 Eur AF | 0.770448548813 |
| dbSNP GMAF | 0.2773 |
| ESP Afr MAF | 0.340933 |
| ESP All MAF | 0.255254 |
| ESP Eur/Amr MAF | 0.215719 |
| ExAC AF | 0.745 |
OMIM Clinical Significance
Eyes:
Agenesis of macula;
Coloboma of macula
Inheritance:
Autosomal dominant
OMIM Title
*120320 COLLAGEN, TYPE XII, ALPHA-1; COL12A1
OMIM Description
CLONING
By screening a cDNA library constructed from tendon fibroblast mRNA for
the presence of collagenous coding sequences, Gordon et al. (1987) found
a clone that encodes a polypeptide that is distinct but homologous to
type IX short-chain collagen polypeptides (see 120210). They named the
type IX-like collagen chain alpha-1(XII) (COL12A1). Gordon et al. (1987)
concluded that types IX and XII collagen are 2 homologous members of a
family of unique collagenous proteins that show tissue-specific patterns
of expression. Based on their structure and the properties of their
genes, this family of collagen appears to be distinct from fibrillar
collagens. This family, which also includes collagen type XIV (120324),
is referred to as the FACIT (fibril-associated collagens with
interrupted triple helices) group. Members of this group show
alternating triple-helical and non-triple-helical domains.
By screening a human genomic library with a chicken Col12a1 cDNA as
probe, Oh et al. (1992) isolated a partial COL12A1 cDNA. The predicted
amino acid sequence showed 91% identity with mouse Col12a1.
Gerecke et al. (1997) isolated overlapping cDNA clones encoding
full-length human COL12A1 polypeptides; a long variant encodes a
predicted 3,063-amino acid protein and a short variant encodes a
1,899-amino acid protein. The proteins are predicted to have a 24-amino
acid signal peptide, fibronectin type III repeats, von Willebrand factor
A domains, and 2 triple-helical domains. Human COL12A1 shares 92% and
78% sequence identity with the mouse and chicken Col12a1 proteins,
respectively. RT-PCR analysis detected both COL12A1 variants in human
amnion, chorion, skeletal muscle, and small intestine, and in cell
cultures of human dermal fibroblasts, keratinocytes, and endothelial
cells. Only the short variant was detected in human lung, placenta,
kidney, and in a squamous cell carcinoma cell line.
GENE STRUCTURE
Gordon et al. (1987) found that the exon/intron structure of the gene
appeared to be homologous to those of the COL9A1 (120210) and COL9A2
(120260) genes.
MAPPING
By linkage analysis using DNA from interspecific backcrosses with Mus
spretus, Oh et al. (1992) demonstrated that the mouse Col12a1 gene is
located on chromosome 9. By blot hybridization to DNA from human/hamster
hybrid cell lines, Oh et al. (1992) mapped the COL12A1 gene to
chromosome 6.
By fluorescence in situ hybridization, Gerecke et al. (1997) mapped the
COL12A1 gene to 6q12-q13.
MYO6
| dbSNP name | rs2647404(G,A); rs276692(T,C); rs73458855(A,C); rs276693(A,G); rs3798458(C,T); rs111696418(G,A); rs2748955(C,G); rs2748956(G,C); rs149184257(C,T); rs11963710(G,A); rs73458869(G,A); rs276695(T,C); rs3798457(G,T); rs276696(C,T); rs73458877(A,G); rs73460939(G,C); rs62414769(G,A); rs276698(T,C); rs181652631(C,T); rs2748957(T,C); rs9447545(G,T); rs182769281(T,G); rs6907476(T,C); rs2748958(G,A); rs9447546(C,G); rs113912075(G,A); rs3798456(G,A); rs72888782(A,G); rs6938349(A,T); rs72888788(C,T); rs3798453(T,C); rs3798452(A,G); rs17189990(A,G); rs2748959(T,G); rs6453838(C,T); rs9359139(C,G); rs190300806(A,T); rs2748960(A,G); rs2842547(T,C); rs9447550(C,T); rs7761217(A,C); rs2842545(C,A); rs6906615(T,C); rs374094668(G,A); rs9447552(G,A); rs2842544(C,T); rs72654762(A,G); rs73460988(C,T); rs2842538(T,G); rs9443189(A,G); rs6905047(C,T); rs67182025(G,C); rs112432305(T,C); rs12660493(G,T); rs2842540(A,G); rs73460999(A,G); rs11964201(A,G); rs2748963(T,G); rs6920348(T,G); rs6903077(A,G); rs72890617(A,T); rs2312940(T,C); rs2748964(G,A); rs2842541(G,A); rs78837814(A,G); rs9360940(A,G); rs9360941(A,G); rs1280038(C,T); rs1280040(T,C); rs721264(G,A); rs1280042(T,A); rs1280043(T,C); rs2842542(A,G); rs2748966(G,A); rs2842543(T,C); rs80324722(C,A); rs180796974(A,T); rs1280044(C,T); rs999209(T,A); rs56338010(G,A); rs1280047(A,G); rs1280048(C,T); rs1322550(A,G); rs6934542(G,A); rs3798448(G,A); rs11970551(G,A); rs2273859(G,A); rs10806048(C,A); rs10943292(G,A); rs72890648(A,G); rs12662659(T,C); rs3798447(C,T); rs1280049(A,C); rs138501851(A,T); rs1280050(A,G); rs1280051(G,A); rs1280052(G,A); rs1280053(G,A); rs910679(T,C); rs1280054(A,G); rs1280055(C,G); rs1280056(A,G); rs1280057(G,C); rs1280058(T,C); rs142748049(G,A); rs2181246(T,A); rs2181245(A,T); rs72890660(T,A); rs140603792(A,G); rs6924528(A,T); rs6453842(A,G); rs12209903(T,C); rs183349817(A,G); rs7760587(G,A); rs7748145(T,A); rs34090650(T,A); rs62414787(A,G); rs9359141(A,C); rs6453843(T,G); rs62414788(G,A); rs62414789(C,A); rs17191306(T,C); rs17794529(A,C); rs2038624(T,C); rs2038625(G,A); rs145290117(A,T); rs7742567(G,A); rs12526227(T,C); rs3798439(T,G); rs45463793(A,G); rs3818309(C,T); rs7773977(C,T); rs2004170(A,G); rs188452619(A,T); rs61237402(G,A); rs140116803(T,A); rs11758543(A,G); rs1322551(C,T); rs62414791(A,G); rs6912277(T,C); rs6932992(G,A); rs3778007(T,C); rs3778006(A,T); rs11756446(C,T); rs6453845(G,T); rs9343325(A,T); rs2312933(C,T); rs3798435(T,G); rs9360950(C,G); rs188998729(C,G); rs7761004(G,C); rs9443195(T,A); rs1407510(A,G); rs13202519(T,C); rs376388488(A,G); rs4476795(A,T); rs1358954(A,T); rs112650707(G,T); rs11755704(G,A); rs62414798(T,G); rs10498904(C,A); rs1335043(G,A); rs9359144(T,G); rs9359145(G,A); rs3798434(C,T); rs3798433(C,T); rs12202491(C,G); rs62414800(C,A); rs2295935(G,A); rs9341539(G,A); rs12664049(C,G); rs145181870(G,A); rs192549902(G,A); rs3798431(G,C); rs17800625(C,G); rs2295936(C,T); rs56006932(C,G); rs11753849(T,C); rs62414802(T,C); rs1535501(A,G); rs7767675(T,C); rs17192223(C,T); rs2295938(G,A); rs55905349(G,A); rs17192279(G,A); rs62414803(A,G); rs149593928(A,C); rs3798429(T,G); rs3798427(A,G); rs3857468(C,T); rs62414804(C,T); rs16886942(C,T); rs9294004(T,C); rs9294005(C,T); rs9343327(A,T); rs3798426(T,C); rs3822957(A,G); rs3798425(C,G); rs720863(G,A); rs720862(T,A); rs9360954(G,A); rs6921523(T,C); rs6453847(A,G); rs6942367(A,G); rs150924844(A,G); rs9447579(A,G); rs189411232(A,G); rs62414824(T,C); rs77554581(T,C); rs3818310(G,A); rs117645416(T,A); rs2104203(G,T); rs1322549(G,T); rs12606(C,T); rs699186(T,C); rs9360957(C,T); rs6914716(T,C); rs7741414(G,T); rs1341567(A,C); rs9443200(T,G); rs7742137(C,T); rs11964034(T,C); rs373146837(G,A); rs7766661(T,A); rs7746476(A,G) |
| ccdsGene name | CCDS34487.1 |
| cytoBand name | 6q14.1 |
| EntrezGene GeneID | 4646 |
| EntrezGene Description | myosin VI |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO6:NM_004999:exon32:c.A3367G:p.N1123D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5402 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UM54-2 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 9.758e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature, mild
SKELETAL:
[Pelvis];
Hip arthrosis;
[Limbs];
Osteoarthritis;
Small, irregular epiphyses;
Late ossifying epiphyses;
[Hands];
Normal hands;
Short metacarpals
MUSCLE, SOFT TISSUE:
Proximal muscle weakness (120270.0002);
Mild variability in muscle fiber size
LABORATORY ABNORMALITIES:
Mildly elevated creatine phosphokinase (CPK) (120270.0002)
MISCELLANEOUS:
Genetic heterogeneity (see EDM1 132400, EDM2 600204, EDM4 226900,
EDM5 607078);
Onset of symptoms in childhood with stiff, painful joints;
Joint replacement often necessary
MOLECULAR BASIS:
Caused by mutation in the collagen IX, alpha-3 polypeptide gene (COL9A3,
120270.0001)
OMIM Title
*600970 MYOSIN VI; MYO6
OMIM Description
DESCRIPTION
Myosin VI, one of the so-called unconventional myosins, is an
actin-based molecular motor involved in intracellular vesicle and
organelle transport (Rock et al., 2001; Hasson and Mooseker, 1994).
Myosin VI participates in 2 steps of endocytic trafficking; it is
recruited to both clathrin (see CLTC; 118955)-coated pits and to ensuing
uncoated endocytic vesicles (Naccache et al., 2006).
CLONING
Hasson and Mooseker (1994) characterized porcine myosin VI. Avraham et
al. (1995) showed that the sequence of the mouse Myo6 gene is 87%
identical to that of the pig. The mouse cDNA predicted a protein of
1,266 amino acids with a relative molecular mass of 142 kD. In the pig,
rat, and mouse, myosin VI is widely expressed. In the mouse, within the
cochlea of the inner ear, myosin VI is expressed specifically within the
sensory hair cells. Avraham et al. (1995) found that the Myo6 gene is
defective in the Snell's waltzer (sv) mouse mutant, which is associated
with deafness. Together with the expression pattern in the sensory hair
cells of the cochlea, this suggested to the authors that myosin VI is
required for normal hearing and that the human homolog is a candidate
for a human recessive deafness gene.
Avraham et al. (1997) cloned and characterized the human MYO6 cDNA.
Expression of MYO6 in human fetal cochlea demonstrated the importance of
myosin VI in the mammalian inner ear and supported its potential role in
human inner ear pathology.
Vreugde et al. (2006) identified 5 putative monopartite nuclear
localization signals and 1 putative bipartite nuclear localization
signal in MYO6, mainly in the tail region. In the first part of the tail
region, they identified a putative protein-protein interaction domain
consisting of glutamic acid- and arginine-rich regions.
Immunofluorescence and cellular fractionation of human and other
mammalian cells revealed a proportion of MYO6 in the nucleus, where it
colocalized with RNA polymerase II (see 180660) and nascent transcripts.
MYO6 in the nuclear fraction had an apparent molecular mass of 150 kD.
GENE STRUCTURE
Ahituv et al. (2000) determined that the MYO6 gene contains 32 exons and
spans 70 kb. They found that exon 30, which contains a putative casein
kinase II (see 115440) site, is alternatively spliced and appears only
in fetal and adult brain.
MAPPING
Avraham et al. (1995) suggested that the human MYO6 gene may map to the
centromeric region of chromosome 6, a region that shows syntenic
homology with the portion of mouse chromosome 9 where the Snell's
waltzer (sv) mouse mutation is located. On the basis of location of the
Myo6 gene in the mouse, Hasson et al. (1996) predicted that the
homologous human gene is located on 6p12-q16.3. By fluorescence in situ
hybridization, Avraham et al. (1997) mapped the MYO6 gene to 6q13. In
the mouse, Myo6 maps between Gsta and Htr1b; the human homologs, GSTA2
(138360) and HTR1B (182131), both map to chromosome 6.
GENE FUNCTION
Wells et al. (1999) visualized the myosin VI construct bound to actin
(see 102560) using cryoelectron microscopy and image analysis, and found
that an ADP-mediated conformational change in the domain distal to the
motor, a structure likely to be the effective lever arm, is in the
opposite direction to that observed for other myosins. Wells et al.
(1999) concluded that myosin VI achieves reverse-direction movement by
rotating its lever arm in the opposite direction to conventional myosin
lever arm movement.
Rock et al. (2001) noted that myosin VI moves toward the pointed end of
actin, whereas all other characterized myosins move toward the barbed
end. They found that porcine myosin VI took much larger steps than
expected. Unlike other characterized myosins, myosin VI stepping was
highly irregular, with a broad distribution of step sizes.
Rock et al. (2005) showed that the proximal tail region of porcine
myosin VI is a flexible domain that permits the myosin heads to separate
and allows the large and variable step size of myosin VI.
MYO6 is thought to function as both a transporter and an anchor. Altman
et al. (2004) noted that in vitro studies had suggested possible
mechanisms for processive stepping, but a biochemical basis for
anchoring had not been demonstrated. Using optical trapping, they
observed MYO6 stepping against applied forces. Step size was not
strongly affected by such loads. At saturating ATP, MYO6 kinetics showed
little dependence on load until, at forces near stall, its stepping
slowed dramatically as load increased. At subsaturating ATP or in the
presence of ADP, stepping kinetics were significantly inhibited by load.
Naccache et al. (2006) found that Myo6 recruitment to uncoated endocytic
vesicles in cultured mouse kidney epithelial cells was dependent on
synectin (GIPC1; 605072). Myo6 bound a C-terminal domain of synectin,
and Myo6 recruitment required the interaction between the PDZ-binding
domains of engulfed receptors, such as megalin (LRP2; 600073), and the
PDZ domain of synectin.
Vreugde et al. (2006) found that colocalization and interaction of MYO6
with RNA polymerase II required transcriptional activity. Pharmacologic
blockade of transcription resulted in redistribution of nuclear MYO6 to
the cytoplasm. Chromatin immunoprecipitation assays showed that MYO6 was
recruited to the promoters and intragenic regions of active genes, but
not to noncoding, nonregulatory intergenic regions. Downregulation of
MYO6 reduced steady-state mRNA levels of the regulated genes in vivo,
and antibodies to MYO6 reduced transcription in vitro. Vreugde et al.
(2006) concluded that MYO6 modulates RNA polymerase II-dependent
transcription of active genes and suggested that an actin-myosin-based
mechanism may be involved in transcription.
Otoferlin (OTOF; 603681) has been proposed to be the calcium sensor in
hair cell exocytosis, compensating for the classic synaptic fusion
proteins synaptotagmin-1 (SYT1; 185605) and synaptotagmin-2 (SYT2;
600104). Heidrych et al. (2009) demonstrated in a yeast 2-hybrid assay
that myosin VI is a novel otoferlin-binding partner.
Coimmunoprecipitation assay and coexpression suggested an interaction of
both proteins within the basolateral part of inner hair cells (IHCs).
Comparison of Otof- and Myo6-mutant mice indicated noncomplementary and
complementary roles of myosin VI and otoferlin for synaptic maturation.
IHCs from Otof-mutant mice exhibited a decoupling of Ctbp2 (602619) and
CaV1.3 (CACNA1D; 114206) and severe reduction of exocytosis. Myo6-mutant
IHCs failed to transport BK channels to the membrane of the apical cell
regions, and the exocytotic Ca(2+) efficiency did not mature. Otof- and
Myo6-mutant IHCs showed a reduced basolateral synaptic surface area and
altered active zone topography. Membrane infoldings in Otof-mutant IHCs
indicated disturbed transport of endocytotic membranes and linked the
above morphologic changes to a complementary role of otoferlin and
myosin VI in transport of intracellular compartments to the basolateral
inner hair cell membrane.
Roux et al. (2009) showed that Myo6 was present at the synaptic active
zone of IHCs by immunogold electron microscopy. In Myo6(sv/sv) mice,
ionic currents and ribbon synapse maturation of IHCs proceeded normally
until at least postnatal day 6. In adult Myo6(sv/sv) mice, however, the
IHCs displayed immature potassium currents and still fired action
potentials, as normally only observed in immature IHCs. In addition, the
number of ribbons per IHC was reduced, and some of the remaining ribbons
were morphologically immature. Calcium-dependent exocytosis was markedly
reduced despite normal calcium currents and a large proportion of
morphologically mature synapses. Yeast 2-hybrid assay, in vitro binding
assays, and immunoprecipitation studies of transfected HEK-293 cells and
mouse cochlear senory epithelium showed direct interaction of Myo6 and
otoferlin (OTOF; 603681). Immunogold electron microscopy showed that
Myo6 and otoferlin colocalized at the edge of the synaptic active zone
in mouse IHCs. Roux et al. (2009) suggested that MYO6/otoferlin
interaction may be involved in the recycling of synaptic vesicles.
BIOCHEMICAL FEATURES
- Crystal Structure
Menetrey et al. (2005) solved the crystal structure of a truncated
version of the reverse-direction myosin motor, myosin VI, containing the
motor domain and binding sites of 2 calmodulin (114180) molecules at a
resolution of 2.4 angstroms. The structure revealed only minor
differences in the motor domain from that in plus end-directed myosins,
with the exception of 2 unique inserts. The first is near the
nucleotide-binding pocket and alters the rates of nucleotide association
and dissociation. The second unique insert forms an integral part of the
myosin VI converter domain along with a calmodulin bound to a novel
target motif within the insert. This serves to redirect the effective
lever arm of myosin VI, which includes a second calmodulin bound to an
IQ motif, towards the pointed (minus) end of the actin filament. This
repositioning largely accounts for the reverse directionality of this
class of myosin motors. Menetrey et al. (2005) proposed a model
incorporating a kinesin-like uncoupling/docking mechanism to provide a
full explanation of the movements of myosin VI.
MOLECULAR GENETICS
In a large family segregating autosomal dominant nonsyndromic
sensorineural hearing loss, Melchionda et al. (2001) demonstrated
linkage of the disorder to 6q13 (DFNA22; 606346) and identified a
missense mutation in the MYO6 gene (C442Y; 600970.0001) in all affected
members.
Ahmed et al. (2003) identified mutations in the MYO6 gene in 3 families
segregating autosomal recessive congenital sensorineural deafness
(DFNB37; 607821); see 600970.0002-600970.0004.
In affected members of a kindred in which autosomal dominant
sensorineural deafness cosegregated with familial hypertrophic
cardiomyopathy, Mohiddin et al. (2004) identified a his246-to-arg
mutation in the MYO6 gene (H246R; 600970.0005).
In a large Danish family with 18 affected members segregating autosomal
dominant nonsyndromic hearing loss (DFNA22; 606346), Sanggaard et al.
(2008) detected heterozygosity for a nonsense mutation in the MYO6 gene
(R849X; 600970.0006).
Hilgert et al. (2008) analyzed the MYO6 gene in 2 Belgian families with
autosomal dominant deafness mapping to the DFNA22 locus and identified a
splice site mutation (600970.0007) in 'family 2.' No mutation was
identified in 'family 1,' although quantitative real-time PCR revealed
1.5- to 1.8-fold overexpression of MYO6 in patients compared to
controls. After exclusion of gene duplication, the authors suggested
that most likely the overexpression in 'family 1' involved a mutation in
an as-yet unidentified regulatory region of the MYO6 gene.
ANIMAL MODEL
Geisbrecht and Montell (2002) found that depletion of Myo6 from a small
group of migratory follicle cells of Drosophila, known as border cells,
inhibited their migration. Cells lacking Myo6 also lacked E-cadherin
(192090) and beta-catenin (116806). Conversely, cells lacking E-cadherin
or beta-catenin showed reduced levels of Myo6. Geisbrecht and Montell
(2002) concluded that, in Drosophila, Myo6 is required for border cell
migration where it stabilizes E-cadherin and beta-catenin.
The MYO15 (602666), MYO6, and MYO7A (276903) genes are essential for
hearing in both humans and mice. Despite widespread expression,
homozygosity for mutations in these genes only results in auditory or
ocular dysfunction. The pirouette (pi) mouse exhibits deafness and inner
ear pathology resembling that of Myo15 mutant mice. Karolyi et al.
(2003) crossed Myo15 mutant mice to Myo6, Myo7a, and pi mutant mouse
strains. Viable double-mutant homozygotes were obtained from each cross,
and hearing in doubly heterozygous mice was similar to singly
heterozygous mice. All critical cell types of the cochlear sensory
epithelium were present in double-mutant mice, and cochlear stereocilia
exhibited a superimposition of single-mutant phenotypes. Karolyi et al.
(2003) suggested that the function of Myo15 is distinct from that of
Myo6, Myo7a, or pi in development and/or maintenance of stereocilia.
HTR1B
| dbSNP name | rs6296(C,G); rs6298(G,A) |
| ccdsGene name | CCDS4986.1 |
| cytoBand name | 6q14.1 |
| EntrezGene GeneID | 3351 |
| EntrezGene Description | 5-hydroxytryptamine (serotonin) receptor 1B, G protein-coupled |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HTR1B:NM_000863:exon1:c.G861C:p.V287V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3526 |
| ESP Afr MAF | 0.224013 |
| ESP All MAF | 0.249423 |
| ESP Eur/Amr MAF | 0.262442 |
| ExAC AF | 0.306 |
OMIM Clinical Significance
Skin:
Seborrheic keratoses;
Congenital seborrheic verrucae
Inheritance:
Autosomal dominant form
OMIM Title
*182131 5-@HYDROXYTRYPTAMINE RECEPTOR 1B; HTR1B
;;SEROTONIN 5-HT-1B RECEPTOR;;
SEROTONIN 5-HT-1D-BETA RECEPTOR;;
5-@HYDROXYTRYPTAMINE-1D-BETA RECEPTOR; HTR1DB
OMIM Description
DESCRIPTION
The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a wide
variety of physiologic functions through a multiplicity of receptors and
may be involved in human neuropsychiatric disorders such as anxiety,
depression, or migraine. These receptors consist of several main groups
subdivided into several distinct subtypes on the basis of their
pharmacologic characteristics, coupling to intracellular second
messengers, and distribution within the nervous system (Zifa and
Fillion, 1992). The serotonergic receptors belong to the multigene
family of receptors coupled to guanine nucleotide-binding proteins.
CLONING
Hamblin et al. (1992) and Jin et al. (1992) isolated genomic clones for
the gene encoding the 5-hydroxytryptamine-1B receptor. They found that
it has the characteristics of a G protein-linked receptor and is most
homologous to the human 5-HT-1D receptor (182133). The gene was most
abundantly expressed in the striatum. Mochizuki et al. (1992) also
cloned the gene from human genomic DNA.
Some investigators (e.g., Demchyshyn et al., 1992) refer to the 5HT1B
receptor as the 5HT1DB receptor. Weinshank et al. (1992) isolated
genomic clones for two 5HT1D receptor genes, alpha (HTR1DA; 182133) and
beta. Demchyshyn et al. (1992) cloned the intronless gene encoding
5HT1D-beta (HTR1DB) and functionally expressed it in mammalian
fibroblast cultures. They concluded on the basis of the deduced amino
acid sequence that the gene encodes a 390-amino acid protein displaying
about 75% identity within putative transmembrane domains to the canine
and human 5HT1D receptors. Demchyshyn et al. (1992) stated: 'Although
the rat 5HT1B and human 5HT1D-beta receptor share an amino acid sequence
homology of more than 93%, we concur with arguments based on both
molecular and pharmacologic grounds, that the human receptor be
classified as a member of the 5HT1D-like family.'
GENE STRUCTURE
The HTR1B gene consists of a single exon (Demchyshyn et al., 1992).
GENE FUNCTION
Svenningsson et al. (2006) found that the 5HT1B receptor interacts with
p11 (114085). p11 increased localization of 5HT1B receptors at the cell
surface. p11 was increased in rodent brains by antidepressants or
electroconvulsive therapy, but decreased in an animal model of
depression and in brain tissue from depressed patients. Overexpression
of p11 increases 5HT1B receptor function in cells and recapitulated
certain behaviors seen after antidepressant treatment in mice. p11
knockout mice exhibited a depression-like phenotype and had reduced
responsiveness to 5HT1B receptor agonists and reduced behavioral
reactions to antidepressants.
BIOCHEMICAL FEATURES
- Crystal Structure
Wang et al. (2013) reported the crystal structures of human HTR1B bound
to the agonist antimigraine medications ergotamine and
dihydroergotamine. The structures reveal similar binding modes for these
ligands, which occupy the orthosteric pocket and an extended binding
pocket close to the extracellular loops. The orthosteric pocket is
formed by residues conserved in the 5-HT receptor family, clarifying the
familywide agonist activity of 5-HT. Compared with the structure of
HTR2B (601122), HTR1B displays a 3-angstrom outward shift at the
extracellular end of helix V, resulting in a more open extended pocket
that explains subtype selectivity. Together with docking and mutagenesis
studies, Wang et al. (2013) concluded that these structures provide a
comprehensive structural basis for understanding receptor-ligand
interactions and designing subtype-selective serotonergic drugs.
Wacker et al. (2013) reported biochemical studies showing that the
hallucinogen lysergic acid diethylamide (LSD), its precursor ergotamine
(ERG), and related ergolines display strong functional selectivity for
beta-arrestin (see ARRB1, 107940) signaling at HTR2B, whereas they are
relatively unbiased at HTR1B. To investigate the structural basis for
biased signaling, Wacker et al. (2013) determined the crystal structure
of human HTR2B bound to ERG and compared it with the HTR1B/ERG
structure.
MAPPING
By Southern blot analysis of a hybrid cell panel, Jin et al. (1992)
assigned the HTR1B gene to chromosome 6 and regionalized it to 6q13 by
chromosomal in situ hybridization. Simon-Chazottes et al. (1993) mapped
the Htr1b gene to mouse chromosome 9. Demchyshyn et al. (1992) suggested
that the presence of a RFLP related to the 5HT1B gene can be used for
linkage mapping.
MOLECULAR GENETICS
Smoller et al. (2006) sought to examine haplotype structure of the
5HTR1B gene in reference to ADHD (143465) by genotyping 21 SNPs in and
around the gene in 12 multigenerational CEPH pedigrees. A haplotype
block encompassing the gene was identified and single-marker association
analyses for 8 SNPs within this block was performed in 229 families of
ADHD probands to include association with inattentive and combined ADHD
subtypes. Although Hawi et al. (2002) and Quist et al. (2003) had
reported association of the G861 variant (861G-C) with ADHD, Smoller et
al. (2006) observed only nonsignificant overtransmission of the G861
allele to ADHD offspring (one-tailed p = 0.07). Single-marker and
haplotype tests of a haplotype block encompassing 5HTR1B revealed no
other associations with ADHD. However, the haplotype block was
associated with the inattentive subtype (global p less than 0.01).
Additionally, 3 polymorphisms in this block were nominally associated
with the inattentive subtype, but the associations did not remain
significant after correction for multiple testing (p less than 0.05).
Paternal overtransmission of G861 alleles to offspring with ADHD was
observed and was largely attributable to inattentive cases.
ANIMAL MODEL
Serotonin, acting through many receptors, can modulate the activity of
neural reward pathways and thus the effects of various drugs of abuse.
Rocha et al. (1998) examined the effects of cocaine in mice lacking one
of the serotonin receptor subtypes, the 5-HT1B-receptor. They showed
that mice lacking this receptor displayed increased locomotor responses
to cocaine and were more motivated to self-administer cocaine. Rocha et
al. (1998) proposed that even drug-naive 5-HT1B knockout mice are in a
behavioral and biochemical state that resembles that of wildtype mice
sensitized to cocaine by repeated exposure to the drug. This altered
state may be responsible for their increased vulnerability to cocaine.
The triptans are an established class of antimigraine drugs that act
selectively via 5-HT1B/1D receptors, particularly in the trigeminal
system. In rats, Bartsch et al. (2004) found that infusion of
naratriptan into the ventrolateral periaqueductal gray matter activated
descending pain-modulating pathways that inhibited dural nociceptive
input; however, similar effects were not observed for facial or corneal
input. The findings implicated a novel mode of action of triptans.
HMGN3-AS1
| dbSNP name | rs372400801(T,C); rs1060419(G,A); rs12202025(T,G); rs149057958(C,G) |
| cytoBand name | 6q14.1 |
| EntrezGene GeneID | 100288198 |
| snpEff Gene Name | HMGN3 |
| EntrezGene Description | HMGN3 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
TPBG
| dbSNP name | rs4590314(A,G); rs700494(G,A); rs700495(T,C) |
| cytoBand name | 6q14.1 |
| EntrezGene GeneID | 7162 |
| EntrezGene Description | trophoblast glycoprotein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3347 |
OMIM Clinical Significance
Eyes:
Tritanopia;
Defective blue and yellow vision;
Normal red and green vision
Lab:
Abnormal blue cone ERG
Inheritance:
Autosomal dominant (7q31.3-q32)
OMIM Title
*190920 TROPHOBLAST GLYCOPROTEIN; TPBG
;;M6P1
OMIM Description
CLONING
The cell surface antigen defined by monoclonal antibody 5T4 is a 72-kD
glycoprotein that is expressed by all types of trophoblasts as early as
9 weeks of development. It is specific for trophoblastic cells except
for amniotic epithelium, which is also antigen-positive. In adult
tissues, the 5T4 expression is limited to a few epithelial cell types
but is found on a variety of carcinomas and has been suggested as a
marker for premalignant dysplastic changes in the cervix (Boyle et al.,
1990).
By micropeptide sequence analysis, PCR with degenerate primers, and
screening of a placenta cDNA library, Myers et al. (1994) obtained a
cDNA encoding 5T4, or TPBG. The deduced 420-amino acid protein contains
an N-terminal putative signal sequence, a 310-residue extracellular
region, a membrane anchorage domain, and a 44-amino acid cytoplasmic
tail with a potential phosphorylation site. The extracellular region has
7 potential N-glycosylation sites and 7 leucine-rich repeats, which are
located in 2 regions separated by a hydrophilic stretch.
Immunoprecipitation analysis showed expression of a 45-kD protein before
N-glycosylation, which gives rise to a 72-kD protein. Northern blot
analysis revealed expression of a major 2.5-kb transcript, as well as a
possible 2.0-kb transcript, in several tumor cell lines.
King et al. (1999) cloned mouse Tpbg, which encodes a protein that is
81% identical to human TPBG. Northern blot and RNase protection analyses
detected most abundant expression of Tpbg in mouse embryo and placenta,
while in adult mouse it was expressed only in brain and ovary.
GENE STRUCTURE
By genomic sequence analysis, King et al. (1999) determined that the
human and mouse TPBG genes contain 2 exons, the second of which encodes
the protein. The promoter region contains no TATA or CAAT boxes, but
does have a number of potential SP1-binding sites.
MAPPING
Boyle et al. (1990) stained human-rodent hybrids by indirect
immunofluorescence with 5T4 and analyzed them by flow cytometry.
Concordance analysis indicated that the M6P1 gene maps to chromosome 6.
Similar analysis with translocation hybrids gave a regional assignment
to 6q14-q15. M6P1 is distinct from NT5 (129190), which codes for
ecto-5-prime-nucleotidase and maps to the same region.
GJB7
| dbSNP name | rs116687492(T,C); rs2240461(G,A); rs142617101(G,C); rs3812130(G,A); rs6934603(A,G); rs111624269(G,A); rs41273281(G,A); rs73754173(C,T); rs35259282(C,T); rs41273283(G,A); rs4707358(G,A); rs6921007(T,C); rs73754174(T,A); rs115767902(C,T); rs187220841(T,C); rs9359743(C,A); rs9344697(T,C); rs73485851(G,A); rs76350186(T,A); rs7753030(C,T); rs60992482(T,G); rs114455461(C,T); rs9450650(T,C); rs9359744(T,C); rs142551071(C,T); rs9344698(A,G); rs9450651(A,G); rs61571427(T,C); rs9353473(T,A); rs148684465(C,T); rs147903272(C,T); rs59138817(A,C); rs6940544(G,A); rs9294376(G,A); rs3857488(A,G); rs6925890(T,C); rs116188986(C,T); rs9450652(A,G); rs9444491(T,G); rs58731649(A,C); rs9362418(C,T); rs11759727(T,C); rs9450653(G,A); rs6921010(A,G); rs6454600(G,T); rs116581236(G,A); rs6921673(C,T); rs16878942(A,G); rs6926686(C,T); rs73485865(G,A); rs56193950(T,C); rs61437530(C,T); rs56678817(G,C); rs138311041(A,G); rs6938885(A,G); rs6939075(C,T); rs57043501(A,G); rs17453321(T,G); rs10498960(C,T); rs440296(G,A); rs57780241(C,T); rs73754184(C,T); rs410683(T,C); rs1328477(T,G); rs11964518(T,A); rs11962012(G,A); rs111665161(C,G); rs55858529(T,C); rs73754185(G,A); rs430861(G,C); rs9342109(C,T); rs371814(C,T); rs77468664(C,T); rs60818849(C,T); rs58915055(A,G); rs425020(C,A); rs112904557(C,G); rs422086(A,C); rs149437320(A,C); rs446274(G,A); rs434994(A,G); rs140435362(G,A); rs113124602(A,C); rs140365586(G,A); rs142640233(A,T); rs140902508(C,T); rs2325045(T,C); rs192095816(A,G); rs184033991(C,T); rs6930255(C,T); rs6930411(C,G); rs242262(A,C); rs242263(C,A); rs6454601(C,T); rs114792970(C,T); rs73754188(A,G); rs59660308(T,C); rs59322(C,A); rs60182652(G,A); rs1145712(G,A); rs413687(A,G); rs1359982(C,A); rs414453(A,G); rs368267(C,T); rs411606(G,A); rs56305030(C,T); rs827433(C,T); rs57552196(C,A); rs111990232(A,C); rs1145713(T,C); rs384318(G,T); rs140517078(T,G); rs382956(A,T); rs150448131(C,T); rs73754193(C,T); rs1145714(T,C); rs1145715(A,G); rs1203162(A,G); rs1145716(G,A); rs12663251(C,T); rs1203163(C,A); rs1203164(C,T); rs1188806(A,G); rs59445510(C,A); rs16878991(T,C); rs2983136(C,G); rs2236048(G,C); rs16878999(A,G); rs242282(C,A); rs9359745(G,A); rs2875533(G,T); rs113978019(G,A); rs242283(C,T); rs142981251(G,A); rs181491(G,C) |
| ccdsGene name | CCDS5008.1 |
| cytoBand name | 6q14.3 |
| EntrezGene GeneID | 375519 |
| EntrezGene Description | gap junction protein, beta 7, 25kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GJB7:NM_198568:exon3:c.C530T:p.T177M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5967 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6PEY0 |
| dbNSFP Uniprot ID | CXB7_HUMAN |
| dbNSFP KGp1 AF | 0.0659340659341 |
| dbNSFP KGp1 Afr AF | 0.19918699187 |
| dbNSFP KGp1 Amr AF | 0.0359116022099 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0435356200528 |
| dbSNP GMAF | 0.06612 |
| ESP Afr MAF | 0.186564 |
| ESP All MAF | 0.088959 |
| ESP Eur/Amr MAF | 0.038953 |
| ExAC AF | 0.049,1.626e-05,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic (episodes last from hours to days);
Weakness;
Dysarthria;
Vertigo;
Normal interictal neurologic examination
MISCELLANEOUS:
Onset before age 20 years;
Symptoms precipitated by exercise and excitement;
Episode frequency is monthly to yearly, and decreases with age
OMIM Title
*611921 GAP JUNCTION PROTEIN, BETA-7; GJB7
;;CONNEXIN 25; CX25
OMIM Description
DESCRIPTION
Connexins, such as GJB7, are involved in the formation of gap junctions,
intercellular conduits that directly connect the cytoplasms of
contacting cells. Each gap junction channel is formed by docking of 2
hemichannels, each of which contains 6 connexin subunits (Sohl et al.,
2003).
CLONING
By database analysis and PCR of human genomic DNA, Sohl et al. (2003)
cloned GJB7, which they called CX25. Northern blot analysis detected
weak expression of a 2.7-kb CX25 transcript in placenta only. Sohl et
al. (2003) stated that there is no ortholog of CX25 in mouse.
MAPPING
Hartz (2008) mapped the GJB7 gene to chromosome 6q15 based on an
alignment of the GJB7 sequence (GenBank GENBANK AJ414563) with the
genomic sequence (build 36.1).
GJA10
| dbSNP name | rs375047219(A,C); rs41273337(T,A) |
| ccdsGene name | CCDS5025.1 |
| cytoBand name | 6q15 |
| EntrezGene GeneID | 84694 |
| EntrezGene Description | gap junction protein, alpha 10, 62kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GJA10:NM_032602:exon1:c.A623C:p.K208T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9804 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q969M2 |
| dbNSFP Uniprot ID | CXA10_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0002033 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic (episodes last from hours to days);
Weakness;
Dysarthria;
Vertigo;
Normal interictal neurologic examination
MISCELLANEOUS:
Onset before age 20 years;
Symptoms precipitated by exercise and excitement;
Episode frequency is monthly to yearly, and decreases with age
OMIM Title
*611924 GAP JUNCTION PROTEIN, ALPHA-10; GJA10
;;CONNEXIN 62; CX62
OMIM Description
DESCRIPTION
Connexins, such as GJA10, are involved in the formation of gap
junctions, intercellular conduits that directly connect the cytoplasms
of contacting cells. Each gap junction channel is formed by docking of 2
hemichannels, each of which contains 6 connexin subunits (Sohl et al.,
2003).
CLONING
By database analysis and PCR of human genomic DNA, Sohl et al. (2003)
cloned GJA10, which they called CX62. CX62 shares 78% amino acid
identity with its mouse ortholog, Cx57. Northern blot analysis detected
a 6.5-kb CX62 transcript in skeletal muscle and heart. Mouse Cx57
appeared to be more widely expressed.
MAPPING
Hartz (2008) mapped the GJA10 gene to chromosome 6q15 based on an
alignment of the GJA10 sequence (GenBank GENBANK AF296766) with the
genomic sequence (build 36.1).
MIR4464
| dbSNP name | rs377173986(G,T) |
| cytoBand name | 6q15 |
| EntrezGene GeneID | 100616109 |
| EntrezGene Description | microRNA 4464 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
MANEA
| dbSNP name | rs9387286(G,C); rs35387650(A,C); rs9400791(G,A); rs4464805(C,T); rs6930923(G,A); rs188676603(A,T); rs9398406(G,C); rs5000127(C,A); rs4256442(T,C); rs11153557(G,C); rs75431892(C,T); rs56286533(G,A); rs9387337(T,C); rs34820653(T,G); rs9384949(T,C); rs4368819(T,G); rs9398417(A,T); rs79858813(A,T); rs12181984(G,A); rs9488739(C,T); rs9387352(G,A); rs4571575(G,A); rs9481588(C,G); rs7758062(C,T); rs9400875(T,C); rs9398423(T,G); rs28750136(A,T); rs28623752(A,G); rs13205436(T,C); rs62417812(C,T); rs9374586(T,C); rs12661585(A,G); rs6904857(A,G); rs6940020(C,T); rs9400886(T,G); rs6568922(T,G); rs12525680(C,A); rs7749186(A,T); rs36064173(G,A); rs9374594(C,T); rs9400893(A,G); rs9372457(T,C); rs9488910(T,C); rs13192906(A,G); rs6568937(C,G); rs6568939(C,T); rs7743199(G,A); rs9320566(T,C); rs7772996(C,A); rs9488970(G,A); rs7773709(C,T); rs6568958(T,C); rs7757276(T,G); rs4461741(C,G); rs4461742(C,T); rs4466257(C,T); rs9387442(T,C); rs9400980(G,C); rs6932114(C,A); rs6903017(T,C); rs6903580(T,C); rs4486026(C,T); rs35381249(A,C); rs6915218(T,A); rs62417816(A,G); rs12663784(G,A); rs4302677(A,T); rs4424094(A,G); rs4467786(T,A); rs9387502(C,T); rs9372484(T,C); rs9387512(T,A); rs35772543(T,A); rs9374688(A,T); rs9401034(G,T); rs1133503(C,T); rs9387522(C,A); rs9481750(G,A); rs76110887(T,A); rs7771284(G,A); rs7771867(G,C); rs7748888(C,T); rs117844878(C,A); rs9387562(G,T) |
| ccdsGene name | CCDS5032.1 |
| cytoBand name | 6q16.1 |
| EntrezGene GeneID | 79694 |
| EntrezGene Description | mannosidase, endo-alpha |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MANEA:NM_024641:exon5:c.T1030A:p.F344I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8694 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0622710622711 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0801104972376 |
| dbNSFP KGp1 Asn AF | 0.0646853146853 |
| dbNSFP KGp1 Eur AF | 0.089709762533 |
| dbSNP GMAF | 0.06198 |
| ESP Afr MAF | 0.019065 |
| ESP All MAF | 0.063365 |
| ESP Eur/Amr MAF | 0.086067 |
| ExAC AF | 0.068 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
External ophthalmoplegia (less common);
Optic atrophy;
Nystagmus;
Strabismus
GENITOURINARY:
[Bladder];
Urinary urgency;
Incontinence (variable)
NEUROLOGIC:
[Central nervous system];
Spasticity, primarily lower limbs, but upper limbs may be involved;
Gait difficulties;
Spastic quadriparesis;
Ataxia;
Hyperreflexia;
Dystonia;
Dysarthria;
Dysmetria;
Cognitive decline;
Poor school performance;
Extensor plantar responses;
Seizures;
Thinning of the corpus callosum;
Brainstem atrophy;
Cerebellar atrophy;
Leukodystrophy, dysmyelinating;
Periventricular white matter abnormalities;
White matter hyperintensities in T2 imaging;
Iron deposition in the globus pallidus (variable)
MISCELLANEOUS:
Onset between 3 and 11 years of age;
Progressive disorder;
Most patients become wheelchair-bound in adolescence or as young adults
MOLECULAR BASIS:
Caused by mutation in the fatty acid 2-hydroxylase gene (FA2H, 611026.0001)
OMIM Title
*612327 MANNOSIDASE, ENDO-ALPHA; MANEA
;;ENDO-ALPHA-1,2-MANNOSIDASE;;
ENDOMANNOSIDASE;;
ENDO
OMIM Description
DESCRIPTION
N-glycosylation of proteins is initiated in the endoplasmic reticulum
(ER) by the transfer of the preassembled oligosaccharide
glucose-3-mannose-9-N-acetylglucosamine-2 from dolichyl pyrophosphate to
acceptor sites on the target protein by an oligosaccharyltransferase
complex. This core oligosaccharide is sequentially processed by several
ER glycosidases and by an endomannosidase (E.C. 3.2.1.130), such as
MANEA, in the Golgi. MANEA catalyzes the release of mono-, di-, and
triglucosylmannose oligosaccharides by cleaving the alpha-1,2-mannosidic
bond that links them to high-mannose glycans (Hamilton et al., 2005).
CLONING
By searching databases for sequences similar to rat liver Manea,
followed by RT-PCR of human fibroblasts and PCR of a liver cDNA library,
Hardt et al. (2005) cloned MANEA. The deduced 462-amino acid protein
contains a putative type II transmembrane domain near the N terminus and
shares about 77.8% identity with rat liver Manea. Fluorescence-tagged
MANEA was expressed in the Golgi of transfected COS-1 cells. Protease
digestion of microsomal membranes confirmed that MANEA has a type II
topology, with the N terminus directed toward the cytosol and most of
the enzyme facing the luminal side of the microsomes.
Hamilton et al. (2005) cloned MANEA, which they called ENDO, by PCR of a
liver cDNA library. The deduced 462-amino acid protein has a calculated
molecular mass of 54 kD. Northern blot analysis detected a 5.1-kb MANEA
transcript in all tissues examined. Expression was highest in liver and
kidney, moderate in muscle, pancreas, heart, placenta, and lung, and low
in brain. Western blot analysis of epitope-tagged MANEA expressed in
yeast suggested that MANEA is proteolytically processed at the C
terminus.
GENE FUNCTION
Hardt et al. (2005) found that recombinant MANEA, and MANEA expressed by
transfected COS-1 cells, displayed endo-alpha-1,2-mannosidase activity
against a radiolabeled substrate at neutral pH.
By domain analysis, Hamilton et al. (2005) showed that the N-terminal
domain of MANEA directs its Golgi localization.
GENE STRUCTURE
Hamilton et al. (2005) determined that the MANEA gene contains 4 exons
and spans about 20 kb.
MAPPING
By genomic sequence analysis, Hamilton et al. (2005) mapped the MANEA
gene to chromosome 6q16.
FHL5
| dbSNP name | rs79655171(A,G); rs80096588(T,A); rs2499777(T,C); rs75505488(T,G); rs116735667(C,T); rs114396335(T,C); rs2499778(C,T); rs56709617(G,T); rs74462104(T,C); rs59771953(G,A); rs76977938(C,T); rs144683510(T,C); rs76126568(T,C); rs79021999(G,A); rs117326818(C,T); rs9285393(C,A); rs72932894(T,G); rs9486613(C,T); rs113432850(C,A); rs57933707(G,T); rs2971602(C,T); rs117126982(T,A); rs143038104(A,G); rs211158(C,G); rs211159(G,A); rs211160(G,A); rs375219857(T,C); rs10485062(T,C); rs77109066(C,G); rs2971610(C,T); rs75121691(A,G); rs3798290(G,A); rs2983896(G,A); rs59043091(A,G); rs59649889(C,T); rs3798293(A,G); rs2983897(G,A); rs1475748(T,C); rs145664984(T,A); rs9400124(C,T); rs115617316(A,G); rs114401110(C,T); rs2971603(C,T); rs75704918(G,A); rs211187(A,G); rs143527941(A,G); rs79583299(T,C); rs113972934(G,T); rs76526104(C,G); rs2971609(A,G); rs2971608(T,C); rs2971607(A,G); rs143325929(T,C); rs147102079(G,T); rs9386653(C,A); rs143966467(G,C); rs138985363(A,G); rs114796221(T,C); rs76934779(A,G); rs2983898(C,T); rs2983899(G,T); rs2971606(C,G); rs115118346(T,C); rs7767682(C,T); rs113292035(A,G); rs78922078(G,A); rs9373959(A,G); rs116790670(A,T); rs17056749(G,C); rs77108040(G,C); rs1010092(G,A); rs9486663(G,C); rs2971605(A,G); rs113524891(T,C); rs2983902(T,C); rs78879360(C,T); rs149811152(G,A); rs113942825(T,C); rs75438651(T,G); rs78331498(C,A); rs211186(T,C); rs3849199(T,C); rs117760394(G,A); rs80206718(A,G); rs137924031(G,A); rs79751319(G,A); rs76632738(C,T); rs77182239(C,T); rs1855533(T,C); rs144606443(T,C); rs2021671(T,C); rs148466297(C,T); rs73492769(T,G); rs111971478(A,C); rs73492770(A,C); rs138076325(G,A); rs140457153(T,A); rs73492775(T,G); rs111802467(G,T); rs113657700(T,A); rs113402280(G,A); rs139419842(G,A); rs7741683(A,G); rs73492783(T,C); rs7775721(C,T); rs17056769(T,A); rs56698553(G,A); rs9386663(T,C); rs2273621(A,G); rs2252816(G,A); rs111924366(A,G); rs112698195(A,G); rs9486705(T,C); rs112937350(G,A); rs9486708(T,C); rs79807176(G,A); rs79239558(A,G); rs77276372(C,A); rs113053309(T,C); rs112050555(G,A); rs11153082(A,G); rs9486715(A,C); rs9486719(G,A); rs9386666(A,T); rs9386670(C,A); rs9486725(C,T); rs111274063(C,G); rs61004809(G,C); rs75510803(T,C); rs376599868(T,A); rs114342218(G,T); rs211161(T,G); rs3798297(C,T); rs6902835(C,G); rs9373985(C,G); rs9398148(A,G); rs9398152(T,G) |
| ccdsGene name | CCDS5035.1 |
| cytoBand name | 6q16.1 |
| EntrezGene GeneID | 9457 |
| EntrezGene Description | four and a half LIM domains 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FHL5:NM_001170807:exon5:c.A610G:p.R204G,FHL5:NM_020482:exon6:c.A610G:p.R204G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5732 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5TD97 |
| dbNSFP Uniprot ID | FHL5_HUMAN |
| dbNSFP KGp1 AF | 0.392399267399 |
| dbNSFP KGp1 Afr AF | 0.558943089431 |
| dbNSFP KGp1 Amr AF | 0.348066298343 |
| dbNSFP KGp1 Asn AF | 0.351398601399 |
| dbNSFP KGp1 Eur AF | 0.336411609499 |
| dbSNP GMAF | 0.3921 |
| ESP Afr MAF | 0.493872 |
| ESP All MAF | 0.392588 |
| ESP Eur/Amr MAF | 0.334419 |
| ExAC AF | 0.348 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Alzheimer disease;
Seizures;
Cerebral cortex with spongiform changes;
Neurofibrillary tangles;
Beta-amyloid-positive senile plaques;
Prion protein-positive senile plaques
MISCELLANEOUS:
Age of onset 43-64 years
OMIM Title
*605126 FOUR-AND-A-HALF LIM DOMAINS 5; FHL5
;;ACTIVATOR OF CREM IN TESTIS; ACT
OMIM Description
DESCRIPTION
ACT is a LIM-only protein that interacts with transcription factor CREM
(123812) in postmeiotic male germ cells and enhances CREM-dependent
transcription (Kotaja et al., 2004). LIM proteins are defined by the
possession of a highly conserved double zinc finger motif called the LIM
domain.
CLONING
By performing a yeast 2-hybrid screen on a mouse testis cDNA expression
library using the CREM activation domain as bait, Fimia et al. (1999)
isolated a cDNA encoding Act (activator of CREM in testis), a LIM-only
protein that specifically associates with CREM. The LIM domain is a
cysteine-rich, double-zinc finger structural motif involved in
protein-protein interactions. Act bypasses the classic requirements for
CREM activation, namely phosphorylation of ser117 and interaction with
CREB-binding protein (CREBBP; 600140). Northern blot analysis revealed
that expression of Act is restricted to testis. Western blot analysis
determined that Act colocalizes in purified spermatids with CREM.
Using the mouse sequence as query, Morgan and Whawell (2000) identified
an EST containing ACT. The deduced 284-amino acid protein contains an
N-terminal half-LIM domain followed by 4 LIM domains. ACT shares 58.5%
identity with FHL2 (602633) and 85% identity with mouse Act. Northern
blot analysis revealed moderate to high levels of expression in all
squamous cell carcinoma, melanoma, and leukemia tumor cell lines tested.
Using the mouse sequence to design primers, Palermo et al. (2001) cloned
ACT by PCR and conventional screening of a testis cDNA library. The
deduced 284-amino acid protein shares 88% homology with mouse Act.
Western blot analysis of mouse and human testis revealed a single band
of about 33 to 34 kD.
GENE FUNCTION
By deletion analysis of mouse Act, Fimia et al. (2000) determined that
the activation function of Act depends on the specific arrangement of
the LIM domains, which are essential for both transactivation and
dimerization with wildtype Act sequences.
ACT is expressed exclusively in round spermatids, where it cooperates
with transcriptional activator CREM in regulating various postmeiotic
genes. Targeted inactivation of CREM leads to a complete block of mouse
spermiogenesis. Macho et al. (2002) sought to identify the regulatory
steps controlling the functional interplay between CREM and ACT. They
found that ACT selectively associates with KIF17b (see 605037), a
kinesin isoform highly expressed in male germ cells. The ACT-KIF17b
interaction is restricted to specific stages of spermatogenesis and
directly determines the intracellular localization of ACT. Sensitivity
to leptomycin B indicates that KIF17b can be actively exported from the
nucleus through the CRM1 receptor (602559). Thus, Macho et al. (2002)
concluded that a kinesin directly controls the activity of a
transcriptional coactivator by a tight regulation of its intracellular
localization.
GENE STRUCTURE
Morgan and Whawell (2000) identified 5 coding exons of the ACT gene
spanning 13 kb. Palermo et al. (2001) determined that the ACT gene
contains 6 exons. The first exon is untranslated.
MAPPING
By genomic sequence analysis, Morgan and Whawell (2000) mapped the FHL5
gene to chromosome 6q16.1-q16.3. By genomic sequence analysis and by
FISH, Palermo et al. (2001) confirmed the assignment of the FHL5 gene to
chromosome 6q16.1-q16.3.
ANIMAL MODEL
To investigate the role of ACT in vivo, Kotaja et al. (2004) used gene
targeting to generate Act-null mice by homologous recombination.
Although the stages of spermatogenesis seemed phenotypically normal,
mutant mice displayed a drastically decreased number of mature germ
cells. In addition, a large proportion of the residual mature cells
showed aberrations in tail and head morphology. These observations
indicated that many genes whose function is crucial to the generation of
mature germ cells are under the regulatory control of ACT. These genes
were thought to represent a subset of the postmeiotic genes controlled
by CREM. Kotaja et al. (2004) concluded that the fine tuning of sperm
development is achieved by the coordinated action of 2 transcriptional
regulators.
POU3F2
| dbSNP name | rs3823036(T,C); rs79872709(C,T) |
| cytoBand name | 6q16.1 |
| EntrezGene GeneID | 5454 |
| EntrezGene Description | POU class 3 homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4118 |
OMIM Clinical Significance
Metabolic:
Malignant hyperthermia;
Acidosis;
Hypoxia
Misc:
Triggered by certain anesthetics, such as halothane or succinylcholine;
Rapid body temperature rise
Muscle:
Masseter or generalized muscle contracture;
Rhabdomyolysis
Inheritance:
Autosomal dominant (3q13.1)
OMIM Title
*600494 POU DOMAIN, CLASS 3, TRANSCRIPTION FACTOR 2; POU3F2
;;POUF3;;
BRN2, MOUSE, HOMOLOG OF; BRN2;;
OCTAMER BINDING TRANSCRIPTION FACTOR 7; OCT7;;
N-OCT-3 GENE
OMIM Description
DESCRIPTION
POU3F2 belongs to a large family of transcription factors that bind to
the octameric DNA sequence ATGCAAAT. Most of these proteins share a
highly homologous region, referred to as the POU domain, that occurs in
several mammalian transcription factors, including the octamer-binding
proteins Oct1 (POU2F1; 164175) and Oct2 (POU2F2; 164176) and the
pituitary protein Pit1 (PIT1; 173110). Class III POU genes are expressed
predominantly in the central nervous system (CNS). It is likely that
CNS-specific transcription factors such as these play an important role
in mammalian neurogenesis by regulating their diverse patterns of gene
expression (Schreiber et al., 1993; Atanasoski et al., 1995).
CLONING
The human counterpart of the mouse brain-2 gene (Brn2) was first
identified in nuclear extracts from brain and was termed N-Oct-3
(Schreiber et al., 1993). The protein is expressed in the CNS during
development and in adult brain. Atanasoski et al. (1995) reported the
isolation and characterization of the human POU3F2 gene, which encodes
the N-Oct-3 protein. Sequencing of 650 bp of the promoter region showed
84% sequence identity of POU3F2 with the mouse Brn2 gene.
GENE FUNCTION
The POU transcription factor Oct6 (602479) plays a role in Schwann cell
development. In sciatic nerve extracts from chick embryos, young chicks,
and mice, Jaegle et al. (2003) showed that Brn2 is expressed and
regulated in developing Schwann cells in a manner similar to that of
Oct6, and that Brn2 gene activation does not depend on Oct6.
Overexpression of Brn2 in Oct6-deficient Schwann cells of mice showed
partial rescue of peripheral nerve developmental delay with an increase
in the number of actively myelinating Schwann cells, suggesting that
Brn2 can functionally substitute for Oct6 in promoting the transition
from promyelinating to myelinating Schwann cells. Compound disruption of
both Oct6 and Brn2 resulted in a much more severe phenotype with
abnormal nerve morphology. Jaegle et al. (2003) concluded that Brn2 and
Oct6 share roles as positive regulators of Schwann cell development.
Activation of Delta genes, such as Delta1 (DLL1; 606582), by proneural
factors is an evolutionarily conserved step in neurogenesis that results
in activation of Notch (see 190198) signaling and maintenance of an
undifferentiated state in a subset of neural progenitors. Castro et al.
(2006) showed that activation of mouse Delta1 involved cooperative
binding of Mash1 (ASCL1; 100790) and Brn1 (POU3F3; 602480)/Brn2 to an
evolutionarily conserved motif in the Delta1 gene. They identified the
MASH1/BRN-binding motif in several other human, mouse, and rat genes,
suggesting that MASH1 and BRN proteins synergistically regulate genes
that control multiple aspects of the neurogenic program.
Vierbuchen et al. (2010) hypothesized that combinatorial expression of
neural lineage-specific transcription factors could directly convert
fibroblasts into neurons. Starting from a pool of 19 candidate genes,
Vierbuchen et al. (2010) identified a combination of only 3 factors,
Ascl1 (100790), Brn2, and Myt1l (613084), that suffice to rapidly and
efficiently convert mouse embryonic and postnatal fibroblasts into
functional neurons in vitro. These induced neuronal cells express
multiple neuron-specific proteins, generate action potentials, and form
functional synapses.
Pang et al. (2011) showed that POU3F2, ASCL1, and MYT1L can generate
functional neurons from human pluripotent stem cells as early as 6 days
after transgene activation. When combined with NEUROD1 (601724), these
factors could also convert fetal and postnatal human fibroblasts into
induced neuronal cells showing typical neuronal morphologies and
expressing multiple neuronal markers, even after downregulation of the
exogenous transcription factors. Importantly, the vast majority of human
induced neuronal cells were able to generate action potentials and many
matured to receive synaptic contacts when cocultured with primary mouse
cortical neurons. Pang et al. (2011) concluded that nonneuronal human
somatic cells, as well as pluripotent stem cells, can be converted
directly into neurons by lineage-determining transcription factors.
GENE STRUCTURE
Atanasoski et al. (1995) determined that the POU3F2 gene is intronless.
MAPPING
By Southern blot analysis of somatic cell hybrids and by in situ
hybridization, Atanasoski et al. (1995) mapped the POU3F2 gene to 6q16.
Xia et al. (1993) mapped the Brn2 (Pou3f2) gene to mouse chromosome 4.
AIM1
| dbSNP name | rs783420(G,C); rs4946759(A,G); rs1340623(C,G); rs4945755(G,A); rs1381552(C,T); rs72939435(A,G); rs72939440(C,T); rs783419(T,A); rs17495053(C,T); rs1340624(T,C); rs72939443(G,A); rs66465674(C,T); rs13218830(G,A); rs783418(G,C); rs17560979(C,G); rs1870866(T,C); rs783417(G,A); rs10499048(A,T); rs6938452(A,G); rs783416(C,T); rs1084698(C,T); rs7740989(A,G); rs35790766(G,A); rs55858175(A,G); rs783414(A,G); rs13194986(T,C); rs1159148(A,C); rs3747787(T,C); rs6906338(T,A); rs17495512(A,C); rs13193036(G,A); rs34550542(G,A); rs2353050(T,C); rs9486378(A,C); rs9480680(G,A); rs710096(T,C); rs9320172(C,T); rs35452551(A,G); rs35090908(C,T); rs9486379(T,G); rs2219666(A,T); rs11153000(T,G); rs11153001(T,G); rs11153002(C,G); rs34590393(G,T); rs17495623(T,C); rs17495644(G,T); rs17495678(A,G); rs783390(A,G); rs62423286(C,T); rs17495720(A,G); rs17495742(A,G); rs2306099(G,A); rs13207381(C,T); rs35534143(T,C); rs34456829(G,A); rs35843244(A,G); rs56361614(C,T); rs17067184(G,A); rs13212508(G,C); rs13212772(G,T); rs35910317(A,G); rs6928187(A,T); rs6928541(C,T); rs6908538(T,C); rs6928874(G,A); rs6929649(G,A); rs2883077(A,G); rs2353049(C,G); rs2353048(T,C); rs2353047(C,T); rs13194254(A,G); rs13197786(G,A); rs13197493(A,T); rs11752138(G,A); rs11752150(C,T); rs11153004(T,A); rs11153005(T,C); rs11153006(A,T); rs2353046(G,A); rs1809321(G,A); rs72941307(G,A); rs1462147(T,C); rs898895(G,T); rs1111830(G,A); rs7454837(G,A); rs898894(T,C); rs13202166(G,A); rs898893(C,T); rs9480681(G,T); rs9486381(T,G); rs936497(A,G); rs9486382(A,G); rs9486383(C,T); rs9480682(G,C); rs13218960(T,C); rs13219061(T,C); rs13202942(C,T); rs783402(G,C); rs9486384(G,A); rs9486385(G,A); rs79744203(G,C); rs9486387(A,T); rs9320173(T,C); rs35546863(G,C); rs11153007(T,C); rs9486388(T,A); rs9320174(A,G); rs9320175(A,C); rs72941340(G,C); rs9486389(A,C); rs783401(G,A); rs3814076(T,C); rs1841689(G,C); rs1841688(T,C); rs1462146(G,A); rs2615208(A,G); rs783400(G,A); rs783399(G,A); rs783398(T,C); rs783397(A,G); rs9486390(C,T); rs783396(A,C); rs783394(T,G); rs783393(A,G); rs783392(G,A); rs783391(T,C); rs9486393(T,A); rs61741114(T,C); rs2792466(G,A); rs4946760(A,G); rs2027561(C,T); rs2247346(T,C); rs1799693(A,G); rs2247335(A,T); rs2066201(C,G); rs1770718(T,C); rs1770719(A,G); rs1770720(G,A); rs11968775(T,C); rs1770721(A,G); rs1676023(C,T); rs9320176(G,A); rs1676024(C,G); rs1676025(A,G); rs1676026(G,A); rs72941373(T,C); rs2219667(G,A); rs2615209(C,A); rs1770723(G,A); rs1676027(A,C); rs1676028(G,A); rs1613722(C,T); rs1616375(G,A); rs6902745(C,T); rs4946761(A,T); rs1676030(T,C); rs4945756(G,A); rs9386565(G,A); rs9386566(G,A); rs1676007(A,C); rs1770724(C,G); rs4946762(T,C); rs1676008(A,G); rs1770725(G,C); rs1676009(A,G); rs1770727(C,T); rs1676010(A,T); rs2297970(G,A); rs1676011(A,G); rs1676012(T,C); rs2353043(C,T); rs76080904(C,G); rs1770728(C,T); rs1770729(G,A); rs1676014(A,G); rs1770730(G,A); rs1676015(A,T); rs1770731(A,T); rs1770732(T,C); rs2126395(G,T); rs1770733(C,T); rs1676016(G,A); rs1676017(A,T); rs9398095(T,A); rs2297971(G,C); rs2066202(T,C); rs7755346(C,T); rs2054366(T,C); rs2615206(G,A); rs2615207(G,C); rs2642469(T,G); rs1037955(T,C); rs9320179(G,C); rs4946763(T,C); rs1981308(A,G); rs9486396(T,C); rs968838(C,T); rs968839(C,T); rs965347(G,A); rs4946764(A,G); rs963683(G,A); rs7749873(G,A); rs72943025(G,C); rs9373878(A,T); rs9400027(T,C); rs9386567(C,T); rs9480684(G,A); rs9486397(G,A); rs9386568(C,G); rs9486398(A,G); rs115132229(G,C); rs7775555(G,A); rs9384622(G,A); rs9486399(C,T); rs11153008(A,G); rs9486400(A,C); rs9486402(C,G); rs9400028(T,C); rs9480685(G,T); rs9486403(A,G); rs6909966(C,T); rs6910512(C,G); rs9480686(G,A); rs9486404(C,T); rs376326550(A,G); rs3747789(T,G); rs371534297(C,A); rs3747790(T,C); rs11537704(C,T); rs1057429(T,C); rs1135384(T,G); rs6922741(C,T); rs9486407(G,A); rs72943042(T,G); rs13319(G,A); rs1057433(C,T); rs8013(A,C) |
| ccdsGene name | CCDS34506.1 |
| cytoBand name | 6q21 |
| EntrezGene GeneID | 202 |
| EntrezGene Description | absent in melanoma 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AIM1:NM_001624:exon9:c.T3704C:p.L1235P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6371 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DU04 |
| dbNSFP KGp1 AF | 0.029304029304 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0386740331492 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.05672823219 |
| dbSNP GMAF | 0.02938 |
| ESP Afr MAF | 0.01566 |
| ESP All MAF | 0.046056 |
| ESP Eur/Amr MAF | 0.061628 |
| ExAC AF | 0.039 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Jerky smooth pursuit
RESPIRATORY:
[Larynx];
Glottic airway narrowing caused by laryngeal abductor paralysis;
Hoarseness;
Laryngeal stridor;
Nocturnal dyspnea
MUSCLE, SOFT TISSUE:
Mild distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Progressive cerebellar ataxia;
Gait ataxia;
Dysmetria;
Limb fasciculations;
Cerebellar atrophy;
EMG shows neurogenic findings
VOICE:
Dysphonia
MISCELLANEOUS:
Onset in adulthood;
May be X-linked
OMIM Title
*606202 SOLUTE CARRIER FAMILY 45, MEMBER 2; SLC45A2
;;MEMBRANE-ASSOCIATED TRANSPORTER PROTEIN; MATP;;
MELANOMA ANTIGEN AIM1; AIM1
OMIM Description
DESCRIPTION
The AIM1 gene encodes a melanocyte differentiation antigen that is
expressed in a high percentage of melanoma cell lines. Its homolog in
medaka fish, 'B,' encodes a transporter that mediates melanin synthesis
(Fukamachi et al., 2001).
CLONING
Harada et al. (2001) identified an antigen in human melanoma that they
called AIM1 protein. The AIM1 gene was expressed in 3 melanoma cell
lines, but not in a fibroblast cell line, and not at significant levels
in any of 15 normal tissues. The human AIM1 gene encodes a protein of
530 amino acids. Northern blot analysis detected 2 transcripts, one of
1.7 kb and the other of 2.8 kb. Harada et al. (2001) concluded that the
AIM1 gene encodes a melanocyte differentiation antigen that is expressed
in a high percentage of melanoma cell lines.
Fukamachi et al. (2001) used a positional cloning effort to isolate a
medaka pigment gene highly homologous to human AIM1. This gene encodes a
transporter that mediates melanin synthesis. The medaka AIM1 protein
consists of 12 transmembrane domains and is 55% identical to human AIM1.
Fukamachi et al. (2001) also isolated a highly homologous gene from the
mouse, indicating a conserved function of vertebrate melanogenesis.
Newton et al. (2001) identified the human AIM1 gene, which they
designated MATP, by study of human chromosome 5p, a region showing
syntenic homology with the proximal region of mouse chromosome 15 where
the underwhite (uw) locus maps. They cloned the human MATP and mouse uw
cDNAs and determined that the deduced human and mouse proteins share 82%
sequence identity. Both proteins are approximately 58 kD and are
predicted to span a lipid bilayer 12 times.
GENE FUNCTION
Du and Fisher (2002) determined that MATP is transcriptionally modulated
by MITF (156845), a melanocyte-specific transcription factor. Chromatin
immunoprecipitation did not detect direct binding of MITF to a 5-prime
flanking region of MATP, suggesting that MITF may act indirectly or may
bind to a remote regulatory sequence.
GENE STRUCTURE
Newton et al. (2001) determined that the SLC45A2 gene contains 7 exons
spanning a region of approximately 40 kb.
MAPPING
By sequence analysis, Newton et al. (2001) mapped the SLC45A2 gene to
chromosome 5p.
EVOLUTION
Sabeti et al. (2007) reported an analysis of over 3 million
polymorphisms from the International HapMap Project Phase 2. The
analysis revealed more than 300 strong candidate regions that appeared
to have undergone recent natural selection. Examination of 22 of the
strongest regions highlighted 3 cases in which 2 genes in a common
biologic process had apparently undergone positive selection in the same
population: LARGE (603590) and DMD (300377), both related to infection
by the Lassa virus, in West Africa; SLC24A5 (609802) and SLC45A2, both
involved in skin pigmentation, in Europe; and EDAR (604095) and EDA2R
(300276), both involved in the development of hair follicles, in Asia.
MOLECULAR GENETICS
- Oculocutaneous Albinism Type IV
In a Turkish patient with oculocutaneous albinism type IV (OCA4;
606574), Newton et al. (2001) identified a homozygous mutation in the
MATP gene (606202.0001).
Rundshagen et al. (2004) screened 176 German patients with albinism for
mutations in the MATP gene; in 5, they identified homozygous or compound
heterozygous mutations (see 606202.0002-606202.0005).
In 18 of 75 (24%) Japanese patients with OCA, Inagaki et al. (2004)
identified 7 mutations in the MATP gene (see, e.g., 606202.0006).
- Normal Pigment Variation
Studying Caucasians, Asians, African Americans, and Australian
Aborigines, Graf et al. (2005) found association particularly with 2
polymorphisms, G272K (606202.0007) and F374L (606202.0008), with normal
variation in human pigmentation (SHEP5; 227240).
Graf et al. (2007) examined the association between normal skin color
variation in several populations and 3 different promoter polymorphisms
in the MATP gene: -1721C-G (dbSNP rs13289), -1169G-A (dbSNP rs6867641),
and a 3-bp duplication, -1174dupAAT. In Caucasian samples, -1721C-G and
-1174dupAAT were in complete linkage disequilibrium. In Caucasians only,
the -1721G, -1169A, and +dup alleles were significantly associated with
olive skin color. Functional analysis in melanoma skin cells showed that
this promoter haplotype decreased MATP transcription, suggesting a
functional significance.
Stokowski et al. (2007) demonstrated an association between the SNP
dbSNP rs16891982 (F374L; 606202.0008) and skin pigmentation variation in
individuals of South Asian descent.
ANIMAL MODEL
Newton et al. (2001) and Du and Fisher (2002) determined that mutations
in the mouse Matp gene underlie the underwhite (uw) pigmentation
phenotype. Underwhite alleles manifest altered pigmentation of both eye
and fur, sometimes in an age-dependent fashion.
Xu et al. (2013) found that white tigers, characterized by white fur and
dark stripes, are homozygous for a C-to-T transition in exon 7 of the
Slc45a2 gene, resulting in an ala477-to-val (A477V) substitution in
transmembrane domain 11. Homology modeling suggested that A477 faces the
inner surface of the transporter cavity and that its mutation may hinder
substrate transport. Xu et al. (2013) hypothesized that Slc45a2 may be a
sucrose/proton symporter that regulates organellar pH and/or osmotic
balance for synthesis of red/yellow pheomelanin, with little or no
effect on the synthesis of black eumelanin.
GPR6
| dbSNP name | rs4267976(A,C); rs7759173(T,C); rs4354185(A,G) |
| cytoBand name | 6q21 |
| EntrezGene GeneID | 2830 |
| EntrezGene Description | G protein-coupled receptor 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1942 |
OMIM Clinical Significance
Growth:
Pre- and postnatal growth retardation
Head:
Microcephaly
Facies:
Distinctive facies
Neuro:
Developmental delay
Heme:
Pancytopenia
Lab:
Normal cellular bone marrow infiltrated with small lymphocytes;
Increased spontaneous chromosome breakage in blood and fibroblasts;
Increased mitomycin C-induced chromosome damage
Inheritance:
Autosomal recessive
OMIM Title
*600553 G PROTEIN-COUPLED RECEPTOR 6; GPR6
OMIM Description
CLONING
Many cell membrane receptors are members of the G protein-coupled
receptor family which are characterized by the presence of 7
transmembrane domains and numerous conserved amino acids. Using
degenerate PCR, Heiber et al. (1995) identified additional members of
this family, one of which was designated GPR6. A genomic DNA library was
screened with the GPR6 PCR-based probe. The characterized gene encoded a
putative 362-amino acid protein. Northern blots showed abundant
expression in the putamen of the brain and, to a lesser extent, in the
frontal cortex, hippocampus, and hypothalamus.
Song et al. (1995) demonstrated that this receptor protein contains 363
amino acids.
GENE STRUCTURE
Heiber et al. (1995) and Song et al. (1995) determined that the GPR6
gene consists of a single exon.
MAPPING
By fluorescence in situ hybridization, Song et al. (1995) mapped the
GPR6 gene to chromosome 6q21.
GSTM2P1
| dbSNP name | rs140098562(C,T) |
| cytoBand name | 6q21 |
| EntrezGene GeneID | 442245 |
| EntrezGene Description | glutathione S-transferase mu 2 (muscle) pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
| ExAC AF | 0.0001952 |
LAMA4
| dbSNP name | rs75232337(C,T); rs7758715(T,A); rs7738331(C,T); rs7758910(T,A); rs6568718(G,T); rs12208872(A,G); rs3734291(T,C); rs12204892(C,T); rs73541478(G,T); rs73541481(C,T); rs73541482(T,C); rs73541483(A,G); rs11962253(A,C); rs11153341(G,A); rs139252187(C,T); rs6941214(A,T); rs6942296(C,T); rs6921882(T,C); rs3777947(T,C); rs3777946(T,C); rs3777945(C,A); rs3777944(T,C); rs3777943(T,G); rs11961355(T,G); rs10456878(T,C); rs12191016(T,G); rs3734290(T,G); rs3734289(A,C); rs6916947(G,A); rs11969913(G,T); rs1050353(A,T); rs73541486(C,T); rs4947169(G,T); rs73541488(C,T); rs9481223(G,A); rs12190980(C,G); rs7764311(C,T); rs6908892(T,C); rs73541491(A,T); rs73541494(C,A); rs1160798(T,C); rs73541498(C,G); rs73541501(T,C); rs73543603(G,C); rs73530790(G,T); rs35679345(G,A); rs73530792(C,T); rs73530795(G,C); rs764196(C,A); rs61459671(A,G); rs10452631(A,G); rs9384821(C,T); rs111326675(G,A); rs10452616(C,T); rs10452617(C,T); rs10452633(C,T); rs10452635(G,T); rs7763664(G,A); rs4945897(G,A); rs77699322(C,A); rs73532603(C,T); rs73532606(G,A); rs73532607(G,A); rs73532610(C,T); rs11962711(C,A); rs73532613(G,A); rs969138(G,C); rs73532615(C,T); rs969139(C,T); rs11153343(A,G); rs73532618(G,A); rs58881810(C,T); rs2157550(G,C); rs9387059(T,C); rs9320393(G,C); rs185585239(T,G); rs9487823(C,T); rs9320394(C,T); rs764587(A,G); rs3734287(T,C); rs60125059(G,A); rs113049519(G,A); rs13191503(C,T); rs13191507(A,G); rs720179(A,T); rs2345806(A,T); rs9320395(C,G); rs12214148(T,C); rs62413966(C,T); rs2032565(A,T); rs2032566(T,C); rs1050349(G,C); rs2032567(C,T); rs2032568(G,A); rs9487824(A,G); rs75417684(A,G); rs6924043(T,G); rs7764213(T,C); rs4947170(A,G); rs7765769(T,C); rs2072019(G,A); rs2072020(G,A); rs7748075(T,C); rs73766941(G,A); rs73766942(T,G); rs1016825(G,A); rs2072026(T,C); rs7742931(G,A); rs17073410(T,C); rs73532640(T,C); rs10872075(T,C); rs60600759(T,C); rs763247(C,A); rs6911058(G,A); rs744006(A,G); rs13205383(T,C); rs28360618(T,C); rs3822941(T,C); rs62413967(C,T); rs3777942(T,A); rs13197881(A,G); rs13198339(G,A); rs13214535(T,C); rs73536582(T,A); rs77178083(G,A); rs12213786(G,T); rs3734286(G,C); rs9487828(A,G); rs62413968(C,A); rs7758334(C,T); rs9487829(T,C); rs73536588(T,G); rs12192292(C,T); rs76303939(C,T); rs3777941(A,G); rs59008060(G,A); rs73766944(G,A); rs11153344(A,G); rs9320396(G,A); rs12196086(G,A); rs34807218(C,T); rs2277086(C,T); rs2277085(C,A); rs2277084(T,C); rs6568719(G,C); rs3798362(T,A); rs3798361(A,G); rs3798360(T,C); rs3798359(G,C); rs3798357(G,A); rs12200170(G,T); rs2227237(A,G); rs2213838(C,T); rs7739355(T,C); rs117220383(C,T); rs41289904(C,G); rs3752577(A,G); rs12190655(A,T); rs9487833(T,C); rs9487834(G,A); rs7739729(A,C); rs78366040(C,T); rs6913656(G,A); rs9320398(G,A); rs12201150(C,T); rs9487835(G,A); rs6919131(G,A); rs763246(A,T); rs1060515(G,A); rs7766236(C,A); rs971402(G,A); rs971403(T,C); rs971404(G,A); rs971405(T,A); rs11961480(T,C); rs116460492(G,A); rs2051649(A,G); rs115476011(C,T); rs9387060(C,T); rs78342329(C,T); rs1050348(A,G); rs75213834(T,C); rs2345807(C,T); rs56227047(C,T); rs6917024(C,T); rs73766947(T,A); rs140989200(A,T); rs6917763(C,A); rs73538515(G,C); rs73538516(G,A); rs9398298(C,A); rs9398299(G,A); rs2157544(G,T); rs2157545(C,T); rs56948541(G,A); rs73766949(A,T); rs9400520(G,T); rs115403553(C,T); rs7757339(T,C); rs7757340(T,C); rs6568720(T,C); rs2213839(A,G); rs6568721(T,G); rs6899453(G,T); rs1158747(T,G); rs115466325(C,T); rs7752289(A,G); rs7752846(C,T); rs7752759(A,C); rs4947172(T,C); rs929124(T,C); rs73766951(T,C); rs6926862(A,G); rs6907109(T,C); rs4526233(G,A); rs58039820(G,A); rs3777934(T,C); rs1894681(A,G); rs12192658(G,A); rs17073485(C,T); rs10872076(C,T); rs73764703(A,T); rs73538594(T,A); rs115178391(G,C); rs9374309(G,A); rs6908219(G,T); rs2301512(G,C); rs2301513(C,T); rs2301514(G,A); rs9400521(C,T); rs6938044(T,C); rs117112795(G,A); rs6938421(T,C); rs9387061(T,G); rs9400522(G,T); rs73540607(G,T); rs56982552(A,T); rs2072029(C,T); rs6901052(G,A); rs764071(T,G); rs2269646(C,T); rs112004601(G,A); rs9487840(G,T); rs7745663(C,A); rs2072021(G,A); rs2072022(C,T); rs2072023(G,T); rs80109681(G,T); rs140715322(C,T); rs144590333(C,A); rs2237237(G,T); rs6919736(G,C); rs2237238(C,A); rs145852286(G,A); rs2237239(C,G); rs2237240(G,A); rs3777932(A,G); rs6930838(G,A); rs117253928(A,T); rs9487841(G,A); rs3777930(C,G); rs3777929(T,C); rs3777928(A,C); rs6568723(T,C); rs6568724(C,A); rs11757069(C,A); rs4947173(A,G); rs4947174(T,C); rs7758871(T,G); rs114148330(T,C); rs9481231(T,C); rs7738951(A,G); rs11153345(T,A); rs74479851(C,T); rs62413990(T,C); rs78644952(C,T); rs6912145(G,A); rs2157546(C,G); rs3948760(A,G); rs4947175(A,G); rs4945898(T,C); rs2237241(T,C); rs2237242(G,A); rs137967103(C,T); rs189492373(G,A); rs6915838(T,C); rs11757455(G,A); rs6942034(G,A); rs4947177(T,C); rs4947178(C,A); rs6926485(T,C); rs6904691(G,T); rs2237243(G,A); rs9374311(T,C); rs2237244(T,C); rs9398301(G,C); rs57432793(C,T); rs60315490(T,C); rs117520289(G,A); rs2237245(A,G); rs3777927(G,A); rs6939619(T,C); rs6916501(A,G); rs74760631(T,G); rs6917160(G,A); rs6916694(A,G); rs6939808(T,C); rs59596549(C,A); rs7754329(C,T); rs59690635(C,T); rs77748844(G,T); rs73542518(T,G); rs73542519(G,T); rs73542521(G,A); rs73542523(C,T); rs73542524(A,C); rs73542527(A,C); rs73542530(G,A); rs17073562(C,G); rs73542534(T,G); rs73542539(A,T); rs73542543(T,C); rs73542545(C,T); rs17073563(T,C); rs12190908(C,T); rs77759681(T,C); rs77329639(G,A); rs73542549(C,G); rs17073565(A,G); rs2239850(G,T); rs6909615(T,A); rs73542553(A,C); rs17073566(A,G); rs75956673(T,C); rs73542558(C,T); rs73542561(G,A); rs9487847(C,T); rs17073570(C,A); rs17073572(G,A); rs13202093(G,A); rs2237247(G,A); rs17073574(A,G); rs76842206(T,G); rs2282853(C,G); rs113210444(C,A); rs2282854(T,C); rs11962048(A,G); rs73544331(A,G); rs79599061(T,G); rs7775033(A,G); rs11153346(C,T); rs4945899(A,C); rs34072237(T,G); rs12198087(A,G); rs28360619(C,A); rs9374312(G,T); rs372782858(C,T); rs2213840(A,G); rs2068770(A,G); rs78871662(A,G); rs9487853(T,C); rs2237248(G,A); rs2237249(A,G); rs9487854(T,C); rs73544359(T,C); rs2345808(T,G); rs2157547(G,C); rs73764716(G,A); rs12110617(T,C); rs12111523(G,T); rs7450379(T,C); rs35563927(G,C); rs2345809(T,C); rs2157548(G,C); rs6900576(C,A); rs12661406(C,G); rs11153347(G,C); rs1006497(T,C); rs78409510(T,C); rs4947179(A,C); rs9320400(C,T); rs9487857(T,C); rs9487858(T,C); rs58704422(G,C); rs7764836(G,C); rs28360620(G,A); rs9398302(G,A); rs12206703(G,C); rs12206921(G,A); rs4947180(T,C); rs1573756(T,C); rs9487861(A,C); rs2072024(C,T); rs79128042(G,T); rs9481239(A,G); rs9481240(C,A); rs13211831(G,A); rs7749238(G,A); rs9487862(T,C); rs113792282(G,A); rs62414016(C,T); rs2051651(T,G); rs35006512(T,C); rs9387064(T,A); rs62414018(T,A); rs370350568(C,A); rs6926573(T,C); rs6909113(C,T); rs62414019(A,G); rs62414020(G,C); rs58010224(G,C); rs9320402(C,G); rs6921858(A,G); rs62414021(C,G); rs1894682(G,A); rs370124052(G,A); rs11153348(A,G); rs9487863(A,C); rs11759718(C,T); rs17757451(T,C); rs3208829(C,G); rs7766787(G,A) |
| ccdsGene name | CCDS34514.1 |
| cytoBand name | 6q21 |
| EntrezGene GeneID | 3910 |
| EntrezGene Description | laminin, alpha 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LAMA4:NM_002290:exon25:c.C3335G:p.P1112R,LAMA4:NM_001105206:exon25:c.C3356G:p.P1119R,LAMA4:NM_001105207:exon25:c.C3335G:p.P1112R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5674 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q16363 |
| dbNSFP Uniprot ID | LAMA4_HUMAN |
| dbNSFP KGp1 AF | 0.232600732601 |
| dbNSFP KGp1 Afr AF | 0.132113821138 |
| dbNSFP KGp1 Amr AF | 0.21546961326 |
| dbNSFP KGp1 Asn AF | 0.34965034965 |
| dbNSFP KGp1 Eur AF | 0.217678100264 |
| dbSNP GMAF | 0.2328 |
| ESP Afr MAF | 0.147299 |
| ESP All MAF | 0.222051 |
| ESP Eur/Amr MAF | 0.260349 |
| ExAC AF | 0.225,1.626e-05 |
OMIM Clinical Significance
Eyes:
Retinitis pigmentosa
Inheritance:
Autosomal recessive (6p)
OMIM Title
*600133 LAMININ, ALPHA-4; LAMA4
;;LAMA3, FORMERLY
OMIM Description
DESCRIPTION
Laminin, a multidomain glycoprotein, is the major noncollagenous
constituent of basement membranes. It is composed of 3 nonidentical
chains: A (LAMA1; 150320), B1 (LAMB1; 150240), and B2 (LAMC1; 150290).
The 3 classical laminin chains form a cruciform structure consisting of
3 short arms, each of which is formed from different chains, and a long
arm composed of all 3 chains. LAMA4 encodes a variant A chain (Richards
et al., 1994).
CLONING
By screening a human keratinocyte cDNA library for type VII collagen
sequences, Richards et al. (1994) isolated a new laminin alpha chain
variant gene, LAMA4 (formerly called LAMA3). Northern blot analysis
indicated that a cDNA encoding LAMA4 hybridized to a 6.45-kb mRNA,
significantly smaller than the 9.5- to 10-kb mRNA of laminin A
(Haaparanta et al., 1991).
Iivanainen et al. (1995) cloned the laminin alpha-4 cDNA by screening a
fetal lung library with a PCR product generated from primers based on a
partial laminin-like sequence reported by GenBank. The complete cDNA is
approximately 6.2 kb long and encodes a predicted protein of 1,816 amino
acids. The domain structure of the protein is similar to the alpha-3
chain (LAMA3, also called BM600), both of which resemble truncated
versions of alpha-1 and alpha-2 in which approximately 1,200 residues at
the amino end have been lost. Northern blots showed strong expression of
the mRNA in adult heart, lung, ovary, small and large intestines, liver,
and placenta.
GENE STRUCTURE
Richards et al. (1997) determined that the LAMA4 gene contains 39 exons
and spans 122 kb.
MAPPING
Using PCR on genomic DNA, flow-sorted chromosomes, and fluorescence in
situ hybridization, Richards et al. (1994) localized the LAMA4 gene to
human chromosome 6q21. In this abstract, the authors referred to the
gene as LAMA3; in the related article, Richards et al. (1994) used the
corrected symbol, LAMA4.
MOLECULAR GENETICS
Knoll et al. (2007) sequenced the LAMA4 gene in 180 Caucasian patients
with severe dilated cardiomyopathy (CMD1JJ; 615235) and identified a
nonsense (R1073X; 600133.0001) and a missense (P943L; 600133.0002)
mutation in 2 patients, respectively. Genotyping an additional 374
Caucasian CMD patients for those mutations identified 1 more patient
with the P943L mutation. Screening the LAMA4 gene by SSCP in an
additional 200 Japanese CMD patients revealed no variants.
ANIMAL MODEL
Thyboll et al. (2002) noted that LAMA4 is expressed in basement
membranes such as those beneath endothelia, the perineurium of
peripheral nerves, and around developing muscle fibers. Lama4-null mice
presented with hemorrhages during the embryonic and neonatal period.
Newborns were lethargic, pale, and yellowish (icteric). They showed
extensive bleeding and deterioration of microvessel growth in
experimental angiogenesis, as well as mild locomotion defects.
Histologic examination of newborn mice revealed delayed deposition of
type IV collagen (120130) and nidogen (131390) into capillary basement
membranes. Electron microscopy showed discontinuities in the lamina
densa.
Wang et al. (2006) generated Lama4 -/- mice and observed gradual
development of cardiac hypertrophy and impaired cardiac function by 40
weeks of age, with histology showing multiple foci of muscle
degeneration and fibrosis throughout the heart. Cardiomyocytes isolated
from Lama4 -/- hearts maintained their contractility in vivo. However,
elevated levels of hypoxia-inducible factor-1-alpha (HIF1A; 603348) and
vascular endothelial growth factor-A (VEGFA; 192240), along with
multiple foci of cardiomyocyte degeneration and fibrosis, suggested
sustained cardiac ischemia. Electron microscopy confirmed malformed
blood vessels and wide pericapillary extracellular matrix (ECM) spaces,
suggesting the presence of microcirculation abnormalities in Lama4 -/-
mutant hearts. Wang et al. (2006) concluded that mutation in the laminin
alpha-4 chain leads to an abnormal cardiovascular ECM structure that
causes insufficient oxygen supply to the heart.
Using Lama4 -/- mice to evaluate active and passive experimental
autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS;
126200), by immunofluorescence, confocal, and electron microscopy and
flow cytometric analysis, Wu et al. (2009) observed a compensatory
ubiquitous expression of Lama5 (601033) in all blood vessels,
independent of responses to proinflammatory cytokines. Lama4 -/- mice
showed significantly lower susceptibility to active EAE and resistance
to passive EAE by transfer of encephalitogenic wildtype T cells compared
with wildtype mice. Elimination of integrin alpha-6 (ITGA6;
147556)/beta-1 (ITGB1; 135630)-positive T cells through Itga6 -/- bone
marrow chimeras also resulted in lower EAE severity. Wu et al. (2009)
concluded that LAMA5 directly inhibits integrin alpha-6/beta-1-mediated
T-cell migration through LAMA4, and that T cells use mechanisms distinct
from other immune cells to penetrate the endothelial basement membrane
barrier.
MARCKS
| dbSNP name | rs352084(A,T); rs45457891(A,C); rs12223(A,G); rs28558559(T,C) |
| cytoBand name | 6q21 |
| EntrezGene GeneID | 4082 |
| EntrezGene Description | myristoylated alanine-rich protein kinase C substrate |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1336 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602940 MARCKS-LIKE PROTEIN 1; MARCKSL1
;;MLP;;
MARCKS-RELATED PROTEIN; MRP;;
MAC-MARCKS;;
F52
OMIM Description
CLONING
Umekage and Kato (1991) identified a cDNA with homology to MARCKS
(PKCSL; 177061) among mouse brain cDNAs with specific brain expression
patterns. The myristoylated, alanine-rich protein MARCKS is a widely
expressed, prominent substrate for protein kinase C (see 176960), a key
enzyme of intracellular signal transduction. The predicted 200-amino
acid protein, which they called F52, shares 52% amino acid identity with
bovine MARCKS. The similarity between the 2 proteins is found in the
consensus myristoylation sequence near the N-terminus and in the
25-amino acid protein kinase C phosphorylation site domain. F52 has a
similar amino acid composition to MARCKS, although its alanine content
is not as high. It is distributed throughout the mouse brain in a
pattern that is distinct from that of MARCKS.
By screening a genomic library with portions of the Mrp cDNA, Stumpo et
al. (1998) isolated the human homolog, which they designated MLP for
'MARCKS-like protein.' They reported that the sequences of the mouse and
human promoters were 71% identical over 433 bp. A transgene containing
this 433-bp fragment from mouse linked to a reporter Mrp
beta-galactosidase gene produced normal patterns of Mrp expression in
the developing mouse embryo.
Using Northern hybridization, Lobach et al. (1993) observed Mrp
expression in various mouse tissues, with highest levels in testis and
uterus.
GENE STRUCTURE
Lobach et al. (1993) reported that the mouse F52, or Mrp, gene contains
a single intron at a position exactly analogous to that of the single
intron in mouse, cow, and human MARCKS.
MAPPING
By analysis of an interspecific backcross, Lobach et al. (1993) mapped
the Mrp gene to a position on mouse chromosome 4 that was closely linked
to the Lck (153390) locus. Based on homology of synteny, they predicted
that the human homolog would map to chromosome 1p35-p32. Using somatic
cell hybrid analysis and fluorescence in situ hybridization, Stumpo et
al. (1998) confirmed that the human MLP gene maps to 1p34.
ANIMAL MODEL
Wu et al. (1996) used gene targeting to generate Mrp-deficient mice.
They observed severe neural tube defects (NTD) including exencephaly,
spina bifida, and tail flexion anomaly in approximately 60% of the
homozygous mutants and in approximately 10% of heterozygous animals. The
homozygous mutants without exencephaly survived despite brain
abnormalities, which appear to occur secondarily to the NTD. Wu et al.
(1996) suggested that mutations in Mrp result in isolated NTD and
therefore may provide an animal model for common human NTD.
TPI1P3
| dbSNP name | rs9398428(C,T); rs77427140(C,G) |
| ccdsGene name | CCDS5103.1 |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 101927818 |
| EntrezGene Symbol | LOC101927818 |
| snpEff Gene Name | FRK |
| EntrezGene Description | uncharacterized LOC101927818 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007805 |
NT5DC1
| dbSNP name | rs73562584(T,A); rs9400888(C,T); rs9387383(G,A); rs509859(T,G); rs509002(T,C); rs373338365(C,G); rs145044346(G,A); rs73772244(T,C); rs564980(C,T); rs564253(T,C); rs534932(T,C); rs75982086(T,C); rs478187(A,T); rs370345284(A,C); rs576791(G,A); rs517352(T,A); rs56116396(A,G); rs493467(A,G); rs1999659(G,A); rs482012(G,T); rs1999658(A,G); rs568725(G,A); rs73772250(C,T); rs563962(G,A); rs563176(C,A); rs73772251(T,G); rs73772252(A,G); rs509236(T,C); rs476330(C,T); rs1999657(G,A); rs17077572(A,C); rs73772253(G,A); rs117763238(G,A); rs17077574(G,C); rs524285(A,C); rs118113509(C,T); rs4945551(T,C); rs9488836(C,T); rs73772254(G,A); rs9488837(G,A); rs62414122(A,T); rs9488838(A,G); rs11153597(G,A); rs9488839(A,G); rs9488840(A,G); rs369135101(C,T); rs9488841(T,C); rs17772211(A,G); rs515745(A,G); rs1931897(A,C); rs1059277(C,T); rs2228548(C,G); rs2228547(C,G); rs3812111(T,A); rs61248677(C,A); rs9488842(A,C); rs3812112(T,A); rs1064583(A,G); rs9488843(C,G); rs180874401(C,G); rs485599(A,G); rs73772263(A,G); rs144444768(A,G); rs60491506(A,G); rs73564686(A,G); rs2145357(A,G); rs62414123(T,C); rs11965969(T,G); rs9488845(C,A); rs549332(G,A); rs11968086(T,A); rs9481606(A,G); rs7763110(G,A); rs9481607(A,G); rs59276499(C,T); rs139036866(A,G); rs75176278(T,C); rs9488847(T,C); rs471766(T,C); rs9488848(C,T); rs57296292(G,A); rs9320557(A,C); rs9488849(T,A); rs62414128(C,T); rs148881866(C,T); rs9481608(T,C); rs79682156(T,C); rs56238603(A,G); rs4946138(A,G); rs958738(A,G); rs145852023(G,A); rs17077603(A,C); rs10440871(C,A); rs60494998(T,C); rs6915372(T,G); rs372803411(T,C); rs3763232(G,A); rs4946140(C,T); rs9488853(C,T); rs6910311(C,T); rs4946141(C,G); rs513218(A,G); rs59949508(C,T); rs12525805(G,A); rs34001069(T,C); rs59777418(A,T); rs9488857(C,T); rs13192249(C,T); rs9488858(A,G); rs7744989(T,A); rs11153598(C,A); rs375597221(A,G); rs7739793(G,A); rs7739896(A,G); rs9481609(T,C); rs372347893(T,G); rs7760208(A,G); rs12527153(G,A); rs62414136(G,T); rs73774208(T,C); rs73774209(C,T); rs7748975(T,C); rs1204777(A,G); rs1204778(C,G); rs9488860(G,T); rs77064202(C,G); rs1204779(G,A); rs73774214(T,C); rs7755367(C,T); rs62414141(A,G); rs1546943(G,A); rs2351141(G,A); rs1114228(T,A); rs9488861(A,G); rs7758930(C,T); rs202163415(G,A); rs9488862(C,T); rs139325716(C,T); rs74986252(T,C); rs140930530(T,C); rs9488864(C,T); rs9488865(G,A); rs115129425(A,T); rs73566413(T,C); rs62414143(T,C); rs77040948(A,G); rs11754116(G,A); rs11754669(G,A); rs12526817(C,T); rs9488867(G,A); rs148506158(G,A); rs1204834(T,A); rs1204835(C,A); rs1204836(A,G); rs1204837(G,A); rs1204838(C,A); rs78640809(G,A); rs6926890(C,T); rs73774225(A,G); rs73774226(A,G); rs9488870(G,A); rs1204841(A,C); rs73566419(A,G); rs1204842(C,A); rs1204843(G,A); rs1204844(T,G); rs1204845(G,A); rs1204846(C,A); rs742930(G,A); rs143897754(C,T); rs150903684(C,T); rs1204848(A,G); rs9481611(T,C); rs115480373(A,G); rs1204849(C,T); rs1204850(C,T); rs7770203(T,C); rs1211388(C,T); rs1210355(T,A); rs1204851(A,G); rs28663996(T,C); rs73566430(T,C); rs73566434(T,C); rs201194526(T,G); rs79259175(G,A); rs1209221(C,T); rs1204780(T,C); rs1204781(G,C); rs73774232(C,T); rs1204782(T,C); rs1204783(A,G); rs1204784(G,T); rs6929423(G,T); rs1204785(C,A); rs7769748(C,T); rs977008(G,C); rs17503192(G,C); rs1204786(A,G); rs73774234(A,G); rs1204787(C,G); rs1204788(A,G); rs1204789(T,A); rs9654610(C,G); rs1204791(T,C); rs1204792(G,A); rs1204793(A,G); rs6909037(G,A); rs1204794(C,T); rs1204795(C,T); rs1204796(T,C); rs1204797(C,T); rs59648240(T,C); rs58725692(A,G); rs1204798(A,G); rs144947746(A,G); rs1204799(A,G); rs1204800(G,A); rs57926671(A,G); rs1204801(G,A); rs73770703(G,T); rs1204802(C,T); rs1204804(A,G); rs73770704(G,C); rs9488873(T,C); rs61068849(A,G); rs1209223(G,A); rs118087568(G,A); rs1204805(T,C); rs1204806(G,C); rs6914038(A,G); rs6914678(G,A); rs6914684(G,A); rs1204807(A,C); rs6920168(G,T); rs1204808(A,G); rs9374593(C,G); rs1204810(C,A); rs1204811(C,T); rs7744809(G,A); rs1204812(G,T); rs6907249(A,G); rs1204814(T,A); rs73566459(A,G); rs926829(T,C); rs74417447(C,T); rs73773829(A,G); rs59075644(A,G); rs73566462(G,C); rs73773831(A,G); rs1204816(G,C); rs73566464(C,T); rs1204817(G,A); rs1204818(A,G); rs12664763(T,A); rs1204819(A,G); rs1204820(G,A); rs1204821(A,G); rs1204822(A,G); rs1204823(C,A); rs1204824(T,C); rs1204825(G,C); rs1204826(A,G); rs2235980(G,A); rs15679(C,A); rs1204828(C,A); rs1048920(G,A); rs1204829(C,T) |
| ccdsGene name | CCDS5105.1 |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 221294 |
| snpEff Gene Name | COL10A1 |
| EntrezGene Description | 5'-nucleotidase domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL10A1:NM_000493:exon3:c.G1633C:p.G545R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7101 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q03692 |
| dbNSFP Uniprot ID | COAA1_HUMAN |
| dbNSFP KGp1 AF | 0.182234432234 |
| dbNSFP KGp1 Afr AF | 0.260162601626 |
| dbNSFP KGp1 Amr AF | 0.102209944751 |
| dbNSFP KGp1 Asn AF | 0.23951048951 |
| dbNSFP KGp1 Eur AF | 0.126649076517 |
| dbSNP GMAF | 0.1823 |
| ESP Afr MAF | 0.25261 |
| ESP All MAF | 0.160926 |
| ESP Eur/Amr MAF | 0.113953 |
| ExAC AF | 0.151,8.132e-06 |
TSPYL4
| dbSNP name | rs6755(G,A); rs56074322(T,C); rs3749893(G,A); rs11789(G,A); rs1204833(A,G); rs1931895(C,G); rs2232472(G,A); rs2232470(C,A); rs17524614(G,T) |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 23270 |
| snpEff Gene Name | NT5DC1 |
| EntrezGene Description | TSPY-like 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3912 |
TSPYL1
| dbSNP name | rs6568924(C,T); rs6568925(T,A); rs6568926(A,T); rs73767709(A,T); rs10484838(C,G); rs1045182(T,C); rs10456904(G,A); rs1128261(A,G); rs9400897(T,C); rs3749894(C,T); rs3828743(G,A) |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 7259 |
| EntrezGene Description | TSPY-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3333 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604714 TSPY-LIKE 1; TSPYL1
;;TSPY-LIKE; TSPYL
OMIM Description
CLONING
The TSPY protein (480100), which is encoded by a repetitive gene family
on the Y chromosome, is expressed specifically in testis. By searching
an EST database for TSPY-related sequences, Vogel et al. (1998)
identified a mouse EST encoding a protein with similarity to human TSPY;
thus, they named the novel protein TSPY-like (Tspyl). Using the EST, the
authors isolated cDNAs representing a full-length mouse Tspyl coding
sequence. Vogel et al. (1998) identified a human TSPYL EST using the
mouse Tspyl sequence. They used this EST to isolate a partial human
testicle TSPYL cDNA lacking 5-prime coding sequence. As with the mouse
Tspyl gene, the human TSPYL gene appears to lack introns. RT-PCR
detected human TSPYL expression in the 3 tissues tested, namely liver,
kidney, and smooth muscle. Northern blot analysis and RT-PCR showed
ubiquitous expression of mouse Tspyl, with testis, ovary, prostate,
brain, spleen, kidney, lung, heart, and liver tested. RT-PCR of
embryonic mouse mRNAs from different developmental stages revealed Tspyl
expression as early as 10.5 days postcoitum, the earliest stage
examined.
MAPPING
By somatic cell hybrid mapping, Vogel et al. (1998) mapped the human
TSPYL gene to chromosome 6. Using FISH, they localized the TSPYL gene to
6q22-q23. Vogel et al. (1998) mapped the mouse Tspyl gene to chromosome
10, which shows homology of synteny with human 6q21-q23.
MOLECULAR GENETICS
In affected infants with sudden infant death with dysgenesis of the
testes syndrome (SIDDT; 608800) from the Belleville Old Order Amish
community, Puffenberger et al. (2004) identified homozygosity for a 1-bp
insertion in the TSPYL1 gene (604714.0001).
GPRC6A
| dbSNP name | rs615199(T,C); rs6901250(G,A); rs6924002(T,A); rs35937022(A,G); rs6901971(G,A); rs76029629(A,G); rs368716060(G,A); rs73559545(C,G); rs1512655(A,G); rs77575032(T,G); rs993394(G,A); rs6919622(C,T); rs1512657(G,C); rs7761872(C,T); rs7766459(C,G); rs7772771(G,C); rs73559547(A,G); rs66806850(C,T); rs73559551(A,G); rs7768739(T,C); rs6917467(G,A); rs1512658(G,A); rs7754941(A,T); rs1398403(T,C); rs7760125(A,C); rs17078381(A,G); rs76671093(C,T); rs57484790(G,T); rs17078385(A,G); rs1398404(A,C); rs9384990(A,G); rs17078388(C,T); rs9374623(C,A); rs368308211(G,A); rs145460545(C,T); rs17078390(A,C); rs28360548(A,C); rs76688215(T,G); rs2274911(G,A); rs72963952(G,A); rs78156659(G,A); rs9489039(A,G); rs9489040(G,A); rs9489041(T,A); rs1606366(C,G); rs2221882(T,C); rs2203191(T,A); rs9400959(G,A); rs151040140(G,A); rs9489042(G,T); rs114959738(A,G); rs151204490(T,C); rs150326214(G,A); rs112830604(T,A); rs375994525(C,T); rs9400962(T,C); rs1117046(G,C); rs11753426(C,T); rs73559567(T,C); rs60350868(C,T); rs9400964(G,T); rs7756165(A,G); rs113104198(A,T); rs11759774(A,G); rs9374624(A,C); rs75522241(G,T); rs9489043(T,A); rs6938235(G,T); rs7740481(G,C); rs73559574(A,C); rs2175622(T,A); rs17078402(T,C); rs11753705(A,T) |
| ccdsGene name | CCDS5112.1 |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 222545 |
| EntrezGene Description | G protein-coupled receptor, family C, group 6, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPRC6A:NM_148963:exon3:c.G560A:p.R187Q,GPRC6A:NM_001286354:exon3:c.G560A:p.R187Q,GPRC6A:NM_001286355:exon3:c.G560A:p.R187Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7886 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0065963060686 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.002615 |
| ESP Eur/Amr MAF | 0.003257 |
| ExAC AF | 0.003497 |
DCBLD1
| dbSNP name | rs62433108(T,G); rs75405122(C,T); rs111889487(A,G); rs74970429(G,A); rs78821513(T,C); rs6914910(G,A); rs78367928(G,T); rs74453060(C,T); rs79556315(A,G); rs13192067(G,A); rs13192130(C,T); rs78295668(T,C); rs79815032(G,A); rs61655408(G,A); rs75757849(A,G); rs142993299(C,A); rs6911915(T,C); rs9489210(T,G); rs2105907(A,G); rs80193228(G,A); rs9481727(A,G); rs9489211(A,G); rs4357172(G,A); rs191459453(G,A); rs9387481(T,C); rs79161840(A,G); rs76041987(C,T); rs79094853(A,G); rs112330592(C,A); rs9489213(A,T); rs75609373(A,C); rs78827408(G,A); rs13216575(G,A); rs75584665(C,T); rs77596863(G,T); rs1123836(T,C); rs75517020(A,G); rs12527127(G,C); rs1321811(A,C); rs1321810(C,G); rs1321809(A,G); rs1321808(C,T); rs7453460(G,A); rs79400398(C,T); rs77394790(T,A); rs79462497(C,A); rs80099295(G,C); rs2018055(T,C); rs74558843(A,G); rs13195478(G,A); rs9387483(G,C); rs75911582(C,T); rs76520220(A,G); rs4945586(T,A); rs72963428(C,T); rs9320604(G,A); rs4946259(A,G); rs75894267(C,T); rs17574269(A,G); rs114885173(G,A); rs17079286(A,G); rs17636431(C,T); rs13207962(G,A); rs13193572(T,C); rs9489215(A,G); rs9481728(C,T); rs9320605(A,G); rs9766117(T,C); rs73766221(A,G); rs929057(T,A); rs9767675(G,A); rs929058(A,G); rs2057314(A,G); rs17574630(G,A); rs79406788(C,T); rs73766223(G,A); rs12182049(C,T); rs9688361(T,G); rs11153663(C,T); rs13206490(G,A); rs11153664(T,C); rs4946260(C,T); rs13210963(C,T); rs10782186(T,C); rs17574718(C,G); rs76481778(A,C); rs80234916(G,T); rs9766914(A,G); rs9285420(C,G); rs79221619(G,A); rs113146958(A,C); rs1015130(C,T); rs79187539(A,G); rs1321813(G,T); rs74749978(A,G); rs78829842(G,A); rs1321812(A,G); rs12179623(G,A); rs9374665(A,C); rs210608(C,T); rs79590790(C,T); rs210609(T,A); rs9767548(A,G); rs210610(C,T); rs11755719(G,T); rs11755781(G,T); rs77578306(C,T); rs9374666(T,C); rs210612(G,A); rs372928604(G,A); rs9387486(T,C); rs11756993(C,A); rs210613(G,A); rs210614(G,A); rs111675849(A,G); rs210615(T,A); rs9689948(T,G); rs74799073(C,T); rs17575094(A,G); rs12665822(A,G); rs80140031(A,G); rs210645(G,A); rs210646(G,C); rs182237981(A,G); rs9285421(A,G); rs9689345(G,A); rs9689349(G,A); rs9285422(G,A); rs9285423(A,G); rs9285424(T,C); rs2173892(A,G); rs210647(C,T); rs2134089(A,G); rs210648(A,G); rs75006787(G,A); rs78830777(A,G); rs73512265(A,G); rs12664604(G,A); rs139412751(A,G); rs77126372(T,C); rs369953872(G,A); rs192407518(G,A); rs210649(T,C); rs9320606(G,A); rs11510517(T,G); rs2173891(A,T); rs11759243(G,A); rs76564059(C,A); rs9387487(C,T); rs11153668(A,G); rs11153669(T,C); rs210650(C,G); rs371369638(G,T); rs76080980(G,A); rs1501473(T,C); rs210651(C,T); rs10872152(C,T); rs9767029(A,G); rs210652(A,G); rs73766230(C,T); rs11153670(G,A); rs60531544(T,C); rs210653(G,T); rs4946263(T,C); rs9320607(C,T); rs3756894(T,G); rs149465960(G,A); rs78917982(T,C); rs17079343(T,G); rs210654(A,G); rs74898445(G,A); rs11153672(T,C); rs9374668(G,A); rs210617(T,C); rs73766231(A,G); rs144469099(G,A); rs2071825(C,A); rs4946264(T,C); rs12197399(C,G); rs4946265(A,G); rs210618(C,T); rs2134088(G,A); rs210619(A,G); rs210620(A,G); rs9320608(C,T); rs9387488(G,A); rs9320609(C,A); rs389663(T,C); rs145793598(T,A); rs929059(G,A); rs210621(G,A); rs210622(C,T); rs9489217(C,T); rs187475922(G,A); rs8088(A,G); rs10457315(T,C); rs9285425(G,A); rs2134087(G,A); rs2134086(C,T); rs210624(C,T); rs9489219(A,G); rs210625(A,G); rs12196716(A,T); rs210626(T,C); rs9489220(G,A); rs113144946(T,G); rs210627(C,A); rs210628(G,C); rs62433150(T,C); rs78518192(A,G); rs210629(A,G); rs210630(A,G); rs210631(A,G); rs916305(C,T); rs210632(A,G); rs12181630(A,G); rs210633(A,G); rs210634(A,G); rs10782187(G,A) |
| ccdsGene name | CCDS34522.1 |
| cytoBand name | 6q22.1 |
| EntrezGene GeneID | 285761 |
| EntrezGene Description | discoidin, CUB and LCCL domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.6539 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0837912087912 |
| dbNSFP KGp1 Afr AF | 0.10162601626 |
| dbNSFP KGp1 Amr AF | 0.0966850828729 |
| dbNSFP KGp1 Asn AF | 0.020979020979 |
| dbNSFP KGp1 Eur AF | 0.11345646438 |
| dbSNP GMAF | 0.08402 |
| ExAC AF | 0.086 |
BRD7P3
| dbSNP name | rs933257(C,T); rs2496353(A,T); rs9489419(C,T); rs9481819(G,A); rs11967375(A,G); rs7755203(T,C); rs7759420(T,C); rs9372506(T,C); rs11963143(C,G) |
| ccdsGene name | CCDS5119.2 |
| cytoBand name | 6q22.31 |
| EntrezGene GeneID | 387119 |
| EntrezGene Symbol | CEP85L |
| snpEff Gene Name | C6orf204 |
| EntrezGene Description | centrosomal protein 85kDa-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3287 |
LAMA2
| dbSNP name | rs78478996(T,A); rs9482950(C,A); rs6922375(G,A); rs17779264(T,C); rs113400405(G,A); rs35704827(C,T); rs192114787(C,T); rs6569571(C,T); rs6919352(C,T); rs80217168(T,A); rs74961358(A,C); rs4316028(A,G); rs9986669(A,G); rs79861131(C,T); rs7761275(G,A); rs188704098(C,T); rs35351239(C,G); rs10499143(A,G); rs4260765(C,T); rs67393504(G,T); rs142560062(G,A); rs77236430(A,G); rs6941938(C,T); rs12208997(G,T); rs117742595(G,T); rs35685785(T,C); rs4551189(T,C); rs111312608(T,G); rs66539661(A,G); rs4398767(G,C); rs66474311(C,A); rs17723027(C,G); rs66922212(C,T); rs66495768(A,G); rs12191680(G,C); rs34215442(T,C); rs35822226(C,A); rs71568928(A,C); rs4243497(G,A); rs13210624(C,T); rs112753303(T,C); rs6909374(A,T); rs73773541(G,T); rs4377807(G,A); rs4452666(A,G); rs7451592(G,A); rs9482953(G,A); rs75278307(A,G); rs6937948(G,A); rs9482954(T,G); rs9482955(A,G); rs9482956(A,G); rs9482957(A,C); rs9492136(C,T); rs9492137(C,T); rs117765281(G,A); rs10499145(C,T); rs76740553(T,A); rs11961191(A,G); rs7745096(C,T); rs17779657(A,C); rs59450971(C,T); rs113579717(A,C); rs13198867(C,T); rs73773564(T,C); rs7738059(G,A); rs6928733(T,C); rs9492140(T,C); rs6917956(A,T); rs75146049(G,A); rs11970719(G,T); rs11970706(C,T); rs11961488(G,A); rs11966354(A,G); rs11961514(C,T); rs7764806(C,T); rs13194404(A,G); rs13194622(C,A); rs34302582(G,T); rs6914675(T,C); rs9492142(T,C); rs150604454(C,A); rs58160199(C,T); rs139909707(T,A); rs6910290(C,A); rs77535925(T,C); rs11969817(G,A); rs76984381(T,C); rs13204384(T,A); rs75746325(G,A); rs112908940(A,G); rs12333077(A,G); rs13192715(C,G); rs9492145(A,T); rs9492146(T,A); rs4510700(T,C); rs28385612(G,A); rs12332864(C,T); rs7773602(A,G); rs7774482(G,T); rs74883915(A,G); rs9492147(T,C); rs9375603(C,G); rs77723793(T,C); rs9402088(G,A); rs34980992(T,C); rs79236766(T,C); rs114609210(G,A); rs116537240(C,T); rs7757326(A,G); rs115541232(C,T); rs7758182(G,A); rs13219139(G,A); rs10223591(G,A); rs9398890(G,C); rs80198703(C,A); rs6938402(C,T); rs4897284(G,A); rs72983366(T,C); rs58925003(T,C); rs78792505(C,T); rs4520028(G,C); rs34328979(G,A); rs7745842(A,G); rs9492149(G,A); rs6936443(T,C); rs66972531(A,G); rs4292545(C,A); rs9492150(C,T); rs116632691(G,T); rs9492152(C,T); rs80258303(G,T); rs9482959(C,T); rs73773588(A,C); rs9385476(A,G); rs117463818(G,A); rs9492154(A,G); rs78531557(G,A); rs9482960(A,G); rs116814861(T,C); rs34590713(T,C); rs9492155(C,T); rs9482962(C,T); rs76213190(A,C); rs9492156(T,G); rs76052980(T,C); rs13208540(C,T); rs4515402(A,T); rs13209032(C,T); rs114878925(C,T); rs9402089(C,T); rs111360049(C,T); rs9388672(C,A); rs76977344(C,G); rs4562164(A,C); rs36027308(C,A); rs13207203(G,A); rs4897285(G,A); rs4585583(A,T); rs35358238(C,T); rs112747657(G,A); rs9482964(C,A); rs7770018(A,G); rs9492160(T,C); rs9492161(A,G); rs9492162(T,C); rs77701884(C,G); rs77272942(A,G); rs68083303(G,A); rs4262207(C,A); rs6915788(A,G); rs116381571(C,T); rs4532463(C,T); rs4563739(A,G); rs11966151(A,G); rs138498630(C,T); rs28485035(C,A); rs12199373(T,A); rs28499898(G,A); rs9492165(A,G); rs76659231(A,G); rs76976821(G,A); rs9492166(C,T); rs60800781(C,T); rs6908604(G,A); rs9375605(G,A); rs4599676(C,T); rs7454382(T,C); rs59063850(T,C); rs9885790(G,C); rs12211283(G,A); rs9492168(C,T); rs192608008(G,A); rs4317429(A,G); rs6914657(G,A); rs4367397(T,A); rs4591878(G,A); rs4323331(A,G); rs4552747(T,C); rs4424111(G,C); rs4243498(G,C); rs74902542(A,T); rs9375606(T,C); rs7450990(T,C); rs71568933(G,T); rs11962584(C,T); rs9492170(A,G); rs9492172(C,T); rs78611355(G,A); rs77028409(A,G); rs9388673(A,T); rs9375607(C,A); rs11154451(T,C); rs68140510(A,G); rs78131474(T,G); rs11154452(T,C); rs78678169(G,C); rs9321142(T,C); rs79934959(C,A); rs9492176(A,G); rs12201645(C,T); rs4897286(G,A); rs12202444(T,C); rs75099130(G,A); rs6906203(C,T); rs9482969(T,C); rs9492177(A,G); rs9492178(G,C); rs4897287(A,G); rs9482970(G,A); rs9492179(A,T); rs9482971(T,C); rs12204661(G,A); rs12204632(C,T); rs4368833(G,T); rs77877998(G,A); rs4594973(A,G); rs76069001(G,A); rs4438974(C,T); rs9402090(C,T); rs9285464(T,C); rs9398891(T,C); rs4599677(A,G); rs4370390(T,G); rs9986606(G,A); rs147349352(T,C); rs9492182(T,A); rs9492183(G,C); rs9492184(C,T); rs117819104(A,C); rs116509118(A,T); rs148912718(A,T); rs7774641(C,G); rs7775367(G,A); rs4897289(T,G); rs79310761(C,T); rs6913063(C,G); rs9492185(A,T); rs17780567(A,C); rs10214572(T,C); rs17724256(A,G); rs6569573(C,T); rs4897290(T,C); rs10499146(G,A); rs6912590(T,C); rs145102412(G,A); rs375302554(G,T); rs6938221(G,A); rs142224259(G,A); rs4897291(C,G); rs9492188(T,C); rs12197539(C,G); rs12204924(T,C); rs17780950(G,A); rs9492191(G,A); rs9398892(C,T); rs9402091(T,C); rs9372913(G,A); rs9385477(C,G); rs9492195(A,G); rs11154454(T,A); rs4897292(T,A); rs6928642(T,C); rs4337952(C,A); rs11154455(G,A); rs4337953(C,T); rs79648833(A,C); rs12209976(T,C); rs9385478(T,C); rs11154456(T,C); rs75177929(A,G); rs9388674(G,A); rs17056726(C,G); rs9388675(G,T); rs78352808(A,G); rs7758064(T,C); rs4895840(T,C); rs4895841(T,C); rs3935856(G,A); rs3935350(C,T); rs4291116(G,T); rs141115329(C,T); rs113042125(T,G); rs9492202(C,T); rs7758291(A,C); rs9402092(G,A); rs9375608(C,T); rs148303153(C,A); rs9388677(A,C); rs9375609(C,T); rs9372914(T,G); rs11154457(C,A); rs11154458(T,C); rs9372915(G,A); rs4576277(A,G); rs4895842(T,C); rs4895843(G,T); rs4449651(T,A); rs80330949(T,A); rs4076090(A,G); rs76006043(C,G); rs4295506(T,C); rs116823660(G,A); rs12215631(C,T); rs9372916(G,A); rs115720190(G,A); rs7762560(A,G); rs9402093(G,T); rs4469321(T,G); rs6928626(G,A); rs78236140(T,C); rs7769389(G,A); rs7751469(T,G); rs74737886(T,C); rs79087886(A,T); rs79188813(A,G); rs116090689(C,T); rs371212434(A,G); rs76129841(T,C); rs4555933(C,T); rs4612192(C,T); rs4285345(G,T); rs9375610(A,G); rs12191829(C,A); rs76207272(A,T); rs12191840(C,A); rs9398893(C,T); rs9388679(A,T); rs6937415(A,T); rs12193898(G,T); rs11154459(G,A); rs75611684(G,A); rs6569574(T,G); rs6569575(G,A); rs6569576(A,C); rs6938812(G,A); rs6569577(A,C); rs6900645(A,G); rs12209058(A,G); rs6569578(C,T); rs77364716(A,T); rs80073995(A,T); rs4997856(A,G); rs137970641(T,G); rs114440512(G,A); rs9492206(A,G); rs75706043(A,C); rs115143968(C,T); rs116167840(A,G); rs113547476(G,A); rs12199446(G,A); rs9321146(T,G); rs9402094(C,T); rs79593520(A,C); rs12206958(T,A); rs10457513(T,C); rs75261374(C,T); rs6919209(C,T); rs74791983(T,C); rs7771363(C,T); rs7771364(A,T); rs7738171(G,C); rs10457514(T,A); rs114123609(G,A); rs9492209(C,T); rs9492210(T,A); rs79557204(C,G); rs9402095(T,C); rs4490684(T,A); rs4392741(G,A); rs114774727(C,T); rs9375611(C,T); rs11154461(G,T); rs9372917(T,C); rs4330550(A,G); rs9492212(T,C); rs111809816(C,T); rs113734771(C,T); rs113183390(T,C); rs9402097(T,C); rs1140366(C,T); rs9402098(G,A); rs12191019(A,G); rs7764746(A,C); rs62422166(G,T); rs12211951(T,C); rs78016723(G,A); rs12206708(G,A); rs4320393(A,G); rs12665278(T,C); rs4345416(G,T); rs4534007(G,A); rs11752846(A,G); rs11757516(C,G); rs12195064(A,G); rs115000394(C,T); rs9689584(C,G); rs9688764(A,G); rs9689594(G,T); rs7763974(T,C); rs12202008(C,T); rs4596506(T,C); rs10457515(G,T); rs55910907(C,T); rs7768567(A,T); rs4475345(C,T); rs7768908(A,G); rs9689333(C,T); rs6914652(T,A); rs3813370(C,A); rs3813369(A,C); rs3813368(A,T); rs12209995(G,A); rs12209961(C,T); rs12210105(G,T); rs12210013(C,G); rs10499147(G,A); rs10499148(C,T); rs74936600(A,G); rs4404787(C,A); rs10457516(C,T); rs10457517(T,G); rs11154463(T,C); rs11154464(G,C); rs9375612(T,A); rs75692583(C,T); rs62423270(G,A); rs12190465(G,A); rs10456976(C,T); rs9321148(G,C); rs4895846(T,C); rs4897295(A,G); rs4515405(A,G); rs78749629(G,A); rs7451237(C,T); rs9388682(G,A); rs4523106(A,G); rs9375613(T,C); rs4590284(T,C); rs4524626(A,G); rs7738996(T,A); rs6569579(A,C); rs6569580(T,C); rs9492218(A,G); rs9398894(C,T); rs9375614(G,A); rs4897297(A,G); rs4897298(G,T); rs9482980(C,T); rs4897299(G,C); rs12210785(A,G); rs117275446(G,A); rs9372918(G,A); rs7750128(A,T); rs7750261(C,T); rs7750276(A,T); rs7750304(A,G); rs7751105(C,T); rs62423276(T,C); rs9492221(T,C); rs13216682(C,T); rs4289675(C,T); rs6941675(T,G); rs4397250(T,A); rs74810388(C,A); rs4612193(A,G); rs4585575(A,T); rs4543385(A,G); rs10457518(T,C); rs12197360(A,G); rs72973201(C,A); rs12198871(A,T); rs9402099(G,A); rs9402100(A,G); rs6569581(A,G); rs7759703(C,T); rs6904476(T,C); rs9385479(G,C); rs9398895(C,T); rs9482981(T,C); rs115593469(A,G); rs9402101(T,A); rs9375615(A,G); rs12174829(T,A); rs6923140(T,C); rs6904911(A,G); rs4327720(G,T); rs4364505(A,G); rs9375616(C,G); rs112829748(G,C); rs4458709(G,A); rs4354176(G,A); rs9492223(G,A); rs9482982(T,G); rs4897301(G,A); rs4144420(C,T); rs4419681(A,G); rs9321150(A,G); rs9402102(T,C); rs9492224(T,C); rs9321151(T,C); rs76434493(G,A); rs7774472(A,C); rs7774997(G,A); rs77907981(G,T); rs7774774(A,C); rs7757097(T,G); rs17056792(C,A); rs4568475(G,A); rs4538727(A,G); rs6921064(A,C); rs9402104(G,A); rs73596777(G,A); rs7741016(T,C); rs72988966(G,T); rs78108541(A,G); rs17056793(C,G); rs6934624(A,G); rs9492232(C,T); rs17056798(T,G); rs4629708(T,C); rs7772780(G,A); rs9375617(T,G); rs9321152(A,C); rs7771065(T,G); rs9402105(G,A); rs9388685(C,T); rs9388686(A,C); rs7764165(T,C); rs9492234(G,A); rs7754666(C,T); rs2381(T,C); rs67392956(A,G); rs10499150(C,A); rs9492235(T,G); rs1478804(G,A); rs1478803(A,G); rs73773674(G,A); rs72988989(C,T); rs17727238(A,G); rs17053356(T,A); rs1026718(A,G); rs1478802(A,G); rs7738316(A,G); rs2448013(G,A); rs9492237(T,C); rs9492238(T,C); rs9482984(G,A); rs77819984(G,T); rs2494935(G,T); rs9482985(G,C); rs899350(C,A); rs727183(T,G); rs7756786(T,C); rs1478800(A,C); rs9492240(C,G); rs1382515(C,T); rs9482986(G,A); rs9492241(G,A); rs4510701(T,A); rs9492242(T,C); rs2494936(A,T); rs1382514(A,G); rs7773094(T,C); rs7758532(G,C); rs2494937(A,G); rs114208582(T,C); rs2448012(T,C); rs7751112(T,C); rs17056825(C,A); rs9492243(A,G); rs9482987(T,C); rs9482988(A,G); rs74975212(C,T); rs79291640(A,G); rs75600207(C,A); rs79702013(T,C); rs77357343(C,T); rs7744609(T,C); rs6569582(G,C); rs77904995(T,C); rs112838065(G,A); rs111541637(C,T); rs77233670(T,C); rs76200266(A,G); rs6569583(G,A); rs77864765(G,A); rs76884597(G,C); rs78418823(A,G); rs115516995(A,G); rs112394430(G,A); rs77920921(A,G); rs78810561(C,A); rs76154091(A,C); rs74698242(C,G); rs3943300(C,T); rs78886700(G,C); rs79727346(T,C); rs79455967(A,G); rs1478799(G,A); rs75255831(C,A); rs11751534(C,T); rs1478798(C,G); rs1478797(C,T); rs113409097(C,T); rs77912118(T,C); rs76772726(G,A); rs12193437(C,A); rs59319869(A,G); rs13206942(C,G); rs11756052(T,C); rs11758207(A,T); rs78304164(G,T); rs9492245(C,T); rs78306398(C,T); rs7754560(G,A); rs17056847(G,A); rs58858833(C,T); rs9482989(A,G); rs3778141(C,T); rs1478796(C,T); rs9492247(T,C); rs138200130(C,T); rs3778140(A,G); rs3778139(A,G); rs2279165(A,T); rs73599023(T,A); rs76148112(A,C); rs7767990(T,C); rs6569584(G,C); rs17056862(T,C); rs9492248(C,A); rs76071557(T,C); rs12664291(T,C); rs3778138(A,G); rs2326758(T,A); rs17056866(C,T); rs116712741(G,A); rs6569585(C,T); rs17056868(C,T); rs114208730(C,A); rs17056871(T,G); rs56397435(C,T); rs76826747(A,T); rs12663088(G,T); rs114378810(A,G); rs113558151(A,G); rs7750547(C,T); rs6569586(T,A); rs144121011(T,C); rs148528579(C,T); rs7762236(G,A); rs9492253(A,G); rs9492254(G,A); rs3778137(T,C); rs57290480(T,C); rs3798674(T,G); rs75249978(T,C); rs728348(A,T); rs7741948(A,C); rs79079043(A,G); rs7748051(C,T); rs75629505(G,C); rs17056894(G,C); rs73599042(C,T); rs2326759(A,C); rs2219787(G,A); rs116797445(T,A); rs73599046(A,G); rs1478793(T,C); rs1478792(C,A); rs58713330(C,G); rs1979404(G,C); rs12664847(A,G); rs60672105(G,A); rs17056909(A,G); rs1478808(A,G); rs9492262(T,C); rs116613994(A,G); rs17056914(C,T); rs9492263(A,G); rs9492264(G,A); rs9482998(A,G); rs9492265(C,T); rs3778135(A,C); rs6902375(G,A); rs6902612(G,C); rs2876021(A,G); rs2306220(T,C); rs17056928(T,C); rs3778134(G,C); rs111381107(C,T); rs17056935(T,C); rs112153290(C,T); rs56066662(C,T); rs6925197(C,T); rs9492271(C,T); rs12210504(G,A); rs56691264(A,C); rs184337336(C,T); rs79257175(C,G); rs12214548(G,A); rs58043974(T,C); rs77308634(C,T); rs76897155(G,A); rs11154466(T,A); rs9492272(T,G); rs74446709(C,T); rs7766548(G,A); rs60220768(C,G); rs3778132(G,A); rs17729201(T,G); rs190161080(A,G); rs3778130(A,G); rs9375619(C,G); rs150596369(G,A); rs73774766(G,T); rs9402107(T,C); rs1871280(A,T); rs9372920(C,G); rs430241(A,G); rs9398898(A,G); rs73599099(G,A); rs265364(G,C); rs265363(G,A); rs265362(T,A); rs265361(G,A); rs265360(T,C); rs181148823(G,A); rs265359(T,A); rs265358(C,A); rs265357(T,C); rs265356(T,C); rs265355(T,C); rs265354(A,C); rs265353(T,C); rs265347(A,C); rs265346(A,G); rs7762690(C,A); rs7748901(T,G); rs9492273(G,A); rs139002636(T,C); rs6569588(C,A); rs6931173(G,A); rs265337(G,A); rs7771079(G,A); rs7753650(T,C); rs7771688(C,G); rs265334(C,G); rs7738096(A,G); rs7739194(G,A); rs9321156(G,A); rs265333(T,C); rs144761571(G,A); rs11963652(A,G); rs9385483(G,T); rs265332(A,G); rs6933843(T,G); rs265331(A,G); rs115094488(A,T); rs78427821(A,C); rs265330(G,A); rs265329(T,G); rs116477346(A,G); rs116585961(A,G); rs112006939(A,T); rs265367(G,T); rs62420985(T,G); rs10447440(A,C); rs17796969(T,C); rs9483002(G,A); rs265366(A,G); rs116248437(T,G); rs9388693(G,A); rs113393627(C,G); rs112304688(G,C); rs990541(G,A); rs265365(G,A); rs114592642(A,C); rs116790221(T,C); rs17740726(G,A); rs62420986(G,A); rs265382(A,T); rs265381(A,T); rs50667(G,A); rs265380(A,G); rs265379(G,A); rs2876038(A,G); rs265378(T,C); rs265377(G,A); rs2127101(G,A); rs265376(C,T); rs265388(G,C); rs265387(G,A); rs116333875(A,G); rs265386(G,A); rs265385(G,T); rs265384(T,C); rs111285812(T,C); rs265383(C,G); rs4897306(G,A); rs113340462(A,G); rs7751571(G,A); rs3778123(T,A); rs3816666(T,G); rs113129540(C,G); rs3816665(G,A); rs2169870(A,T); rs7754620(T,G); rs147016855(T,C); rs115807670(A,T); rs11966599(G,A); rs3778122(T,C); rs3823007(T,C); rs75636484(A,G); rs9492285(T,C); rs9492286(G,A); rs3778121(A,G); rs265401(G,A); rs11961288(T,A); rs143987313(G,A); rs11963584(A,G); rs11961329(T,C); rs737515(G,T); rs899352(T,G); rs114612623(T,C); rs3823006(G,A); rs12661540(T,C); rs193037788(A,G); rs265328(G,T); rs9492287(T,C); rs9483006(G,T); rs58821164(T,C); rs111337582(A,C); rs79875611(T,C); rs17057029(T,A); rs265327(C,A); rs3778119(G,A); rs265326(G,C); rs265325(C,T); rs4897307(C,A); rs187851(C,T); rs2448011(C,T); rs265400(A,C); rs265399(A,C); rs265398(A,G); rs265397(G,C); rs148132911(G,T); rs265396(T,G); rs265395(G,A); rs265394(C,T); rs265393(A,C); rs265392(T,A); rs265391(A,T); rs6907984(C,T); rs265390(T,A); rs265375(C,T); rs265374(C,T); rs150792994(G,A); rs265373(C,T); rs265372(A,G); rs3778114(G,A); rs265371(C,T); rs265370(G,A); rs148398501(C,T); rs146832716(A,T); rs9492290(A,G); rs954161(A,G); rs1490391(A,T); rs74930412(G,A); rs902370(A,G); rs902369(G,T); rs744909(C,A); rs902368(T,C); rs140970137(C,A); rs145694652(G,A); rs970064(A,G); rs77638028(C,T); rs9321157(A,G); rs9321158(C,T); rs9492292(A,C); rs57008513(C,T); rs9492296(T,C); rs3778112(T,C); rs902371(A,G); rs9385484(A,G); rs6917996(G,A); rs147847417(T,C); rs1032323(T,A); rs1032324(T,C); rs1015845(G,T); rs35277491(G,T); rs1027199(A,G); rs113160498(G,A); rs6921593(T,C); rs74297190(C,T); rs9492298(C,T); rs6420741(T,A); rs2087566(C,G); rs2101575(A,C); rs11967042(G,A); rs1027200(G,A); rs4280978(G,T); rs12206487(C,T); rs13217768(T,C); rs3798668(G,A); rs13202296(A,C); rs12208401(C,T); rs6902957(A,G); rs6926104(T,C); rs9385485(G,A); rs902372(C,T); rs9385486(C,A); rs2326798(A,G); rs3798666(A,G); rs902373(A,G); rs3798664(A,G); rs2451689(G,T); rs13215801(G,A); rs2501460(C,T); rs12195889(T,C); rs2451683(G,T); rs79053593(G,A); rs9402115(A,G); rs73585571(C,G); rs12204350(A,G); rs2451682(C,T); rs74317209(A,G); rs78704874(G,A); rs2501459(C,T); rs73585572(G,T); rs9375623(A,G); rs9402116(G,A); rs9321159(T,C); rs9372923(T,A); rs9388694(A,C); rs3798663(G,A); rs3798662(G,A); rs2130606(A,G); rs2306942(G,A); rs17741922(T,G); rs13203042(A,G); rs1490392(C,T); rs1948307(C,T); rs9321160(G,A); rs12527452(T,A); rs3798660(G,C); rs2451686(C,A); rs12200836(C,T); rs114492855(A,C); rs1873330(A,G); rs12208367(T,C); rs74859844(G,A); rs12201387(G,C); rs192302746(C,T); rs4642505(G,A); rs7766689(G,A); rs17057149(C,T); rs7752897(A,T); rs12200538(G,A); rs7753862(C,T); rs2451688(A,G); rs115877874(T,G); rs12663564(C,T); rs1994619(T,C); rs12206166(G,T); rs12206081(C,T); rs12208111(C,G); rs9388695(G,A); rs12213554(C,A); rs9492301(A,G); rs1472057(T,C); rs2501466(A,T); rs6420742(T,C); rs114816402(T,G); rs76723111(A,G); rs142217106(A,T); rs4143753(T,C); rs2451680(T,C); rs2501467(G,A); rs78055215(A,T); rs9372924(C,T); rs2451679(T,G); rs186483056(C,T); rs2501468(G,A); rs11154471(A,G); rs144616009(C,G); rs2451678(T,C); rs10155762(A,C); rs1873329(C,T); rs11154472(G,A); rs140842795(C,T); rs1387918(T,C); rs2494582(T,A); rs9492302(C,T); rs11154473(G,A); rs2501458(G,A); rs12660510(G,A); rs7766742(G,T); rs6936981(C,T); rs9372925(T,A); rs1490390(G,A); rs9398900(T,C); rs112104015(G,A); rs2494583(T,A); rs9398901(G,A); rs9492305(G,A); rs17799083(A,C); rs6930568(A,C); rs17057159(T,C); rs59174664(T,C); rs57420975(T,C); rs3813367(G,T); rs13193413(G,T); rs4452667(A,T); rs7453910(C,T); rs4489171(G,A); rs12190405(T,A); rs12215657(C,T); rs9372926(A,G); rs9388696(G,A); rs13209300(G,A); rs6907994(C,G); rs9372927(G,A); rs73587394(A,G); rs17057176(C,T); rs4296900(A,G); rs141073487(T,C); rs11751751(G,A); rs35579821(C,A); rs17057184(C,G); rs4897309(G,A); rs7739173(A,G); rs13194587(T,C); rs76809868(A,G); rs6569593(A,G); rs4298368(T,G); rs7758642(T,A); rs7738438(C,G); rs149120794(C,T); rs115879084(G,T); rs9388700(C,T); rs9402119(G,A); rs7356971(C,T); rs6904763(T,C); rs116465194(G,A); rs17057200(C,T); rs9388701(A,T); rs11754670(T,G); rs6899448(C,T); rs2437089(C,T); rs2437088(G,A); rs66497175(G,A); rs7769749(G,A); rs7770270(G,A); rs58558234(A,G); rs78500609(A,T); rs12529278(A,G); rs2437099(T,G); rs7753331(G,A); rs4599678(G,A); rs2437098(C,T); rs2437097(C,T); rs73591271(G,A); rs2437096(T,A); rs2437095(G,T); rs2437094(A,G); rs2437093(A,G); rs6914003(C,T); rs2437092(A,G); rs2437091(C,T); rs77768478(A,C); rs17057244(A,G); rs2437090(T,G); rs12662729(C,T); rs7763317(G,A); rs41524649(T,A); rs113941946(T,C); rs115239099(T,A); rs113194090(G,A); rs13216380(T,G); rs17057259(T,C); rs190189417(C,A); rs7356972(T,C); rs2876041(C,A); rs2437086(T,G); rs6902480(A,G); rs2326816(T,C); rs6907500(A,G); rs6908321(G,A); rs6930710(T,C); rs115630988(G,T); rs3749877(A,G); rs3749878(G,A); rs3749879(A,G); rs4897310(T,C); rs4897311(C,T); rs4897312(C,T); rs3749880(T,C); rs3749881(A,G); rs4562158(T,C); rs1961971(C,T); rs4897313(G,A); rs4897314(T,C); rs4897315(G,A); rs2326817(A,G); rs3828737(C,G); rs34988037(A,C); rs6906791(T,C); rs6926812(A,G); rs6906956(T,G); rs6899685(G,A); rs6899815(G,A); rs6900181(G,T); rs6922936(T,C); rs6900123(A,G); rs9388703(G,A); rs6923141(T,A); rs2326818(A,G); rs2326819(T,C); rs6905843(A,G); rs9321162(A,G); rs4897316(T,A); rs4897317(A,G); rs6906869(G,C); rs9388704(T,C); rs9372928(G,C); rs9385489(T,G); rs9402121(A,G); rs9398902(G,C); rs9388705(C,A); rs9402122(A,G); rs4397251(A,C); rs4580897(T,C); rs4541768(A,C); rs4512239(A,G); rs9402123(A,G); rs6903654(T,G); rs7760596(C,T); rs7761156(G,A); rs7761165(G,A); rs4406255(G,T); rs4406256(G,A); rs4406257(G,A); rs4397252(C,T); rs4305743(A,G); rs6929916(A,G); rs6930250(C,T); rs6910113(T,C); rs6930649(C,T); rs9492320(A,C); rs9321163(T,A); rs9321164(C,A); rs9321165(A,G); rs9321167(T,G); rs9321168(A,C); rs10457521(G,C); rs10456977(T,C); rs10457522(G,C); rs146817692(T,G); rs10456978(T,C); rs10456979(A,T); rs6569600(A,G); rs190945886(A,G); rs6569601(A,C); rs2326801(C,T); rs4143751(A,G); rs4143749(A,G); rs4143750(A,G); rs7764300(T,G); rs9285465(T,C); rs6928963(T,C); rs6933947(T,C); rs138744745(C,T); rs6933974(T,G); rs6911075(A,G); rs6911685(G,A); rs55737366(G,A); rs9402124(C,A); rs9402125(G,A); rs9402126(C,G); rs9492322(G,T); rs9402127(C,T); rs9385490(C,T); rs9402128(A,G); rs7764094(G,A); rs4897318(G,A); rs2326802(A,G); rs2326803(T,C); rs140929335(G,A); rs10872339(G,A); rs2326804(C,T); rs10872340(A,G); rs10872341(G,A); rs10456980(T,G); rs10457523(C,T); rs2326805(T,G); rs11154475(C,G); rs9483029(G,T); rs151238783(T,A); rs9402129(C,T); rs9402130(G,A); rs1986342(C,T); rs12205965(G,A); rs7745957(G,A); rs6908451(A,G); rs9492323(A,G); rs7756981(G,C); rs7756862(C,G); rs10872342(C,T); rs10872343(G,A); rs9398903(C,G); rs9388706(G,T); rs4897321(C,G); rs4897322(C,A); rs2494577(G,A); rs4897323(C,A); rs2326820(C,T); rs12192806(T,A); rs2437087(T,C); rs11154477(A,G); rs11753445(T,C); rs2297738(G,A); rs1889892(G,A); rs7738519(C,T); rs11154478(G,A); rs151280823(C,T); rs7748719(A,G); rs9402132(C,T); rs73775417(A,G); rs1414740(G,C); rs1414739(C,T); rs1414738(G,T); rs9375626(C,T); rs62421014(A,C); rs79292623(C,T); rs6569602(T,C); rs9385491(A,G); rs138585792(T,C); rs9372929(G,C); rs73775422(T,G); rs11154479(C,A); rs62421015(T,C); rs141058341(C,T); rs77432719(C,T); rs9402133(G,A); rs9402134(G,A); rs9375627(C,A); rs10456981(A,G); rs12523994(A,T); rs1336255(G,A); rs9375628(G,T); rs9375629(C,T); rs41500045(A,G); rs9388707(T,G); rs9398905(A,G); rs2784891(T,G); rs11154480(C,T); rs11154481(G,T); rs1811970(C,T); rs9372930(C,T); rs9402135(G,C); rs9375630(T,A); rs62421017(T,C); rs41369446(A,G); rs4897324(A,G); rs10499157(T,C); rs10499158(G,A); rs10499159(C,A); rs11154482(T,C); rs7755729(C,T); rs9375631(T,C); rs4897325(C,G); rs4897326(C,T); rs17057338(G,T); rs62421032(G,A); rs1414737(C,T); rs2297741(G,A); rs1414736(T,C); rs77457449(G,T); rs7450969(A,G); rs9492325(G,A); rs6917532(G,A); rs9388708(C,T); rs9388709(A,C); rs12191417(G,C); rs9372932(G,C); rs4897327(A,G); rs12195178(C,T); rs6899741(A,G); rs6569603(C,A); rs6905196(A,G); rs1336256(T,C); rs73777430(G,T); rs4897328(T,C); rs7741996(C,T); rs56125261(A,C); rs988551(T,C); rs988550(A,G); rs67603776(A,T); rs2571577(T,C); rs2784892(C,A); rs2571578(T,G); rs141773436(A,G); rs2571579(G,A); rs9483031(C,A); rs9483032(G,A); rs2784893(C,G); rs2571580(A,G); rs2784894(C,T); rs2784895(C,T); rs7741035(T,C); rs2784896(G,C); rs9483033(G,A); rs9483034(C,T); rs116320738(G,A); rs2275210(C,T); rs2275211(C,T); rs2275212(C,T); rs2275213(G,T); rs7764858(A,G); rs9483035(C,T); rs9492329(T,A); rs2784897(T,G); rs2784898(C,T); rs2275214(G,C); rs2571581(A,T); rs2571582(A,G); rs7775030(A,G); rs2784899(T,A); rs117077066(G,A); rs2784900(T,A); rs2571583(A,C); rs2571584(A,G); rs188429776(G,A); rs145655167(G,A); rs181904729(G,A); rs2571586(G,A); rs76367994(A,G); rs2571587(G,A); rs2784904(T,C); rs9372933(T,A); rs73776179(A,G); rs113119531(A,G); rs6569604(C,G); rs2229848(C,T); rs2229849(G,C); rs2229850(G,A); rs6938825(C,A); rs9402136(C,T); rs9402137(C,A); rs9385495(C,T); rs9372934(A,G); rs7740029(C,T); rs7740552(G,T); rs7740321(C,T); rs7740749(G,A); rs2784905(C,T); rs9483037(C,T); rs2017299(G,A); rs1889890(C,T); rs9375632(C,T); rs185969552(T,G); rs9372935(C,T); rs2571594(G,T); rs2784906(T,A); rs2571593(A,G); rs2571592(C,T); rs115398539(T,C); rs73776182(T,A); rs2784907(G,T); rs73776184(G,A); rs35313209(T,C); rs1889891(C,T); rs34997144(T,A); rs73776188(A,T); rs112637380(A,G); rs76158781(C,T); rs62421036(C,T); rs1414741(G,A); rs73776189(A,G); rs10499160(T,C); rs9372936(T,C); rs73776190(C,T); rs112858053(A,C); rs112226670(A,G); rs77802019(G,T); rs12208392(T,G); rs10080659(C,T); rs77172518(G,A); rs12203042(C,T); rs61078343(T,C); rs149376300(T,C); rs73776191(C,T); rs12193446(A,G); rs147436549(G,A); rs55835842(C,T); rs17752721(C,T); rs55813773(A,G); rs56929613(T,C); rs56000744(C,G); rs73776193(T,A); rs58564339(A,G); rs56056014(C,T); rs56387145(C,T); rs56077289(A,T); rs56030366(T,G); rs58347039(C,T); rs73776194(C,G); rs73776195(T,C); rs73776196(G,A); rs73776198(C,G); rs9321170(G,A); rs78213933(T,C); rs78188269(C,T); rs116634083(G,A); rs7774592(T,C); rs7754167(A,G); rs6923431(A,C); rs9483039(C,G); rs11154483(C,T); rs12523864(T,C); rs9492334(A,G); rs56257418(A,G); rs2571570(G,A); rs2571571(A,G); rs73600882(C,G); rs2571572(C,T); rs2571573(G,T); rs2571574(A,C); rs58336000(A,G); rs2571575(T,G); rs2571576(T,C); rs12205363(T,C); rs55877366(A,G); rs2297740(G,A); rs9402138(C,G); rs13208666(T,C); rs1049476(T,C) |
| ccdsGene name | CCDS5138.1 |
| CosmicCodingMuts gene | LAMA2 |
| cytoBand name | 6q22.33 |
| EntrezGene GeneID | 3908 |
| EntrezGene Description | laminin, alpha 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LAMA2:NM_001079823:exon55:c.C7748T:p.A2583V,LAMA2:NM_000426:exon56:c.C7760T:p.A2587V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5838 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.604395604396 |
| dbNSFP KGp1 Afr AF | 0.432926829268 |
| dbNSFP KGp1 Amr AF | 0.638121546961 |
| dbNSFP KGp1 Asn AF | 0.592657342657 |
| dbNSFP KGp1 Eur AF | 0.708443271768 |
| dbSNP GMAF | 0.3958 |
| ESP Afr MAF | 0.46709 |
| ESP All MAF | 0.361372 |
| ESP Eur/Amr MAF | 0.273488 |
| ExAC AF | 0.668 |
OMIM Clinical Significance
Neuro:
Anesthesia and discomfort localized to nerve branch
Inheritance:
Autosomal dominant
OMIM Title
*156225 LAMININ, ALPHA-2; LAMA2
;;LAMININ 2, HEAVY CHAIN
MEROSIN, INCLUDED;;
LAMININ 2, INCLUDED;;
LAMININ M, INCLUDED; LAMM, INCLUDED
OMIM Description
DESCRIPTION
Laminin is a heterotrimeric extracellular matrix protein consisting of 3
chains: alpha-1 (LAMA1; 150320), beta-1 (LAMB1; 150240), and gamma-1,
formerly called beta-2 (LAMC1; 150290). Several isoforms of each chain
have been identified. Laminin-2 (merosin) is a heterotrimer composed of
laminin subunits alpha-2, beta-1, and gamma-1. It is the main laminin
found in muscle fibers. The LAMA2 gene encodes the alpha-2 chain of
laminin-2.
CLONING
Merosin is a protein specifically found in the basement membranes of
striated muscle and Schwann cells. It is also found in the basement
membrane of placental trophoblasts. Ehrig et al. (1990) compared merosin
with laminin, which is thought to be present in all basement membranes.
They found that a cDNA clone derived from a merosin fragment contained a
3.4-kb open reading frame encoding 1,130 amino acids. The deduced amino
acid sequence of the merosin polypeptide is similar to that of the
C-terminal region of the laminin alpha-1 chain. The sequence identity
between merosin and laminin is nearly 40% in this region. Like laminin,
merosin is associated with the light chains laminin B1 and laminin B2,
and the whole molecule has a cross-like structure similar to that of
laminin. The authors estimated that the LAMA2 chain is at least 380 kD.
Vuolteenaho et al. (1994) determined the primary structure of the
laminin M chain (symbolized LAMM by them) from cDNA clones isolated from
human placental libraries. The complete chain contains a 22-residue
signal peptide and 3,088 residues of the mature M chain (3110 residues
total). The M chain has a domain structure similar to that of the human
and mouse A chains. Northern blot analysis of human fetal tissues showed
that the M chain was expressed in most tissues, but not in liver,
thymus, or bone. In situ hybridization localized the expression of the M
chain gene to cells of mesenchymal origin. In contrast, expression of
the A chain was observed only in kidney, testis, neuroretina, and some
regions of the brain, as determined by Northern analyses. Epithelial and
endothelial cells were negative for both M and A chain gene transcripts.
Pegoraro et al. (2000) identified a novel alternatively spliced isoform
of LAMA2. Direct sequencing showed that the isoform has a 138-bp
in-frame deletion from nucleotides 4629 to 4766 of the coding sequence
corresponding to about 70% of exon 31. This splicing event removes 46
amino acids in the cysteine-rich domain IIIa, just proximal to the
triple coiled-coil region that associates with the beta-1 and gamma-1
chains of laminin. Immunofluorescent studies suggested that this isoform
may impair proper laminin chain assembly.
GENE FUNCTION
Arahata et al. (1993) indicated that merosin is the same as laminin M, a
striated muscle-specific, basal-lamina-associated protein. They found
that the protein was reduced in the muscle fibers in Fukuyama congenital
muscular dystrophy (253800), suggesting that it may play a primary role
in the pathogenesis of that disorder.
The laminin alpha-2 subunit is expressed in Schwann cells. Ng et al.
(2000) provided evidence for the involvement of the specific
trisaccharide unit of the phenolic glycolipid-1 (PGL1) of Mycobacterium
leprae (see 246300) in determining the bacterial predilection to the
peripheral nerve. PGL1 binds specifically to the native laminin-2 in the
basal lamina of Schwann cell-axon units. This binding is mediated by the
LG1, LG4, and LG5 modules present in the naturally cleaved fragments of
the peripheral nerve LAMA2 chain, and is inhibited by the synthetic
terminal trisaccharide of PGL1. PGL1 is involved in the M. leprae
invasion of Schwann cells through the basal lamina in a
laminin-2-dependent pathway. The results indicated a novel role of a
bacterial glycolipid in determining the nerve predilection of a human
pathogen.
GENE STRUCTURE
Zhang et al. (1996) determined the genomic structure of the human LAMA2
gene. The gene spans over 260 kb and contains 64 exons. Two of the exons
are unusually small, being 6 and 12 bp, respectively.
MAPPING
Vuolteenaho et al. (1994) localized the human LAMA2 gene to 6q22-q23 by
a combination of somatic cell hybrid analysis and in situ hybridization.
By FISH, Sallinen et al. (1999) mapped the mouse Lama2 gene to
chromosome 10A4-B1.
MOLECULAR GENETICS
In affected members of 2 families with congenital merosin-deficient
muscular dystrophy type 1A (MDC1A; 607855), Helbling-Leclerc et al.
(1995) identified 2 different homozygous mutations
(156225.0001-156225.0002) in the LAMA2 gene. They suggested that 'the
extracellular location of laminin-2 may allow new therapeutic strategies
to restore its presence at the periphery of the muscle fibres and to
modify the severe course of this very disabling disease.'
Complete LAMA2 deficiency causes approximately half of CMD cases. Tezak
et al. (2003) noted that many loss-of-function mutations had been
reported in these severe, neonatal-onset patients, but only missense
mutations had been found in milder CMD with partial LAMA2 deficiency.
They studied 9 patients with CMD who showed abnormal white matter signal
on brain MRI and partial deficiency of LAMA2 on immunofluorescence of
muscle biopsy, and identified changes in the LAMA2 sequence in 6. Except
for one, each of the gene changes identified was novel, including 3
missense changes (see, e.g., 156225.0009-156225.0010) and 2 splice site
mutations. The finding of partial LAMA2 deficiency by immunostaining was
not specific for carriers of a LAMA2 gene mutation, as only 2 patients
showed clear causative mutations, and an additional 3 showed possible
mutations. The clinical presentation and disease progression were the
same in LAMA2 mutation-positive and mutation-negative CMD patients.
Di Blasi et al. (2005) identified 10 LAMA2 mutations, including 9 novel
mutations, in 10 of 15 patients with congenital muscular dystrophy and
undetectable or greatly reduced muscle expression of LAMA2 protein. All
the mutation-positive patients had generalized hypotonia and severe
weakness from birth, and all had abnormal MRI changes. One founder
mutation (156225.0013) was identified and determined to originate from
Albania. Two of the 5 patients without detectable LAMA2 mutations and
who also did not have white matter changes were found to have mutations
in the FKRP gene (606596).
Oliveira et al. (2008) identified 18 different mutations in the LAMA2
gene, including 14 novel mutations, in 50 (96%) of 52 disease alleles
from 26 patients with a clinical presentation suggestive of MDC1A. Only
heterozygous mutations were identified in 2 patients. Ten (31%) patients
carried a common 5-kb deletion encompassing exon 56 of the LAMA2 gene
(156225.0015).
ANIMAL MODEL
Gawlik et al. (2004) generated mice expressing a Lama1 transgene in
skeletal muscle of Lama2-deficient mice. Lama1 is not normally expressed
in muscle, but transgenic Lama1 was incorporated into muscle basement
membranes, and normalized the compensatory changes of expression of
certain other laminin chains (LAMA4, 600133; LAMB2, 150325). In
4-month-old mice, Lama1 could fully prevent development of muscular
dystrophy in several muscles, and partially in others. Gawlik et al.
(2004) concluded that the Lama1 transgene not only reversed the
appearance of histopathologic features of the disease to a remarkable
degree, but also greatly improved health and longevity of the mice.
Dominov et al. (2005) generated mdx (300377) or Lama2-null mice that
also overexpressed muscle-specific human BCL2 (151430). In mdx mice,
overexpression of BCL2 failed to produce any significant differences in
muscle pathology; however, in Lama2-null mice, muscle-specific
overexpression of BCL2 led to a several-fold increase in life span and
an increased growth rate. Dominov et al. (2005) concluded that
BCL2-mediated apoptosis appeared to play a significant role in
pathogenesis of congenital muscular dystrophy type 1A due to LAMA2
deficiency but not in Duchenne muscular dystrophy (DMD; 310200) due to
dystrophin deficiency.
In mice, Millay et al. (2008) showed the deletion of the gene encoding
cyclophilin D, Ppif (604486), rendered mitochondria largely insensitive
to the calcium overload-induced swelling associated with a defective
sarcolemma, thus reducing myofiber necrosis in 2 distinct models of
muscular dystrophy. Mice lacking delta-sarcoglycan (Scgd-null mice; see
601411) showed markedly less dystrophic disease in both skeletal muscle
and heart in the absence of Ppif. Moreover, the premature lethality
associated with deletion of Lama2 was rescued, as were other indices of
dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025
similarly reduced mitochondrial swelling and necrotic disease
manifestations in mdx mice, a model of Duchenne muscular dystrophy, and
in Scgd-null mice. Thus, mitochondrial-dependent necrosis represents a
prominent disease mechanism in muscular dystrophy, suggesting that
inhibition of cyclophilin D could provide a new pharmacologic treatment
strategy for these diseases.
TAAR9
| dbSNP name | rs2842899(T,A) |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 134860 |
| EntrezGene Description | trace amine associated receptor 9 (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | polymorphic_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1924 |
| ESP Afr MAF | 0.175549 |
| ESP All MAF | 0.238574 |
| ESP Eur/Amr MAF | 0.270131 |
| ExAC AF | 0.753 |
TAAR6
| dbSNP name | rs17061401(G,A); rs8192624(G,A); rs8192625(G,A) |
| ccdsGene name | CCDS5155.1 |
| CosmicCodingMuts gene | TAAR6 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 319100 |
| EntrezGene Description | trace amine associated receptor 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAAR6:NM_175067:exon1:c.G493A:p.G165S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0633 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RI8 |
| dbNSFP Uniprot ID | TAAR6_HUMAN |
| dbNSFP KGp1 AF | 0.0114468864469 |
| dbNSFP KGp1 Afr AF | 0.0467479674797 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.036768 |
| ESP All MAF | 0.012456 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 3.513e-03,8.946e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Myopia, high-grade (average spherical refractive error of -22.00D)
MISCELLANEOUS:
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae SCO2 gene (SCO2,
604272.0001)
OMIM Title
*608923 TRACE AMINE-ASSOCIATED RECEPTOR 6; TAAR6
;;TRACE AMINE RECEPTOR 4; TRAR4
OMIM Description
DESCRIPTION
The TAAR6 (TRAR4) gene belongs to the trace amine receptor family. Trace
amines are endogenous amine compounds that are chemically similar to
classic biogenic amines like dopamine, norepinephrine, serotonin, and
histamine. Trace amines were thought to be 'false transmitters' that
displace classic biogenic amines from their storage and act on
transporters in a fashion similar to the amphetamines, but the
identification of brain receptors specific to trace amines indicates
that they also have effects of their own (Duan et al., 2004).
CLONING
Using RT-PCR, Duan et al. (2004) found that TRAR4 was expressed at low
abundance in various human brain tissues as well as in human fetal
liver, but not in the cerebellum or placenta. Quantitative RT-PCR
revealed that TRAR4 has comparable levels of expression in basal
ganglia, frontal cortex, substantia nigra, amygdala, and hippocampus,
with the highest expression in hippocampus and the lowest expression in
basal ganglia. These results were consistent with a previous expression
study that included TRAR4 (Borowsky et al., 2001).
By screening the genomic sequence using a nonredundant set of all
vertebrate G protein-coupled receptors as queries, Lindemann et al.
(2005) identified TAAR6. The deduced 345-amino acid protein shows
several structural features characteristic of the rhodopsin
(180380)/beta-adrenergic receptor (see 109630) superfamily, including 7
transmembrane regions, which provide a common ligand-binding pocket, and
short N- and C-terminal domains.
GENE STRUCTURE
Lindemann et al. (2005) determined that the coding region of TAAR6 is
contained within a single exon.
MAPPING
Duan et al. (2004) showed that the TRAR4 gene is located within a gene
cluster spanning 132.8 cM on chromosome 6q23.2 which contains all known
TRAR genes, 3 TRAR pseudogenes, MOXD1, and STX7 (603217).
MOLECULAR GENETICS
Duan et al. (2004) genotyped 192 pedigrees with schizophrenia (see
603175), of European or African American ancestry, from samples that
previously showed linkage evidence to 6q13-q26. They selected 31
screening SNPs in the gene cluster on 6q23.2 that contains the TRAR4
gene. An association of schizophrenia with 1 SNP within the TRAR4 gene
(dbSNP rs4305745) remained significant after correction for multiple
testing. This and/or 2 other polymorphisms in perfect linkage
disequilibrium with the first appeared to be the most likely variants
underlying the association of the TRAR4 region with schizophrenia.
Comparative genomic analyses suggested that these polymorphisms could
potentially affect gene expression. Moreover, RT-PCR studies of various
human tissues, including brain, confirmed that TRAR4 is preferentially
expressed in those brain regions that have been implicated in the
pathophysiology of schizophrenia. Duan et al. (2004) concluded that
these data provided strong preliminary evidence that TRAR4 is a
candidate gene for schizophrenia.
TAAR5
| dbSNP name | rs36116159(G,A); rs3813355(G,A) |
| ccdsGene name | CCDS5156.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 9038 |
| EntrezGene Description | trace amine associated receptor 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAAR5:NM_003967:exon1:c.C681T:p.T227T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0225 |
| ESP Afr MAF | 0.075579 |
| ESP All MAF | 0.026065 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.007945 |
TAAR3
| dbSNP name | rs3813353(C,G); rs3813352(C,T); rs3813351(A,G); rs3813350(T,C); rs35751778(T,C); rs7759004(T,C); rs7738600(A,C) |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 9288 |
| EntrezGene Description | trace amine associated receptor 3 (gene/pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1405 |
| ExAC AF | 0.05 |
TAAR2
| dbSNP name | rs73775145(A,G); rs61745666(G,A); rs61731216(G,A); rs8192647(G,A); rs73775147(C,T); rs117859207(C,T); rs6907047(T,C); rs151122208(G,T); rs79084987(T,C); rs4451148(C,T); rs74569039(C,G); rs7764168(C,T); rs73555868(A,G); rs56823002(C,T); rs7769453(G,A); rs9389012(G,A); rs9389013(C,T); rs9385617(G,A); rs117367388(G,A); rs111234170(A,G); rs9389014(C,T); rs202019298(A,C); rs79531069(G,A); rs35606556(G,A); rs9483487(A,G); rs9321355(A,G); rs9321356(A,G); rs9389015(C,T); rs9375901(A,T); rs4598104(A,G); rs9493403(A,G); rs149219151(T,C); rs9389016(G,A); rs9385618(T,G); rs145218196(A,C); rs9385619(C,T); rs12213507(G,A); rs17061534(G,C) |
| ccdsGene name | CCDS5157.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 9287 |
| EntrezGene Description | trace amine associated receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAAR2:NM_001033080:exon2:c.C389T:p.S130F,TAAR2:NM_014626:exon1:c.C254T:p.S85F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5243 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9P1P5 |
| dbNSFP Uniprot ID | TAAR2_HUMAN |
| dbNSFP KGp1 AF | 0.0343406593407 |
| dbNSFP KGp1 Afr AF | 0.142276422764 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03444 |
| ESP Afr MAF | 0.081026 |
| ESP All MAF | 0.02768 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.008255 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Normal height
HEAD AND NECK:
[Face];
Flat midface;
Micrognathia;
[Ears];
Sensorineural hearing loss;
[Eyes];
Myopia (onset before 6 years);
Cataract;
Type 2 vitreous phenotype (irregularly thickened fiber bundles throughout
vitreous cavity);
Glaucoma;
Retinal detachment;
[Nose];
Depressed nasal bridge;
Anteverted nares;
[Mouth];
Cleft palate;
Pierre-Robin sequence;
Bifid uvula
SKELETAL:
Mild spondyloepiphyseal dysplasia;
[Limbs];
Slender extremities;
Joint hypermobility;
Arthropathy (onset third-fourth decade);
[Hands];
Long fingers
MISCELLANEOUS:
Allelic to Marshall syndrome (154780)
MOLECULAR BASIS:
Caused by mutation in the collagen XI, alpha-1 polypeptide gene (COL11A1,
120280.0001)
OMIM Title
*604849 TRACE AMINE-ASSOCIATED RECEPTOR 2; TAAR2
;;G PROTEIN-COUPLED RECEPTOR 58; GPR58
OMIM Description
CLONING
G protein-coupled receptors (GPCRs, or GPRs) contain 7 transmembrane
domains and transduce extracellular signals through heterotrimeric G
proteins. Lee et al. (2000) obtained the sequences of a human cerebellum
cDNA encoding phBL5, which they called GPR58, and a rabbit smooth muscle
cDNA encoding GPR58 from the patent literature. They isolated the
complete human GPR58 coding region from genomic DNA. The deduced
306-amino acid human GPR58 protein shares 42% identity with the putative
neurotransmitter receptor PNR (TAAR5; 607405) and 34% identity with the
serotonin receptor 5-HT4 (HTR4; 602164). GPR58 shares highest identity
with HNHCI32, or GPR57, a human hippocampus cDNA from the patent
literature; however, genomic library screening showed that GPR57
represents a pseudogene. GPR58 contains 7 predicted transmembrane
domains, potential PKC phosphorylation sites, and residues corresponding
to those in biogenic amine-binding receptors that are important for
ligand binding. Northern blot analysis did not detect GPR58 expression
in human pons, thalamus, hypothalamus, hippocampus, caudate, putamen,
frontal cortex, basal forebrain, midbrain, or liver.
By screening the genomic sequence using a nonredundant set of all
vertebrate G protein-coupled receptors as queries, Lindemann et al.
(2005) identified a long isoform of TAAR2. The deduced 353-amino acid
protein shows several structural features characteristic of the
rhodopsin (180380)/beta-adrenergic receptor (see 109630) superfamily,
including 7 transmembrane regions, which provide a common ligand-binding
pocket, and short N- and C-terminal domains.
GENE STRUCTURE
Lindemann et al. (2005) determined that the coding region of TAAR2 is
contained within 2 exons. All other members of the TAAR family are
encoded by a single exon.
MAPPING
By FISH, Lee et al. (2000) mapped the GPR58 gene to chromosome 6q24.
TAAR1
| dbSNP name | rs8192621(T,C); rs8192620(T,C) |
| ccdsGene name | CCDS5158.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 134864 |
| EntrezGene Description | trace amine associated receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAAR1:NM_138327:exon1:c.A936G:p.R312R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04913 |
| ESP Afr MAF | 0.00522 |
| ESP All MAF | 0.014538 |
| ESP Eur/Amr MAF | 0.019316 |
| ExAC AF | 0.031 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature (<3rd percentile)
SKELETAL:
Generalized joint laxity;
[Spine];
Increased lumbar lordosis;
Normal vertebrae;
[Pelvis];
Abnormal proximal femur with miniepiphyses;
Wide, deformed femoral neck;
[Limbs];
Genua vara;
Small, secondary ossification centers (miniepiphyses);
Small, irregular patellae
OMIM Title
*609333 TRACE AMINE-ASSOCIATED RECEPTOR 1; TAAR1
;;TAR1; TA1
OMIM Description
DESCRIPTION
TAAR1 is a G protein-coupled receptor activated by trace amines. Trace
amines are endogenous amine compounds that account for less than 1% of
the biogenic amines in most brain regions (Bunzow et al., 2001).
CLONING
Using rat Taar1 to probe a human placenta genomic library, followed by
5-prime and 3-prime RACE of a kidney and stomach cDNA library, Borowsky
et al. (2001) cloned TAAR1, which they designated TA1. The deduced
339-amino acid protein has a 7-transmembrane structure. TAAR1 shares 79%
and 76% amino acid identity with rat and mouse Taar1, respectively.
RT-PCR of human tissues and brain regions detected moderate expression
in stomach, lower expression in amygdala, kidney, lung, and small
intestine, and little to no expression in all other tissues and specific
brain regions examined. In situ hybridization and immunohistochemical
localization of Taar1 in mouse brain detected variable region-specific
expression. Taar1 localized to the cytoplasm of cells showing neuronal
profiles.
Using rat Taar1 to probe a human genomic DNA library, Bunzow et al.
(2001) cloned TAAR1. The deduced protein contains 340 amino acids. It
has 2 N-glycosylation sites at its N terminus and several potential
protein kinase sites at its C terminus, including 2 serines not present
in rat Taar1. Human embryonic kidney (HEK293) cells transfected with rat
cDNA for epitope-tagged Taar1 expressed the protein in a punctate
intracellular distribution, with exclusion from the nucleus.
Lindemann et al. (2005) found that the TAARs show several structural
features characteristic of the rhodopsin (180380)/beta-adrenergic
receptor (see 109630) superfamily, including the positions of the 7
transmembrane regions, which provide a common ligand-binding pocket, and
short N- and C-terminal domains. TAAR1 has 2 N-glycosylation sites in
the N-terminal domain and a single disulfide bridge.
GENE FUNCTION
Borowsky et al. (2001) found that Xenopus oocytes expressing human TAAR1
with CFTR (602421) produced inward currents in response to tyramine.
HEK293 cells transfected with TAAR1 increased intracellular cAMP
accumulation in response to beta-phenylethylamine (PEA) and tyramine.
TAAR1 was less responsive to tryptamine, histamine, serotonin, and
norepinephrine.
Bunzow et al. (2001) found that rat Taar1 was activated by a wide
variety of clinically and socially important drugs, including
amphetamines, ergot derivatives, and adrenergic agents. Rat Taar1 was
more potently activated by the catecholamine metabolites
3-methoxytyramine, normetanephrine, and metanephrine than by the
neurotransmitters dopamine, norepinephrine, and epinephrine.
Lindemann et al. (2005) found that TAAR1 expressed by transfected HEK293
cells was highly responsive to beta-PEA, p-tyramine, N-methyl-beta-PEA,
and N-methyl-p-tyramine. It showed lower cAMP accumulation in response
to octopamine, tryptamine, and dopamine. TAAR1 was unresponsive to the
classical biogenic amines norepinephrine, serotonin, and histamine.
Liberles and Buck (2006) reported that genes encoding trace
amine-associated receptors (TAARs) are present in human, mouse, and
fish. Like odorant receptors, individual mouse TAARs recognize volatile
amines found in urine: one detects a compound linked to stress, whereas
the other 2 detect compounds enriched in male versus female urine. The
evolutionary conservation of the TAAR family suggests a chemosensory
function distinct from odorant receptors. Ligands identified for TAARs
suggested a function associated with the detection of social cues.
GENE STRUCTURE
Lindemann et al. (2005) determined that the coding region of TAAR1 is
contained within a single exon.
MAPPING
By radiation hybrid analysis, Borowsky et al. (2001) mapped the TAAR1
gene to a TAAR gene cluster on chromosome 6q23.3. By FISH, Bunzow et al.
(2001) mapped the TAAR1 gene to chromosome 6q23.2.
Lindemann et al. (2005) determined that the TAAR genes map to a 109-kb
region on chromosome 6q23.1. They mapped the mouse genes to a 192-kb
region on chromosome 10A4 and identified a similar clustering of TAAR
genes in other mammalian species.
NOMENCLATURE
In an effort to resolve inconsistencies in the naming of the trace amine
receptor family, Lindemann et al. (2005) proposed a uniform nomenclature
using the designation 'trace amine-associated receptors' (TAARs). They
noted that this nomenclature acknowledges the observation that several
TAARs do not respond to trace amines, hence the term 'associated.'
VNN1
| dbSNP name | rs2064312(G,A); rs2745425(C,T); rs45575344(T,C); rs2745426(C,T); rs41286178(C,G); rs1044593(A,T); rs9389025(T,A); rs2840813(T,G); rs375278631(C,T); rs2745427(C,A); rs2251455(C,A); rs2251449(C,T); rs2745429(T,A); rs2745430(C,T); rs2745431(G,C); rs3798801(C,T); rs2745432(G,A); rs3798800(A,C); rs35228045(G,C); rs2840814(A,G); rs742516(C,T); rs909975(G,A); rs909977(C,T); rs2272996(T,C); rs6930032(G,A); rs2840815(C,T); rs2745434(T,A); rs2745435(G,A); rs2840816(C,T); rs2840817(A,G); rs9389026(C,T); rs2840818(C,T); rs2840819(A,T); rs2745436(G,A); rs2745437(T,C); rs2262437(T,C); rs2840820(A,G); rs2262438(A,G); rs2840821(G,T); rs2840822(C,T); rs2840823(C,T); rs2745439(G,A); rs2745440(G,A); rs9375912(G,A); rs9389027(T,C); rs4897600(G,A); rs4897604(G,A); rs9689939(T,A); rs2247285(T,C); rs2247284(A,T); rs17604042(T,C); rs2247269(G,A); rs2223613(T,C); rs2267950(A,G); rs2840824(A,G); rs2745441(G,A); rs2745442(G,A); rs3798794(T,C); rs2745443(T,C); rs2745444(T,C); rs2840825(C,A); rs2745445(T,C); rs2840826(A,G); rs2840827(C,T); rs990499(T,A); rs990500(A,G); rs77020716(A,G); rs9399038(A,T); rs74658049(G,A); rs77581542(C,G); rs12660840(G,C); rs6936833(G,A); rs2327275(C,T); rs4897605(T,A); rs6938196(T,A); rs6938355(T,C); rs6938367(T,G); rs6915807(C,A); rs9399039(G,A); rs2179536(G,A); rs78323340(C,T); rs1073954(C,T); rs4897607(G,T); rs9399040(G,A); rs2300076(G,C); rs2300077(T,C); rs6941705(G,A); rs4897608(C,T); rs4897609(A,G); rs4897610(T,C); rs7742200(C,A); rs3823026(G,A); rs3798793(C,T); rs3798792(A,G); rs4897611(A,C); rs2294757(G,A) |
| ccdsGene name | CCDS5159.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 8876 |
| EntrezGene Description | vanin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | VNN1:NM_004666:exon3:c.A392G:p.N131S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6775 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95497 |
| dbNSFP Uniprot ID | VNN1_HUMAN |
| dbNSFP KGp1 AF | 0.273351648352 |
| dbNSFP KGp1 Afr AF | 0.184959349593 |
| dbNSFP KGp1 Amr AF | 0.171270718232 |
| dbNSFP KGp1 Asn AF | 0.377622377622 |
| dbNSFP KGp1 Eur AF | 0.300791556728 |
| dbSNP GMAF | 0.2736 |
| ESP Afr MAF | 0.190649 |
| ESP All MAF | 0.242965 |
| ESP Eur/Amr MAF | 0.269767 |
| ExAC AF | 0.272 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary urgency;
Urinary incontinence;
Sphincter disturbances
SKELETAL:
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Atrophy of shins
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Upper limb spasticity (in some patients);
Spastic gait;
Hyperreflexia;
Extensor plantar responses;
Degeneration of the lateral corticospinal tracts;
[Peripheral nervous system];
Decreased vibratory sense in the lower limbs
MISCELLANEOUS:
Adult onset (18 to 60 years);
Insidious onset;
Progressive disorder;
Severe phenotype
MOLECULAR BASIS:
Caused by mutation in the KIAA0196 gene (KIAA0196, 610657.0001)
OMIM Title
+603570 VANIN 1; VNN1
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
8, INCLUDED; HDLCQ8, INCLUDED
OMIM Description
CLONING
Hematopoietic precursor cells migrate to the thymus, where they
differentiate into mature T lymphocytes. Aurrand-Lions et al. (1996)
reported the cDNA cloning and functional analysis of mouse vanin-1
(vascular noninflammatory molecule-1), a novel cell surface molecule
that is involved in the thymus homing of bone marrow cells. Vanin-1 is a
glycosylphosphatidylinositol (GPI)-anchored molecule expressed by
perivascular thymic stromal cells. Antibody against vanin-1 blocked
thymus colonization by hematopoietic progenitor cells in both short- and
long-term assays and interfered with lymphostromal cell adhesion. The
authors suggested that vanin-1 regulates late adhesion steps of thymus
homing under physiologic, noninflammatory conditions.
By searching an EST database with mouse vanin-1 and human vanin-2 (VNN2;
603571) cDNA sequences, Galland et al. (1998) identified cDNAs encoding
human vanin-1 (VNN1). The deduced 513-amino acid VNN1 protein shares
78%, 64%, and 43% sequence identity with mouse vanin-1, VNN2, and
biotinidase (BTD; 609019), respectively. Like mouse vanin-1, human VNN1
has a leader peptide and a C-terminal GPI cleavage motif. VNN1 protein
translated in vitro migrated as 55- and 53-kD polypeptides. Northern
blot analysis revealed that the 3.4-kb VNN1 mRNA is expressed in spleen,
thymus, peripheral blood lymphocytes, and small intestine; minor
transcripts were also detected.
Martin et al. (2001) found that the vanin family is encoded by at least
2 mouse genes, vanin-1 and vanin-3, and 3 human orthologous genes, VNN1,
VNN2, and VNN3 (606592). They showed that the vanin genes encode
different isoforms of the mammalian pantetheinase activity.
Pantetheinase is an amidohydrolase involved in the dissimilative pathway
of CoA, allowing the turnover of the pantothenate moiety. By sequencing
purified pantetheinase from pig kidney and searching databases, Maras et
al. (1999) identified mouse and human VNN1 as homologs. They also
identified human VNN2 and BTD as related proteins.
GENE STRUCTURE
Martin et al. (2001) reported the structural characterization of the
human and mouse vanin genes. All contain 7 exons.
MAPPING
By in situ hybridization, Galland et al. (1998) mapped the mouse vanin-1
gene to the proximal third of chromosome 10, which shows homology of
synteny with human 6q21-q24. Using fluorescence in situ hybridization
and analysis of somatic cell hybrids, they localized the human VNN1 gene
to 6q23-q24. Galland et al. (1998) identified a YAC clone from 6q23-q24
that contained both the VNN1 and VNN2 genes.
Martin et al. (2001) found that the 3 human vanin genes are closely
linked on 6q23-q24 and are aligned in the same transcriptional
orientation. The 2 mouse vanin genes are located on chromosome 10A2B1.
GENE FUNCTION
The mouse vanin-1 molecule plays a role in thymic reconstitution
following damage by irradiation. Pitari et al. (2000) demonstrated that
the mouse vanin-1 molecule is a pantetheinase, i.e., an amidohydrolase
that catalyzes the hydrolysis of D-pantetheine, permitting the recycling
of pantothenate (vitamin B5) and the generation of an antioxidant
metabolite, cysteamine.
The mammalian sex-determining pathway is controlled by the presence or
absence of SRY (480000) expression in the embryonic gonad. To identify
additional sex-determining or gonadal differentiation genes, Grimmond et
al. (2000) screened for genes exhibiting sexually dimorphic patterns of
expression in the mouse gonad at 12.5 and 13.5 days postcoitum, after
overt gonad differentiation, by comparing complex cDNA probes derived
from male and female gonadal tissue at these stages on microarrays
constructed from a normalized urogenital ridge library. Using in situ
hybridization analysis, they determined that mouse protease nexin-1
(177010) and Vnn1 exhibit male-specific expression prior to overt
gonadal differentiation and are detected in the somatic portion of the
developing gonad, suggesting to the authors a possible direct link to
the testis-determining pathway for both genes.
VNN1 is a membrane-bound enzyme that regulates tissue adaptation to
stress. Using immunohistochemistry, Rommelaere et al. (2013) found that
Vnn1 was expressed in mouse liver in centrolobular hepatocytes. They
identified a soluble form of VNN1 in mouse and human serum that was
produced in liver, and they showed that cys213 contributed to the
catalytic activity of mouse Vnn1. Ppara (170998) controlled Vnn1
expression in mouse liver and secretion in serum. Rommelaere et al.
(2013) suggested that VNN1 could be a reliable reporter for
PPARA-regulated liver responses to metabolic challenge.
MOLECULAR GENETICS
Quantitative differences in gene expression are thought to contribute to
phenotypic differences between individuals. Goring et al. (2007)
generated genomewide transcriptional profiles of lymphocyte samples from
1,240 participants in the San Antonio Family Heart Study. Evidence of
significant heritability was found for the expression levels of 85% of
the 19,648 detected autosomal transcripts. By linkage analysis, the
authors uncovered more than 1,000 cis-regulated transcripts and showed
that the expression quantitative trait loci with the most significant
linkage evidence are often located at the structural locus of a given
transcript. To highlight the usefulness of this much-enlarged map of
cis-regulated transcripts for the discovery of genes that influence
complex traits in humans, Goring et al. (2007) selected high density
lipoprotein cholesterol (HDLC) concentration as a phenotype of clinical
importance, and identified the cis-regulated VNN1 gene as harboring
sequence variants that influence HDLC concentrations. Several VNN1
promoter variants showed highly significant association with HDLC
concentration. Bioinformatic analysis revealed that one of these, the
-137T allele (603570.0001), is embedded in a consensus Sp1 binding site.
This and other information provided indirect support for functionality
of this promoter variant.
ANIMAL MODEL
Martin et al. (2004) generated Vnn1-deficient mice that lacked free
cysteamine and examined their susceptibility to intestinal inflammation,
either acute (NSAID administration) or chronic (Schistosoma mansoni
infection). They found that Vnn1 -/- mice better controlled inflammatory
reaction and intestinal injury in both experiments, and had increased
gamma-glutamylcysteine synthetase (see 606857) activity and increased
stores of reduced glutathione, as well as reduced inflammatory cell
activation in inflamed tissues. Oral administration of cystamine
reversed all aspects of the deficient phenotype. Martin et al. (2004)
concluded that the pantetheinase activity of the vanin-1 molecule is a
major regulator of intestinal inflammation, acting through cysteamine
release.
Berruyer et al. (2004) observed resistance to oxidative injury induced
by whole-body irradiation and paraquat poisoning, as well as improved
thymic reconstitution, in mice lacking Vnn1. Protection from oxidative
injury correlated with reduced apoptosis and inflammation and could be
reversed by treatment with cystamine. Vnn1 -/- mice had enhanced
gamma-glutamylcysteine synthetase activity in liver and elevated stores
of glutathione. Expression of Vnn1 in wildtype mice was biphasic and
regulated by antioxidant response elements in the Vnn1 promoter region.
Berruyer et al. (2004) proposed that VNN1 is a key molecule in the
regulation of the glutathione-dependent responses to oxidative injury in
epithelial tissue and suggested that VNN1 inhibitors may be useful in
treatment of radiation-induced damage.
Berruyer et al. (2006) found that Vnn1 deficiency protected mice from
colitis in a mouse model. The protection was reversed by administration
of cystamine or bisphenol A diglycidyl ether, an antagonist of PPARG
(601487). By antagonizing Pparg, Vnn1 permitted production of
inflammatory mediators by intestinal epithelial cells. Berruyer et al.
(2006) proposed that VNN1 is an epithelial stress sensor that exerts
dominant control over innate immune responses in tissue.
Meghari et al. (2007) infected mice lacking Vnn1 with Coxiella burnetii,
a bacterium that survives in macrophages, and observed no differences in
bacterial clearance or mortality, but they did note decreased formation
of granulomas in the spleen and liver. Infected Vnn1 -/- mice exhibited
slight impairment of macrophage recruitment and significant impairment
of macrophage activation, with decreased expression of Inos (NOS2A;
163730) and Mcp1 (CCL2; 158105) and increased expression of arginase
(ARG1; 608313) and Il10 (124092). Meghari et al. (2007) concluded that
VNN1 has a role in granuloma formation in response to C. burnetii
infection.
VNN3
| dbSNP name | rs9483495(C,T); rs45606334(A,G); rs6569832(G,A); rs2294758(G,A); rs2294759(A,G); rs115546338(T,G); rs6569833(A,C); rs45460092(G,A); rs45487696(T,C); rs6569834(A,G); rs9493417(G,A); rs45471497(G,A); rs45553535(G,T); rs12208948(C,T); rs6927410(T,C); rs45599039(C,A); rs7744297(G,A); rs13211436(A,T); rs45553436(G,A); rs4897614(A,T); rs45487797(C,T); rs6917978(C,T); rs45466492(C,A); rs6918343(C,T); rs6569835(G,A); rs6569836(C,T); rs6569837(C,G); rs6569839(A,C); rs45462601(A,G); rs3756974(A,G); rs6924414(C,T); rs4895943(C,T); rs6915259(T,A); rs6569841(T,G); rs7770949(A,G); rs6569842(C,T); rs114454598(A,G); rs11965457(T,A); rs11154693(C,A); rs6899338(G,A); rs6942306(C,A); rs6899733(G,A); rs13203382(G,C); rs36012859(T,C); rs764262(G,T); rs764263(G,C) |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 55350 |
| EntrezGene Description | vanin 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Function | VNN3:NM_001291702:exon5:c.T272C:p.F91S,VNN3:NM_001291703:exon5:c.T272C:p.F91S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6735 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NY84 |
| dbNSFP Uniprot ID | VNN3_HUMAN |
| dbNSFP KGp1 AF | 0.266941391941 |
| dbNSFP KGp1 Afr AF | 0.158536585366 |
| dbNSFP KGp1 Amr AF | 0.400552486188 |
| dbNSFP KGp1 Asn AF | 0.234265734266 |
| dbNSFP KGp1 Eur AF | 0.298153034301 |
| dbSNP GMAF | 0.2672 |
| ESP Afr MAF | 0.166667 |
| ESP All MAF | 0.273631 |
| ESP Eur/Amr MAF | 0.320693 |
| ExAC AF | 0.314 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Headache;
[Ears];
Tinnitus;
[Eyes];
Diplopia;
Visual blurring
ABDOMEN:
[Gastrointestinal];
Nausea;
Vomiting
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic;
Vertigo;
Myokymia;
Weakness
MISCELLANEOUS:
Variable age at onset;
Symptoms precipitated by sudden movement, stress, exertion, fatigue;
Response to acetazolamide;
Attacks typically last for minutes
OMIM Title
*606592 VANIN 3; VNN3
OMIM Description
CLONING
By EST database analysis, Granjeaud et al. (1999) identified a novel
human VNN gene, VNN3. Martin et al. (2001) cloned a full-length VNN3
cDNA encoding a deduced 501-amino acid protein with strong similarity to
the mouse vnn3 molecule. Both the mouse and human proteins lack the
GPI-anchor motif found in VNN1 (603570) and VNN2 (603571). Northern blot
analysis detected a 1.8-kb VNN3 mRNA in human liver, placenta, and
peripheral blood leukocytes (PBLs). A 3.8-kb mRNA was observed in PBLs.
GENE FUNCTION
Martin et al. (2001) found that all vanin proteins are ectoenzymes with
pantetheinase activity. They showed that mouse vanin-3 and, by analogy,
human VNN3 are secreted molecules.
GENE STRUCTURE
Martin et al. (2001) determined that the human VNN1, VNN2, and VNN3
genes, as well as the mouse vnn1 and vnn3 genes, all contain 7 exons.
MAPPING
By sequence analysis, Martin et al. (2001) mapped the VNN3 gene to human
chromosome 6q23-q24 and mouse chromosome 10 in a cluster with VNN1 and
VNN2. All 3 genes are aligned in the same transcriptional orientation.
VNN2
| dbSNP name | rs34171909(T,C); rs12211125(T,C); rs36031989(G,A); rs34045817(T,G); rs13208524(C,G); rs72994294(C,T); rs144744256(A,G); rs33944856(A,G); rs12663367(T,C); rs12663385(T,C); rs12663711(T,C); rs2267952(T,C); rs33966619(G,C); rs34454463(T,C); rs9321362(T,C); rs9321363(C,A); rs35954051(A,G); rs35744530(A,G); rs9321364(C,T); rs9493421(A,G); rs33961073(T,C); rs9483497(G,A); rs9321365(C,G); rs6925157(C,T); rs33986412(C,T); rs9321366(A,G); rs9483498(C,T); rs9493422(A,G); rs6926968(G,C); rs4895944(G,T); rs33938039(C,A); rs181978791(A,T); rs1883617(A,G); rs36100139(C,T); rs72996105(G,A); rs12209262(C,T); rs13204496(A,T); rs35229014(G,A); rs9493423(G,A); rs9493424(T,C); rs9493425(A,G); rs9493426(T,C); rs9493427(A,G); rs6936594(T,C); rs2300078(A,G); rs2300079(C,A); rs56739181(C,A); rs9483499(A,G); rs1883613(T,C); rs9493430(C,T); rs34625012(C,T); rs9493431(T,C); rs33950336(G,T); rs4897615(T,C); rs373379409(A,G); rs11154695(C,T); rs6911025(C,T); rs80065641(G,A); rs6569845(C,A); rs35812919(A,G); rs145314192(G,A); rs12194625(T,A); rs116756421(C,T); rs3756971(C,T); rs149084961(T,G); rs6569847(C,A); rs7747544(T,C); rs79966634(G,A); rs9493434(G,C); rs9321367(G,T); rs9321368(C,T) |
| ccdsGene name | CCDS5161.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 8875 |
| EntrezGene Description | vanin 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | VNN2:NM_004665:exon6:c.C1210A:p.L404M,VNN2:NM_001242350:exon4:c.C547A:p.L183M,VNN2:NM_078488:exon7:c.C1051A:p.L351M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5631 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95498-2 |
| dbNSFP KGp1 AF | 1.0 |
| dbNSFP KGp1 Afr AF | 1.0 |
| dbNSFP KGp1 Amr AF | 1.0 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000538 |
| ESP Eur/Amr MAF | 0.000814 |
| ExAC AF | 1.0 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary urgency;
Urinary incontinence;
Sphincter disturbances
SKELETAL:
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Atrophy of shins
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Upper limb spasticity (in some patients);
Spastic gait;
Hyperreflexia;
Extensor plantar responses;
Degeneration of the lateral corticospinal tracts;
[Peripheral nervous system];
Decreased vibratory sense in the lower limbs
MISCELLANEOUS:
Adult onset (18 to 60 years);
Insidious onset;
Progressive disorder;
Severe phenotype
MOLECULAR BASIS:
Caused by mutation in the KIAA0196 gene (KIAA0196, 610657.0001)
OMIM Title
*603571 VANIN 2; VNN2
OMIM Description
CLONING
Mouse vanin-1 (see VNN1; 603570) is a glycosylphosphatidylinositol
(GPI)-anchored cell surface molecule that is involved in the thymus
homing of bone marrow cells. By screening cDNA libraries with a mouse
vanin-1 cDNA, Galland et al. (1998) identified a partial human cDNA
encoding vanin-2 (VNN2), a vanin-like protein. Using RACE PCR to isolate
additional cDNAs, they determined the entire VNN2 coding sequence. The
deduced VNN2 protein shares 64% sequence identity with mouse vanin-1 and
VNN1, the human homolog of mouse vanin-1. Like VNN1, VNN2 contains a
C-terminal GPI cleavage motif; however, it lacks a leader peptide. VNN2
translated in vitro migrated as a 53-kD protein. Northern blot analysis
revealed that the 2.3-kb VNN2 mRNA is expressed in spleen, thymus,
peripheral blood lymphocytes, and kidney.
MAPPING
By fluorescence in situ hybridization and analysis of somatic cell
hybrids, Galland et al. (1998) mapped the VNN2 gene to 6q23-q24. They
identified a YAC clone from 6q23-q24 that contained both the VNN1 and
VNN2 genes.
SNORD100
| dbSNP name | rs9389034(T,C) |
| ccdsGene name | CCDS5164.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 594838 |
| snpEff Gene Name | RPS12 |
| EntrezGene Description | small nucleolar RNA, C/D box 100 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4261 |
| ESP Afr MAF | 0.464612 |
| ESP All MAF | 0.433031 |
| ESP Eur/Amr MAF | 0.387996 |
| ExAC AF | 0.415 |
EYA4
| dbSNP name | rs473055(G,C); rs3777779(C,T); rs6911555(G,A); rs76738042(G,A); rs511490(T,C); rs3777781(T,A); rs1338009(T,C); rs3777783(G,A); rs73007667(G,T); rs6569873(G,A); rs9402493(T,C); rs6922463(G,A); rs519332(A,G); rs9389060(G,A); rs3777785(G,A); rs722488(A,G); rs61210342(C,T); rs6903443(A,G); rs12190309(T,C); rs60285302(G,C); rs9375948(G,A); rs9389061(T,G); rs76181767(A,G); rs533729(G,T); rs4895959(C,A); rs9402497(G,A); rs561355(A,G); rs115111645(C,T); rs79624704(G,A); rs7762680(A,T); rs3777787(C,A); rs973714(G,A); rs1022695(C,T); rs971589(G,A); rs572004(G,T); rs2180729(G,A); rs211442(G,T); rs3777794(A,G); rs74708887(T,C); rs211443(A,G); rs3777797(C,T); rs73776008(T,C); rs79963286(A,G); rs111227086(G,A); rs7745129(G,A); rs35047285(A,T); rs211440(A,G); rs9493574(G,T); rs114230804(A,G); rs9375951(T,C); rs9373041(A,G); rs59770556(G,C); rs3777799(C,T); rs9389062(A,T); rs211441(G,A); rs75106170(T,C); rs2145347(C,T); rs2095604(C,T); rs2104031(G,A); rs505227(T,C); rs115327712(C,T); rs2015979(G,A); rs211439(A,G); rs2327321(A,G); rs1811876(C,T); rs73557737(G,C); rs56153760(G,A); rs3734277(C,A); rs9385642(C,T); rs144183740(G,T); rs76587409(T,A); rs6569874(C,T); rs73557740(A,G); rs9389063(C,G); rs2145348(C,T); rs2180730(C,T); rs111879407(G,A); rs73557742(C,A); rs9321395(G,A); rs9321396(A,G); rs9321397(T,C); rs9321398(C,T); rs6941113(G,A); rs9321399(G,A); rs6941848(G,A); rs9483564(A,T); rs9483565(C,A); rs9483566(T,C); rs9493578(C,T); rs80244863(G,T); rs9483567(T,C); rs9493579(T,G); rs9493580(G,A); rs9493581(T,C); rs9493582(A,G); rs78889842(T,C); rs7747638(C,T); rs78364359(A,G); rs115759188(C,T); rs9483568(G,A); rs7753529(A,G); rs9493584(C,T); rs77570610(C,T); rs141891139(T,A); rs79234622(G,A); rs76833833(T,A); rs73557747(G,A); rs141922981(T,G); rs144930756(A,G); rs9385643(G,A); rs60411491(T,C); rs9389065(A,G); rs73557751(A,G); rs76996882(C,T); rs73009604(T,C); rs17062266(T,G); rs17062270(G,A); rs116093454(C,T); rs56321302(C,T); rs140794836(T,C); rs118011914(A,G); rs9493585(T,C); rs9483570(A,T); rs9483571(A,C); rs12196330(G,C); rs17062277(T,A); rs454953(A,G); rs372437(A,G); rs375189(C,A); rs75135276(C,T); rs112687509(C,G); rs73009608(A,T); rs402020(T,C); rs113824196(G,A); rs4895960(T,C); rs9375953(G,A); rs211432(G,A); rs211433(A,G); rs9402500(G,T); rs454877(C,T); rs412771(C,G); rs2224382(C,A); rs211434(G,A); rs6926146(G,T); rs211435(T,C); rs17301249(G,C); rs211436(C,T); rs138469808(G,A); rs211437(T,C); rs211438(C,T); rs34395775(G,T); rs189963797(C,T); rs407038(G,A); rs72991903(A,G); rs433294(G,A); rs6923945(T,C); rs370735(T,A); rs4278037(T,C); rs139238908(T,C); rs146500927(A,G); rs75822474(G,A); rs954917(T,C); rs9399056(C,T); rs9373044(A,G); rs9373045(C,T); rs4493757(C,T); rs6569875(G,T); rs6569876(G,A); rs9402501(G,A); rs9389067(G,A); rs9493586(G,A); rs9373046(T,C); rs73776021(A,G); rs9402502(A,G); rs13212740(A,G); rs6924144(G,T); rs72991915(G,A); rs9399058(C,G); rs9373048(G,A); rs7762780(T,A); rs11154722(C,T); rs2027210(T,G); rs74382814(T,C); rs17062322(G,A); rs10872404(T,C); rs7449915(T,C); rs72991923(T,G); rs2210891(T,C); rs2210890(A,G); rs1932747(T,G); rs1932746(G,T); rs7764052(G,T); rs9399059(A,G); rs147224071(T,C); rs17301622(G,A); rs950375(A,G); rs950374(G,A); rs1336528(A,G); rs72991933(A,G); rs62430320(A,G); rs6941879(G,A); rs67684955(G,A); rs9493589(G,A); rs115911663(T,A); rs62430323(G,A); rs72991942(T,C); rs62431672(G,A); rs140047968(G,A); rs949767(C,G); rs7747163(C,T); rs11754045(C,A); rs17301712(T,G); rs55977000(C,T); rs75971553(A,G); rs17242333(A,C); rs17242354(G,A); rs17301754(A,G); rs189898307(A,G); rs17242410(G,A); rs1336527(T,C); rs17242466(G,A); rs56256859(A,T); rs17301858(G,A); rs17301872(C,T); rs17301914(G,A); rs17301942(A,T); rs7454561(G,T); rs10485232(G,A); rs11757185(A,G); rs114232702(G,T); rs12525252(C,T); rs12525309(G,C); rs115063055(C,T); rs62431678(C,A); rs113094416(C,T); rs1336526(G,A); rs1336525(T,G); rs116562601(A,G); rs1336524(T,C); rs72993929(G,A); rs17062339(G,A); rs6937974(T,C); rs17302199(G,A); rs13218103(C,T); rs74983813(A,T); rs13218570(G,A); rs11759873(A,G); rs72993941(T,C); rs6926046(C,T); rs116164678(G,A); rs12523816(A,G); rs78870159(C,T); rs1336522(T,A); rs12524250(A,G); rs12527741(C,T); rs370621746(C,T); rs12524730(A,G); rs138829897(A,G); rs62428661(G,A); rs62428662(G,C); rs1336521(G,C); rs181238120(C,G); rs78172687(T,A); rs17302366(T,C); rs79403019(A,G); rs1962598(C,T); rs1015726(G,A); rs2184784(C,A); rs12201595(G,A); rs9493593(T,A); rs116205563(C,A); rs147294076(G,A); rs12527527(C,T); rs114980620(C,T); rs372357075(G,T); rs17062356(C,T); rs114541750(T,G); rs115965217(C,T); rs75851211(C,A); rs7771444(C,T); rs73557789(C,T); rs76175895(A,G); rs139242184(G,A); rs1814195(G,C); rs6900552(C,G); rs75289277(A,G); rs9493594(G,A); rs2785238(G,A); rs1799679(A,G); rs142708132(A,G); rs448167(C,T); rs450881(T,C); rs512268(G,A); rs373884(G,A); rs114679436(A,G); rs115593623(T,C); rs401913(T,G); rs72993973(T,C); rs6569877(G,A); rs6569878(G,A); rs68021023(T,C); rs296414(G,C); rs6924629(A,G); rs9483575(A,C); rs296415(G,C); rs296416(G,C); rs190572997(T,G); rs296417(C,G); rs6930942(A,G); rs6903792(A,G); rs296418(A,G); rs114765620(G,A); rs1336519(G,T); rs66480937(A,G); rs72993984(G,A); rs745091(A,G); rs2094198(A,G); rs72993988(A,T); rs296419(G,A); rs2765784(C,G); rs34751763(C,T); rs11154723(A,G); rs35677071(C,G); rs34585135(A,G); rs10457606(A,C); rs34353709(C,T); rs35350600(G,A); rs439123(C,T); rs72995906(T,C); rs72995908(C,T); rs9493600(G,C); rs73559608(T,A); rs57814773(T,G); rs377962(A,C); rs9493601(A,G); rs114993593(G,T); rs191791405(A,C); rs9483577(A,G); rs72995914(A,G); rs74298542(T,C); rs1336529(G,A); rs9375957(G,T); rs114861695(C,T); rs76287990(C,T); rs112525437(C,T); rs296421(G,A); rs9402504(C,T); rs9389068(A,G); rs73559619(C,G); rs142048499(T,C); rs114793232(G,A); rs1886982(A,G); rs115070345(A,G); rs9399061(A,G); rs114099656(G,T); rs73559624(A,G); rs9375958(G,A); rs9373049(C,T); rs58715540(A,C); rs9389069(G,A); rs9389070(C,T); rs9399062(G,T); rs9389071(G,A); rs73559628(T,C); rs115135786(T,C); rs76980268(A,C); rs1336530(A,G); rs2184783(C,T); rs9373050(G,A); rs9389072(A,G); rs9389073(T,C); rs1414981(T,C); rs1414982(A,G); rs9493605(C,T); rs73559632(T,A); rs79822173(G,T); rs73559633(G,T); rs9389074(A,T); rs73559634(T,C); rs9493606(C,A); rs112181847(G,T); rs9373051(C,T); rs9483579(G,A); rs189831911(A,G); rs6569879(G,A); rs6917055(T,G); rs141159390(A,G); rs9375959(A,C); rs72996001(C,G); rs77755603(A,C); rs9493608(C,T); rs145198515(C,T); rs7743259(A,T); rs116233942(A,G); rs73559641(A,G); rs9389075(G,A); rs144435008(A,G); rs77643952(T,C); rs7749769(G,C); rs7749773(G,A); rs116324165(G,A); rs7750244(C,T); rs77910661(G,A); rs7774860(T,A); rs7754854(C,G); rs7755198(A,G); rs141650296(T,C); rs79600023(T,G); rs116725776(C,T); rs212831(C,T); rs9493610(C,T); rs79027645(A,G); rs186667058(G,A); rs56043945(A,C); rs7765967(A,T); rs7766140(C,T); rs77139100(T,C); rs211627(C,G); rs78940292(G,C); rs75612804(C,G); rs211628(T,C); rs76010042(A,G); rs9402506(G,A); rs211629(A,G); rs9493611(A,T); rs116724776(T,C); rs211630(A,C); rs212826(C,G); rs742298(T,C); rs9375960(T,C); rs742297(A,G); rs72997724(G,A); rs76912996(A,G); rs74618358(A,G); rs1414980(C,T); rs114315808(C,T); rs211610(T,A); rs9385645(A,G); rs211609(A,C); rs9402507(G,A); rs9402508(C,T); rs714176(T,C); rs714178(G,A); rs714177(T,C); rs211608(T,A); rs141749690(A,T); rs9402509(G,A); rs75114759(G,A); rs211607(T,C); rs211606(G,T); rs184422151(A,T); rs211605(G,A); rs9373052(G,A); rs375221780(T,C); rs145745540(A,G); rs159416(T,A); rs2031596(T,C); rs9389076(C,A); rs211604(C,T); rs1926093(A,G); rs9493613(C,T); rs212818(C,A); rs9493614(T,G); rs72997742(A,G); rs1926092(G,T); rs159407(G,T); rs159408(A,T); rs211601(T,G); rs2235485(A,G); rs10484668(T,C); rs150532(T,G); rs373146228(C,T); rs159409(G,A); rs17062411(G,A); rs159410(G,A); rs17062414(G,A); rs159411(G,C); rs159412(A,G); rs212814(G,A); rs212813(G,T); rs211602(A,T); rs3777804(A,T); rs159413(A,C); rs159414(C,T); rs2223435(C,T); rs7760570(G,A); rs375381976(T,G); rs212811(A,G); rs73559678(G,T); rs211611(G,A); rs73559682(G,A); rs159417(T,C); rs159418(C,T); rs114650806(G,A); rs159419(T,G); rs3777811(A,G); rs34925767(A,G); rs465147(G,A); rs455704(C,T); rs212807(G,C); rs212806(A,T); rs212805(T,C); rs212804(T,C); rs212803(G,C); rs212802(T,C); rs120490(G,A); rs169827(C,T); rs3777817(A,G); rs159423(G,A); rs149730111(G,A); rs211612(G,A); rs3777819(A,C); rs3777820(G,A); rs159424(G,A); rs62429386(G,C); rs76294565(A,G); rs66938915(C,G); rs11969822(G,C); rs159425(A,G); rs2327322(T,C); rs28734790(T,A); rs1855989(G,A); rs159427(A,T); rs211613(G,A); rs211614(A,G); rs211615(A,G); rs211616(T,G); rs9385646(G,T); rs211617(A,G); rs159420(T,C); rs296422(G,A); rs296423(G,C); rs296424(A,G); rs296425(C,T); rs11968392(G,A); rs296426(G,A); rs159421(G,T); rs211618(A,T); rs296428(C,G); rs17062478(A,G); rs211619(T,C); rs296429(G,A); rs3777827(A,G); rs3822930(G,C); rs3822931(A,G); rs159422(T,G); rs211620(G,C); rs296430(G,C); rs211621(G,A); rs296431(C,T); rs75320439(G,A); rs211622(G,A); rs211623(T,G); rs77962843(C,T); rs75966950(T,C); rs147875744(C,T); rs79609485(C,G); rs75461859(A,T); rs3822932(T,G); rs211624(G,A); rs5022972(T,C); rs3777832(T,G); rs3777833(C,T); rs211625(A,G); rs3777835(T,C); rs191186308(C,G); rs211626(T,A); rs75279330(T,C); rs11963218(C,A); rs211600(T,C); rs211599(C,T); rs56241016(T,A); rs211598(G,A); rs76147185(C,T); rs79507446(G,A); rs74479039(A,G); rs143061672(G,T); rs11963948(C,T); rs9483581(G,A); rs211597(A,G); rs56088418(G,A); rs80127503(T,C); rs211596(G,T); rs79619857(T,C); rs78164607(A,C); rs74748914(C,T); rs211595(C,T); rs75015869(C,T); rs76327434(C,T); rs77096240(T,C); rs142427153(C,G); rs211594(T,C); rs76532798(A,T); rs1932748(C,T); rs211593(A,G); rs211592(C,T); rs11967280(A,G); rs117021697(C,T); rs211591(A,T); rs211590(A,G); rs3777839(T,A); rs117054335(C,G); rs3777840(G,A); rs1014980(T,G); rs212790(C,G); rs78634521(T,C); rs74432100(C,T); rs6934520(T,G); rs6912802(C,A); rs212789(G,A); rs79171374(G,A); rs76487397(G,A); rs3777842(G,A); rs9389077(A,G); rs6941577(T,C); rs212788(G,A); rs212787(A,G); rs212786(C,G); rs3777846(A,G); rs114797550(G,A); rs212785(C,T); rs9402510(G,A); rs6899927(A,G); rs112945320(C,T); rs57243011(C,T); rs145468604(T,G); rs1889946(T,G); rs9493621(G,A); rs150462(C,A); rs1889947(C,T); rs3777849(G,A); rs77793961(C,T); rs150367659(A,C); rs3798355(C,T); rs9385647(T,C); rs73561754(A,T); rs73561755(A,T); rs211589(C,T); rs73561756(A,C); rs78972730(A,C); rs77044119(C,T); rs3777853(A,T); rs6933900(T,A); rs76524044(T,A); rs1336534(C,T); rs3777859(A,G); rs149941879(G,T); rs9375963(A,C); rs12664324(G,A); rs80147015(G,A); rs3777860(G,A); rs79657141(C,A); rs9373053(C,G); rs148441594(G,A); rs111346291(C,T); rs78888630(C,T); rs1012605(T,C); rs12665159(G,C); rs117883133(T,C); rs78914037(T,C); rs12665690(G,T); rs55963818(C,T); rs77723504(T,C); rs760861(G,C); rs126403(T,C); rs76537908(C,T); rs7756044(T,C); rs1926091(A,G); rs1926090(C,T); rs115076144(A,C); rs79615317(G,A); rs6907872(C,T); rs9399064(A,T); rs9375964(G,A); rs12663756(T,C); rs380367(T,C); rs12665147(A,C); rs11961662(G,C); rs78236375(A,G); rs76937911(A,G); rs9385648(C,T); rs73544919(G,A); rs2076256(G,C); rs117278899(A,G); rs17062561(A,G); rs212782(G,A); rs10872405(C,T); rs3736704(A,G); rs6912844(A,G); rs212781(C,T); rs4895966(G,C); rs212770(C,T); rs4895967(A,G); rs58450371(C,T); rs212769(C,T); rs78938461(T,C); rs212768(G,T); rs9399065(C,T); rs115974013(G,A); rs9373054(C,T); rs56140782(G,A); rs7753629(G,A); rs10872406(C,T); rs3777863(C,T); rs73001787(A,T); rs3777864(C,T); rs2025705(A,G); rs6940775(C,A); rs56182562(T,A); rs116298120(C,T); rs73544941(C,T); rs183393868(G,T); rs28360637(G,T); rs12211899(C,T); rs6933143(T,C); rs9483582(T,C); rs3756873(T,A); rs2076255(A,G); rs6922694(A,G); rs146364754(G,A); rs75593700(G,A); rs73544945(G,A); rs149025910(A,G); rs41286198(T,C); rs13362743(G,T); rs77306214(T,G); rs766541(T,C); rs212767(T,G); rs75934561(C,G); rs118114204(A,G); rs79334372(C,T); rs73544950(C,A); rs9493626(G,A); rs212766(G,A); rs9493627(G,A); rs9493628(G,C); rs212765(C,A); rs1022514(G,A); rs212764(G,A); rs75400703(G,A); rs73544958(T,C); rs212778(T,G); rs9493629(G,C); rs9321402(G,A); rs73544961(G,T); rs73544963(T,G); rs212777(T,A); rs9321403(G,T); rs212776(A,C); rs509453(T,C); rs3777866(C,T); rs114220156(T,G); rs115841041(T,G); rs9373056(C,T); rs73544971(G,A); rs212775(A,G); rs113282799(G,A); rs112217244(G,C); rs77728319(G,A); rs212774(G,C); rs59342392(G,A); rs9385649(G,A); rs114952570(C,A); rs79421234(C,T); rs78111930(C,T); rs34950020(G,A); rs77801925(A,G); rs212773(G,A); rs73544978(C,T); rs75792193(C,T); rs80200896(A,G); rs113193957(A,G); rs41286202(G,A); rs212772(C,G); rs6900743(A,C); rs75898269(G,A); rs6905892(C,T); rs112867457(A,G); rs73544985(A,T); rs3822936(G,C); rs7750265(A,G); rs3777867(T,C); rs79800864(T,C); rs75402922(C,T); rs6942295(G,A); rs6921578(T,G); rs77280950(G,C); rs6899314(C,A); rs149767108(C,T); rs11963580(C,T); rs2143012(C,T); rs7773315(T,C); rs111357967(A,G); rs111922013(G,T); rs611186(G,A); rs60226395(A,G); rs598699(A,T); rs60958336(G,A); rs598286(G,A); rs58569374(C,A); rs547545(T,A); rs596428(A,C); rs115535706(G,A); rs7764488(G,A); rs12663242(C,T); rs114798048(A,T); rs11962716(A,C); rs75455958(T,A); rs523571(G,A); rs643202(G,A); rs73544998(A,T); rs73544999(A,G); rs9493631(A,G); rs79400895(A,G); rs568911(G,T); rs77338548(G,C); rs6927198(C,G); rs1883388(T,G); rs114800462(G,A); rs3777871(C,T); rs17062630(G,A); rs78316030(A,G); rs182875306(G,A); rs17641157(T,G); rs478907(A,T); rs73546816(A,G); rs3777876(T,C); rs9493632(C,T); rs561826(T,A); rs3777878(C,A); rs58305346(A,C); rs73546821(C,A); rs144796609(G,A); rs77391066(A,G); rs3777879(A,T) |
| ccdsGene name | CCDS5165.1 |
| cytoBand name | 6q23.2 |
| EntrezGene GeneID | 101928164 |
| EntrezGene Symbol | LOC101928164 |
| EntrezGene Description | uncharacterized LOC101928164 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | EYA4:NM_172105:exon11:c.G829A:p.G277S,EYA4:NM_004100:exon11:c.G829A:p.G277S,EYA4:NM_172103:exon10:c.G760A:p.G254S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5326 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F2Z2Y1 |
| dbNSFP KGp1 AF | 0.393315018315 |
| dbNSFP KGp1 Afr AF | 0.571138211382 |
| dbNSFP KGp1 Amr AF | 0.334254143646 |
| dbNSFP KGp1 Asn AF | 0.384615384615 |
| dbNSFP KGp1 Eur AF | 0.312664907652 |
| dbSNP GMAF | 0.3926 |
| ESP Afr MAF | 0.480027 |
| ESP All MAF | 0.382977 |
| ESP Eur/Amr MAF | 0.312791 |
| ExAC AF | 0.341 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Midface hypoplasia
SKELETAL:
Spondyloepimetaphyseal dysplasia;
Joint laxity;
[Spine];
Scoliosis;
Caudal narrowing of interpedicular distances;
Vertebral endplate irregularity;
Posterior vertebral body scalloping;
Sacral spinal dysraphism;
[Pelvis];
Congenital hip dislocation;
Small flattened capital femoral epiphyses;
Narrow femoral necks;
Tapered ischia;
[Limbs];
Large joint dislocations (especially knees);
Small, flattened irregular epiphyses;
Irregular, flared metaphyses with streaky sclerosis;
Radial head dislocation;
Genu valgum;
Severely delayed patellae ossification;
[Hands];
Gracile metacarpals;
Long, slender middle and proximal phalanges;
Broad, square ends of distal phalanges;
Prominent distal phalangeal tufts;
Small carpal bones;
Severe delay in phalangeal epiphyseal bone maturation
SKIN, NAILS, HAIR:
[Skin];
Velvety skin;
Normal wound healing
NEUROLOGIC:
[Central nervous system];
Hypotonia
OMIM Title
*603550 EYES ABSENT 4; EYA4
;;EYES ABSENT, DROSOPHILA, HOMOLOG OF, 4
OMIM Description
CLONING
Borsani et al. (1999) presented the detailed characterization of a
fourth vertebrate gene, designated EYA4, that is homologous to 'eyes
absent' (eya), a key regulator of ocular development in Drosophila. See
also EYA1 (601653), EYA2 (601654), and EYA3 (601655). The authors found
that EYA4 encodes a 640-amino acid protein containing a highly conserved
C-terminal domain of 271 amino acids, which has been designated the
eya-homologous region (eya-HR) or eya domain. In Drosophila, eya is
known to mediate developmentally important protein-protein interactions.
In the developing mouse embryo, Eya4 was expressed primarily in the
craniofacial mesenchyme, the dermamyotome, and the limb.
GENE FUNCTION
Okabe et al. (2009) found that mouse Eya4, which was originally
identified as a cotranscription factor, stimulated expression of Ifnb
(147640) and Cxcl10 (147310) in response to the undigested DNA of
apoptotic cells. Eya4 enhanced the innate immune response against
Newcastle disease virus and vesicular stomatitis virus, and it could
associate with the signaling molecules Ips1 (609676), Sting (TMEM173;
612374), and Nlrx1 (611947). Okabe et al. (2009) showed that mouse EYA
family members acted as phosphatases for both phosphotyrosine and
phosphothreonine. The haloacid dehalogenase domain at the C terminus of
Eya4 contained the tyrosine-phosphatase activity, and the N-terminal
half carried the threonine-phosphatase activity. Mutations of the
threonine-phosphatase, but not the tyrosine-phosphatase, abolished the
ability of Eya4 to enhance the innate immune response, suggesting that
EYA proteins regulate the innate immune response by modulating the
phosphorylation state of signal transducers for intracellular pathogens.
MAPPING
By radiation hybrid analysis and fluorescence in situ hybridization,
Borsani et al. (1999) mapped the human EYA4 gene to 6q23. They also
detected linkage, with a lod score of greater than 3, to previously
mapped reference markers. They genetically mapped the mouse Eya4 gene to
chromosome 10 in the vicinity of Aco2 (100850), in a region homologous
to human chromosome 6q22-q23.
MOLECULAR GENETICS
- Autosomal Dominant Nonsyndromic Sensorineural Deafness 10
In an American and a Belgian family with autosomal dominant nonsyndromic
postlingual progressive hearing loss mapping to the DFNA10 locus
(601316), Wayne et al. (2001) identified 2 different mutations in the
EYA4 gene (603550.0001 and 603550.0002, respectively). Just as EYA
proteins interact with members of the SIX (601205) and DACH (603803)
protein families during early embryonic development, the authors
suggested that EYA4 is also important postdevelopmentally for continued
function of the mature organ of Corti.
In a family segregating autosomal dominant nonsyndromic postlingual
progressive sensorineural hearing loss (SNHL), Makishima et al. (2007)
identified a heterozygous 2-bp insertion (603550.0004) in the EYA4 gene.
Noting that the 3 EYA4 mutations reported to date causing nonsyndromic
SNHL are predicted to encode truncated EYA proteins with a deleted Eya
domain but an intact variable domain, whereas the deletion (603550.0003)
causing syndromic hearing loss with DCM partially truncates the variable
domain of the protein as well, Makishima et al.(2007) proposed a
correlation between EYA4 mutation position and the presence or absence
of DCM.
In a 5-generation Australian family with nonsyndromic SNHL, Hildebrand
et al. (2007) identified heterozygosity for a splice site mutation
(603550.0005) in the EYA4 gene, predicted to cause a frameshift
affecting the C-terminal eya-HR domain (residues 369-639).
- Dilated Cardiomyopathy with Sensorineural Hearing Loss,
Autosomal Dominant
In affected members of a kindred with dilated cardiomyopathy (DCM) and
heart failure preceded by sensorineural hearing loss mapping to 6q23-q24
(CMD1J; 605362) previously described by Schonberger et al. (2000),
Schonberger et al. (2005) identified a large deletion in the EYA4 gene
(603550.0003) resulting in a truncated protein that they designated
E193. Analysis of biochemical interactions of E193 and of E342
(603550.0001), the shortest mutant protein associated with nonsyndromic
hearing loss, revealed that E342 retained partial function, binding
wildtype EYA4 and associating with SIX proteins, whereas E193 did not.
ANIMAL MODEL
To elucidate the role of EYA4 in heart function, Schonberger et al.
(2005) studied zebrafish embryos injected with antisense morpholino
oligonucleotides and found that attenuated Eya4 transcript levels
produced morphologic and hemodynamic features of heart failure.
Depreux et al. (2008) found that Eya4-null mice had severe hearing
deficits and developed otitis media with effusion. All 50 mutant mice
showed hypervascularity of the tympanic membrane, marked retraction of
the tympanic membrane, and middle ear effusions consistent with otitis
media. Fifty control mice showed no such abnormalities. Anatomic studies
of mutant mice showed an abnormal middle ear cavity and dysmorphology of
the eustachian tube. The authors postulated that susceptibility to human
otitis media (166760) may involve genetic variation in genes such as
EYA4 that regulate middle ear and eustachian tube anatomy.
SLC35D3
| dbSNP name | rs1055268(T,C) |
| cytoBand name | 6q23.3 |
| EntrezGene GeneID | 340146 |
| EntrezGene Description | solute carrier family 35, member D3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3434 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Microcephaly;
Brachycephaly;
[Face];
Receding, short forehead;
Bitemporal narrowing;
Smooth, long philtrum;
Retrognathia;
[Ears];
Large ears;
Hearing loss, sensorineural (reported in 1 patient);
[Eyes];
Telecanthus;
Widened inner canthal distance;
Short palpebral fissures;
Downslanting palpebral fissures;
Ptosis;
Epicanthal folds;
Strabismus;
Long, straight eyelashes;
Optic nerve hypoplasia;
[Nose];
Broad nasal root;
High nasal root;
Prominent nasal tip;
[Mouth];
Smooth upper vermilion border;
Everted lower lip;
High narrow palate
CARDIOVASCULAR:
[Heart];
Valvular defects (reported in 1 patient)
RESPIRATORY:
Frequent upper respiratory infections;
[Larynx];
Laryngomalacia (reported in 1 patient)
CHEST:
[External features];
Widely spaced nipples;
Pectus excavatum
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
GENITOURINARY:
[External genitalia, male];
Small testes;
Micropenis;
[Kidneys];
Hydronephrosis
SKELETAL:
[Spine];
Kyphoscoliosis (reported in 1 patient);
[Hands];
Camptodactyly;
Arachnodactyly;
[Feet];
Metatarsus adductus;
Calcaneovalgus
SKIN, NAILS, HAIR:
[Hair];
Long, straight eyelashes
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Spasticity of the lower limbs;
Cortical dysplasia;
Pachygyria;
[Behavioral/psychiatric manifestations];
Autistic features;
Attention deficit
VOICE:
Nasal speech
ENDOCRINE FEATURES:
Hypogonadism (reported in 1 patient)
MISCELLANEOUS:
A contiguous gene deletion syndrome caused by a deletion (3.9 Mb)
of chromosome 2p16.1-p15
OMIM Title
*612519 SOLUTE CARRIER FAMILY 35, MEMBER D3; SLC35D3
OMIM Description
CLONING
Chintala et al. (2007) cloned mouse Slc35d3. Northern blot analysis
detected an Slc35d3 doublet around 2.6 kb in brain, but not in any other
mouse tissues examined. Quantitative real-time PCR detected expression
in all mouse tissues examined, with the highest level in platelets.
MAPPING
Hartz (2008) mapped the SLC35D3 gene to chromosome 6q23.3 based on an
alignment of the SLC35D3 sequence (GenBank GENBANK BC067217) with the
genomic sequence (build 36.1).
Chintala et al. (2007) mapped the mouse Slc35d3 gene to chromosome 10.
ANIMAL MODEL
Platelet dense granules are acidic organelles involved in normal blood
hemostasis that contain high concentrations of calcium, serotonin,
adenine nucleotides, and pyrophosphates in an insoluble complex. Mutant
ashen-Roswell mice are characterized by dense granules that lack normal
contents, and they have a defect in pigmentation. Chintala et al. (2007)
stated that hypopigmentation in ashen-Roswell mice is caused by a
mutation in the Rab27a gene (603868), and they determined that the dense
granule defect is caused disruption of the Slc35d3 gene by insertion of
a retroviral intracisternal A-particle (IAP) element within exon 1.
Homozygous mutant mice expressed no normal Slc35d3, but they expressed
abnormally sized Slc35d3 transcripts in a wide range of tissues, likely
due to utilization of IAP promoters. The mutation behaved as a typical
recessive loss-of-function trait in platelets, implying that the mutant
protein, if stable, is nonfunctional. Chintala et al. (2007) concluded
that SLC35D3 has a role in regulating the contents of platelet dense
granules.
CITED2
| dbSNP name | rs1131400(G,T) |
| ccdsGene name | CCDS5195.1 |
| cytoBand name | 6q24.1 |
| EntrezGene GeneID | 10370 |
| EntrezGene Description | Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CITED2:NM_006079:exon2:c.C21A:p.A7A,CITED2:NM_001168389:exon2:c.C36A:p.A12A,CITED2:NM_001168388:exon2:c.C21A:p.A7A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1364 |
| ESP Afr MAF | 0.147753 |
| ESP All MAF | 0.177303 |
| ESP Eur/Amr MAF | 0.192442 |
| ExAC AF | 0.171,8.136e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602937 CBP/p300-INTERACTING TRANSACTIVATOR, WITH GLU/ASP-RICH C-TERMINAL
DOMAIN, 2; CITED2
;;MELANOCYTE-SPECIFIC GENE 1-RELATED GENE 1; MRG1;;
MSG1-RELATED GENE 1;;
p35SRJ
OMIM Description
CLONING
By searching sequence databases with a mouse Msg1 cDNA (see 300149),
Shioda et al. (1996) identified human endothelial cell and neonatal
brain ESTs encoding the C-terminal region of MRG1. Shioda et al. (1997)
isolated a full-length human melanocyte MRG1 cDNA by 5-prime RACE using
oligonucleotides based on the MRG1 ESTs identified by Shioda et al.
(1996). The predicted 213-amino acid human MRG1 protein contains 3
histidine clusters and shares 2 conserved domains with MSG1: the
14-amino acid CR1 (conserved region 1) and the acidic 49-amino acid CR2.
The CR2 domain includes 12 aspartic acid and glutamic acid residues that
are strictly conserved among the human and mouse MRG1 and MSG1 proteins.
Northern blot analysis detected MRG1 expression in normal human
epidermal melanocytes and in melanoma cells; mouse Mrg1 transcripts were
found in all adult mouse tissues examined except muscle. By Western blot
analysis, recombinant MSG1 had an estimated molecular mass of 25 kD in
mammalian cells. Immunofluorescence cytochemistry localized recombinant
MRG1 to the mammalian cell nucleus.
By probing a HeLa cell expression library with the CH1 domain of p300
(EP300; 602700), Bhattacharya et al. (1999) obtained cDNAs encoding
STAT2 (600556), HIF1A (603348), and an alternatively spliced major
isoform of CITED2. Sequence analysis predicted that the 270-amino acid
isoform is 95% identical to the mouse protein and contains an unusual,
35-residue serine-glycine-rich junction (SRJ) that is not present the
shorter MRG1 isoform. Because of the SRJ, the authors designated this
protein isoform p35SRJ. The p35SRJ protein has no DNA-binding or other
known protein motifs. Northern blot analysis revealed ubiquitous
expression of a 2.4-kb p35SRJ transcript. Western blot and pulse-chase
analyses revealed unstable expression of a 36-kD protein.
Immunofluorescence microscopy demonstrated nuclear colocalization with
p300.
GENE STRUCTURE
Leung et al. (1999) determined that the CITED2 gene contains 3 exons
separated by 2 small introns. Both introns are spliced out in MRG1,
whereas only intron 1 is spliced out in p35SRJ. CITED2 also has a 3-kb
CpG island, which extends from -1562 to +1711, and several repeat
elements. The promoter lacks a TATA box but has several SP1 sites and 22
putative STAT-binding sites.
MAPPING
By STS database analysis followed by FISH, Leung et al. (1999) mapped
the CITED2 gene to chromosome 6q23.3. They noted a weaker second signal
at 1q22.
GENE FUNCTION
Shioda et al. (1997) demonstrated that a fusion protein consisting of
MRG1 and a DNA-binding domain activated transcription in mammalian
cells; this activation was dependent upon the acidic CR2 domain of MRG1.
By immunoprecipitation and mutation analyses, Bhattacharya et al. (1999)
showed an interaction between the C terminus of p35SRJ and both p300-CH1
and CBP (600140). Most p300/CBP, however, is not bound to p35SRJ, but
p35SRJ does compete efficiently with HIF1A for p300-CH1 binding, and it
inhibits HIF1A transactivation. Like HIF1A, p35SRJ mRNA and protein are
induced by hypoxia or deferoxamine. Promoter analysis identified 3
consensus HIF1 response elements. Bhattacharya et al. (1999) proposed
that the constitutive interaction of p35SRJ with p300/CBP may serve as a
safety mechanism to prevent illegitimate transcription at promoters
containing HIF1 sites.
MOLECULAR GENETICS
As indicated by the work of Bamforth et al. (2001, 2004), Cited2-null
mice died in utero showing various cardiac malformations (Bamforth et
al., 2001, 2004). Sperling et al. (2005) screened the CITED2 gene in a
cohort of 392 well-characterized patients with congenital heart defects
and 192 control individuals using DHPLC, sequencing, and genotyping
techniques. They identified 7 CITED2 nucleotide alterations in patients
with congenital heart defects that were not detected in controls,
including 3 mutations that led to alterations of the amino acid
sequence: a 27-bp deletion (602937.0001) in a patient with ventricular
septal defect (VSD2; 614431) and a 27-bp insertion and a 6-bp deletion
(602937.0002 and 602937.0003, respectively) in 2 patients with atrial
septal defect (ASD8; 614433). All 3 mutations were clustered in the
serine/glycine-rich junction of the protein, to which no functionality
had hitherto been assigned. Sperling et al. (2005) showed that these
mutations significantly reduced the capacity of CITED2 to transrepress
HIF1A, and that one of them, a 27-bp deletion (602937.0001),
significantly diminished TFAP2C (601602) coactivation. These results
revealed a modifying role for the serine/glycine-rich region in CITED2
function. The presence of these mutations in patients with septal
defects indicated that the CITED2 gene has a causative impact in the
development of congenital heart defects in humans.
ANIMAL MODEL
Bamforth et al. (2001) generated mice deficient in Cited2. Cited2 -/-
embryos died with cardiac malformations, adrenal agenesis, abnormal
cranial ganglia, and exencephaly. The cardiac defects included atrial
and ventricular septal defects, overriding aorta, double-outlet right
ventricle, persistent truncus arteriosus, and right-sided aortic arches.
Bamforth et al. (2001) found increased apoptosis in the midbrain region
and a marked reduction in Erbb3 (190151)-expressing neural crest cells
in midembryogenesis. Bamforth et al. (2001) showed that Cited2 interacts
with and coactivates all isoforms of transcription factor AP2 (TFAP2A;
107580 and TFAP2B; 601601). Transactivation of TFAP2 isoforms is
defective in Cited2 -/- embryonic fibroblasts and is rescued by
ectopically expressed Cited2. Since certain TFAP2 isoforms are essential
in neural crest, neural tube, and cardiac development, Bamforth et al.
(2001) proposed that abnormal embryogenesis in mice lacking Cited2
results, at least in part, from its role as a TFAP2 coactivator.
Martinez Barbera et al. (2002) introduced a null mutation into the
Cited2 locus. Cited2 -/- mutants died at late gestation and exhibited
heart defects and exencephaly, arising from defective closure of the
midbrain and hindbrain. Initiation of neural tube closure at the
forebrain-midbrain boundary, an essential step for closure of the
cranial neural tube, was impaired in the Cited2 -/- mutants. Gene marker
analysis using in situ hybridization revealed that the patterning of the
anterior neural plate and head mesenchyme was little affected or normal
in the Cited2 -/- embryos. However, Cited2 was required for the survival
of neuroepithelial cells and its absence led to massive apoptosis in
dorsal neuroectoderm around the forebrain-midbrain boundary and in a
restricted transverse domain in the hindbrain. Treatment with folic acid
significantly reduced the exencephalic phenotype in the Cited2 -/-
embryos both in vivo and in vitro. However, assessment of folate
metabolism revealed no defect in the Cited2 -/- mutants, and the
elevated apoptosis observed in the neuroepithelium of the Cited2 -/-
mutants was apparently not decreased by folic acid supplementation.
Yin et al. (2002) found that disruption of the gene encoding Cited2 is
embryonic lethal because of defects in the development of heart and
neural tube. Morphologic and Doppler echocardiographic analyses of
Cited2 -/- embryos reveal severe cardiovascular abnormalities, including
pulmonic arterial stenosis and ventricular septal defects accompanied by
high peak outflow velocities, features of human tetralogy of Fallot
(187500). The mRNA levels of several genes that are responsive to HIF1A,
such as VEGF (192240), SLC2A1 (138140), and PGK1 (311800), increased in
the Cited2 -/- hearts. The increase in VEGF levels was significant
because defects in the Cited2 -/- embryos closely resemble the major
defects in the VEGF transgenic embryos. Finally, compared with wildtype,
cultured fibroblasts from Cited2 -/- embryos demonstrated an enhanced
expression of HIF1A-responsive gene under hypoxic conditions. These
observations suggested that functional loss of Cited2 is responsible for
defects in heart and neural tube development, in part because of the
modulation of HIF1 transcriptional activities in the absence of Cited2.
Yin et al. (2002) concluded that Cited2 is an indispensable regulatory
gene during prenatal development.
Kranc et al. (2003) found that the proliferation of Cited2-null mouse
embryonic fibroblasts ceased prematurely. This was associated with a
reduction in growth fraction, senescent cellular morphology, and
increased expression of the Ink4/Arf (600160) cell proliferation
inhibitors, p16(Ink4), p19(Arf), and p15(Ink4b). Deletion of the
Ink4a/Arf gene completely rescued the defective proliferation of
Cited2-null fibroblasts, but it did not rescue the embryonic
malformations observed in Cited2-null mice, indicating that other
pathways are likely involved. Cited2-null fibroblasts also showed
reduced expression of the polycomb-group genes, Bmi1 (164831) and Mel18
(600346), which function as INK4A/ARF and Hox repressors.
Complementation with Cited2-expressing retrovirus enhanced
proliferation, induced Bmi1 and Mel18 expression, and decreased
Ink4a/Arf expression. Bmi1- and Mel18-expressing retroviruses enhanced
the proliferation of Cited2-null fibroblasts, indicating that they
function downstream of Cited2. Kranc et al. (2003) concluded that CITED2
controls the expression of INK4A/ARF and fibroblast proliferation, at
least in part, via the polycomb-group genes BMI1 and MEL18.
Malformations of the septum, outflow tract, and aortic arch are the most
common congenital cardiovascular defects in humans and occur in mice
lacking Cited2, a transcriptional coactivator of TFAP2. Bamforth et al.
(2004) showed that Cited2 -/- mice also developed laterality defects,
including right isomerism, abnormal cardiac looping, and hyposplenia,
which are suppressed on a mixed genetic background. Cited2 -/- mice
lacked expression of the Nodal target genes Pitx2c, Nodal (601265), and
Ebaf (601877) in the left lateral plate mesoderm, where they are
required for establishing laterality and cardiovascular development.
CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic
hearts, and they activate Pitx2c transcription in transient transfection
assays. Bamforth et al. (2004) proposed that an abnormal Nodal-Pitx2c
pathway represents a unifying mechanism for the cardiovascular
malformations observed in Cited2 -/- mice, and that such malformations
may be the sole manifestation of a laterality defect.
The early bipotential mammalian gonad requires the expression of a
Y-linked gene, SRY (480000), during a brief window of time to ensure
proper testis development. WT1 (607102) and its direct target gene SF1
(NR5A1; 184757) function during sex determination, as well as in the
specified testes and ovaries. In mouse, Buaas et al. (2009) showed that
the transcription cofactor Cited2 interacted with Wt1 to stimulate the
expression of Sf1 in the adrenogonadal primordium to ensure adrenal
development. Cited2 acted in the gonad with Wt1 and Sf1 to increase the
expression of Sry levels to a critical threshold to efficiently initiate
testis development. Reducing the gene dosage of Wt1 or Sf1 in
Cited2-mutant gonads was sufficient to produce partial XY sex reversal,
while full sex reversal was attained in mutants containing a hypomorphic
Sry(Pos) allele. A direct correlation was observed between XY sex
reversal and reduced expression levels of Sry and Sf1 during sex
determination in mouse, suggesting that SRY is a downstream target of
the CITED2/WT1/SF1 regulatory pathway.
Deficiency of the transcription factor Cited2 in mice results in cardiac
malformation, adrenal agenesis, neural tube and placental defects, and
partially penetrant cardiopulmonary laterality defects due to disruption
of the Nodal-Pitx2c pathway. Bentham et al. (2010) showed that a
maternal high-fat diet more than doubled the penetrance of laterality
defects and, surprisingly, induced palatal clefting in Cited2-deficient
embryos. Both maternal diet and Cited2 deletion reduced embryo weight
and kidney and thymus volume. Expression profiling identified 40
embryonic transcripts including Pitx2 that were significantly affected
by embryonic genotype-maternal diet interaction. A high-fat diet reduced
Pitx2c levels more than 2-fold in Cited2-deficient embryos. Taken
together, these results defined a novel interaction between maternal
high-fat diet and embryonic Cited2 deficiency that affects Pitx2c
expression and results in abnormal laterality.
SF3B5
| dbSNP name | rs7744101(A,C) |
| cytoBand name | 6q24.2 |
| EntrezGene GeneID | 83443 |
| EntrezGene Description | splicing factor 3b, subunit 5, 10kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02938 |
EPM2A
| dbSNP name | rs73568389(G,A); rs1045820(C,T); rs7753694(A,C); rs9376955(T,A); rs9376956(T,C); rs59135568(C,T); rs73568401(C,T); rs73568402(A,G); rs61121433(C,A); rs142805814(C,T); rs117221388(A,G); rs6941429(G,A); rs6925909(T,C); rs6904060(G,T); rs4896827(T,A); rs4896828(A,C); rs4896829(T,A); rs6570701(A,G); rs6570702(G,A); rs7772717(T,C); rs9497380(T,C); rs7773780(T,G); rs9373467(C,T); rs9399561(G,C); rs12205454(A,C); rs13200495(G,C); rs75572793(C,T); rs6570703(C,T); rs6570704(A,C); rs6902273(G,A); rs4896831(T,C); rs73577358(A,C); rs6570705(C,T); rs73577363(G,T); rs9403737(G,T); rs75535907(T,C); rs6570706(T,C); rs3918991(G,A); rs56116838(G,A); rs75291044(A,G); rs4896832(G,A); rs76965296(C,T); rs4896833(T,G); rs6940930(T,C); rs10872579(C,G); rs75629784(T,C); rs1292339(G,A); rs1292338(A,C); rs1292337(A,G); rs1292336(T,C); rs1292335(A,C); rs1292334(G,A); rs857883(G,T); rs857882(T,G); rs73577384(C,A); rs857881(C,A); rs145363288(A,G); rs857880(T,C); rs73579444(G,A); rs73579446(G,C); rs35587488(C,T); rs74693501(C,T); rs702305(A,G); rs857879(C,A); rs28703599(C,G); rs147332582(G,C); rs719030(C,T); rs857877(A,C); rs864148(T,C); rs6909417(C,T); rs78051094(G,C); rs857876(A,C); rs76514014(C,T); rs857875(T,G); rs112716792(G,T); rs76107086(A,G); rs78041218(G,A); rs1292333(C,T); rs2179323(T,G); rs13206047(G,T); rs6570707(C,T); rs75634794(G,A); rs151172313(G,A); rs146930463(A,G); rs9766595(C,A); rs6570708(C,T); rs697053(T,C); rs6570709(T,C); rs702304(T,C); rs702306(T,C); rs56864636(G,A); rs182472437(T,C); rs702307(C,G); rs78380057(G,C); rs12111476(T,C); rs115064988(G,A); rs80133860(G,T); rs146878526(C,G); rs7772012(C,T); rs7759254(T,C); rs1070517(A,G); rs1070518(A,G); rs1070519(G,C); rs139748802(T,C); rs702309(T,C); rs6918350(C,T); rs702313(C,T); rs702314(G,A); rs697054(A,G); rs697055(G,C); rs697056(C,T); rs702316(C,A); rs702317(C,T); rs702318(G,T); rs702319(T,C); rs702320(G,A); rs702321(A,G); rs702322(G,A); rs6902952(T,A); rs35230590(C,T); rs702323(A,G); rs702324(T,C); rs12111090(C,G); rs117128711(C,T); rs6940415(A,G); rs1337839(A,G); rs9390343(A,T); rs141557203(C,T); rs9376957(C,T); rs73579478(G,T); rs2142978(T,C); rs9390344(C,G); rs9497395(A,G); rs4896837(C,T); rs7758839(A,G); rs7745722(T,C); rs148514523(T,A); rs9497396(C,A); rs9403739(A,G); rs4896838(T,C); rs146734389(A,G); rs6913497(A,G); rs141454771(G,C); rs7756614(C,T); rs4896839(T,G); rs7744082(T,A); rs2328704(T,C); rs6932863(A,T); rs77723755(A,G); rs73579498(T,C); rs116954615(A,G); rs1415744(T,C); rs11963225(C,T); rs9376958(C,T); rs6901864(C,A); rs6901888(A,G); rs9485017(T,C); rs991507(G,A); rs111864497(C,T); rs6914491(C,G); rs6930154(C,T); rs9485018(T,C); rs73566113(T,G); rs115926447(G,A); rs118113226(G,A); rs76561685(G,A); rs2223411(T,C); rs2206142(C,T); rs111440089(T,G); rs73566121(G,A); rs1591698(C,G); rs2092263(G,A); rs117850795(G,A); rs11964415(G,T); rs73566126(G,A); rs9403741(G,A); rs28587324(G,C); rs55810423(T,G); rs62433835(C,G); rs6931280(G,A); rs57105639(A,G); rs79774233(G,A); rs6570710(T,C); rs55746945(C,T); rs735535(C,T); rs735536(A,C); rs55658016(C,T); rs2092262(C,T); rs6927960(C,T); rs1004752(G,A); rs6928780(C,T); rs9373471(A,C); rs4896841(T,C); rs1337840(T,C); rs78389762(T,C); rs77633523(A,T); rs6901219(T,C); rs9390347(G,T); rs9390348(C,T); rs73566139(T,C); rs73566140(A,C); rs12195987(A,G); rs9485019(C,G); rs7751660(C,T); rs9376961(T,C); rs6920248(C,T); rs9386128(G,A); rs6900158(T,C); rs6921110(C,T); rs6921423(G,A); rs7763273(G,A); rs9497401(T,C); rs58588227(A,G); rs7741139(G,A); rs7761251(T,C); rs2328707(G,A); rs7745379(C,G); rs9390349(T,G); rs9497403(T,G) |
| ccdsGene name | CCDS5206.1 |
| cytoBand name | 6q24.3 |
| EntrezGene GeneID | 7957 |
| EntrezGene Description | epilepsy, progressive myoclonus type 2A, Lafora disease (laforin) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EPM2A:NM_001018041:exon2:c.G402A:p.G134G,EPM2A:NM_005670:exon2:c.G402A:p.G134G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8566 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbNSFP KGp1 AF | 0.141483516484 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.35635359116 |
| dbNSFP KGp1 Asn AF | 0.0034965034965 |
| dbNSFP KGp1 Eur AF | 0.233509234828 |
| dbSNP GMAF | 0.141 |
| ESP Afr MAF | 0.0463 |
| ESP All MAF | 0.179225 |
| ESP Eur/Amr MAF | 0.247326 |
| ExAC AF | 0.205 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Bilateral macular retinal pigment epithelial mottling;
Bilateral macular retinal pigment epithelial atrophy;
Bilateral red-speckled retinal pigment epithelium;
Ring of moderately increased perifoveal autofluorescence;
Dyschromatopsia;
Gradual progressive loss of central visual acuity;
Central scotomata;
Electro-oculogram (EOG), flash electroretinogram (ERG) and pattern
ERG (PERG) initially normal;
Greatly reduced light-adapted scotopic and photopic ERG by 7th decade;
Unrecordable PERG by 7th decade
MOLECULAR BASIS:
Caused by mutation in the prominin 1 gene (PROM1, 604365.0003)
OMIM Title
*608072 NHL REPEAT-CONTAINING 1 GENE; NHLRC1
;;EPM2B GENE; EPM2B;;
MALIN
OMIM Description
DESCRIPTION
The NHLRC1 gene encodes malin, a single subunit E3 ubiquitin (UBB;
191339) ligase, which contains a RING-HC-type zinc finger and 6 NHL
domains and is subclassified as a member of the RING-HCa family (Gentry
et al., 2005).
CLONING
Within an 840-kb region on chromosome 6p22.3 in which the putative EPM2B
locus for Lafora disease (254780) was mapped, Chan et al. (2003)
identified a single-exon gene, termed NHLRC1. The gene is predicted to
encode a 395-amino acid protein, termed malin ('mal' for seizure in
French), containing a zinc finger of the RING type and 6 NHL-repeat
protein-protein interaction domains. The presence of the RING finger
predicts an E3 ubiquitin ligase function. Northern blot analysis
indicated 2 transcripts of 1.5 kb and 2.4 kb in all tissues examined,
including multiple subregions of the brain. In cultured cells, malin was
localized at the endoplasmic reticulum and, to a lesser extent, in the
nucleus. These results were similar to those observed for laforin
(EPM2A; 607566).
MAPPING
Chan et al. (2003) identified the NHLRC1 gene between markers D6S1688
and D6S1567 on chromosome 6p22.3.
GENE FUNCTION
By yeast 2-hybrid screen of a human brain cDNA library, Gentry et al.
(2005) found that malin directly bound and interacted with laforin in
HEK293T cells in vivo. Laforin is polyubiquitinated in a malin-dependent
manner, which leads to laforin degradation. Ubiquitination depended on
malin's RING domain but not on its NHL domains, whereas the NHL domains
functioned as a substrate-interacting motif to bind laforin. Mutations
in the NHLRC1 gene abolished both laforin polyubiquitination and
degradation. Gentry et al. (2005) concluded that malin is a
single-subunit E3 ligase, that laforin is a malin substrate, and that
malin regulates laforin protein concentration. They further suggested
that mutations in the NHLRC1 gene resulting in loss of the E3 ligase
activity of malin underlie the onset of Lafora disease.
Lohi et al. (2005) showed that laforin is a GSK3B (605004) ser9
phosphatase, and therefore capable of inactivating glycogen synthase
(GYS1; 138570) through GSK3. Laforin also interacted with malin, which
has been shown to bind GYS1. The authors proposed that laforin, in
response to appearance of polyglucosans, directs 2 negative feedback
pathways: polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity and
polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal
degradation.
Cori disease (232400) is a glycogen storage disease characterized by
deficiency of the glycogen debranching enzyme AGL (610860). Cheng et al.
(2007) showed that malin interacted with mouse Agl and promoted its
ubiquitination. Transfection studies in HepG2 cells showed that Agl was
cytoplasmic, whereas malin was predominantly nuclear. However, after
depletion of glycogen stores, about 90% of transfected cells exhibited
partial nuclear Agl staining. Elevation of cAMP increased malin levels
and malin/Agl complex formation. Cheng et al. (2007) concluded that
ubiquitination of AGL may play a role in the pathophysiology of both
Lafora disease and Cori disease.
Mittal et al. (2007) showed that laforin and malin were recruited to
aggresomes upon proteasomal blockade, possibly to clear misfolded
proteins through the ubiquitin-proteasome system (UPS). Garyali et al.
(2009) tested this possibility using a variety of cytotoxic misfolded
proteins, including the expanded polyglutamine protein, as potential
substrates. Laforin and malin, together with Hsp70 (HSPA1A; 140550) as a
functional complex, suppressed the cellular toxicity of misfolded
proteins; all 3 members of the complex were required for this function.
Laforin and malin interacted with misfolded proteins and promoted their
degradation through the UPS, and they were recruited to the
polyglutamine aggregates and reduced the frequency of aggregate-positive
cells. Garyali et al. (2009) suggested that the malin-laforin complex is
a novel player in the neuronal response to misfolded proteins.
MOLECULAR GENETICS
In 34 probands with Lafora disease, Chan et al. (2003) identified 17
different mutations in the NHLRC1 gene in 26 families, including 8
deletions, 1 insertion, 7 missense changes, and 1 nonsense change (see,
e.g., 608072.0001). Eighteen families were homozygous and 8 were
compound heterozygous for the mutations.
Gomez-Abad et al. (2005) identified 18 mutations, including 12 novel
mutations, in the malin gene (see, e.g., 608072.0005-608072.0007) in 23
of 25 patients with Lafora disease who did not have mutations in the
laforin gene. P69A (608072.0002) was the predominant mutation,
identified in 14 chromosomes from 9 unrelated patients; haplotype
analysis suggested a founder effect for only 2 of these families.
Singh et al. (2005) identified 6 different mutations in the NHLRC1 gene
in 5 of 8 Japanese families with Lafora disease. Another Japanese family
had a mutation in the EPM2A gene, and 2 Japanese families did not have
mutations in either gene. Singh et al. (2005) concluded that mutations
in the NHLRC1 gene are a common cause of Lafora disease in Japan.
Singh et al. (2006) identified 7 different mutations, including 2 novel
mutations, in the NHLRC1 gene in affected members of 8 families with
Lafora disease. The authors stated that 39 different mutations had been
identified in the NHLRC1 gene.
Ianzano et al. (2005) reported the creation of a Lafora progressive
myoclonus epilepsy mutation database.
ANIMAL MODEL
More than 5% of purebred miniature wirehaired dachshunds (MWHDs) in the
United Kingdom suffer an autosomal recessive progressive myoclonic
epilepsy (PME), which Lohi et al. (2005) showed to be Lafora disease
(254780). Using homozygosity and linkage analysis, they mapped the MWHD
disease locus to canine chromosome 35, which is syntenic in its entirety
to human 6p25-p21. They then cloned canine Epm2b (NHLRC1). PCR
identified a repeat region in affected dogs and revealed biallelic
expansion of the dodecamer repeat with 19 to 26 copies of the D
sequence. Comparing the amount of Epm2b mRNA in skeletal muscle from 3
affected dogs and 2 controls with quantitative RT-PCR showed that
affected mRNA levels were more than 900 times reduced. To determine
whether the extra D sequence is specific to MWHDs, Lohi et al. (2005)
sequenced Epm2b from 2 normal unrelated dogs from each of 128 breeds.
Sixty percent of their chromosomes had 3 repeats (2 Ds and 1 T) and 40%,
2 repeats (1 D and 1 T). Almost all breeds had examples of both variants
in homozygous or heterozygous state. They tested the next non-MWHD PME
case to present to the clinic, a basset hound, and found a homozygous
14-copy expansion of the repeat. Lohi et al. (2005) devised a test to
detect and counteract the mutant allele through controlled breeding.
RPS18P9
| dbSNP name | rs3734295(C,T); rs9765961(T,C) |
| cytoBand name | 6q25.1 |
| EntrezGene GeneID | 645958 |
| snpEff Gene Name | C6orf72 |
| EntrezGene Description | ribosomal protein S18 pseudogene 9 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4729 |
SYNE1
| dbSNP name | rs2813558(C,A); rs12681(C,T); rs2250122(G,T); rs2295192(C,T); rs371151061(T,C); rs2813559(A,G); rs7760864(C,T); rs2813560(T,G); rs114310989(T,C); rs146445910(G,A); rs6904980(A,C); rs368958735(A,G); rs2747653(T,C); rs2813561(C,T); rs2813562(C,T); rs2813563(C,T); rs2747654(A,G); rs192069026(G,A); rs2747655(T,C); rs144783182(T,C); rs2747656(G,T); rs725467(C,T); rs375461449(G,A); rs11757691(C,A); rs11757692(C,A); rs150681370(A,C); rs2673781(C,T); rs9397486(G,A); rs2459111(C,T); rs2459110(C,A); rs58450883(C,T); rs9397487(G,A); rs17082167(T,C); rs2295193(G,A); rs2295194(G,C); rs2295195(G,A); rs57299193(C,T); rs80161830(G,A); rs66553845(C,T); rs6900329(T,C); rs193032663(G,A); rs12529355(C,T); rs117389517(A,C); rs3818109(A,G); rs35658027(G,A); rs2813566(G,A); rs2813567(C,G); rs9322361(A,G); rs2813568(A,G); rs2747657(A,C); rs2813569(A,G); rs17082195(G,A); rs2813570(A,T); rs13202108(G,A); rs6936626(T,C); rs9383609(T,G); rs3818110(G,A); rs60263503(G,A); rs2813480(T,C); rs2813481(T,C); rs2813482(T,C); rs2459112(G,A); rs146806171(G,A); rs2813483(G,A); rs2747659(G,T); rs11155834(G,C); rs2813484(A,G); rs2747660(C,A); rs2256135(A,G); rs2813485(C,T); rs2813486(A,G); rs2813487(A,G); rs2747662(T,C); rs116201306(G,A); rs2813488(A,G); rs2747663(T,G); rs2813489(C,G); rs2747664(T,C); rs2673790(A,G); rs74402015(C,T); rs9371241(G,C); rs2813490(C,T); rs2813491(A,T); rs2747665(T,C); rs2252837(C,T); rs2252755(C,G); rs2252748(C,T); rs718528(T,C); rs115557362(A,G); rs718527(T,C); rs17082233(T,C); rs17082236(C,A); rs2813493(C,G); rs73632499(C,T); rs147748083(T,C); rs7743748(G,A); rs114160341(C,T); rs2103809(T,C); rs910415(T,C); rs2747640(A,G); rs2747641(A,G); rs2747642(T,C); rs181417822(C,T); rs2813494(C,T); rs9397084(T,C); rs2747643(A,G); rs139757056(G,A); rs1040635(T,C); rs1344419(T,A); rs147508147(C,T); rs73633307(T,G); rs2635475(G,A); rs6557199(T,C); rs2813495(G,C); rs67566067(T,G); rs6937954(T,A); rs149544621(C,A); rs6912041(C,T); rs9397085(G,T); rs7754314(C,T); rs113633463(G,A); rs17082253(C,A); rs57964718(G,T); rs116801939(C,T); rs78869636(A,T); rs4870077(C,T); rs183273583(C,T); rs6908985(A,C); rs138646388(G,A); rs112573044(G,A); rs6935288(C,T); rs6934344(G,A); rs6935868(C,T); rs2348262(G,A); rs12198873(T,C); rs2635474(G,A); rs2813496(A,G); rs4870079(G,A); rs114740842(A,C); rs377113267(C,T); rs6901280(T,C); rs2673785(T,A); rs2635473(T,C); rs2635472(G,A); rs11970498(C,G); rs2635471(G,A); rs11965522(A,T); rs2673784(G,T); rs2673783(G,C); rs117597571(G,A); rs2813497(G,A); rs2673782(T,A); rs1324453(T,C); rs13193574(A,T); rs1324451(G,A); rs142326692(C,G); rs997389(T,G); rs997769(T,C); rs78594564(G,A); rs998147(T,C); rs182509469(A,G); rs41291049(G,A); rs2635447(A,G); rs9479232(A,G); rs11962846(G,C); rs77766315(G,A); rs72995350(C,T); rs77677138(C,T); rs9479233(T,C); rs2813498(T,C); rs6920938(C,G); rs2813499(G,A); rs6905193(T,C); rs6900828(A,C); rs9322363(A,C); rs58361810(C,T); rs2763031(G,T); rs2635470(C,G); rs2763033(C,T); rs73780617(T,C); rs2635469(C,T); rs2763034(C,G); rs1324452(G,T); rs2635468(A,G); rs2635467(A,G); rs2763035(C,T); rs79730312(T,C); rs145117858(T,C); rs7774467(C,T); rs2813500(T,C); rs2813501(A,G); rs2635465(A,C); rs2813502(C,A); rs2813503(G,A); rs2813504(A,G); rs2813505(T,C); rs2635440(C,T); rs2813507(A,G); rs75300464(A,C); rs2247922(C,G); rs1000864(C,T); rs2763010(C,T); rs112642031(C,T); rs117734706(G,A); rs78832315(G,A); rs112647537(G,A); rs11155836(T,C); rs2763011(A,C); rs2763012(G,C); rs2763013(T,C); rs2813509(C,T); rs61684587(C,T); rs59225654(T,G); rs2813510(T,G); rs76956138(C,G); rs2813511(A,T); rs2813512(T,G); rs73780634(G,A); rs80347544(C,T); rs2813513(C,T); rs2813514(G,T); rs55842704(T,C); rs141934894(G,A); rs2635436(G,A); rs111259031(G,A); rs142564987(C,T); rs141940036(G,T); rs2763015(A,C); rs113734748(T,A); rs2635432(C,A); rs73619305(T,A); rs144180118(C,T); rs2635431(T,A); rs2635430(C,G); rs2635459(A,G); rs2813523(A,G); rs2813524(A,G); rs2635458(T,A); rs2813525(C,T); rs148075609(G,T); rs2813526(C,T); rs2763016(T,C); rs114420560(C,T); rs2635457(T,C); rs2813527(C,T); rs2813528(T,G); rs2635456(A,G); rs2635455(T,C); rs9479254(A,G); rs60299720(G,C); rs115199782(G,A); rs2635454(C,A); rs2813529(C,T); rs2635453(T,C); rs140725356(G,T); rs2635452(T,C); rs2813530(A,T); rs2635451(T,C); rs2813531(C,T); rs7741849(G,A); rs2763017(A,G); rs73619308(C,A); rs188536321(A,G); rs9918328(C,T); rs2763018(C,A); rs4869751(C,T); rs9478296(G,A); rs9478297(T,C); rs186786134(G,A); rs4870081(T,C); rs77580838(G,A); rs115718673(C,T); rs9479255(G,A); rs2635461(T,C); rs9479256(T,C); rs2813532(A,G); rs2813533(T,C); rs79612840(G,A); rs2635462(C,T); rs73780646(G,A); rs73619318(A,G); rs73780647(T,C); rs9479258(G,A); rs115488385(G,A); rs2763020(A,C); rs2635463(T,C); rs73780839(C,T); rs73780841(G,A); rs2763021(C,A); rs2763022(C,T); rs60523764(T,C); rs2635464(G,A); rs2763023(T,A); rs76748422(C,T); rs74990586(G,T); rs74336001(A,G); rs2635444(C,T); rs55746901(T,C); rs2813535(G,T); rs4142053(G,T); rs2763024(C,T); rs2635443(T,C); rs75137341(C,G); rs11962878(G,T); rs11967756(A,C); rs2813536(C,G); rs147851712(T,C); rs2813537(C,T); rs2813538(C,A); rs61131661(C,T); rs6920422(C,T); rs2813539(A,G); rs9371577(A,G); rs2813540(C,T); rs6900213(A,G); rs74706335(C,A); rs1408460(G,C); rs2635442(G,A); rs719764(G,C); rs2673776(T,G); rs2253512(G,A); rs2635441(G,A); rs116710739(G,A); rs2253407(G,T); rs58209940(C,A); rs145347117(A,T); rs11968197(T,C); rs11755392(C,T); rs73780845(T,C); rs56317515(G,A); rs116624864(C,G); rs79490105(C,A); rs6929139(T,A); rs2763025(C,T); rs17082323(T,C); rs116292261(C,T); rs80349291(C,T); rs73780847(A,C); rs2763026(A,G); rs3798756(G,A); rs2763027(A,G); rs10485255(A,T); rs7774714(T,C); rs58745145(T,C); rs2763028(G,A); rs112946219(T,C); rs17082343(A,T); rs4869752(T,A); rs684807(T,A); rs2763029(T,A); rs9479265(T,C); rs74618791(A,C); rs75035851(T,C); rs2763030(T,A); rs2763032(G,A); rs684321(T,C); rs621831(A,G); rs9397490(C,T); rs73781102(T,C); rs1408461(A,C); rs1408462(C,T); rs9371578(G,A); rs9371243(C,G); rs2813541(T,C); rs78900103(T,C); rs2147377(A,C); rs2147378(A,T); rs58810620(C,A); rs9478303(T,C); rs9397088(A,G); rs9383975(G,A); rs190668373(A,G); rs9397492(G,T); rs9383976(A,G); rs9397493(G,T); rs186842649(T,C); rs9383977(T,C); rs7768921(A,G); rs9371244(T,G); rs6557208(T,C); rs1971577(G,A); rs7741405(A,T); rs17082358(T,C); rs1998620(G,A); rs1359323(T,C); rs201988372(C,A); rs200445058(C,T); rs4870085(T,C); rs17803505(T,G); rs9479272(C,A); rs1535909(A,C); rs9383978(A,G); rs13206305(C,T); rs12528883(C,G); rs9478305(G,T); rs651306(A,T); rs4142054(A,G); rs4142055(C,T); rs4142056(C,T); rs1359324(C,T); rs1359325(C,G); rs1359326(T,A); rs113794610(G,A); rs73005444(G,A); rs2274142(G,A); rs17803970(A,T); rs4870086(C,G); rs71575922(C,G); rs9383614(T,A); rs12110479(C,T); rs35764603(G,A); rs2296254(C,T); rs9383979(C,G); rs35194179(G,A); rs9397494(G,A); rs12111427(C,T); rs11751190(G,A); rs13192494(C,T); rs6927162(T,A); rs9397089(C,A); rs6928675(A,G); rs6905741(G,A); rs4869757(C,A); rs190673256(C,T); rs9479275(G,A); rs1830820(C,T); rs9371245(C,A); rs9322364(G,A); rs58415480(C,G); rs13210209(G,A); rs13195723(T,C); rs4869758(A,G); rs3843915(A,G); rs3888239(T,C); rs4035028(A,G); rs147169719(C,T); rs17082383(T,C); rs6901631(T,C); rs6940845(A,G); rs56073566(C,T); rs6557210(G,A); rs7757670(A,G); rs6940851(G,A); rs4870087(G,T); rs4870088(C,A); rs7775378(G,A); rs7740449(T,C); rs9479280(T,A); rs377247710(G,A); rs4870089(G,A); rs73783816(T,C); rs9397495(A,G); rs9397091(A,C); rs4869759(A,G); rs4869761(C,A); rs4869762(C,T); rs9383615(T,C); rs9397092(A,G); rs73783819(T,C); rs1324455(C,G); rs57786327(T,C); rs17082392(A,T); rs6903292(C,G); rs62428358(T,A); rs9383982(A,G); rs4870090(A,G); rs4870091(G,C); rs58297095(G,A); rs6921228(T,C); rs6937888(C,A); rs9383983(C,T); rs61473208(C,T); rs6939382(T,G); rs633891(C,T); rs6904737(A,C); rs9478307(T,A); rs9478308(C,T); rs12200050(G,A); rs142346541(C,G); rs187586545(C,T); rs6926929(T,G); rs1359322(G,A); rs117866066(G,A); rs7356992(G,A); rs6940317(G,A); rs78404593(C,T); rs2025496(C,T); rs9478310(T,C); rs9479283(C,T); rs9397093(G,C); rs112914912(G,C); rs113423931(C,T); rs9397499(A,G); rs9397500(A,G); rs201909463(A,T); rs78971980(G,A); rs76984077(G,A); rs75645874(G,A); rs7747166(C,T); rs9479284(T,G); rs9479285(G,T); rs34462224(G,C); rs35764964(T,C); rs182348907(C,T); rs13211170(A,G); rs181845238(G,A); rs111656910(C,T); rs6931508(G,A); rs2788381(C,A); rs630548(C,A); rs10485256(C,T); rs113962905(C,T); rs584336(G,A); rs620768(C,G); rs183277013(T,C); rs1408458(C,T); rs17216894(T,C); rs10485257(A,G); rs7751093(C,T); rs76045328(C,T); rs1010714(T,A); rs1408459(C,T); rs640698(A,G); rs674724(C,T); rs34689334(T,C); rs1951925(G,A); rs12530184(A,C); rs11752464(G,A); rs9383984(A,G); rs6914583(T,A); rs112911573(G,A); rs6929804(G,A); rs6557212(A,G); rs141591474(G,A); rs36019875(A,G); rs9479289(C,T); rs111659009(G,A); rs9371581(G,A); rs9383985(C,T); rs76160752(C,T); rs4112833(C,T); rs7742927(G,A); rs6906189(C,T); rs12206761(G,A); rs9397501(G,A); rs9371582(C,T); rs1962702(C,T); rs1982820(T,C); rs116551901(C,T); rs13194149(T,A); rs55990866(T,G); rs7757046(A,C); rs9371583(T,C); rs9371248(A,G); rs59071593(A,T); rs765338(C,G); rs2013767(C,T); rs117407502(C,T); rs1890100(A,G); rs931423(T,C); rs6901934(A,G); rs75556600(C,T); rs3816850(A,T); rs17082448(C,G); rs2306915(G,T); rs75227783(A,G); rs9397095(T,C); rs1472023(A,G); rs17082463(A,G); rs1844356(G,C); rs4472361(G,T); rs7741183(C,T); rs13192881(C,G); rs9322367(T,C); rs141428742(A,G); rs9397096(C,G); rs73783833(C,T); rs7776230(T,C); rs7776399(T,C); rs73783834(C,T); rs7738189(T,C); rs9479291(C,T); rs9479292(G,C); rs73783837(A,G); rs80093341(G,A); rs9479294(T,C); rs2306916(A,T); rs9371585(C,T); rs184014243(C,G); rs6557213(A,G); rs13206045(G,C); rs75968444(G,A); rs35085679(G,A); rs3734365(C,G); rs6911096(A,T); rs111511993(G,A); rs10499268(G,A); rs9478314(T,C); rs13218956(C,T); rs725235(T,C); rs959024(A,G); rs4486029(G,T); rs149536991(C,A); rs6912991(C,A); rs35337997(G,A); rs1999829(T,C); rs1999830(G,T); rs115341936(C,T); rs6929609(C,T); rs9397097(C,T); rs9397099(C,G); rs6914571(T,A); rs13217146(G,A); rs117656461(T,G); rs34186293(C,T); rs28385621(C,A); rs9479297(T,C); rs9479298(T,C); rs9479299(A,G); rs35950798(T,A); rs9397100(T,A); rs28385620(A,G); rs9383990(C,G); rs9478315(T,C); rs9478316(T,C); rs11155846(C,T); rs9478317(T,C); rs6931597(T,C); rs11756362(A,C); rs183353820(A,G); rs34056981(G,A); rs13196107(G,A); rs4870095(A,G); rs71575926(G,A); rs9371587(G,T); rs11155847(A,G); rs9478318(T,C); rs11755383(T,C); rs9371588(C,G); rs9397503(G,C); rs9397101(A,G); rs9371589(T,G); rs6940741(A,G); rs7740546(A,T); rs6907303(T,C); rs7759171(G,A); rs7746517(A,C); rs7747005(A,G); rs35569312(C,T); rs4870096(A,G); rs4870097(T,C); rs9371590(G,A); rs4645434(C,A); rs9383617(C,T); rs9479301(T,A); rs7738089(T,G); rs4869765(C,T); rs9322368(C,T); rs9322369(T,A); rs144596829(C,T); rs7762904(C,G); rs7749078(T,A); rs4869766(C,T); rs10223515(G,A); rs6911990(T,C); rs3860811(T,C); rs3860812(G,C); rs10872684(C,T); rs4870098(G,A); rs150758664(T,C); rs114367594(G,A); rs9478320(A,C); rs9478321(A,G); rs13210127(T,G); rs1387549(A,G); rs9478322(T,C); rs12211794(T,C); rs117798046(T,C); rs12206277(G,A); rs12206330(G,T); rs4632900(T,C); rs12206458(G,C); rs6908204(G,A); rs6908392(G,A); rs6932325(A,C); rs7751117(G,T); rs7776076(T,C); rs7772001(A,T); rs2029413(T,G); rs2029412(T,C); rs6905339(T,C); rs6921495(C,T); rs9397102(A,G); rs9478323(G,T); rs6906442(G,C); rs150319705(C,T); rs2171758(C,T); rs9478325(G,A); rs9478326(G,A); rs76264086(T,C); rs34082537(T,C); rs4286796(A,T); rs186481077(C,T); rs190553440(G,T); rs13218505(G,A); rs6557214(G,A); rs13218536(C,T); rs6557215(A,G); rs7771657(G,T); rs7771662(G,A); rs4407724(G,T); rs34721749(G,A); rs9322370(A,C); rs111541082(G,A); rs9383991(C,T); rs138693624(A,G); rs9383618(G,A); rs9383619(G,A); rs4870100(T,A); rs187340630(A,T); rs7775637(C,T); rs192853060(A,G); rs9371592(G,A); rs1873176(G,A); rs13203258(C,T); rs6557216(G,A); rs6913579(T,C); rs1811616(C,A); rs34405703(C,T); rs200590972(C,T); rs2348551(A,G); rs4870101(A,T); rs4870102(A,G); rs191958442(T,G); rs214955(C,T); rs7751175(A,C); rs9479306(A,G); rs114499022(T,C); rs4870104(A,G); rs4870105(G,A); rs61472249(T,A); rs926695(G,A); rs214957(T,C); rs214958(C,T); rs214959(G,A); rs6557217(T,C); rs28375096(C,T); rs77226975(G,A); rs1933689(G,A); rs74415572(C,T); rs12526738(C,G); rs114160002(A,G); rs116688233(T,C); rs60779840(A,C); rs144738016(G,A); rs77249508(C,T); rs9478329(C,T); rs76581988(A,G); rs7764344(A,C); rs7744978(C,T); rs214949(G,T); rs214950(G,A); rs6557218(G,C); rs77305955(A,G); rs113031090(C,A); rs7755618(G,T); rs7756948(C,T); rs214941(C,G); rs214942(T,C); rs214943(T,A); rs56877632(G,A); rs58905396(G,A); rs7766519(C,T); rs9942536(C,A); rs75053394(G,A); rs9942542(C,T); rs214944(C,T); rs214945(A,G); rs214946(G,A); rs214947(A,G); rs963656(T,C); rs76322236(G,A); rs4506057(C,A); rs143525430(A,G); rs20585(C,A); rs147226715(T,C); rs1203233(G,T); rs537675(A,G); rs502950(C,T); rs75387096(T,C); rs473101(T,C); rs79795662(C,T); rs551900(G,A); rs550070(A,G); rs550065(A,G); rs578359(C,G); rs551681(G,T); rs550685(G,A); rs549981(C,T); rs549720(C,G); rs548985(C,G); rs548978(T,C); rs17082605(C,T); rs113648733(C,T); rs522437(C,G); rs488673(G,A); rs493994(C,T); rs492904(A,G); rs490448(T,A); rs79428643(A,T); rs214951(T,C); rs75207158(A,G); rs79680388(A,T); rs17082630(A,C); rs17082632(C,A); rs177330(A,G); rs58111491(G,C); rs2281370(G,A); rs145910219(T,A); rs78517884(T,C); rs6919643(T,C); rs28402070(C,T); rs78660529(T,C); rs214954(G,C); rs114155048(G,A); rs17082645(T,C); rs127196(C,A); rs2746418(G,A); rs544098(C,T); rs544125(C,T); rs544863(C,A); rs113815259(C,T); rs6924769(T,C); rs7741296(C,T); rs7741485(C,T); rs76358023(G,A); rs214978(A,C); rs214979(C,A); rs169975(A,C); rs214980(G,T); rs214981(A,G); rs214987(G,A); rs77908834(C,T); rs147542851(T,C); rs114864911(A,C); rs1873177(C,T); rs75965502(C,T); rs742784(A,C); rs742783(C,T); rs761408(C,T); rs2092602(T,C); rs7738528(A,C); rs214989(A,G); rs7738706(A,G); rs7756247(G,A); rs214991(G,A); rs78194734(T,C); rs77675469(T,A); rs6557219(G,A); rs6913500(C,T); rs6935911(A,C); rs9479313(T,C); rs77287211(C,T); rs111250109(A,T); rs9397104(T,C); rs116563189(T,C); rs563263(G,A); rs1738438(G,C); rs515258(T,C); rs79851045(C,T); rs117138149(C,T); rs17082669(T,C); rs548400(G,A); rs554608(A,C); rs553642(C,T); rs80225287(C,G); rs492233(C,A); rs525210(T,C); rs521514(C,T); rs115654294(G,A); rs189831742(G,A); rs169977(T,C); rs169976(T,C); rs112804945(T,A); rs215006(C,T); rs139721483(G,A); rs77463454(T,A); rs215005(C,G); rs215004(G,A); rs150933140(G,T); rs215003(C,G); rs77522975(T,C); rs215002(T,G); rs116961812(A,G); rs147007689(G,A); rs146124709(C,T); rs215001(G,A); rs7770926(T,C); rs215000(C,T); rs214999(T,C); rs214998(C,T); rs112309215(C,T); rs6915736(C,T); rs214997(A,G); rs214996(A,G); rs180808090(G,A); rs75932808(C,T); rs56263396(T,C); rs214995(G,A); rs17054427(T,C); rs12526147(T,C); rs214994(C,G); rs214993(G,A); rs17082695(G,A); rs17082697(T,G); rs214992(A,C); rs182526439(C,T); rs73003057(C,T); rs527021(C,T); rs502268(T,G); rs79189504(A,C); rs17082700(T,C); rs75977585(C,T); rs117735559(G,T); rs112992904(G,T); rs214977(T,C); rs17366321(G,A); rs17082701(G,A); rs214976(A,G); rs214975(T,C); rs191189051(G,T); rs214974(A,G); rs114160591(T,A); rs70015(A,C); rs70016(T,C); rs70017(T,G); rs70018(G,A); rs189988637(C,T); rs214973(A,G); rs169974(T,C); rs78366430(G,T); rs499914(A,G); rs214972(G,A); rs214971(A,G); rs214970(A,G); rs214969(G,C); rs17082707(G,A); rs148626610(T,C); rs214968(G,A); rs17082709(A,C); rs17082710(A,G); rs214967(G,A); rs214966(C,T); rs214964(C,A); rs214963(C,G); rs214962(G,C); rs17082717(C,T); rs78908871(C,G); rs214961(A,G); rs183342(C,T); rs214960(G,A); rs182480(T,C); rs506181(C,T); rs579464(G,A); rs9383994(G,A); rs6925067(T,A); rs67723248(C,A); rs7775181(G,A); rs7776344(C,T); rs80134660(T,C); rs7762190(G,A); rs77063378(T,A); rs7763343(C,A); rs13211693(C,T); rs142467232(G,A); rs6557226(G,A); rs6557227(G,A); rs6557228(G,A); rs7756410(A,G); rs4304177(T,C); rs6902037(G,T); rs6904183(C,T); rs9371599(C,T); rs9371600(G,A); rs9371601(G,T); rs6908747(C,T); rs75207375(G,A); rs7747960(C,A); rs7771568(A,C); rs7751874(C,T); rs77037637(A,C); rs4318888(T,C); rs4523096(C,A); rs4331993(T,A); rs4343926(A,G); rs4530871(C,T); rs188710161(C,T); rs118135299(T,C); rs12055686(T,C); rs6557229(T,C); rs6557230(C,G); rs79835838(C,A); rs7755437(A,C); rs9478332(C,A); rs9383995(T,A); rs9397510(G,A); rs7751588(C,T); rs7755692(C,A); rs7775384(A,G); rs1554782(C,G); rs6557231(C,T); rs6915547(T,C); rs58873909(C,T); rs189559726(C,G); rs181126261(A,G); rs185931820(C,A); rs9383622(C,A); rs9371252(C,T); rs11155853(T,C); rs11155854(C,T); rs9397511(A,G); rs7759578(A,G); rs7740022(C,T); rs7763880(T,C); rs115610513(T,C); rs79777093(G,A); rs115687108(G,A); rs7744498(G,C); rs9371253(T,C); rs80033011(C,T); rs187661399(A,G); rs76740728(T,C); rs7755453(G,A); rs116461251(T,C); rs9397512(C,T); rs9397513(T,C); rs148411361(T,A); rs9397514(T,C); rs117594316(C,T); rs4574653(A,G); rs9397515(A,T); rs9397516(A,C); rs9322372(A,G); rs117610833(T,C); rs9371602(C,T); rs9322373(C,T); rs9322374(A,C); rs9383997(A,G); rs9397106(A,T); rs9371254(T,C); rs9371603(A,G); rs9397518(C,T); rs139036403(C,T); rs9383623(G,T); rs117234770(C,T); rs62427696(C,G); rs62427697(C,T); rs12201105(A,G); rs9383624(G,A); rs9384000(C,T); rs138404542(T,C); rs144340657(C,T); rs117863090(T,C); rs116825230(G,A); rs62427698(C,A); rs150502148(A,G); rs9384001(C,T); rs12202199(A,G); rs12215935(C,A); rs35339721(C,T); rs115621118(G,A); rs7774755(C,A); rs147354502(A,G); rs6557233(C,T); rs7771605(T,A); rs76584112(C,T); rs181503573(C,T); rs1973833(A,T); rs76984171(T,G); rs17090956(T,C); rs765785(T,C); rs765784(T,A); rs1534298(G,A); rs1949963(A,T); rs1949962(C,T); rs56207224(C,T); rs115783606(A,T); rs2623961(G,C); rs17771489(A,G); rs7772823(G,C); rs9397519(A,G); rs9371604(T,A); rs13200897(C,T); rs17054436(G,A); rs71549135(A,T); rs189886260(A,G); rs12194509(C,T); rs76984897(A,T); rs11155856(C,T); rs17842542(A,G); rs2623972(G,A); rs141657428(C,T); rs192885108(G,A); rs17699049(T,A); rs2623971(C,T); rs17842543(G,A); rs12192150(A,G); rs17842544(T,C); rs11155857(G,A); rs113604455(A,G); rs2623970(C,T); rs145383262(G,A); rs116473894(C,T); rs115922092(A,G); rs17545391(A,G); rs9371605(G,A); rs9384004(C,T); rs2623969(T,C); rs150069645(T,C); rs2695263(G,A); rs13210676(T,C); rs2623968(A,G); rs2449116(A,T); rs114580510(G,A); rs115136894(G,A); rs181554156(C,A); rs2695264(G,C); rs1609125(C,T); rs2623958(G,A); rs2623980(T,C); rs17699371(C,T); rs2623981(C,T); rs75503847(A,G); rs9384005(T,C); rs2623934(A,G); rs116351342(T,C); rs6934124(A,G); rs2449113(A,T); rs2623933(G,A); rs1405701(G,A); rs1405700(G,T); rs186174006(T,C); rs75402198(G,T); rs2141152(G,A); rs17772087(C,G); rs12192594(G,A); rs11155858(G,A); rs74860550(A,G); rs2623932(A,G); rs2178010(G,A); rs116771215(T,C); rs79213949(C,T); rs186502155(G,A); rs77834113(A,T); rs148103037(T,C); rs77249378(A,T); rs186757965(G,C); rs2449112(C,T); rs2496123(A,G); rs4509131(C,G); rs7745725(A,G); rs73008911(A,T); rs7763330(G,A); rs187063971(T,G); rs2623966(T,C); rs7756085(A,G); rs75964806(C,T); rs79710998(T,C); rs2449114(A,T); rs2449115(T,A); rs2695256(A,G); rs6908571(G,A); rs114591216(A,G); rs73782879(T,C); rs12154168(A,G); rs9322377(A,G); rs75346243(T,C); rs115220590(A,C); rs2695259(A,G); rs2695260(C,A); rs1405695(G,T); rs1405696(C,A); rs2623988(C,T); rs9384009(A,C); rs74861532(G,T); rs2623987(A,T); rs76495394(A,G); rs77111191(C,T); rs78328250(T,C); rs2257075(C,T); rs13436996(T,C); rs73010954(G,T); rs11968876(G,C); rs75904871(T,G); rs11962260(T,C); rs11964581(A,G); rs75465479(C,T); rs17082766(G,A); rs11969020(T,C); rs11966444(C,A); rs1527369(A,T); rs74710949(T,A); rs1358317(A,G); rs11966511(C,T); rs79586559(C,A); rs17778172(T,C); rs2623986(G,T); rs137964733(C,T); rs13437567(T,C); rs12528071(G,A); rs2882022(G,A); rs114413636(C,T); rs1405699(A,G); rs1830219(C,T); rs1830218(T,A); rs1830217(T,C); rs7454809(A,T); rs75655791(C,T); rs73782883(T,C); rs2141150(T,G); rs112098660(C,T); rs76465413(T,C); rs1405698(T,C); rs2695261(A,G); rs73782885(A,G); rs2623973(A,G); rs17082786(T,C); rs112750889(C,T); rs2141149(A,G); rs2141148(G,A); rs75515987(C,T); rs6916221(A,C); rs1527368(C,A); rs73782887(A,G); rs9397523(A,C); rs78539144(C,T); rs9322378(G,A); rs9322379(C,T); rs11155859(A,G); rs6916524(G,C); rs6557234(C,T); rs9383626(T,G); rs6923710(C,G); rs76121078(T,C); rs1554784(A,G); rs1554783(A,G); rs9371606(C,G); rs12199541(T,A); rs12201313(T,C); rs7738912(A,G); rs7739404(A,G); rs143128890(G,A); rs10872686(A,G); rs9383628(T,A); rs73633252(T,G); rs1744366(C,A); rs9371608(G,A); rs2758790(G,A); rs2758791(T,C); rs9397525(C,G); rs2623964(C,T); rs9384012(T,C); rs2950447(A,C); rs866015(T,G); rs818449(C,G); rs818448(A,C); rs818447(A,G); rs818446(G,A); rs818445(C,T); rs76776697(C,T); rs818443(G,A); rs9371609(A,G); rs17082807(G,A); rs818442(A,C); rs818441(G,A); rs2623960(T,C); rs818440(A,C); rs2141153(G,A); rs4870113(G,A); rs9479345(A,T); rs1853280(G,A); rs12213593(T,A); rs1322509(A,T); rs12528046(G,A); rs1407484(T,G); rs7749912(C,G); rs78829654(A,G); rs7755451(C,G); rs4870115(T,C); rs79532630(A,T); rs79072687(T,C); rs2348799(C,T); rs9479353(C,T); rs7756114(T,C); rs2093500(A,G); rs56312058(T,C); rs9384013(G,A); rs7775639(C,T); rs17779152(G,A); rs17700972(T,C); rs17779212(T,C); rs2146248(T,A); rs2178009(A,G); rs139975812(C,A); rs9371610(G,A); rs9397529(A,G); rs140183032(A,G); rs144670171(G,A); rs17701297(G,A); rs58100937(A,G); rs147936604(C,T); rs1322517(A,G); rs1322520(C,T); rs9478339(C,T); rs112427300(C,T); rs138707071(C,T); rs140130646(T,C); rs9397111(A,T); rs9478342(C,T); rs140887186(C,T); rs10499269(C,T); rs76612580(C,T); rs10457880(A,T); rs1727070(C,T); rs1358950(T,C); rs1358951(T,C); rs1744396(A,G); rs1744397(G,C); rs190610742(G,T); rs75643118(A,C); rs860173(A,C); rs78455245(A,G); rs76621026(A,G); rs818451(T,G); rs7766856(C,A); rs9397532(A,C); rs1918334(G,T); rs2695255(G,A); rs2695254(A,C); rs2695253(C,T); rs2758792(A,G); rs2695252(C,T); rs12213941(T,C); rs2695251(T,C); rs2038615(A,G); rs6909384(A,G); rs6909400(A,G); rs6930228(C,T); rs6910147(A,G); rs139748644(T,C); rs12210370(G,C); rs12210466(G,A); rs56338450(A,G); rs3117744(A,G); rs3108459(G,A); rs75583601(C,T); rs1727061(C,T); rs1727060(C,A); rs11759468(G,A); rs1727059(C,T); rs1727058(G,A); rs114785114(G,C); rs115559999(G,A); rs1727057(C,T); rs7742496(G,A); rs2758793(G,A); rs2758794(T,C); rs2623977(C,T); rs2800647(C,T); rs2800648(C,T); rs2758795(C,T); rs2758796(G,A); rs150241871(A,G); rs9397533(G,T); rs2984655(G,T); rs149314421(A,G); rs183880760(G,A); rs148203116(A,G); rs75906077(C,T); rs116315046(T,C); rs137922941(A,C); rs144816498(A,C); rs141902916(G,A); rs139258553(G,A); rs75036628(C,T); rs148235344(A,C); rs9371618(A,G); rs116174435(C,A); rs2758797(G,A); rs2178008(C,A); rs1744393(A,G); rs1744392(G,T); rs1405691(A,G); rs1744391(T,C); rs1405692(G,A); rs1405693(T,C); rs1727039(A,T); rs9371619(G,A); rs12190571(G,C); rs1744390(C,T); rs1727040(G,A); rs1727041(A,T); rs1744389(G,A); rs1028651(T,C); rs1028650(G,T); rs1727042(C,T); rs2695245(T,A); rs6557235(G,C); rs7758168(G,A); rs1744387(A,G); rs75514691(G,A); rs7749155(T,C); rs1631241(T,C); rs1631244(C,T); rs1631293(T,C); rs180883846(A,G); rs1744385(A,G); rs1727043(T,A); rs1407491(C,T); rs58904784(G,T); rs1407490(C,T); rs1407489(G,T); rs188790262(T,C); rs60483197(T,C); rs1744383(G,A); rs9397537(C,T); rs6940651(C,T); rs1727046(A,T); rs1744382(A,G); rs77339859(A,G); rs76607279(G,C); rs1527367(A,T); rs1727047(T,A); rs2030918(T,A); rs76216034(C,T); rs1744380(G,A); rs1727048(A,G); rs1744379(C,A); rs1727049(A,G); rs190460685(T,A); rs75047023(A,T); rs1744378(T,C); rs7766225(T,A); rs78136621(C,T); rs73003601(A,G); rs1744377(T,C); rs114210717(T,C); rs2758798(A,G); rs1918331(T,G); rs1744376(A,G); rs1744375(C,T); rs12110355(A,G); rs1727050(C,G); rs1744374(C,T); rs74608294(T,C); rs77148627(C,T); rs1727051(A,C); rs1744372(C,G); rs12110509(T,C); rs1407488(G,T); rs1407487(T,C); rs1631457(C,T); rs1744369(T,A); rs1405694(C,T); rs1727052(T,C); rs1727053(A,G); rs1727054(A,G); rs78574673(T,G); rs1322512(C,A); rs2695246(T,C); rs2623985(T,C); rs7744697(G,A); rs7744715(G,A); rs7765586(A,G); rs9371620(T,G); rs2057399(G,A); rs2623941(A,C); rs2623942(T,A); rs2623943(A,G); rs1322511(C,T); rs9383634(A,G); rs2758802(A,G); rs732496(A,C); rs4870122(A,T); rs4870123(C,T); rs2011836(A,G); rs2758803(G,A); rs2758804(T,A); rs188888774(T,C); rs182015300(T,A); rs9478345(G,A) |
| ccdsGene name | CCDS5235.1 |
| cytoBand name | 6q25.2 |
| EntrezGene GeneID | 23345 |
| EntrezGene Description | spectrin repeat containing, nuclear envelope 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SYNE1:NM_033071:exon26:c.T3125C:p.V1042A,SYNE1:NM_182961:exon26:c.T3104C:p.V1035A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5358 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.585622710623 |
| dbNSFP KGp1 Afr AF | 0.772357723577 |
| dbNSFP KGp1 Amr AF | 0.395027624309 |
| dbNSFP KGp1 Asn AF | 0.743006993007 |
| dbNSFP KGp1 Eur AF | 0.436675461741 |
| dbSNP GMAF | 0.4141 |
| ESP Afr MAF | 0.266455 |
| ESP All MAF | 0.467477 |
| ESP Eur/Amr MAF | 0.429535 |
| ExAC AF | 0.481 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Reduced head circumference;
[Face];
Prominent supraorbital ridges;
Maxillary hypoplasia;
[Eyes];
Proptosis, mild;
[Nose];
Prominent nasal bridge
SKELETAL:
[Skull];
Craniosynostosis
NEUROLOGIC:
[Central nervous system];
Calcification of the basal ganglia;
Normal intelligence
OMIM Title
*608441 SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1; SYNE1
;;SYNAPTIC NUCLEAR ENVELOPE PROTEIN 1;;
NUCLEAR ENVELOPE SPECTRIN REPEAT PROTEIN 1;;
NESPRIN 1;;
KIAA0796;;
KIAA1756;;
KIAA1262
CPG2 ISOFORM, INCLUDED; CPG2, INCLUDED;;
CPG2B ISOFORM, INCLUDED; CPG2B, INCLUDED
OMIM Description
DESCRIPTION
The SYNE1 gene encodes a member of the spectrin family of structural
proteins that link the plasma membrane to the actin cytoskeleton
(summary by Schuurs-Hoeijmakers et al., 2013).
CLONING
Apel et al. (2000) isolated a cDNA encoding Syne1 by yeast 2-hybrid
analysis of an embryonic mouse cDNA library using mouse Musk (601296) as
bait. By screening additional mouse cDNA libraries, they identified
cDNAs encoding at least 3 Syne1 variants. Syne1 contains multiple
spectrin repeats and a 60-amino acid C-terminal region homologous to the
Drosophila protein Klarsicht. By database analysis, Apel et al. (2000)
identified KIAA0796 (Nagase et al., 1998) as a partial human ortholog of
Syne1. Northern blot analysis of mouse and human tissues detected a
4.7-kb SYNE1A transcript in skeletal and cardiac muscle and a 10-kb
SYNE1B transcript in multiple tissues, including heart, muscle, kidney,
liver, and brain. RT-PCR analysis showed moderate to high expression of
both transcripts in most human tissues examined. Immunofluorescence on
adult mouse tissues localized Syne1 to nuclei in skeletal, smooth, and
cardiac muscle cells. In skeletal muscle, high levels of expression were
detected in nuclei associated with synaptic sites.
Zhang et al. (2001) obtained a rat Syne1 cDNA that was upregulated in
differentiated aortic vascular smooth muscle cells. By searching
sequence databases using rat Syne1 as probe, followed by PCR and RACE of
human spleen and heart cDNA libraries, Zhang et al. (2001) isolated
human cDNAs encoding 2 SYNE1 proteins, which they called nesprin-1-alpha
and nesprin-1-beta. Nesprin-1-alpha contains 982 amino acids and
nesprin-1-beta contains 3,221 amino acids. They also identified a rare
splice variant of nesprin-1-alpha, nesprin-1-alpha-2, that contains an
additional 31 amino acids at its N terminus. Both nesprin-1 proteins
contain multiple spectrin repeats, a bipartite nuclear localization
signal, a transmembrane domain within the C-terminal Klarsicht homology
(KASH) region, and several N-glycosylation and phosphorylation sites.
Nesprin-1-beta also contains a protein-DNA binding motif. Northern blot
analysis detected ubiquitous expression of 3.8- and 10.7-kb transcripts,
with highest levels in spleen, peripheral blood leukocytes, and heart.
Immunogold and immunofluorescence analyses localized nesprin-1 primarily
to the nuclear envelope, with occasional nuclear staining showing
colocalization with heterochromatin and the nucleolus.
By genomic sequence analysis, RT-PCR, and RACE, Zhang et al. (2002)
extended the sequence of SYNE1 and showed that it encodes an 8,797-amino
acid protein with an actin-binding region containing 2 tandem calponin
(see 600806) homology domains at its N terminus. They also identified
SYNE1 homologs in Drosophila and C. elegans. Zhang et al. (2002)
generated antibody to the newly identified N-terminal portion of SYNE1
and showed that SYNE1 localized to the sarcomeres of cardiac and
skeletal muscle.
Cottrell et al. (2004) identified 2 brain-specific splice variants of
rat Syne1, which they called Cpg2 and Cpg2b, that encode proteins of 941
and 965 amino acids, respectively. The 3-prime UTR of Cpg2 contains an
unspliced intron between exons 33 and 34 of the Syne1 gene, and exon 34
is followed by a noncanonical polyadenylation hexamer that is conserved
in rats and humans. Compared with Cpg2, Cpg2b has an additional exon at
its 5-prime end. RT-PCR detected the 2 Cpg2 transcripts only in rat
brain. Immunohistochemical analysis localized Cpg2 to the postsynaptic
side of excitatory synapses on rat glutamatergic neurons.
GENE FUNCTION
Using fusion proteins, Zhang et al. (2001) determined that SYNE1
requires its C-terminal transmembrane domain to localize to the nuclear
envelope. When the transmembrane domain was deleted, the remaining
C-terminal domain directed nuclear targeting.
Cottrell et al. (2004) found that RNA interference-mediated knockdown of
Cpg2 in cultured rat hippocampal neurons increased the number of
postsynaptic clathrin-coated vesicles, some of which trafficked
NMDA-type glutamate receptors (see GRIN1; 138249), disrupted
constitutive internalization of glutamate receptors, and inhibited
activity-induced internalization of synaptic AMPA-type glutamate
receptors (see GRIA1; 138247). Manipulating Cpg2 levels also affected
dendritic spine size. Cottrell et al. (2004) concluded that CPG2 is a
component of a specialized postsynaptic endocytic mechanism devoted to
internalization of synaptic proteins, including glutamate receptors.
Puckelwartz et al. (2009) noted that nesprins, including nesprin-1,
participate in a complex that links the nucleoskeleton to the
cytoskeleton (LINC). Longer nesprin isoforms with actin-binding domains
reside in the outer nuclear membrane, while short nesprin isoforms are
tethered to the inner nuclear membrane. The transmembrane KASH domain is
required for tethering to the nuclear membrane, and the luminal portion
of the KASH domain binds to SUN1 (607723) and SUN2 (613569). Both SUN
proteins and nesprin can interact with lamins (LMNA; 150330) at the
inner nuclear membrane.
GENE STRUCTURE
Zhang et al. (2002) determined that the SYNE1 gene contains 147 exons
and spans 550 kb.
MAPPING
By FISH, Zhang et al. (2001) mapped the SYNE1 gene to chromosome 6q25.
MOLECULAR GENETICS
- Spinocerebellar Ataxia 8
Gros-Louis et al. (2007) mapped a candidate interval for a pure form of
autosomal recessive cerebellar ataxia (ARCA1, or SCAR8; 610743) to
chromosome 6q using genomewide linkage analysis. The candidate interval
contained only 1 gene, SYNE1, which spans over 0.5 Mb of genomic DNA.
Direct sequencing of SYNE1 identified 2 disease-segregating
single-nucleotide polymorphisms (SNPs) that were not detected among 380
age- and ethnicity-matched control chromosomes. This observation led
Gros-Louis et al. (2007) to believe that these 2 variants may be
causative mutations for ARCA1. The first mutation affected the invariant
A of the AG splice acceptor site at the junction of exon 85 and intron
84 (608441.0001), and the second mutation was located in intron 81, 12
bp upstream of exon 82 (608441.0002), creating a new AG cryptic splice
acceptor site. RT-PCR and sequencing analysis showed that the detected
intronic mutations had functional consequences on the proper splicing of
the gene and resulted in premature termination of the protein. Based on
the haplotype reconstructions of affected individuals from all of the
other families, they identified 3 other different disease haplotypes,
suggesting that other mutations could be associated with the disease. A
second mutational screen by direct sequencing uncovered 3 additional
mutations that segregated with their respective haplotypes and were all
predicted to lead to premature termination of the protein: R2906X
(608441.0003), a 5-bp deletion (608441.0004), and Q7640X (608441.0005).
These additional mutations were not detected among the 380 age- and
ethnicity-matched control chromosomes. Because they had identified 5
different mutations in a relatively homogeneous population, Gros-Louis
et al. (2007) predicted that mutations in this gene may be responsible
for a substantial fraction of all adult-onset autosomal recessive ataxia
syndromes with cerebellar atrophy.
In 2 unrelated Japanese patients with adult-onset SCAR8, Izumi et al.
(2013) identified different homozygous truncating mutations in the SYNE1
gene (see, e.g., 608441.0015).
- Emery-Dreifuss Muscular Dystrophy 4
In 2 unrelated probands with Emery-Dreifuss muscular dystrophy (EDMD4;
612998), Zhang et al. (2007) identified 2 different heterozygous
mutations in the SYNE1 gene (R257H; 608441.0008 and E646K; 608441.0010).
Patient fibroblasts and muscle cells showed loss of nuclear envelope
integrity with mislocalization of LMNA and emerin (EMD; 300384).
Immunofluorescent studies showed loss of SYNE1 expression in the nuclear
envelope and mitochondria of patient fibroblasts. These same changes
were also observed in fibroblasts from patients with other genetic forms
of EDMD, indicating that loss of nesprin is a characteristic of all
forms of EDMD. RNA interference of SYNE1 recapitulated the nuclear
defects membrane defects and changes in the organization of intranuclear
heterochromatin observed in patient cells. Overall, the findings showed
the importance of the nesprin/emerin/lamin complex in the maintenance of
nuclear stability and suggested that changes in the binding
stoichiometry of these proteins is a feature of EDMD. Zhang et al.
(2007) concluded that the disorder is caused in part by uncoupling of
the nucleoskeleton and cytoskeleton and postulated a dominant-negative
effect of the SYNE1 mutations.
Attali et al. (2009) reported an autosomal recessive form of congenital
muscular dystrophy, which they described as a myogenic arthrogryposis,
in members of a consanguineous Palestinian family. The disorder was
characterized by bilateral clubfoot, decreased fetal movements,
hypotonia, delayed motor milestones, and progressive motor decline after
the first decade. Muscle biopsies in affected individuals revealed
variation in size of muscle fibers without necrosis or fibrosis.
Genomewide linkage analysis revealed a single locus on chromosome 6q25.
Sequence analysis of the SYNE1 gene identified homozygosity for a splice
site mutation (608441.0011) in affected family members.
- Associations Pending Confirmation
See 608441.0012 for discussion of a possible association of intellectual
disability with variation in the SYNE1 gene.
See 608441.0014 for discussion of a possible association of autism with
variation in the SYNE1 gene.
ANIMAL MODEL
Puckelwartz et al. (2009) generated mice with C-terminal deletion of
Syne1, including the KASH domain. Mice homozygous for this mutation died
at or near birth from respiratory failure, whereas surviving mice
displayed hindlimb weakness and an abnormal gait. With increasing age,
kyphoscoliosis, muscle pathology, and cardiac conduction defects
developed. The protein components of the LINC complex, including mutant
nesprin-1-alpha, lamin A/C, and Sun2 (Unc84b), were localized at the
nuclear membrane in mutant mouse skeletal muscle myofibers; however,
mutant nesprin-1 interaction with Sun2 was disrupted in primary
myoblasts, resulting from loss of the C-terminal KASH domain. The
findings demonstrated the role of the LINC complex and nesprin-1 in
EDMD.
Zhang et al. (2009) showed that Sun1 and Sun2 double-knockout (Sun1/2
DKO) mice and Syne1 and Syne2 (608442) double-knockout (Syne1/2 DKO)
mice had similar defects in brain development. Sun1/2 DKO and Syne1/2
DKO brains were small and showed defective laminary structures in many
brain regions. Examination of neocortex revealed failure of radial
neuronal migration, but not tangential migration of interneurons, in
both Sun1/2 DKO and Syne1/2 DKO mice. Intracellular movement of nuclei
is a prerequisite for proper neuron migration and development, and Zhang
et al. (2009) found that Sun1 and Sun2 anchored Syne2 to the nuclear
envelope, while Syne1 and Syne2 connected the nuclear envelope to the
microtubule network, permitting nuclear movement. Zhang et al. (2009)
concluded that a complex made up of SUN1, SUN2, SYNE1, and SYNE2 is
required for neuronal nuclear movement and for neuronal migration and
development.
Zhang et al. (2010) generated a mouse model in which all isoforms of
nesprin-1 containing the C-terminal spectrin-repeat region with or
without the KASH domain were ablated. Syne1-knockout mice were marked by
decreased survival rates, growth retardation and increased variability
in body weight. Additionally, nuclear positioning and anchorage were
dysfunctional in skeletal muscle from Syne1-knockout mice. Physiologic
testing demonstrated no significant reduction in stress production in
nesprin-1-deficient skeletal muscle in either neonatal or adult mice,
but a significantly lower exercise capacity in knockout mice. Nuclear
deformation testing revealed ineffective strain transmission to nuclei
in muscle fibers lacking nesprin-1. Zhang et al. (2010) concluded that
nesprin-1 is essential for normal positioning and anchorage of nuclei in
skeletal muscle.
LOC100129518
| dbSNP name | rs2025187(G,A); rs11759329(G,C); rs2342478(C,T); rs927450(A,G); rs2273819(G,C) |
| cytoBand name | 6q25.3 |
| EntrezGene GeneID | 100129518 |
| snpEff Gene Name | WTAP |
| EntrezGene Description | uncharacterized LOC100129518 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.27 |
ACAT2
| dbSNP name | rs9347339(C,T); rs12528772(G,A); rs11758660(G,C); rs11758661(G,A); rs3798212(T,C); rs3798211(A,C); rs9347340(T,C); rs9364535(A,T); rs6905133(T,C); rs10945632(G,A); rs9365095(T,G); rs9347341(A,C); rs9347342(T,C); rs12662666(C,A); rs9347343(A,T); rs7758895(T,C); rs4276525(G,A); rs7759086(A,G); rs7738253(G,T); rs13194896(G,A); rs9355748(G,A); rs9355749(G,C); rs372164017(G,A); rs25683(A,G); rs11751480(T,C); rs11758384(C,T); rs9355750(A,G); rs41258114(T,C); rs3464(C,T); rs3465(G,A); rs911845(A,C); rs35625689(A,G) |
| ccdsGene name | CCDS5268.1 |
| cytoBand name | 6q25.3 |
| EntrezGene GeneID | 39 |
| EntrezGene Description | acetyl-CoA acetyltransferase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACAT2:NM_005891:exon5:c.A632G:p.K211R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6574 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B7Z233 |
| dbNSFP KGp1 AF | 0.365384615385 |
| dbNSFP KGp1 Afr AF | 0.168699186992 |
| dbNSFP KGp1 Amr AF | 0.57182320442 |
| dbNSFP KGp1 Asn AF | 0.148601398601 |
| dbNSFP KGp1 Eur AF | 0.558047493404 |
| dbSNP GMAF | 0.365 |
| ESP Afr MAF | 0.219927 |
| ESP All MAF | 0.454329 |
| ESP Eur/Amr MAF | 0.425581 |
| ExAC AF | 0.515 |
OMIM Clinical Significance
Skin:
Jaundice
Lab:
Impaired acetaminophen glucuronidation in Gilbert syndrome (143500)
Inheritance:
Autosomal dominant
OMIM Title
*100678 ACETYL-CoA ACETYLTRANSFERASE 2; ACAT2
;;ACETOCOENZYME A ACETYLTRANSFERASE 2;;
ACETOACETYL-CoA THIOLASE, CYTOSOLIC
OMIM Description
DESCRIPTION
The ACAT2 gene encodes cytosolic acetoacetyl-CoA thiolase (EC 2.3.1.9),
which is important in the utilization of ketone bodies (de Groot et al.,
1977). Mitochondrial acetoacetyl-CoA thiolase is encoded by the ACAT1
gene (607809).
CLONING
Song et al. (1994) cloned an ACAT2 cDNA by use of an antibody against
the human enzyme. The deduced amino acid sequence had 34 to 57% homology
with 4 other human thiolases and 4 acetoacetyl-CoA thiolases of
microorganisms.
MAPPING
The TCP1 gene (186980) is located on 6p in the vicinity of the major
histocompatibility complex, and the murine homolog, Tcp1, is located in
the t-complex region of mouse chromosome 17. In the mouse, a related
gene, Tcp1x, is tightly linked to Tcp1. Ashworth (1993) showed that 2
genes located 3-prime to the murine Tcp1 and Tcp1x genes code for
proteins highly homologous to acetyl-CoA acetyltransferases. These Acat
genes are in opposite orientation to the Tcp1 genes, and transcription
results in mRNA species that contain the last exon of Tcp1 or Tcp1x
within the 3-prime untranslated region of the respective Acat mRNA.
Willison et al. (1987) showed that in humans the TCP1 and ACAT2 genes
also overlap. Retention of this close linkage during mammalian evolution
suggests the possibility of some functional significance. Transcription
of both DNA strands at a given locus is common in prokaryotic and viral
systems. For examples of overlapping transcriptional units in humans,
see Morel et al. (1989) and Laudet et al. (1991).
As the human TCP1 gene had been assigned to 6q25-q27 by study of somatic
cell hybrids and by in situ hybridization, the ACAT2 gene was suspected
to be localized to the same chromosome region. By fluorescence in situ
hybridization, Masuno et al. (1996) demonstrated that the ACAT2 gene is
located on 6q25.3-q26.
MAS1
| dbSNP name | rs220721(C,T) |
| ccdsGene name | CCDS5272.1 |
| cytoBand name | 6q25.3 |
| EntrezGene GeneID | 4142 |
| EntrezGene Description | MAS1 oncogene |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAS1:NM_002377:exon1:c.C633T:p.V211V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3811 |
| ESP Afr MAF | 0.286882 |
| ESP All MAF | 0.241196 |
| ESP Eur/Amr MAF | 0.217791 |
| ExAC AF | 0.282 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Weakness of the facial muscles;
[Eyes];
Slow eye movements (onset in second decade);
Ocular gaze palsies (onset in second decade)
GENITOURINARY:
[Bladder];
Incontinence
ABDOMEN:
[Gastrointestinal];
Dysphagia (onset in second decade);
Chewing difficulties;
Incontinence
SKELETAL:
[Spine];
Scoliosis (less common);
[Feet];
Shortening of the Achilles tendon;
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness;
Normal muscle biopsy;
EMG shows reduction of voluntary recruitment
NEUROLOGIC:
[Central nervous system];
Upper and lower motor neuron degeneration;
Spastic paraplegia, lower limb;
Stiffness of the lower limbs;
Delayed motor development;
Loss of motor milestones;
Upper limb involvement (onset in the first decade);
Spastic tetraplegia (onset in the second decade);
Bulbar involvement;
Dysarthria;
Anarthria;
Hyperreflexia;
Extensor plantar responses;
Early involvement of the corticospinal pathways;
Weakness of the facial muscles;
Normal cognition and intellectual function;
Atrophy of the motor cortex in older patients seen on MRI;
T2-weighted hyperintensities in the corticospinal tracts and posterior
arms of the internal capsule in older patients seen on MRI;
Decreased or absent motor evoked potentials (MEP), indicating dysfunction
of the corticospinal tracts
MISCELLANEOUS:
Onset within first 2 years of life;
Progressive disorder;
Some patients never achieve walking or running;
Most patients become wheelchair-bound;
Allelic disorder to juvenile-onset amyotrophic lateral sclerosis (ALS2,
205100);
Allelic disorder to juvenile primary lateral sclerosis (PLSJ, 606353)
MOLECULAR BASIS:
Caused by mutation in the alsin gene (ALS2, 606352.0005)
OMIM Title
*607235 MAS1 ONCOGENE-LIKE; MAS1L
;;MRG
OMIM Description
CLONING
Dong et al. (2001) identified, in the mouse and human genomes, a family
of G protein-coupled receptors (GPCRs) related to the MAS1 oncogene
(165180), including MRG. Several pseudogenes were also identified. The
predicted MRG proteins contain transmembrane, extracellular, and
cytoplasmic domains. A subset of MRGs was expressed in specific
subpopulations of sensory neurons that detect painful stimuli. The
expression patterns of these genes thus revealed an unexpected degree of
molecular diversity among nociceptive neurons. Some MRGs could be
specifically activated in heterologous cells by RFamide neuropeptides
such as NPFF and NPAF (see 604643), which are analgesic in vivo. The
authors concluded that MRGs may regulate nociceptor function and/or
development, including the sensation or modulation of pain.
AIRN
| dbSNP name | rs73596435(A,G); rs9355772(A,T); rs4596512(T,C); rs3822843(T,C); rs3798192(A,G); rs8191714(G,A); rs8191715(C,T); rs9347379(C,T); rs10945647(A,T); rs10945648(G,C); rs4709388(T,C); rs9364540(G,A); rs9364541(T,C); rs6933622(G,T); rs10945649(T,A) |
| ccdsGene name | CCDS5273.1 |
| cytoBand name | 6q25.3 |
| EntrezGene GeneID | 100271873 |
| snpEff Gene Name | IGF2R |
| EntrezGene Description | antisense of IGF2R non-protein coding RNA |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01194 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
*604893 ANTISENSE IGF2R RNA, NONCODING; AIRN
;;ANTISENSE IGF2R RNA; AIR
OMIM Description
CLONING
The gene encoding insulin-like growth factor type-2 receptor (IGF2R;
147280) is maternally expressed and imprinted in mouse (Barlow et al.,
1991), whereas imprinting of human IGF2R is a polymorphic trait (Xu et
al., 1993). A CpG island in mouse Igf2r intron 2 that carries a
maternal-specific methylation imprint was shown in a transgenic model to
be essential for Igf2r imprinting and for the production of an antisense
RNA from the paternal allele (Stoger et al., 1993; Wutz et al., 1997).
Lyle et al. (2000) reported that the endogenous region 2 is the promoter
for the antisense RNA, which they called Air, and that the 3-prime end
lies 107,796 basepairs distant in an intron of the flanking, but
nonimprinted, gene Mas1 (165180). Air transcription is antisense; thus,
it is transcribed towards the Igf2r promoter and Mas1, the next upstream
gene. Lyle et al. (2000) sequenced 4 cosmids that span the region 2-Mas1
interval to give a 138,490-bp contig. BLAST searches identified multiple
ESTs. The sequence of the 12 EST clones available for analysis was
contiguous with the genomic sequence, indicating a few small or possibly
no introns. All ESTs lacked significant open reading frames, and most
contained common interspersed repeats, implying that they do not encode
proteins. The EST data suggested abundant antisense transcription
between Igf2r intron 2 and Mas1. This was confirmed by RNase protection
assays. Lyle et al. (2000) found an abundant paternal-specific antisense
transcript with no introns. Overlap between Air and Mas1 includes all of
the last exon of Mas1. A polyadenylation signal, which generated a
poly(A) tail, was found in intron 3 of Mas1, indicating the end of the
Air transcript.
By EST database analysis, Yotova et al. (2008) identified both spliced
and unspliced human AIR transcripts, and many of these were expressed in
the nervous system. Yotova et al. (2008) amplified AIR transcripts from
16 to 40% of Wilms tumor (see 194070) tissue samples.
GENE FUNCTION
In mouse, a bidirectional silencer for a 400-kb region that contains 3
imprinted, maternally expressed protein-coding genes (IGF2R; SLC22A2,
602608; SLC22A3, 604842) is located in a 3.7-kb sequence that also
contains the promoter for the imprinted, paternally expressed noncoding
Air RNA. Expression of Air is correlated with repression of all 3 genes
on the paternal allele; however, Air RNA overlaps just 1 of these genes
in an antisense orientation. By inserting a polyadenylation signal that
truncated 96% of the RNA transcript, Sleutels et al. (2002) demonstrated
that Air RNA is required for silencing. The truncated Air allele
maintained imprinted expression and methylation of the Air promoter, but
showed complete loss of silencing of the Igf2r/Slc22a2/Slc22a3 gene
cluster on the paternal chromosome. Sleutels et al. (2002) concluded
that noncoding RNAs have an active role in genomic imprinting.
Vu et al. (2004) found that Air was imprinted and expressed from the
maternal allele in both mouse liver and brain. They noted that the
expression of Igf2r is imprinted in liver and biallelic in brain,
suggesting that Air is only 1 component of a complex control mechanism
for Igf2r expression. In human fetal skin cells, no AIR expression was
detected, and expression of IGF2R appeared to be biallelically
controlled by epigenetic changes in its upstream promoter region only.
In murine glial cells and fibroblasts, Yamasaki et al. (2005) found that
Igf2r was maternally expressed and that the Air transcript was
paternally expressed. In murine primary cultured neurons, Igf2r was
biallelically expressed, and Air was not expressed. In the
differentially methylated region-2 (DMR2), which includes the Air
promoter, allele-specific DNA methylation, differential H3 and H4
acetylation, and H3K4 and K9 dimethylation were maintained in each
cultured cell type. In DMR1, which includes the Igf2r promoter, maternal
allele-specific DNA hypomethylation, histones H3 and H4 acetylation, and
H3K4 dimethylation were apparent in glial cells and fibroblasts.
However, in neurons, biallelic DNA hypomethylation and biallelic
histones H3 and H4 acetylation and H3K4 dimethylation were detected.
Yamasaki et al. (2005) concluded that lack of reciprocal imprinting of
Igf2r and Air in the brain may result from neuron-specific relaxation of
Igf2r imprinting associated with neuron-specific histone modifications
in DMR1 and lack of Air expression.
Nagano et al. (2008) demonstrated that Air interacted with the Slc22a3
promoter chromatin and the H3K9 histone methyltransferase G9a (604599)
in mouse placenta. Air accumulated at the Slc22a3 promoter in
correlation with localized H3K9 methylation and transcriptional
repression. Genetic ablation of G9a resulted in nonimprinted, biallelic
transcription of Slc22a3. Truncated Air failed to accumulate at the
Slc22a3 promoter, resulting in reduced G9a recruitment and biallelic
transcription. Nagano et al. (2008) concluded that Air, and potentially
other large noncoding RNAs, target repressive histone-modifying
activities through molecular interaction with specific chromatin domains
to epigenetically silence transcription.
Yotova et al. (2008) found that 3 of 6 Wilms tumor samples with the
highest AIR expression showed reduced IGF2R expression. However, this
inverse expression pattern was weak in Wilms tumor samples with reduced
AIR expression, possibly due to tumor cell heterogeneity. Yotova et al.
(2008) also found that the promoter region of the paternal AIR allele
was hypomethylated and contained a DNase1 hypersensitivity site,
suggesting the potential for expression. They showed that the CpG island
within the promoter region of human AIR had promoter activity when
expressed in transgenic mice.
Mammalian imprinted genes often cluster with long noncoding (lnc) RNAs.
Three lncRNAs that induce parental-specific silencing show hallmarks
indicating that their transcription is more important than their
product. To test whether Airn transcription or product silences the
Igf2r (147280) gene, Latos et al. (2012) shortened the endogenous lncRNA
to different lengths. The results excluded a role for spliced and
unspliced Airn lncRNA products and for Airn nuclear size and location in
silencing Igf2r. Instead, silencing required only Airn transcriptional
overlap of the Igf2r promoter, which interferes with RNA polymerase II
recruitment in the absence of repressive chromatin. Such a repressor
function for lncRNA transcriptional overlap reveals a gene silencing
mechanism that may be widespread in the mammalian genome, given the
abundance of lncRNA transcripts.
GENE STRUCTURE
The promoter region of the AIRN gene lies within intron 2 of the IGF2R
gene in both mouse and human and is characterized by the presence of a
CpG island (Lyle et al., 2000; Yotova et al., 2008).
MAPPING
The AIRN gene overlaps the IGF2R gene in the opposite orientation on
human chromosome 6q26 (Yotova et al., 2008) and mouse chromosome 17
(Lyle et al., 2000).
LPA
| dbSNP name | rs114322360(G,T); rs3124784(G,A); rs3127596(A,G); rs3124785(G,A); rs7449650(T,G); rs142163689(C,T); rs9355808(T,C); rs73012278(C,T); rs9457933(C,T); rs73594859(A,T); rs6919346(T,C); rs112801858(G,T); rs7767084(T,C); rs41266344(G,A); rs76062330(C,A); rs41265936(C,G); rs112171168(G,A); rs9365169(G,C); rs73594866(C,T); rs144281871(C,A); rs4708871(C,T); rs1801693(A,G); rs10755578(C,G); rs7761293(G,A); rs62441900(C,G); rs73594872(A,T); rs73012297(T,C); rs116223426(C,T); rs74490667(A,C); rs62441901(C,G); rs10945675(G,C); rs12207195(G,A); rs9457938(A,G); rs6415084(T,C); rs73784287(A,G); rs148022303(T,C); rs9365171(C,A); rs10945677(C,T); rs12665784(A,G); rs9346820(T,C); rs12526589(C,T); rs189950381(T,C); rs9365172(C,A); rs145783310(A,G); rs79563112(C,T); rs115689904(C,A); rs9365173(C,T); rs137903940(C,T); rs7450719(G,T); rs116384640(C,T); rs9346821(C,T); rs6938647(A,C); rs145457812(G,A); rs142613583(C,T); rs12525447(G,A); rs9365174(C,A); rs6903649(C,T); rs35189165(G,A); rs6906412(A,G); rs115814410(G,A); rs9457943(G,A); rs35358746(A,G); rs78244027(A,G); rs7454595(C,T); rs146430065(C,T); rs7454656(C,T); rs6455688(A,G); rs6923877(A,G); rs3798221(G,T); rs77372228(T,G); rs9364564(G,A); rs7775704(T,C); rs143073837(T,C); rs6910635(T,C); rs62441908(C,T); rs78199196(T,C); rs9346824(A,G); rs148121795(C,A); rs9355295(A,G); rs6939089(T,C); rs80220946(G,A); rs147706970(C,T); rs6903340(T,C); rs41272114(C,T); rs41272112(C,T); rs41272110(T,G); rs139038544(C,T); rs6455689(T,C); rs9365178(C,T); rs7765781(G,C); rs7765803(G,C); rs7771801(C,G); rs4073498(C,T); rs61120739(G,T); rs56346562(G,C); rs113572208(T,C); rs3902910(T,C); rs7450411(C,A); rs7450279(G,C); rs7453899(A,T); rs9457946(C,T); rs9456551(T,C); rs193224291(T,C); rs62441936(C,G); rs6927129(A,G); rs77348928(G,A); rs34600300(G,A); rs13198987(C,T); rs41272050(T,G); rs41272044(T,C); rs34620808(C,T); rs6921516(G,A); rs9456552(G,T); rs6913833(T,C); rs41271022(C,G); rs9355296(G,A); rs7770628(C,T); rs7771129(C,G); rs12175867(T,C); rs142219342(G,C); rs6926458(A,G); rs41270998(A,G); rs7752408(G,C); rs13192132(T,C); rs115018991(G,A); rs9355297(C,G); rs6455691(T,A); rs79263878(T,C); rs6455692(G,A); rs6415085(T,G); rs35499210(G,T); rs7769720(C,T); rs6940254(C,G); rs41270988(C,G); rs9365179(C,T); rs184929473(G,A); rs74536224(G,A); rs6902102(G,A); rs149360334(C,T); rs6930342(T,G); rs79327486(A,G); rs78347018(T,C); rs6455693(C,T); rs6932014(A,G); rs35600881(G,A); rs6455694(T,C); rs202077933(C,T); rs41269890(G,A); rs6926896(C,G); rs13202636(T,C); rs75692336(C,A); rs115704782(T,C); rs6455695(T,C); rs6937879(G,A); rs9355813(T,C); rs9355814(C,T); rs76249505(G,A); rs6919497(A,G); rs6923917(A,T); rs9355815(C,G); rs6929299(T,C); rs6455696(G,C); rs7761377(A,G); rs6906446(C,A); rs116187392(C,T); rs62442784(T,C); rs6905422(G,C); rs6933576(T,G); rs78822335(A,G); rs4708876(C,G); rs12526465(T,C); rs9295130(G,A); rs115852011(C,T); rs115600662(T,C); rs7770685(A,T); rs148923997(T,C); rs10945682(G,A); rs10945683(T,C); rs41269878(C,T); rs79653994(C,T); rs7760585(C,G); rs150161088(T,C); rs7759633(G,A); rs1569933(T,A); rs41269874(G,A); rs2983236(G,A); rs41269870(T,C); rs115366121(A,G); rs74865159(T,C); rs3011437(T,G); rs1406889(C,A); rs2144726(A,G); rs1950564(T,C); rs1950563(C,T); rs145774913(G,C); rs2872764(G,T); rs1830522(T,G); rs77186616(T,A); rs143554982(C,T); rs1740428(A,G); rs1321196(C,T); rs1652507(T,C); rs1367211(T,C); rs1367210(C,T); rs1367209(G,A); rs80106498(G,A); rs9365200(T,C); rs9365201(T,C); rs9347437(C,G); rs9347438(T,C); rs41269852(G,C); rs1321195(A,G); rs9346833(C,T); rs183021680(A,T); rs75694417(T,C); rs41269844(G,C); rs2315129(T,A); rs41269142(G,A); rs41269140(C,T); rs1800589(T,C); rs142471331(T,C); rs78634584(G,A) |
| ccdsGene name | CCDS43523.1 |
| cytoBand name | 6q25.3 |
| EntrezGene GeneID | 4018 |
| EntrezGene Description | lipoprotein, Lp(a) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LPA:NM_005577:exon40:c.C6046T:p.R2016C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6636 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P08519 |
| dbNSFP Uniprot ID | APOA_HUMAN |
| dbNSFP KGp1 AF | 0.212454212454 |
| dbNSFP KGp1 Afr AF | 0.25406504065 |
| dbNSFP KGp1 Amr AF | 0.162983425414 |
| dbNSFP KGp1 Asn AF | 0.108391608392 |
| dbNSFP KGp1 Eur AF | 0.287598944591 |
| dbSNP GMAF | 0.2112 |
| ESP Afr MAF | 0.232864 |
| ESP All MAF | 0.261648 |
| ESP Eur/Amr MAF | 0.276395 |
| ExAC AF | 0.246 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Risk factor for coronary heart disease;
[Vascular];
Risk factor for carotid atherosclerosis
LABORATORY ABNORMALITIES:
Elevated plasma levels of Lp(a)
MOLECULAR BASIS:
Caused by mutations in the apolipoprotein Lp(a) gene (LPA, 152200.0001)
OMIM Title
+152200 APOLIPOPROTEIN(a); LPA
LIPOPROTEIN(a), INCLUDED; Lp(a), INCLUDED;;
LIPOPROTEIN TYPES--Lp SYSTEM Lp(a) HYPERLIPOPROTEINEMIA, INCLUDED;;
SINKING PRE-BETA-LIPOPROTEIN, INCLUDED; SPB, INCLUDED;;
LIPOPROTEIN(a) DEFICIENCY, CONGENITAL, INCLUDED;;
Lp(a) DEFICIENCY, CONGENITAL, INCLUDED;;
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED
OMIM Description
Berg and Mohr (1963) discovered a new serum protein system, called Lp
(for lipoprotein), by the intravenous injection of rabbits with human
serum beta-lipoprotein isolated from 1 individual. The resulting
antibody distinguishes 2 distinct types of human beta-lipoprotein. Berg
and Mohr (1963) demonstrated regular dominant inheritance. The Lp(a)
allele has a frequency of 0.19 in Norwegians. The authors concluded that
this system is independent of the Ag system of Blumberg (which
subsequently proved to be a variation in the APOB gene; see 107730).
Berg (1967) suggested that at least 4 lipoprotein systems exist: Ag, Lp,
Ld, and Lt. Schultz and Shreffler (1972) espoused a polygenic
determination of Lp antigen, whereas Berg (1972) defended his monolocus
hypothesis. Dahlen and Berg (1976) found that over a period of time mean
fasting cholesterol and triglyceride concentrations in blood rose in
Lp(a+) persons but not in Lp(a-) persons. Berg et al. (1979) found an
association between phenotype Lp(a+) and coronary heart disease. Hewitt
et al. (1982) confirmed the correlation between the Lp(a) antigen and
the presence of a sinking pre-beta component of low density lipoprotein
fraction of serum cholesterol (Breckenridge and Maguire, 1981). Studying
a large Utah pedigree, Hasstedt et al. (1983) concluded that 'a dominant
major gene with polygenic background' determines the quantitative plasma
Lp(a) level. The Lp(a) glycoprotein is joined to apoB-100 (APOB) by one
or more disulfide bridges. Utermann et al. (1987) studied the
glycoprotein directly by sodium dodecyl sulfate-gel electrophoresis.
Family studies were compatible with the concept that Lp(a) glycoprotein
phenotypes are controlled by a series of autosomal alleles at a single
locus. A highly significant association was found between
electrophoretic phenotype and concentration of Lp(a) lipoprotein. This
suggested that the same gene locus is involved in determining the Lp(a)
glycoprotein phenotypes and the Lp(a) lipoprotein concentrations in
plasma and was the first indication for structural differences
underlying the quantitative genetic Lp(a)-trait. Because in other
respects it resembles LDL, the atherogenicity of Lp(a) is probably due
to the presence of the apolipoprotein(a) component (apoa). Kane and
Havel (1989) discussed Lp(a) hyperlipoproteinemia as a separate
disorder. Also see Utermann (1989).
Namboodiri et al. (1977) concluded that Lp and esterase D (ESD; 133280)
are closely linked; the maximum lod score was 2.32 at a recombination
fraction of 0.0. Ott and Falk (1982), however, reanalyzed the data of
Namboodiri et al. (1977) in connection with a theoretic consideration of
the confounding effects of epistatic association on linkage. Namboodiri
et al. (1977) had noted a strong association between the phenotypes a-
and a+ at the Lp locus and the phenotypes 2-1 and 1-1 at the ESD locus
(no 2-2 persons were found in the pedigree). The reanalysis resulted in
a considerable drop in the lod score for linkage. Greger et al. (1988)
excluded linkage of LPA not only with ESD but also with the
retinoblastoma locus (RB; 180200), which is closely situated on
chromosome 13.
McLean et al. (1987) sequenced a cloned human LPA cDNA and showed
striking similarities to human plasminogen (PLG; 173350). Consistent
with this close similarity in nucleotide sequence and amino acid
sequence is the finding of close linkage of the LPA locus and the PLG
locus on 6q26-q27 in family studies (Weitkamp et al., 1988). The locus
that determines quantitative variation in Lp(a) lipoprotein was linked
to PLG; peak lod score = 12.73. Weitkamp (1988) was suspicious that
apparent recombinants may in fact have represented typing problems
because of the ambiguities in the Lp(a) system. Indeed, in some of the
molecular genetics work determining the assignment of plasminogen, a DNA
probe defining the LPA locus, rather than a plasminogen probe, may in
fact have been used. Frank et al. (1988) showed that the LPA locus is on
chromosome 6 by blot hybridization analysis of DNA from a panel of
mouse-human somatic cell hybrids. In situ hybridization yielded a single
peak of grain density located at 6q26-q27. Apolipoprotein(a) has been
reported only in Old World primates and in one species of hedgehog; it
has not been found in New World primates, rabbits, rats, cattle, mice,
or the marsupial Monodelphis domestica. By a linkage study using
polymorphisms at the LPA and PLG loci, VandeBerg et al. (1991)
demonstrated that the 2 loci are tightly linked in the baboon; the
maximum lod score was 30.2 with no recombinants. This was said to be the
first genetic linkage identified in a nonhuman primate species by family
studies. It would be of interest to determine whether the 2 loci are
also tightly linked in hedgehogs. It is possible that LPA arose
independently on 2 different occasions during mammalian evolution, by
duplication of the PLG locus.
Apolipoprotein(a) is a very large molecule, larger than plasminogen; it
contains duplications of many kringles present in small numbers in
plasminogen. Utermann et al. (1988) demonstrated that the size
heterogeneity of the Lp(a) glycoprotein is genetically controlled. In a
large family with early coronary artery disease and high plasma levels
of Lp(a), Drayna et al. (1988) found tight linkage between LPA size
isoforms and a DNA polymorphism in the plasminogen gene. No linkage was
found with alleles of the apoB DNA polymorphism. See review by Scanu
(1988). In studies of three 2-generation families, Lindahl et al. (1989)
found no recombination in 18 meioses, indicating again very close
linkage of LPA and the plasminogen locus. Berg (1989) demonstrated close
linkage between the LPA locus and the SacI restriction site polymorphism
at the PLG locus. Gavish et al. (1989) showed that the variable number
of kringle 4-like domains encoded by the LPA gene is the main factor
determining the size of the lipoprotein(a) and its plasma concentration.
In a review, Kondo and Berg (1990) pointed out that the Lp(a) antigen
resides in a polypeptide chain that is attached to apolipoprotein B by a
disulfide bridge. They studied a variant 2-kb DNA fragment of the LPA
gene detectable after digestion with the restriction enzyme MspI. It is
related to the 'kringle 4' region of the LPA gene. A proportion of
people appeared to lack (or have an undetectable level of) the 2-kb
fragment and there were quantitative differences between samples from
persons who had the fragment. Presence and amount of the fragment
segregated as a mendelian trait. The variation probably reflects
differences between individuals in the number of 'kringle 4' repeats at
the LPA locus.
Sandholzer et al. (1991) found that the mean level of Lp(a) varied
widely in 7 ethnic groups studied: from a mean of 7.2 mg/dl in Chinese
to a mean of 45.7 in Sudanese. They found, furthermore, that differences
in apo(a) allele frequencies alone did not explain the differences in
Lp(a) levels among populations. Kamboh et al. (1991) demonstrated that
Lp(a) is a highly polymorphic protein. The average heterozygosity at the
LPA structural locus is 94%. Plasma lipoprotein(a) shows wide
quantitative variation among individuals. These variations in
concentration are heritable and inversely related to the number of
kringle 4 repeats in the LPA gene. Boerwinkle et al. (1992) compared
Lp(a) concentrations and LPA genotypes in 48 nuclear Caucasian families.
Genotypes were determined by a pulsed field gel electrophoresis method
that distinguished 19 genotypes at the LPA locus. They showed that the
LPA gene itself accounts for almost all genetic variability in plasma
Lp(a) levels. Among 72 sibs who shared both LPA alleles, the correlation
coefficient for plasma concentration was 0.95, whereas in 52 sibs who
shared no LPA alleles, the correlation coefficient was -0.23. The LPA
gene was estimated to be responsible for 91% of the variance of plasma
concentration. The number of kringle 4 repeats in the LPA gene accounted
for 69% of the variation; yet-to-be defined cis-acting sequences at the
LPA locus accounted for the remaining 22% of interindividual variation.
During the course of the studies, Boerwinkle et al. (1992) observed the
de novo generation of an LPA allele, an event that occurred once in 376
meioses. Marcovina et al. (1993) identified 34 isoforms of
apolipoprotein(a) in a sample of 806 American whites and 701 American
blacks, using a high resolution SDS-agarose gel electrophoretic method
followed by immunoblotting. The frequency of the various isoforms
differed between blacks and whites. Lackner et al. (1993) cloned and
characterized the region of the LPA gene responsible for its
extraordinary size polymorphism; this glycoprotein varies in size over a
range of approximately 500 kD. Lackner et al. (1993) found that the LPA
alleles of different lengths contain varying numbers of a subset of a
tandemly repeated, 5.5-kb, kringle IV encoding sequence. A total of 34
LPA alleles and corresponding glycoproteins could be distinguished using
pulsed field gel electrophoresis and genomic blotting and
immunoblotting. Molecular analysis of a newly generated LPA allele of
different length suggested that the high degree of length polymorphism
is in part due to recombination between sister chromatids.
By a combination of pulsed field gel electrophoresis and genome walking
experiments, Malgaretti et al. (1992) cloned in YAC vectors DNA
fragments comprising the linked LPA and PLG genes. They identified the
5-prime portion and flanking regions of the LPA gene.
Rath and Pauling (1990) hypothesized that Lp(a) is a surrogate for
ascorbate in humans and other species that do not synthesize vitamin C
(240400) and 'marshaled the evidence bearing on this hypothesis.' They
pointed out that the guinea pig, for which vitamin C is essential,
develops atherosclerotic deposits in arteries, as does the rabbit and
other animals, but these occur on an ascorbate-deficient diet without
additional cholesterol. Lp(a) shares with ascorbate the acceleration of
wound healing and other cell-repair mechanisms, the strengthening of the
extracellular matrix (e.g., in blood vessels), and the prevention of
lipid peroxidation. Since apo(a) is associated with low-density
lipoprotein by disulfide bridges, and since in vitro N-acetylcysteine
(NAC) dissociates this complex, Gavish and Breslow (1991) administered
NAC to 2 patients with high Lp(a) levels and found reductions of an
order not hitherto achieved by either drugs or diet. Knapp et al. (1993)
followed up on the observation that Lp(a) levels are approximately twice
as high in black adults and children compared with whites by studying
the levels in 113 white men (average age = 71 years +/- 6) and 83 black
men (average age = 72 years +/- 9). The distribution was skewed in both
whites and blacks. The skewed distribution in elderly black men was in
contrast to the bell-shaped distribution commonly reported for younger
blacks. The data suggested a shift to lower values among elderly as
compared to younger men, with the greatest shift occurring among the
black men. For black men who had survived to the seventh, eighth, and
ninth decades of life, Lp(a) levels approached the lower levels of white
men.
Nowak-Gottl et al. (1997) studied 72 children with arterial or venous
thrombosis and found that 13 had elevated serum Lp(a) levels. Of these,
3 were also heterozygous for the factor V Leiden mutation (612309.0001)
and 1 also had protein C deficiency (176860). The authors concluded that
familial raised Lp(a) levels play an important role in childhood
thrombosis. Debus et al. (1998) examined the possible role of Lp(a) in
the etiology of perinatal porencephalic cysts resulting from presumed
cerebrovascular occlusion. Elevated Lp(a) levels were seen in 5 of 24
children with such cysts. Two of these children were also heterozygous
for the factor V Leiden mutation; in both cases there was a positive
family history of thrombosis. Debus et al. (1998) commented that an
elevated Lp(a) level is an important etiologic factor in perinatal
cerebroarterial occlusion and that other potential interacting factors,
such as infection, placental insufficiency, and fetal cardiac
arrhythmias, should also be considered as causative factors.
Apolipoprotein(a) varies in size over a range of approximately 500 kD
due to interallelic differences in the number of tandemly repeated
kringle 4 (K4)-encoding 5.5-kb sequences in the LPA gene. Only 1 of the
10 different types of K4 repeats in the LPA gene, the so-called type 2
K4 repeats, vary in number between LPA alleles. Mancini et al. (1995)
showed that there is microheterogeneity within the sequence of the type
2 K4 repeat. Digestion with the restriction enzyme DraIII and genomic
blotting revealed that a subset of the type 2 K4-encoding sequences
contain a DraIII site, which Mancini et al. (1995) referred to as K4-D.
The proportion of LPA alleles that had at least one K4-D repeat ranged
from 25% in Caucasians to 50% in Chinese. K4-D repeats were clustered at
the end(s) of the type 2 K4 tandem array and the number in patterns of
the K4-D repeats were in linkage disequilibrium with flanking sequence
polymorphisms; these features were remarkably similar to the
minisatellite variant repeats (MVRs) found in variable number of tandem
repeat sequences (VNTRs). In addition, a DraIII pattern that comprised
9% of the sample was found to be invariably associated with low plasma
levels of Lp(a) in Caucasians.
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
Ichinose (1995) and Ichinose and Kuriyama (1995) demonstrated, by
nucleotide sequence analysis of the LPA gene, the presence of
polymorphisms in its 5-prime flanking region: G/A at position -773, C/T
at position +93, and G/A at position +121, relative to the transcription
start site. Since the nucleotide substitutions can be distinguished by
the presence or absence of restriction sites for TaqI, MaeII, and HhaI
endonucleases, respectively, the LPA alleles among individuals could be
classified by restriction digestion analysis into 4 types, A through D.
To elucidate whether these polymorphisms affect the expression of the
gene, Suzuki et al. (1997) measured plasma Lp(a) concentrations in vivo
by ELISA and examined expression of the gene by an in vitro assay using
its 5-prime flanking region. Homozygotes of type C had significantly
higher Lp(a) levels than those of type D. The relative expression of
type C was also about 3 times higher than that of type D, which was
consistent with the in vivo results. Deletion analysis revealed that the
substitution of C by T at position +93 led to negative regulation in
expression of the gene, while a change of G to A at position +121 led to
positive regulation. These results indicated that the polymorphisms in
the 5-prime flanking region of the LPA gene affect the efficiency of its
expression and, in part, play a role in regulating plasma Lp(a) levels.
(The 4 alleles, designated A, B, C, and D by Suzuki et al. (1997),
showed the following pattern of presence or absence of the restriction
site at the 3 positions (-773, +93, +121): A = +/+/+; B = -/+/+; C =
-/+/-; D = -/-/+.)
Ogorelkova et al. (1999) demonstrated that a G-to-A transition at the +1
donor splice site of the K4 type 8 intron of the LPA gene (152200.0003)
is associated with congenital deficiency of Lp(a) in plasma and occurs
with a high frequency (approximately 6%) in Caucasians but not in
Africans. This mutation alone accounts for a quarter of all 'null' LPA
alleles in Caucasians. RT-PCR analysis based on LPA illegitimate
transcription in lymphoblastoid cells demonstrated that the donor splice
site mutation results in alternative splicing of the K4 type 8 intron
and encodes a truncated form of apo(a). Expression of the alternatively
spliced cDNA analog in cultured HepG2 cells showed that the truncated
apo(a) form is secreted but is unable to form the covalent Lp(a)
complex. Taken together, the data indicated that a failure in complex
formation followed by fast degradation in plasma of the truncated free
apo(a) is one mechanism which underlies the null Lp(a) type associated
with the donor splice site mutation. Patients with congenital Lp(a)
deficiency appeared to be healthy. Ogorelkova et al. (1999) suggested
that Lp(a) may exert its normal function only in certain situations,
e.g., when challenged by environmental factors such as pathogens. In
such situations, low or absent Lp(a) may represent a susceptibility
state, and high Lp(a) may be protective. Hence, association of
congenital Lp(a) deficiency with a specific clinical phenotype may be
difficult to detect and may not or only rarely occur in some ethnic
groups or geographic areas. Such a scenario would explain the low Lp(a)
levels and the presence of the splice site mutation in Caucasians as
opposed to Africans. It appeared that the splice site mutation occurred
after the separation of African and non-African populations.
Ogorelkova et al. (2001) identified 14 single-nucleotide polymorphisms
(SNPs) in apo(a) K4 types 6, 8, 9, and 10; no sequence variants common
to Africans and Caucasians were found. A substitution in K4 type 6 and
another in K4 type 8 were associated with Lp(a) levels significantly
below average in Africans. In contrast, a substitution in K4 type 9,
which occurred with a frequency of 8% in Khoi San Africans, resulted in
a significantly increased Lp(a) concentration. The authors concluded
that several SNPs in the coding sequence of apo(a) may affect Lp(a)
levels.
Caplice et al. (2001) showed that Lp(a) binds and inactivates tissue
factor pathway inhibitor (TFPI; 152350) in vitro. They found that apo(a)
binds to a region spanning the last 37 amino acids of the C terminus of
TFPI. In human atherosclerotic plaque, apo(a) and TFPI immunostaining
coexisted in smooth muscle cell-rich areas of the intima. These data
suggested a novel mechanism whereby Lp(a), through its apo(a) moiety,
may promote thrombosis by binding and inactivating TFPI.
Ariyo et al. (2003) found that among older adults in the United States,
an elevated level of Lp(a) lipoprotein was an independent predictor of
stroke, death from vascular disease, and death from any cause in men but
not in women. The conclusion was based on studies of 3,972 adults 65
years of age or older: 2,375 women and 1,597 men who were free of
vascular disease and were followed for a median of 7.4 years.
Scanu (2003) explained the heterogeneity of Lp(a) lipoprotein particles
as compared with particles of low density lipoprotein (LDL). Small and
large particles of LDL differ mainly in the cholesteryl ester content of
the lipid core (the greater the content of cholesteryl ester, the larger
the particle), which in the case of both large LDL and small LDL is
surrounded by a monolayer of unesterified cholesterol, phospholipids,
and apolipoprotein B100. The small and large LDL particles become small
and large Lp(a) lipoproteins as a result of the linkage of
apolipoprotein(a) to the apolipoprotein B100 ring that surrounds the LDL
particle with a single disulfide bond. Apolipoprotein(a) is made of 10
different types of kringles followed by kringle V and a nonfunctional
protease domain. Apolipoprotein(a) varies in length as a function of the
number of repeats of kringle IV type 2. The length of apolipoprotein(a)
is genetically determined; its variability has an effect on the density
of Lp(a) lipoprotein.
Parson et al. (2004) described a C-to-T transversion at nucleotide 61 in
exon 1 of the kringle IV type 2 domain of the LPA gene, predicted to
result in an arg21-to-ter (R21X) truncated protein (152200.0004). The
allele frequency of this single-nucleotide polymorphism was 0.02. Parson
et al. (2004) stated that this mutation represented the second apparent
apo(a) null allele in humans (the first being that described by
Ogorelkova et al. (1999), 152200.0003).
In an aboriginal African population from Gabon in central Africa
consisting of 31 families with 54 children, Schmidt et al. (2006)
determined that the correlation of plasma lipoprotein(a) levels
associated with LPA alleles resulted in a heritability estimate of
0.801. The authors concluded that LPA is the major quantitative trait
locus for plasma lipoprotein(a) in this population.
Chretien et al. (2006) investigated the basis of the 2-fold higher Lp(a)
levels in African populations compared with non-African populations by
comparing sequence variations in the LPA gene. They studied 534 European
Americans and 249 African Americans. Isoform-adjusted Lp(a) level was
2.23-fold higher among African Americans. Three SNPs were independently
associated with Lp(a) level in both populations. The Lp(a)-increasing
SNP (-21G/A, which increases promoter activity) was more common in
African Americans, whereas the Lp(a)-lowering SNPs (T3888P and
G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European
Americans, but all had a frequency of less than 20% in one or both
populations. Chretien et al. (2006) concluded that multiple
low-prevalence alleles in LPA can account for the large
between-population difference in serum Lp(a) levels between European
Americans and African Americans.
Lopez et al. (2008) measured Lp(a) levels and performed genomewide
linkage analysis in 387 individuals from 21 extended Spanish families
and found the strongest evidence of linkage with Lp(a) levels at
chromosome 6q25.2-q27, at the locus for the structural LPA gene (lod
score, 13.8). The overall heritability of Lp(a) concentration was
estimated at 0.79, indicating that approximately 79% of the phenotypic
variation in the trait is due to the additive effect of genes.
- Association with Coronary Artery Disease
In 3,145 individuals with coronary artery disease (CAD) and 3,352
controls, Clarke et al. (2009) performed a genomewide association study
involving 48,742 SNPs in 2,100 candidate genes and found the strongest
association at the LPA locus on chromosome 6q26-q27, with a corrected p
of less than 0.05 for 27 SNPs, 16 of which were also significantly
associated with Lp(a) level. Clarke et al. (2009) noted that the 2 SNPs
most strongly associated with Lp(a) level, dbSNP rs3798220 and dbSNP
rs10455872, were also the most strongly associated with increased risk
of CAD (odds ratio (OR) of 1.92 and 1.70, respectively). In addition,
the rare alleles of both dbSNP rs3798220 and dbSNP rs10455872 were each
correlated with a smaller Lp(a) isoform and a lower copy number.
Metaanalysis showed increased risk of CAD for 1 LPA variant allele (OR,
1.51) and 2 or more variant alleles (OR, 2.57).
- Association with Aortic Valve Calcification
For discussion of a possible association between variation in the LPA
gene and calcification of the aortic valve, see AOVD1 (109730).
ANIMAL MODEL
Elevated plasma levels of Lp(a) are associated with increased risk for
atherosclerosis and its manifestations--myocardial infarction, stroke
and restenosis. As the plasma concentration of Lp(a) is strongly
influenced by heritable factors and is refractory to most drug and
dietary manipulation, the effects of modulating it are difficult to
mimic experimentally. In addition, the absence of apolipoprotein(a) from
virtually all species other than primates precludes the use of
convenient animal models. However, Lawn et al. (1992) demonstrated that
transgenic mice expressing human apolipoprotein(a) are more susceptible
than control mice to the development of lipid-staining lesions in the
aorta, and that apolipoprotein(a) colocalizes with lipid deposition in
the artery walls. As an extension of these studies, Grainger et al.
(1994) established that the major in vivo action of apolipoprotein(a) is
inhibition of conversion of plasminogen to plasmin, resulting in a
decreased activation of latent transforming growth factor-beta (TGFB;
190180). TGFBs are negative regulators of smooth muscle cell migration
and proliferation, pointing to a possible mechanism for
apolipoprotein(a) induction of atherosclerotic lesions.
Lou et al. (1998) crossed apo(a) transgenic mice with fibrinogen
knockout mice to generate fibrinogen-deficient apo(a) transgenic mice
and control mice. In the vessel wall of apo(a) transgenic mice,
fibrinogen deposition was found to be essentially colocalized with focal
apo(a) deposition and fatty streak-type atherosclerotic lesions.
Fibrinogen deficiency in apo(a) transgenic mice decreased the average
accumulation of apo(a) in vessel walls by 78% and the average lesion
(fatty streak type) development by 81%. Fibrinogen deficiency in
wildtype mice did not significantly reduce lesion development. The
results suggested that fibrinogen provides one of the major sites to
which apo(a) binds to the vessel wall and participates in the generation
of atherosclerosis.
Lipoprotein(a) (Lp(a)) is formed by the disulfide linkage of
apolipoprotein B100 (APOB; 107730) of a low-density lipoprotein particle
to apolipoprotein(a). Previous studies had suggested that one of the
C-terminal cysteine residues of apo-B100 is involved in the disulfide
linkage of apo-B100 to apo(a). To identify the apo-B100 cysteine
residues involved in the formation of Lp(a), McCormick et al. (1995)
constructed a YAC spanning the human APOB gene and used gene-targeting
techniques to change cysteine-4326 to glycine. The mutated YAC DNA was
used to generate transgenic mice expressing the mutant human APOB
(cys4326-to-gly). Unlike the wildtype human APOB, the mutant human APOB
completely lacked the ability to bind to apo(a) and form Lp(a). The
study succeeded in demonstrating that the cysteine residue was involved
in the disulfide linkage and showed that gene targeting in YACs,
followed by the generation of transgenic mice, is a useful approach for
analyzing the structure of large proteins encoded by large genes.
PARK2
| dbSNP name | rs1122470(C,T); rs77283740(C,T); rs143810946(T,C); rs3734464(T,C); rs74701717(T,A); rs71653629(G,A); rs71653628(G,T); rs62637702(T,C); rs9458229(T,C); rs3798963(A,T); rs3798964(A,G); rs3798965(G,A); rs73021248(C,T); rs7739854(C,T); rs117687416(C,T); rs62435870(G,C); rs71567604(C,T); rs62435871(T,C); rs12207487(C,A); rs9456663(T,C); rs73021251(G,A); rs143581691(C,T); rs142319373(G,A); rs75151084(G,A); rs74927971(T,G); rs61046460(G,A); rs13210239(C,T); rs7752498(T,C); rs11754481(G,A); rs150676196(G,A); rs2145573(C,T); rs139827161(G,A); rs142607493(A,G); rs6929657(G,A); rs28826441(C,T); rs9456664(C,T); rs9456665(C,T); rs6942109(C,T); rs60104698(G,A); rs57778962(C,A); rs57804277(G,A); rs7767600(T,C); rs7744494(C,T); rs1475032(A,G); rs73600951(A,G); rs13206689(G,A); rs35280474(C,T); rs6924178(C,T); rs111849614(C,T); rs13207820(G,A); rs7765200(G,A); rs7766508(T,G); rs182655529(C,T); rs193209293(G,A); rs9456666(A,G); rs62435877(G,A); rs62435878(G,C); rs9458238(T,C); rs62435879(T,C); rs6907632(A,G); rs62435880(A,G); rs77322401(G,A); rs192007550(G,A); rs35996169(G,A); rs62435882(G,A); rs9458239(C,T); rs62435883(A,T); rs185250640(C,G); rs146639562(C,T); rs62435884(A,T); rs9347501(T,G); rs9347502(C,T); rs62435885(T,C); rs12215325(A,G); rs147424159(C,T); rs17560782(A,T); rs3890730(T,C); rs9458240(T,C); rs144422525(A,G); rs62435886(A,G); rs189586240(C,G); rs9355894(G,T); rs115310353(T,C); rs1801582(C,G); rs118068201(G,A); rs12191193(T,C); rs7738646(A,G); rs4574609(T,C); rs4640873(T,C); rs62435887(C,T); rs62435888(G,C); rs188754844(T,A); rs62435889(A,G); rs12199584(G,A); rs73021293(A,C); rs62435890(C,A); rs4131770(T,C); rs9365283(G,A); rs62435891(G,T); rs9346851(G,A); rs144829055(C,T); rs11964284(T,C); rs10945747(T,C); rs16892490(T,A); rs3924680(C,T); rs113983650(C,T); rs4371833(T,C); rs146521192(C,T); rs9365284(C,T); rs9365285(C,T); rs73606925(C,T); rs114987419(A,G); rs116645547(T,A); rs66515020(C,T); rs79551042(A,G); rs62435892(C,T); rs73606928(G,A); rs16892492(A,G); rs62435893(A,T); rs144108182(T,C); rs62435926(G,A); rs115658622(A,T); rs9355897(T,C); rs73606930(C,T); rs10945748(A,G); rs117751440(C,T); rs62435928(C,G); rs9347505(G,A); rs6455724(C,T); rs56143991(T,C); rs62435931(T,C); rs4709514(A,G); rs62435932(A,T); rs9347506(A,G); rs10945749(C,G); rs10945750(G,A); rs4708906(T,A); rs141760738(A,G); rs9355347(T,C); rs7757859(G,T); rs10945751(T,C); rs7770643(T,G); rs62435934(C,A); rs62435935(T,C); rs4708909(C,G); rs62435936(G,C); rs62435937(T,A); rs16892509(T,C); rs13202365(T,C); rs6455726(T,C); rs4709517(C,T); rs117528201(T,A); rs7745681(C,G); rs9458244(T,G); rs4454114(C,T); rs4235928(C,T); rs4374805(T,C); rs4624848(A,G); rs35164999(T,C); rs9346852(G,C); rs11960950(G,A); rs6906964(C,A); rs13211741(A,G); rs9355898(C,T); rs9458246(T,C); rs9458247(C,T); rs35924095(C,T); rs117195922(C,T); rs7746813(T,C); rs7760109(G,T); rs6455728(T,G); rs4296877(T,G); rs4263565(A,C); rs4437447(C,T); rs4235929(A,C); rs4709524(G,T); rs4235930(C,T); rs4455643(T,C); rs9347509(A,G); rs2872894(G,C); rs6902700(A,G); rs6926716(G,T); rs145098858(A,G); rs4709525(G,A); rs142512755(T,C); rs4709526(C,T); rs59485988(C,T); rs9347510(C,T); rs9347511(C,T); rs9355900(T,C); rs9347512(T,C); rs12662364(G,A); rs114914735(A,T); rs12661014(A,G); rs114425544(A,T); rs9346853(T,C); rs9355901(C,T); rs9458251(C,A); rs9347513(T,C); rs6909600(G,A); rs62436573(T,G); rs12526387(A,G); rs6909832(G,A); rs11755661(T,C); rs9458252(C,T); rs79840400(C,A); rs6921435(C,T); rs10806745(T,C); rs9458254(C,T); rs9458255(G,A); rs9458256(G,C); rs9458257(C,T); rs78224461(C,T); rs12205669(G,A); rs9458258(T,G); rs7770642(A,G); rs7774827(T,C); rs7771517(A,G); rs11752647(C,A); rs12196262(C,T); rs60857780(C,T); rs6904671(T,C); rs6920968(C,T); rs76461921(A,G); rs12154057(A,C); rs13209308(G,A); rs112820829(T,C); rs7767517(G,A); rs62436575(C,G); rs11970122(G,A); rs13218649(C,T); rs13207204(T,C); rs55778121(C,G); rs17647823(G,T); rs9295148(A,T); rs9295149(T,A); rs62436576(G,A); rs11966738(C,G); rs7745686(C,G); rs9456674(A,G); rs11966929(C,T); rs11969983(T,C); rs73026936(G,A); rs73785922(C,T); rs73785923(A,C); rs75236863(A,C); rs76355624(C,T); rs6941589(T,C); rs60551655(C,T); rs61302486(T,C); rs60472571(T,C); rs11969972(G,A); rs57403788(A,G); rs11968360(T,C); rs6921904(A,G); rs79335614(C,T); rs6927578(T,C); rs76000632(G,A); rs145195098(A,T); rs78240756(G,A); rs79038206(C,T); rs79280529(C,T); rs9458266(T,A); rs76164488(G,T); rs77508409(T,C); rs6935279(G,C); rs6941063(G,C); rs192183684(T,G); rs9346856(T,C); rs77938288(T,C); rs2209247(C,T); rs2209248(C,T); rs16892546(A,G); rs78513922(C,G); rs78436131(A,G); rs1886237(C,A); rs6908094(A,G); rs9458272(T,G); rs2224852(T,C); rs2209249(C,T); rs16892547(A,G); rs114049180(G,A); rs57547591(T,A); rs7774498(G,T); rs718319(A,G); rs6903203(G,A); rs80105610(A,G); rs140823940(G,A); rs137879685(C,G); rs16892554(G,A); rs73589745(C,T); rs9458273(A,G); rs6906519(T,C); rs73589753(T,C); rs76550481(C,T); rs115335942(T,C); rs16892570(G,A); rs73589766(C,T); rs16892573(G,A); rs13209191(G,A); rs61114332(C,T); rs13202614(T,C); rs13213352(G,A); rs6912352(A,G); rs9458277(T,C); rs9458278(T,A); rs6937182(G,T); rs6922432(T,A); rs9456676(C,T); rs9458281(G,A); rs4709530(T,C); rs4709531(T,C); rs9456677(T,C); rs7764467(T,G); rs9364598(T,G); rs9346859(C,T); rs73782907(G,A); rs11961684(G,A); rs7774267(T,C); rs2315314(T,C); rs2315315(T,G); rs16892599(T,G); rs4142070(G,C); rs9458284(T,C); rs9365292(A,T); rs9364599(A,G); rs9355902(G,C); rs9346860(T,C); rs4142069(C,T); rs4142068(G,T); rs4142066(G,T); rs6939489(T,C); rs6455730(G,A); rs9355903(T,A); rs79891336(T,C); rs188074150(C,G); rs61646226(G,A); rs80144397(C,T); rs12175609(C,T); rs9355349(T,C); rs766313(T,C); rs10455886(C,T); rs10455887(T,C); rs9365293(C,G); rs4709532(T,C); rs9346861(T,C); rs74459900(G,A); rs9355905(C,G); rs9347515(A,G); rs12198768(C,T); rs9364600(G,A); rs10455786(T,A); rs10455889(T,G); rs9365294(G,C); rs35234723(C,T); rs9347516(G,C); rs16892626(C,A); rs6936393(C,T); rs555637(C,T); rs493806(T,C); rs186189672(A,T); rs58571912(A,T); rs7742141(C,G); rs523995(A,G); rs77946527(C,A); rs992421(C,T); rs114571407(C,T); rs76859828(T,C); rs142736377(A,G); rs10755582(C,T); rs9458289(C,T); rs372431285(G,T); rs6937817(T,C); rs6909919(G,A); rs372705082(G,C); rs143873342(T,C); rs6914971(G,T); rs74640124(A,G); rs58130083(C,T); rs35115995(C,G); rs12191995(T,C); rs6922154(G,C); rs960430(G,C); rs6928820(C,G); rs114068766(T,C); rs16892642(G,A); rs188081182(C,G); rs539455(T,C); rs11969944(C,T); rs565301(T,C); rs497002(T,C); rs545749(G,A); rs6940073(G,A); rs13208945(T,C); rs577876(A,G); rs150850330(G,A); rs57350839(A,G); rs693282(G,A); rs75823988(G,A); rs73782913(T,A); rs7758341(C,T); rs526207(G,A); rs515801(T,A); rs528061(G,T); rs517656(C,T); rs517658(A,G); rs142087742(G,A); rs505845(A,G); rs1474767(G,C); rs482845(T,A); rs16892658(G,A); rs508517(T,A); rs508605(T,C); rs143899755(G,A); rs73782915(C,T); rs73782916(G,A); rs12190800(C,T); rs12203897(G,A); rs76435528(C,T); rs73782919(G,C); rs116104381(C,A); rs7769352(T,C); rs568893(A,C); rs569645(A,G); rs569646(A,C); rs513141(T,C); rs7769870(T,A); rs7769885(T,C); rs7770358(T,A); rs34702820(C,A); rs7746936(C,T); rs541480(T,G); rs56854318(C,T); rs59880761(A,G); rs6941476(T,C); rs60538195(T,C); rs59598263(A,G); rs4708914(G,A); rs77532263(C,T); rs115683337(G,T); rs73782921(C,G); rs77536713(T,C); rs6927018(T,C); rs62436448(C,T); rs16892673(G,A); rs76203566(A,T); rs12200329(T,A); rs517010(T,G); rs520732(A,G); rs521641(A,G); rs78759043(C,T); rs545310(T,C); rs34268780(A,C); rs17649505(C,T); rs548060(A,G); rs475158(G,C); rs476105(A,C); rs551770(G,A); rs551962(A,G); rs57163100(G,A); rs57074669(C,T); rs480470(T,G); rs17570942(T,C); rs576613(A,G); rs17649761(T,C); rs483366(T,C); rs9458295(G,A); rs509205(T,A); rs509315(G,A); rs571496(C,T); rs145144122(C,T); rs572290(A,G); rs142446701(G,A); rs492267(G,A); rs11965303(C,T); rs12203094(C,T); rs150708396(C,T); rs523179(T,C); rs73782924(C,T); rs526020(A,T); rs11969675(T,C); rs1535054(T,A); rs1535055(G,A); rs505319(C,T); rs56085387(C,T); rs2223768(T,C); rs558209(A,G); rs370135547(C,T); rs510849(T,C); rs11967382(C,T); rs476161(A,C); rs59341317(G,T); rs16892698(G,A); rs503890(T,C); rs505693(T,C); rs490167(G,A); rs12209107(T,G); rs507499(T,C); rs16892700(G,A); rs142879472(G,A); rs518666(A,G); rs6455732(T,A); rs371588744(T,C); rs55979469(A,G); rs146292525(G,A); rs12194826(G,C); rs543888(C,T); rs12190386(A,G); rs2064416(A,C); rs496759(T,C); rs189965846(G,A); rs17650323(C,T); rs146203669(G,A); rs10223880(C,T); rs9458296(A,C); rs186190405(G,A); rs480557(T,G); rs482420(T,C); rs16892727(G,A); rs505555(T,G); rs506428(T,G); rs537738(G,A); rs536667(C,T); rs510968(T,C); rs12189751(A,G); rs6905156(T,C); rs6900584(A,G); rs34703849(G,A); rs12193185(T,C); rs495991(A,G); rs12195005(T,C); rs574165(A,G); rs368282590(G,T); rs11755180(G,C); rs6928997(T,G); rs60049713(A,T); rs7745470(C,G); rs28619035(T,C); rs475221(G,A); rs12527638(G,A); rs12527640(G,A); rs503783(T,C); rs35796302(T,G); rs530128(T,C); rs17651062(T,A); rs568670(T,C); rs12198150(C,A); rs55845596(C,T); rs527960(G,A); rs12198566(A,G); rs9458298(C,T); rs12203959(T,C); rs117848597(C,T); rs115438898(G,A); rs17651312(G,A); rs509495(T,A); rs2315319(T,C); rs9355907(G,A); rs9346865(C,T); rs9458300(G,A); rs6910938(G,A); rs9346866(G,A); rs9346867(G,C); rs7765268(C,A); rs7746827(A,C); rs34946635(A,G); rs2064419(G,T); rs2064420(A,T); rs2315321(A,T); rs9364602(G,A); rs9365299(C,T); rs9346868(T,C); rs9346869(C,G); rs2315322(C,T); rs6455734(A,G); rs6455735(G,A); rs9355908(A,G); rs7747796(C,T); rs7747958(C,A); rs16892792(G,A); rs17573150(T,C); rs147567343(C,T); rs2872895(T,G); rs6921987(C,T); rs6901951(A,G); rs761393(G,T); rs761394(A,T); rs761395(T,C); rs7749872(T,G); rs7750550(T,G); rs376495009(C,T); rs11759523(C,T); rs7770392(C,T); rs2024587(T,C); rs147262114(T,A); rs2024588(T,C); rs7771837(A,T); rs151295851(G,T); rs6900355(A,G); rs6909754(T,C); rs12662290(G,A); rs79103464(C,T); rs9365300(C,T); rs9458305(T,C); rs9456684(G,A); rs12179397(A,G); rs9355351(A,G); rs138594892(C,T); rs2006029(T,C); rs737715(T,C); rs10945756(G,A); rs3765474(C,T); rs3765475(G,C); rs35744731(C,T); rs3765476(C,T); rs3765477(A,G); rs77630686(T,G); rs13206609(A,G); rs13206635(A,G); rs13206753(A,G); rs9295155(A,G); rs9347520(G,A); rs10945757(A,C); rs10945758(C,T); rs7755681(C,T); rs183918398(T,G); rs1009753(A,T); rs2143741(A,G); rs2143742(T,A); rs9295156(C,T); rs9364604(A,G); rs13205523(T,C); rs1883875(C,G); rs1009751(C,T); rs992037(T,C); rs9346871(C,T); rs112746345(C,T); rs13211948(C,A); rs994465(G,A); rs1015156(C,G); rs9456686(G,A); rs910177(T,A); rs111427285(C,T); rs7747994(C,T); rs78581025(G,T); rs9295157(A,C); rs10484814(T,A); rs2315323(A,T); rs2872896(C,T); rs76489461(A,T); rs6927285(G,A); rs74385424(G,C); rs11969861(C,T); rs6940957(C,T); rs9355914(T,C); rs6455736(G,C); rs9456687(G,A); rs742769(T,C); rs742771(G,A); rs75309434(A,G); rs2003713(T,C); rs113587886(T,C); rs9458311(A,G); rs9458312(T,C); rs11961613(T,C); rs9458313(T,A); rs1883874(A,G); rs10440818(T,C); rs12055483(T,C); rs9458314(C,T); rs35507624(A,G); rs11962263(G,A); rs11970014(A,C); rs9458315(G,A); rs742773(G,A); rs180773901(A,C); rs112295114(G,A); rs11963420(T,C); rs974725(C,G); rs76111385(C,G); rs114096297(T,C); rs9365305(G,A); rs9458317(T,C); rs112699784(T,C); rs6924602(C,T); rs10945759(G,T); rs2206950(G,A); rs9458318(T,C); rs9347525(C,T); rs187495516(C,T); rs113392634(T,C); rs111820081(A,G); rs7773136(A,C); rs6455737(C,T); rs12210797(T,C); rs9295158(C,T); rs6455738(A,G); rs6455739(A,G); rs6930403(T,C); rs9355356(A,G); rs9365308(T,C); rs9365309(G,A); rs9458319(C,T); rs13195756(A,G); rs16892831(A,C); rs35477712(G,A); rs115787767(C,T); rs12206113(C,T); rs1884155(C,T); rs6914170(C,T); rs114840498(A,G); rs73782956(C,T); rs116375496(G,A); rs12211755(C,G); rs80035959(G,C); rs12213314(C,T); rs145299059(T,C); rs36088355(G,T); rs17653033(A,T); rs77172450(G,A); rs114265803(C,T); rs115554008(T,A); rs1024189(C,T); rs74757108(C,T); rs115617431(A,C); rs368802756(T,A); rs35265056(T,C); rs138789566(C,T); rs71567617(C,T); rs12525451(A,T); rs12198452(T,C); rs6901169(C,T); rs12191610(C,A); rs12199909(T,G); rs6455740(T,C); rs6455741(C,A); rs6455742(T,C); rs6455743(A,G); rs141088780(C,T); rs114915194(G,A); rs6455744(C,T); rs12527261(T,C); rs74820509(A,C); rs2315546(A,G); rs2315547(T,C); rs2315548(T,C); rs2315549(C,T); rs2315550(T,C); rs6455745(G,A); rs12202700(A,C); rs6455746(G,C); rs115803614(G,C); rs114102275(C,T); rs6455747(A,G); rs1071891(C,T); rs1071892(A,G); rs1071890(G,A); rs117014981(T,C); rs7756491(A,G); rs7775023(C,T); rs116351093(T,A); rs4286750(C,T); rs79298141(A,G); rs10945760(T,C); rs7742460(G,A); rs10945761(T,C); rs6455748(T,C); rs6455749(G,A); rs13190938(T,C); rs13202402(C,T); rs13202411(C,G); rs13201589(G,A); rs13201596(G,A); rs13201737(G,C); rs6916828(C,T); rs6939123(A,G); rs9647609(C,A); rs9647610(A,G); rs9355916(C,G); rs74534538(C,G); rs10945762(C,T); rs112540712(C,T); rs10945763(T,A); rs10945764(A,G); rs10945765(T,G); rs6455750(C,T); rs6455751(G,C); rs6933783(G,T); rs6455752(C,T); rs6919446(T,C); rs6925527(T,C); rs2064523(A,G); rs2064522(G,A); rs74766886(A,G); rs7762383(A,G); rs2076701(A,G); rs2076700(T,A); rs2281404(A,T); rs2281403(C,T); rs17575768(T,C); rs2144211(A,G); rs11756322(A,G); rs7744246(A,G); rs7761957(G,A); rs7763093(C,G); rs7763253(C,T); rs7763400(C,T); rs6931101(G,A); rs6931289(G,A); rs6911845(A,G); rs16892840(A,G); rs6455754(T,C); rs372706841(A,G); rs17576062(C,T); rs58060266(C,G); rs142852374(G,C); rs73597111(G,A); rs115987320(G,C); rs77166092(G,A); rs17576146(T,G); rs4413589(A,G); rs1121036(T,C); rs17654202(A,G); rs4134103(T,C); rs183477891(C,A); rs2207398(G,T); rs1121035(G,T); rs77877945(T,A); rs6935513(T,C); rs12206076(C,T); rs144054408(C,G); rs6908041(G,A); rs6908057(G,A); rs142085076(G,A); rs58875125(G,A); rs57142311(A,G); rs7757239(C,T); rs78050632(C,T); rs6905965(A,T); rs10945766(C,A); rs993253(C,G); rs2207397(G,A); rs993252(C,T); rs993251(G,C); rs7749966(A,C); rs9365310(C,T); rs10945767(C,T); rs9365311(C,T); rs62436833(A,T); rs9365312(C,T); rs12524559(G,A); rs76498940(G,A); rs6912798(C,A); rs115153613(G,A); rs75617339(C,A); rs12525018(G,A); rs60259253(C,G); rs60785278(G,A); rs12528600(C,T); rs9355917(G,T); rs9364606(A,G); rs12530434(A,T); rs12210817(C,T); rs9347530(G,A); rs9365313(G,T); rs9458331(C,T); rs139135572(A,G); rs7771341(C,G); rs78172804(T,C); rs17595725(T,C); rs60161080(G,A); rs10945768(T,C); rs56412929(C,T); rs910417(A,G); rs56016730(C,A); rs16888746(G,A); rs36177664(C,A); rs2024687(T,A); rs139335697(G,A); rs150035718(A,T); rs16888749(C,T); rs73786421(G,T); rs7742566(A,G); rs141003165(C,T); rs192888681(T,C); rs9347531(T,G); rs9355357(T,C); rs10484813(A,G); rs9355921(T,C); rs12197876(A,G); rs9347532(A,G); rs6904356(C,T); rs12205900(G,A); rs4708918(A,G); rs4708919(A,G); rs4708920(T,C); rs4708921(C,T); rs16892910(C,T); rs118180252(C,T); rs79026473(A,C); rs2144210(A,G); rs2180026(T,C); rs9355922(C,T); rs9295159(A,G); rs9689649(A,C); rs9346875(T,C); rs4709537(C,A); rs4709538(C,T); rs4709539(T,C); rs4709540(A,G); rs4709541(G,A); rs4709542(C,A); rs6923410(A,G); rs9355924(G,A); rs6455759(C,T); rs9295160(C,G); rs12214138(T,C); rs7766368(A,G); rs77760580(A,G); rs147092416(G,A); rs190010389(C,T); rs6455760(G,A); rs2013459(T,C); rs182084608(C,G); rs73031058(G,A); rs116901771(A,G); rs9346876(C,T); rs9346877(A,T); rs4709545(A,G); rs73031062(G,T); rs73031065(T,C); rs9365319(T,C); rs9364608(G,A); rs10945769(G,T); rs969761(C,G); rs969760(A,G); rs969759(T,A); rs67965942(T,C); rs9456701(T,C); rs56065723(T,A); rs4708922(C,A); rs9355925(T,C); rs9364609(C,T); rs67956908(C,T); rs116373328(C,T); rs114603928(A,G); rs1033575(T,C); rs7770757(C,T); rs17596816(G,T); rs35115923(A,G); rs4292503(G,A); rs13220282(C,G); rs10484812(A,G); rs35626845(T,C); rs35273090(C,A); rs13208987(T,A); rs13208989(T,C); rs13220690(C,T); rs13209225(T,C); rs6942285(C,T); rs6921226(A,G); rs13206130(A,C); rs13209587(A,G); rs4709546(A,G); rs7742310(G,A); rs6455761(T,C); rs3019423(G,A); rs3019422(G,A); rs7772203(T,C); rs7748610(C,T); rs11755155(T,G); rs4708923(C,T); rs57921265(G,A); rs6923047(C,T); rs7773436(C,T); rs6455762(T,G); rs7739689(G,A); rs60135428(T,G); rs6935243(T,C); rs2315551(T,C); rs6935429(T,C); rs6907603(G,A); rs6936211(T,C); rs6931881(A,T); rs11962671(C,A); rs11962721(C,T); rs35852327(A,G); rs73783352(C,T); rs9458342(T,C); rs77332950(C,T); rs6921599(C,A); rs78895012(C,T); rs6925313(G,A); rs1004826(T,G); rs6911376(T,C); rs73783357(C,T); rs6455763(T,A); rs73013498(G,A); rs6455764(A,G); rs76711297(C,T); rs113315227(G,A); rs79001190(A,G); rs73783360(T,C); rs10945770(A,G); rs11966195(C,T); rs2982906(A,G); rs16892961(A,G); rs73013501(G,T); rs1884156(C,A); rs111785159(T,A); rs1018462(A,G); rs73783362(C,A); rs6935137(T,C); rs6935325(T,C); rs6907739(G,A); rs6909190(C,T); rs12529600(A,G); rs9458343(C,T); rs9458345(C,T); rs9458346(A,G); rs6455765(G,A); rs6930783(G,C); rs74910833(T,C); rs10455892(G,A); rs12529287(T,C); rs146874499(A,G); rs7769089(A,T); rs6912086(C,T); rs61167500(C,T); rs6934779(A,G); rs142710451(G,A); rs6455767(T,C); rs77659883(G,C); rs16892965(T,C); rs140149432(C,T); rs9458348(T,C); rs73783367(C,T); rs6917048(A,G); rs148791635(C,T); rs6908944(G,A); rs111373936(G,T); rs985061(T,G); rs75381489(C,T); rs56909889(T,C); rs137929157(C,T); rs34604493(C,T); rs79888830(C,A); rs76014858(G,C); rs76325977(G,T); rs17597474(G,A); rs76715964(C,T); rs2982904(G,A); rs11759503(C,G); rs7770712(C,T); rs7770726(C,T); rs143342694(C,G); rs4708924(G,A); rs4708925(G,A); rs4708926(G,A); rs4708927(T,C); rs4708928(A,G); rs4708929(A,C); rs80175408(G,A); rs2982903(G,A); rs6941719(C,A); rs6940636(G,A); rs6920879(A,G); rs12526947(G,A); rs2180025(A,G); rs2982902(T,C); rs4709547(C,A); rs4709548(G,A); rs964863(T,C); rs79733510(T,C); rs78118665(C,A); rs9355358(A,G); rs2180024(C,T); rs73783378(T,C); rs16892983(T,C); rs144055813(C,G); rs3019451(A,T); rs367693883(C,T); rs111719343(C,T); rs78093581(G,A); rs79152937(C,T); rs10806750(C,T); rs78569680(G,A); rs77255775(C,T); rs926849(C,T); rs1884158(C,T); rs74703779(C,T); rs111694408(C,T); rs76858028(A,G); rs113812050(T,C); rs737631(G,A); rs77561195(G,A); rs761620(C,T); rs9364611(C,T); rs74947212(T,C); rs76123287(A,G); rs74746052(T,G); rs80174955(T,C); rs79134877(T,G); rs3019450(G,A); rs3019449(A,C); rs375859155(C,T); rs16892988(A,G); rs3019448(C,T); rs16892989(C,G); rs77574885(C,T); rs78195232(A,G); rs371448324(C,T); rs59407549(G,T); rs112074533(G,A); rs113266789(G,A); rs3019447(C,A); rs113569140(A,G); rs16892990(A,G); rs74658339(G,A); rs374610010(A,C); rs3019446(C,T); rs12198163(C,T); rs9365321(A,T); rs763753(G,A); rs3019444(A,G); rs113567716(C,T); rs3019443(T,C); rs1012750(A,C); rs7750085(A,T); rs16893004(T,C); rs16893009(T,C); rs1569836(C,T); rs9355359(C,T); rs9346878(A,T); rs3019442(G,C); rs78384804(A,C); rs11751111(G,T); rs111329397(C,A); rs113585246(G,A); rs12190299(G,T); rs73015248(T,C); rs112904254(C,A); rs4709550(T,C); rs7760443(C,T); rs113378014(C,T); rs111234224(A,C); rs9458354(G,A); rs56298608(C,T); rs149155818(G,A); rs113910201(A,C); rs6922016(A,G); rs112904546(C,G); rs7739359(C,T); rs79661713(G,C); rs9355928(G,A); rs9295161(C,T); rs79323720(C,T); rs77700697(G,C); rs9295162(C,T); rs4339430(C,A); rs9355929(G,C); rs6906858(C,T); rs6907382(C,T); rs113252552(G,A); rs111283338(G,C); rs113343854(G,A); rs111652814(A,G); rs7454759(T,C); rs6941334(A,G); rs6903093(T,A); rs190119806(C,T); rs6908289(T,C); rs10806751(G,A); rs149629020(G,T); rs28374661(G,A); rs6455769(T,C); rs4618496(G,C); rs5019036(T,C); rs112213731(C,G); rs111508406(T,C); rs4288182(G,A); rs9458356(T,C); rs4383787(A,C); rs9295163(G,A); rs113745422(C,A); rs4709552(T,C); rs4709553(G,A); rs9458358(T,C); rs9458359(C,T); rs9458360(T,G); rs113622686(T,C); rs9355931(A,C); rs111504246(T,C); rs76115061(C,A); rs4235931(A,G); rs4634431(G,T); rs147445956(C,T); rs4537112(G,A); rs6455770(A,T); rs145242469(C,T); rs6455771(A,G); rs142606264(A,T); rs112837988(G,A); rs55840634(T,C); rs60034523(C,T); rs113257874(C,T); rs61030762(A,G); rs150334954(G,A); rs9295164(C,T); rs9365323(C,T); rs6455772(C,T); rs149197015(A,G); rs113645179(C,T); rs7750784(T,C); rs111962317(C,T); rs9346879(C,T); rs7774759(C,T); rs9365324(G,T); rs9347538(T,C); rs9347539(T,C); rs9355932(G,A); rs6455773(A,G); rs7741770(G,A); rs139291187(C,T); rs4512198(C,A); rs4299802(T,G); rs4432964(C,A); rs9355933(A,T); rs9347540(T,C); rs114012692(C,T); rs4708930(T,C); rs4708931(C,A); rs3019440(C,T); rs3016567(C,A); rs4519992(C,T); rs3016566(G,A); rs3016565(G,A); rs7759380(C,T); rs147793635(C,T); rs3016563(C,A); rs3016562(G,A); rs9458363(G,T); rs141778833(A,G); rs9458364(A,G); rs6923728(T,C); rs138754393(C,T); rs9456708(A,G); rs4084131(A,G); rs201054950(A,G); rs183932569(A,G); rs3019439(C,T); rs191574086(A,T); rs9458366(C,T); rs10945776(G,A); rs9458368(G,T); rs12208429(T,C); rs12208431(T,G); rs12207168(A,G); rs12208587(T,C); rs12200225(C,A); rs12208634(T,G); rs7754162(A,G); rs7754325(A,G); rs60151691(A,G); rs11758231(T,C); rs73601031(G,A); rs10945777(T,C); rs10945778(A,C); rs3016559(A,G); rs1954796(G,C); rs60225405(A,G); rs61667398(C,G); rs61211291(A,T); rs7745115(G,C); rs11968578(G,T); rs146347467(T,C); rs141246153(C,T); rs148944280(C,T); rs4308533(G,A); rs138458975(A,T); rs75723313(C,T); rs3016558(A,C); rs111241031(T,C); rs3019437(C,T); rs3019436(C,A); rs9456711(T,C); rs9458372(G,A); rs117570383(T,C); rs3019435(G,T); rs3019434(A,G); rs3019433(A,G); rs3019432(A,T); rs3019431(G,T); rs3016557(T,C); rs3019430(A,C); rs112442100(C,T); rs3016556(T,C); rs34972597(G,A); rs2186809(G,A); rs3019429(A,C); rs3019428(A,G); rs3016554(C,G); rs3016552(G,A); rs3019426(A,G); rs183680944(G,A); rs3019425(G,A); rs74486181(T,C); rs3016551(A,G); rs3019424(C,A); rs3016548(C,T); rs3016547(G,C); rs3016545(T,G); rs3016543(C,G); rs3016541(C,T); rs3019441(A,G); rs7739802(C,T); rs1122327(T,C); rs11751911(C,T); rs3016540(G,A); rs3016539(C,T); rs3016538(G,A); rs3019427(C,G); rs1001092(C,T); rs1001091(G,A); rs1001090(G,A); rs78693906(C,T); rs6917867(G,A); rs79427193(G,T); rs3016537(G,A); rs7755434(G,A); rs60117510(G,C); rs3016536(C,T); rs9458385(C,A); rs3016535(G,A); rs3019438(T,C); rs3016534(C,T); rs7766680(C,G); rs6455774(G,C); rs6926426(T,C); rs2000594(T,C); rs9346881(C,T); rs1016085(T,C); rs2186805(G,C); rs74732312(T,C); rs6912903(T,C); rs9458392(T,C); rs9346883(A,T); rs6455776(G,A); rs9355360(T,C); rs2022993(G,A); rs2022992(G,A); rs9364613(T,C); rs9355934(C,T); rs6904662(C,T); rs6931587(T,A); rs4571545(T,C); rs6937010(T,C); rs6908991(G,A); rs2022991(C,T); rs4286747(A,C); rs7749204(C,T); rs6455777(G,T); rs6455779(T,C); rs7758666(C,A); rs12210267(C,T); rs4280941(G,A); rs6907465(A,T); rs4307152(A,T); rs7764896(C,T); rs12665009(C,T); rs73785431(C,G); rs6914515(A,T); rs9347543(A,G); rs59026066(A,G); rs62436130(T,C); rs6909357(C,T); rs6909515(C,G); rs10945780(G,A); rs12665471(A,G); rs147745377(G,A); rs10155686(G,A); rs6913813(G,A); rs6915318(C,T); rs7738279(T,C); rs9347544(G,A); rs9458393(G,T); rs73785435(G,A); rs55892588(G,A); rs60572908(T,A); rs9458397(G,A); rs73601102(A,G); rs6939636(C,T); rs6939637(C,G); rs6940374(C,T); rs181732732(T,A); rs74636094(C,T); rs9346884(G,C); rs11966665(G,A); rs58551010(G,A); rs145868512(T,C); rs6919629(G,C); rs35028120(T,G); rs116428513(C,T); rs6922518(A,G); rs2022990(C,T); rs9355936(G,A); rs10945781(A,C); rs9355937(C,G); rs35545044(C,T); rs62436137(G,A); rs62436138(C,T); rs12111115(G,A); rs62436139(G,A); rs12664148(G,C); rs7755755(C,T); rs13216183(G,A); rs10945782(G,A); rs3798218(A,C); rs141142304(T,A); rs6926642(T,C); rs6922039(A,G); rs6900026(C,T); rs9365328(C,A); rs9365329(T,G); rs7743041(G,T); rs9365330(T,A); rs62436140(C,A); rs74318177(C,T); rs10945783(G,A); rs12527789(A,G); rs12528179(T,C); rs62436141(G,A); rs12664264(T,C); rs12663993(A,T); rs12665316(G,A); rs148009582(A,G); rs4523065(G,A); rs6455781(A,C); rs1893098(C,T); rs1893097(G,A); rs1893096(T,C); rs1893095(T,C); rs28396991(A,G); rs6927082(A,G); rs6905082(C,G); rs35378660(C,A); rs6932149(A,G); rs35261474(C,T); rs34092912(C,T); rs9364615(T,C); rs9355361(G,A); rs9355362(G,A); rs9364616(A,G); rs59178444(T,G); rs2186804(A,G); rs2155487(G,T); rs7738577(T,C); rs7752114(G,A); rs9347545(C,A); rs7773102(A,T); rs57321208(C,T); rs148137838(G,A); rs4279411(A,G); rs4529278(T,C); rs11759902(A,G); rs9355938(A,C); rs9355939(A,C); rs11752805(G,A); rs60591937(C,A); rs13205685(G,A); rs74463475(A,G); rs66535930(C,T); rs9347547(G,A); rs75783146(A,G); rs78109640(C,T); rs13206632(G,A); rs57979725(A,T); rs78724176(G,A); rs7750002(T,G); rs12524695(T,C); rs7763475(G,A); rs7746201(A,G); rs7750426(T,G); rs7764729(C,T); rs7746351(A,T); rs2186803(A,C); rs2186802(G,C); rs2155486(T,A); rs2155485(A,G); rs75060091(T,A); rs2155484(A,G); rs2155483(C,T); rs9365331(G,T); rs6919453(T,A); rs6906994(G,A); rs6935164(T,C); rs9355942(G,C); rs62438260(C,A); rs6935718(T,C); rs35029799(A,G); rs9295172(G,A); rs9689943(T,C); rs9347550(T,C); rs77643823(C,G); rs9295173(C,G); rs2022989(A,T); rs55794706(A,G); rs59914664(A,T); rs6919134(G,A); rs78317518(T,G); rs73603137(T,G); rs6920809(C,T); rs7743144(T,C); rs7756795(G,A); rs7739287(A,G); rs143477728(A,T); rs7739430(A,G); rs7743756(T,C); rs146679910(T,C); rs7743757(A,G); rs56767358(A,C); rs9355364(C,T); rs57003786(G,A); rs11969031(C,A); rs7745104(A,G); rs2155482(A,G); rs2155481(C,T); rs187190958(T,A); rs192121180(A,G); rs76764436(G,A); rs62438261(G,T); rs58186444(T,A); rs9365332(G,A); rs10945785(G,T); rs10945786(A,T); rs55797505(A,T); rs2000593(G,A); rs1893094(G,T); rs2000592(T,G); rs4265013(A,T); rs2155480(C,G); rs73785450(T,C); rs9295174(C,T); rs55767138(C,T); rs9365333(T,C); rs6937081(C,T); rs9355365(T,G); rs6936525(G,A); rs73603168(T,C); rs73603169(C,T); rs73603171(A,G); rs34139189(A,G); rs12333051(G,A); rs9355944(C,T); rs9458401(T,C); rs4467753(C,A); rs9458402(T,C); rs9458403(T,C); rs9458404(A,G); rs9458405(A,C); rs11966164(T,C); rs9347551(C,T); rs11966256(T,C); rs11966260(T,C); rs6909000(T,C); rs9347552(C,T); rs7753190(A,G); rs9456721(A,C); rs34050874(T,C); rs57236720(G,C); rs9365334(C,G); rs768150(C,T); rs76388920(T,C); rs9355945(A,G); rs9355366(C,G); rs34486110(C,T); rs59080739(C,G); rs138418031(T,C); rs9364619(G,A); rs9346885(A,C); rs12111075(A,G); rs12110765(C,T); rs187750029(G,C); rs73603193(T,G); rs117669566(A,T); rs148720668(G,T); rs9347553(C,T); rs73785455(C,T); rs62438276(G,A); rs7775448(C,T); rs4552706(C,G); rs4464764(G,A); rs58207999(C,T); rs5023205(G,A); rs185199629(C,G); rs9346886(A,G); rs9346887(A,C); rs73020576(G,A); rs73020577(G,A); rs4596453(C,T); rs73020580(G,A); rs9364621(C,T); rs9355947(G,A); rs9365337(T,A); rs9355948(G,C); rs7449540(T,A); rs12665599(A,T); rs9365338(C,A); rs4546460(C,T); rs78031131(C,G); rs9346888(C,T); rs76350372(C,A); rs60428151(A,C); rs9355949(G,A); rs9355950(A,G); rs55744616(G,A); rs9355951(A,G); rs9355952(C,T); rs9355368(T,C); rs12193920(A,G); rs73785459(G,A); rs9365339(G,A); rs9346889(G,A); rs7756242(G,C); rs9346890(A,T); rs188124634(A,G); rs9347554(C,T); rs6905968(T,A); rs75528155(T,G); rs80053206(A,T); rs73604814(G,C); rs9347555(C,T); rs12207186(A,T); rs9365340(T,C); rs56853464(T,C); rs12208988(T,C); rs73785463(A,G); rs9364622(T,C); rs149289555(G,A); rs73785464(G,A); rs9355954(G,A); rs9458413(A,G); rs6455782(G,A); rs9355955(G,A); rs9365341(C,G); rs67890034(A,T); rs9365344(A,G); rs73022579(A,G); rs9458414(A,G); rs80229830(C,T); rs13437405(C,T); rs112105452(C,T); rs114100932(C,T); rs9355370(C,T); rs9355958(C,T); rs73022590(G,T); rs9365346(A,G); rs9355960(C,T); rs75861900(G,A); rs73022592(G,C); rs77480504(T,A); rs9355373(C,G); rs6455783(T,C); rs9347559(G,A); rs9458415(C,A); rs59619314(T,C); rs73022593(G,C); rs12214649(A,G); rs9365347(C,T); rs59277805(G,A); rs9355962(T,C); rs6455784(T,C); rs6455785(G,C); rs73024503(C,T); rs4709556(C,T); rs6455786(T,A); rs12211295(C,A); rs76988288(A,C); rs118116993(T,A); rs10945788(C,T); rs11752865(A,G); rs9347562(T,C); rs34892597(T,A); rs6941928(G,A); rs6922334(A,G); rs9365349(G,A); rs6899750(G,A); rs6899760(G,A); rs7767909(T,C); rs875785(C,A); rs4333390(A,C); rs9347563(C,G); rs9458417(C,A); rs186987764(G,A); rs2004619(C,T); rs11756721(G,C); rs147842654(A,C); rs9355374(C,T); rs9364626(T,A); rs73024528(A,G); rs73024530(T,C); rs9355965(A,G); rs9355966(A,C); rs12111273(G,A); rs10945789(T,C); rs9355967(G,T); rs9364627(T,C); rs9364628(T,C); rs9458418(C,T); rs73024539(A,G); rs116485097(T,C); rs9365351(T,A); rs75666827(C,T); rs9365352(C,T); rs73604855(A,T); rs6920479(A,G); rs6920803(A,C); rs150266870(T,C); rs138729655(C,T); rs12211392(T,C); rs140022955(C,T); rs2155490(T,G); rs73024546(G,A); rs9355968(G,T); rs4145609(C,A); rs75567417(T,C); rs9365353(G,T); rs9347566(C,A); rs9458419(C,T); rs74940029(G,A); rs12110810(C,A); rs9458420(G,C); rs12526904(C,T); rs79750448(T,G); rs73024553(T,A); rs9458421(A,C); rs111292552(A,G); rs7775183(T,C); rs4709557(A,T); rs9347567(G,A); rs4709558(A,G); rs9355375(C,T); rs4709559(C,G); rs1893103(G,C); rs13194166(T,C); rs74852505(G,A); rs28678944(A,G); rs9355969(A,G); rs28608044(G,T); rs78419504(G,A); rs61089869(T,C); rs60967831(G,A); rs60254676(G,A); rs6917764(T,C); rs73024565(A,T); rs7744171(G,A); rs9347569(A,C); rs7774091(T,C); rs62435965(T,C); rs113459850(C,T); rs115017968(T,C); rs9458422(T,C); rs7746164(T,C); rs9355376(G,C); rs7759885(G,T); rs6909226(T,G); rs116050692(A,G); rs78548992(G,A); rs9458423(T,C); rs149545528(G,C); rs7759273(A,C); rs1955058(G,A); rs116545030(A,G); rs77947786(G,A); rs1954797(A,C); rs1790025(T,C); rs1790024(T,C); rs5011188(G,T); rs139332327(C,T); rs5011907(G,A); rs1790023(T,G); rs9347572(A,G); rs1790022(C,T); rs1790021(A,G); rs1790020(C,T); rs115510858(C,G); rs6910144(G,A); rs1613942(A,G); rs1790019(A,C); rs145190824(T,C); rs9458424(T,C); rs1790018(T,C); rs1790017(G,A); rs9346891(G,A); rs9346892(C,T); rs1784604(G,A); rs1784602(G,A); rs6934432(G,A); rs1790016(T,C); rs1784601(A,G); rs28392951(G,A); rs9456726(C,G); rs1790015(A,C); rs6902304(G,T); rs1784600(G,A); rs11965957(A,C); rs1784599(G,C); rs1784598(T,C); rs1790014(C,T); rs1790013(C,T); rs1790012(G,C); rs1790011(G,T); rs1784597(A,G); rs1784596(G,A); rs1790009(T,C); rs149225654(G,A); rs9458425(C,T); rs1624390(T,C); rs1790008(C,T); rs1619358(C,T); rs1790007(C,T); rs1790006(C,T); rs1784595(A,G); rs78106982(C,T); rs78768123(A,G); rs113563478(A,C); rs62435966(C,T); rs1790005(C,G); rs141490775(A,G); rs1790004(C,T); rs60975422(G,A); rs114728126(C,T); rs1784594(A,G); rs56934321(C,G); rs1626020(G,A); rs76014090(T,C); rs1790003(G,T); rs1893101(G,C); rs1790002(G,T); rs11961293(T,C); rs77958649(T,C); rs1784593(A,T); rs61413123(G,T); rs145525124(G,C); rs113912899(T,C); rs1784592(T,A); rs1790001(C,A); rs147987265(A,G); rs3018089(C,T); rs56402349(T,C); rs3016568(G,A); rs9456727(G,C); rs1790000(C,T); rs7762314(T,C); rs1784591(C,G); rs7455008(G,A); rs1789999(A,G); rs1789998(C,T); rs1784590(C,A); rs1784589(A,G); rs140627147(A,T); rs1784588(T,A); rs3016555(T,C); rs113574552(G,A); rs1789997(T,C); rs1789996(T,C); rs75209168(T,G); rs75453767(G,T); rs11964796(G,A); rs3016544(T,C); rs3016542(T,C); rs55674794(T,A); rs137853054(G,A); rs1784586(A,G); rs75431673(C,T); rs77036739(C,T); rs113906318(T,A); rs112532272(C,T); rs79987488(C,T); rs1789995(C,T); rs1789994(C,T); rs7752386(G,A); rs1784585(C,G); rs79629595(T,C); rs77487162(G,T); rs1789993(T,C); rs74546717(A,T); rs75023344(C,A); rs1621456(C,T); rs1619122(G,T); rs1618170(C,T); rs1616604(A,G); rs1615717(C,T); rs1784582(A,G); rs1614672(G,A); rs1784581(A,C); rs139573264(C,T); rs1784608(G,A); rs1789992(A,G); rs79704354(A,G); rs79894051(C,T); rs56362106(C,G); rs13194019(T,C); rs9456728(A,T); rs78872432(G,T); rs1784607(T,C); rs1784606(A,T); rs80057069(C,A); rs79629513(C,T); rs1623209(C,T); rs55672112(A,G); rs56000213(T,C); rs1789990(G,T); rs80122418(C,G); rs2096814(T,G); rs1789989(T,C); rs7745683(G,A); rs1789988(C,T); rs78351136(T,C); rs66475311(T,C); rs1789987(T,C); rs1789986(C,T); rs1784583(C,T); rs67219025(C,T); rs6455787(G,A); rs9347575(T,C); rs9885762(G,A); rs7451121(A,G); rs4709561(G,A); rs4708933(T,C); rs7738080(A,G); rs6455788(T,A); rs7742640(T,C); rs55872086(G,A); rs111289864(A,C); rs74355905(C,G); rs9365355(A,G); rs11964513(C,T); rs9365356(A,G); rs9365357(A,G); rs55913773(C,T); rs80126182(G,A); rs10945791(T,C); rs149329817(A,G); rs9364629(T,G); rs9346893(C,G); rs75201074(G,A); rs6455789(C,T); rs6415086(C,T); rs56291666(G,T); rs6455790(A,G); rs6455791(G,A); rs7765446(A,G); rs7773818(T,C); rs9295178(T,A); rs73785306(T,G); rs77956607(G,T); rs9295179(G,A); rs9295180(T,C); rs9355971(A,G); rs9355378(T,C); rs9355379(C,T); rs7453474(C,T); rs7764877(G,A); rs4131681(T,G); rs73028496(A,G); rs7752870(T,C); rs7741742(G,T); rs9355972(G,A); rs73785310(C,A); rs7767219(T,C); rs10945792(C,T); rs9458427(G,C); rs9365359(C,A); rs75564974(C,T); rs9458428(C,T); rs55711245(G,A); rs7753425(G,A); rs6455793(A,G); rs7452475(G,C); rs9458430(T,G); rs77562214(C,G); rs9347576(T,C); rs75731632(T,C); rs7765624(C,A); rs7755404(T,C); rs58957516(C,A); rs7768986(G,C); rs56034645(T,C); rs80224321(G,C); rs9347577(A,G); rs75426044(C,T); rs143255324(G,A); rs2156747(G,C); rs2156746(C,T); rs9355973(C,T); rs113717855(T,A); rs80001184(G,A); rs9346894(T,C); rs9365360(C,T); rs77644023(T,C); rs7741581(C,T); rs79843024(G,T); rs7770651(T,A); rs7746052(G,A); rs7746243(G,C); rs79939145(G,A); rs13201582(C,T); rs2156745(C,A); rs1006650(A,G); rs55708256(C,T); rs79132184(A,G); rs7758559(C,A); rs73030429(A,G); rs111953284(G,C); rs6455794(A,G); rs111597433(G,A); rs6455795(C,T); rs73030431(G,A); rs73785320(A,C); rs73030432(G,A); rs6415087(T,C); rs6415088(T,C); rs1893896(C,T); rs7754703(T,C); rs1893895(C,T); rs9347579(A,G); rs1893894(G,A); rs4709563(G,C); rs9456731(T,C); rs73785322(G,A); rs6918462(G,A); rs2851399(A,C); rs2097130(T,C); rs2105723(A,G); rs2097129(G,C); rs10223525(C,T); rs150202076(C,T); rs2849571(A,G); rs9355976(G,C); rs2849570(G,A); rs2849569(G,A); rs2851395(A,C); rs2849568(G,C); rs1954917(G,A); rs12110423(G,A); rs78348414(G,T); rs7753907(G,T); rs7755917(C,T); rs2849567(A,C); rs1893545(G,T); rs67284712(C,T); rs1893544(G,C); rs884193(A,G); rs2849565(G,A); rs116156164(A,G); rs10214526(T,C); rs80264586(G,A); rs1105056(C,T); rs9458435(T,C); rs1893893(G,A); rs9458436(T,C); rs1954915(A,G); rs2187200(T,G); rs375643357(C,A); rs68137025(G,C); rs145783272(G,A); rs10945793(G,T); rs9347580(T,C); rs67460610(G,A); rs58812843(G,A); rs2851402(A,G); rs9456732(G,A); rs7738197(C,T); rs2849564(C,T); rs2851401(C,T); rs192686104(T,A); rs9458437(C,T); rs374094970(A,G); rs6911067(C,T); rs884995(A,G); rs112041845(T,C); rs6916361(G,A); rs79004823(A,G); rs9458438(G,A); rs6918272(T,C); rs111733178(A,C); rs111441681(T,C); rs2849563(C,G); rs79176071(G,T); rs67549943(C,G); rs9364636(G,A); rs9458439(C,T); rs67526650(C,T); rs9458440(C,T); rs7766377(A,G); rs6908660(G,T); rs7750668(G,T); rs7771997(A,T); rs67461649(A,T); rs9458441(C,T); rs11755670(A,T); rs9365363(T,C); rs151233408(T,C); rs12211530(G,C); rs10755584(C,T); rs10806753(T,C); rs115234534(T,C); rs113446424(A,G); rs111499392(G,T); rs113749535(T,C); rs7769166(C,T); rs146065098(C,T); rs2023048(C,T); rs2023047(A,G); rs2023046(T,C); rs114118238(C,T); rs79055533(G,A); rs2187198(C,T); rs2187197(A,G); rs28580413(C,T); rs4599606(G,A); rs28715907(C,T); rs4576222(T,C); rs4348296(C,T); rs12527027(A,G); rs1893543(C,T); rs59003394(G,C); rs79152317(C,T); rs7764792(G,A); rs9456734(A,G); rs112448533(A,G); rs9456735(T,G); rs41268561(G,A); rs9365364(A,C); rs2023045(C,T); rs9456736(G,A); rs115638063(G,A); rs13217335(G,A); rs13191078(C,A); rs114302939(C,T); rs78129045(C,T); rs114392075(T,G); rs9458442(G,A); rs143831411(A,G); rs9458443(A,C); rs9295181(C,T); rs4708934(T,C); rs57290174(A,G); rs4582353(A,T); rs9295182(G,A); rs9458444(G,A); rs59721338(C,T); rs9456738(C,A); rs1954913(A,C); rs73030499(A,G); rs10455788(G,C); rs9458445(T,C); rs7740268(A,G); rs58526316(T,C); rs7744761(T,C); rs7744806(T,G); rs1954937(C,T); rs12526005(G,A); rs10945795(C,T); rs2023066(A,C); rs2023065(A,T); rs2023064(G,A); rs78635630(T,C); rs2187209(G,A); rs4235932(A,G); rs4709565(G,T); rs76670990(T,A); rs4709566(A,G); rs4365905(G,A); rs4485989(T,C); rs2187208(G,A); rs2187207(A,G); rs2156267(C,T); rs78566323(G,T); rs6908962(G,A); rs7767694(A,C); rs73785339(G,A); rs2023063(T,C); rs2023062(G,A); rs2023061(A,G); rs2023060(C,T); rs9458447(T,C); rs6900778(T,C); rs6915796(G,A); rs57734107(G,A); rs6455796(C,G); rs114684792(C,T); rs7754120(T,C); rs73032222(A,G); rs9458448(T,C); rs79050994(G,C); rs77015433(G,A); rs76470654(C,T); rs9458449(T,C); rs114492897(A,G); rs2187206(T,C); rs9355381(C,A); rs9355977(C,T); rs11757111(G,A); rs62436044(C,T); rs149944835(G,A); rs35310155(T,A); rs9456739(G,A); rs9355978(A,G); rs2023059(A,G); rs9347584(C,A); rs147092493(T,C); rs9456740(A,G); rs4346836(A,G); rs4538684(T,G); rs4601100(G,C); rs4346837(A,G); rs4412175(T,C); rs35039475(G,C); rs79597924(T,C); rs77361056(C,T); rs9365365(T,C); rs9355382(G,A); rs9365366(T,C); rs9346897(A,T); rs9365368(G,A); rs9346898(C,T); rs9365369(G,A); rs9365370(T,C); rs1893552(C,A); rs77001194(C,G); rs80277838(C,G); rs1954936(G,A); rs1954934(G,A); rs9458452(T,C); rs73032254(A,C); rs9364637(G,A); rs2023058(C,T); rs2023057(G,A); rs77618018(G,A); rs9346899(C,T); rs74676357(C,T); rs9458453(A,T); rs146103654(T,C); rs4709569(A,C); rs73032261(C,A); rs76442782(C,T); rs9458454(A,G); rs9458455(A,G); rs7747241(T,C); rs80245724(T,C); rs7766064(C,T); rs6455797(G,C); rs6917031(A,G); rs6917371(A,C); rs139545430(G,C); rs1893551(A,G); rs1893550(T,C); rs151302431(C,A); rs7743774(G,C); rs4709570(G,A); rs73014603(G,T); rs10945796(A,G); rs4709571(A,G); rs6939848(T,C); rs4709572(C,T); rs4708936(C,T); rs9456741(T,G); rs9456742(A,G); rs79936851(T,C); rs61475387(C,T); rs2156265(C,T); rs2187205(C,T); rs6908394(T,C); rs6924502(C,T); rs6928713(G,A); rs7766005(C,T); rs6915059(T,A); rs1954930(G,C); rs1954929(A,C); rs114203121(G,A); rs1954928(T,C); rs139440432(G,A); rs1954927(T,C); rs4406201(A,C); rs4533966(A,G); rs115806987(C,T); rs4379266(T,C); rs4618497(G,C); rs4288183(A,G); rs9346900(T,A); rs58371083(T,C); rs6917337(G,A); rs9346901(T,C); rs9355383(C,A); rs9346902(T,C); rs9347587(C,T); rs80090689(A,G); rs7759298(G,A); rs114253301(G,A); rs12663550(T,G); rs78380303(C,G); rs12663262(A,G); rs116194135(G,A); rs57816545(C,T); rs62436046(G,A); rs55985710(G,A); rs6928889(G,T); rs6934066(G,A); rs141165092(T,C); rs1954926(G,T); rs4256407(G,T); rs9365371(T,C); rs7766924(T,C); rs9346903(C,T); rs139129520(A,T); rs57197174(A,T); rs58306087(A,G); rs2187204(T,C); rs7768722(A,G); rs7772803(T,C); rs183683149(C,T); rs6901071(T,G); rs116004812(G,A); rs9458458(T,C); rs56025249(G,A); rs79813355(A,C); rs9456743(G,A); rs375760461(G,A); rs6902605(C,T); rs11966255(C,A); rs112257508(T,C); rs150333729(T,C); rs73783412(C,A); rs73783413(T,A); rs139365183(C,T); rs11970332(A,G); rs77180464(T,C); rs74984008(G,A); rs181078916(G,A); rs6921072(G,T); rs1954925(T,G); rs147544945(T,A); rs6932255(G,A); rs9355384(C,G); rs76796544(C,T); rs114235638(T,G); rs9458459(C,T); rs10455896(G,A); rs10455897(G,A); rs7761505(A,G); rs9458460(C,T); rs77590741(A,G); rs9458461(A,G); rs78274360(T,C); rs80106087(G,A); rs79574304(G,A); rs9347589(C,T); rs76822436(T,A); rs56910994(T,C); rs9365372(G,C); rs191423178(G,T); rs78908691(C,T); rs1954922(T,G); rs9347590(A,T); rs6939051(C,T); rs9355979(C,T); rs6927146(T,C); rs201879787(A,G); rs6913155(C,T); rs9458464(C,T); rs77468489(C,T); rs35649227(C,T); rs73783416(C,T); rs9456744(A,G); rs7756400(C,T); rs9689232(A,T); rs11966520(A,T); rs112324843(C,T); rs9456745(A,G); rs9458465(T,C); rs2023053(G,T); rs10223563(C,A); rs3892751(C,G); rs6921354(T,C); rs876145(G,T); rs9355980(T,C); rs9365374(C,G); rs9355981(G,C); rs1954921(T,A); rs6940203(A,G); rs7758686(G,A); rs9347591(C,A); rs9355982(T,C); rs955164(G,A); rs62437976(C,A); rs80180004(A,G); rs78158771(G,A); rs11752210(G,A); rs74978987(T,A); rs76644185(T,C); rs115798525(C,T); rs10945797(T,C); rs2023051(C,A); rs4311492(C,T); rs114870399(A,G); rs75009774(G,A); rs2156261(C,A); rs6455798(G,A); rs9458466(G,A); rs6455799(C,G); rs6455800(A,G); rs7751044(T,G); rs75606404(G,A); rs116676333(C,T); rs114363541(A,C); rs73590401(C,T); rs184214673(A,G); rs74968461(T,A); rs144067664(C,T); rs150863797(C,T); rs6455801(G,T); rs6920356(G,A); rs1954920(G,A); rs74652220(T,A); rs7759555(T,A); rs7773019(G,A); rs78530656(G,A); rs76842557(G,A); rs114809812(C,T); rs1954919(T,C); rs79390117(T,A); rs9365375(G,A); rs7748369(A,C); rs7765614(G,A); rs74454071(T,C); rs11963472(T,C); rs10945798(A,T); rs78542246(A,C); rs184926488(C,A); rs55832918(C,T); rs4605857(T,C); rs59036433(C,A); rs76779177(A,G); rs2849574(A,G); rs12202992(A,G); rs6904579(A,G); rs28709182(C,T); rs9458469(T,C); rs2849613(A,G); rs9347592(A,G); rs9355385(C,T); rs6935386(G,C); rs713053(G,A); rs713055(C,T); rs713054(G,A); rs713056(T,A); rs2023050(G,A); rs2023049(T,C); rs59052032(G,C); rs2849566(C,T); rs73592311(C,A); rs2000751(A,G); rs73783425(T,C); rs73783426(C,T); rs111542049(T,C); rs2000750(C,T); rs6922241(G,A); rs6922385(G,A); rs2849562(A,G); rs73592320(G,A); rs75509918(G,A); rs2187199(A,G); rs73592323(G,A); rs869296(G,C); rs77338585(C,T); rs114163141(G,A); rs869297(C,G); rs869298(C,T); rs869299(G,A); rs9791255(C,T); rs73592329(A,G); rs1893542(C,A); rs34123624(T,C); rs73592331(A,C); rs2023044(T,C); rs115788202(G,A); rs2849611(C,T); rs2849610(T,C); rs2849609(C,T); rs2849608(C,T); rs2849607(T,C); rs2849587(C,A); rs2849586(C,T); rs2849585(T,C); rs2849606(C,T); rs1954933(T,C); rs1954932(G,T); rs1954931(T,C); rs2023056(G,A); rs2023055(G,A); rs2849584(C,A); rs2849583(C,T); rs2849605(A,G); rs2849604(T,A); rs2849601(T,C); rs2849600(C,T); rs2849580(C,A); rs2849599(C,T); rs2849579(G,A); rs1893549(G,T); rs1893548(G,A); rs1893547(C,T); rs145398467(G,A); rs55820779(T,G); rs9347593(G,T); rs2187203(G,A); rs2156264(C,G); rs76256006(G,A); rs9295183(G,T); rs2187202(G,A); rs2187201(A,C); rs9365377(A,T); rs78316447(T,A); rs4312964(C,A); rs73592353(C,T); rs2849591(G,T); rs1893546(C,T); rs2849590(C,G); rs1893541(T,C); rs1893554(C,T); rs1893553(T,C); rs2849576(G,T); rs13194829(T,C); rs13205287(G,A); rs2849588(C,T); rs116530352(G,A); rs2023086(T,G); rs2023085(G,A); rs2023083(T,C); rs113975546(G,A); rs73783432(T,C); rs73783433(G,A); rs73592363(C,T); rs9347594(T,C); rs34091491(T,C); rs34394707(T,C); rs11969738(C,T); rs62437987(T,C); rs183713333(T,G); rs9355985(G,A); rs9365378(G,A); rs9456748(G,A); rs2023082(T,C); rs9365380(T,C); rs2023081(C,T); rs2023080(C,T); rs4709577(G,A); rs11969427(C,T); rs10945799(A,C); rs9346905(T,C); rs116601343(G,C); rs12201119(G,A); rs1574210(A,G); rs871387(C,T); rs9347595(A,C); rs73783435(C,T); rs7453183(T,C); rs58395696(G,A); rs74966585(T,C); rs185627901(C,T); rs9458470(A,G); rs9458471(G,A); rs13215921(A,T); rs12202396(T,C); rs9347596(C,T); rs2023078(T,C); rs73592397(C,T); rs73592398(T,A); rs952901(A,G); rs139432746(T,C); rs4132024(T,C); rs12202701(A,G); rs73783437(G,C); rs9458472(C,G); rs9456749(G,A); rs9458473(C,T); rs12205861(T,C); rs9458474(C,T); rs116588408(G,C); rs9458475(G,A); rs62437988(A,T); rs12212768(G,A); rs9347597(T,C); rs4709578(A,T); rs6935949(G,T); rs2023077(A,T); rs12201650(C,T); rs12201696(C,A); rs1954948(A,G); rs9365381(C,T); rs4708942(C,T); rs4709579(G,T); rs4708943(C,T); rs12208027(G,C); rs34872012(A,C); rs6939040(A,G); rs1954946(G,A); rs2226771(G,C); rs73594228(T,G); rs191510139(C,A); rs10945801(A,G); rs1954945(G,T); rs9355987(T,C); rs7765100(C,A); rs144544961(T,C); rs141264217(G,A); rs57933654(C,T); rs113094556(C,T); rs183431474(C,G); rs6914284(A,C); rs9458476(G,T); rs6934514(G,A); rs6915212(A,G); rs1954944(G,A); rs183305210(G,A); rs115150717(T,C); rs9347598(A,G); rs76274865(C,T); rs58454330(C,T); rs28609710(T,G); rs9365382(A,G); rs76253100(G,A); rs76578599(G,T); rs9295184(G,C); rs112309952(A,C); rs143700593(T,C); rs200507988(T,G); rs12173327(T,A); rs12110591(G,T); rs60883055(T,C); rs78514501(A,T); rs9355988(A,G); rs114312450(C,T); rs58841741(T,C); rs7764353(C,T); rs9347600(T,C); rs115598323(G,A); rs73594259(C,T); rs59669922(G,A); rs74982664(T,A); rs59852728(A,G); rs73594265(T,C); rs73594271(T,C); rs2023075(G,T); rs143423777(C,T); rs11756469(A,C); rs12529283(G,T); rs77329262(C,T); rs115961846(G,A); rs1954943(T,C); rs9456751(A,G); rs6929127(T,C); rs4708944(A,G); rs7741375(C,A); rs140352010(T,C); rs59184402(G,C); rs58997221(A,G); rs10945802(G,A); rs4127461(T,C); rs9458480(C,T); rs10455789(T,C); rs149719704(C,T); rs142720391(C,T); rs4709583(A,G); rs76574117(G,T); rs7759069(A,G); rs10945803(T,G); rs6923402(A,G); rs6901583(C,T); rs6928213(T,A); rs1954942(T,C); rs114942060(T,A); rs9456752(T,A); rs9355388(C,A); rs9355389(A,G); rs9458481(G,A); rs13193285(T,C); rs9456753(C,A); rs9458485(C,T); rs9458486(A,C); rs141826326(G,A); rs9365386(C,T); rs115905289(C,T); rs116253613(C,T); rs9295185(C,T); rs2023074(T,G); rs76667746(C,T); rs116755856(C,T); rs7740230(C,G); rs5007361(A,G); rs73596207(T,C); rs75216055(A,C); rs2023073(T,C); rs2023072(T,G); rs2023071(T,C); rs1954940(A,G); rs4546464(T,C); rs142511612(T,G); rs111421151(A,G); rs2187213(G,A); rs2187212(G,A); rs11967000(G,A); rs9347601(G,C); rs2187211(A,G); rs6455802(G,A); rs2156268(A,G); rs7746036(T,A); rs6908241(A,G); rs6908440(A,G); rs6908593(A,T); rs146880810(A,G); rs116600548(T,C); rs181399205(C,T); rs6941947(C,T); rs77499296(C,T); rs9346906(T,C); rs957374(C,T); rs9364642(G,T); rs6905079(T,A); rs72573881(T,A); rs80027091(T,C); rs78554119(T,G); rs4235934(T,G); rs12664209(T,C); rs141313618(C,T); rs12662431(C,G); rs9355990(T,A); rs9365388(A,G); rs9365389(G,C); rs55920659(G,A); rs56857445(C,T); rs5012012(C,A); rs7766877(A,G); rs56784729(G,A); rs9347602(G,T); rs114489107(G,A); rs77063901(T,C); rs6910505(T,A); rs6926858(C,T); rs6927026(C,G); rs59939703(T,C); rs58366666(C,A); rs9355991(C,A); rs10945805(G,A); rs6455803(G,A); rs6455804(G,C); rs6930012(A,G); rs60497046(C,T); rs12663868(C,T); rs114656786(C,T); rs6935521(A,G); rs6940616(T,G); rs6912577(G,A); rs77788523(A,C); rs6940944(T,C); rs6912912(G,A); rs4385285(C,T); rs75599293(T,C); rs2023070(C,T); rs2023069(T,C); rs140830733(C,T); rs7759824(G,A); rs7760173(G,C); rs61230634(G,A); rs4709584(A,G); rs111860249(C,T); rs58925858(G,A); rs4709585(A,G); rs9365390(G,T); rs7757872(T,A); rs7771463(G,C); rs6922088(T,C); rs6926663(T,C); rs882844(C,T); rs12203066(G,A); rs2096982(A,C); rs77164548(G,A); rs12175150(G,C); rs7745538(C,T); rs951196(T,C); rs80326076(T,A); rs11754161(G,C); rs77191287(A,T); rs76678030(A,G); rs11759595(C,T); rs2023068(T,G); rs80346353(G,A); rs75830796(T,A); rs58729079(C,A); rs1954939(A,G); rs2023067(A,G); rs60175166(C,T); rs9365392(T,C); rs111878811(A,G); rs189155896(T,G); rs6922813(C,T); rs4709587(C,T); rs79053820(C,A); rs7741527(A,C); rs75409254(C,A); rs2105724(T,C); rs182450668(C,T); rs12206070(A,G); rs7756070(T,C); rs7769292(G,T); rs7770626(C,A); rs7770788(C,T); rs75224280(A,G); rs114772275(T,C); rs75861008(G,A); rs2187210(C,G); rs6455805(T,C); rs9365393(A,G); rs77028280(C,T); rs75636042(A,T); rs6921358(C,T); rs368465371(G,A); rs6920131(G,A); rs12211493(G,A); rs79501706(A,T); rs6918198(T,C); rs6934605(C,G); rs75758097(C,A); rs112102243(C,T); rs78877634(A,T); rs77546658(G,A); rs74914781(T,C); rs56330409(G,A); rs77936607(A,C); rs7743065(T,A); rs115605404(G,C); rs9355994(A,G); rs75380702(A,C); rs76952638(A,G); rs78440185(C,T); rs77531763(C,G); rs7744798(C,T); rs80315562(A,C); rs116812494(C,T); rs73598106(G,A); rs79268454(C,G); rs7773880(T,A); rs7750058(C,T); rs112799770(G,T); rs191771851(T,A); rs62429432(C,A); rs79887484(C,A); rs10945807(C,T); rs142148457(A,C); rs77144638(G,A); rs4623220(T,G); rs75375879(C,T); rs79711914(C,T); rs6930862(C,T); rs6929750(G,C); rs78590835(A,C); rs9347606(A,G); rs9355391(T,G); rs115494175(A,G); rs9347607(T,A); rs77033472(C,G); rs6942198(G,A); rs1954954(C,T); rs77690304(A,G); rs58088140(G,A); rs4708947(A,G); rs7744581(C,T); rs59827674(C,T); rs11966606(G,T); rs10455790(A,T); rs10455900(A,C); rs11964364(A,G); rs6939604(T,A); rs113216267(T,C); rs6912294(G,A); rs111508676(C,T); rs11969329(C,A); rs150946838(T,A); rs9458493(T,A); rs75827152(T,A); rs141892314(T,G); rs9365395(C,T); rs5006726(G,T); rs2023090(A,G); rs7766403(T,A); rs74298776(A,G); rs9355996(C,T); rs79032964(C,A); rs9355392(T,C); rs111266939(C,T); rs75315089(C,T); rs12153904(C,G); rs9347608(C,A); rs59548612(A,G); rs76165579(T,C); rs4708948(C,T); rs79604661(C,A); rs75398762(G,T); rs2023089(A,C); rs7750134(T,A); rs7764592(C,T); rs147751467(C,T); rs60261629(C,G); rs9355998(T,C); rs140444806(C,T); rs115516380(A,G); rs56247201(T,C); rs9347609(C,T); rs9355393(A,T); rs9347610(C,T); rs9355394(C,T); rs111561849(G,A); rs7751716(G,A); rs76143543(A,G); rs79628474(C,A); rs4709589(C,T); rs4709590(A,T); rs111273325(C,T); rs4709591(C,T); rs116065223(C,A); rs12661914(C,T); rs76909358(G,C); rs140823045(C,T); rs9346909(T,C); rs9347611(C,T); rs9364645(T,C); rs79853576(C,T); rs189216734(G,A); rs78941778(A,C); rs75217733(C,G); rs76323692(G,A); rs79184789(C,T); rs76685694(G,A); rs76942277(G,A); rs61617264(T,A); rs869779(C,T); rs7740578(G,C); rs77171789(C,G); rs1893560(C,T); rs1893559(G,A); rs1077708(C,T); rs74352937(C,T); rs77718255(A,G); rs9364646(A,G); rs9347612(G,C); rs112144804(C,T); rs61514110(C,T); rs2002682(A,G); rs4235935(A,C); rs9364647(C,A); rs73598162(T,C); rs77424716(A,G); rs75066231(C,T); rs143008742(C,G); rs7341370(T,C); rs9458499(C,T); rs9355395(T,A); rs7451077(G,A); rs1893558(T,A); rs78514611(T,C); rs1893557(G,C); rs77743401(C,T); rs114067512(T,C); rs9347613(G,T); rs7746112(T,C); rs77146432(C,T); rs876596(C,T); rs9355999(G,A); rs952388(G,A); rs147199655(T,A); rs7738783(C,G); rs76237115(A,T); rs57947219(A,G); rs140093793(A,G); rs77395491(T,A); rs76909191(C,A); rs7744424(C,T); rs116810901(G,A); rs148979361(G,A); rs141851809(T,G); rs143157860(T,C); rs77000927(A,C); rs77005532(C,T); rs75544575(T,C); rs77617920(T,C); rs78515129(C,T); rs148472377(A,G); rs77625767(T,C); rs74482294(G,A); rs78689508(C,T); rs9458501(A,C); rs74866167(G,C); rs79888866(A,G); rs7776024(C,T); rs9347614(T,C); rs4392700(A,C); rs9456757(G,C); rs116250478(C,G); rs9458503(C,T); rs188207070(A,G); rs9456758(G,A); rs9458504(G,A); rs9456759(C,A); rs116721378(T,C); rs9456760(T,C); rs9458505(C,T); rs9456761(G,C); rs6914984(G,A); rs9456762(A,G); rs10945809(A,C); rs115114420(A,T); rs4302649(G,C); rs9364648(A,T); rs114640010(A,G); rs9347616(C,A); rs9364649(A,T); rs77396572(T,C); rs10945810(C,T); rs115713054(A,C); rs114077157(A,G); rs34902005(C,T); rs61501471(A,G); rs61526712(A,G); rs12198792(C,T); rs113089418(C,T); rs111859811(T,C); rs114766403(C,T); rs112193178(C,T); rs4235937(A,G); rs4709595(G,T); rs2156270(G,A); rs138760183(T,C); rs190503899(A,T); rs73024756(G,A); rs12663189(C,T); rs79836673(T,G); rs6930668(T,C); rs12214761(T,G); rs76023159(G,C); rs7761333(G,C); rs10447368(G,A); rs79413956(G,C); rs78595747(T,A); rs7762805(C,G); rs10447369(C,A); rs7744521(A,T); rs7748665(A,G); rs7752706(T,C); rs75547218(G,A); rs73024766(A,G); rs7771396(G,A); rs75918720(A,C); rs12208921(A,G); rs146795934(T,C); rs9365399(T,C); rs9458508(G,T); rs12189990(G,A); rs6455807(G,A); rs7760647(A,G); rs7740928(C,G); rs9458511(A,G); rs73024778(C,T); rs9458512(G,A); rs9458513(T,C); rs9347618(G,A); rs191966026(G,A); rs7771045(A,G); rs9456764(T,G); rs9456765(T,A); rs9458514(T,C); rs9458515(C,T); rs9458516(G,A); rs116590709(C,T); rs7756134(C,T); rs9458517(T,G); rs9458518(T,C); rs7742255(T,A); rs9458519(T,G); rs9458520(A,G); rs76668821(G,C); rs9356000(T,C); rs9456766(C,A); rs80010420(T,C); rs76840546(G,A); rs77397400(T,C); rs9365401(C,T); rs80189425(A,G); rs1954952(G,A); rs2156269(G,A); rs4327667(T,C); rs138914235(C,G); rs78810006(C,T); rs12193354(G,A); rs12191007(A,C); rs9458521(C,G); rs9458522(C,A); rs4708953(G,C); rs6930880(C,T); rs7769694(G,A); rs4709597(T,A); rs76522582(C,T); rs74829296(G,T); rs7776148(C,T); rs9356003(A,C); rs9458523(A,G); rs79473416(C,T); rs75642238(G,A); rs6905464(C,T); rs78157085(G,A); rs140728242(T,A); rs13198166(G,T); rs9347620(C,T); rs9347621(C,T); rs9347622(C,T); rs73600126(C,G); rs3944451(A,T); rs12205467(T,C); rs1954950(A,G); rs76098174(T,C); rs2000753(A,G); rs10945813(C,T); rs9347623(A,G); rs9458526(C,T); rs9347624(A,G); rs116361077(C,G); rs4544885(A,G); rs2023088(G,T); rs73600140(C,A); rs2023087(T,C); rs115861831(A,C); rs9365402(T,G); rs73600144(A,T); rs7743612(T,C); rs77786549(G,A); rs7743791(T,C); rs77302543(T,C); rs74468607(G,A); rs9346911(T,C); rs9365403(G,A); rs74583445(A,T); rs9295186(C,T); rs6911138(T,G); rs6911853(T,A); rs76285697(C,A); rs6455809(C,A); rs75520765(A,G); rs148881157(G,A); rs6931595(A,G); rs6931596(A,G); rs139110458(A,G); rs6921784(T,C); rs78240083(A,G); rs6455810(T,C); rs9356006(C,A); rs9365405(G,C); rs9365406(A,G); rs76664785(C,T); rs73028966(T,C); rs76843671(T,A); rs78163132(A,C); rs10945814(C,A); rs6935149(A,G); rs9458528(A,G); rs59107748(T,G); rs6924362(G,C); rs112279940(G,T); rs114054422(T,C); rs9456769(A,G); rs9458532(G,T); rs2023076(C,T); rs80105049(G,A); rs77460805(C,G); rs732434(T,C); rs732435(G,A); rs113528750(A,T); rs10945815(C,G); rs980255(T,C); rs73028987(T,C); rs6940443(G,A); rs7775868(C,T); rs78762890(A,C); rs67940311(G,C); rs66976885(T,C); rs9356010(A,T); rs9458534(C,A); rs9458535(C,T); rs9356011(C,T); rs10945816(C,T); rs73028993(T,C); rs113903404(G,A); rs79976653(T,C); rs16893736(C,T); rs16893740(G,T); rs6925291(A,C); rs7449827(G,A); rs9365407(A,G); rs57190343(C,T); rs12201187(T,A); rs78154915(C,T); rs1954951(A,T); rs10806756(C,T); rs182698826(C,T); rs10945817(T,C); rs10945818(T,G); rs12203792(A,C); rs4709599(T,C); rs77345852(C,A); rs12205305(T,C); rs12206724(T,C); rs12206970(T,C); rs1954947(A,G); rs7768039(G,A); rs7750708(A,G); rs375418691(A,G); rs7769367(C,T); rs17437766(T,C); rs7755272(A,G); rs10945819(C,A); rs2023079(A,G); rs6455813(C,T); rs4709600(G,A); rs4709601(G,A); rs76536669(T,C); rs12204428(C,T); rs12211436(A,C); rs12212933(T,C); rs79024585(C,A); rs12212927(A,G); rs78381749(G,A); rs10806757(T,C); rs114145674(T,A); rs9365409(C,T); rs75391808(A,G); rs10755587(T,C); rs10945820(C,T); rs10945821(G,A); rs7761682(G,T); rs7761683(G,C); rs7752516(T,C); rs7748491(A,T); rs7752854(T,C); rs75171137(A,T); rs9365410(C,T); rs9458536(A,T); rs77590257(C,T); rs114101070(A,T); rs9365411(C,T); rs10945822(C,G); rs11758854(A,T); rs11758878(A,C); rs962900(G,A); rs12205742(C,T); rs1474556(A,G); rs1008676(C,T); rs1555013(C,A); rs1555012(G,A); rs1555011(T,C); rs10484501(T,C); rs77930174(C,A); rs11759064(C,T); rs35285809(T,C); rs111564445(T,C); rs2272786(C,A); rs3817728(C,A); rs2056909(T,G); rs6912641(C,A); rs2142527(T,C); rs75888372(T,G); rs76780873(G,A); rs73032959(G,A); rs9456772(A,G); rs77789493(C,T); rs12192200(T,C); rs10945823(C,A); rs10945824(A,C); rs73015605(C,T); rs73015608(G,A); rs7746467(T,C); rs7764714(C,G); rs9365412(C,A); rs13201368(T,C); rs10452577(C,T); rs13201506(A,C); rs17529104(T,C); rs58997917(C,G); rs9365413(G,A); rs6899614(C,G); rs190011496(G,C); rs9347625(A,T); rs10945825(C,A); rs185720351(C,T); rs79016691(A,C); rs75351567(C,T); rs10945826(A,G); rs11756493(T,G); rs114696305(G,A); rs12665151(A,G); rs12665527(T,G); rs7738188(T,C); rs189750887(C,T); rs181855925(T,C); rs9347629(G,A); rs113356330(T,C); rs16893771(G,A); rs182848933(A,G); rs9347630(T,A); rs9364652(C,T); rs73033866(C,T); rs73033870(G,A); rs73033871(G,A); rs760505(G,C); rs10455903(T,G); rs10455904(C,T); rs9356012(C,T); rs10455905(G,A); rs78938030(T,G); rs73033882(A,G); rs9347631(C,T); rs2205626(C,T); rs2205625(A,C); rs73033888(A,G); rs9365415(A,G); rs10455906(G,A); rs10455907(T,A); rs16893784(A,T); rs9347632(A,G); rs2056908(C,A); rs9458544(T,C); rs12190407(C,G); rs73033902(C,T); rs58415269(C,T); rs6903035(C,T); rs9356013(C,A); rs6934149(T,G); rs4709605(C,G); rs6455821(G,A); rs7746190(C,T); rs77521019(G,A); rs12661006(C,T); rs79281406(G,C); rs75053028(C,G); rs6904788(T,A); rs139646818(T,C); rs6924255(G,C); rs75485706(C,T); rs4709606(C,T); rs9364653(G,A); rs146947229(A,T); rs9364654(G,A); rs78044978(A,G); rs7767625(C,T); rs6455822(T,C); rs6455823(T,G); rs16893810(T,C); rs73035711(C,T); rs75923621(T,A); rs77620495(T,C); rs74562044(G,A); rs201316085(T,C); rs6455824(A,G); rs7739680(G,C); rs79084151(T,G); rs145856875(G,C); rs7452748(C,G); rs79908848(T,G); rs76325134(A,C); rs79699210(G,A); rs74892485(C,T); rs79483124(A,T); rs6455825(A,G); rs79220797(A,G); rs6937352(C,T); rs6937539(C,T); rs6916768(A,G); rs6937726(C,G); rs6921297(T,G); rs9689466(A,C); rs67567168(C,G); rs17438732(G,C); rs17438759(C,T); rs67745844(A,T); rs67157417(A,G); rs66492141(G,T); rs67315289(G,T); rs67044637(T,C); rs17529632(T,C); rs60338266(A,G); rs17438842(T,C); rs13191310(C,T); rs57650124(T,C); rs12191146(G,C); rs61156795(G,A); rs12213306(T,C); rs6904287(G,A); rs79729905(T,C); rs78964633(C,T); rs6455826(T,G); rs6455827(A,G); rs6938401(T,C); rs6911575(C,T); rs6910346(G,T); rs6933748(A,G); rs6938624(T,G); rs6911768(C,A); rs10945828(A,G); rs9689396(C,A); rs9295187(G,C); rs9295188(T,C); rs9295189(C,T); rs7775238(A,G); rs6455829(T,C); rs6455830(A,G); rs6903308(A,C); rs9458546(G,C); rs77797484(A,T); rs78162852(C,T); rs9365416(C,T); rs1555010(C,T); rs4708954(C,G); rs1555009(C,T); rs1973885(C,T); rs1973884(T,A); rs4709607(G,C); rs9365417(G,A); rs9347634(T,A); rs9365418(G,C); rs10806758(C,T); rs9365419(G,A); rs2874364(A,C); rs2874365(C,T); rs2320810(A,G); rs2320811(A,T); rs2320812(C,A); rs7746087(G,A); rs7766912(A,G); rs7746196(G,C); rs79940882(A,C); rs9364655(A,G); rs10455908(T,C); rs6911087(C,G); rs6937748(A,C); rs6937749(A,C); rs140432232(C,G); rs2205624(T,A); rs111807325(C,T); rs147669952(C,T); rs6921270(G,A); rs142325028(G,A); rs12192429(A,G); rs9456777(T,C); rs9347636(T,G); rs6902041(G,A); rs6902370(G,C); rs10945829(T,C); rs9365420(A,G); rs9365421(G,A); rs4426976(C,T); rs78896859(C,T); rs10945830(G,A); rs73037809(T,C); rs7773233(A,G); rs9458548(C,T); rs986313(C,T); rs9365422(G,A); rs9347637(A,G); rs9365423(G,A); rs7740355(A,T); rs16893831(G,C); rs12215312(C,T); rs78676725(C,T); rs9365425(C,A); rs9347638(T,C); rs10945831(G,A); rs9364656(C,T); rs6918427(A,G); rs4709608(G,A); rs6939674(C,T); rs77485529(G,T); rs13211450(T,G); rs9365426(G,A); rs9356016(C,T); rs9365427(A,G); rs9365428(G,A); rs9458549(A,C); rs11961949(C,T); rs13215957(T,C); rs9365430(A,G); rs9365431(T,C); rs28360621(G,A); rs9365432(T,C); rs9365433(T,C); rs9347639(C,G); rs6899470(A,G); rs67451997(A,C); rs73604292(G,C); rs9356017(G,A); rs115843031(A,T); rs73037826(G,A); rs6927019(C,G); rs9346913(C,A); rs9365434(T,C); rs9364657(T,A); rs7771086(G,A); rs80330859(C,G); rs7758319(T,C); rs7758320(T,C); rs7758339(T,C); rs7754380(A,G); rs10806759(T,A); rs7771809(G,A); rs7758844(T,C); rs9458551(G,T); rs9356018(G,A); rs9458555(T,A); rs9365435(A,C); rs9356019(T,C); rs9356020(G,A); rs9356021(G,C); rs7768935(T,C); rs2105643(A,G); rs741982(A,C); rs1078259(G,A); rs6923741(G,A); rs149960727(T,C); rs10945832(G,A); rs112942853(G,A); rs2075923(A,G); rs77795533(C,T); rs10455909(A,G); rs10455910(T,A); rs4708955(A,C); rs74676464(G,A); rs74934592(A,G); rs6455831(C,T); rs7757594(A,G); rs6455832(A,G); rs4709609(C,T); rs7762203(T,C); rs79657304(C,T); rs10945833(C,T); rs10945834(A,C); rs12203408(C,T); rs78716895(A,T); rs12213254(T,C); rs12211750(A,C); rs10455911(T,C); rs6905594(C,T); rs77032761(C,T); rs9458556(A,T); rs145855057(C,T); rs2142525(G,A); rs9364659(C,G); rs2179048(A,G); rs186668288(G,T); rs6933733(A,G); rs73028153(G,A); rs66461365(C,T); rs12193297(G,C); rs16888779(T,C); rs12214107(A,T); rs12207190(C,T); rs12215584(T,C); rs12193367(G,A); rs12193416(G,C); rs56140904(G,A); rs9365436(C,T); rs13202259(G,A); rs11759920(A,G); rs9347642(G,A); rs4708956(A,G); rs4709610(C,T); rs4708957(T,C); rs4708958(C,A); rs4708959(G,A); rs4708960(G,A); rs35876041(C,T); rs73606333(C,G); rs9458557(C,A); rs73606338(G,A); rs74444280(C,T); rs139542472(C,T); rs2142524(A,G); rs6913878(T,C); rs10945835(C,T); rs6914057(T,C); rs79319598(A,T); rs6914080(T,C); rs73783585(T,C); rs77406085(G,A); rs62430724(T,C); rs9458559(T,G); rs75526346(G,A); rs77617108(T,C); rs9346914(T,C); rs6909474(G,T); rs6909476(G,A); rs9458560(G,A); rs9458561(C,T); rs9295190(C,T); rs76676045(T,A); rs9295191(A,C); rs78965483(G,A); rs76347122(A,C); rs10945836(A,G); rs112206364(C,T); rs78071928(T,C); rs4708961(C,T); rs7758914(C,G); rs2022997(G,A); rs4709611(A,T); rs4709612(T,C); rs80015234(A,G); rs4709613(G,C); rs4709614(T,C); rs115081440(T,C); rs4709615(G,C); rs4709616(A,C); rs77911415(A,G); rs185501515(G,C); rs2022996(C,T); rs78718632(G,A); rs12215735(C,A); rs74475107(A,G); rs9458562(G,A); rs10945837(T,C); rs12661450(A,C); rs9347645(T,C); rs35792237(C,T); rs111557621(G,A); rs73035827(T,C); rs9365439(T,C); rs9365440(A,T); rs62430728(A,G); rs59249092(G,A); rs2056907(C,T); rs4709617(G,A); rs12207728(G,A); rs73606368(T,C); rs76077091(G,C); rs7451668(C,A); rs2223192(A,C); rs74471690(A,G); rs12665583(C,G); rs28360518(G,A); rs12174063(A,G); rs73783596(T,C); rs12174214(T,C); rs7740256(C,T); rs62430736(C,G); rs114092345(G,A); rs1893116(A,G); rs148853662(G,A); rs73606380(A,G); rs77148667(C,T); rs74935660(A,G); rs73783598(C,T); rs73783599(C,T); rs4709618(C,A); rs2186815(G,A); rs115995783(A,G); rs74525401(A,G); rs1893115(T,G); rs4357111(C,T); rs77247891(T,C); rs12525824(C,T); rs747295(T,C); rs4709619(A,G); rs4709620(A,G); rs2186814(A,G); rs73785503(T,C); rs2155498(A,G); rs7454474(C,A); rs9365441(A,G); rs74994778(A,G); rs58229574(C,T); rs67648143(G,A); rs73035850(C,T); rs55731347(A,G); rs55699634(A,C); rs75803316(A,G); rs77878430(C,T); rs145069262(C,T); rs56149161(T,C); rs79419693(T,C); rs6923407(C,T); rs6907497(T,C); rs7450537(T,C); rs7452477(G,C); rs144991618(C,T); rs6930121(C,A); rs9365442(A,T); rs78541492(G,A); rs4709622(A,T); rs4709623(G,A); rs74753519(A,G); rs4709626(G,A); rs145527589(C,T); rs9365443(T,G); rs9356024(C,A); rs58118739(C,T); rs62428772(T,A); rs62428773(C,A); rs62428774(C,A); rs9364660(C,G); rs4632875(A,G); rs12529018(C,T); rs56883440(T,C); rs62428776(G,C); rs78036399(C,T); rs62428777(G,A); rs62428778(G,A); rs10945838(C,T); rs12524790(T,C); rs9356026(A,C); rs12529491(C,T); rs9365444(C,T); rs12526423(G,A); rs9365445(C,T); rs9365446(C,T); rs9347648(A,G); rs9365447(G,T); rs9347649(T,C); rs12525250(T,C); rs62428780(G,A); rs9347650(A,C); rs79405915(A,G); rs9365448(C,G); rs62428781(C,T); rs59528012(A,T); rs13197661(C,T); rs12530035(T,C); rs183150885(G,T); rs2023005(T,C); rs4493732(T,C); rs57490888(A,T); rs114942872(T,C); rs9347652(G,A); rs62428782(C,T); rs4709631(A,C); rs7740239(A,T); rs73785517(A,G); rs6455833(G,A); rs1893114(A,G); rs1954801(C,G); rs1954800(C,A); rs1893113(T,C); rs60707138(T,C); rs9347653(C,T); rs9365449(C,T); rs117647056(G,C); rs118173104(C,T); rs1893111(C,T); rs4709632(T,G); rs2155497(T,C); rs57110552(T,G); rs62428841(C,T); rs76428263(C,T); rs79719219(T,C); rs2186813(T,C); rs7758475(C,G); rs7758619(C,T); rs6907418(G,A); rs2212513(C,T); rs117873460(C,T); rs2155500(C,T); rs61084735(C,A); rs9346916(C,T); rs9346917(C,T); rs10945839(T,C); rs2023004(T,C); rs1893110(T,C); rs1893109(C,A); rs1893108(G,T); rs1893107(C,T); rs73785519(T,C); rs9365450(G,T); rs4708963(C,T); rs58005250(C,T); rs58933539(T,G); rs139414564(G,A); rs34665264(G,T); rs9346918(T,C); rs9356028(C,A); rs9356029(C,T); rs149221870(T,C); rs62428847(C,T); rs9347654(C,T); rs9356030(A,T); rs9346919(T,C); rs9347655(C,T); rs9346920(T,C); rs9347656(C,T); rs76539686(A,G); rs6918583(G,A); rs6942202(A,G); rs6920074(C,T); rs6920233(C,G); rs6455836(C,T); rs6455837(A,G); rs62428848(C,T); rs80180570(T,C); rs61172080(C,T); rs60124387(C,A); rs141057735(G,A); rs60813622(T,G); rs58655840(T,C); rs12525867(T,C); rs183784215(G,C); rs141756550(C,T); rs9458570(T,C); rs56061352(T,C); rs9365453(T,C); rs9365454(T,C); rs12524159(C,T); rs12524175(C,T); rs12524214(C,T); rs12526400(T,C); rs12524235(C,T); rs12526046(A,G); rs61142875(T,C); rs62428854(T,C); rs61051845(G,T); rs58980789(G,T); rs6934419(A,G); rs6939169(T,C); rs62428857(C,T); rs75002637(G,A); rs62428858(C,T); rs4605859(A,G); rs6916874(G,A); rs76921497(T,C); rs62428859(G,C); rs143135350(G,A); rs2023003(A,G); rs2023002(T,C); rs62429608(G,A); rs2023001(C,T); rs56843876(T,C); rs143462831(T,C); rs6930136(C,T); rs56387691(G,A); rs12110846(C,A); rs9365455(A,C); rs78201968(C,T); rs2023000(T,G); rs112834302(A,G); rs74778695(G,A); rs4708965(G,C); rs6455838(T,C); rs7767381(T,C); rs34235347(C,A); rs13194743(G,A); rs2022999(T,C); rs7741160(A,G); rs7759761(C,T); rs12528066(T,C); rs7764218(C,T); rs4708966(T,C); rs4709633(G,A); rs77490665(G,A); rs73037925(G,A); rs9456783(A,T); rs9456784(T,C); rs113234434(C,T); rs113492773(G,A); rs62429613(T,C); rs9458572(C,T); rs7755989(A,G); rs6941157(C,T); rs11966297(C,T); rs6925670(A,G); rs79618438(G,C); rs9356031(C,T); rs77884815(T,C); rs73037932(C,A); rs113970780(A,G); rs188702576(T,A); rs115812111(G,C); rs6455839(G,T); rs139407033(C,T); rs56329613(T,G); rs113611895(C,T); rs73037937(G,T); rs73037939(A,G); rs71567651(A,T); rs73037940(A,T); rs73037942(G,A); rs114023397(T,A); rs73037947(G,A); rs9356032(A,G); rs77496358(C,T); rs77645751(A,G); rs142477608(C,T); rs7757630(G,A); rs2155494(C,T); rs6906781(A,C); rs9365457(C,T); rs9347657(T,C); rs11961845(A,T); rs67303732(C,T); rs67511878(C,T); rs11962498(T,C); rs2022998(C,T); rs6913981(A,G); rs56232315(A,T); rs6908330(C,A); rs6935003(T,C); rs6935012(T,C); rs6930739(A,G); rs6931162(A,G); rs9456785(A,G); rs9347658(G,A); rs73037959(A,G); rs113614388(T,C); rs12530445(A,G); rs11961456(T,C); rs9356033(A,C); rs71567652(T,C); rs6904379(T,C); rs6904956(T,C); rs6921203(C,G); rs73037964(G,A); rs2846483(C,T); rs2803079(C,A); rs2846482(A,G); rs9356034(T,C); rs2846509(T,C); rs2846508(T,C); rs2846507(T,C); rs35418022(T,A); rs2846481(C,T); rs34343523(T,G); rs2846480(C,T); rs2846479(A,C); rs6933096(C,T); rs2846505(A,G); rs6936895(G,C); rs34665989(G,A); rs2846477(C,T); rs73591851(C,T); rs34505509(G,A); rs2803078(C,A); rs2846476(G,A); rs2846503(A,C); rs2846502(C,T); rs2846501(G,A); rs2846475(A,G); rs2846499(A,G); rs2846498(A,G); rs2846474(A,T); rs2846497(T,G); rs2846496(G,A); rs2846495(C,G); rs73591855(C,G); rs2803077(G,A); rs34194390(C,T); rs143449568(G,A); rs2846494(G,C); rs2846473(C,A); rs2846472(C,T); rs2846493(T,A); rs2803076(C,A); rs79100388(C,T); rs2846491(A,G); rs2803075(G,A); rs2846471(A,G); rs73023493(G,A); rs13201986(A,G); rs34011835(C,T); rs35894147(C,T); rs36123943(G,A); rs35509683(G,A); rs34925881(C,T); rs34693799(G,A); rs35707282(G,A); rs73591861(G,T); rs73591863(G,A); rs66507030(G,A); rs6941224(G,T); rs34141091(T,A); rs67337490(G,A); rs35826472(C,T); rs7763118(A,G); rs13194936(C,T); rs4343902(C,T); rs34749438(T,G); rs4273664(T,G); rs724790(A,G); rs73591865(G,A); rs373648033(T,C); rs71567653(A,G); rs13202905(G,A); rs2846470(C,T); rs73591867(G,A); rs76233578(G,T); rs35931896(T,C); rs1954798(G,C); rs2846469(T,C); rs142923805(G,A); rs60162353(C,T); rs2803074(T,C); rs59674301(A,C); rs881829(G,C); rs881830(C,G); rs13209784(T,C); rs4708968(A,C); rs13206521(A,G); rs61546427(G,T); rs59890627(A,T); rs73591873(G,A); rs80340488(G,A); rs2846468(A,G); rs13194488(G,T); rs73023502(G,A); rs13206450(C,T); rs2803073(G,A); rs35100164(T,C); rs2846467(A,G); rs13206447(G,A); rs2846490(A,G); rs34885328(C,T); rs73591879(G,A); rs66962088(C,T); rs13210901(C,T); rs2803072(C,A); rs35136541(C,A); rs66635391(G,A); rs2846466(A,G); rs2846488(C,T); rs13214183(G,C); rs2846465(A,G); rs73591881(G,A); rs2846464(G,A); rs35171017(C,A); rs2803071(G,C); rs36022778(T,C); rs34623056(T,C); rs2846463(C,T); rs13193473(C,A); rs111837489(C,T); rs71567654(A,T); rs6930532(T,C); rs35457953(G,A); rs35494059(T,G); rs35190589(T,A); rs67368176(A,T); rs35049401(T,G); rs71567656(C,T); rs2803069(T,C); rs7757772(C,T); rs1954803(T,G); rs2803068(T,C); rs7757113(G,A); rs13206396(C,A); rs9458581(G,A); rs7740421(A,G); rs73591884(C,T); rs2846569(C,T); rs2846487(C,T); rs34234130(G,A); rs9456788(G,C); rs9456789(G,A); rs7745918(A,G); rs7750033(T,A); rs73591891(C,T); rs9458583(T,C); rs7755248(T,C); rs7746152(C,T); rs58108999(G,A); rs2846486(G,A); rs2846567(G,A); rs9458584(T,C); rs9356038(G,A); rs7771224(A,G); rs9347660(G,A); rs35451526(A,G); rs12664317(C,T); rs73025321(G,A); rs10945840(G,C); rs9356039(A,C); rs9356041(T,C); rs2846484(G,A); rs9356042(A,G); rs58903244(C,A); rs2846565(G,A); rs9356043(A,G); rs9347661(G,A); rs35052392(G,A); rs2846478(C,T); rs9356044(C,T); rs9365460(C,T); rs9356045(T,G); rs9356047(A,G); rs9365461(G,T); rs9347663(C,T); rs9365462(G,A); rs9347664(T,A); rs9347665(A,G); rs9365463(C,G); rs75745707(G,C); rs1893106(T,A); rs1893105(G,A); rs1893104(G,A); rs112315644(G,A); rs13206549(T,G); rs4527674(C,A); rs4441935(G,A); rs13207671(A,G); rs4636000(C,T); rs9355398(A,C); rs9458589(T,G); rs9458590(T,C); rs9458591(C,G); rs9458592(C,T); rs57982196(C,T); rs9458593(G,C); rs2846563(G,A); rs9347666(T,G); rs9356049(C,T); rs9295192(G,T); rs9295193(T,A); rs9295194(C,G); rs13201023(C,G); rs10945841(A,C); rs9458595(C,T); rs2803067(T,C); rs9355399(A,G); rs9364662(G,A); rs9347667(C,T); rs9346922(T,C); rs9365464(G,A); rs9346923(A,C); rs76113749(G,C); rs35017019(A,G); rs73593933(G,T); rs9458597(G,T); rs12194834(A,G); rs2846561(T,C); rs7762482(T,C); rs2803065(C,T); rs12189949(C,T); rs12196897(A,G); rs9458598(C,A); rs9458599(C,T); rs9456792(G,A); rs9456793(A,G); rs56139936(A,C); rs10945842(C,T); rs2023013(A,C); rs9458600(C,T); rs113559032(A,C); rs9458601(G,A); rs4709635(G,T); rs4709636(T,C); rs4709637(A,G); rs4709638(C,A); rs9458602(T,C); rs9458603(G,A); rs56239968(T,C); rs10945843(A,G); rs2846559(T,C); rs10945844(G,A); rs2023012(C,A); rs10945845(A,G); rs2803064(C,G); rs7745790(T,C); rs67084568(C,A); rs9458604(G,T); rs6914377(T,C); rs28578538(T,C); rs6929604(G,A); rs10945846(G,A); rs6936107(C,G); rs6919746(T,C); rs6919747(T,C); rs6915303(A,G); rs6934979(G,A); rs114491504(G,A); rs10945847(A,G); rs10945848(T,C); rs12215884(G,A); rs9365465(C,T); rs1954813(A,G); rs9347668(T,A); rs1954812(T,A); rs9365466(A,C); rs1954811(T,C); rs9456794(A,C); rs34914103(T,C); rs9456795(A,C); rs56153292(C,A); rs7742980(C,G); rs11968987(A,T); rs2803063(G,A); rs11969575(T,C); rs9458607(T,C); rs7767382(T,C); rs7763226(A,T); rs75289248(C,T); rs9458608(T,C); rs4709639(T,A); rs191500130(C,T); rs4709640(C,G); rs4709641(A,G); rs9365467(G,A); rs9365468(A,C); rs11966654(T,C); rs34344906(T,C); rs10080795(T,C); rs9295195(G,C); rs10080731(A,G); rs6906849(A,G); rs10080853(T,C); rs6927670(C,T); rs9458609(T,C); rs35911566(T,C); rs4091546(G,C); rs7450548(A,T); rs7450566(A,G); rs7451147(T,C); rs2803062(G,A); rs2186818(G,C); rs2186817(G,A); rs2155510(T,C); rs1012424(G,A); rs2155509(G,A); rs1012423(T,G); rs2155508(A,G); rs1012422(C,T); rs3949079(G,C); rs11967554(A,T); rs9456796(C,T); rs11968095(T,A); rs9456797(A,G); rs9456798(T,C); rs9365469(T,C); rs7773363(G,T); rs9458610(A,G); rs9458611(C,T); rs2846556(T,G); rs79496503(T,C); rs28360533(A,G); rs66921603(G,A); rs73035006(G,T); rs73035012(G,A); rs9458612(A,G); rs36107456(T,G); rs60948081(C,T); rs28360532(T,C); rs13209728(A,C); rs112572858(A,T); rs13213408(A,T); rs76252016(T,C); rs112267986(G,A); rs113230685(C,T); rs112200878(T,C); rs113908371(A,G); rs35211042(A,G); rs73593991(T,C); rs73593994(C,T); rs34398656(G,T); rs73593999(G,C); rs73595904(T,G); rs34697913(T,C); rs115614188(G,A); rs73035023(C,T); rs73035025(T,C); rs13199223(T,C); rs13196631(A,G); rs2803060(G,A); rs71567659(G,A); rs73595906(G,A); rs35818596(C,G); rs75306008(G,A); rs13204013(T,A); rs34306375(C,T); rs35518396(G,A); rs35383933(G,A); rs2846554(T,C); rs9356052(G,C); rs73595908(A,G); rs67646369(T,C); rs66534429(A,G); rs2846553(A,T); rs55847707(G,A); rs71567660(T,C); rs2846552(C,T); rs34931503(T,C); rs78403634(T,C); rs34637087(T,G); rs35044651(G,A); rs13219926(T,C); rs13220048(T,A); rs13220181(T,A); rs13200329(G,A); rs73595914(A,C); rs36113695(T,A); rs36042757(A,C); rs112768431(G,C); rs10945850(A,G); rs150436916(T,C); rs13204087(G,A); rs112469274(C,T); rs34918316(A,G); rs13208970(G,T); rs13195226(A,G); rs67042566(A,T); rs60719662(A,C); rs146110294(C,T); rs143873244(C,T); rs9347669(G,A); rs12332883(T,C); rs34009353(T,G); rs35575481(T,A); rs34177053(T,C); rs34714603(C,T); rs35723993(C,T); rs34228197(A,G); rs2846551(T,C); rs35395472(G,A); rs13190742(G,A); rs13207239(A,C); rs2846550(C,A); rs13210756(T,A); rs2846549(A,C); rs112300591(G,A); rs111253067(C,T); rs2846548(C,T); rs7769048(T,A); rs13212137(A,G); rs73595931(G,T); rs13215491(T,C); rs116735807(A,G); rs13215748(A,C); rs34066731(A,G); rs73595932(G,A); rs13200053(G,A); rs57441108(A,G); rs34192365(T,G); rs35126854(C,T); rs2803059(G,T); rs9364663(T,C); rs73008453(G,A); rs112119583(C,T); rs113967636(G,A); rs2846546(T,C); rs13204439(C,A); rs13193282(T,C); rs13208136(G,A); rs75623476(A,G); rs73595943(G,A); rs73595945(T,C); rs2846545(A,C); rs13210412(T,C); rs2846544(T,C); rs113024642(C,T); rs78556811(T,C); rs35760705(G,A); rs6910134(G,A); rs2846543(G,A); rs9365471(T,G); rs2846542(C,T); rs59393142(C,T); rs2846541(C,T); rs2803058(T,C); rs13219524(A,C); rs56398852(T,G); rs10945851(A,G); rs9364664(C,T); rs9458616(G,C); rs35449999(A,G); rs77718229(G,A); rs114549593(T,G); rs7756486(A,G); rs73595960(C,T); rs73595961(C,A); rs1002435(C,T); rs9365472(T,G); rs4708970(C,T); rs2803056(T,C); rs9365473(G,T); rs2846540(C,T); rs2846539(C,T); rs9456801(T,A); rs35156252(T,A); rs2803055(C,T); rs2803054(C,A); rs68045643(A,G); rs35424047(T,C); rs34619021(C,T); rs10806760(G,T); rs59067610(C,A); rs114205777(T,C); rs2846538(C,T); rs9364665(T,C); rs9364667(C,T); rs185519524(C,G); rs2846537(C,T); rs13191362(A,G); rs2846536(C,T); rs2803053(C,T); rs2846535(T,C); rs2803052(A,G); rs2803051(G,A); rs2155507(C,T); rs2155506(G,A); rs2155505(T,C); rs2155504(C,T); rs2155503(C,A); rs2155502(C,A); rs2846534(A,T); rs1954809(A,C); rs75362816(T,A); rs1893119(T,G); rs2023010(G,A); rs2803050(G,A); rs2803049(G,T); rs2846532(G,A); rs2803048(C,G); rs58763955(G,A); rs13215538(T,C); rs3132817(A,G); rs3132816(C,T); rs60345613(C,G); rs73595980(T,C); rs2846531(T,C); rs7454819(T,C); rs2846530(C,T); rs2846529(G,A); rs12193969(G,C); rs12207841(C,T); rs57929033(C,T); rs2846528(C,T); rs2803047(C,T); rs2803046(A,G); rs2803045(A,C); rs2846527(C,G); rs142701101(C,T); rs2803044(C,T); rs2846526(A,G); rs73595989(A,G); rs2803043(T,C); rs2803042(C,T); rs2803041(T,G); rs34063386(T,C); rs2155501(T,A); rs2846525(C,T); rs6455842(G,A); rs2846523(T,G); rs2803040(T,C); rs2803039(T,G); rs59684475(T,G); rs2803038(T,C); rs2846520(G,A); rs73595993(T,C); rs2803037(A,G); rs2803036(T,G); rs2846519(G,A); rs116643862(T,G); rs67889271(T,G); rs73595998(T,C); rs113772548(C,T); rs2803035(T,C); rs35820211(C,T); rs7746652(T,G); rs2846518(T,G); rs57639705(A,G); rs2849510(G,T); rs76404909(A,T); rs1954807(A,G); rs2849509(T,C); rs2846517(C,T); rs2803118(T,A); rs67840803(C,T); rs2023009(C,T); rs189926225(C,A); rs2849508(A,G); rs73597910(G,A); rs2849507(A,T); rs61253773(C,T); rs6911406(C,T); rs10455913(T,C); rs2849560(C,T); rs111287950(G,A); rs2849559(C,T); rs2846516(C,T); rs34594856(C,T); rs1954806(G,C); rs13192894(T,A); rs2023008(A,G); rs2803116(T,G); rs2846515(T,C); rs2846514(C,T); rs2846513(A,C); rs2186816(G,A); rs2846512(C,T); rs2155499(C,A); rs149775021(G,A); rs2803115(T,A); rs2803114(A,G); rs2846511(G,A); rs2803113(T,C); rs2846510(A,C); rs142235689(T,C); rs34347104(C,T); rs11756579(G,C); rs35443919(C,T); rs137934612(G,T); rs2849558(G,A); rs59277455(T,A); rs2077934(T,C); rs7451729(C,A); rs73597921(G,A); rs1954805(T,C); rs56171620(G,A); rs2846489(A,G); rs2849557(A,G); rs2023006(C,T); rs2803112(T,C); rs2849556(A,T); rs2849555(T,C); rs2846568(A,G); rs2849554(T,C); rs2846566(G,A); rs2846564(G,C); rs140141721(A,G); rs2849553(G,A); rs2023015(A,T); rs2023014(C,A); rs2846562(A,G); rs2846560(T,C); rs2846557(A,C); rs1954810(C,T); rs2846555(T,G); rs9456802(T,C); rs2803111(C,T); rs73597939(T,C); rs9458619(G,A); rs144863888(C,T); rs373325206(T,C); rs7451965(G,T); rs2023011(T,C); rs2849551(G,T); rs2846547(T,C); rs2803110(C,T); rs2803109(C,A); rs2849550(G,A); rs73597944(T,C); rs2803108(T,C); rs57387338(C,T); rs2803106(T,C); rs2846533(A,G); rs2849549(G,A); rs73597950(T,C); rs73016459(C,A); rs1954808(C,T); rs1893118(C,T); rs1079020(C,T); rs2849547(G,A); rs2012428(T,C); rs2012473(C,T); rs2803105(T,G); rs1893117(C,T); rs719650(C,T); rs67046187(C,A); rs2803103(T,C); rs2846521(G,A); rs6941209(T,C); rs56263105(C,T); rs2803101(T,C); rs2803100(C,A); rs143774603(T,C); rs59233075(T,G); rs114158734(T,C); rs7752984(T,C); rs6932746(C,T); rs73597968(C,T); rs73597969(A,T); rs55641858(T,A); rs57483155(C,T); rs2849545(C,T); rs956005(C,T); rs4425570(T,C); rs2803099(C,T); rs151135257(C,A); rs9456805(A,T); rs2803098(G,A); rs2849544(A,G); rs146664840(C,T); rs199780686(G,A); rs1954912(C,T); rs73597973(A,C); rs55798877(T,G); rs150230576(G,T); rs73597975(G,A); rs2803097(T,C); rs2803096(G,A); rs6455843(A,G); rs34714518(G,A); rs59121403(T,C); rs73597979(C,T); rs13218900(T,C); rs13202339(G,A); rs6916679(G,A); rs34934114(G,A); rs62429104(G,A); rs141253159(C,T); rs2803095(C,T); rs10806761(T,C); rs146794866(A,G); rs34520442(T,C); rs116574103(C,A); rs6909156(G,T); rs1954911(C,T); rs2803093(G,A); rs2510207(T,C); rs2490470(C,T); rs34591938(C,G); rs9458638(T,G); rs9458639(C,A); rs2156258(G,A); rs34773528(G,C); rs115244953(A,G); rs73022433(C,T); rs2849543(G,C); rs1954909(G,C); rs35092540(A,G); rs142701063(T,C); rs2849542(G,C); rs4360108(C,T); rs2803091(C,T); rs2849540(G,A); rs10945856(C,T); rs2849539(C,T); rs10806762(A,C); rs2849538(G,C); rs2849537(C,T); rs2849536(A,T); rs113904715(A,G); rs111725570(T,A); rs2997509(A,G); rs2849535(A,T); rs2803089(C,T); rs2803088(C,T); rs2849533(A,G); rs373898379(G,C); rs113177195(A,T); rs113575615(T,C); rs28868638(T,G); rs2803087(T,C); rs2849532(T,A); rs113363066(A,T); rs2803086(T,C); rs2156257(G,T); rs2849531(C,G); rs2849530(A,G); rs6925156(G,A); rs375092169(A,C); rs113649534(C,T); rs67487119(A,C); rs112683177(T,C); rs2105721(C,T); rs112915227(T,G); rs112993830(T,C); rs116571022(T,C); rs1893539(C,T); rs2803084(T,A); rs67673890(T,C); rs138964109(T,A); rs4709647(C,T); rs113638782(C,T); rs2849529(A,G); rs6926073(T,C); rs115200679(T,C); rs2803083(C,A); rs151305230(A,G); rs368010164(T,C); rs2023041(A,G); rs6909907(C,G); rs149383140(C,G); rs34653853(C,T); rs192583982(G,A); rs192656847(G,A); rs144006251(C,T); rs145546648(A,C); rs11969819(C,T); rs2023039(A,T); rs11969840(C,T); rs77078465(G,A); rs2849527(A,C); rs368296577(A,G); rs79854045(A,T); rs2023038(C,G); rs2023037(A,G); rs2803081(A,G); rs2803080(A,G); rs7772318(T,C); rs13214516(A,T); rs112769406(T,C); rs2023036(A,G); rs7773065(C,T); rs35378894(T,C); rs2187195(T,A); rs148941149(G,C); rs141285782(G,A); rs145038497(G,C); rs148395788(T,C); rs10945858(A,G); rs2849525(A,C); rs2849524(C,T); rs34725898(C,T); rs2849523(C,T); rs2849522(T,G); rs2849521(C,G); rs145057969(G,A); rs112733245(G,C); rs111449161(A,G); rs372244323(C,A); rs374022030(A,T); rs2849520(T,C); rs2849519(C,T); rs13192618(T,C); rs76456812(C,T); rs73599982(G,A); rs2849518(T,C); rs2849517(C,T); rs112927973(G,A); rs2849516(A,G); rs2803057(C,T); rs11967632(T,C); rs2849515(C,G); rs2849514(G,A); rs7752539(A,G); rs2849513(G,C); rs373077182(C,A); rs4260737(T,C); rs4489133(C,T); rs112409887(G,C); rs2849512(T,C); rs2803107(G,C); rs2849511(C,G); rs2803104(T,G); rs112043213(A,G); rs2187194(G,A); rs180974932(A,G); rs61355959(T,C); rs143498439(A,G); rs2849552(G,A); rs112284792(T,A); rs2156259(T,C); rs146382582(C,T); rs2803085(A,C); rs144306872(A,T); rs147620484(A,T); rs140137934(C,G); rs150293729(C,T); rs144963616(T,C); rs149065540(C,T); rs111343406(T,C); rs2849534(T,A); rs9347682(G,A); rs34138336(A,G); rs116670729(G,T); rs67094146(G,C); rs2803061(C,T); rs35537826(G,A); rs2023042(T,C); rs145664354(C,T); rs62429135(A,G); rs150936122(A,G) |
| ccdsGene name | CCDS5281.1 |
| CosmicCodingMuts gene | PARK2 |
| cytoBand name | 6q26 |
| EntrezGene GeneID | 5071 |
| EntrezGene Description | parkin RBR E3 ubiquitin protein ligase |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=5071&%3Brs=137853054|http://www.ncbi.nlm.nih.gov/omim/600116,600116|http://omim.org/entry/602544#0021|http://omim.org/entry/602544#0003 |
| Annovar Function | PARK2:NM_013987:exon5:c.C635T:p.T212M,PARK2:NM_004562:exon6:c.C719T:p.T240M,PARK2:NM_013988:exon3:c.C272T:p.T91M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7607 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=5071&%3Brs=137853054|http://www.ncbi.nlm.nih.gov/omim/600116,600116|http://omim.org/entry/602544#0021|http://omim.org/entry/602544#0003 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 2.927e-04,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Respiratory insufficiency due to muscle weakness (in some patients)
CHEST:
[Ribs, sternum, clavicle, and scapulae];
Scapular winging
SKELETAL:
Joint contractures (in some patients);
[Spine];
Rigid spine (in some patients)
MUSCLE, SOFT TISSUE:
Pelvic girdle muscle weakness (occurs earlier);
Difficulty running and jumping;
Shoulder girdle muscle weakness;
Distal muscle weakness occurs later;
Proximal and distal muscle atrophy;
Respiratory muscles may be involved (more common in juvenile-onset);
EMG shows myopathic changes;
Biopsy shows myopathic and dystrophic changes;
Increased fiber size variability;
Central nuclei;
Enlarged nuclei with central pallor;
Filamentous inclusions in muscle fibers;
Abnormal Z bands;
Rimmed vacuoles;
Autophagic vacuoles;
Increased connective tissue;
Increased mitochondria with rare paracrystalline inclusions
NEUROLOGIC:
[Central nervous system];
Delayed walking, mild (in some patients);
Abnormal gait due to muscle weakness
LABORATORY ABNORMALITIES:
Serum creatine kinase may be normal or elevated
MISCELLANEOUS:
Clinical variability;
Variable progression;
Juvenile-onset (before 15 years of age);
Adult-onset in third to fourth decade;
Some patients may become wheelchair-bound;
One large Spanish family and 1 unrelated patient have been reported
(last curated June 2014)
MOLECULAR BASIS:
Caused by mutation in the transportin 3 gene (TNPO3, 610032.0001)
OMIM Title
*608427 PARKIN COREGULATED GENE; PACRG
OMIM Description
CLONING
During an analysis of the parkin (PARK2; 602544) promoter region, West
et al. (2003) identified a partial PACRG sequence transcribed in the
opposite orientation. By database analysis, RT-PCR of brain, kidney,
testis, and heart, and 5-prime RACE of a brain cDNA library, West et al.
(2003) cloned full-length PACRG. The deduced 257-amino acid protein has
a calculated molecular mass of 29 kD. The PACRG sequence shows potential
links to the ubiquitin/proteasome system. Northern blot analysis
detected a 1.4-kb transcript in all tissues examined except placenta.
Western blot analysis of mouse and human brain extracts and
neuroblastoma cell lines detected PACRG migrating at an apparent
molecular mass of 30 kD.
GENE FUNCTION
By assaying for the activation of a dual-reporter plasmid transfected
into a neuroblastoma cell line, West et al. (2003) identified a 35-bp
site of bidirectional transcription activation within the overlapping
PACRG/parkin promoter region. Using a gel shift assay, they found that a
probe spanning the MYC (190080) consensus site within the activation
region bound protein contained in substantia nigra nuclear extracts.
Probes spanning the AP4 (600743) and GC-rich regions did not interact
with nuclear protein in this assay.
GENE STRUCTURE
West et al. (2003) determined that the PACRG gene contains 5 exons and
spans about 600 kb. PACRG and parkin are linked in a head-to-head
arrangement on opposite DNA strands and share a common 5-prime flanking
promoter region. The putative region of bidirectional transcription
activation contains an AP4-like site, a GC-rich region, and a MYC-like
site.
MAPPING
By genomic sequence analysis, West et al. (2003) mapped the PACRG gene
to chromosome 6q25-q27.
MOLECULAR GENETICS
Using a positional cloning strategy in 197 Vietnamese leprosy simplex
families (i.e., families with 2 unaffected parents and 1 affected
child), Mira et al. (2004) found significant associations between
leprosy (see 607572) and 17 markers in the 5-prime regulatory region
shared by PARK2 and PACRG. Possession of 2 or more of the 17 risk
alleles was highly predictive of leprosy, particularly the SNP markers
denoted PARK2_e01(-2599) and dbSNP rs1040079, with P values calculated
using genomic controls (Devlin and Roeder, 1999). Mira et al. (2004)
confirmed these results in 587 Brazilian leprosy cases and 388
unaffected controls. RT-PCR analysis detected wide expression of both
PARK2 and PACRG in tissues, including immune tissues, and suggested
that, in addition to the common bidirectional promoter, gene-specific
transcriptional activators may be involved in regulating cell- and
tissue-specific gene expression. In addition, PARK2, and to a lesser
extent, PACRG, were found to be expressed in Schwann cells and
macrophages, the primary host cells of Mycobacterium leprae, the
causative agent of leprosy. Mira et al. (2004) noted that both genes are
linked to the ubiquitin-mediated proteolysis system, which heretofore
has received little attention in the study of leprosy pathogenesis and
the control of M. leprae in the human host.
Malhotra et al. (2006) studied an ethnically homogeneous population of
Indian leprosy patients and controls for associations with SNPs in the
common regulatory region of PARK2 and PACRG. After Bonferroni
corrections, they found no significant associations, in contrast with
the findings in Vietnamese and Brazilian populations reported by Mira et
al. (2004). Malhotra et al. (2006) concluded that risks associated with
these SNPs vary in different populations.
Using multivariate analysis, Alter et al. (2013) replicated the findings
of Mira et al. (2004) showing a susceptibility locus in the shared PARK2
and PACRG promoter region in a Vietnamese population. They also found
that 2 of the SNPs, dbSNP rs1333955 and dbSNP rs2023004, were associated
with susceptibility to leprosy in a northern Indian population. The
populations varied in terms of linkage disequilibrium, possibly
explaining differences in univariate analysis between the 2 populations.
There was also a stronger association in younger patients in the 2
populations.
POPULATION GENETICS
Bakija-Konsuo et al. (2011) found that the frequencies of 2 regulatory
polymorphisms in the PARK2 and PACRG promoter region, dbSNP rs1040079
and dbSNP rs9356058, differed in 2 isolated Croatian island populations,
Mljet and Rab. Mljet, near Dubrovnik, was the site of a medieval
leprosarium established under a quarantine policy, whereas Rab, in the
north, has no record of leprosy patients. There was a significantly
higher frequency of allele C of dbSNP rs9356058 and also an increase in
allele A of dbSNP rs1040079 in the Mljet population compared with the
Rab population. Bakija-Konsuo et al. (2011) proposed that the increased
frequency of the protective alleles in the Mljet population may be due
to positive selection as a result of exposure to leprosy.
ANIMAL MODEL
The quaking(viable) mouse, qk(v), is a spontaneous recessive mouse
mutant with a deletion of approximately 1.1 Mb in the proximal region of
chromosome 17. The deletion affects the expression of 3 genes: quaking
(Qk; 609590), Pacrg, and parkin. The resulting phenotype, which includes
dysmyelination of the central nervous system and male sterility, is due
to reduced expression of Qk and a complete lack of Pacrg expression,
respectively. Since Pacrg is required for correct development of the
spermatozoan flagella (a specialized type of motile cilia), Wilson et
al. (2010) analyzed qk(v) mutant mice for evidence of cilial
dysfunction. Histologic and magnetic resonance imaging analyses
demonstrated that qk(v) mutant mice were affected by acquired,
communicating hydrocephalus (HC). Structure of axonemal microtubules and
density of ciliated cells were normal, and cilia length was similar to
wildtype littermates. There was a reduction in ependymal cilial beat
frequency and cilial-mediated flow in qk(v) mutant mice compared with
wildtype littermate controls. Transgenic expression of Pacrg was
necessary and sufficient to correct this deficit and rescue the HC
phenotype in the qk(v) mutant. The authors concluded that Pacrg is
required for motile cilia function and may be involved in the
pathogenesis of human ciliopathies, such as HC, asthenospermia, and
primary ciliary dyskinesia.
CAHM
| dbSNP name | rs73013596(A,T) |
| cytoBand name | 6q26 |
| EntrezGene GeneID | 100526820 |
| snpEff Gene Name | QKI |
| EntrezGene Description | colon adenocarcinoma hypermethylated (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03214 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Poor linear growth
HEAD AND NECK:
[Head];
Microcephaly, postnatal (up to -6.4 SD);
[Face];
Prominent forehead;
Well-grooved philtrum;
Retrognathia;
[Eyes];
Deep-set eyes;
Blindness, postretinal
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux
GENITOURINARY:
[External genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis;
Vesicoureteral reflux;
[Bladder];
Neurogenic bladder
SKELETAL:
[Pelvis];
Hip dislocation
NEUROLOGIC:
[Central nervous system];
Global developmental delay, severe;
Seizures;
Spasticity;
Abnormal hypothalamo-pituitary axis;
Absent posterior pituitary bright spot;
Thin pituitary stalk;
Hypoplastic anterior pituitary gland;
Thin corpus callosum;
Frontotemporal hypoplasia;
Delayed myelination
ENDOCRINE FEATURES:
Pituitary insufficiency;
Hypothalamic insufficiency;
Growth hormone deficiency;
Adrenocorticotropin deficiency;
Cortisol insufficiency;
Thyroid stimulating hormone deficiency;
Hypernatremia;
Diabetes insipidus;
Hypothyroidism, central
LABORATORY ABNORMALITIES:
Hypernatremia
MISCELLANEOUS:
Onset soon after birth;
One consanguineous Saudi Arabian family has been reported (last curated
August 2014)
MOLECULAR BASIS:
Caused by mutation in the aryl hydrocarbon receptor nuclear translocator-2
gene (ARNT2, 606036.0001)
OMIM Title
*615930 COLORECTAL ADENOCARCINOMA HYPERMETHYLATED GENE, NONCODING; CAHM
;;LONG INTERGENIC NONCODING RNA 468; LINC00468
OMIM Description
CLONING
Using a genomewide screen for DNA methylation in colorectal
adenocarcinomas, Pedersen et al. (2014) identified CAHM. CAHM produces a
long noncoding RNA.
GENE FUNCTION
Using methylation-specific PCR analysis, Pedersen et al. (2014)
confirmed that CAHM was hypermethylated in a high proportion of
colorectal adenomas and cancers, but not in normal colorectal tissue.
CAHM methylation correlated with loss of CAHM RNA in colorectal tissue
and colorectal cancer cell lines. Hypermethylated CAHM was also found in
a few breast cancer specimens, but not in lung or prostate cancers.
Methylated CAHM was detected in plasma of colorectal cancer patients,
but not in adenoma patients, possibly due to the higher architectural
distortion and vascularity of cancer tissues, as well as greater lesion
size, compared with adenomas.
GENE STRUCTURE
Pedersen et al. (2014) determined that CAHM is an intronless gene. A CpG
island extends across the CAHM gene and into the transcriptional start
site of the QKI gene (609590), which is located about 730 bp downstream
on the opposite strand.
MAPPING
By genomic sequence analysis, Pedersen et al. (2014) mapped the CAHM
gene to chromosome 6q26.
LINC00602
| dbSNP name | rs697475(T,A); rs73787125(G,A); rs73787126(C,A) |
| cytoBand name | 6q27 |
| EntrezGene GeneID | 441177 |
| snpEff Gene Name | C6orf176 |
| EntrezGene Description | long intergenic non-protein coding RNA 602 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0303 |
PRR18
| dbSNP name | rs1108821(C,T) |
| cytoBand name | 6q27 |
| EntrezGene GeneID | 285800 |
| EntrezGene Description | proline rich 18 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06474 |
RPS6KA2-AS1
| dbSNP name | rs184350177(C,T); rs9457237(A,G) |
| cytoBand name | 6q27 |
| snpEff Gene Name | RPS6KA2 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
GPR31
| dbSNP name | rs148093951(G,A); rs6902566(T,C) |
| ccdsGene name | CCDS5299.1 |
| CosmicCodingMuts gene | GPR31 |
| cytoBand name | 6q27 |
| EntrezGene GeneID | 2853 |
| EntrezGene Description | G protein-coupled receptor 31 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR31:NM_005299:exon1:c.C901T:p.R301X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 4.473e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Absent eyebrows;
Absent eyelashes;
[Teeth];
Normal teeth
SKIN, NAILS, HAIR:
[Skin];
Normal sweating;
[Nails];
Onychodystrophy;
Micronychia;
Onycholysis;
[Hair];
Alopecia;
Brittle hair (in some patients);
Pili torti (in some patients);
Sparse body hair (in some patients);
Absent body hair
NEUROLOGIC:
[Central nervous system];
No mental retardation
METABOLIC FEATURES:
Normal sweating
MISCELLANEOUS:
Three families described (last curated January 2014)
MOLECULAR BASIS:
Caused by mutation in the keratin 85 gene (KRT85, 602767.0001)
OMIM Title
*602043 G PROTEIN-COUPLED RECEPTOR 31; GPR31
;;12-(S)-@HYDROXYEICOSATETRAENOIC ACID RECEPTOR;;
12-(S)-@HETE RECEPTOR;;
12-@HETER
OMIM Description
DESCRIPTION
GPR31 belongs to the rhodopsin (RHO; 180380) family of G protein-coupled
receptors (GPCRs, or GPRs). GPR31 is a specific receptor for
12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-(S)-HETE), a
biologically active metabolite of arachidonic acid (Guo et al., 2011).
CLONING
Zingoni et al. (1997) cloned a novel GPCR from a human placenta cDNA
library. They reported that the gene encodes a 319-amino acid
polypeptide with 7 predicted transmembrane domains and 25 to 33%
homology to other members of the GPCR superfamily. Zingoni et al. (1997)
were unable to detect a GPR31 transcript using Northern blotting. By
using RT-PCR, they detected a transcript at low levels in several cell
lines of varied origins.
GENE FUNCTION
Guo et al. (2011) found that Chinese hamster ovary cells expressing
GPR31 acquired the ability to bind 12-(S)-HETE with high affinity. GPR31
did not bind several positional isomers of 12-(S)-HETE or the enantiomer
12-(R)-HETE. Binding by 12-(S)-HETE activated GPR31, which in turn
activated downstream signaling via MEK (see 176872), ERK1 (MAPK3;
601795)/ERK2 (MAPK1; 176948), and NF-kappa-B (see 164011), depending
upon the cell line examined. Activation of GPR31 was inhibited by
pertussis toxin, suggesting the involvement of Gi (139310)/Go (139311)
trimeric G proteins. Knockdown of GPR31 via short hairpin RNA eliminated
the responsiveness of PC3M human prostate cancer cells to 12-(S)-HETE
and reduced their invasive capacity in an in vitro invasion assay. Guo
et al. (2011) concluded that GPR31 is a high-affinity receptor for the
hydroxyl fatty acid 12-(S)-HETE.
MAPPING
Zingoni et al. (1997) used fluorescence in situ hybridization to map
GPR31 to human chromosome 6q27. They noted that 2 other GPCRs, the MAS
protooncogene (165180) and the GPRCY4 gene (601835), have also been
mapped to this locus.
C6orf120
| dbSNP name | rs149834038(G,C); rs17860603(C,A); rs41265395(A,G) |
| cytoBand name | 6q27 |
| EntrezGene GeneID | 387263 |
| EntrezGene Description | chromosome 6 open reading frame 120 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01423 |
LINC00242
| dbSNP name | rs9371173(A,G); rs60553678(G,C); rs9478008(G,A); rs41266281(G,A); rs3823466(G,A); rs3807066(A,T) |
| cytoBand name | 6q27 |
| EntrezGene GeneID | 401288 |
| snpEff Gene Name | NCRNA00242 |
| EntrezGene Description | long intergenic non-protein coding RNA 242 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2654 |
GPR146
| dbSNP name | rs61910751(A,G); rs55677825(G,A); rs6953080(C,T); rs77434655(G,A); rs75398423(T,G); rs73267962(A,G) |
| ccdsGene name | CCDS5321.1 |
| cytoBand name | 7p22.3 |
| EntrezGene GeneID | 115330 |
| EntrezGene Description | G protein-coupled receptor 146 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR146:NM_138445:exon1:c.A744G:p.P248P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.06566 |
| ESP Afr MAF | 0.046776 |
| ESP All MAF | 0.119982 |
| ESP Eur/Amr MAF | 0.157478 |
| ExAC AF | 0.129 |
TFAMP1
| dbSNP name | rs6970313(A,G); rs142242114(T,G); rs58680379(A,G); rs151185309(A,G); rs10429166(C,T); rs10429241(T,C) |
| cytoBand name | 7p22.3 |
| EntrezGene GeneID | 260341 |
| EntrezGene Description | transcription factor A, mitochondrial pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4031 |
MIR6836
| dbSNP name | rs62442513(C,T) |
| ccdsGene name | CCDS5331.1 |
| cytoBand name | 7p22.3 |
| EntrezGene GeneID | 29886 |
| EntrezGene Symbol | SNX8 |
| snpEff Gene Name | SNX8 |
| EntrezGene Description | sorting nexin 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1189 |
| ExAC AF | 0.156,8.167e-06 |
GRIFIN
| dbSNP name | rs61743600(T,C) |
| cytoBand name | 7p22.3 |
| EntrezGene GeneID | 402635 |
| EntrezGene Description | galectin-related inter-fiber protein |
| EntrezGene Type of gene | pseudo |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04224 |
| ESP Afr MAF | 0.075499 |
| ESP All MAF | 0.025667 |
| ESP Eur/Amr MAF | 0.000828 |
| ExAC AF | 0.022 |
PAPOLB
| dbSNP name | rs35559543(T,C); rs11972290(C,T); rs11972309(C,G); rs6966356(G,A); rs77600238(G,A); rs34928860(T,G); rs2292495(A,C); rs78826751(A,T); rs17135241(A,G); rs77680119(T,C); rs1553960(A,G); rs17135247(G,A); rs3750010(T,C) |
| ccdsGene name | CCDS43544.1 |
| cytoBand name | 7p22.1 |
| EntrezGene GeneID | 56903 |
| snpEff Gene Name | RADIL |
| EntrezGene Description | poly(A) polymerase beta (testis specific) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2576 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
HEAD AND NECK:
[Head];
Microcephaly, postnatal
NEUROLOGIC:
[Central nervous system];
Developmental delay, severe;
Mental retardation;
Axial hypotonia;
Spastic quadriparesis;
No language development;
Sleep disorders;
Seizures, refractory;
Lissencephaly (anterior to posterior increasing gradient of severity
and more prominent in posterior brain regions);
Agyria;
Pachygyria;
Subcortical band heterotopia;
Corpus callosum abnormalities;
Cerebellar hypoplasia;
Brainstem hypoplasia;
Enlarged ventricles;
White matter abnormalities;
Prominent perivascular spaces;
[Behavioral/psychiatric manifestations];
Autistic features
MISCELLANEOUS:
All reported cases have resulted from de novo mutations;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the platelet-activating factor acetylhydrolase,
isoform 1B, alpha subunit gene (PAFAH1B1, 601545.0001)
OMIM Title
*607436 POLY(A) POLYMERASE, BETA; PAPOLB
;;POLY(A) POLYMERASE, TESTIS-SPECIFIC; PAPT; TPAP
OMIM Description
CLONING
Lee et al. (2000) cloned mouse Papolb, which they called Papt, from a
testis cDNA library. Northern blot and RT-PCR analyses revealed
expression limited to testis. The transcription level of Papolb in a
2-week-old mouse was much lower than that of the general poly(A)
polymerase gene, Pap (PAPOLA; 605553). The ratio of Papt to Pap was
reversed in testis of a 4-week-old mouse. Transient expression in HeLa
cells showed fluorescence-tagged Papolb protein in both the nucleus and
the cytoplasm.
By screening a human testis cDNA library using mouse Papt as probe, Lee
et al. (2001) cloned PAPOLB, which they designated PAPT. The deduced
636-amino acid protein contains a catalytic core, an RNA-binding region,
and a putative nuclear localization signal. Compared with human PAPII
(PAPOLA), PAPT lacks about 100 C-terminal amino acids, including a
second putative nuclear localization signal and part of the
serine/threonine-rich domain. The 5-prime UTR of the PAPT cDNA shows
features of a CpG island. Northern blot analysis detected major
transcripts of 2.8 and 4.5 kb and a minor transcript of 8.0 kb in human
testis. The 4.5-kb transcript was expressed at much lower levels in
other tissues examined.
GENE STRUCTURE
Lee et al. (2001) determined that the PAPOLB gene contains no introns.
MAPPING
Hartz (2006) mapped the PAPOLB gene to chromosome 7p22.1 based on an
alignment of the PAPOLB sequence (GenBank GENBANK AF218840) with the
genomic sequence (build 35).
By Southern blot analysis, Lee et al. (2001) determined that PAPOLB is a
single-copy gene.
ANIMAL MODEL
Kashiwabara et al. (2002) developed mice deficient in Papolb, which they
called Tpap. Both male and female mice were normal in health, size, and
behavior; the males, however, were infertile. The absence of Tpap
resulted in the arrest of spermiogenesis. Papolb-deficient mice
displayed impaired expression of haploid-specific genes required for the
morphogenesis of germ cells. Papolb deficiency also caused incomplete
elongation of poly(A) tails of specific transcription factor mRNAs.
Kashiwabara et al. (2002) concluded that Tpap governs germ cell
morphogenesis by modulating specific transcription factors at the
posttranscriptional and posttranslational levels.
LOC100131257
| dbSNP name | rs4724936(C,T); rs2979760(T,C); rs2965495(C,A); rs4720718(G,C); rs7796782(T,C); rs76924796(G,C); rs73347069(A,G); rs114951664(A,G); rs4724937(G,C); rs7797660(T,C); rs10268821(C,T); rs10268838(C,T); rs114457245(C,T); rs10271901(C,A); rs9784942(G,A); rs9784919(A,G); rs2979759(T,C); rs10272510(C,G); rs73347079(T,G); rs113467759(C,T); rs2979758(C,T); rs59432987(A,G); rs2205543(T,G); rs12532663(T,C); rs2205542(C,T); rs2205541(C,T); rs61742328(A,G); rs13242820(C,G); rs13229689(A,G); rs61739548(C,G); rs28609720(C,T); rs13245377(G,A); rs144674895(A,G); rs12113977(C,A); rs2280918(G,A); rs4720719(G,A); rs4720720(G,T); rs4720721(G,A); rs11765855(T,C); rs10258751(G,T); rs7803463(G,A); rs7803582(G,A); rs13230603(C,T); rs7804657(G,A); rs71533349(C,A); rs79081790(C,T); rs7796108(T,C); rs34671993(T,A); rs7459238(C,G); rs7779257(C,T); rs143141967(T,C); rs118092646(C,G); rs114027797(T,A); rs368970123(C,T); rs2195824(G,C); rs149013363(T,C); rs2195823(C,T); rs4302756(G,C); rs71533350(A,G); rs192329072(G,A); rs4724938(G,A); rs4724939(C,T); rs139378234(C,T); rs191181781(T,G); rs115149363(G,A); rs185827333(C,T); rs7795797(T,C); rs2347886(C,T); rs73331829(C,A); rs4305803(T,C); rs10952031(G,A); rs141806652(G,A); rs34297319(G,C); rs10270231(G,A); rs1897414(G,A); rs1835802(T,C); rs148637892(C,T); rs1594576(T,G); rs1368054(C,T); rs76372357(C,G); rs12539368(G,A); rs10260787(A,G); rs2043223(C,T); rs78770530(A,G); rs2043222(T,C); rs985055(A,C); rs985054(A,G); rs1319628(A,T); rs1319627(A,G); rs1160673(A,G); rs6978588(T,C); rs367877020(T,G); rs6954437(G,T); rs116297538(C,T); rs149152124(G,C); rs1432195(A,C); rs74760985(G,A); rs143135569(C,G); rs7793247(C,T); rs2064048(C,G); rs75123340(T,G); rs11982991(T,C); rs2060162(G,T); rs28666740(A,G); rs6463645(A,T); rs13228156(G,T); rs6463646(C,A); rs6463647(C,T); rs988565(C,T); rs79059913(C,T); rs6947100(C,G); rs10243998(C,G); rs112192120(C,T); rs111882559(C,T); rs6971973(A,G); rs6951453(G,C); rs6951583(G,A); rs76100534(A,G); rs59642807(T,C); rs78345697(C,T); rs6976810(T,A); rs17163287(C,A); rs182369632(T,C) |
| cytoBand name | 7p22.1 |
| EntrezGene GeneID | 100131257 |
| snpEff Gene Name | RP11-397J20.1 |
| EntrezGene Description | zinc finger protein 655 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4972 |
COL28A1
| dbSNP name | rs2348042(T,G); rs73345211(G,T); rs2109776(T,C); rs16877721(G,T); rs16877728(C,T); rs2159710(T,G); rs4724976(T,C); rs10952050(C,A); rs11773303(T,G); rs10952051(G,C); rs10486158(C,T); rs10807956(A,G); rs10952052(T,C); rs80125888(G,A); rs78070148(C,T); rs3752644(T,C); rs7786515(A,G); rs7807595(C,G); rs1541502(A,G); rs79690987(G,A); rs1541503(T,C); rs73345230(T,G); rs138293647(T,C); rs3890981(C,T); rs3857760(C,G); rs186991275(A,G); rs7800159(T,G); rs10952053(A,T); rs2348027(T,C); rs146423875(A,G); rs1014172(G,C); rs2348028(T,C); rs4724977(T,C); rs79275291(T,C); rs113709448(T,C); rs143285174(A,G); rs61562461(A,T); rs6974119(A,G); rs190125535(G,A); rs181771968(A,C); rs113404943(T,C); rs147102579(T,C); rs113132563(C,G); rs113487434(A,G); rs9640038(C,T); rs7781861(C,T); rs1860730(A,C); rs7800737(A,G); rs1014419(G,C); rs148440056(C,T); rs60169910(C,T); rs79498130(G,A); rs116380523(T,A); rs17166996(T,C); rs56734683(C,T); rs7796385(G,A); rs16877792(T,C); rs116468384(C,T); rs78118298(T,A); rs185557869(C,T); rs115610547(C,T); rs6960947(T,C); rs111550728(T,C); rs61745696(T,A); rs61744841(T,C); rs17167050(T,A); rs4720731(G,A); rs73040616(T,C); rs17167051(T,C); rs1294651(C,T); rs75414286(A,G); rs35702040(C,A); rs114218318(G,A); rs17167055(A,G); rs116299835(A,G); rs11980272(C,T); rs55990737(C,G); rs57872664(T,C); rs73040628(C,T); rs12530748(A,G); rs7779522(C,G); rs7798559(A,G); rs77627355(G,A); rs36026452(T,C); rs17167072(T,C); rs115370943(A,C); rs56095716(C,T); rs56057387(C,T); rs17167088(T,C); rs17167090(G,A); rs78270182(T,C); rs79950420(C,T); rs61739533(C,T); rs17167099(A,C); rs200507350(G,C); rs17167102(C,T); rs1294625(T,C); rs57792544(T,C); rs143557605(T,C); rs116691795(C,T); rs61244384(G,A); rs1294626(C,A); rs1294627(A,G); rs114343166(C,T); rs1294628(T,C); rs146148026(T,C); rs1294629(T,C); rs116414371(T,C); rs146933640(A,G); rs141707075(C,G); rs76252646(T,C); rs1296104(C,A); rs1294632(T,C); rs116554921(G,C); rs115529501(C,T); rs146113057(C,T); rs71533369(A,G); rs1294633(G,A); rs1294634(A,G); rs1294635(G,C); rs34781753(C,T); rs71533370(C,T); rs1296106(G,T); rs76369477(A,C); rs71533371(A,C); rs17167202(T,C); rs114240897(T,C); rs17167203(C,T); rs149028802(T,C); rs11525818(G,C); rs11526212(G,A); rs7803541(C,T); rs7786335(A,G); rs142291618(T,C); rs115827635(G,A); rs138167078(A,T); rs114840640(G,A); rs7795296(T,G); rs142128936(T,A); rs116496264(T,C); rs4724978(G,A); rs4724979(C,T); rs145340391(G,A); rs4724980(G,A); rs4720732(C,T); rs4452714(C,T); rs149936561(A,G); rs143999625(G,C); rs7801024(T,C); rs1294641(A,G); rs1299912(T,A); rs71533372(G,C); rs34977692(G,T); rs149230977(C,T); rs143389415(G,C); rs139071983(T,C); rs1294642(C,T); rs1294643(G,A); rs150562692(T,C); rs1294644(A,G); rs114397554(G,C); rs1294645(C,A); rs143998755(T,C); rs146410876(T,C); rs141035213(C,T); rs147962424(G,C); rs1294647(C,T); rs1294648(A,C); rs1294649(A,G); rs1294650(G,A); rs2109779(T,C); rs17167227(G,A); rs10952057(T,C); rs10952058(C,A); rs73674521(G,A); rs4724985(T,C); rs4724986(T,C); rs115674713(C,A); rs17167230(A,C); rs12702612(C,T); rs140986184(G,A); rs2109780(T,G); rs2159711(T,C); rs6964205(C,T); rs116403069(G,A); rs56205616(G,C); rs13230887(G,T); rs10235363(G,A); rs10235505(G,A); rs6979399(G,A); rs6962404(A,C); rs1860724(C,G); rs73347174(T,G); rs28669774(T,C); rs6946659(G,C); rs6971476(T,C); rs73347183(C,T); rs17167323(A,C); rs1997518(C,T); rs7800782(C,G); rs150899220(C,T); rs73347189(C,T); rs73347194(A,G); rs74737999(T,G); rs12702613(A,C); rs73347196(A,G); rs1294597(C,T); rs73347201(C,T); rs73348905(A,G); rs1294598(A,G); rs1297791(C,G); rs1294600(C,T); rs7807860(T,C); rs1294601(A,C); rs1294602(G,A); rs59026019(C,T); rs6962725(C,G); rs1294603(T,C); rs10248825(T,C); rs13227277(C,G); rs1024714(T,A); rs1024715(A,G); rs75625495(C,T); rs13230547(C,T); rs118150289(A,C); rs6977488(G,T); rs6977661(G,A); rs6960608(A,G); rs6979055(C,G); rs6953394(G,C); rs78620473(C,T); rs35462098(A,G); rs138142942(C,T); rs7812265(A,G); rs11975449(A,T); rs78066683(G,A); rs1860725(G,A); rs10255190(T,G); rs78669955(G,C); rs725934(C,G); rs75947296(G,T); rs725933(T,C); rs10085771(G,A); rs115211979(G,T); rs73348969(A,G); rs7800860(A,T); rs17167528(A,G); rs80277782(T,C); rs7804915(T,G); rs77125208(A,G); rs80074674(A,G); rs60120688(C,T); rs60020853(A,T); rs10268438(T,A); rs10216249(G,A); rs149545507(C,T); rs10085761(A,G); rs144116838(G,A); rs10085830(T,C); rs10269244(A,G); rs79674894(G,A); rs10085695(T,C); rs10085797(G,A); rs17167601(G,A); rs6947175(C,T); rs76924771(G,T); rs6946064(G,A); rs73334111(T,C); rs115401707(G,C); rs149912858(G,A); rs17167617(A,G); rs17167618(A,G); rs79632774(T,C); rs78290555(A,G); rs28505765(A,G); rs17167624(C,T); rs10486160(G,T); rs75191139(G,A); rs75501822(G,T); rs79255499(C,T); rs115518049(A,G); rs57930817(C,G); rs113754234(G,C); rs147309525(G,A); rs10234561(G,A); rs10234818(G,C); rs10280546(A,G); rs75332860(T,C); rs28636895(C,G); rs28493883(A,G); rs73334126(G,A); rs114104368(C,G); rs145419398(G,C); rs6463692(A,G); rs113755272(T,G); rs80268263(C,A); rs28522448(G,A); rs58681001(T,G); rs73334139(A,C); rs28680470(C,T); rs17167720(T,C); rs115583759(T,C); rs60815257(A,G); rs80008306(C,A); rs4503020(T,G); rs73334145(C,G); rs6945047(G,C); rs6946354(C,T); rs76291952(G,C); rs73334153(A,G); rs7802944(A,T); rs4035103(C,G); rs2348046(C,T); rs117027652(G,A); rs2348047(G,C); rs4035104(C,G); rs4035105(G,A); rs7789262(G,A); rs16878052(A,G); rs59714813(C,T); rs115455928(T,C); rs6948753(A,G); rs6967835(C,T); rs28399265(G,T); rs115927565(C,A); rs78238635(T,C); rs115593231(T,A); rs17167804(A,T); rs28454801(T,A); rs28753676(T,C); rs75614131(G,A); rs10249422(G,A); rs141983459(T,C); rs77998566(A,T); rs6960158(C,G); rs10225403(C,A); rs10228597(C,T); rs10246954(T,C); rs73346304(A,C); rs78999154(G,A); rs77562227(C,G); rs116084543(C,G); rs10236946(C,A); rs10255201(T,C); rs77665547(T,G); rs10265808(G,A); rs116384363(T,C); rs28498082(C,T); rs76963331(A,C); rs10263223(T,C); rs73346306(C,T); rs80184376(G,T); rs10263962(T,C); rs149386074(G,A); rs2109772(C,T); rs76070793(G,T); rs73346309(C,T); rs116239003(C,G); rs77154721(A,G); rs10486164(A,G); rs7787580(G,C); rs17167922(C,T); rs4455736(G,C); rs114542562(A,T); rs17167926(C,T); rs17167927(C,G); rs73346316(G,C); rs73346319(T,C); rs55745506(T,C); rs116001505(G,A); rs77567240(G,C); rs12234520(C,T); rs138811881(T,C); rs148942459(G,A); rs113335718(T,C); rs113625926(T,C); rs58537294(A,C); rs56677263(C,A); rs73346330(C,T); rs79802013(C,T); rs115000853(G,A); rs141849996(A,G); rs73346335(T,C); rs76188924(C,A); rs56058922(A,G); rs56330916(C,T); rs55841745(A,G); rs79493064(G,C); rs56022797(T,A); rs112870157(G,A); rs55827101(G,C); rs56084871(C,G); rs73346346(G,A); rs116621057(G,A); rs148883139(C,A); rs74633601(T,C); rs137967182(G,A); rs6971367(A,C); rs114701901(G,C); rs115069442(G,T); rs60917148(T,C); rs148009762(G,C); rs115237969(T,C); rs55798422(T,G); rs55954412(T,C); rs56103225(T,C); rs56177814(C,T); rs113444665(A,G); rs58115252(A,G); rs115837250(T,C); rs12666561(T,A); rs55980077(T,G); rs6950825(C,T); rs61404535(T,C); rs6952195(C,G); rs6965546(C,T); rs78040428(A,G); rs111248678(A,G); rs6957880(T,A); rs60977515(T,A); rs10226811(T,C); rs150550415(G,A); rs183143146(C,G); rs6943692(C,T); rs11982762(C,T); rs6954909(C,T); rs6463694(A,G); rs6463695(T,C); rs144789023(A,G); rs17168154(C,T); rs74498675(T,C); rs143215717(T,C); rs17168170(G,C); rs6962939(T,A); rs56913410(C,A); rs79250838(T,C); rs76168794(T,C); rs76826748(T,C); rs56220786(T,C); rs77391890(T,C); rs74340761(A,T); rs6964593(C,T); rs4724995(C,T); rs10250746(T,C); rs17168217(C,A); rs10486172(A,G); rs12671912(G,A); rs6463696(C,T); rs76379500(T,C); rs2158755(G,T); rs6946913(G,A); rs6948300(C,T); rs6972069(T,C); rs2348335(C,T); rs2881888(G,A); rs11772657(G,A); rs188101235(T,C); rs929378(C,A); rs79377874(T,C); rs929379(T,C); rs150950381(C,T); rs972766(G,A); rs73352229(A,T); rs77979808(T,C); rs13312659(G,A); rs143636376(C,T); rs10486174(A,G); rs79763029(G,T); rs78516769(C,A); rs62453192(C,T); rs12386742(G,A); rs58798360(T,C); rs80014938(T,C); rs6942414(T,C); rs59100951(C,T); rs62453193(A,T); rs76909382(A,G); rs17168279(G,T); rs11971297(G,A); rs138245448(C,A); rs10952059(T,C); rs17168290(G,A); rs146686557(G,T); rs6463697(A,G); rs111233915(C,T); rs6463698(C,T); rs186389550(A,G); rs76347026(C,T); rs7810134(G,A); rs17168311(G,C); rs58336356(G,T); rs764555(G,A); rs74345229(C,A); rs139823676(G,T); rs116032032(A,G); rs10276745(T,A); rs17168333(T,C); rs10486176(G,C); rs6967447(T,A); rs10952060(G,C); rs59318672(G,A); rs73674572(G,T); rs75141477(C,T); rs58029842(A,G); rs191045442(C,G); rs57928001(T,G); rs28490326(T,G); rs6946425(T,C); rs10247890(T,C); rs149615796(A,G); rs7795005(T,G); rs75729484(G,A); rs7809551(T,C); rs7791808(C,T); rs7778306(T,C); rs73674573(T,G); rs10227453(C,G); rs10242691(A,G); rs17168408(C,A); rs75325544(G,T); rs78775719(T,A); rs78624881(T,C); rs1016028(T,C); rs61110737(A,G); rs7789187(T,C); rs73674574(G,A); rs2214842(A,G); rs149995188(G,A); rs17151551(A,G); rs17151557(A,C); rs10486178(C,T); rs17168444(C,G); rs17168446(G,C); rs60498098(A,G); rs10486179(G,A); rs10486180(T,C); rs115526956(G,A); rs2190248(A,G); rs17168463(A,G); rs6964397(C,G); rs2023999(G,A); rs142231736(T,G); rs78583728(T,C); rs28460422(G,A); rs28553401(C,T); rs141962411(G,A); rs28483212(G,A); rs115849478(C,T); rs9648107(C,T); rs2006880(G,C); rs720288(C,A); rs114424196(C,T); rs77463654(A,G); rs2348336(G,A); rs2881889(A,G); rs17168516(T,G); rs7804532(G,C); rs17168526(T,C); rs7810456(C,T); rs2108066(T,G); rs6977800(G,A); rs115567879(G,T); rs1978189(G,C); rs1978190(C,T); rs17168530(T,C); rs2190249(G,A); rs57830645(A,G); rs61285017(T,C) |
| ccdsGene name | CCDS43553.1 |
| cytoBand name | 7p21.3 |
| EntrezGene GeneID | 340267 |
| EntrezGene Description | collagen, type XXVIII, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL28A1:NM_001037763:exon30:c.C2321G:p.T774R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8963 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2UY09 |
| dbNSFP Uniprot ID | COSA1_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000337 |
| ESP Eur/Amr MAF | 0.000488 |
| ExAC AF | 0.000425 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation;
Postnatal growth retardation;
Poor overall growth
HEAD AND NECK:
[Head];
Microcephaly
RESPIRATORY:
Recurrent respiratory infections;
Respiratory failure (in some patients);
[Lung];
Lung fibrosis
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation
NEUROLOGIC:
[Central nervous system];
Delayed cognitive development, mild (reported in 1 family)
ENDOCRINE FEATURES:
Adrenal insufficiency;
Corticosteroid deficiency
IMMUNOLOGY:
Decreased numbers of circulating NK cells (less than 5%);
Lymphadenopathy;
Recurrent viral infections
NEOPLASIA:
Increased susceptibility to cancer;
Lymphoproliferative disorders
LABORATORY ABNORMALITIES:
Cell studies show increased DNA breakage;
Increased ACTH
MISCELLANEOUS:
Growth retardation onset in utero;
Glucocorticoid deficiency occurs in mid-childhood;
Founder effect in Irish Traveler population
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. Cerevisiae minichromosome
maintenance 4 gene (MCM4, 602638.0001)
OMIM Title
*609996 COLLAGEN, TYPE XXVIII, ALPHA-1; COL28A1
OMIM Description
DESCRIPTION
COL28A1 belongs to a class of collagens containing von Willebrand factor
(VWF; 613160) type A (VWFA) domains (Veit et al., 2006).
CLONING
By screening a genomic database with collagen (see COL1A1; 120150) and
matrilin (see MATN1; 115437) sequences as query, followed by PCR of a
lung cDNA library, Veit et al. (2006) cloned COL28A1. The deduced
1,125-amino acid protein contains an N-terminal signal peptide, followed
by a VWFA domain, a central collagen domain, a second VWFA domain, a
unique region, and a C-terminal Kunitz-type serine protease inhibitor
domain. The C-terminal end of the collagen domain contains an RGD motif.
Human COL28A1 shares 86.5% amino acid identity with the 1,141-amino acid
mouse Col28a1 protein, with highest identity (91.5%) in the collagen
domain and lowest identity (63.9%) in the unique domain, which is 16
amino acids shorter in human. Veit et al. (2006) identified several
partial human and mouse cDNAs for splice variants encoding truncated
proteins. SDS-PAGE showed mouse Col28a1 secreted into the culture medium
from transfected human embryonic kidney cells as a 135-kD monomer under
reducing conditions and as a homotrimer under nonreducing conditions.
Northern blot analysis of newborn mouse tissues detected 5.2- and 4.0-kb
transcripts in skin, intestine, sternum, brain, and kidney. In addition,
RT-PCR showed expression in heart, lung, sciatic nerve, and calvaria of
newborn mice, and in intestine and brain of adult mice.
Immunohistochemical analysis of mouse embryos revealed major expression
of Col28a1 in dorsal root ganglia and peripheral nerves, with small
amounts in connective tissues like calvaria and skin. Immunogold
electron microscopy detected Col28a1 in the basement membrane
surrounding a particular subset of Schwann cells in adult mouse sciatic
nerve.
GENE STRUCTURE
Veit et al. (2006) determined that the COL28A1 gene spans 178 kb and
contains 34 coding exons and 1 upstream noncoding exon. The mouse
Col28a1 gene spans 195 kb and has the same organization as human
COL28A1.
MAPPING
By genomic sequence analysis Veit et al. (2006) mapped the COL28A1 gene
to chromosome 7p21.3. They mapped the mouse Col28a1 gene to a region of
chromosome 6A1 that shares homology of synteny with human chromosome
7p21.3.
PER4
| dbSNP name | rs3921617(T,C); rs60730199(A,C); rs2062925(T,G); rs73049071(T,C); rs77707585(A,T); rs78327764(C,T); rs78362369(A,G) |
| cytoBand name | 7p21.3 |
| EntrezGene GeneID | 168741 |
| EntrezGene Description | period circadian clock 3 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3301 |
MEOX2
| dbSNP name | rs10777(G,T); rs17168900(C,G); rs12672203(T,C); rs17199(C,T); rs2237492(A,T); rs2237493(T,G); rs2237494(T,G); rs7783223(T,G); rs7800473(A,C); rs9638727(T,A); rs10259769(G,A); rs71540714(A,G); rs13227097(G,A); rs6955921(T,G); rs6949297(G,A); rs10950573(T,G); rs6950541(G,A); rs6970492(T,C); rs73298592(T,C); rs6461196(T,C); rs6461197(T,G); rs10275641(A,G); rs10261835(T,C); rs10246570(G,A); rs7788980(A,T); rs73298595(C,G); rs118111792(T,A); rs7793128(C,A); rs17168904(A,G); rs7793310(C,T); rs7812247(T,G); rs7793334(A,G); rs7793459(A,C); rs7793498(A,G); rs6960768(A,G); rs17168905(G,A); rs6943140(T,C); rs6961370(G,T); rs17168906(C,G); rs10266294(T,C); rs17168907(C,T); rs10254079(G,A); rs74707316(T,C); rs10224510(A,G); rs10254129(C,A); rs17334243(T,C); rs12216628(C,G); rs12216674(T,G); rs12216556(A,C); rs4377858(A,T); rs4527782(C,T); rs4492268(T,C); rs4527783(C,T); rs4466293(T,C); rs4326285(G,C); rs10486768(G,A); rs7458404(A,T); rs2214505(A,T); rs2189449(C,T); rs10486769(C,T); rs10262513(C,T); rs73300557(A,C); rs2107267(A,G); rs2107268(A,G); rs3823870(C,T); rs73300560(T,A); rs17168915(T,G); rs10242014(A,T); rs75652552(C,T); rs10231999(T,A); rs7788718(C,T); rs17419441(A,T); rs7793546(C,T); rs7793547(C,T); rs73300564(G,A); rs7806599(C,T); rs10261246(G,A); rs7807094(A,G); rs2282932(C,G); rs2282933(T,C); rs6962943(T,G); rs3779405(A,T); rs3779406(C,T); rs7800593(T,C); rs7781465(C,T); rs17168920(G,C); rs17168924(A,T); rs3801416(G,C); rs73300577(G,A); rs28452656(G,A); rs7786092(A,T); rs7786661(G,T); rs7805746(T,C); rs6461198(C,A); rs6953784(C,G); rs4436006(G,C); rs17168926(C,G); rs1548691(G,A); rs2892794(A,G); rs17168927(C,T); rs6959221(G,C); rs6958841(A,G); rs17168931(G,C); rs2237495(C,A); rs2237496(G,T); rs77686454(T,A); rs17168933(C,G); rs12666514(C,T); rs16878569(A,C); rs2389537(A,G); rs74367680(C,T); rs17168935(C,G); rs17168936(G,A); rs17168937(C,T); rs17168938(G,A); rs28667059(G,C); rs17168940(A,G); rs10281319(G,A); rs17420659(G,T); rs3801419(G,A); rs978993(G,A); rs3823871(G,A); rs73302414(C,T); rs75741923(A,C); rs55774621(C,T); rs116271424(A,G); rs6945762(G,A); rs13438001(C,T); rs151081252(C,A); rs76902068(T,C); rs2282934(T,G); rs2282935(G,T); rs41343244(A,G); rs34460507(A,G); rs62439049(G,A); rs116148055(G,A); rs76054184(A,G); rs3801421(G,C); rs10486770(G,C); rs10270030(T,C); rs10228856(A,C); rs17336581(A,G); rs10486771(A,G); rs11982768(G,A); rs10249754(A,G); rs2389538(T,G); rs6461200(A,G); rs7811538(A,G); rs6942877(G,C); rs12056299(T,C); rs917437(T,C); rs117108264(C,A); rs7786884(C,A); rs7787043(C,T); rs62439053(G,A); rs981597(G,C); rs17421415(T,A); rs10278557(G,A); rs10282109(C,A); rs6969225(C,T); rs17336881(G,C); rs10236046(C,A); rs17336916(C,A); rs6947658(C,T); rs6972599(G,T); rs143363167(G,C); rs12533130(G,A); rs758297(G,A); rs12533863(C,T); rs34994232(A,C); rs57483785(T,G); rs73288145(C,T); rs76448893(C,T); rs4532497(C,T); rs10046550(G,A); rs10046551(G,C); rs6461202(T,C); rs17168971(T,A); rs6980299(T,C); rs957104(A,G); rs4380818(C,T); rs79242086(T,C); rs6942739(C,T); rs3801423(A,G); rs7781366(A,G); rs7800748(T,C); rs13224011(T,C); rs3801426(T,C); rs3801427(C,T); rs6959056(G,A); rs35565542(T,C); rs114069070(C,T); rs16878585(C,T); rs12540302(C,G); rs75325422(T,C); rs3801430(G,A); rs917438(C,T); rs917439(C,A); rs917440(C,T); rs6461204(T,G); rs144533382(G,T); rs1050290(G,A) |
| ccdsGene name | CCDS34605.1 |
| cytoBand name | 7p21.2 |
| EntrezGene GeneID | 4223 |
| EntrezGene Description | mesenchyme homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MEOX2:NM_005924:exon1:c.C61A:p.P21T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5995 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P50222 |
| dbNSFP Uniprot ID | MEOX2_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000908 |
| ESP All MAF | 0.000461 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0004965 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Motor seizures, nocturnal, usually occur in clusters (up to 8 per
night) during dozing or on awakening;
Arm flexion;
Tonic head extension;
Unintelligible speech;
Mouth movements;
Aura may occur;
Ictal EEG showed partial seizures with frontal lobe origin;
Mental retardation (rare)
MISCELLANEOUS:
Onset in childhood;
May be misdiagnosed as nightmares, night terrors, parasomnias, or
psychiatric disorders;
Incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the neuronal nicotinic cholinergic receptor,
alpha polypeptide 4 gene (CHRNA4, 118504.0002)
OMIM Title
*600535 MESENCHYME HOMEOBOX 2; MEOX2
;;MOX2 DIVERGED HOMEOBOX GENE;;
MOX2, MOUSE, HOMOLOG OF;;
GROWTH ARREST-SPECIFIC HOMEOBOX; GAX
OMIM Description
CLONING
Candia et al. (1992) isolated the mouse Mox2 gene, which belongs to a
family of nonclustered, diverged homeobox genes. In situ hybridization
analysis during murine embryogenesis indicated that the Mox2 gene is
expressed in a wide range of mesodermal structures, including somites
and vertebrae, the developing limbs, groups of muscles of the head, and
the developing palate. These findings suggested that mutations in the
human homolog of the Mox2 gene may be involved in craniofacial and/or
skeletal abnormalities.
Gorski et al. (1993) isolated a clone corresponding to a homeoprotein
gene from an adult rat aorta cDNA library, and termed it Gax, for
'growth arrest-specific homeobox,' to reflect the regulation of its
expression in vascular smooth muscle cells. The deduced 303-amino acid
protein contains a conserved homeodomain identical to that reported by
Candia et al. (1992) for the Mox2 protein. Northern blot analysis
detected a single mRNA transcript only in adult rat aorta smooth muscle
cells, adult renal mesangial cells, and adult lung. Gax was more widely
expressed in the developing cardiovascular system, multiple mesodermal
tissues, and some ectodermal tissues.
LePage et al. (1994) isolated and characterized the human GAX gene. The
human and rat GAX protein sequences showed 98% identity. Similar to the
rat, the human homolog contains a CAX trinucleotide repeat N-terminal to
the homeodomain that encodes a stretch of 17 consecutive histidine or
glutamine residues.
Grigoriou et al. (1995) isolated and characterized cDNA clones for the
human MOX2 gene. The MOX2 protein contains all of the characteristic
features of Mox2 proteins of other vertebrate species, namely the
homeobox, the polyhistidine stretch, and a number of potential
serine/threonine phosphorylation sites. The homeodomain of the Mox2
protein is identical to that in all other vertebrate species studied to
that time (rodents and amphibians).
MAPPING
By fluorescence in situ hybridization, LePage et al. (1994) mapped the
human GAX gene to chromosome 7p22. Using the same method, Grigoriou et
al. (1995) mapped the gene to 7p22.1-p21.3.
Gorski et al. (1993) mapped the mouse Gax gene to chromosome 12 by
interspecific backcross analysis.
GENE FUNCTION
Gorski et al. (1993) found that expression of the GAX gene in vascular
smooth muscle cells was rapidly downregulated when these cells were
stimulated by mitogens to reenter the cell cycle. GAX expression was
induced when proliferating cells were deprived of serum. The data
suggested that GAX may have a regulatory role in the cell cycle.
Wu et al. (2005) cited reports suggesting that neurovascular dysfunction
contributes to Alzheimer disease (AD; 104300), as manifest by altered
cerebral blood flow, aberrant angiogenesis and vascular remodeling, and
insufficient clearance of beta-amyloid. Using cDNA microarray analysis
to examine human brain endothelial cells, Wu et al. (2005) found that
expression of the MEOX2 gene was reduced in cells from 16 patients with
Alzheimer disease compared to age-matched controls. Total capillary
length in AD cortical brain tissue was reduced by approximately 60%
compared to age-matched controls, and was inversely related to dementia
scores. Transduction of the AD brain endothelial cells with the human
MEOX2 gene increased vascular endothelial growth factor (VEGF;
192240)-mediated capillary tube formation and increased the levels of
the low-density lipoprotein receptor-related protein-1 (LRP1; 107770), a
major beta-amyloid clearance receptor at the blood-brain barrier.
Partial deletion of the Meox gene in mice (Meox +/-) resulted in
decreased brain capillary density and resting cerebral blood flow, loss
of the angiogenic response to hypoxia in the brain, and deficient
clearance of beta-amyloid from the brain associated with from decreased
levels of LRP1 at the blood-brain barrier. Wu et al. (2005) concluded
that MEOX2 is linked to neurovascular dysfunction in AD.
Using a yeast 2-hybrid assay, Lin et al. (2005) found that MEOX2 had 11
putative interacting proteins, including RNF10 (615998). Using protein
interaction assays, they confirmed a specific interaction between MEOX2
and RNF10. Domain analysis revealed that the C-terminal region of RNF10
interacted with a central region of MEOX2 between the
histidine/glutamine-rich region and the homeodomain. Expression of RNF10
or MEOX2 in NIH-3T3 cells activated a p21(WAF1) (CDKN1A; 116899)
reporter, and expression of both synergistically elevated reported
activation.
Chen and Gorski (2008) identified 2 miR130A (MIRN130A; 610175) target
sites within a 280-bp sequence of the GAX 3-prime UTR and showed that
these sites were required for rapid downregulation of GAX expression by
serum and proangiogenic factors in human umbilical vein endothelial
cells. This 280-bp sequence of GAX mediated serum-induced downregulation
of a reporter gene when ligated 3-prime of it. Conversely, forced
expression of miR130A inhibited endogenous GAX expression.
Cao et al. (2010) found that MIR301 (MIR301A; 615675) indirectly
upregulated expression of its host gene, SKA2. They determined that
MIR301 inhibited expression of MEOX2, a negative regulator of the
ERK/MAPK signaling pathway (see MAPK1, 176948) and downstream CREB
(CREB1; 123810) phosphorylation, via 2 MIR301-binding sites in the MEOX2
3-prime UTR. Inhibitor, binding, and expression studies suggested that
downregulation of MEOX2 via MIR301 first permitted ERK1 (MAPK3;
601795)/ERK2 (MAPK1) expression and activation, then CREB
phosphorylation and binding of phosphorylated CREB to the SKA2 promoter,
resulting in CREB-dependent induction of SKA2 expression.
Zhou et al. (2012) found that expression of MIR301A was significantly
upregulated in hepatocellular carcinomas compared with matching normal
tissues, concomitant with downregulation of GAX. Expression of an
MIR301A inhibitor in HepG2 cells reduced cell proliferation, migration,
and invasion and induced apoptosis, coincident with increased GAX mRNA
expression.
NOMENCLATURE
The symbol MOX2 is used for a gene on chromosome 3 that encodes a
membrane glycoprotein defined by a monoclonal antibody; see 155970.
ANIMAL MODEL
Mankoo et al. (1999) generated mice homozygous for a null mutation of
Mox2 by targeted disruption. Mox2 -/- mice had a developmental defect of
the limb musculature characterized by an overall reduction in muscle
mass and elimination of specific muscles. Mox2 was not needed for the
migration of myogenic precursors into the limb bud, but it was essential
for normal appendicular muscle formation and for the normal regulation
of myogenic genes, as demonstrated by the downregulation of Pax3
(600535) and Myf5 (159990), but not MyoD (159970), in Mox2-deficient
limb buds. Mankoo et al. (1999) concluded that MOX2 homeoprotein is an
important regulator of vertebrate limb myogenesis.
PRPS1L1
| dbSNP name | rs3800962(C,A); rs73313931(G,A) |
| ccdsGene name | CCDS47552.1 |
| cytoBand name | 7p21.1 |
| EntrezGene GeneID | 221823 |
| EntrezGene Description | phosphoribosyl pyrophosphate synthetase 1-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRPS1L1:NM_175886:exon1:c.G837T:p.E279D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P21108 |
| dbNSFP Uniprot ID | PRPS3_HUMAN |
| dbNSFP KGp1 AF | 0.300824175824 |
| dbNSFP KGp1 Afr AF | 0.172764227642 |
| dbNSFP KGp1 Amr AF | 0.425414364641 |
| dbNSFP KGp1 Asn AF | 0.162587412587 |
| dbNSFP KGp1 Eur AF | 0.428759894459 |
| dbSNP GMAF | 0.2998 |
| ESP Afr MAF | 0.227851 |
| ESP All MAF | 0.357176 |
| ESP Eur/Amr MAF | 0.423372 |
| ExAC AF | 0.365 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Microphthalmia;
[Mouth];
Cleft lip;
Cleft palate
ABDOMEN:
[Liver];
Bile duct proliferation
GENITOURINARY:
[Kidneys];
Cystic renal disease
SKELETAL:
[Limbs];
Bowing of the long bones;
[Hands];
Postaxial polydactyly;
[Feet];
Postaxial polydactyly
NEUROLOGIC:
[Central nervous system];
Occipital encephalocele;
Anencephaly
MISCELLANEOUS:
Prenatal or perinatal death;
Genetic heterogeneity;
See Joubert syndrome 7 (611560), an allelic disorder with a less
severe phenotype
MOLECULAR BASIS:
Caused by mutation in the RPGRIP1-like gene (RPGRIP1L, 610937.0005).
OMIM Title
*611566 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE 1-LIKE 1; PRPS1L1
;;PRPS1-LIKE 1;;
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE 3; PRPS3
OMIM Description
CLONING
Using rat Prps1 (311850) to screen a human testis cDNA library, Taira et
al. (1990) cloned PRPS1L1, which they called PRPS3. The deduced
318-amino acid protein has a calculated molecular mass of 34.7 kD.
Peptide sequencing and mutagenesis experiments showed that translation
of PRPS3 initiates at an ACG codon that specifies methionine rather than
threonine, and that this methionine is subsequently removed, resulting
in a mature protein with an N-terminal proline. In vitro transcription
and cell-free translation resulted in a protein with an apparent
molecular mass of 38 kD. Northern blot analysis detected a 1.4-kb
transcript in human testis. Prps3 expression was not detected in testis
of 3-week-old rats, but its expression increased after 4 weeks, roughly
correlating with the appearance of primary spermatocytes.
MAPPING
By Southern blot and somatic cell hybrid analyses, Taira et al. (1990)
mapped the PRPS1L1 gene to chromosome 7.
FERD3L
| dbSNP name | rs17140719(G,A) |
| ccdsGene name | CCDS5368.1 |
| cytoBand name | 7p21.1 |
| EntrezGene GeneID | 222894 |
| EntrezGene Description | Fer3-like bHLH transcription factor |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FERD3L:NM_152898:exon1:c.C351T:p.L117L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.047889 |
| ESP All MAF | 0.016454 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.004741 |
ABCB5
| dbSNP name | rs2106562(C,G); rs7809674(G,A); rs74989588(C,G); rs79217266(T,C); rs78824213(C,T); rs73276516(C,T); rs186008080(C,A); rs116342675(G,T); rs55973507(T,G); rs80113141(T,C); rs115302678(A,G); rs59381215(A,G); rs59103173(T,A); rs111423359(G,A); rs4446638(G,T); rs12667658(T,A); rs113671828(A,G); rs59769002(T,C); rs74780938(C,T); rs76218383(A,G); rs9791568(T,A); rs9791579(T,A); rs183721084(A,G); rs56080217(C,T); rs73684571(T,C); rs78019691(T,A); rs78293595(A,G); rs59953213(C,A); rs75076396(G,C); rs60463597(T,G); rs111872870(C,T); rs75494098(C,T); rs7777864(G,C); rs75396930(G,A); rs73684573(T,C); rs76810225(C,A); rs149821908(T,G); rs73684574(A,G); rs73684575(T,C); rs146655216(T,G); rs11766004(A,G); rs368670705(G,A); rs11773775(G,A); rs73684577(A,G); rs73684578(T,A); rs76128634(G,A); rs17143187(G,C); rs75495305(T,G); rs7802291(G,A); rs7802772(C,T); rs114276553(G,A); rs11543624(A,C); rs10236436(G,A); rs187883871(G,A); rs1476484(C,G); rs1476485(T,C); rs78815065(T,C); rs79904744(T,A); rs6947743(C,G); rs16872578(G,A); rs111398159(A,G); rs17143197(G,A); rs189556129(T,C); rs4721925(C,T); rs75353400(A,T); rs76859629(T,G); rs191352840(T,C); rs58361444(C,A); rs6963630(C,T); rs6964702(G,A); rs34322449(T,A); rs55653237(A,G); rs34259677(G,A); rs6946005(C,T); rs6946293(G,T); rs6946164(C,A); rs6946054(A,G); rs56144764(T,G); rs6966528(T,C); rs58241579(A,G); rs13238912(G,T); rs13226131(T,G); rs73276596(C,A); rs77245016(A,T); rs77726188(C,G); rs17143206(A,G); rs35484201(G,A); rs2893005(G,T); rs6461510(C,T); rs73276599(C,G); rs59623110(T,C); rs6967789(G,T); rs34724473(T,G); rs2188594(G,A); rs79448643(A,C); rs75465236(A,G); rs4721926(G,C); rs1004060(T,C); rs77923898(A,G); rs73688304(G,C); rs77072593(G,A); rs11772341(T,C); rs11773053(T,C); rs2106563(C,T); rs7793193(T,C); rs7810173(C,T); rs73276602(A,C); rs77414882(A,T); rs73688305(A,G); rs10216013(G,C); rs7783959(A,C); rs11982947(C,A); rs73278603(C,T); rs6957205(A,C); rs7786228(T,G); rs3922365(A,T); rs11983326(T,G); rs11769236(G,A); rs11772926(T,C); rs1858948(A,C); rs756885(A,G); rs2893006(C,T); rs75784515(C,T); rs58976125(A,G); rs6949755(C,G); rs6950224(G,C); rs6950237(G,A); rs6950370(G,A); rs4721927(G,C); rs11981909(G,A); rs6954971(A,C); rs55663200(C,T); rs6955287(A,C); rs916737(A,C); rs916738(C,T); rs2188595(T,C); rs11976848(A,G); rs11973722(T,A); rs10950825(T,C); rs10950826(C,T); rs11983804(C,T); rs191703449(C,T); rs56833101(T,C); rs77707831(A,G); rs3213622(T,C); rs3213623(C,T); rs34603556(T,C); rs73278647(T,C); rs6952503(T,C); rs78879263(C,T); rs78848969(A,G); rs17816709(C,A); rs2285554(G,T); rs2285555(C,G); rs2285556(A,C); rs150777917(G,A); rs77926987(C,A); rs2285557(T,G); rs73684657(A,G); rs2285558(C,T); rs2285559(A,C); rs2285560(G,A); rs1108864(C,A); rs76157869(T,G); rs57779704(T,C); rs58835955(C,G); rs73684658(T,C); rs6958493(G,A); rs79760827(C,G); rs13243492(A,G); rs6958596(C,T); rs12700226(C,A); rs2097681(G,T); rs2078905(T,C); rs115583554(T,A); rs7796207(C,T); rs7796543(A,T); rs7779761(T,C); rs35359563(C,T); rs58797611(C,T); rs67368461(G,A); rs6946594(T,C); rs68180882(G,A); rs73278664(C,G); rs35120147(T,G); rs73278668(C,T); rs1079907(G,C); rs59488551(C,A); rs7784984(T,C); rs6951722(T,C); rs7802093(A,G); rs7785407(T,C); rs7806279(C,G); rs17143253(A,G); rs7806753(C,A); rs182644687(T,C); rs7807360(C,G); rs2301641(A,G); rs73278680(C,G); rs73278683(C,A); rs73278684(C,T); rs73684671(T,C); rs73684672(A,G); rs73278686(C,T); rs111725798(C,T); rs112762761(C,T); rs11763916(G,C); rs11770673(A,T); rs6947250(C,G); rs11763925(C,T); rs6967746(T,G); rs11770822(A,G); rs11764054(C,T); rs11764057(C,T); rs58540449(A,G); rs60844047(G,A); rs13223438(T,C); rs6948334(G,A); rs58976477(T,C); rs6952128(A,C); rs73684676(T,A); rs73684678(A,G); rs5011448(C,T); rs5011447(G,A); rs2893007(A,T); rs5011446(C,T); rs2390348(G,T); rs73684679(C,T); rs5011445(T,C); rs5011444(T,C); rs73684681(G,A); rs74809645(G,T); rs111313937(T,C); rs75731479(G,T); rs113686902(G,C); rs7792001(G,C); rs6958928(G,A); rs7792341(G,C); rs77663125(T,C); rs67397922(A,T); rs66744319(T,C); rs76827596(C,G); rs12155194(T,C); rs144864002(C,T); rs111905715(A,G); rs139104534(G,C); rs13223600(A,G); rs13238268(T,C); rs7801455(A,G); rs7784593(T,A); rs7801468(A,G); rs1011559(A,C); rs1011560(T,C); rs916739(G,A); rs916740(C,T); rs916741(C,G); rs1011561(T,G); rs6949607(C,T); rs59088839(G,A); rs1059006(C,T); rs73280614(C,A); rs4476902(C,G); rs10950827(C,G); rs111241327(G,T); rs113010173(A,G); rs12535128(G,T); rs114319712(T,A); rs12537843(T,C); rs12540337(A,T); rs28656113(A,C); rs73280628(T,C); rs62456151(T,C); rs1548642(C,T); rs138603104(G,A); rs113390180(T,C); rs1972525(C,G); rs7455102(A,G); rs6943237(C,T); rs28491716(C,G); rs186099471(C,G); rs73280636(T,C); rs12700228(A,G); rs1859777(C,T); rs13220972(T,C); rs7782507(A,T); rs114740566(G,A); rs75188110(G,A); rs6970012(T,C); rs13240297(A,G); rs10275105(C,G); rs113448324(T,C); rs192572587(C,G); rs2097941(G,C); rs59078559(G,A); rs145914918(C,A); rs146633577(A,G); rs7806967(G,A); rs2158852(C,T); rs6980367(G,T); rs10236314(A,C); rs10281505(T,C); rs10266137(G,A); rs75353779(C,T); rs77506013(A,G); rs10240441(A,T); rs34258758(C,G); rs7785558(A,T); rs7785736(A,G); rs7805048(T,G); rs7786008(C,T); rs7786149(C,A); rs7805940(T,C); rs4721933(G,A); rs4719622(T,C); rs7795777(A,C); rs77035892(A,G); rs73280657(T,A); rs12666434(G,C); rs11764760(T,C); rs6974315(G,C); rs141194214(G,A); rs113593309(A,C); rs61529054(G,C); rs111507058(T,C); rs113369941(T,G); rs2158851(A,T); rs73280668(C,G); rs7812159(C,T); rs7812181(C,A); rs10215589(T,C); rs188858220(C,T); rs147712289(T,G); rs112963348(A,G); rs140749056(C,A); rs150076025(C,A); rs17817117(G,C); rs28515741(T,C); rs113449905(G,A); rs78978349(G,A); rs73280674(G,A); rs116201787(C,T); rs77606090(C,T); rs76022765(C,T); rs73263605(T,C); rs73263606(C,T); rs112572841(C,T); rs17143258(C,T); rs75761559(A,G); rs10230205(C,T); rs17143260(C,T); rs77959988(G,A); rs112377573(T,C); rs73263611(G,C); rs7805806(A,G); rs67937303(T,C); rs2190411(G,C); rs2190410(A,G); rs11974407(G,C); rs73263618(G,T); rs12700229(T,C); rs75204054(C,A); rs2158858(G,A); rs2158857(A,G); rs2190409(C,T); rs4721937(A,G); rs115017163(G,A); rs2158856(G,A); rs137947585(G,A); rs59582697(T,G); rs7793093(A,G); rs114854568(A,T); rs2024046(G,C); rs2024045(C,T); rs6965084(A,G); rs143651658(G,A); rs12673236(T,G); rs11762180(A,C); rs13229035(A,C); rs138448958(G,A); rs7459042(G,C); rs191152069(A,G); rs13229481(A,G); rs17218190(G,A); rs17218211(A,G); rs17218253(G,T); rs17143279(C,T); rs9655200(A,T); rs17218378(G,T); rs4142216(C,T); rs10488579(A,T); rs10488578(C,A); rs1859779(A,G); rs142165703(C,T); rs80339097(C,T); rs12700231(G,C); rs78902135(T,C); rs12700232(A,G); rs13244742(G,T); rs6960526(G,T); rs2158855(A,C); rs2158854(C,T); rs17841821(C,G); rs17218839(G,A); rs2158853(G,A); rs2108259(A,G); rs10950828(T,C); rs10269226(G,A); rs10239567(A,T); rs62453366(G,T); rs76199937(T,G); rs10230796(T,A); rs73085670(C,T); rs77358554(T,G); rs115223442(T,G); rs114357577(T,C); rs62453367(G,A); rs12673841(G,T); rs75967195(C,G); rs60288861(A,G); rs12674332(G,C); rs111486917(C,A); rs112475034(T,G); rs4719623(T,C); rs62453368(C,T); rs4719624(G,A); rs4719625(G,C); rs10950829(C,T); rs35500007(C,T); rs60057191(A,G); rs149497846(C,T); rs112711422(G,A); rs78059780(G,A); rs73684817(A,G); rs77036336(G,A); rs111826952(G,A); rs78540120(G,C); rs77229821(C,A); rs115020864(C,T); rs112463413(C,T); rs73684819(A,T); rs73684820(A,G); rs11978030(T,G); rs73684821(T,C); rs73684822(T,C); rs28539094(A,G); rs7781063(C,T); rs28483721(G,C); rs7781446(G,A); rs7781367(C,T); rs10280354(G,A); rs113949418(C,T); rs6461511(C,T); rs61664241(T,G); rs6961926(G,A); rs10280562(C,G); rs6961718(A,G); rs6961999(C,G); rs6944236(T,C); rs10429254(G,A); rs6962189(A,C); rs10251502(A,T); rs77431988(A,C); rs10081180(C,G); rs28517520(G,A); rs6967102(A,G); rs6949373(T,C); rs6967386(C,A); rs6949505(T,A); rs28733347(T,C); rs57856977(G,A); rs10255864(A,T); rs10259000(A,G); rs6972085(C,T); rs12700234(A,G); rs10259493(A,G); rs10230194(C,A); rs10230211(C,G); rs10230482(C,G); rs56118169(G,A); rs10234365(G,C); rs73684826(G,A); rs12700235(T,C); rs12700236(G,A); rs73684827(C,T); rs73684828(C,A); rs57055940(T,G); rs60249999(A,T); rs60806604(G,A); rs78938560(A,G); rs78089198(G,A); rs142524674(G,T); rs10272566(A,G); rs112298506(C,G); rs34972642(C,T); rs6461512(C,T); rs10266338(T,G); rs143272506(T,G); rs1023541(A,G); rs6948504(T,A); rs73085689(T,C); rs62453384(G,T); rs62453385(T,C); rs10255466(G,A); rs10950830(C,T); rs11971339(A,C); rs114263536(G,A); rs10274681(T,C); rs6461513(C,T); rs6461514(A,T); rs10275163(T,C); rs35890743(A,G); rs7805095(A,G); rs10230270(A,G); rs10259771(C,T); rs10950831(G,T); rs58366303(A,G); rs116480617(T,C); rs139851575(G,C); rs73687881(A,T); rs6949442(C,T); rs73085700(T,A); rs4721938(C,T); rs4721939(T,C); rs10260951(T,G); rs116835727(C,T); rs11982664(A,G); rs184908266(G,T); rs12671464(T,C); rs111905956(T,A); rs112606766(C,A); rs6959530(C,T); rs141788929(A,G); rs11976861(C,G); rs7780859(T,C); rs4721940(C,T); rs17143304(G,A); rs10254317(G,A); rs34706780(A,T); rs66517007(T,C); rs4719626(T,C); rs17143308(C,T); rs4721941(G,A); rs28542123(A,T); rs28589888(T,A); rs10277477(T,C); rs146190350(A,G); rs116102182(C,G); rs11972818(A,G); rs56839020(G,T); rs7791932(T,A); rs7808708(A,G); rs17143311(C,T); rs9886279(C,T); rs4142217(A,G); rs73687887(T,C); rs73687888(A,C); rs113588235(C,T); rs148403905(C,T); rs17219864(G,T); rs113800362(G,C); rs6960186(G,C); rs17819135(A,G); rs55668814(C,A); rs6974423(G,A); rs73687889(T,C); rs73687891(C,T); rs113473125(A,G); rs189389191(G,A); rs17819195(G,C); rs35621824(C,A); rs10269525(C,T); rs9638774(T,G); rs149791597(T,C); rs9638775(T,A); rs10273704(G,C); rs10244045(A,G); rs6461515(G,A); rs6461516(C,G); rs1859778(T,G); rs2005762(T,C); rs62453390(G,T); rs6950727(T,C); rs6968883(G,A); rs62453391(C,T); rs10231520(C,T); rs12669400(T,C); rs12669866(T,C); rs117971876(G,C); rs13231600(A,G); rs11763853(G,A); rs6947306(C,G); rs6967583(T,C); rs11973873(T,A); rs10236887(T,C); rs10280418(C,T); rs60197951(T,C); rs6461517(C,T); rs6461518(T,A); rs4719627(C,T); rs10263244(A,T); rs6978285(A,T); rs17220780(C,T); rs58810883(A,G); rs60967689(T,G); rs1023540(C,G); rs4721945(C,T); rs150818104(C,A); rs149643958(G,C); rs76916500(G,A); rs10266329(T,C); rs2528800(A,T); rs142099907(C,T); rs13225659(A,T); rs1015646(T,A); rs2709747(A,G); rs2528801(G,A); rs143451572(C,T); rs12112555(G,T); rs3210441(G,A); rs966717(T,C) |
| ccdsGene name | CCDS55090.1 |
| cytoBand name | 7p21.1 |
| EntrezGene GeneID | 340273 |
| EntrezGene Description | ATP-binding cassette, sub-family B (MDR/TAP), member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCB5:NM_001163941:exon11:c.A1105G:p.I369V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5268 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A7BKA4 |
| dbNSFP KGp1 AF | 0.0123626373626 |
| dbNSFP KGp1 Afr AF | 0.0447154471545 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.0124 |
| ESP Afr MAF | 0.040816 |
| ESP All MAF | 0.012629 |
| ESP Eur/Amr MAF | 0.000279 |
| ExAC AF | 0.003892 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Retinal arteriolar tortuosity;
Retinal hemorrhage
CARDIOVASCULAR:
[Heart];
Arrhythmias, supraventricular;
[Vascular];
Aneurysms of right internal carotid artery, intracranial segment;
Aneurysm of right middle cerebral artery, horizontal segment;
Raynaud phenomenon
GENITOURINARY:
[Kidneys];
Hematuria, microscopic;
Hematuria, gross (in some patients);
Renal cysts;
Renal failure, mild;
Basement membrane alterations in Bowman capsule, tubules, and interstitial
capillaries, with irregular thickening, splitting into multiple layers,
and electron-lucent areas;
Glomerular basement membrane normal
SKIN, NAILS, HAIR:
[Skin];
ELECTRON MICROSCOPY:;
Basement membrane duplications at dermoepidermal junction;
Dermal arteriole dissociation in vascular smooth muscle cells;
Basement membrane abnormally spread in vascular smooth muscle cells
[Nails];
Capillary tortuosity in nail beds
MUSCLE, SOFT TISSUE:
Muscle cramps
NEUROLOGIC:
[Central nervous system];
Leukoencephalopathy, periventricular;
Microvascular spaces, dilated;
Cerebrovascular accident (in some patients)
LABORATORY ABNORMALITIES:
Creatine kinase, serum, elevated;
Glomerular filtration rate, decreased
MOLECULAR BASIS:
Caused by mutation in the collagen IV, alpha-1 polypeptide gene (COL4A1,
120130.0007)
OMIM Title
*611785 ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 5; ABCB5
OMIM Description
DESCRIPTION
ABCB5 belongs to the ATP-binding cassette (ABC) transporter superfamily
of integral membrane proteins. These proteins participate in
ATP-dependent transmembrane transport of structurally diverse molecules
ranging from small ions, sugars, and peptides to more complex organic
molecules (Chen et al., 2005).
CLONING
By searching a database for homologs of ABCB1 (171050), followed by
RT-PCR of RNA from human primary epidermal melanocytes and a malignant
melanoma cell line, Frank et al. (2003) cloned ABCB5. The deduced
812-amino acid protein has 5 transmembrane helices flanked by both
extracellular and intracellular ATP-binding domains. ABCB5 shares 54%
and 56% amino acid identity with ABCB1 and ABCB4 (171060), respectively.
RT-PCR detected ABCB5 in melanocytes and melanoma cells, but not in
peripheral blood mononuclear cells or nonmelanoma tumor cell lines.
Western blot analysis revealed an 89-kD endogenous ABCB5 protein in
melanocytes and melanoma cells. Flow cytometry showed ABCB5 expressed on
the cell surface of transfected breast cancer cells.
By screening a melanoma cDNA library, Chen et al. (2005) cloned 2 ABCB5
splice variants, which they called ABCB5-alpha and -beta. ABCB5-alpha
and -beta diverge after exon 6, with ABCB5-alpha including a seventh
exon that encodes its 3-prime UTR, and ABCB5-beta including 14 more
exons. The 131-amino acid ABCB5-alpha protein has a calculated molecular
mass of 15 kD. It has an ABC signature motif and a Walker B consensus
sequence, but no Walker A consensus sequence. In contrast, ABCB5-beta
has an N-terminal ABC signature motif and Walker B motif, followed by 6
transmembrane domains and C-terminal Walker A, ABC signature, and Walker
B motifs. RT-PCR detected preferential expression of both ABCB5-alpha
and -beta in melanomas, with no expression in normal uterus, lung, or
placenta. Northern blot analysis detected ABCB5 transcripts of 2.4 to
7.5 kb in melanoma cells, but not in any normal human tissues examined.
RT-PCR showed expression of ABCB5-alpha and -beta in normal melanocytes
and of ABCB5-beta in retinal pigment epithelial cells.
GENE FUNCTION
Frank et al. (2003) found that ABCB5, like ABCB1, induced rhodamine
efflux in transfected breast cancer cell lines. ABCB5 was highly
expressed in mono- and multinucleated human epidermal melanocytes with a
CD133 (PROM1; 604365)-positive progenitor phenotype. Frank et al. (2003)
showed that polyploid ABCB5-positive cells were generated by cell
fusion, and this process was specifically enhanced by ABCB5 blockade.
Multinucleated cell hybrids gave rise to mononucleated progeny,
demonstrating that fusion contributed to culture growth and
differentiation.
Frank et al. (2005) showed that ABCB5 was expressed in clinical
malignant melanomas and preferentially marked a subset of hyperpolarized
tumor cells with a CD133-positive stem cell phenotype in malignant
melanoma cultures and clinical melanomas. Blocking ABCB5 with anti-ABCB5
monoclonal antibody reversed doxorubicin resistance in a melanoma cell
line and increased intracellular doxorubicin accumulation, indicating
that ABCB5-mediated efflux was the mechanism of doxorubicin resistance
in these cells. Expression of ABCB5 in a cancer cell line panel
correlated significantly with tumor resistance to doxorubicin.
Schatton et al. (2008) identified a subpopulation of tumor-initiating
cells enriched for human malignant melanoma-initiating cells (MMIC)
defined by expression of the chemoresistance mediator ABCB5 and showed
that specific targeting of this tumorigenic minority population inhibits
tumor growth. ABCB5-positive tumor cells detected in human melanoma
patients showed a primitive molecular phenotype and correlated with
clinical melanoma progression. In serial human-to-mouse
xenotransplantation experiments, ABCBA5-positive melanoma cells
possessed greater tumorigenic capacity than ABCB5-negative bulk
populations and reestablished clinical tumor heterogeneity. In vivo
genetic lineage tracking demonstrated a specific capacity of
ABCB5-positive subpopulations for self-renewal and differentiation,
because ABCB5-positive cancer cells generated both ABCB5-positive and
ABCB5-negative progeny, whereas ABCB5-negative tumor populations gave
rise, at lower rates, exclusively to ABCB5-null cells. In an initial
proof-of-principle analysis designed to test the hypothesis that MMIC
are also required for growth of established tumors, systemic
administration of a monoclonal antibody directed at ABCB5, shown to be
capable of inducing antibody-dependent cell-mediated cytotoxicity in
ABCB5-positive MMIC, exerted tumor-inhibitory effects.
GENE STRUCTURE
Frank et al. (2003) determined that the ABCB5 gene contains 19 exons and
spans 108 kb. Chen et al. (2005) determined that the ABCB5 gene contains
at least 20 exons.
MAPPING
By genomic sequence analysis, Frank et al. (2003) mapped the ABCB5 gene
to chromosome 7p21-p15.3. Frank et al. (2005) stated that the ABCB5 gene
maps to chromosome 7p15.3.
CLK2P
| dbSNP name | rs227931(G,A); rs227932(A,G); rs227933(G,C); rs111540643(A,C) |
| cytoBand name | 7p15.3 |
| EntrezGene GeneID | 1197 |
| snpEff Gene Name | AC006026.10 |
| EntrezGene Description | CDC-like kinase 2, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4545 |
STK31
| dbSNP name | rs950934(C,T); rs6461727(C,T); rs4722256(A,G); rs7779633(A,G); rs73080921(A,G); rs145672799(A,G); rs7784817(C,T); rs146208583(A,C); rs55919851(C,T); rs4722257(A,T); rs6962197(C,T); rs1559012(G,A); rs73080932(T,C); rs11974206(T,A); rs67476427(T,C); rs11971262(C,G); rs6461728(G,A); rs149154224(G,A); rs9691851(G,A); rs6944078(A,G); rs2058995(T,G); rs12672950(C,T); rs78660981(A,C); rs4722260(A,C); rs9655237(A,T); rs1987389(A,T); rs12535750(A,G); rs9690014(G,A); rs9654971(G,A); rs1035334(C,T); rs6971076(G,A); rs6970861(A,G); rs140723749(G,A); rs150109890(C,T); rs186912182(G,A); rs6953685(T,A); rs138417043(T,A); rs10233021(G,A); rs62468592(G,A); rs62468593(C,G); rs10950957(A,G); rs73080951(A,T); rs61571409(G,A); rs62468595(C,T); rs62468596(A,T); rs6461729(G,A); rs73080956(C,T); rs6955516(C,T); rs73080960(A,C); rs10231712(G,A); rs6975244(C,T); rs139601656(G,T); rs12176610(A,G); rs7777380(G,A); rs6947502(G,A); rs188340101(C,T); rs143868262(A,G); rs71526027(G,A); rs78227357(A,G); rs9690707(G,C); rs6958062(A,G); rs146451319(C,T); rs6958848(A,T); rs2112035(G,A); rs10215618(G,C); rs71526028(G,A); rs56189157(A,G); rs10227056(A,T); rs1981796(C,T); rs10272642(T,C); rs139455022(G,A); rs144155984(G,A); rs10264952(G,A); rs10264967(G,T); rs73080967(A,G); rs10265560(C,T); rs7776862(C,T); rs12539789(A,G); rs6958009(G,A); rs13246754(G,T); rs6963050(A,T); rs34281173(C,T); rs10252515(G,C); rs112800077(T,C); rs10234251(A,G); rs140938908(T,G); rs6979276(G,C); rs7779336(A,G); rs141274246(C,T); rs11982084(G,C); rs111433228(C,T); rs2390809(C,T); rs7785680(G,T); rs78620082(C,T); rs59957543(C,A); rs79586340(G,A); rs75405201(C,T); rs2216499(G,T); rs78238937(G,A); rs11971694(T,C); rs74904363(G,T); rs10271351(G,A); rs11971819(T,C); rs10950958(A,G); rs34006918(T,C); rs12669134(A,G); rs140012178(G,A); rs74550204(C,T); rs6955603(C,T); rs2893126(C,T); rs4722263(C,G); rs4719734(T,C); rs151188102(C,T); rs67334442(C,A); rs10279703(C,T); rs4722265(G,C); rs6966588(A,G); rs140201507(G,C); rs12700462(A,G); rs73080988(C,A); rs189641675(C,T); rs12532929(C,T); rs35995607(C,T); rs4722266(G,A); rs4722267(A,G); rs4722268(C,T); rs4722269(C,T); rs186451817(G,A); rs4722270(A,G); rs186413708(A,G); rs10241235(C,T); rs77740373(G,A); rs76804110(A,G); rs147608046(G,A); rs140525630(G,A); rs6969275(C,G); rs2390811(G,A); rs12531249(C,T); rs150933225(A,C); rs10231702(G,A); rs12531940(C,T); rs7807336(G,C); rs7807397(C,A); rs62468636(G,A); rs7791090(T,C); rs145894677(A,G); rs12700463(C,G); rs138349501(A,G); rs12670018(T,C); rs1988373(C,A); rs4566942(C,A); rs28406908(T,A); rs6948669(G,A); rs1544729(G,T); rs35607606(A,G); rs6953242(G,T); rs6953133(C,G); rs6461730(A,T); rs6461731(G,A); rs7791410(G,C); rs7810431(T,A); rs7791629(C,T); rs10278268(A,G); rs10248895(C,T); rs3801898(T,C); rs2193826(G,C); rs2193827(C,T); rs59317812(T,G); rs142654496(C,T); rs10268973(T,C); rs2390812(G,A); rs145313918(C,G); rs6973861(A,G); rs12667016(A,C); rs7811536(G,A); rs62468640(C,T); rs193155224(G,C); rs35955133(A,G); rs12700464(A,G); rs12531019(C,G); rs16873450(A,G); rs12536120(A,G); rs2193828(T,A); rs9784992(A,G); rs12531828(C,T); rs55744621(T,C); rs62468659(A,G); rs61564984(C,A); rs115069580(T,C); rs1017192(C,T); rs78177212(T,A); rs7785154(G,A); rs41273996(C,G); rs1469000(T,C); rs1469001(G,A); rs79780544(T,C); rs11982297(A,G); rs10263079(T,G); rs10247878(G,T); rs56237352(G,A); rs112018382(C,T); rs11771195(T,G); rs7800132(A,C); rs114346715(A,C); rs10950960(C,T); rs7805634(G,A); rs11761765(A,G); rs11983694(T,G); rs10263759(C,T); rs4722271(G,C); rs7811322(G,C); rs7811219(A,G); rs4601208(C,G); rs4621700(T,C); rs12234445(G,C); rs144272264(C,G); rs6976647(T,C); rs6960694(C,T); rs145405277(A,G); rs6966250(G,T); rs149103859(G,C); rs6461733(T,G); rs2216500(T,C); rs111353204(C,G); rs117012150(G,A); rs6461734(T,C); rs10258916(G,C); rs73082932(G,A); rs138054865(G,C); rs6461735(G,A); rs7787706(T,A); rs201733444(A,G); rs6461736(A,C); rs6944575(C,T); rs6944883(A,T); rs73082939(A,T); rs62470067(A,G); rs150975415(A,G); rs10950961(A,G); rs6461737(A,G); rs12700465(T,C); rs12700466(A,G); rs16873451(G,A); rs6955786(C,G); rs12333757(A,G); rs7793777(C,G); rs1862068(A,G); rs10265802(C,T); rs73082952(T,C); rs62470068(T,C); rs191120666(T,C); rs73082955(C,G); rs7782389(C,T); rs7782946(G,A); rs6973657(T,C); rs4722272(A,G); rs6461738(G,C); rs10245296(A,G); rs73082958(A,G); rs7792188(C,T); rs62470069(T,C); rs13244337(A,G); rs61741952(G,C); rs10224014(G,A); rs12374932(A,G); rs10253205(A,C); rs182968529(C,T); rs2193829(A,T); rs12533973(T,C); rs12666547(C,A); rs12666580(G,A); rs73082965(A,G); rs73082967(A,G); rs75444706(C,T); rs4722273(A,C); rs73082969(T,C); rs7791283(T,C); rs2216501(T,C); rs4719736(C,G); rs6461739(C,G); rs150328384(C,T); rs7777127(A,G); rs112174086(T,G); rs7781439(G,A); rs62470070(G,T); rs2112036(G,C); rs12533472(G,A); rs59295056(A,G); rs10215404(C,T); rs10215408(C,T); rs62470072(A,G); rs9648306(C,G); rs78734023(A,G); rs4418236(C,A); rs12533715(T,C); rs10255699(A,G); rs10226714(G,C); rs10226724(G,A); rs185298851(G,A); rs182524777(A,G); rs10215363(T,G); rs10215446(T,G); rs10215107(C,T); rs10215115(G,A); rs57174181(C,T); rs141997013(C,G); rs114152132(A,G); rs186967025(A,G); rs12700480(T,C); rs6979438(C,T); rs59353417(A,G); rs60722869(T,A); rs55745002(C,G); rs78442231(T,A); rs139057339(C,G); rs79130239(G,A); rs7780158(C,T); rs147071955(C,T); rs111395142(G,A); rs10807817(A,G); rs12536714(T,C); rs10950964(C,T); rs10277285(A,C); rs113949653(A,C); rs77731788(G,A); rs74580191(T,C); rs73084758(C,A); rs28735578(G,A); rs10275301(T,G); rs112064032(C,T); rs148124980(G,A); rs7805668(G,A); rs138046278(C,T); rs78804926(A,G); rs57858910(A,G); rs4722275(C,A); rs10279416(T,C); rs7811090(A,T); rs184021283(A,T); rs148416343(A,G); rs10247028(G,A); rs73084776(T,C); rs10270093(T,C); rs77919738(G,T); rs60065849(C,A); rs79041262(C,T); rs7786857(T,C); rs7778206(C,T); rs11980860(G,T); rs28800319(C,T); rs6949764(C,T); rs6970042(T,C); rs73086949(A,G); rs28696102(A,T); rs2390813(G,C); rs2390814(C,T); rs28671330(A,G); rs17148396(A,G); rs73086951(A,C); rs4722278(G,A); rs2188851(T,C); rs7777348(C,G); rs7777396(A,G); rs10240624(A,G); rs73086958(C,T); rs2893127(T,C); rs2390817(A,G); rs2390819(G,A); rs2390820(C,T); rs12700483(T,A); rs73086967(C,A); rs74487951(T,C); rs73086969(G,A); rs6461740(C,T); rs112550668(G,A); rs10239832(T,C); rs35145944(A,C); rs118171642(T,C); rs10257431(A,G); rs112280780(C,T); rs6461741(G,C); rs6461742(T,G); rs28868045(C,T); rs141394486(A,G); rs28833254(G,A); rs116587423(G,C); rs10231325(G,A); rs10231356(C,T); rs12671779(A,G); rs10263712(A,G); rs2390823(G,A); rs79494985(A,G); rs28768099(C,T); rs28800309(T,C); rs12700490(A,T); rs1123459(T,C); rs73086986(T,A); rs12533328(C,T); rs10242933(G,A); rs10242844(C,A); rs74691659(A,T); rs73086991(A,G); rs7789993(G,A); rs6461743(A,G); rs35517396(A,G) |
| ccdsGene name | CCDS43556.1 |
| cytoBand name | 7p15.3 |
| EntrezGene GeneID | 56164 |
| EntrezGene Description | serine/threonine kinase 31 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | STK31:NM_001260504:exon22:c.G2675C:p.G892A,STK31:NM_001260505:exon22:c.G2744C:p.G915A,STK31:NM_032944:exon22:c.G2675C:p.G892A,STK31:NM_031414:exon22:c.G2744C:p.G915A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7929 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.008398 |
| ESP All MAF | 0.002922 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0009763 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Nails];
Longitudinal angular ridges;
Reddish dome-shaped prominence at origin of ridges (in some nails);
Thinning of nail plate;
Free margin notched or split;
Lunulae poorly developed or absent;
Platonychia (in some nails);
Koilonychia (in some nails)
MISCELLANEOUS:
Most patients have involvement of all nails, with more severe changes
in the nails of the thumbs and great toes
OMIM Title
*605790 SERINE/THREONINE KINASE 31; STK31
OMIM Description
CLONING
In a systematic search for genes expressed in mouse spermatogonia but
not in somatic tissues, Wang et al. (2001) identified 25 genes, 19 of
which were novel, that are expressed in only male germ cells. One of
these genes, Stk31, maps to chromosome 6 and encodes a putative protein
kinase with a tudor domain, found in RNA-interacting proteins, and a
coiled-coil domain. Stk31 shows testis-specific expression. Wang et al.
(2001) identified an orthologous, full-length human STK31 cDNA sequence.
MAPPING
By radiation hybrid analysis, Wang et al. (2001) mapped the human STK31
gene to chromosome 7.
NFE2L3
| dbSNP name | rs77857993(C,T); rs2158359(C,A); rs10270359(C,T); rs6964215(G,A); rs2049843(G,A); rs35919326(T,G); rs3753098(T,C); rs3753097(A,G); rs757371(A,G); rs2237335(A,G); rs10268883(C,T); rs11982270(C,T); rs189763438(G,A); rs12334200(C,G); rs12334205(G,A); rs11973275(T,A); rs11972585(G,C); rs10951126(A,T); rs77211084(G,A); rs57693267(C,T); rs2040786(G,A); rs2040785(C,T); rs2040784(G,A); rs7806294(C,A); rs2237331(C,A); rs10238831(A,G); rs149871679(T,A); rs6461919(G,A); rs6976408(T,G); rs2237330(G,A); rs73093883(C,G); rs6461920(G,T); rs35838658(T,A); rs148813993(G,C); rs11974650(T,C); rs11971002(C,T); rs3753096(T,G); rs12113404(A,G); rs17153360(A,G); rs201193253(T,C); rs12669830(C,T); rs2269893(C,T) |
| ccdsGene name | CCDS5396.1 |
| cytoBand name | 7p15.2 |
| EntrezGene GeneID | 9603 |
| EntrezGene Description | nuclear factor, erythroid 2-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NFE2L3:NM_004289:exon4:c.T1799C:p.L600S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9067 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y4A8 |
| dbNSFP Uniprot ID | NF2L3_HUMAN |
| ExAC AF | 0.0001464 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Epidermolysis bullosa, dystrophic;
Blistering, recurrent;
Skin fragility;
Erosions;
Pruritis, intense;
Prurigo;
Nodular lesions;
Lichenified lesions;
Hypertrophic scarring;
Milia;
Albopapuloid lesions may occur;
ELECTRON MICROSCOPY:;
Sublamina densa level of tissue separation beneath basal membrane;
Decreased number of anchoring fibrils at dermal-epidermal junction;
Hypotrophic anchoring fibrils;
Decreased staining for collagen VII;
[Nails];
Dystrophic nails;
Nail atrophy
MISCELLANEOUS:
Variable age at onset from childhood to adulthood;
Blisters are precipitated by minor skin trauma;
Blistering and erosions tend to occur on extensor surfaces or over
bony prominences;
Blistering frequency may decrease with age;
Intrafamilial variability;
See also dominant DEB (131750), an allelic disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by mutation in the collagen type VII, alpha-1 gene (COL7A1,
120120.0009).
OMIM Title
*604135 NUCLEAR FACTOR ERYTHROID 2-LIKE 3; NFE2L3
;;NFE2-RELATED FACTOR 3; NRF3
OMIM Description
DESCRIPTION
NFE2-binding sites and Maf recognition elements (MAREs) are essential
cis-acting elements in the regulatory regions of erythroid-specific
genes recognized by the erythroid transcription factor NFE2, which is
composed of p45 (NFE2; 601490) and a small MAF protein (e.g., MAFK;
600197). The p45 subunit and p45-related factors, such as NFE2L3,
contain a cap'n'collar (CNC)-type basic leucine zipper (bZIP) domain and
are collectively grouped as the CNC family. CNC factors bind to MARE
through heterodimer formation with small Maf proteins (summary by
Kobayashi et al., 1999).
CLONING
Kobayashi et al. (1999) searched a human EST database for novel CNC
factors and identified an EST clone encoding an amino acid sequence
similar to that of NRF1 (NFE2L1; 163260). They isolated cDNAs
corresponding to this EST by screening a human placenta cDNA library
with the EST. The cDNA sequence encodes a 694-amino acid polypeptide,
NFE2L3, which the authors called NRF3. NRF3 contains a bZIP domain that
is similar to those of other CNC transcription factors. Northern blot
analysis detected 2 human NRF3 transcripts in all tissues examined, with
the highest levels in placenta. NRF3 was expressed in B-cell and
monocytic cell lines but not in T-cell lines.
GENE FUNCTION
Kobayashi et al. (1999) demonstrated that mouse Nrf3 could bind to a
MARE as a heterodimer with Mafk and that Nrf3 functioned as a
transcriptional activator.
MAPPING
By FISH, Kobayashi et al. (1999) mapped the NFE2L3 gene to chromosome
7p15-p14, near the HOXA gene cluster (see 142955).
ANIMAL MODEL
Chevillard et al. (2011) stated that Nrf3 deletion in mice causes no
obvious abnormalities. However, they found that Nrf3 -/- mice were more
sensitive than wildtype mice to the carcinogen benzo(a)pyrene, which is
found in cigarette smoke. Benzo(a)pyrene, delivered weekly by gavage
over 4 weeks, caused premature death in 6 (32%) of 19 of Nrf3 -/- mice,
but in only 1 (6%) of 16 wildtype animals. All Nrf3 -/- animals that
died had lymphomas originating mostly from thymus, with a few
originating from spleen, and a majority exhibited metastasis to the
lung. Chevillard et al. (2011) concluded that NRF3 is a tumor suppressor
transcription factor that is protective against hematopoietic
malignancies.
HOXA4
| dbSNP name | rs4722660(G,T); rs4722661(C,G); rs4722662(C,T); rs2158218(T,G) |
| cytoBand name | 7p15.2 |
| EntrezGene GeneID | 285943 |
| EntrezGene Symbol | HOXA-AS2 |
| snpEff Gene Name | HOXA3 |
| EntrezGene Description | HOXA cluster antisense RNA 2 |
| EntrezGene Type of gene | unknown |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03214 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142953 HOMEOBOX A4; HOXA4
;;HOMEOBOX 1D; HOX1D;;
Hox-1.4, MOUSE, HOMOLOG OF;;
Dfd, DROSOPHILA, HOMOLOG OF
OMIM Description
MAPPING
Acampora et al. (1989) identified 8 homeoboxes in 90 kb of DNA on
chromosome 7. These are located in the following order, 5-prime to
3-prime: HOXA13 (HOX1J; 142959), HOXA11 (HOX1I; 142958), HOXA10 (HOX1H;
142957), HOXA9 (HOX1G; 142956), HOXA7 (HOX1A; 142950), HOXA6 (HOX1B;
142951), HOXA5 (HOX1C; 142952), and HOXA4 (HOX1D).
HOXA9
| dbSNP name | rs10259620(A,G); rs145905865(T,C); rs7810502(G,A); rs17500987(C,G) |
| cytoBand name | 7p15.2 |
| EntrezGene GeneID | 100534589 |
| EntrezGene Symbol | HOXA10-HOXA9 |
| EntrezGene Description | HOXA10-HOXA9 readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2994 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142956 HOMEOBOX A9; HOXA9
;;HOMEOBOX 1G; HOX1G;;
Hox-1.7, MOUSE, HOMOLOG OF;;
Abd-B, DROSOPHILA, HOMOLOG OF
HOXA9/NUP98 FUSION GENE, INCLUDED;;
HOXA9/MSI2 FUSION GENE, INCLUDED
OMIM Description
DESCRIPTION
In vertebrates, HOX genes exhibit spatially restricted patterns of
expression coincident with the morphogenesis of body-segmented
structures. The specific combination of HOX genes expressed in a
particular segment determines tissue identity. The HOXA9 gene encodes a
class I homeodomain protein potentially involved in myeloid
differentiation.
CLONING
Kim et al. (1998) cloned the HOXA9 gene and identified several splice
variants. Using exon-specific probes in Northern blot analysis, they
detected a 1.8-kb homeobox-containing transcript in all fetal tissues
tested (brain, lung, liver, and kidney); 2.2- and 3.3-kb transcripts in
fetal and adult kidney and in adult skeletal muscle; and a 1.0-kb
transcript in all adult and fetal tissues tested.
GENE FUNCTION
Vijapurkar et al. (2004) found that mouse Hoxa9 was phosphorylated by
protein kinase C (PKC; see 176960) and more weakly by casein kinase II
(see 115440). PKC phosphorylated Hoxa9 on ser204 and thr205, which are
located within a highly conserved N-terminal sequence (STRK). PKC
phosphorylation on ser204 decreased Hoxa9 DNA binding affinity in vitro
and blocked formation of DNA-binding complexes between endogenous HOXA9
and PBX (176310) in a human hematopoietic cell line. Phorbol ester
induction of myeloid cell differentiation correlated with
phosphorylation of HOXA9 on ser204 and the loss of in vivo DNA binding
activity, suggesting that PKC regulates the role of HOXA9 in myeloid
cell proliferation and differentiation.
Cheng et al. (2005) found that HOX genes, which normally regulate
mullerian duct differentiation, are not expressed in normal ovarian
surface epithelium, but are expressed in epithelial ovarian cancer
subtypes according to the pattern of mullerian-like differentiation of
the cancers. Ectopic expression of Hoxa9 in tumorigenic mouse ovarian
surface epithelial cells gave rise to papillary tumors resembling serous
ovarian cancers. In contrast, Hoxa10 (142957) and Hoxa11 (142958)
induced morphogenesis of endometrioid-like and mucinous-like tumors,
respectively. Hoxa7 (142950) showed no lineage specificity, but promoted
the abilities of Hoxa9, Hoxa10, and Hoxa11 to induce differentiation
along their respective pathways.
GENE STRUCTURE
Kim et al. (1998) determined that the HOXA9 gene contains 3 exons and
spans about 7.2 kb. The upstream region contains 2 TATA boxes, a CAAT
box, a GC box, and body segmentation-specific factor-binding sites. A
CpG island and 2 retinoic acid response elements (RAREs) are located
within intron 1.
MAPPING
By genomic sequence analysis, Kim et al. (1998) mapped the HOXA9 gene to
chromosome 7p15.
CYTOGENETICS
- HOXA9/NUP98 Fusion Gene
Expression of Hoxa7 (142950) and Hoxa9 is activated by proviral
integration in BXH2 murine myeloid leukemias. This result, combined with
the mapping of the HOXA cluster to 7p15, suggested that one of the HOXA
genes may be involved in the human t(7;11)(p15;p15) translocation found
in some myeloid leukemia patients. Nakamura et al. (1996) showed that in
3 patients with t(7;11), the chromosome rearrangement created a genomic
fusion between the HOXA9 gene and the nucleoporin gene NUP98 (601021), a
member of the GLFG nucleoporin family, on 11p15. The translocation
produced an invariant chimeric NUP98/HOXA9 transcript containing the
N-terminal half of NUP98 fused in-frame to HOXA9. These studies
identified HOXA9 as an important human myeloid leukemia gene and
suggested an important role for nucleoporins in human myeloid leukemia,
given that a second nucleoporin, NUP214 (114350), has also been
implicated in human myeloid leukemia.
Borrow et al. (1996) likewise identified the HOXA9 and NUP98 genes as
the parents of the fusion in t(7;11)(p15;p15) in acute myeloid leukemia
of the FABM2 and M4 types. They suggested that the predicted NUP98/HOXA9
fusion protein may promote leukemogenesis through inhibition of
HOXA9-mediated terminal differentiation and/or aberrant
nucleocytoplasmic transport.
Barr (1996) provided a table listing 9 types of gene fusions occurring
in myeloid leukemia.
- HOXA9/MSI2 Fusion Gene
Barbouti et al. (2003) identified a cryptic balanced translocation in a
chronic myeloid leukemia patient whose disease had progressed to the
accelerated phase and blast crisis. The translocation, t(7;17)(p15;q23),
resulted in a chimeric gene that fused exon 9 of MSI2 (607897) in-frame
with the intermediate exon (exon 1b) of HOXA9. The fusion protein
retained the 2 intact RRM domains of MSI2 fused to the homeobox domain
of HOXA9. The reciprocal HOXA9/MSI2 chimeric protein was not detected.
TRIL
| dbSNP name | rs137864032(C,A); rs112659735(C,T); rs115502262(A,G); rs221152(G,A); rs221153(C,G); rs6968194(G,A); rs740250(T,C); rs6950750(G,C); rs740252(C,G) |
| cytoBand name | 7p14.3 |
| EntrezGene GeneID | 9865 |
| snpEff Gene Name | AC005013.1 |
| EntrezGene Description | TLR4 interactor with leucine-rich repeats |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01148 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Weight];
Low birth weight;
[Other];
Postnatal growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Facial dysmorphism, mild, variable;
[Ears];
Hearing loss (2 patients)
CARDIOVASCULAR:
[Heart];
Patent ductus arteriosus;
Atrial septal defect;
Bicuspid aortic valve;
[Vascular];
Pulmonary hypertension
SKELETAL:
Ossification defects (2 patients);
[Hands];
Long fingers;
Thin fingers;
[Feet];
Clubfoot (in 2 sibs);
Long toes;
Thin toes
NEUROLOGIC:
[Central nervous system];
Developmental delay, mild to moderate;
[Behavioral/psychiatric manifestations];
Aggressive behavior (2 patients)
MISCELLANEOUS:
7 unrelated patients have been reported
MOLECULAR BASIS:
Contiguous gene syndrome caused by deletion (2.2 Mb) of chromosome
17q23.1-q23
OMIM Title
*613356 TLR4 INTERACTOR WITH LEUCINE-RICH REPEATS; TRIL
;;KIAA0644
OMIM Description
DESCRIPTION
TRIL is a component of the TLR4 (603030) complex and is induced in a
number of cell types by lipopolysaccharide (LPS) (Carpenter et al.,
2009).
CLONING
By screening for cDNAs encoding large proteins expressed in brain,
Ishikawa et al. (1998) isolated a cDNA encoding KIAA0644. The predicted
protein contains 811 amino acids. RT-PCR analysis detected strong
expression in brain, kidney, and ovary. Weaker expression was detected
in heart, lung, spleen, and skeletal muscle, and no expression was
detected in other tissues examined.
By microarray analysis of embryonic stem cells to identify LPS-induced
genes, Carpenter et al. (2009) identified human TRIL. The predicted
811-amino acid protein has a calculated molecular mass of 83 kD and is
highly conserved across species. It contains a 23-residue N-terminal
signal sequence, followed by 13 leucine-rich repeats (LRRs), a type III
fibronectin (135600) domain, a putative transmembrane domain, and an
intracellular C-terminal domain, as well as numerous N-linked
glycosylation sites. RT-PCR analysis showed widespread expression in
human tissues, with highest levels in brain, ovary, small intestine, and
spleen. Tril was highly expressed in rat cortical astrocytes and day-5
cerebellar granule neurons.
GENE FUNCTION
Carpenter et al. (2009) found that LPS treatment enhanced TRIL
expression in various cell types. Overexpression of TRIL in a human
astrocytoma line that expressed TLR4, but not CD14 (158120), resulted in
increased induction of inflammatory cytokines and chemokines in response
to LPS. Immunoprecipitation analysis indicated that TRIL interacted with
TLR4 and with LPS. Knockdown of TRIL with small interfering RNA caused a
delay in the degradation of IKBA (NFKBIA; 164008) in response to LPS,
but it did not affect TNF (191160) signaling. Carpenter et al. (2009)
concluded that TRIL is a component of the TLR4 complex that may have
particular relevance for the functional role of TLR4 in brain.
GENE STRUCTURE
Carpenter et al. (2009) determined that the TRIL gene contains a single
coding exon.
MAPPING
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the KIAA0644
gene to chromosome 7. Carpenter et al. (2009) stated that the TRIL gene
maps to chromosome 7q15.1. However, Gross (2010) mapped the TRIL gene to
chromosome 7p14.3 based on an alignment of the TRIL sequence (GenBank
GENBANK BC036337) with the genomic sequence (GRCh37).
DKFZP586I1420
| dbSNP name | rs42602(T,C) |
| cytoBand name | 7p14.3 |
| EntrezGene GeneID | 222161 |
| snpEff Gene Name | ZNRF2 |
| EntrezGene Description | uncharacterized protein DKFZp586I1420 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
LOC100130673
| dbSNP name | rs3801328(T,C); rs3801329(A,C); rs3801331(G,A); rs12539807(G,C); rs1580021(T,G); rs1580022(C,A); rs1580023(G,A); rs1580024(T,C) |
| cytoBand name | 7p14.3 |
| EntrezGene GeneID | 100130673 |
| snpEff Gene Name | AC018641.7 |
| EntrezGene Description | phosphoribosyl pyrophosphate synthetase 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4169 |
LINC00997
| dbSNP name | rs12669162(G,C); rs62467034(G,C); rs12701245(A,G); rs191750720(A,C); rs6942644(T,A); rs112608535(C,T); rs13221082(G,T); rs1964488(T,G); rs13225132(A,G); rs112848048(C,T); rs13228599(C,A); rs11769075(G,C) |
| cytoBand name | 7p14.3 |
| EntrezGene GeneID | 401321 |
| snpEff Gene Name | AVL9 |
| EntrezGene Description | long intergenic non-protein coding RNA 997 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1988 |
EEPD1
| dbSNP name | rs75667053(A,G); rs10247827(T,C); rs1882057(C,G); rs1882058(G,A); rs2726056(A,G); rs11769988(A,T); rs2002958(T,C); rs2002959(G,A); rs12155215(A,G); rs12154572(C,A); rs12154575(G,T); rs2254765(C,A); rs2726055(G,A); rs2726054(C,T); rs2700908(T,C); rs2726053(C,G); rs11760954(G,A); rs2700909(T,C); rs2726052(G,A); rs6973326(G,T); rs2726050(C,T); rs6973372(A,G); rs58049112(C,G); rs2726049(G,A); rs57780096(T,G); rs61632633(C,T); rs4720197(A,G); rs4723483(C,T); rs2726048(G,C); rs6462657(G,A); rs11974488(G,T); rs17172276(A,G); rs2726099(A,G); rs1420187(A,G); rs1420188(T,A); rs1833178(C,G); rs1833179(A,G); rs11496028(A,G); rs2700910(A,T); rs2726108(T,C); rs4723484(T,A); rs28488583(G,A); rs4723485(G,T); rs2700911(C,T); rs4723486(C,G); rs2700912(C,A); rs2700913(C,G); rs4723487(G,T); rs10260500(C,T); rs6974287(G,A); rs2700914(C,T); rs2700915(C,T); rs2540679(T,A); rs11984108(G,A); rs2700916(C,A); rs34134022(T,C); rs6971879(G,A); rs2700917(G,A); rs6972272(A,G); rs10230457(G,A); rs2726106(T,A); rs6973373(G,A); rs2466829(A,G); rs6977418(C,T); rs2700918(G,A); rs2700919(G,A); rs1420194(G,A); rs1420195(C,T); rs73094203(A,G); rs9648427(A,G); rs9648428(C,T); rs56354179(C,T); rs59122714(T,C); rs4270864(G,A); rs2392429(C,G); rs10261900(T,C); rs974478(A,G); rs75306470(C,T); rs2726109(A,G); rs2726110(A,C); rs113712074(A,G); rs2700920(C,G); rs2540659(C,T); rs13225662(A,G); rs759408(A,T); rs2700921(A,G); rs3021413(A,G); rs71535852(C,T); rs16880939(C,T); rs2540660(G,A); rs2540661(G,A); rs4723489(C,T); rs2540662(C,T); rs2540663(G,C); rs56289531(G,T); rs2540664(C,G); rs28712776(A,G); rs2540665(A,G); rs17170523(T,A); rs2700923(T,C); rs2540666(G,A); rs2540667(G,A); rs759409(A,G); rs730580(T,C); rs2700924(T,G); rs759411(T,G); rs759412(G,A); rs2700925(C,T); rs1833180(T,A); rs4236343(G,C); rs10227634(T,C); rs2726063(T,C); rs2052262(T,C); rs2052263(G,A); rs2726062(C,T); rs2540668(A,G); rs62445397(C,T); rs888043(A,G); rs888044(C,T); rs1420189(A,G); rs2726059(C,G); rs2024443(A,T); rs111318679(A,G); rs79039074(G,A); rs35996243(C,T); rs2024444(G,C); rs2726058(A,G); rs2726057(A,G); rs1420190(G,A); rs1420191(C,G); rs5008246(A,T); rs1558661(C,G); rs17272724(A,G); rs2540669(A,T); rs116472915(C,T); rs888045(T,C); rs62445400(G,A); rs2726104(A,G); rs2700926(T,C); rs35629273(G,C); rs2540670(A,T); rs1011005(A,G); rs4720198(G,A); rs2726100(C,A); rs2726101(T,C); rs2726102(G,A); rs2726103(T,C); rs141774837(C,T); rs114866346(A,T); rs2726083(G,A); rs73338927(C,T); rs113977102(T,C); rs7799198(G,A); rs2726084(T,C); rs7799138(C,T); rs2726085(T,C); rs112219743(C,T); rs2726086(C,T); rs113283688(A,G); rs1420192(C,T); rs2726087(C,T); rs6462663(G,A); rs2726088(T,C); rs73338931(G,A); rs10234535(G,A); rs888046(C,T); rs2726090(G,T); rs62445433(C,T); rs4720199(C,G); rs75884150(A,G); rs1420193(G,A); rs10246058(C,T); rs7807784(T,A); rs6960355(A,G); rs2726091(G,C); rs6462664(G,A); rs7794961(G,A); rs2726092(G,T); rs77620582(T,C); rs2726095(T,C); rs73338937(C,T); rs2726096(G,A); rs11979124(G,A); rs76641463(T,G); rs2110812(G,A); rs2726097(G,T); rs73338940(A,G); rs2540671(C,G); rs10248971(C,T); rs73338943(A,G); rs4349900(C,G); rs59157829(T,C); rs1861313(A,G); rs2540672(C,T); rs60955952(G,A); rs62445436(T,A); rs10951464(G,A); rs112540564(C,T); rs73338950(G,T); rs7802978(C,T); rs7786121(T,G); rs7803000(A,C); rs57060990(C,T); rs4723493(G,T); rs9785046(T,C); rs4723494(T,C); rs144617743(G,A); rs9785001(G,T); rs10277506(T,C); rs9785007(C,T); rs73338956(T,C); rs73338958(T,C); rs73338960(G,A); rs76444535(C,T); rs377686324(A,C); rs4723496(C,A); rs77265304(C,T); rs28734793(C,T); rs74454602(C,T); rs2540673(T,C); rs10951466(A,G); rs2540674(A,G); rs72622358(G,A); rs10260648(C,T); rs2540675(G,A); rs17273471(G,A); rs12701487(C,A); rs7780846(C,T); rs7781004(C,G); rs2540677(C,A); rs2540678(A,G); rs75398556(G,A); rs2110813(A,T); rs17170539(A,G); rs75846975(C,A); rs11983103(C,T); rs2726118(T,C); rs10277543(G,T); rs12532979(T,C); rs12540704(G,C); rs60623700(A,G); rs2726117(T,C); rs138817629(C,T); rs2024442(A,G); rs929638(T,C); rs929639(A,G); rs2726064(G,C); rs111511214(G,A); rs2726065(T,G); rs2726066(A,C); rs2098368(C,T); rs759413(C,T); rs2540680(G,A); rs2540681(A,C); rs2017535(A,G); rs75738854(G,A); rs1558662(T,C); rs1477009(A,G); rs1477010(G,A); rs143661155(G,A); rs4723497(C,T); rs67061364(G,A); rs10951467(C,T); rs2726098(A,G); rs6948025(T,A); rs10274036(T,C); rs10258284(C,G); rs2540682(T,A); rs13236999(C,T); rs180790889(G,A); rs34725500(G,A); rs78432484(G,A); rs4723498(C,T); rs4723499(G,A); rs111948313(A,G); rs196535(T,A); rs4723500(A,G); rs4723501(T,A); rs4723502(T,C); rs196536(T,G); rs196537(C,G); rs196539(C,A); rs918028(A,G); rs196540(T,C); rs196541(G,A); rs196542(T,C); rs6943929(G,C); rs196543(T,C); rs196544(T,G); rs196545(T,A); rs147250927(G,A); rs196546(T,C); rs142918749(G,A); rs888047(C,T); rs4723504(T,C); rs11762654(A,G); rs196547(C,A); rs196548(T,A); rs7799511(T,A); rs7780655(G,A); rs17274258(A,C); rs196549(G,A); rs35580606(A,G); rs196550(C,T); rs10282140(G,T); rs196551(G,T); rs9801303(A,G); rs139398787(G,T); rs6973430(A,G); rs196552(T,A); rs146979684(C,T); rs196554(G,A); rs196555(T,C); rs150158383(C,T); rs196556(A,G); rs142758764(T,G); rs196557(C,T); rs196559(C,G); rs196560(C,G); rs28634634(A,C); rs196562(T,C); rs196563(C,T); rs28405188(T,C); rs196564(A,G); rs73326621(G,A); rs73326625(G,A); rs986875(C,T); rs196565(A,G); rs83311(G,A); rs741296(T,C); rs196566(G,T); rs196567(G,A); rs9655369(A,G); rs201091925(A,T); rs10242613(C,T); rs196568(C,T); rs11765494(C,A); rs196569(T,G); rs2192845(G,A); rs17208592(G,A); rs17274411(C,T); rs196570(G,A); rs196571(G,A); rs196572(A,G); rs34720943(G,A); rs196573(C,A); rs196574(T,G); rs1017147(G,A); rs196575(A,G); rs12536525(A,G); rs28469221(T,C); rs196576(A,G); rs6975993(G,A); rs10951469(G,A); rs7791599(T,G); rs196577(G,A); rs196578(G,C); rs79508737(C,G); rs142591283(G,A); rs196579(A,G); rs73105469(G,A); rs117186(G,A); rs196580(A,G); rs11765384(G,A); rs11765336(C,G); rs6462666(C,T); rs196581(T,C); rs34852941(A,G); rs1124802(C,T); rs196582(T,A); rs2160273(G,C); rs196583(T,C); rs72622379(C,T); rs196584(A,G); rs6946846(C,T); rs11764972(G,A); rs10244327(G,A); rs17274649(G,A); rs7790611(A,G); rs12154765(C,T); rs12154768(C,T); rs1477011(A,G); rs196586(G,A); rs196587(C,T); rs10256757(C,T); rs885638(C,T); rs151177561(G,A); rs122025(G,C); rs196589(C,T); rs13232200(G,A); rs17274957(G,A); rs124364(A,G); rs196590(T,C); rs10951470(C,A); rs196591(T,C); rs196592(A,G); rs196593(A,T); rs58191891(A,T); rs196594(C,T); rs196595(A,G); rs196596(G,A); rs918023(T,G); rs196597(C,T); rs28431055(A,G); rs196599(G,C); rs196600(A,G); rs11770421(G,C); rs77730096(G,A); rs196601(G,A); rs196602(A,G); rs196604(C,T); rs196605(A,G); rs16879335(A,G); rs10280938(G,A); rs138191434(C,A); rs17275193(A,G); rs34260728(G,A); rs196607(C,G); rs139171071(G,A); rs10262791(A,G); rs140394885(G,A); rs2270319(C,G); rs196608(A,G); rs196609(C,T); rs196610(A,G); rs196611(G,A); rs196612(T,C); rs11773170(C,T); rs2241141(G,A); rs11773889(C,T); rs196613(T,C); rs196614(T,C); rs7803174(G,A); rs196617(T,C); rs196618(A,G); rs196619(T,C); rs196620(A,G); rs196621(G,A); rs196622(G,A); rs1046455(C,T); rs3735402(T,G) |
| ccdsGene name | CCDS34619.1 |
| CosmicCodingMuts gene | EEPD1 |
| cytoBand name | 7p14.2 |
| EntrezGene GeneID | 80820 |
| EntrezGene Description | endonuclease/exonuclease/phosphatase family domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EEPD1:NM_030636:exon7:c.G1414A:p.A472T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6359 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7L9B9 |
| dbNSFP Uniprot ID | EEPD1_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 8.132e-05 |
GPR141
| dbSNP name | rs73691196(G,T) |
| ccdsGene name | CCDS5451.1 |
| cytoBand name | 7p14.1 |
| EntrezGene GeneID | 353345 |
| EntrezGene Description | G protein-coupled receptor 141 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR141:NM_181791:exon1:c.G96T:p.L32L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.040172 |
| ESP All MAF | 0.013994 |
| ESP Eur/Amr MAF | 0.000581 |
| ExAC AF | 0.004359 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Bladder];
Spastic/hyperactive bladder
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb hyperreflexia;
Extensor plantar responses;
Dysarthria;
Normal muscle strength;
Decreased vibration sense in feet;
Decreased somatosensory-evoked potentials
MISCELLANEOUS:
Adult onset (25-45 years)
OMIM Title
*609045 G PROTEIN-COUPLED RECEPTOR 141; GPR141
;;PGR13
OMIM Description
DESCRIPTION
GPR141 is a member of the rhodopsin family of G protein-coupled
receptors (GPRs) (Fredriksson et al., 2003).
CLONING
By searching databases for sequences similar to rhodopsin-like GPRs,
Fredriksson et al. (2003) identified GPR141. The deduced 299-amino acid
protein assumes a classic 7-transmembrane (TM) topology. Instead of the
DRY motif in the intracellular side of TM3, GPR141 has a TRY motif, and
it has no classic NSxxNPxxY motif in TM7. GPR141 shares 67% amino acid
identity with mouse Gpr141. EST database analysis indicated that GPR141
is expressed in bone marrow.
GENE STRUCTURE
Fredriksson et al. (2003) determined that the mouse and human GPR141
genes contain a single coding exon.
MAPPING
By genomic sequence analysis, Fredriksson et al. (2003) mapped the
GPR141 gene to chromosome 7p14.1. They mapped the mouse Gpr141 gene to
chromosome 13.
POU6F2
| dbSNP name | rs182464631(A,G); rs74625022(T,C); rs10263813(A,G); rs17171503(T,A); rs17171504(T,A); rs75378855(T,C); rs116304371(T,C); rs17171505(A,C); rs186217283(T,C); rs57126589(C,T); rs1229028(G,A); rs183187587(C,T); rs60123963(A,G); rs1229027(G,A); rs141934021(C,T); rs146312852(C,A); rs73697909(C,T); rs1229026(T,A); rs17171507(A,G); rs10488571(A,T); rs1881133(T,G); rs859519(G,C); rs859518(T,G); rs859517(T,G); rs859516(C,A); rs859515(T,C); rs17171509(T,C); rs859514(T,C); rs1229025(C,A); rs74600213(G,A); rs139464300(A,T); rs17171511(C,A); rs859535(T,A); rs859534(A,T); rs17176235(G,A); rs859533(C,T); rs859532(T,C); rs859531(T,C); rs7777970(G,A); rs151216329(T,G); rs10951584(A,G); rs145669681(T,C); rs372822414(A,G); rs979030(G,T); rs1229024(G,A); rs1229023(A,G); rs1229022(A,G); rs113439433(T,A); rs1229021(G,C); rs75521893(T,C); rs17176375(G,A); rs16879987(C,T); rs1229020(C,G); rs17176480(G,T); rs1229019(C,A); rs77547557(C,A); rs3905335(G,A); rs952624(A,G); rs4644141(C,T); rs4336514(A,G); rs1229018(A,C); rs2568689(T,G); rs1229016(C,T); rs17171514(G,A); rs1918723(C,G); rs1229014(T,C); rs10951587(C,A); rs17171516(G,A); rs1229013(C,T); rs1229012(G,A); rs859555(T,C); rs6945106(T,C); rs859554(G,A); rs7784348(T,C); rs859553(T,C); rs859552(G,C); rs859550(A,G); rs2696187(T,C); rs859549(T,G); rs77673071(C,T); rs3930047(C,T); rs144490407(G,T); rs142329279(A,G); rs940876(A,G); rs12669446(G,A); rs6957686(C,A); rs12671733(T,A); rs35987668(C,T); rs141518949(C,T); rs10251322(G,C); rs1229058(T,C); rs116648223(A,G); rs144664520(C,T); rs62443626(G,A); rs859513(A,G); rs35787066(C,T); rs6944670(A,G); rs13234105(G,C); rs7779583(C,A); rs7779853(G,A); rs116055807(A,T); rs702819(C,A); rs13244920(C,T); rs702820(T,C); rs11976952(C,T); rs859548(G,A); rs17171519(T,C); rs17171520(A,G); rs147503350(C,T); rs17171521(T,C); rs34099272(A,G); rs702821(G,C); rs702822(C,G); rs1116813(T,C); rs859530(G,T); rs1116811(A,G); rs6462886(A,T); rs2893569(A,G); rs859545(G,C); rs372463496(A,G); rs859544(A,G); rs859543(T,G); rs859542(A,T); rs6462887(A,G); rs34013745(C,T); rs4512300(A,G); rs10951588(A,G); rs12534015(A,C); rs201975731(G,T); rs9886128(A,G); rs10234710(T,G); rs143150496(C,T); rs35218421(C,A); rs12674371(G,A); rs34191717(G,A); rs371633676(G,T); rs2177798(G,A); rs7801660(C,T); rs6974522(G,C); rs12532009(G,A); rs12667652(C,G); rs12538487(A,G); rs79141493(G,A); rs6952464(C,T); rs12701690(G,A); rs10248136(C,T); rs10277485(A,G); rs76818358(C,T); rs74677739(C,A); rs9691458(T,C); rs1405987(A,G); rs12671046(T,C); rs139458498(T,A); rs1000869(A,G); rs1527949(G,A); rs12670003(G,A); rs138444892(C,T); rs149625283(C,G); rs11972294(A,G); rs143951363(T,C); rs1358422(G,C); rs139114729(T,G); rs11973171(A,G); rs78589061(G,C); rs10085472(A,G); rs182409437(C,A); rs73120483(A,G); rs1527953(A,G); rs12538569(T,G); rs79886972(G,A); rs76230312(A,G); rs12701691(T,G); rs7802955(A,G); rs9987012(T,G); rs12531458(A,C); rs10951590(C,T); rs12540036(T,A); rs1818940(C,T); rs114326382(T,A); rs1525797(G,A); rs6948756(A,T); rs6462888(G,A); rs6462889(A,G); rs6462890(A,G); rs12539432(G,A); rs7786896(C,T); rs12531789(T,A); rs12667577(T,G); rs10235506(T,C); rs6960250(A,T); rs1949880(T,C); rs6969723(C,T); rs6969605(A,G); rs149840185(A,T); rs1527951(C,T); rs1527950(G,A); rs2141277(A,G); rs7804890(T,G); rs35891708(A,C); rs115352180(A,G); rs6462891(A,G); rs6462892(T,C); rs115175835(A,C); rs7779278(T,C); rs7779586(T,C); rs150375863(G,A); rs9648065(C,T); rs34381038(T,A); rs35004215(A,G); rs6462893(T,C); rs6979668(G,A); rs2140911(C,T); rs2140912(G,A); rs2030960(G,A); rs10480173(C,T); rs10480175(A,T); rs12537542(T,A); rs2392618(G,A); rs35319478(A,G); rs2893570(G,C); rs12531476(T,C); rs1525790(C,G); rs10951591(A,G); rs10951592(A,G); rs13242209(C,T); rs6957662(C,T); rs4723819(C,T); rs10081389(G,A); rs1527957(G,A); rs1525798(A,C); rs6971923(A,G); rs6945380(C,T); rs79614121(T,C); rs885352(A,G); rs75155630(G,A); rs10258862(T,C); rs17171526(C,T); rs17171527(T,C); rs1534415(T,C); rs1534416(G,A); rs112929982(C,T); rs1527952(A,C); rs5008508(G,A); rs12535553(T,C); rs10951593(G,A); rs1404999(C,T); rs10464366(A,T); rs1405000(T,G); rs10464368(C,T); rs10499612(G,A); rs1881132(A,C); rs1881131(A,C); rs6959715(A,G); rs16880005(C,G); rs17171531(G,A); rs36065581(T,C); rs17171532(G,A); rs144320041(A,C); rs80254191(C,A); rs1950001(T,G); rs4573153(G,A); rs12672089(G,A); rs140347318(A,G); rs12701692(A,G); rs148016905(C,T); rs1525800(G,A); rs1525801(A,T); rs111691817(G,C); rs377218661(G,A); rs12216704(C,T); rs12216590(T,C); rs4723821(A,G); rs4723822(C,T); rs12674262(G,T); rs12670510(A,G); rs11760807(G,A); rs4723823(G,A); rs28461975(G,A); rs6945402(A,T); rs6945547(C,G); rs17171537(C,T); rs11763728(C,T); rs34792397(G,A); rs62442212(A,C); rs62442213(C,T); rs6956307(C,T); rs6976461(T,C); rs953874(G,A); rs35331179(G,A); rs10951595(A,G); rs1525799(G,C); rs147493637(C,A); rs4723824(T,C); rs11767080(G,C); rs10269214(T,C); rs6952466(T,A); rs4723825(G,C); rs4355688(C,T); rs11972468(A,T); rs145439198(T,C); rs6979829(A,G); rs2091323(C,T); rs2392619(G,T); rs10234489(T,C); rs34866559(G,A); rs4723826(A,G); rs4484588(T,C); rs36052669(T,C); rs7794776(A,T); rs2280668(A,G); rs2280667(A,C); rs73124439(T,G); rs10230421(G,C); rs1525794(T,A); rs6960769(T,C); rs13231075(G,T); rs1525796(C,A); rs10951596(A,G); rs12701695(C,G); rs4723827(C,T); rs6976988(A,C); rs4720310(A,G); rs115901870(T,C); rs6462894(A,G); rs149258972(G,T); rs12701697(C,T); rs116269931(A,T); rs4540324(G,C); rs73365542(A,G); rs12701698(A,G); rs73124456(G,A); rs7777072(G,A); rs1525793(G,A); rs13233049(C,T); rs12701699(G,A); rs6968730(C,G); rs9639811(T,A); rs73695675(G,T); rs9639812(C,T); rs78459861(A,T); rs11770808(C,G); rs10273694(G,A); rs10244167(A,C); rs28459466(T,C); rs116861428(C,T); rs10242528(T,G); rs113005874(G,C); rs6462895(A,G); rs71536632(C,A); rs10228432(T,C); rs2049496(T,C); rs144960262(T,C); rs10234092(C,T); rs10234560(C,G); rs10237781(C,T); rs17511572(A,G); rs4720311(T,G); rs143879544(A,C); rs955591(A,G); rs11773046(C,T); rs10244776(T,A); rs10229456(G,C); rs10951597(T,C); rs147080539(G,A); rs10246388(G,A); rs6974609(C,T); rs10252129(T,C); rs77308399(C,T); rs139745307(T,C); rs4537223(G,C); rs4262244(A,C); rs10248402(C,T); rs35138561(T,G); rs35631433(G,A); rs4723830(C,T); rs10235824(A,G); rs10263259(T,C); rs58647599(G,A); rs59249283(A,G); rs11768425(G,C); rs150911782(C,T); rs10224345(T,C); rs35136533(T,C); rs4452709(G,T); rs10250849(A,C); rs76130687(G,C); rs10254999(A,G); rs9986786(T,C); rs7783839(G,A); rs7783932(G,A); rs7802746(T,C); rs7784092(G,A); rs7806520(T,A); rs7787883(G,A); rs7787466(A,G); rs7787601(A,C); rs4499996(A,G); rs112858656(G,A); rs56395837(C,T); rs4499997(A,G); rs6955746(G,A); rs10246046(A,G); rs6955619(C,T); rs6975659(T,A); rs6955924(G,A); rs6955794(C,G); rs3924710(C,T); rs4478468(A,G); rs4401749(C,T); rs4720314(T,C); rs4720315(A,G); rs4472423(T,C); rs4588755(A,G); rs4473925(T,C); rs4279508(G,A); rs12534084(T,C); rs12536501(A,T); rs12531437(G,A); rs12531464(G,A); rs61003868(T,G); rs4507668(A,G); rs35792719(T,A); rs35489214(A,G); rs74713643(G,A); rs4478480(T,A); rs4294102(G,C); rs7777684(A,C); rs7778249(G,C); rs115490146(G,C); rs7778299(C,T); rs76938547(A,G); rs4723832(C,T); rs141307276(T,A); rs10268316(T,G); rs10253095(G,A); rs112362532(A,G); rs74530714(G,A); rs3923506(C,T); rs7792953(T,C); rs111422473(C,T); rs6966337(T,C); rs6462896(G,A); rs10272458(G,A); rs7789925(G,A); rs6462897(G,T); rs10237780(T,G); rs10240990(T,C); rs7799983(G,A); rs10241425(T,C); rs10241803(T,C); rs4236356(T,G); rs4442033(T,C); rs4291171(T,G); rs73378985(T,C); rs28599716(G,A); rs78374676(C,T); rs73378991(C,G); rs4398807(T,G); rs6958617(T,C); rs10265739(A,G); rs12672115(A,G); rs12667875(G,C); rs12667891(G,A); rs11764181(C,T); rs61748985(C,T); rs11771925(A,G); rs6954406(G,C); rs73379002(C,T); rs10951598(G,A); rs28408659(G,A); rs28667878(C,T); rs28534765(G,C); rs28575461(G,A); rs6974432(C,T); rs75621211(A,G); rs6956858(T,C); rs6974806(A,G); rs6974992(A,G); rs6462898(C,T); rs371819875(A,G); rs6962811(T,A); rs11505524(G,T); rs62453435(G,A); rs4723833(C,G); rs4574755(C,T); rs76626643(C,T); rs4404830(G,A); rs35439815(C,T); rs4416740(G,A); rs4629763(A,G); rs4410807(T,G); rs10272803(T,G); rs76758952(C,T); rs73380916(A,T); rs78921541(C,T); rs78947926(C,T); rs4563790(T,C); rs10081326(G,A); rs7789406(G,A); rs73380918(C,T); rs4599718(C,T); rs75582427(C,T); rs4446648(G,A); rs77625925(T,C); rs9655034(G,T); rs9648476(G,A); rs10242061(A,G); rs73126482(C,T); rs79184302(G,A); rs73380930(C,T); rs6462899(T,A); rs11760662(C,A); rs10085664(A,T); rs6967316(C,A); rs73380932(C,T); rs4294089(C,T); rs114418463(A,C); rs115069711(A,G); rs113718989(T,G); rs73695224(A,G); rs78558645(A,G); rs13241248(A,G); rs73126493(C,T); rs11773042(G,C); rs10279204(G,A); rs62453447(A,G); rs11762957(T,A); rs62453453(C,T); rs10224140(G,A); rs61350796(T,A); rs12701705(T,C); rs73695231(T,G); rs73128408(T,A); rs10257516(A,G); rs73128410(G,A); rs10228416(C,T); rs57958250(C,T); rs4469355(T,C); rs4316059(C,G); rs4302750(A,G); rs185867743(T,C); rs4557603(G,C); rs4302751(A,G); rs4314553(T,C); rs35967316(A,G); rs11972970(G,A); rs4628166(C,G); rs59690097(T,A); rs73128418(G,A); rs11973905(C,T); rs12701706(A,G); rs11981474(A,C); rs74431356(C,T); rs4317479(A,G); rs4273761(G,A); rs58852609(C,T); rs113921891(G,A); rs73128425(C,G); rs73695235(G,A); rs183820207(G,T); rs62453457(A,G); rs11979297(T,C); rs142571078(G,A); rs79682948(T,A); rs3923296(C,T); rs73128430(G,A); rs3923295(A,G); rs73695238(A,G); rs4524676(G,A); rs4723834(A,G); rs4723835(C,A); rs34985861(G,A); rs12531819(T,C); rs35787907(C,A); rs12701709(T,A); rs4577868(G,C); rs4283935(T,C); rs68122495(A,C); rs28397895(T,C); rs4629764(G,A); rs34403589(A,G); rs35460329(T,A); rs114791710(A,T); rs4357192(G,A); rs4333492(T,C); rs12701711(C,G); rs12536943(T,C); rs4723836(A,G); rs4723837(G,A); rs4723838(T,C); rs4723839(G,A); rs6967976(C,T); rs62455873(A,G); rs6968147(A,G); rs55928878(G,A); rs12701712(T,C); rs6968851(G,A); rs201858449(C,T); rs73695240(G,A); rs6462900(A,G); rs7805282(G,C); rs7805702(A,G); rs7806189(G,A); rs7810302(C,T); rs7793509(T,C); rs67835487(G,A); rs12113287(A,T); rs10951599(C,G); rs12112084(C,G); rs12113296(A,G); rs12113417(A,C); rs4723840(G,A); rs61172252(T,C); rs11974414(G,A); rs4599719(A,G); rs6976186(T,C); rs7790372(G,A); rs11514783(C,T); rs7790521(G,A); rs73695247(C,G); rs73128456(A,G); rs7790421(C,G); rs4318977(G,A); rs190187097(C,T); rs13246220(G,T); rs11535192(C,G); rs13246263(C,A); rs13233706(T,C); rs11514715(C,G); rs6462901(G,A); rs10807900(C,T); rs6949876(T,C); rs6949878(T,C); rs9648478(G,A); rs12701714(G,A); rs4549685(C,T); rs4339541(G,A); rs4345472(G,T); rs4551233(A,G); rs4336506(T,C); rs6955599(C,A); rs6960329(G,A); rs6462902(A,G); rs4723841(G,A); rs34074172(T,C); rs6462903(T,C); rs7803411(G,C); rs12701715(T,C); rs12701716(C,T); rs12701717(C,G); rs4504545(T,G); rs4989072(T,G); rs7807925(A,G); rs4509216(T,C); rs12673726(T,C); rs4330591(T,C); rs4530944(T,C); rs4582444(T,A); rs4498449(G,A); rs4358689(T,A); rs12701718(G,T); rs74652274(G,C); rs4364548(A,G); rs4498450(G,C); rs73695253(C,T); rs4072719(C,A); rs4072718(A,G); rs3935112(T,G); rs12701719(A,T); rs34421793(C,T); rs6949610(A,G); rs6462904(T,C); rs12669066(A,G); rs4549686(T,C); rs73130472(A,G); rs12701720(T,C); rs12701721(A,C); rs6960580(G,C); rs4723843(A,G); rs4723844(G,A); rs114633321(G,A); rs4723845(T,C); rs4723846(C,T); rs12701722(C,T); rs12701723(T,A); rs35939093(A,T); rs35489723(G,A); rs4130697(C,T); rs4130698(T,C); rs4723847(C,T); rs4723848(G,A); rs4723849(G,T); rs4723850(C,G); rs12701725(T,C); rs12701726(C,T); rs4236357(T,C); rs4236358(C,T); rs6964993(G,A); rs6462905(C,T); rs7797767(G,A); rs6462906(A,G); rs6951074(T,A); rs6951119(T,G); rs145381901(T,C); rs7806341(C,T); rs7806608(G,T); rs113985620(C,T); rs62455902(G,A); rs6462907(G,T); rs6979956(A,G); rs6962243(T,A); rs6962816(T,C); rs34905355(C,A); rs151040648(T,C); rs4288259(A,G); rs4256493(A,G); rs4442035(A,T); rs6462908(T,C); rs147928956(T,C); rs6462909(T,C); rs137959948(G,A); rs185071585(A,G); rs6968121(C,T); rs115890835(G,A); rs73695267(G,A); rs73382999(C,T); rs6972647(A,G); rs6972937(C,T); rs60467141(G,A); rs35354413(C,T); rs73695270(G,A); rs4723851(G,A); rs4720317(T,C); rs4723853(G,A); rs4723854(G,A); rs73118076(T,C); rs56055019(A,G); rs6971018(T,C); rs6971051(T,G); rs34629959(C,T); rs12673488(A,G); rs77319894(A,G); rs4486096(C,G); rs13222559(C,A); rs60529254(C,T); rs4723855(C,T); rs4723856(A,T); rs10447663(C,A); rs10447664(A,G); rs12671222(C,A); rs12666828(A,G); rs12671242(C,G); rs7805623(A,G); rs4723857(T,C); rs4720318(A,G); rs4720319(A,G); rs35579113(G,A); rs12701727(A,G); rs61642750(A,G); rs35052359(C,T); rs12701728(G,C); rs58167875(C,G); rs79585386(G,A); rs75899609(G,A); rs143552103(T,C); rs12701729(G,A); rs4584055(A,G); rs7803241(G,A); rs35130226(C,T); rs73121825(T,G); rs36145227(G,T); rs12701731(G,A); rs6954206(T,C); rs34413240(G,C); rs140403724(C,T); rs76832345(C,T); rs12701732(T,C); rs12538092(C,G); rs73121828(C,T); rs187325456(A,C); rs12701733(G,C); rs3923702(G,T); rs115417458(T,C); rs4723858(C,T); rs62455931(G,T); rs78833939(A,T); rs62455932(A,T); rs4723859(G,A); rs12701734(G,A); rs17171572(A,G); rs2159153(C,G); rs7786697(C,T); rs146128764(G,C); rs150712615(T,C); rs73384963(G,C); rs17171573(T,C); rs6462910(T,C); rs7795826(A,G); rs12540793(C,G); rs17686527(C,T); rs2329387(A,C); rs79535620(T,A); rs12701735(T,G); rs79679619(T,C); rs10268735(A,G); rs79337985(C,G); rs10255235(T,C); rs11514785(C,T); rs17686557(C,T); rs147144505(G,A); rs77734541(C,T); rs17171574(G,A); rs2237414(T,C); rs2237413(A,G); rs2190887(C,T); rs11976849(T,A); rs113531274(T,G); rs2299141(C,T); rs3823620(A,T); rs3800854(G,T); rs3800853(C,A); rs2329388(C,T); rs2329389(G,A); rs2329390(A,G); rs2329391(T,C); rs10251004(G,A); rs10251013(G,A); rs2073538(C,A); rs6962623(C,T); rs71536641(A,G); rs2299140(G,A); rs76617180(G,A); rs6462911(A,G); rs76776337(G,A); rs2237411(A,G); rs1558159(C,A); rs740509(G,C); rs17686709(T,A); rs114025448(C,T); rs17619378(C,T); rs2299138(A,C); rs2299137(A,G); rs111491643(G,A); rs148518979(A,G); rs35380149(G,T); rs34744674(C,T); rs2299136(A,T); rs6953747(A,G); rs2237410(C,T); rs4370441(G,C); rs6965821(A,G); rs2299135(G,A); rs6952747(C,A); rs2876835(G,C); rs17701573(A,G); rs10282049(G,A); rs6946515(T,C); rs7801145(A,G); rs11971775(G,C); rs112733704(G,A); rs112680019(C,T); rs2159152(T,C); rs6979897(G,A); rs116140675(C,T); rs11981229(A,G); rs55751785(G,T); rs76596374(G,A); rs17171575(C,G); rs4720320(A,G); rs59419831(T,C); rs58804492(T,C); rs12666115(T,C); rs12672997(G,A); rs12112401(A,G); rs12113628(G,A); rs6951850(A,G); rs146433236(T,C); rs17686795(T,C); rs17619480(C,T); rs4723861(T,C); rs75616374(T,C); rs17619492(T,A); rs2237408(G,C); rs17686832(G,T); rs77909300(G,A); rs3800851(A,G); rs2237407(G,C); rs60464047(T,A); rs4540309(C,T); rs6462913(T,C); rs6462914(T,G); rs141135239(G,A); rs6977566(A,G); rs4723862(G,A); rs6942833(T,C); rs73125521(T,C); rs60586729(C,T); rs150250697(A,G); rs10258232(C,T); rs17619548(G,T); rs7807957(C,A); rs1990243(A,G); rs887013(A,T); rs13438025(G,A); rs4623320(G,C); rs41402647(A,G); rs73125532(T,G); rs10256992(C,T); rs10227915(A,G); rs58695218(A,G); rs61105243(T,C); rs61543464(T,G); rs10951603(A,G); rs75943124(G,A); rs73695747(A,T); rs2190893(A,G); rs917401(A,C); rs73695748(G,A); rs10248165(A,G); rs2237404(A,G); rs4720323(A,T); rs933370(T,C); rs76112522(T,C); rs10269183(G,C); rs76868431(G,T); rs7789243(A,G); rs6462915(T,A); rs56408610(G,A); rs34812541(G,T); rs112140236(T,C); rs2074934(C,T); rs57694192(T,G); rs61223906(G,A); rs112637973(T,G); rs2237403(C,T); rs2237402(G,A); rs2237401(T,A); rs2237400(A,G); rs180700231(T,A); rs117417741(A,T); rs144907027(T,C); rs141110531(A,G); rs140326731(A,G); rs78337157(C,T); rs79450866(A,T); rs2024101(C,A); rs150928608(G,A); rs143191045(C,T); rs2024100(T,C); rs10262012(C,A); rs7792157(T,G); rs17619647(C,T); rs143804016(A,G); rs7459210(T,C); rs139410692(C,T); rs142735943(C,T); rs2073546(C,G); rs150145898(T,C); rs147683847(C,G); rs2299133(T,C); rs2190891(T,C); rs3819426(G,A); rs2190890(T,C); rs2215138(T,C); rs3819423(T,G); rs3819422(T,C); rs3819421(G,A); rs3819420(G,A); rs1860115(G,A); rs180979604(A,G); rs186111621(C,G); rs190919018(T,G); rs10269280(G,A); rs10269203(C,T); rs10239767(A,G); rs2329394(A,C); rs192215303(A,G); rs148693996(A,C); rs17769600(C,T); rs17712872(A,T); rs57998785(A,C); rs17769607(A,G); rs17769624(T,G); rs6462917(C,T); rs2237395(G,A); rs2237393(A,G); rs140431836(G,A); rs2237391(A,G); rs2299132(T,C); rs2299131(C,T); rs2299129(T,C); rs2299128(C,T); rs2299127(C,T); rs2237390(C,T); rs2237389(C,G); rs11769625(G,A); rs2073544(C,T); rs2073543(G,A); rs2073542(G,C); rs2073541(A,G); rs137973404(G,T); rs2073540(A,G); rs10951604(T,C); rs28473216(G,C); rs28627325(C,T); rs28651247(T,C); rs28625432(A,G); rs2302125(C,T); rs2302123(A,G); rs2302122(G,A); rs887015(T,C); rs887014(C,G); rs10242113(T,A); rs116740244(G,A); rs11979059(A,T); rs11972350(G,A); rs2876836(A,C); rs10249501(T,A); rs117597523(G,T); rs115393489(G,A); rs117216944(A,G); rs118084925(A,G); rs116957680(G,C); rs117254721(T,G); rs117427342(G,A); rs59085311(G,C); rs10267900(A,G); rs10254703(T,C); rs56222058(C,T); rs141017345(G,A); rs117752933(G,A); rs10239968(T,C); rs6947866(T,C); rs6966246(G,A); rs6948191(T,C); rs6948501(T,G); rs60003380(G,T); rs58810887(T,G); rs67717647(A,G); rs113742845(T,G); rs141934815(G,A); rs34731084(A,G); rs12531581(G,A); rs35650049(G,A); rs56132347(T,A); rs10261831(A,G); rs4535636(C,T); rs4554374(C,T); rs112987222(C,T); rs4419726(G,C); rs4629765(A,G); rs35222279(A,T); rs2190889(C,T); rs2159154(G,A); rs2190888(A,C); rs2108720(G,A); rs2876837(T,C); rs2108719(A,G); rs12112809(T,C); rs2876838(T,C); rs2237385(T,C); rs2237383(G,A); rs2237382(G,A); rs2237381(A,C); rs2237380(A,C); rs2237379(G,A); rs2237378(T,C); rs2237377(C,T); rs2237376(T,G); rs10261375(T,G); rs3819419(C,T); rs3819418(A,G); rs3819417(C,A); rs3819415(C,T); rs3819414(T,G); rs3819413(A,G); rs80099909(G,T); rs73129692(A,T); rs11970896(A,C); rs2282918(C,G); rs2299126(T,C); rs1155269(T,G); rs2299123(T,G); rs186945893(A,G); rs3778933(T,C); rs3823618(G,A); rs7797301(A,T); rs7801100(A,C); rs2299122(G,A); rs2299121(G,A); rs2282917(A,G); rs2282916(A,C); rs10273545(C,A); rs2237374(T,C); rs2237373(C,A); rs2237372(A,C); rs2237371(T,G); rs2237370(A,T); rs2237369(G,A); rs2237368(A,G); rs115096053(T,A); rs74493777(G,A); rs4723864(G,T); rs885689(C,G); rs740510(G,A); rs10233706(T,C); rs763894(G,C); rs2282915(C,G); rs4723865(T,C); rs12533673(T,G); rs145961110(A,C); rs7804851(G,A) |
| ccdsGene name | CCDS34620.2 |
| cytoBand name | 7p14.1 |
| EntrezGene GeneID | 11281 |
| EntrezGene Description | POU class 6 homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POU6F2:NM_007252:exon11:c.A1885C:p.N629H,POU6F2:NM_001166018:exon11:c.A1777C:p.N593H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9043 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P78424 |
| dbNSFP Uniprot ID | PO6F2_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0005286 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Head];
Microcephaly, mild;
[Eyes];
Poor eye contact;
Nystagmus
ABDOMEN:
[Liver];
Fulminant hepatic failure (in 2 sibs);
Liver necrosis;
Cholestasis;
Hepatomegaly;
[Gastrointestinal];
Feeding problems
NEUROLOGIC:
[Central nervous system];
'Stiffness';
Decreased spontaneous movement;
Delayed motor development;
Axial hypotonia;
Spasticity;
Hyperreflexia;
Seizures, refractory;
Hypoplasia of the corpus callosum;
Delayed myelination;
Generalized brain atrophy;
Cystic lesions in the basal ganglia
METABOLIC FEATURES:
Metabolic acidosis, severe
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased cerebrospinal fluid lactate;
Increased serum direct bilirubin;
Fibroblasts show decreased activity of mitochondrial respiratory complex
I, complex III, complex IV, and complex V
MISCELLANEOUS:
Onset at birth;
Death within first months or years of life;
Four patients have been reported (as of July 2011)
MOLECULAR BASIS:
Caused by mutation in the mitochondrial elongation factor G1 gene
(GFM1, 606639.0001)
OMIM Title
*609062 POU DOMAIN, CLASS 6, TRANSCRIPTION FACTOR 2; POU6F2
;;RETINA-DERIVED POU-DOMAIN FACTOR 1; RPF1
OMIM Description
DESCRIPTION
POU6F2 is a member of a gene family characterized by the presence of a
bipartite DNA-binding domain, consisting of a POU-specific domain and a
POU heterodomain, separated by a variable polylinker. POU domain family
members are transcriptional regulators, many of which show highly
restricted patterns of expression and are known to control cell
type-specific differentiation pathways (see review by Phillips and
Luisi, 2000).
CLONING
Zhou et al. (1996) isolated human POU6F2, which they designated
retina-derived POU-domain factor-1, from a retina cDNA library. POU6F2
encodes a deduced 648-amino acid protein. Alternative splicing
potentially generates 24 distinct mRNA isoforms with different
DNA-binding activity. Zhou et al. (1996) found that in adult mouse
Pou6f2 is expressed only within the central nervous system, where its
expression is restricted to the medial habenula, to a dispersed
population of neurons in the dorsal hypothalamus, and to subsets of
ganglion and amacrine cells in the retina.
RT-PCR analysis of the mouse Pou6f2 gene by Perotti et al. (2004)
revealed expression in kidney, adrenal gland, heart, stomach, muscle,
and eye, but not in lung or skin, of mouse fetuses at embryonic day (E)
18, and in kidney, heart, muscle, spleen, and ovary, but not in lung, of
adult mice.
GENE FUNCTION
Zhou et al. (1996) found that the most abundant POU6F2 isoforms in human
retina have an insertion of an evolutionarily conserved 36-amino acid
peptide into the DNA recognition helix of the POU-specific domain. In
vitro, the POU6F2 POU domain lacking the insert binds to a consensus
OCT1-binding site, whereas the alternatively spliced POU domain does
not. POU6F2 protein first appears in the developing mouse retina at E11,
where it localizes to neuroblasts that have recently migrated from the
mitotic zone to the future ganglion cell layer. Zhou et al. (1996)
suggested that POU6F2 may be involved in the early steps of
differentiation of amacrine and ganglion cells.
GENE STRUCTURE
Zhou et al. (1996) determined that the POU6F2 gene contains at least 10
exons and encompasses over 125 kb. Sequence analysis revealed 4
positions at which alternate splicing occurs, potentially generating
multiple transcripts.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the POU6F2
gene to chromosome 7 (TMAP RH71269).
MOLECULAR GENETICS
Perotti et al. (2004) noted that the POU6F2 gene is located within an
interval on chromosome 7p14 associated with loss of heterozygosity (LOH)
in cases of Wilms tumor (see WT5; 194070), a kidney malignancy of
childhood characterized by highly heterogeneous genetic alterations. By
sequencing the POU6F2 gene in 12 WTs showing LOH on chromosome 7p14,
they identified 2 germline mutations of possible pathogenic significance
(609062.0001-609062.0002).
PURB
| dbSNP name | rs8840(A,G); rs6956751(G,A); rs138379592(A,G); rs6971158(C,T); rs9701(G,A); rs192241029(T,C); rs117778349(T,G) |
| cytoBand name | 7p13 |
| EntrezGene GeneID | 5814 |
| EntrezGene Description | purine-rich element binding protein B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3099 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
HEAD AND NECK:
[Mouth];
Cleft lip, isolated;
Cleft palate, isolated;
Cleft lip and cleft palate
MISCELLANEOUS:
Genetic heterogeneity (see OFC1, 119530);
Allelic disorder to van der Woude syndrome (VWS, 119300) and popliteal
pterygium syndrome (PPS, 119500)
MOLECULAR BASIS:
Susceptibility conferred by mutation in the interferon regulatory
factor 6 gene (IRF6, 607199.0013)
OMIM Title
*608887 PURINE-RICH ELEMENT-BINDING PROTEIN B; PURB
;;PUR-BETA
OMIM Description
CLONING
By probing a HeLa cell cDNA library with a fragment of the PURA (600473)
sequence, Bergemann et al. (1992) identified a partial sequence of a
homologous cDNA, designated PURB, encoding a protein with a 23-amino
acid class I motif and an amphipathic helix similar to those found in
PURA.
Kelm et al. (1997) cloned mouse Purb (p44) and Pura (p46) and identified
them as the 2 components of the previously designated vascular actin
single-stranded DNA-binding factor-2, which specifically bound to
purine-rich regions within an enhancer and an exon of vascular actin
(Kelm et al., 1996). Like Pura, the deduced 324-amino acid Purb protein
contains class I and class II repeats and a 23-amino acid PSYC motif
that is homologous to the Rb-binding region of SV-40 large T antigen.
Purb differs from Pura in that the second class II repeat is interrupted
by a glycine-rich region, the N-terminal glycine-rich region is
interrupted by a 6-amino acid region, and there is no glutamine-rich
C-terminal region.
SNORA9
| dbSNP name | rs138966080(T,C) |
| cytoBand name | 7p13 |
| EntrezGene GeneID | 101928927 |
| EntrezGene Symbol | LOC101928927 |
| snpEff Gene Name | C7orf40 |
| EntrezGene Description | uncharacterized LOC101928927 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 4.315e-05 |
CDC14C
| dbSNP name | rs61731347(G,A); rs56195314(G,A); rs13230839(G,C); rs10279457(C,G) |
| cytoBand name | 7p12.3 |
| EntrezGene GeneID | 168448 |
| snpEff Gene Name | AC006024.4 |
| EntrezGene Description | cell division cycle 14C |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1901 |
| ExAC AF | 0.195 |
POM121L12
| dbSNP name | rs72598684(G,T); rs72598685(G,T); rs11238247(C,G); rs11238248(G,A); rs1184320(C,A); rs72598686(G,A) |
| ccdsGene name | CCDS43584.1 |
| cytoBand name | 7p12.1 |
| EntrezGene GeneID | 285877 |
| EntrezGene Description | POM121 transmembrane nucleoporin-like 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POM121L12:NM_182595:exon1:c.G7T:p.A3S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N7R1 |
| dbNSFP Uniprot ID | P1L12_HUMAN |
| dbNSFP KGp1 AF | 0.285714285714 |
| dbNSFP KGp1 Afr AF | 0.142276422764 |
| dbNSFP KGp1 Amr AF | 0.259668508287 |
| dbNSFP KGp1 Asn AF | 0.437062937063 |
| dbNSFP KGp1 Eur AF | 0.277044854881 |
| dbSNP GMAF | 0.2865 |
| ESP Afr MAF | 0.138542 |
| ESP All MAF | 0.209688 |
| ESP Eur/Amr MAF | 0.244556 |
| ExAC AF | 0.261 |
HPVC1
| dbSNP name | rs6971391(A,G) |
| cytoBand name | 7p11.2 |
| EntrezGene GeneID | 3262 |
| EntrezGene Description | human papillomavirus (type 18) E5 central sequence-like 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3857 |
OMIM Clinical Significance
Facies:
Orofacial cleft
Inheritance:
? Autosomal dominant (19q13)
OMIM Title
*600762 HUMAN PAPILLOMAVIRUS E5 CENTRAL SEQUENCE-LIKE 1; HPVC1
;;PAPILLOMAVIRUS E5-LIKE PROTEIN; PE5L
OMIM Description
CLONING
The human papillomavirus (HPV) E5 genes play an important role in the
induction of proliferation of infected cells. Geisen et al. (1995) noted
that these HPV E5 genomic regions are affected by the events leading to
integration of genital HPVs. Following up on the description of 2 HPV18
E5-related, transcribed mouse sequences, Geisen et al. (1995) searched
for human equivalents to these sequences. They isolated a clone with a
9.6-kb insert from a laryngeal carcinoma DNA library that strongly
cross-hybridized with the 2 mouse sequences. Restriction and Southern
blot analyses showed that the insert was a single-copy sequence without
rearrangements or viral sequences. The E5-related region was transcribed
and produced a 1.9-kb RNA band detected in the poly(A)+ RNA from
different cell lines tested. The human gene was designated PE5L (for
papillomavirus E5-like) by the authors.
MAPPING
By fluorescence in situ hybridization, Geisen et al. (1995) mapped the
HPVC1 gene to 7p14-p13. They concluded that this gene belongs to an
E5-like family of intracellular sequences and that it may constitute a
target for HPV recombination.
SUMF2
| dbSNP name | rs3813505(C,T); rs12535749(C,T); rs7793614(C,T); rs11772545(T,A); rs4585698(G,C); rs13242830(T,C); rs145943799(G,A); rs9767946(T,C); rs7808729(C,T); rs4245575(C,A); rs62457281(C,T); rs141580660(G,A); rs7806994(A,T); rs7811270(A,G); rs13238899(T,G); rs55697950(G,A); rs117523577(C,G); rs4948104(A,G); rs114774908(T,G); rs13226516(A,G); rs62457284(G,T); rs58571234(C,A); rs149838149(C,T); rs11765364(T,C); rs13226699(G,A); rs13244654(T,C); rs10800(A,G) |
| ccdsGene name | CCDS55111.1 |
| cytoBand name | 7p11.2 |
| EntrezGene GeneID | 25870 |
| EntrezGene Description | sulfatase modifying factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SUMF2:NM_001146333:exon7:c.C544T:p.R182W,SUMF2:NM_001042469:exon7:c.C820T:p.R274W,SUMF2:NM_015411:exon8:c.C865T:p.R289W,SUMF2:NM_001042470:exon5:c.C613T:p.R205W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9356 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000908 |
| ESP All MAF | 0.000385 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 1.303e-04,8.143e-06 |
DKFZp434L192
| dbSNP name | rs10281482(C,T) |
| cytoBand name | 7p11.2 |
| EntrezGene GeneID | 222029 |
| snpEff Gene Name | RBM22P3 |
| EntrezGene Description | uncharacterized protein DKFZp434L192 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.247 |
ZNF679
| dbSNP name | rs10230388(A,G); rs6969216(C,T); rs1534102(G,C); rs10282614(C,T); rs2164110(A,T); rs371738312(T,G); rs61753909(C,T); rs1987396(A,G); rs1985508(C,T); rs1005037(C,G); rs892591(G,C); rs185894563(G,A); rs1525168(C,T); rs1852106(G,A); rs28605249(C,T); rs62461226(A,G); rs10259007(T,G); rs66894657(G,A); rs62461227(A,G); rs79083888(A,G); rs75855553(C,T); rs62461228(G,A); rs1404682(C,A); rs11761995(C,G); rs6460128(A,T); rs10085751(G,A); rs10085613(A,G); rs10949882(T,C); rs11769591(G,T); rs10085616(A,G); rs78130027(G,T); rs1880569(A,G); rs11978020(A,G); rs10085727(T,C); rs10276465(G,A); rs2014921(T,C); rs10251372(C,T); rs11984011(G,T); rs139352694(T,C); rs11980921(A,G); rs11980936(A,G); rs77540239(C,A); rs6951009(G,A); rs11769553(C,G); rs2082662(A,C); rs10275001(G,C); rs62461243(C,T); rs7795087(T,C); rs28782007(G,A); rs10266003(A,C); rs28824554(C,G); rs2082661(A,G); rs148745340(C,T); rs4718044(A,G); rs4718045(C,T); rs1852104(T,A); rs62461245(C,T); rs67938138(A,G); rs115477737(C,T); rs146758078(A,C); rs10949883(G,T); rs10949884(T,C); rs10241481(G,A); rs142066733(T,C); rs56210558(T,C); rs11773364(C,T); rs1608778(A,G); rs4718047(G,A); rs10229109(T,A); rs6949304(T,A); rs10229536(T,C); rs112578781(T,C); rs73132069(C,T); rs66691729(A,G); rs62461249(C,T); rs7801114(G,A); rs6460129(C,T); rs149841404(C,G); rs62461250(T,C); rs62461251(A,G); rs146880063(G,T); rs112368936(A,G); rs199528622(T,A); rs12154469(A,C); rs12154540(A,G); rs17767341(A,G); rs10238937(A,G); rs10224003(C,T); rs9690958(T,A); rs112643360(C,T); rs73132071(C,T); rs114664455(C,G); rs55654798(G,C); rs1852105(T,C); rs10262403(T,C); rs1830035(T,C); rs1830036(T,A); rs34967493(T,C); rs10949885(G,A) |
| ccdsGene name | CCDS47592.1 |
| cytoBand name | 7q11.21 |
| EntrezGene GeneID | 168417 |
| EntrezGene Description | zinc finger protein 679 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF679:NM_153363:exon5:c.T733C:p.C245R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6657 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IYX0 |
| dbNSFP Uniprot ID | ZN679_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.002168 |
| ESP All MAF | 0.005037 |
| ESP Eur/Amr MAF | 0.006285 |
| ExAC AF | 0.003769 |
YWHAEP1
| dbSNP name | rs10258736(G,A); rs7783150(G,A); rs10233199(C,T); rs73125103(A,C); rs7792478(G,A) |
| cytoBand name | 7q11.21 |
| EntrezGene GeneID | 649395 |
| EntrezGene Symbol | LOC649395 |
| snpEff Gene Name | RP11-321E8.1-001 |
| EntrezGene Description | tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2374 |
MIR6839
| dbSNP name | rs73361890(T,C); rs35559940(G,A) |
| cytoBand name | 7q11.21 |
| EntrezGene GeneID | 51427 |
| EntrezGene Symbol | ZNF107 |
| snpEff Gene Name | ZNF107 |
| EntrezGene Description | zinc finger protein 107 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.073 |
| ExAC AF | 0.007306 |
LOC101929736
| dbSNP name | rs6963583(G,A); rs4718532(T,C) |
| cytoBand name | 7q11.21 |
| EntrezGene GeneID | 101929736 |
| snpEff Gene Name | RP11-166O4.5 |
| EntrezGene Description | uncharacterized LOC101929736 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_splicing |
| snpEff Effect | splice_site_donor |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | high |
| dbSNP GMAF | 0.2039 |
DNAJC30
| dbSNP name | rs1056750(G,A); rs1376(T,A); rs4717803(G,A); rs3828974(C,T); rs8891(T,C); rs1128349(C,T) |
| cytoBand name | 7q11.23 |
| EntrezGene GeneID | 84277 |
| EntrezGene Description | DnaJ (Hsp40) homolog, subfamily C, member 30 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4564 |
CLDN4
| dbSNP name | rs8629(T,C); rs1127155(A,G); rs1127156(C,T); rs11316(C,G) |
| cytoBand name | 7q11.23 |
| EntrezGene GeneID | 1364 |
| EntrezGene Description | claudin 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.3916 |
| ESP Afr MAF | 0.480708 |
| ESP All MAF | 0.333718 |
| ESP Eur/Amr MAF | 0.258376 |
| ExAC AF | 0.656 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602909 CLAUDIN 4; CLDN4
;;CLOSTRIDIUM PERFRINGENS ENTEROTOXIN RECEPTOR 1; CPETR1;;
CLOSTRIDIUM PERFRINGENS ENTEROTOXIN RECEPTOR, HIGH AFFINITY;;
ENTEROTOXIN OF CLOSTRIDIUM PERFRINGENS, RECEPTOR OF, 1;;
CPER
OMIM Description
DESCRIPTION
Claudins, such as CLDN4, are components of epithelial cell tight
junctions. Tight junctions regulate movement of solutes and ions through
the paracellular space and prevent mixing of proteins and lipids in the
outer leaflet of the apical and basolateral plasma membrane domains
(Acharya et al., 2004).
CLONING
The enterotoxin produced by the bacterium Clostridium perfringens is a
simple protein with a molecular mass of approximately 35 kD. Known as a
causative agent of diarrhea, it elicits fluid accumulation in the
intestinal tract by altering the membrane permeability of intestinal
epithelial cells. Pore formation in the cytoplasmic membrane is accepted
as the underlying mechanism of this effect. The cytotoxic action of C.
perfringens enterotoxin (CPE) requires its binding to specific
receptors. At least 2 molecules with different affinities to CPE are
considered to exist in various organs of a wide range of species. By
searching an expressed sequence tag database for sequences showing
homology to the high-affinity CPE receptor (CPER) of monkey kidney
cells, Katahira et al. (1997) identified an infant human brain cDNA
encoding CPETR1. The deduced 209-amino acid protein contains 4 putative
transmembrane domains. Northern blot analysis of mouse tissues detected
abundant Cpetr1 expression in small intestine and kidney, and lower
levels in heart, lung, liver, and skeletal muscle; no expression was
found in brain or spleen. In situ hybridization demonstrated that the
expression of mouse Cpetr1 mRNA in the small intestine was restricted to
cryptic enterocytes, indicating that the receptor is expressed in
intestinal epithelial cells.
Using Northern blot analysis, Paperna et al. (1998) found a 1.8-kb
CPETR1 transcript in adult and fetal human tissues. Expression was
highest in adult thyroid, placenta, pancreas, lung, and kidney, and
moderate in small intestine. Little to no CPETR1 was detected in other
adult tissues examined. CPETR1 was detected in fetal lung and kidney,
but not in fetal brain or liver. In whole embryonic mice, expression was
low on embryonic day 7 and increased during development to embryonic day
17.
By sequence analysis, Morita et al. (1999) determined that CPER is a
member of the claudin family and designated it claudin-4.
GENE FUNCTION
Katahira et al. (1997) confirmed that CPETR1 is a functional
high-affinity receptor for CPE.
Using immunofluorescence and immunoelectron microscopy, Morita et al.
(1999) found that claudin-4 localized specifically to tight junctions in
mouse kidney.
By immunofluorescence microscopy of normal mouse skin, Furuse et al.
(2002) found that Cldn1 (603718) and Cldn4 concentrated within
continuous tight junctions in the stratum granulosum.
Colegio et al. (2002) found that expression of human claudin-4 in
Madin-Darby canine kidney (MDCK) cells increased transmonolayer
electrical resistance by selectively decreasing the paracellular
permeability for Na+, but not for Cl-. The first extracellular domain of
human claudin-4 has a single basic residue, lys65. Colegio et al. (2002)
found that replacing lys65 with aspartic acid (K65D) via site-specific
mutagenesis eliminated the ability of claudin-4 to discriminate against
Na+.
Coyne et al. (2003) determined that human bronchi and bronchioles
express CLDN1, CLDN3 (602910), CLDN4, CLDN5 (602101), and CLDN7
(609131). CLDN1 and CLDN4 localized to the apical tight junction region
and in lateral intercellular junctions, with staining surrounding basal
cells that anchor the columnar epithelium to the basal lamina. In
contrast, CLDN3 and CLDN5 localized exclusively to the apical-most
region of the tight junction. CLDN7 colocalized with ZO1 (TJP1; 601009)
in lateral intercellular junctions, with little or no staining near
tight junctions.
Using immunofluorescence microscopy, Acharya et al. (2004) showed that
Cldn4, Cldn8 (611231), and Cldn12 (611232) localized to the bladder
epithelium of rat, mouse, and rabbit. These claudins specifically
localized to tight junctions of the superficial umbrella cell layer,
consistent with the high-resistance, low-permeability barrier function
of this cell type.
Using immunohistochemical analysis, Dube et al. (2007) found that CLDN1,
CLDN3, CLDN4, and CLDN8 were associated with the blood-epididymal
barrier of the epididymal duct. In all 3 epididymal segments, CLDN1,
CLDN3, and CLDN4 localized to tight junctions, along the lateral margins
of adjacent principal cells, and at the interface between basal and
principal cells. In contrast, CLDN8 localized to tight junctions in all
3 segments, along the lateral margins of principal cells in the caput,
and at the interface between basal and principal cells in the corpus.
GENE STRUCTURE
Paperna et al. (1998) determined that CLDN4 is an intronless gene.
MAPPING
By somatic cell hybrid analysis, Paperna et al. (1998) mapped the CLDN4
gene to chromosome 7q11.23. They mapped the mouse Cldn4 gene to a region
of chromosome 5G1 that shares homology of synteny with human chromosome
7q11.23.
LOC101409256
| dbSNP name | rs7803012(A,T); rs11972149(G,T); rs10232627(G,A); rs74596672(A,G) |
| cytoBand name | 7q21.13 |
| EntrezGene GeneID | 101409256 |
| snpEff Gene Name | CLDN12 |
| EntrezGene Description | cell division cycle 42 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4509 |
FZD1
| dbSNP name | rs2232161(C,T); rs3750145(T,C); rs1052015(A,C) |
| ccdsGene name | CCDS5620.1 |
| CosmicCodingMuts gene | FZD1 |
| cytoBand name | 7q21.13 |
| EntrezGene GeneID | 8321 |
| EntrezGene Description | frizzled family receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FZD1:NM_003505:exon1:c.C1749T:p.H583H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.054017 |
| ESP All MAF | 0.018376 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.005304 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Small birth length
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Frontal bossing;
[Eyes];
Large eyes;
Blindness;
Pale optic nerves;
Wide palpebral fissures;
Eyelid ptosis;
[Nose];
Low bridge;
[Mouth];
Tent-shaped mouth;
Prominent philtral groove;
Submucous cleft palate (rare)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Vascular ring;
Mitral regurgitation, mild;
[Vascular]
GENITOURINARY:
[Kidneys];
Duplicated kidneys (rare)
SKELETAL:
[Spine];
Kyphosis;
S-scoliosis of thoracic spine;
[Limbs];
Flexion contractures at both knees;
[Hands];
Postaxial polydactyly
MUSCLE, SOFT TISSUE:
Muscle atrophy
NEUROLOGIC:
[Central nervous system];
Diffuse hypotonia;
Axial hypotonia;
Developmental delay;
Mental retardation, profound;
No language;
Increased tendon reflex;
Seizures;
Megalencephaly;
Thick corpus callosum;
Mildly thin corpus callosum;
Enlarged white matter;
Focal pachygyria;
Polymicrogyria;
Wide Sylvian fissures with incomplete opercularization;
Ventricles slightly enlarged;
Hydrocephalus;
Cavum septi pellucidi;
Cavum vergae;
Small cavum septum;
[Behavioral/psychiatric manifestations];
Asperger-like features
NEOPLASIA:
Increased risk of medulloblastoma (rare)
MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol 3-kinase, regulatory
subunit 2 gene (PIK3R2, 603157.0001)
OMIM Title
*603408 FRIZZLED, DROSOPHILA, HOMOLOG OF, 1; FZD1
;;FZ1
OMIM Description
DESCRIPTION
Frizzled proteins, such as FZD1, are 7-transmembrane domain-containing
receptors whose extracellular cysteine-rich domains (CRDs) bind to Wnt
proteins (see 164975). Wnts are secreted cell signaling proteins
involved in development and homeostasis (summary by Zilberberg et al.,
2004).
CLONING
Sagara et al. (1998) cloned fetal lung cDNAs encoding FZD1, FZD2
(600667), and FZD7 (603410). The predicted 647-amino acid FZD1 protein
contains a signal peptide, a CRD in the N-terminal extracellular region,
7 transmembrane domains, and a C-terminal PDZ domain-binding motif. FZD1
shares 77% and 74% protein sequence identity with FZD2 and FZD7,
respectively. Northern blot analysis revealed that FZD1 is expressed as
a 4.5-kb mRNA in various tissues.
MAPPING
By fluorescence in situ hybridization, Sagara et al. (1998) mapped the
FZD1 gene to 7q21.
GENE FUNCTION
Liu et al. (2001) constructed a chimeric receptor with the
ligand-binding and transmembrane segments from the beta-2-adrenergic
receptor (109690) and the cytoplasmic domains from rat frizzled-1.
Stimulation of mouse F9 clones expressing the chimera with the
beta-adrenergic agonist isoproterenol stimulated stabilization of
beta-catenin (116806), activation of a beta-catenin-sensitive promoter,
and formation of primitive endoderm. The response was blocked by
inactivation of pertussis toxin-sensitive, heterotrimeric G proteins,
and by depletion of G-alpha-q (600998) and G-alpha-o (139311). Thus, Liu
et al. (2001) concluded that G proteins are elements of Wnt/frizzled-1
signaling to the beta-catenin-lymphoid-enhancer factor (LEF)-T-cell
factor (Tcf) pathway.
Hematopoietic stem cells (HSCs) have the ability to renew themselves and
to give rise to all lineages of the blood. Reya et al. (2003) showed
that the WNT signaling pathway has an important role in this process.
Overexpression of activated beta-catenin expands the pool of HSCs in
long-term cultures by both phenotype and function. Furthermore, HSCs in
their normal microenvironment activate a LEF1/TCF (153245) reporter,
which indicates that HSCs respond to WNT signaling in vivo. To
demonstrate the physiologic significance of this pathway for HSC
proliferation, Reya et al. (2003) showed that the ectopic expression of
axin (603816) or a frizzled ligand-binding domain, inhibitors of the WNT
signaling pathway, led to inhibition of HSC growth in vitro and reduced
reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs
induced increased expression of HOXB4 (142965) and NOTCH1 (190198),
genes previously implicated in self-renewal of HSCs. Reya et al. (2003)
concluded that the WNT signaling pathway is critical for normal HSC
homeostasis in vitro and in vivo, and provide insight into a potential
molecular hierarchy of regulation of HSC development.
Zilberberg et al. (2004) noted that members of the low density
lipoprotein receptor family, including LRP5 (603506) and LRP6 (603507),
interact with frizzled receptors and function as Wnt coreceptors. Using
transfected HEK293 cells, they showed that LRP1 (107770), as well as a
C-terminal fragment of LRP1 that mimics the full-length protein, bound
the CRD of human FZ1 and inhibited FZ1-dependent Wnt signaling. LRP1 did
not mediate FZ1 internalization and degradation, but sequestered FZ1 and
inhibited its formation of a functional Wnt signaling complex with LRP6.
PEX1
| dbSNP name | rs376251385(C,A); rs6955699(A,G); rs35892336(G,C); rs972923(C,G); rs144664835(G,A); rs41278791(T,A); rs143584442(A,C); rs7804789(C,T); rs111643445(A,G); rs6944105(C,T); rs6954806(C,T); rs77634815(T,A); rs140430384(T,C); rs35766680(C,T); rs116765078(G,T); rs74784449(C,A); rs10266304(C,A); rs10269874(G,T); rs10953071(T,A); rs3213609(A,G); rs10278857(G,T); rs142838522(C,G); rs112284415(A,G); rs35996821(T,C); rs368809504(G,A); rs10236856(C,T); rs6465359(T,A); rs79003837(A,G); rs7809455(T,C); rs7791858(G,A); rs139332538(G,C); rs11767684(A,G); rs374370783(A,T); rs150978102(A,G); rs38805(T,C); rs111642561(C,T); rs38806(A,T); rs2111200(C,T); rs10239762(G,A); rs117899596(G,A); rs146300704(A,G); rs139438933(G,A); rs38807(G,T); rs112904813(C,T); rs38808(G,C); rs73404416(G,T); rs138183109(T,C); rs2066743(C,T); rs113104510(C,G); rs38809(C,T); rs74720435(T,C); rs147567045(C,T); rs55915451(C,G); rs111347920(C,T); rs111558205(G,A); rs6944715(C,G); rs143231398(C,T); rs17759720(T,C); rs6976142(T,C); rs139468733(C,T); rs181560954(T,C) |
| ccdsGene name | CCDS5627.1 |
| cytoBand name | 7q21.2 |
| EntrezGene GeneID | 5189 |
| EntrezGene Description | peroxisomal biogenesis factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PEX1:NM_001282678:exon14:c.G1647C:p.L549F,PEX1:NM_001282677:exon13:c.G2100C:p.L700F,PEX1:NM_000466:exon14:c.G2271C:p.L757F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8331 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PE75 |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.007944 |
| ESP All MAF | 0.002768 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 9.270e-04,8.132e-06 |
OMIM Clinical Significance
Neuro:
Essential tremor;
Postural tremor of arms;
Variable tremor of head, legs, trunk, voice, jaw, and facial muscles
Misc:
Aggravated by emotions, hunger, fatigue, and temperature extremes;
Beta-adrenergic blocking agents and primidone partially effective;
Significant side-effects of therapy;
Anticipation suggested in one family
Inheritance:
Autosomal dominant
OMIM Title
*602136 PEROXISOME BIOGENESIS FACTOR 1; PEX1
;;PEROXIN 1
OMIM Description
CLONING
Reuber et al. (1997) and Portsteffen et al. (1997) identified the human
ortholog of yeast PEX1, a gene required for peroxisomal matrix protein
import. The gene encodes a 147-kD member of the AAA protein family
(ATPases associated with diverse cellular activities).
By functional complementation of peroxisome deficiency of a mutant
Chinese hamster ovary (CHO) cell line, ZP107, transformed with
peroxisome targeting signal type 1-tagged 'enhanced' green fluorescent
protein, Tamura et al. (1998) isolated a human PEX1 cDNA. This cDNA
encoded a hydrophilic protein comprising 1,283 amino acids, with high
homology to the AAA-type ATPase family. A stable transformant of ZP107
with human PEX1 was morphologically and biochemically restored for
peroxisome biogenesis.
GENE STRUCTURE
Portsteffen et al. (1997) detected 24 exons in the human PEX1 gene.
MAPPING
By computer-based 'homology probing' using the yeast sequence to screen
a database of expressed sequence tags (dbEST) for human cDNA clones,
Portsteffen et al. (1997) found a contig sequence localized to 7q21-q22
that exactly matched their cDNA. They identified the human PEX1 homolog
and characterized its exon/intron structure.
MOLECULAR GENETICS
Reuber et al. (1997) found that expression of human PEX1 restored
peroxisomal protein import in fibroblasts from 30 patients with
peroxisomal biogenesis disorders of complementation group 1 (CG1).
Additionally, they detected PEX1 mutations in multiple CG1 probands. A
common PEX1 allele, gly843-to-asp (G843D; 602136.0001), was present in
approximately half of the CG1 patients and was shown to have a
deleterious effect on PEX1 activity. Phenotypic analysis of
PEX1-deficient cells revealed severe defects in peroxisomal matrix
protein import and destabilization of PEX5 (600414), the receptor for
the type 1 peroxisomal targeting signal, even though peroxisomes were
present in these cells and capable of importing peroxisomal membrane
proteins. These data demonstrated an important role for PEX1 in
peroxisome biogenesis and suggested that mutations in PEX1 are the most
common cause of the peroxisomal biogenesis disorders (see 601539).
Homozygosity for the G843D mutation was found in at least 1 case of
neonatal adrenoleukodystrophy (NALD; see 601539) and in several cases of
infantile Refsum disease (IRD; see 601539). Heterozygosity for the G843D
mutation (with other alleles not characterized) was found in cases of
NALD, IRD, and Zellweger syndrome (ZS; 214100) (Reuber et al., 1997).
These 3 disorders appeared to represent a continuum of clinical features
that are most severe in ZS, milder in NALD, and least severe in IRD.
Portsteffen et al. (1997) identified 3 mutant alleles in CG1 patients.
One of these, a G-to-A transition in exon 15 resulting in G843D,
(602136.0001), was found in homozygosity in 1 patient and heterozygosity
in another.
Tamura et al. (1998) demonstrated that human PEX1 expression restored
peroxisomal protein import in fibroblasts from 3 patients with Zellweger
syndrome and neonatal adrenoleukodystrophy of complementation group 1,
which is the peroxisome biogenesis disorder (PBD) of highest incidence.
Tamura et al. (1998) found that a patient with Zellweger syndrome was a
compound heterozygote for 2 inactivating mutations of the PEX1 gene. The
cDNAs corresponding to these PEX1 mutations were defective in
peroxisome-restoring activity when expressed in the patient's
fibroblasts as well as in ZP107 cells. This method of identifying PEX1
cDNA complements that used by Reuber et al. (1997) and Portsteffen et
al. (1997) who isolated the human PEX1 gene by a homology search of a
human EST database using a yeast PEX1 sequence. All 3 studies
demonstrated unequivocally that PEX1 is the causative gene for
complementation group 1 peroxisomal disorders.
In fibroblasts from all CG1 infantile Refsum disease (IRD) patients
examined, Imamura et al. (1998) found that peroxisomes were
morphologically and biochemically formed at 30 degrees centigrade but
not at 37 degrees centigrade; on the other hand, almost no peroxisomes
were seen in Zellweger syndrome and neonatal adrenoleukodystrophy cells,
even at 30 degrees centigrade. The mutation G843D (602136.0001) was
found in the PEX1 allele of most CG1 IRD patients. The mutant PEX1 G843D
gave rise to the same temperature-sensitive phenotype on CG1 CHO cell
mutants upon transfection. Collectively, these results demonstrated
temperature-sensitive peroxisome assembly to be responsible for the
mildness of the clinical features of PEX1-defective IRD of
complementation group 1. Imamura et al. (1998) suggested that the
severity of peroxisome biogenesis disorder can be prognosticated by
examining the temperature-sensitive complementation of peroxisomes in
patient fibroblasts. This prognostic tool may encourage pediatricians to
treat the milder PBD variants with therapies such as an oral
administration of docosahexaenoic acid.
To address the molecular basis of the disorder in Zellweger syndrome
patients of complementation group 1 (CG1), Collins and Gould (1999)
examined all 24 PEX1 exons in 4 patients, including both patients that
had mutations in PMP70 (170995). PEX1 mutations were detected in all 4
patients, including a 1-bp insertion, 2097insT, in exon 13 that was
present in 3 of the 4 patients.
Mutations in PEX1 account for approximately 65% of patients with PBDs.
Walter et al. (2001) found that complete lack of PEX1 protein is
associated with severe Zellweger syndrome; however, residual amounts of
PEX1 protein were found in patients with the milder phenotypes neonatal
adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). Most of
the IRD patients carried at least 1 copy of the common G843D allele.
When patient fibroblasts harboring this allele were grown at 30 degrees
centigrade, a 2- to 3-fold increase in PEX1 protein levels was observed,
associated with the recovery of peroxisomal function. This suggested
that the G843D missense mutation results in a misfolded protein, which
is more stable at lower temperatures. Walter et al. (2001) concluded
that their search for the factors and/or mechanisms that determine the
stability of mutant PEX1 proteins can be a first step in the development
of therapeutic strategies for patients with mild PBDs.
In the subgroup of PBD patients with ZS, NALD, and IRD, more than half
have mutations in the PEX1 gene. Maxwell et al. (2002) identified 5
novel mutations in an Australasian cohort of PEX1-deficient PBD
patients, including a frameshift mutation in exon 18 (602136.0005) that
was present in moderately high frequency (approximately 10% of alleles).
In 21 of 31 patients with PBDs, Poll-The et al. (2004) identified
mutations in the PEX1 gene. The most common mutations were G843D
(602136.0001) and 2097insT (602136.0004), which were associated with
mild and severe Zellweger syndrome, respectively. Patients homozygous
for G843D tended to have a better developmental outcome than did
patients compound heterozygous for the 2 mutations. However, there were
exceptions, suggesting that unknown factors influence the ultimate
phenotype.
GENOTYPE/PHENOTYPE CORRELATIONS
Maxwell et al. (2002) found a close correlation between cellular
phenotype, disease severity, and PEX1 genotype in an Australasian cohort
of PEX1-deficient PBD patients. Preuss et al. (2002) also found a close
correlation between PEX1 genotype and age of survival in 16
well-documented Zellweger spectrum patients, which supported the
usefulness of determining the exact PEX1 mutations in patients. Missense
mutations caused milder disease, while insertions, deletions, and
nonsense mutations were associated with severe clinical disease.
In a study of 168 Zellweger spectrum patients, including 33 of their
own, Rosewich et al. (2005) found that the G843D and 2097insT mutations
accounted for over 80% of all abnormal PEX1 alleles. Most of the
mutations were distributed over the 2 AAA cassettes with the 2
functional protein domains, D1 and D2, and the highly conserved Walker
motifs. PEX1 mutations could be divided into 2 classes: class I
mutations led to residual PEX1 protein levels and function and a milder
phenotype; class II mutations almost abolished PEX1 protein levels and
function, resulting in a severe phenotype. Patients who were compound
heterozygous for a class I and a class II mutation had an intermediate
phenotype.
Crane et al. (2005) provided a detailed review of the mutations
identified in the PEX1 gene. Mutations that produce premature
termination codons are distributed throughout the PEX1 gene, whereas the
majority of missense mutations segregate with the 2 essential AAA
domains of the PEX1 protein.
MGC16142
| dbSNP name | rs10488516(G,A) |
| cytoBand name | 7q21.2 |
| EntrezGene GeneID | 84849 |
| snpEff Gene Name | C7orf64 |
| EntrezGene Description | uncharacterized protein MGC16142 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09688 |
FAM200A
| dbSNP name | rs10238965(C,T) |
| ccdsGene name | CCDS5668.1 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 221786 |
| EntrezGene Description | family with sequence similarity 200, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FAM200A:NM_145111:exon2:c.G186A:p.L62L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.399 |
| ESP Afr MAF | 0.21104 |
| ESP All MAF | 0.36221 |
| ESP Eur/Amr MAF | 0.143671 |
| ExAC AF | 0.258 |
OR2AE1
| dbSNP name | rs17161997(G,C); rs2572023(A,G) |
| ccdsGene name | CCDS34696.1 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 81392 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AE, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AE1:NM_001005276:exon1:c.C799G:p.L267V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NHA4 |
| dbNSFP Uniprot ID | O2AE1_HUMAN |
| dbNSFP KGp1 AF | 0.125457875458 |
| dbNSFP KGp1 Afr AF | 0.418699186992 |
| dbNSFP KGp1 Amr AF | 0.0690607734807 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0554089709763 |
| dbSNP GMAF | 0.1258 |
| ESP Afr MAF | 0.32887 |
| ESP All MAF | 0.143857 |
| ESP Eur/Amr MAF | 0.04907 |
| ExAC AF | 0.069 |
GJC3
| dbSNP name | rs2527907(C,T); rs75126895(T,C); rs2527906(C,T); rs2527905(G,A); rs192187705(T,C); rs1121592(T,C); rs2527904(C,T); rs2527903(A,G); rs2527902(G,A); rs2527901(A,T); rs2527900(A,G); rs11977827(G,A); rs143828671(G,T) |
| ccdsGene name | CCDS34697.1 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 349149 |
| EntrezGene Description | gap junction protein, gamma 3, 30.2kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GJC3:NM_181538:exon1:c.C597A:p.S199R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8635 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NFK1 |
| dbNSFP Uniprot ID | CXG3_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.001488 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic (episodes last from hours to days);
Weakness;
Dysarthria;
Vertigo;
Normal interictal neurologic examination
MISCELLANEOUS:
Onset before age 20 years;
Symptoms precipitated by exercise and excitement;
Episode frequency is monthly to yearly, and decreases with age
OMIM Title
*611925 GAP JUNCTION PROTEIN, GAMMA-3; GJC3
;;CONNEXIN 30.2; CX30.2;;
CONNEXIN 31.3; CX31.3;;
CONNEXIN 29; CX29;;
GAP JUNCTION PROTEIN, EPSILON-1, FORMERLY; GJE1, FORMERLY
OMIM Description
DESCRIPTION
Connexins, such as GJC3, are involved in the formation of gap junctions,
intercellular conduits that directly connect the cytoplasms of
contacting cells. Each gap junction channel is formed by docking of 2
hemichannels, each of which contains 6 connexin subunits (Sohl et al.,
2003).
CLONING
Altevogt et al. (2002) cloned the mouse ortholog of GJC3, Cx29, and
identified human GJC3, which they called CX31.3, by database analysis.
The deduced mouse and human proteins contain 258 and 279 amino acids,
respectively. They share 61% amino acid identity, and the human protein
has a C-terminal extension relative to mouse Cx29. Northern blot
analysis detected highest expression of Cx29 in mouse sciatic nerve,
with lower levels in brain and spinal cord. Expression of Cx29 mRNA in
the developing central nervous system paralleled that of other
myelin-related mRNAs, including Cx32 (GJB1; 304040). Immunohistochemical
analysis revealed Cx29 expression in internodal and juxtaparanodal
regions of small myelin sheaths, whereas Cx32 was restricted to large
myelinated fibers. In the peripheral nervous system, Cx29 expression
preceded that of Cx32 and declined to levels below that of Cx32 in
adulthood. In adult sciatic nerve, Cx29 primarily localized to the
innermost aspects of the myelin sheath, the paranode, the juxtaparanode,
and the inner mesaxon. Cx29 colocalized with Kv1.2 (KCNA2; 176262) in
axonal membranes. Both Cx29 and Cx32 were detected in incisures.
By database analysis and PCR of human genomic DNA, Sohl et al. (2003)
cloned GJC3, which they called CX30.2. Northern blot analysis detected a
major 1.9-kb transcript that was expressed predominantly in skeletal
muscle, liver, and heart and more weakly in kidney. A 1.6-kb transcript
was weakly expressed in pancreas. No CX30.2 expression was detected in
brain.
By RT-PCR and immunohistochemical analysis of mouse and rat tissues,
Yang et al. (2005) found that Cx29 was expressed in cochlea neurons,
spiral limbus, spiral ligament, organ of Corti, stria vascularis, and
lateral wall. Higher Cx29 mRNA was detected in spiral ligament and
spiral limbus than in whole cochlea or other parts of cochlea.
Using Western blot and immunohistochemical analyses, Tang et al. (2006)
found that Cx29 was strongly and exclusively expressed in Schwann cells
myelinating the auditory nerve in mouse cochlea.
By RT-PCR, Hong et al. (2010) cloned GJC3 from human glioma cells. The
deduced 279-amino acid protein has 4 transmembrane domains, 1
cytoplasmic loop, 2 extracellular loops, and cytoplasmic N and C
termini. Transfected HeLa cells expressed epitope-tagged GJC3 at the
plasma membrane as small plaques at points of contact between adjacent
cells.
GENE STRUCTURE
Yang et al. (2005) stated that the GJC3 gene contains 2 exons.
MAPPING
Yang et al. (2005) stated that the GJC3 gene maps to chromosome 7q22.1.
GENE FUNCTION
Altevogt et al. (2002) found that mouse Cx29 did not induce
intercellular conductances when expressed alone in mouse neuroblastoma
cells, but that it participated in formation of active channels when
coexpressed with Cx32.
ANIMAL MODEL
Tang et al. (2006) stated that hearing sensitivity in mice is fully
developed to the adult level by 3 weeks after birth. They found that
Cx29 -/- mice were delayed in developing hearing sensitivity and that
the phenotype showed about 50% penetrance. Ultrastructurally, Cx29 -/-
mice exhibited elevated sensitivity to noise damage, with demyelination
and vacuolization at the soma of spiral ganglion neurons. Cx29 -/-
auditory nerve fibers appeared normal. Tang et al. (2006) concluded that
CX29 has a unique role in myelination of spiral ganglion cell bodies.
NOMENCLATURE
Although GJC3 was formerly designated GJE1 and has been referred to as
GJE1 in the literature (e.g., Yang et al., 2005), GJE1 now refers to a
distinct gene that should not be confused with GJC3. The GJC3 gene is
located on human chromosome 7q22.1 and is associated with the aliases
CX31.3, CX30.2, and CX29. Sonntag et al. (2009) showed that GJE1, which
is associated with the alias CX23, has been inactivated in all primate
genomes and is therefore a pseudogene. Gje1 appears to be functional in
mouse and zebrafish. In human, the GJE1 pseudogene is located on
chromosome 6q24.1 and overlaps with the VTA1 gene (610902) (Scott,
2014).
STAG3L5P
| dbSNP name | rs1636980(G,A) |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 101752399 |
| EntrezGene Symbol | STAG3L5P-PVRIG2P-PILRB |
| snpEff Gene Name | PILRB |
| EntrezGene Description | STAG3L5P-PVRIG2P-PILRB readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1061 |
GNB2
| dbSNP name | rs150086689(C,T) |
| ccdsGene name | CCDS5703.1 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 2783 |
| EntrezGene Description | guanine nucleotide binding protein (G protein), beta polypeptide 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GNB2:NM_005273:exon9:c.C738T:p.D246D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.032683 |
| ESP All MAF | 0.011149 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.003163 |
OMIM Clinical Significance
Thorax:
Gynecomastia
Inheritance:
Male-limited autosomal dominant vs. autosomal recessive or X-linked
OMIM Title
*139390 GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-2; GNB2
OMIM Description
DESCRIPTION
Heterotrimeric G proteins, made up of an alpha subunit (see GNAS,
139320), a beta subunit, like GNB2, and a gamma subunit (see GNG2,
606981), relay signals from cell surface receptors to internal
effectors. The alpha subunit is a GTPase that interacts in the GDP-bound
state with beta-gamma dimers (Rosskopf et al., 2003).
CLONING
Gao et al. (1987) isolated a cDNA that encodes a second form of the
beta-subunit of signal-transducing guanine nucleotide-binding regulatory
proteins (G proteins). The cDNA corresponded to a 1.8-kb mRNA, and
nucleotide sequence analysis indicated that the encoded polypeptide
consists of 340 amino acid residues with a molecular weight of 37,335.
Although the deduced polypeptide was found to be of the same size as
that reported previously for the beta subunit (beta-1), 10% of the amino
acid residues were different.
GENE FUNCTION
Peng et al. (1992) pointed out that although the alpha subunit shows
great diversity and is thought to confer functional specificity to a
particular G protein, the beta subunit, which is much less diverse, is
believed to have no role in G protein specificity. Using
immunocytochemistry, they found, however, distinct distribution patterns
for different beta and gamma subunits in the retina. In particular, rod
and cone photoreceptors, which both subserve phototransduction but
differ in light-response properties, have different beta and gamma
subunits in their outer segments. Thus, the G protein mediating
phototransduction shows cell-specific forms of the beta and gamma
subunits in addition to the alpha subunit. This surprising finding
supported the hypothesis that these subunits contribute to functional
specificity of the G protein.
Wolfe et al. (2003) demonstrated that inhibition of the alpha-1H
(Ca(v)3.2) (CACNA1H; 607904), but not alpha-1G (Ca(v)3.1) (CACNA1G;
604065), low voltage-activated calcium channels is mediated selectively
by G protein beta-2-gamma-2 subunits (GNB2 and GNG2) subunits that bind
to the intracellular loop connecting channel transmembrane domains II
and III. This region of the alpha-1H channel is crucial for inhibition,
because its replacement abrogates inhibition and its transfer to
nonmodulated alpha-1G channels confers beta-2-gamma-2-dependent
inhibition. Beta-gamma reduces channel activity independent of voltage,
a mechanism distinct from the established beta-gamma-dependent
inhibition of non-L-type high voltage-activated channels of the Ca(v)2
family. Wolfe et al. (2003) concluded that their studies identified the
alpha-1H channel as a new effector for G protein beta-gamma subunits,
and highlight the selective signaling roles available for particular
beta-gamma combinations.
GENE STRUCTURE
Rosskopf et al. (2003) determined that the GNB2 gene contains 10 exons.
The first exon is noncoding.
MAPPING
Blatt et al. (1988) assigned the GNB2 gene to human chromosome 7 by
hybridization of clones to DNA from somatic cell hybrids. By studying a
YAC containing the EPO gene (133170), Kere et al. (1991) demonstrated
that the GNB2 gene is located within 30 to 80 kb of EPO and most likely
centromeric of it. GNAI1 (139310) is located in the same area.
Lovett et al. (1991) developed a strategy for the rapid enrichment and
identification of cDNAs encoded by large genomic regions. The basis of
this 'direct selection' scheme was the hybridization of an entire
library of cDNAs to an immobilized genomic clone. The scheme was tested
using a 550-kb YAC clone that contained the EPO gene. Using this clone
and a fetal kidney cDNA library, they achieved a 1,000-fold enrichment
of EPO cDNAs in one cycle of enrichment. An anonymous cDNA encoded by
the YAC was greatly enriched and found to represent the GNB2 gene.
Restriction mapping located it within 30-70 kb of the EPO gene. Parimoo
et al. (1991) likewise developed a method of cDNA selection based on
hybridization of cDNA fragments to immobilized DNA and recovery of the
selected cDNAs by polymerase chain reaction (PCR). These methods address
the recurrent problem in genome mapping and positional cloning, namely,
identification of coding segments in large fragments of genomic DNA.
POP7
| dbSNP name | rs112721366(G,A); rs75293890(G,A); rs11559028(C,A) |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 10248 |
| EntrezGene Description | processing of precursor 7, ribonuclease P/MRP subunit (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0326 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps with exercise;
Muscle pain with exercise;
Muscle stiffness with exercise;
Muscle hyperirritability;
Muscle hypertrophy;
Muscle mounding;
Muscle activity is electrically silent on EMG;
Percussion-induced rapid rolling muscle contractions (PIRC);
Decreased caveolin-3 expression on muscle biopsy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Mean age of onset 22 years (range 5-54);
Genetic heterogeneity (see RMD1, 600332);
Autosomal recessive inheritance has been reported (see 601253.0010);
Allelic disorder to limb girdle muscular dystrophy type 1C (LGMD1C,
607801)
MOLECULAR BASIS:
Caused by mutations in the caveolin 3 gene (CAV3, 601253.0001)
OMIM Title
*606113 PROCESSING OF PRECURSOR 7, S. CEREVISIAE, HOMOLOG OF; POP7
;;RIBONUCLEASE P, 20-KD SUBUNIT; RPP20
OMIM Description
DESCRIPTION
Ribonuclease P (RNase P) removes the 5-prime leader sequences from
precursor tRNA molecules. RNase P consists of an RNA species (H1 RNA),
the POP1 protein (602486), and at least 7 proteins called RPPs. The RPPs
have apparent molecular masses of 14 kD (RPP14; 606112), 20 kD (RPP20),
25 kD (RPP25), 29 kD (RPP29; 606114), 30 kD (RPP30; 606115), 38 kD
(RPP38; 606116), and 40 kD (RPP40; 606117). Patients with scleroderma
(181750) have serum reactive with RNase P, the Th antigen, which is also
referred to as the To antigen, and RPP30 and RPP38 (summary by Jarrous
et al., 1998, 1999).
CLONING
By biochemical purification of RNase P, micropeptide sequence analysis,
and EST database searching, Jarrous et al. (1998) obtained a cDNA
encoding RPP20. The deduced protein contains 140 amino acids with a
predicted molecular mass of nearly 16 kD. Immunologic analysis
determined that RPP20, unlike RPP30 and RPP38, is not a target for
antisera from systemic sclerosis patients. Immunoprecipitation analysis
showed that polyclonal antibodies raised against RPP20, RPP30, RPP38, or
RPP40 interact with RNase P from HeLa cells.
MAPPING
Gross (2013) mapped the POP7 gene to chromosome 7q22.1 based on an
alignment of the POP7 sequence (GenBank GENBANK BC001430) with the
genomic sequence (GRCh37).
ZAN
| dbSNP name | rs117726678(T,C); rs3895793(G,C); rs111408615(C,T); rs73170778(C,T); rs74895811(G,T); rs113727587(G,A); rs75348008(T,C); rs138384801(G,A); rs73170781(G,T); rs139615857(A,G); rs10239266(G,C); rs111957162(C,G); rs41280986(C,T); rs2293769(T,C); rs80134072(G,A); rs138363573(G,A); rs79163323(C,T); rs78456030(G,A); rs3891039(T,C); rs112138417(C,T); rs3847057(G,A); rs17162410(C,T); rs2293768(T,C); rs148531950(G,A); rs2075669(T,C); rs140036951(C,A); rs221824(T,C); rs6942733(T,G); rs76322232(C,T); rs28645997(A,G); rs6971700(A,G); rs11770083(C,G); rs78780353(G,A); rs73170784(C,T); rs76926298(C,T); rs59854860(C,A); rs59111982(G,T); rs314293(A,G); rs111396438(G,A); rs138698792(T,G); rs143716534(G,A); rs2293767(G,A); rs11773696(C,T); rs189461624(C,T); rs113659265(G,T); rs2553023(G,A); rs62483597(G,T); rs7801875(G,A); rs79558495(G,A); rs10953302(C,T); rs10953303(G,T); rs10232130(C,G); rs10247980(T,C); rs146343271(G,A); rs17147735(T,C); rs78389571(C,T); rs62483598(C,G); rs62483599(A,G); rs11772464(T,C); rs314296(T,C); rs489951(T,C); rs314298(C,T); rs2293766(G,A); rs314299(C,T); rs78193191(G,A); rs17147741(A,G); rs75734008(A,T); rs570087(T,C); rs2571603(G,A); rs111515032(C,T); rs542137(C,G); rs540330(G,T); rs539445(G,C); rs17147747(C,T); rs17147750(A,G); rs117054545(G,A); rs559208(G,A); rs56872215(C,T); rs314302(A,G); rs75119362(G,T); rs314303(T,C); rs531503(T,C); rs314304(G,A); rs75409262(C,T); rs314305(C,T); rs314306(G,A); rs489830(G,A); rs112810346(C,T); rs73411137(C,T); rs112408570(G,T); rs3888105(G,A); rs3847058(A,G); rs149508616(C,T); rs160602(T,A); rs221805(C,T); rs113597237(A,G); rs73411155(C,T); rs73411157(C,T); rs221804(G,A); rs61256171(C,G); rs60783739(A,C); rs314333(A,C); rs314334(A,C); rs7808101(G,C); rs191137(T,C); rs7808311(C,T); rs57438406(A,G); rs314335(A,G); rs73711190(C,T); rs62483602(C,A); rs314336(T,G); rs116292203(A,G); rs314337(C,T); rs12540135(A,G); rs314339(T,C); rs314340(T,C); rs74881141(C,A); rs77752321(C,T); rs112018695(A,G); rs79990258(T,A); rs314341(A,G); rs314343(C,G); rs144283181(A,G); rs117779130(C,T); rs314344(G,C) |
| CosmicCodingMuts gene | ZAN_ENST00000542585 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 7455 |
| EntrezGene Description | zonadhesin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6205 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | polymorphic_pseudogene |
| snpEff Impact | moderate |
| ExAC AF | 0.469,6.055e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive, severe
HEAD AND NECK:
[Face];
Prominent forehead;
[Eyes];
Microphthalmia;
Aniridia;
[Mouth];
Ankyloglossia
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Thin ribs and clavicles
ABDOMEN:
Ascites;
[Spleen];
Hypoplastic spleen;
Asplenia (rare)
GENITOURINARY:
[External genitalia, male];
Micropenis
SKELETAL:
Bones dense but thin;
Obliteration of medullary cavity seen on radiography;
[Skull];
Cloverleaf-shaped skull;
Hypoplastic cranial bones;
Decreased mineralization of skull (in some patients);
[Limbs];
Micromelic short limbs;
Flared metaphyses;
Long bone fractures prenatally;
[Hands];
Brachydactyly
NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Seizures;
Developmental delay
LABORATORY ABNORMALITIES:
Hypocalcemia
MISCELLANEOUS:
Death in utero or in early infancy is common
MOLECULAR BASIS:
Caused by mutation in the family with sequence similarity 111, member
A, gene (FAM111A, 615292.0002)
OMIM Title
*602372 ZONADHESIN; ZAN
OMIM Description
CLONING
Zonadhesin (ZAN) is a sperm membrane protein that binds the zona
pellucida of the egg in a species-specific manner. Gao et al. (1997)
cloned a partial-length ZAN cDNA by directly screening a human testis
cDNA library with a pig Zan cDNA.
GENE STRUCTURE
Gasper and Swanson (2006) stated that the ZAN gene comprises 47 coding
exons.
GENE FUNCTION
Gasper and Swanson (2006) summarized the mammalian fertilization
cascade, many steps of which exhibit species specificity (Vacquier,
1998). For example, the sperm first bind in a species-specific manner
with the zona pellucida, the extracellular coat of the egg (Wassarman et
al., 2001). In general, when eggs and sperm come from heterospecific
species, the initial binding to the zona pellucida does not occur as
efficiently as in homospecific mixtures. Once bound, the acrosomal
reaction is triggered, involving exocytosis of the acrosome, creating an
acrosomal shroud. Next, the sperm penetrates the egg zona pellucida,
enters the perivitelline space between the zona pellucida and the plasma
membrane, and then fuses with the plasma membrane. The zonadhesin
protein, encoded by the ZAN gene, localizes to the anterior part of the
sperm head and acts as a receptor to the zona pellucida matrix of the
egg. Like other male reproductive proteins located in the acrosome or
sperm head and proposed to be involved in species-specific binding to
eggs, ZAN possesses high levels of divergence between closely related
species.
MAPPING
Gao et al. (1997) mapped the human ZAN gene to 7q22 by fluorescence in
situ hybridization and the mouse Zan gene to chromosome 5 by
interspecific backcross analysis. Since the ZP3A (182889) gene is also
located on chromosome 7, Gao et al. (1997) speculated that a chromosomal
linkage of various fertilization-specific molecules might exist.
EVOLUTION
Gasper and Swanson (2006) sequenced 47 coding exons of the ZAN gene in
12 primate species and showed that 3 domains of the gene are under
positive selection and rapidly evolving, and thus may be involved in
binding to the zona pellucida in a species-specific manner in primates.
Polymorphism data from 48 humans revealed significant
polymorphism-to-divergence heterogeneity and significant departure from
equilibrium-neutral expectations in the frequency spectrum, suggesting
balancing selection and positive selection occurring in zonadhesin
within human populations.
UFSP1
| dbSNP name | rs13241786(T,G) |
| ccdsGene name | CCDS34710.1 |
| CosmicCodingMuts gene | UFSP1 |
| cytoBand name | 7q22.1 |
| EntrezGene GeneID | 402682 |
| EntrezGene Description | UFM1-specific peptidase 1 (non-functional) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UFSP1:NM_001015072:exon1:c.A237C:p.V79V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3388 |
| ESP Afr MAF | 0.392873 |
| ESP All MAF | 0.432723 |
| ESP Eur/Amr MAF | 0.45314 |
| ExAC AF | 0.606 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Macrocephaly (less common);
[Face];
Noonan-like facies in a minority of patients;
Triangular face with age;
[Ears];
Low-set posteriorly rotated ears;
[Eyes];
Ptosis;
Hypertelorism;
Downslanting palpebral fissures;
Epicanthal folds;
[Mouth];
Deeply grooved philtrum;
High peaks of upper lip vermilion border;
High arched palate;
Micrognathia;
Short neck
CHEST:
[External features];
Pectus deformities (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Cafe-au-lait spots;
Axillary freckling;
[Hair];
Low posterior hairline
MUSCLE, SOFT TISSUE:
Lipomas;
Hypotonia
NEUROLOGIC:
[Central nervous system];
Learning difficulties;
No neurofibromas;
[Behavioral/psychiatric manifestations];
Attention deficit-hyperactivity
MISCELLANEOUS:
Phenotypic overlap with neurofibromatosis 1 (NF1, 162200);
Some patients do not have dysmorphic features
MOLECULAR BASIS:
Caused by mutation in the sprouty-related EVH1 domain-containing protein
1 gene (SPRED1, 609291.0001)
OMIM Title
*611481 UFM1-SPECIFIC PEPTIDASE 1; UFSP1
;;UFM1-SPECIFIC PROTEASE 1
OMIM Description
DESCRIPTION
Like ubiquitin (see 191339), ubiquitin-fold modifier-1 (UFM1; 610553)
must be processed by a protease before it can conjugate with its target
proteins. In mouse, the thiol protease Ufsp1 specifically processes the
C terminus of Ufm1 (Kang et al., 2007).
CLONING
Kang et al. (2007) identified 2 novel mouse proteases, designated Ufsp1
and Ufsp2 (611482), by using a tagged Ufm1 recombinant and fractionation
of proteins that bound to it. The bound proteins were characterized by
tandem mass spectrometry to obtain sufficient sequence to perform
database searches. Ufsp1 encodes a deduced 217-amino acid protein with a
molecular mass of 23 kD. Northern blot analysis detected Ufsp1
transcripts in all tissues tested, with significantly higher expression
in brain, heart, kidney, and skeletal tissues. Two Ufsp1 transcripts
were detected in most of the tissues.
GENE FUNCTION
Functional studies by Kang et al. (2007) showed that both Ufsp1 and
Ufsp2 required specific cysteine residues in their reactive sites to
catalyze cleavage of the C-terminal extension of a Ufm1 precursor. Ufsp1
showed much higher activity than Ufsp2, suggesting that the maturation
of the Ufm1 precursor is catalyzed mainly by Ufsp1 in cells. Neither
protein cleaved to ubiquitin or to other ubiquitin-like proteins.
MAPPING
Scott (2007) mapped the UFSP1 gene to chromosome 7q22.1 based on an
alignment of the UFSP1 sequence (GenBank GENBANK AC011895)with the
genomic sequence (build 36.2).
LINC01004
| dbSNP name | rs4730066(T,G); rs116001267(G,C); rs3735377(C,G); rs3823752(C,T); rs28588491(G,C); rs193078579(T,C); rs888086(G,A); rs73716467(G,C); rs11974928(A,G); rs11971732(T,C); rs116542472(T,C); rs73716468(A,G); rs34558707(C,T) |
| cytoBand name | 7q22.3 |
| EntrezGene GeneID | 100216546 |
| snpEff Gene Name | RP11-325F22.3 |
| EntrezGene Description | long intergenic non-protein coding RNA 1004 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1299 |
KMT2E-AS1
| dbSNP name | rs13230660(A,G); rs74365863(C,G); rs2891761(T,C); rs6950894(G,A); rs77205034(C,T); rs2192932(A,G) |
| cytoBand name | 7q22.3 |
| EntrezGene GeneID | 100216545 |
| snpEff Gene Name | MLL5 |
| EntrezGene Description | KMT2E antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3398 |
CCDC71L
| dbSNP name | rs7808289(G,A); rs73421982(G,C); rs73184255(T,C); rs10266131(C,G); rs10236648(A,C); rs2190093(A,G); rs60442468(C,T); rs2286148(T,A); rs2286149(T,C) |
| cytoBand name | 7q22.3 |
| EntrezGene GeneID | 168455 |
| snpEff Gene Name | C7orf74 |
| EntrezGene Description | coiled-coil domain containing 71-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2718 |
SLC26A4-AS1
| dbSNP name | rs61640190(A,T); rs79214660(A,C); rs73421424(T,A); rs2701684(G,A); rs2701685(A,G); rs2712228(A,C); rs17154282(C,G) |
| cytoBand name | 7q22.3 |
| EntrezGene GeneID | 286002 |
| snpEff Gene Name | SLC26A4 |
| EntrezGene Description | SLC26A4 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09137 |
SLC26A3
| dbSNP name | rs142908255(C,G); rs41664(G,A); rs2269778(G,A); rs41665(A,T); rs41666(A,G); rs10245370(G,A); rs10487275(T,C); rs2395889(T,C); rs41667(G,T); rs41668(G,A); rs73727206(G,A); rs62467979(T,A); rs187066837(G,A); rs17154420(T,G); rs41669(A,G); rs2894467(T,C); rs7800642(T,A); rs77038827(T,C); rs11771791(G,A); rs6973044(T,C); rs58589956(C,T); rs112457369(G,C); rs41670(C,T); rs41671(A,G); rs41672(G,A); rs113986754(C,T); rs34907697(T,C); rs10247487(C,T); rs73727208(A,G); rs10263826(T,C); rs113473612(G,A); rs77791783(A,G); rs55858834(G,C); rs3735605(C,T); rs35576676(G,A); rs41280236(T,C); rs6466182(A,C); rs2283043(G,C); rs1008707(A,T); rs55976107(G,A); rs34407351(A,C); rs3801938(C,G); rs79604012(A,G); rs73191641(G,T); rs2395890(G,A); rs6415341(C,T); rs76668774(A,G); rs6960886(C,T); rs6961051(C,A); rs77143147(C,T); rs58062593(A,G); rs6466183(G,A); rs61344002(T,C); rs2237680(C,T); rs4730260(T,G); rs17154444(T,C); rs1476673(C,G); rs10953547(A,G); rs10953548(G,A); rs1548639(T,A); rs929393(C,T); rs4730261(A,G); rs12673380(G,A); rs10275353(C,T); rs10248785(A,G); rs4730265(G,C); rs4730266(G,C); rs73725109(C,T); rs2283044(G,A); rs2283045(G,A); rs4618632(T,G); rs2051954(G,C); rs2051955(C,T); rs2051956(G,C); rs73725110(A,C); rs2237681(A,T); rs990402(A,G); rs6975731(A,C); rs6976022(C,T); rs7800588(T,C) |
| ccdsGene name | CCDS5748.1 |
| cytoBand name | 7q31.1 |
| EntrezGene GeneID | 1811 |
| EntrezGene Description | solute carrier family 26 (anion exchanger), member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC26A3:NM_000111:exon19:c.G2169C:p.K723N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7935 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G5E9U3 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000615 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 6.993e-04,2.440e-05,8.132e-06 |
OMIM Clinical Significance
Eyes:
Honeycomb retinal degeneration;
Small round white retinal spots;
Failing vision
Inheritance:
Autosomal dominant;
? same as drusen of Bruch membrane
OMIM Title
*126650 SOLUTE CARRIER FAMILY 26, MEMBER 3; SLC26A3
;;DOWNREGULATED IN ADENOMA; DRA
OMIM Description
CLONING
By subtractive hybridization, Schweinfest et al. (1993) isolated a cDNA
for a tumor suppressor candidate gene, which they called DRA
(downregulated in adenoma), from a normal colon tissue cDNA library. Its
expression, which appeared to be limited to the mucosa of normal colon,
was significantly decreased in adenomas and adenocarcinomas of the colon
and was downregulated early in tumorigenesis.
Dorwart et al. (2008) showed that SLC26A3 was highly glycosylated and
that both the N and C termini of SLC26A3 were cytosolic.
GENE STRUCTURE
Haila et al. (1998) found that the CLD/DRA gene spans approximately 39
kb and comprises 21 exons. All exon/intron boundaries conformed to the
GT/AG rule. Genomic sequencing of a BAC clone revealed the presence of
another, highly homologous gene 3-prime of the CLD gene, with a similar
genomic structure, identified as the Pendred syndrome gene (SLC26A4;
605646).
MAPPING
By somatic cell hybridization and use of a cDNA probe, Schweinfest et
al. (1993) assigned the DRA gene, which was present in single copy, to
chromosome 7. Based on the structure of the predicted 84-kD DRA
polypeptide, Schweinfest et al. (1993) suggested that DRA is a
transcription factor or a protein that interacts with transcription
factors. By fluorescence in situ hybridization, Taguchi et al. (1994)
refined the assignment to 7q22-q31.1. The small intestinal mucin-3 gene
(158371) is located in the same region.
MOLECULAR GENETICS
Hoglund et al. (1996) found 2 missense mutations and 1 frameshift
mutation in the DRA gene in 32 Finnish and 4 Polish congenital chloride
diarrhea (CLD; 214700) patients. The disease-causing nature of the
val317-to-del missense mutation (126650.0001) was supported by genetic
data in relation to the population history of Finland. By mRNA in situ
hybridization, Hoglund et al. (1996) demonstrated that the expression of
DRA occurs preferentially in highly differentiated colonic epithelial
cells and is low in undifferentiated (including neoplastic) cells. The
expression of DRA is unchanged in Finnish CLD patients with the
val317-to-del mutation; however, the function of the mutant protein must
be severely impaired. The finding of low DRA expression in neoplastic
cells had previously been taken as a suggestion that DRA is a tumor
suppressor; clearly, the low expression is related solely to the
undifferentiated state of the neoplastic cells. The demonstration of the
relationship between DRA mutations and chloride diarrhea indicated that
DRA is an intestinal and transport molecule.
As noted in 126650.0001, all cases of CLD in the Finnish founder
population studied by Hoglund et al. (1996) had a 3-bp deletion
resulting in the loss of valine-317 in the predicted CLD/DRA protein.
Two additional mutations, H124L (126650.0002) and 344delT (126650.0003),
were found in Polish CLD patients. Hoglund et al. (1998) screened for
additional mutations in a set of 14 CLD families of Polish, Swedish,
North American, and Finnish origin, using primers that allowed mutation
searches directly from genomic DNA samples. They found 8 novel
mutations, including 2 transversions, 1 transition, 1 insertion, and 4
small deletions. They pointed out that of 11 sequence alterations
detected to that time, 9 lie clustered in 3 short segments of 49 bp, 39
bp, and 65 bp, respectively. These short segments span only 6.7% of the
total cDNA length, suggesting functional importance or mutation-prone
DNA regions of the corresponding CLD/DRA protein domains.
Hoglund et al. (2001) stated that a total of 3 founder and 17 private
mutations underlying congenital chloride diarrhea had been described in
various ethnic groups. They screened for mutations in 7 unrelated
families with CLD and found 7 novel mutations as well as 2 previously
identified ones. They reported for the first time rearrangement
mutations in SLC26A3 (see 126650.0004). Molecular features predisposing
SLC26A3 for the 2 rearrangements may include repetitive elements and
palindromic-like sequences.
Makela et al. (2002) noted that the only extraintestinal tissues showing
SLC26A3 expression are eccrine sweat glands and seminal vesicles. They
presented a summary of published mutations and polymorphisms of the
SLC26A3 gene and reported 2 novel mutations of the gene: a 13-bp
deletion (126650.0007) and a trp462-to-ter change (W462X; 126650.0008).
The authors described the geographic and population distributions of 3
founder mutations: the Finnish V317del mutation (126650.0001), the
Polish I675-676ins mutation (126650.0005), and the Arabic gly187-to-ter
mutation (G187X; 126650.0006). They also tabulated genetic disorders
with congenital or neonatal diarrhea as a main symptom.
Choi et al. (2009) used whole-exome capture and massively parallel DNA
sequencing to identify a homozygous pathogenic mutation in the SLC26A3
gene in a Turkish infant with congenital chloride diarrhea who was
initially thought to have renal Bartter syndrome. Sequencing this gene
in 39 additional patients referred with a suspected diagnosis of Bartter
syndrome identified recessive SLC26A3 mutations in 5 patients. All
except 1 presented in infancy with watery diarrhea associated with
hypokalemia, increased serum bicarbonate, and high aldosterone. High
stool chloride was documented in 2 patients studied. Choi et al. (2009)
emphasized the utility of this novel approach for the identification of
pathogenic mutations.
TAS2R16
| dbSNP name | rs1204014(C,T); rs860170(C,T); rs846664(A,C); rs2233989(A,G); rs2692396(C,G); rs2233988(G,A) |
| ccdsGene name | CCDS5785.1 |
| cytoBand name | 7q31.32 |
| EntrezGene GeneID | 50833 |
| EntrezGene Description | taste receptor, type 2, member 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R16:NM_016945:exon1:c.G846A:p.T282T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0932 |
| ESP Afr MAF | 0.282796 |
| ESP All MAF | 0.12402 |
| ESP Eur/Amr MAF | 0.042674 |
| ExAC AF | 0.059 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
+604867 TASTE RECEPTOR, TYPE 2, MEMBER 16; TAS2R16
;;T2R16
BETA-GLYCOPYRANOSIDE TASTING, INCLUDED
OMIM Description
See also TAS2R10 (604791).
CLONING
Adler et al. (2000) identified members of a family of 40 to 80 human and
rodent G protein-coupled receptors expressed in subsets of taste
receptor cells of the tongue and palate epithelia. These candidate taste
receptors, which the authors called T2Rs, are organized in the genome in
clusters and are genetically linked to loci that influence bitter
perception in mice and humans. Each T2R gene encodes a 7-transmembrane
receptor protein. The amino acid sequence identities between human and
mouse T2Rs range from 46 to 67%. The authors determined that a single
taste receptor cell expresses a large repertoire of T2Rs, suggesting
that each cell may be capable of recognizing multiple tastants. In situ
hybridization demonstrated that T2Rs are exclusively expressed in taste
receptor cells that contain the G protein subunit gustducin, implying
that they function as gustducin-linked receptors. Adler et al. (2000)
identified T2R16 in chromosome 7.
GENE FUNCTION
Kinnamon (2000) reviewed the role of taste receptors in taste
transduction.
Bitter taste generally causes aversion, which protects humans from
ingesting toxic substances. On the other hand, bitter flavors contribute
to the palatability of food and beverages, thereby influencing
nutritional habits in humans (Drewnowski, 2001). Anatomic, functional,
and genetic data from rodents had suggested the existence of a family of
receptors that are responsive to bitter components (e.g., Adler et al.,
2000). Bufe et al. (2002) reported that a human member of this family of
receptors, TAS2R16, is present in taste receptor cells on the tongue and
is activated by bitter beta-glucopyranosides. Responses to these
phytonutrients show a similar concentration dependence and
desensitization in transfected cells and in experiments assessing taste
perception in humans. Bitter compounds consisting of a hydrophobic
residue attached to glucose by a beta-glycosidic bond activate TAS2R16.
Thus, TAS2R16 links the recognition of a specific chemical structure to
the perception of bitter taste. If the ability of TAS2R16 to detect
substances with common molecular properties is typical of the bitter
receptor family, it may explain how a few receptors permit the
perception of numerous bitter substances.
Using a combination of genetic, behavioral, and physiologic studies,
Mueller et al. (2005) demonstrated that T2R receptors are necessary and
sufficient for the detection and perception of bitter compounds and
showed that differences in T2Rs between species (human and mouse) can
determine the selectivity of bitter taste responses. In addition, they
showed that mice engineered to express T2R16 in 'sweet cells' became
strongly attracted to its cognate bitter tastants, whereas expression of
the same receptor (or even a novel G protein-coupled receptor) in
T2R-expressing cells resulted in mice that were averse to the respective
compounds. Mueller et al. (2005) concluded that their results
illustrated the fundamental principle of bitter taste coding at the
periphery; dedicated cells act as broadly tuned bitter sensors that are
wired to mediate behavioral aversion.
MOLECULAR GENETICS
In 262 families with alcoholism from the Collaborative Study of the
Genetics of Alcoholism (COGA) and in 85 trios consisting of an
alcohol-dependent individual and 2 parents, Hinrichs et al. (2006) found
a significant association (p = 0.00018) between alcohol dependence
(103780) and a K172N SNP (dbSNP rs846664; 604867.0001) in the TAS2R16
gene. This gene is located on chromosome 7q31 in a region reported to
exhibit linkage with alcohol dependence (Reich et al., 1998; Foroud et
al., 2000).
WASL
| dbSNP name | rs13044(T,A); rs192898738(C,T); rs3802009(T,A); rs2109723(A,G); rs2109724(C,T); rs2109725(C,T); rs10270877(T,C); rs3958047(G,C); rs73224177(T,A); rs189132404(C,T); rs11979929(C,T); rs13230230(G,A); rs11983604(T,G); rs13244694(T,C); rs10953984(A,C); rs371192595(G,A); rs139182916(T,A); rs1000204(T,G); rs7776792(A,G); rs113527460(T,G); rs370267773(T,C); rs10270793(G,A); rs57689089(T,C); rs6466881(G,C); rs1006764(C,T); rs3807640(G,C); rs4624965(A,G); rs6960373(C,T); rs7798111(C,T); rs111886448(C,A); rs13225110(C,T); rs17146251(G,C); rs142072256(A,C); rs6466882(C,T); rs7791183(A,G); rs1073670(A,C); rs138380295(G,T); rs34824298(T,C); rs2215554(A,C); rs3779260(C,T); rs9641715(A,G); rs12706545(C,T); rs1506640(T,G); rs4588795(G,A); rs56396297(T,C); rs149225498(C,T); rs12706546(G,A); rs10238422(G,C); rs1472808(A,G); rs141298870(G,C); rs7803287(T,C); rs2402671(T,C); rs12333705(C,T); rs2299982(A,C); rs2299984(A,C); rs143587823(G,A); rs10225428(A,G); rs114671530(G,C); rs35735244(T,G); rs2267874(A,C); rs6950373(C,T); rs6950659(C,T); rs6951138(G,A); rs144884784(C,T); rs11765478(A,C); rs1911145(A,G); rs768680(T,C); rs10261566(C,T); rs12537287(G,A); rs73224186(T,C); rs1019220(G,A); rs11770041(C,T); rs982655(C,T); rs2896334(A,C); rs3807636(G,A); rs141006882(C,T); rs62472098(G,A); rs2299985(T,C); rs2299986(T,C); rs7357252(C,T); rs60689684(C,T); rs13224762(A,G); rs143152986(C,G); rs10228367(C,T); rs13225220(C,A); rs143604586(A,G); rs148023723(T,C); rs13230338(T,C); rs1605285(A,G); rs6963231(A,G); rs10282073(G,A); rs1468656(G,C); rs4727975(G,A); rs9649465(G,A); rs2896335(A,T); rs12531955(G,A); rs12537072(A,G); rs7780086(C,A); rs182451527(G,A); rs4731118(T,C); rs149651786(A,C); rs2052128(T,A); rs10215473(C,G); rs13230294(T,C); rs76875852(T,C); rs1035016(G,C); rs3807635(A,C); rs3807634(C,T); rs3779258(C,T); rs145771909(A,G); rs148964633(G,A); rs17701547(G,A); rs148100107(T,C); rs2267875(T,C); rs139633244(C,G); rs10255400(G,A) |
| ccdsGene name | CCDS34743.1 |
| cytoBand name | 7q31.32 |
| EntrezGene GeneID | 8976 |
| EntrezGene Description | Wiskott-Aldrich syndrome-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | WASL:NM_003941:exon9:c.C1013T:p.P338L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8272 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O00401 |
| dbNSFP Uniprot ID | WASL_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 4.904e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
ABDOMEN:
[Liver];
Intrahepatic cholestasis;
Jaundice;
Hepatomegaly;
Nonspecific portal inflammation shown on biopsy;
Abnormal bile duct proliferation shown on biopsy;
Portal fibrosis shown on biopsy;
Cirrhosis;
End-stage liver disease before adulthood;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea;
Malabsorption of fat and fat-soluble vitamins
SKIN, NAILS, HAIR:
[Skin];
Jaundice;
Pruritus
LABORATORY ABNORMALITIES:
Increased serum gamma-GGT (231950);
Abnormal liver function tests;
Increased serum bile acids
MISCELLANEOUS:
Genetic heterogeneity (see PFIC1, 211600);
Onset in early infancy;
Carrier females may develop intrahepatic cholestasis of pregnancy
(ICP, 147480)
MOLECULAR BASIS:
Caused by mutation in the ATP-binding cassette, subfamily B, member
4 gene (ABCB4, 171060.0001)
OMIM Title
*602357 WAS/WASL-INTERACTING PROTEIN FAMILY, MEMBER 1; WIPF1
;;WISKOTT-ALDRICH SYNDROME PROTEIN-INTERACTING PROTEIN; WASPIP;;
WASP-INTERACTING PROTEIN; WIP
OMIM Description
DESCRIPTION
A major function of WIPF1 is to stabilize WASP (300392) and prevent its
degradation, and WASP is almost totally complexed with WIPF1 in T cells
(Lanzi et al., 2012).
CLONING
In an attempt to understand better the function of WASP (300392), which
is mutant in Wiskott-Aldrich syndrome (WAS; 301000), Ramesh et al.
(1997) used the yeast 2-hybrid system and cloned a novel human gene
whose 503-amino acid product interacted with WASP. They named the
protein WIP, for WASP-interacting protein.
Lanzi et al. (2012) reported that the WIPF1 protein has 2 N-terminal
WASP homology-2 (WH2) domains that interact with actin (see 102560),
followed by a cortactin (CTTN; 164765)-interacting domain, an NCK (NCK1;
600508)/CRKL (602007)-interacting domain, and a C-terminal WASP/N-WASP
(WASL; 605056)-interacting domain.
GENE STRUCTURE
Lanzi et al. (2012) reported that the WIPF1 gene contains 8 exons. The
first exon is noncoding.
MAPPING
Gross (2012) mapped the WIPF1 gene to chromosome 2q31.1 based on an
alignment of the WIPF1 sequence (GenBank GENBANK BC110288) with the
genomic sequence (GRCh37).
GENE FUNCTION
Ramesh et al. (1997) showed that overexpression of WIP increased F-actin
(see 102610) content and induced actin-containing structures in a human
B-cell line, suggesting an important role for WIP in the organization of
the actin cytoskeleton.
Sasahara et al. (2002) showed that the adaptor protein CRKL binds
directly to WIP and that, following T-cell receptor ligation, a
CRKL-WIP-WASP complex is recruited by ZAP70 (176947) to lipid rafts and
immunologic synapses.
Using mass spectrometric analysis, Scott et al. (2002) identified 25
potential binding partners in a human monocyte cell line for the SH3
domain of HCK (142370). Analysis with purified proteins and in intact
cells confirmed the interactions with WIP, WASP, and ELMO1 (606420).
Scott et al. (2002) concluded that WIP, WASP, and ELMO1 may be
activators or effectors of HCK.
Weisswange et al. (2009) analyzed the dynamics of N-WASP, WIP, GRB2
(108355), and NCK, which are required to stimulate actin-related protein
(ARP)2/3 complex (see 604221 and 604222)-dependent actin-based motility
of vaccinia virus, using fluorescence recovery after photobleaching.
Weisswange et al. (2009) showed that all 4 proteins are rapidly
exchanging, albeit at different rates, and that the turnover of N-WASP
depends on its ability to stimulate ARP2/3 complex-mediated actin
polymerization. Conversely, disruption of the interaction of N-WASP with
GRB2 and/or the barbed ends of actin filaments increases its exchange
rate and results in a faster rate of virus movement. Weisswange et al.
(2009) suggested that the exchange rate of N-WASP controls the rate of
ARP2/3 complex-dependent actin-based motility by regulating the extent
of actin polymerization by antagonizing filament capping.
MOLECULAR GENETICS
In a Moroccan infant with Wiskott-Aldrich syndrome-2 (WAS2; 602357),
Lanzi et al. (2012) identified a homozygous ser434-to-ter (S434X;
602357.0001) mutation in the WIPF1 gene. The patient's parents, who were
consanguineous, were heterozygous for the mutation.
ANIMAL MODEL
Anton et al. (2002) generated Wip -/- mice. These mice had normal
lymphocyte development, but their T lymphocytes failed to proliferate,
secrete interleukin-2 (IL2; 147680), increase their F-actin content,
polarize, and extend protrusions following T-cell receptor (see 186880)
ligation. In contrast, B cells had enhanced proliferation and CD69
(107273) activation marker expression following B-cell receptor
ligation. B cells also mounted normal antibody responses to
T-cell-independent antigens. Serum IgM and IgE levels were elevated in
the mutant mice, but IgA and IgG levels were normal. Both B and T cells
from Wip-deficient mice showed a profound defect in their subcortical
actin filament networks. Anton et al. (2002) proposed that WIP is
important for immunologic synapse formation and T-cell activation.
Kettner et al. (2004) found that mouse Wip -/- bone marrow-derived mast
cells (BMMCs) developed normally, but IgE-mediated anaphylaxis, as
measured by plasma histamine, was greatly diminished, as was Fcer1 (see
147140)-mediated Il6 (147620) production. After Fcer1 ligation, Wip
associated with Syk (600085) in wildtype BMMCs; however, Syk protein
expression, but not mRNA expression, was severely reduced in mutant
mice. Expression levels in mutant BMMCs could be restored by proteasome
and calpain inhibitors, suggesting that WIP inhibits the degradation of
SYK in mast cells. Electron microscopy demonstrated an impairment of
actin polymerization-dependent spreading, protrusion formation, F-actin
content change, and cell shape change in Wip -/- BMMCs. Kettner et al.
(2004) concluded that WIP regulates FCER1-mediated mast cell activation
by regulating SYK levels and actin cytoskeleton rearrangement.
TMEM229A
| dbSNP name | rs7785878(T,C); rs73720339(A,G) |
| cytoBand name | 7q31.32 |
| EntrezGene GeneID | 730130 |
| EntrezGene Description | transmembrane protein 229A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1841 |
SND1-IT1
| dbSNP name | rs17151639(A,G); rs61743021(T,C); rs1362897(G,A); rs17733783(A,G); rs2241291(C,T); rs1345509(T,C); rs17151650(C,G) |
| ccdsGene name | CCDS34747.1 |
| cytoBand name | 7q32.1 |
| EntrezGene GeneID | 27099 |
| snpEff Gene Name | SND1 |
| EntrezGene Description | SND1 intronic transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2342 |
| ESP Afr MAF | 0.42828 |
| ESP All MAF | 0.326695 |
| ESP Eur/Amr MAF | 0.274651 |
| ExAC AF | 0.227 |
LRRC4
| dbSNP name | rs6944446(G,A); rs3808058(C,T); rs117070316(G,T); rs74330692(G,A); rs73238074(T,C); rs3823994(A,T) |
| ccdsGene name | CCDS34747.1 |
| cytoBand name | 7q32.1 |
| EntrezGene GeneID | 64101 |
| EntrezGene Description | leucine rich repeat containing 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4977 |
MGC27345
| dbSNP name | rs2402889(C,T); rs921398(T,C); rs921399(A,G); rs12532999(C,T); rs12538722(A,G); rs36102951(C,T); rs73228315(C,T); rs13308439(T,A); rs13308097(C,A); rs6954888(G,C); rs6954653(C,T); rs117993322(C,T); rs6964936(C,T); rs7811392(C,A); rs7794771(T,C); rs11069(C,G); rs6467168(T,C); rs6467169(G,T); rs6467170(T,C); rs12706848(G,A); rs6947825(A,T); rs6972262(T,C); rs6952533(A,G); rs17151983(C,T); rs3750035(T,C); rs3750036(C,T); rs73230631(G,A) |
| cytoBand name | 7q32.1 |
| EntrezGene GeneID | 157247 |
| EntrezGene Description | uncharacterized protein MGC27345 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.483 |
TPI1P2
| dbSNP name | rs2242029(A,G); rs75312020(A,G); rs143093538(A,T) |
| cytoBand name | 7q32.1 |
| EntrezGene GeneID | 286016 |
| snpEff Gene Name | TNPO3 |
| EntrezGene Description | triosephosphate isomerase 1 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2948 |
LOC407835
| dbSNP name | rs61740498(C,T); rs61740497(G,A); rs10247566(A,G); rs7809681(T,C); rs6467231(A,G) |
| cytoBand name | 7q32.1 |
| EntrezGene GeneID | 407835 |
| snpEff Gene Name | RP11-286H14.4 |
| EntrezGene Description | mitogen-activated protein kinase kinase 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | transcribed_processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01974 |
| ExAC AF | 0.005927 |
KLF14
| dbSNP name | rs3909553(G,A) |
| cytoBand name | 7q32.3 |
| EntrezGene GeneID | 136259 |
| EntrezGene Description | Kruppel-like factor 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03811 |
TTC26
| dbSNP name | rs28372957(G,A); rs7789074(G,A); rs17160806(C,G); rs28571193(T,G); rs55634976(A,G); rs28526625(G,A); rs114963147(C,A); rs142639982(C,T); rs7804077(G,T); rs7809077(A,G); rs7809243(A,T); rs80084465(C,T); rs6467827(C,T); rs142518816(G,A); rs143361681(C,T); rs10275015(G,C); rs3847128(T,C); rs200364043(C,T); rs10214947(G,A); rs10224579(C,A); rs79622545(A,C); rs13221853(G,A); rs115913917(G,A); rs2354977(G,A); rs7803251(C,A); rs59018042(G,A); rs145889391(A,G); rs59306217(T,C); rs59593435(G,A); rs28576881(A,G); rs76647991(A,T); rs28882234(C,A); rs6467828(A,T); rs59350209(A,G); rs9969201(G,A); rs10241467(G,T); rs10270744(A,G); rs28529836(T,C); rs139805629(A,G); rs7788151(G,A); rs10248924(C,T); rs10264998(T,G); rs78757630(C,T); rs10264120(A,G); rs10441416(G,C); rs115283633(G,A); rs10235393(C,T); rs143078208(G,A); rs116771549(G,A); rs114902200(G,A); rs114106317(T,C); rs10247639(G,T); rs57045138(C,T); rs28393985(G,A); rs10252024(G,A); rs28797233(T,C); rs117684722(C,A); rs76705914(C,T); rs58051473(G,C); rs56396866(C,T); rs57475183(A,G); rs28882423(G,T); rs6980025(C,A); rs10268763(G,A); rs73473325(A,G); rs13437990(A,G); rs10225128(A,G); rs114973011(A,G); rs13438237(G,A); rs10255619(G,A); rs150828616(C,T); rs1839607(A,G); rs181150069(G,A); rs6944116(A,G); rs28491224(G,A); rs7799000(C,T); rs10464729(G,A); rs74788338(C,T); rs6972409(G,C); rs6972510(C,T); rs151196100(G,A); rs17133455(A,G); rs10085848(G,T); rs28374499(T,C); rs6960137(C,T); rs10085504(T,G); rs10085642(A,G); rs7781313(T,A); rs114316724(A,G); rs115558767(G,C); rs4732357(C,T); rs55825532(G,T); rs28415898(C,T); rs111549569(G,T); rs56898075(A,C); rs60032227(G,A); rs59269998(A,G); rs58013295(A,G); rs7786800(A,G); rs7786932(A,G); rs7787241(C,T); rs10263969(T,C); rs10248900(C,T); rs138232771(T,C); rs58341174(A,G); rs116992937(C,G); rs28613815(C,T); rs7791966(A,G); rs3896550(T,C); rs3896551(A,G); rs6955929(T,C); rs73475324(G,A); rs60076917(G,A); rs79377626(A,C); rs73735105(T,C); rs115322243(G,A); rs58436548(C,T); rs116306711(G,A); rs7790956(A,G); rs57825076(C,T); rs2249153(T,C); rs10480886(A,G); rs2249070(C,A); rs142388606(A,G); rs61701200(T,C); rs6945420(G,C); rs6965490(T,C); rs137896807(T,G); rs377005298(G,A); rs7807858(T,C) |
| ccdsGene name | CCDS5852.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 79989 |
| EntrezGene Description | tetratricopeptide repeat domain 26 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TTC26:NM_001144923:exon3:c.C217T:p.L73F,TTC26:NM_001287512:exon4:c.C310T:p.L104F,TTC26:NM_024926:exon4:c.C310T:p.L104F,TTC26:NM_001144920:exon4:c.C310T:p.L104F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5769 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B7Z2T3 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.000122 |
JHDM1D-AS1
| dbSNP name | rs6967957(T,C); rs4726674(C,T); rs78855706(A,G); rs6464578(T,C); rs6464579(T,G); rs190141605(A,G) |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 100134229 |
| snpEff Gene Name | JHDM1D |
| EntrezGene Description | JHDM1D antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3852 |
TAS2R3
| dbSNP name | rs765007(T,C); rs2270009(C,T) |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 50831 |
| snpEff Gene Name | SSBP1 |
| EntrezGene Description | taste receptor, type 2, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4288 |
| ESP Afr MAF | 0.495007 |
| ESP All MAF | 0.498462 |
| ESP Eur/Amr MAF | 0.495116 |
| ExAC AF | 0.523 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
*604868 TASTE RECEPTOR, TYPE 2, MEMBER 3; TAS2R3
;;T2R3
OMIM Description
See also TAS2R10 (604791).
CLONING
Adler et al. (2000) identified members of a family of 40 to 80 human and
rodent G protein-coupled receptors expressed in subsets of taste
receptor cells of the tongue and palate epithelia. These candidate taste
receptors, which the authors called T2Rs, are organized in the genome in
clusters and are genetically linked to loci that influence bitter
perception in mice and humans. Each T2R gene encodes a 7-transmembrane
receptor protein. The amino acid sequence identities between human and
mouse T2Rs range from 46 to 67%. The authors determined that a single
taste receptor cell expresses a large repertoire of T2Rs, suggesting
that each cell may be capable of recognizing multiple tastants. In situ
hybridization demonstrated that T2Rs are exclusively expressed in taste
receptor cells that contain the G protein subunit gustducin, implying
that they function as gustducin-linked receptors. Adler et al. (2000)
identified T2R3 in a PAC clone from 7q31.3-q32.
Kinnamon (2000) reviewed the role of taste receptors in taste
transduction.
TAS2R4
| dbSNP name | rs2233998(T,C); rs2234001(G,C); rs2234002(G,A) |
| ccdsGene name | CCDS5868.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 50832 |
| EntrezGene Description | taste receptor, type 2, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R4:NM_016944:exon1:c.T20C:p.F7S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYW5 |
| dbNSFP Uniprot ID | TA2R4_HUMAN |
| dbNSFP KGp1 AF | 0.468406593407 |
| dbNSFP KGp1 Afr AF | 0.201219512195 |
| dbNSFP KGp1 Amr AF | 0.527624309392 |
| dbNSFP KGp1 Asn AF | 0.673076923077 |
| dbNSFP KGp1 Eur AF | 0.459102902375 |
| dbSNP GMAF | 0.4688 |
| ESP Afr MAF | 0.226055 |
| ESP All MAF | 0.401661 |
| ESP Eur/Amr MAF | 0.491628 |
| ExAC AF | 0.471 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
*604869 TASTE RECEPTOR, TYPE 2, MEMBER 4; TAS2R4
;;T2R4
OMIM Description
See also TAS2R10 (604791).
CLONING
Adler et al. (2000) identified members of a family of 40 to 80 human and
rodent G protein-coupled receptors expressed in subsets of taste
receptor cells of the tongue and palate epithelia. These candidate taste
receptors, which the authors called T2Rs, are organized in the genome in
clusters and are genetically linked to loci that influence bitter
perception in mice and humans. Each T2R gene encodes a 7-transmembrane
receptor protein. The amino acid sequence identities between human and
mouse T2Rs range from 46 to 67%. The authors determined that a single
taste receptor cell expresses a large repertoire of T2Rs, suggesting
that each cell may be capable of recognizing multiple tastants. In situ
hybridization demonstrated that T2Rs are exclusively expressed in taste
receptor cells that contain the G protein subunit gustducin (139395),
implying that they function as gustducin-linked receptors.
GENE FUNCTION
Chandrashekar et al. (2000) used a heterologous expression system to
show that specific T2Rs function as bitter taste receptors. They found
that the mouse mT2R5 responds to the bitter tastant cycloheximide, while
the human T2R4 and mouse mT2R8 respond to denatonium and
6-N-propyl-2-thiouracil. Mice strains deficient in their ability to
detect cycloheximide had amino acid substitutions in the mT2R5 gene;
these changes rendered the receptor significantly less responsive to
cycloheximide. Chandrashekar et al. (2000) also expressed mT2R5 in
insect cells and demonstrated specific tastant-dependent activation of
gustducin, a G protein implicated in bitter signaling. Since a single
taste receptor cell expresses a large repertoire of T2Rs, these findings
provided a plausible explanation for the uniform bitter taste evoked by
many structurally unrelated toxic compounds.
Kinnamon (2000) reviewed the role of taste receptors in taste
transduction.
Shah et al. (2009) found that motile cilia emerging from human airway
epithelial cells express sensory bitter taste receptors, including T2R4,
T2R43 (612668), T2R38 (607751), and T2R46 (612774). Only ciliated
epithelial cells expressed these receptors, and they specifically
localized in cilia. The receptors appeared to localize preferentially at
different places along the cilium. T2R4 seemed to sit near the tips of
cilia, whereas T2R43 appeared to reside more proximally. Bitter
compounds increased the intracellular calcium ion concentration and
stimulated ciliary beat frequency. Shah et al. (2009) found that
alpha-gustducin and the enzyme phospholipase C-beta-2 (PLCB2; 604114)
are also expressed in airway epithelia. Alpha-gustducin resides in the
cilia, and PLCB2 appears to sit below the cilia in the apical portion of
the cell. Shah et al. (2009) concluded that airway epithelia contain a
cell-autonomous system in which motile cilia both sense noxious
substances entering airways and initiate a defensive mechanism to
eliminate the offending compound. Hence, like primary cilia, classical
motile cilia also contain sensors to detect the external environment.
MAPPING
Adler et al. (2000) identified T2R4 in a PAC clone from 7q31.3-q32.
TAS2R5
| dbSNP name | rs2234009(C,T); rs2234012(A,G); rs2234013(G,A); rs2227264(G,T); rs151221895(C,G); rs2234017(G,C) |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 54429 |
| EntrezGene Description | taste receptor, type 2, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01469 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Alzheimer disease;
Seizures;
Cerebral cortex with spongiform changes;
Neurofibrillary tangles;
Beta-amyloid-positive senile plaques;
Prion protein-positive senile plaques
MISCELLANEOUS:
Age of onset 43-64 years
OMIM Title
*605062 TASTE RECEPTOR, TYPE 2, MEMBER 5; TAS2R5
;;T2R5
OMIM Description
See also TAS2R10 (604791).
CLONING
Adler et al. (2000) identified members of a family of 40 to 80 human and
rodent G protein-coupled receptors expressed in subsets of taste
receptor cells of the tongue and palate epithelia. These candidate taste
receptors, which the authors called T2Rs, are organized in the genome in
clusters and are genetically linked to loci that influence bitter
perception in mice and humans. Each T2R gene encodes a 7-transmembrane
receptor protein. The amino acid sequence identities between human and
mouse T2Rs range from 46 to 67%. The authors determined that a single
taste receptor cell expresses a large repertoire of T2Rs, suggesting
that each cell may be capable of recognizing multiple tastants. In situ
hybridization demonstrated that T2Rs are exclusively expressed in taste
receptor cells that contain the G protein subunit gustducin, implying
that they function as gustducin-linked receptors.
MAPPING
Adler et al. (2000) identified the T2R5 gene in a PAC clone from
chromosome 7q31.3-q32.
TAS2R38
| dbSNP name | rs10246939(T,C); rs1726866(G,A); rs713598(C,G) |
| ccdsGene name | CCDS34765.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 5726 |
| EntrezGene Description | taste receptor, type 2, member 38 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=5726&%3Brs=10246939|http://www.ncbi.nlm.nih.gov/omim/171200,607751|http://omim.org/entry/607751#0003 |
| Annovar Function | TAS2R38:NM_176817:exon1:c.A886G:p.I296V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P59533 |
| dbNSFP Uniprot ID | T2R38_HUMAN |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=5726&%3Brs=10246939|http://www.ncbi.nlm.nih.gov/omim/171200,607751|http://omim.org/entry/607751#0003 |
| dbNSFP KGp1 AF | 0.548534798535 |
| dbNSFP KGp1 Afr AF | 0.516260162602 |
| dbNSFP KGp1 Amr AF | 0.635359116022 |
| dbNSFP KGp1 Asn AF | 0.646853146853 |
| dbNSFP KGp1 Eur AF | 0.45382585752 |
| dbSNP GMAF | 0.4509 |
| ESP Afr MAF | 0.477985 |
| ESP All MAF | 0.463171 |
| ESP Eur/Amr MAF | 0.455581 |
| ExAC AF | 0.475 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Apnea during seizure spells;
Cyanosis
NEUROLOGIC:
[Central nervous system];
Seizures, partial, afebrile;
Secondary generalized tonic-clonic seizures may occur;
Seizures occur in clusters over 1 or several days;
Seizures often begin focally with head and eye deviation;
Rigidity during seizures;
Staring episodes during seizures;
Ictal EEG shows focal onset, often posterior region of brain;
Normal psychomotor development;
Normal interictal EEG
MISCELLANEOUS:
Onset ranges from 2 days to 7 months (most at 2-3 months);
Seizures are easily controlled by medications;
Spontaneous resolution by 12 months of age with no recurrence later
in life;
See also benign familial infantile convulsions (BFIC1, 601764);
See also benign neonatal epilepsy (EBN1, 121200)
MOLECULAR BASIS:
Caused by mutation in the alpha-1-subunit of the voltage-gated type
II sodium channel gene (SCN2A, 182390.0002)
OMIM Title
*607751 TASTE RECEPTOR, TYPE 2, MEMBER 38; TAS2R38
;;PTC;;
T2R61
OMIM Description
DESCRIPTION
TAS2R38 belongs to the large TAS2R receptor family. TAS2Rs are expressed
on the surface of taste receptor cells and mediate the perception of
bitterness through a G protein-coupled second messenger pathway (summary
by Conte et al., 2002). For further information on the TAS2R gene
family, see 604791.
CLONING
By screening the human genome for sequences relate to TAS2Rs, Conte et
al. (2002) cloned TAS2R38, which they called T2R61. The deduced
333-amino acid protein contains the 7-transmembrane structure and short
N- and C-terminal domains conserved in TAS2Rs. The intracellular domains
share significant conservation with other TAS2R family members. TAS2R38
shares highest sequence similarity with TAS2R5 (605062).
Kim et al. (2003) identified a small region on chromosome 7q that showed
strong linkage disequilibrium between SNP markers and PTC taste
sensitivity (see 171200) in unrelated subjects. This region was narrowed
to a 2.6-Mb interval using the Utah CEPH families and further narrowed
to a 150-kb interval of linkage disequilibrium extending from about
139,835,000 to 139,981,000 basepairs on the chromosome 7 sequence.
Further narrowing identified only 1 gene in this interval, a TAS2R
bitter receptor gene that they designated PTC. The gene encodes a
7-transmembrane-domain, heterotrimeric guanine nucleotide-binding
protein (G protein)-coupled receptor that shows 30% amino acid identity
with human TAS2R7 (604793), the most closely related member of this
family.
GENE STRUCTURE
The TAS2R38 gene consists of 1,002 basepairs in a single exon (Kim et
al., 2003).
MAPPING
By somatic cell hybrid and genomic sequence analyses, Conte et al.
(2002) mapped the TAS2R38 gene to an approximately 3-Mb cluster on
chromosome 7q.
Gross (2011) mapped the TAS2R38 gene to chromosome 7q34 based on an
alignment of the TAS2R38 sequence (GenBank GENBANK AY258597) with the
genomic sequence (GRCh37).
GENE FUNCTION
Shah et al. (2009) found that motile cilia emerging from human airway
epithelial cells express sensory bitter taste receptors, including T2R4
(604869), T2R43 (612668), T2R38, and T2R46 (612774). Only ciliated
epithelial cells expressed these receptors, and they specifically
localized in cilia. The receptors appeared to localize preferentially at
different places along the cilium. T2R4 seemed to sit near the tips of
cilia, whereas T2R43 appeared to reside more proximally. Bitter
compounds increased the intracellular calcium ion concentration and
stimulated ciliary beat frequency. Shah et al. (2009) found that
alpha-gustducin (139395) and the enzyme phospholipase C-beta-2 (PLCB2;
604114) are also expressed in airway epithelia. Alpha-gustducin resides
in the cilia, and PLCB2 appears to sit below the cilia in the apical
portion of the cell. Shah et al. (2009) concluded that airway epithelia
contain a cell-autonomous system in which motile cilia both sense
noxious substances entering airways and initiate a defensive mechanism
to eliminate the offending compound. Hence, like primary cilia,
classical motile cilia also contain sensors to detect the external
environment.
MOLECULAR GENETICS
Kim et al. (2003) identified 3 common SNPs within the PTC gene, all of
which result in amino acid changes in the protein. One, ala49 to pro
(607751.0001), demonstrated a strong association overall with taster
status in 2 separate samples. The association of taster status with the
val262-to-ala (607751.0002) allele was similarly strong in 2 samples.
The third polymorphism was ile296 to val (607751.0003). Named in the
order of the 3 SNPs, the nontaster haplotype is AVI; this and the taster
haplotype PAV accounted for 47% and 49% of all haplotypes, respectively,
in the European sample and for 30% and 70%, respectively, in the East
Asian sample. Europeans possessed the presumed recombinant taster
haplotype AAV at a frequency of 3%. The haplotype association with
taster status was more definitive than for individual SNPs; the
strongest association with nontaster status was with the AVI homozygote,
followed by the compound heterozygote AVI/AAV.
Mangold et al. (2008) presented evidence suggesting that the 3 SNPs in
the TAS2R38 gene identified by Kim et al. (2003) may play a role in the
development of nicotine dependence (see 188890) among African Americans.
The taster haplotype PAV was inversely associated (p = 0.0165), and the
nontaster haplotype AVI was positively associated (p = 0.0120), with
smoking quantity in a study of 1,053 African American smokers. The
nontaster haplotype was positively associated with all measures of
nicotine dependence in female African American smokers (p = 0.01-0.003).
No significant associations were observed in a sample of 515 European
smokers. Mangold et al. (2008) postulated that heightened oral
sensitivity confers protection against nicotine dependence.
In a study of 2,309 individuals from 262 families with alcohol
dependence (103780) comprising both European American and African
American individuals, Wang et al. (2007) found an association between
the nontaster AVI haplotype in the TAS2R38 gene and maximum alcohol
consumption only among African American females. The taster PAV/PAI
haplotype was associated with lower maximum alcohol consumption (p =
0.035). However, there was no evidence that TAS2R38 haplotypes influence
alcohol dependence.
EVOLUTION
Kim et al. (2003) sequenced the PTC gene in 6 primate species (including
humans) to determine the original form of the PTC gene. All nonhuman
primates were homozygous for the PAV form, which indicates that the AVI
form arose in humans after they diverged from the nearest common primate
ancestors. Five different haplotypes were observed worldwide. In
Europeans and Asians, the taster haplotype PAV and the nontaster
haplotype AVI made up the vast majority of haplotypes present. Two
additional haplotypes, PVI and AAI, were observed only in individuals of
sub-Saharan African ancestry, which is consistent with other reports of
increased gene haplotype diversity in this population. The common
nontaster AVI haplotype was observed in all populations except southwest
Native Americans, who were exclusively homozygous for the PAV haplotype,
consistent with the reported low frequency of nontasters in this
population. Thus, overall, the worldwide distribution of these
haplotypes is consistent with the large anthropologic literature on the
distribution of this phenotype.
Wooding et al. (2006) showed that in chimpanzees, as in humans, PTC
taste sensitivity is controlled by 2 common alleles of TAS2R38; however,
neither of these alleles is shared with humans. Instead, a mutation of
the initiation codon results in the use of an alternative downstream
start codon and production of a truncated receptor variant that fails to
respond to PTC in vitro. Association testing of PTC sensitivity in a
cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype
accurately predicts taster status in vivo. Therefore, although the
observations of Fisher et al. (1939) were accurate, their explanation
was wrong. Humans and chimpanzees share variable taste sensitivity to
bitter compounds mediated by PTC receptor variants, but the molecular
basis of this variation has arisen twice, independently, in the 2
species.
MTRNR2L6
| dbSNP name | rs57870414(C,T); rs62471364(T,G); rs62471365(A,G); rs17133581(A,G); rs58504986(A,G); rs56784185(A,G) |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 100463482 |
| snpEff Gene Name | AC231380.1 |
| EntrezGene Description | MT-RNR2-like 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | Mt_tRNA_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1763 |
OR9A2
| dbSNP name | rs9885986(C,T) |
| ccdsGene name | CCDS34767.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 135924 |
| EntrezGene Description | olfactory receptor, family 9, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR9A2:NM_001001658:exon1:c.G158A:p.R53H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGT5 |
| dbNSFP Uniprot ID | OR9A2_HUMAN |
| dbNSFP KGp1 AF | 0.0782967032967 |
| dbNSFP KGp1 Afr AF | 0.170731707317 |
| dbNSFP KGp1 Amr AF | 0.0718232044199 |
| dbNSFP KGp1 Asn AF | 0.041958041958 |
| dbNSFP KGp1 Eur AF | 0.0488126649077 |
| dbSNP GMAF | 0.07851 |
| ESP Afr MAF | 0.127326 |
| ESP All MAF | 0.088344 |
| ESP Eur/Amr MAF | 0.068372 |
| ExAC AF | 0.076 |
OR6V1
| dbSNP name | rs17164103(C,T); rs28563993(G,A); rs11975892(C,T); rs10245778(C,T) |
| ccdsGene name | CCDS47728.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 346517 |
| EntrezGene Description | olfactory receptor, family 6, subfamily V, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6V1:NM_001001667:exon1:c.C300T:p.Y100Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.135 |
| ESP Afr MAF | 0.264678 |
| ESP All MAF | 0.143838 |
| ESP Eur/Amr MAF | 0.083021 |
| ExAC AF | 0.094 |
OR6W1P
| dbSNP name | rs6971445(T,A); rs12668105(G,A) |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 89883 |
| EntrezGene Description | olfactory receptor, family 6, subfamily W, member 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05051 |
TAS2R40
| dbSNP name | rs10260248(C,A) |
| ccdsGene name | CCDS43662.1 |
| cytoBand name | 7q34 |
| EntrezGene GeneID | 259286 |
| EntrezGene Description | taste receptor, type 2, member 40 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R40:NM_176882:exon1:c.C560A:p.S187Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P59535 |
| dbNSFP Uniprot ID | T2R40_HUMAN |
| dbNSFP KGp1 AF | 0.0677655677656 |
| dbNSFP KGp1 Afr AF | 0.136178861789 |
| dbNSFP KGp1 Amr AF | 0.0883977900552 |
| dbNSFP KGp1 Asn AF | 0.0244755244755 |
| dbNSFP KGp1 Eur AF | 0.0461741424802 |
| dbSNP GMAF | 0.06795 |
| ESP Afr MAF | 0.133947 |
| ESP All MAF | 0.082919 |
| ESP Eur/Amr MAF | 0.059443 |
| ExAC AF | 0.071 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Mouth];
Perioral eczema;
Aphthous ulcers
RESPIRATORY:
Recurrent sinusitis
ABDOMEN:
[Gastrointestinal];
Chronic granulomatous colitis;
Diarrhea;
Perianal infections
IMMUNOLOGY:
Recurrent infections;
Neutrophils show defective intracellular NADPH oxidase production
MISCELLANEOUS:
Onset in early childhood;
One patient has been reported (as of May 2011)
MOLECULAR BASIS:
Caused by mutation in the neutrophil cytosolic factor 4 gene (NCF4,
601488.0001)
OMIM Title
*613964 TASTE RECEPTOR, TYPE 2, MEMBER 40; TAS2R40
;;T2R40
OMIM Description
DESCRIPTION
TAS2R40 belongs to a family of intronless genes that encode highly
related bitter taste receptors (TAS2Rs). TAS2Rs are G protein-coupled
receptors, which are characterized by 7 transmembrane domains (summary
by Fischer et al., 2005). For further information on the TAS2R gene
family, see 604791.
MAPPING
By genomic sequence analysis, Fischer et al. (2005) mapped the TAS2R40
gene to a TAS2R gene cluster on chromosome 7q31. Gross (2011) mapped the
TAS2R40 gene to chromosome 7q34 based on an alignment of the TAS2R40
sequence (GenBank GENBANK AF494229) with the genomic sequence (GRCh37).
FAM115C
| dbSNP name | rs7811904(T,G); rs61482968(T,G); rs183015502(C,T); rs7795149(C,A); rs140081344(T,C) |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 285966 |
| EntrezGene Description | family with sequence similarity 115, member C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4463 |
OR2F2
| dbSNP name | rs2240359(C,T); rs13229174(A,G); rs61740239(G,A); rs13235235(T,C) |
| ccdsGene name | CCDS43666.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 135948 |
| EntrezGene Description | olfactory receptor, family 2, subfamily F, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2F2:NM_001004685:exon1:c.C293T:p.A98V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95006 |
| dbNSFP Uniprot ID | OR2F2_HUMAN |
| dbNSFP KGp1 AF | 0.457417582418 |
| dbNSFP KGp1 Afr AF | 0.686991869919 |
| dbNSFP KGp1 Amr AF | 0.42817679558 |
| dbNSFP KGp1 Asn AF | 0.526223776224 |
| dbNSFP KGp1 Eur AF | 0.270448548813 |
| dbSNP GMAF | 0.4573 |
| ESP Afr MAF | 0.374035 |
| ESP All MAF | 0.404538 |
| ESP Eur/Amr MAF | 0.291017 |
| ExAC AF | 0.341 |
OR2F1
| dbSNP name | rs73464587(A,G); rs2072164(C,T); rs2072165(A,G); rs2072166(A,G) |
| ccdsGene name | CCDS5887.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 26211 |
| EntrezGene Description | olfactory receptor, family 2, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2F1:NM_012369:exon1:c.A169G:p.T57A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q13607 |
| dbNSFP Uniprot ID | OR2F1_HUMAN |
| dbNSFP KGp1 AF | 0.043956043956 |
| dbNSFP KGp1 Afr AF | 0.172764227642 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.04408 |
| ESP Afr MAF | 0.148888 |
| ESP All MAF | 0.051923 |
| ESP Eur/Amr MAF | 0.002211 |
| ExAC AF | 0.016 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608497 OLFACTORY RECEPTOR, FAMILY 2, SUBFAMILY F, MEMBER 1; OR2F1
;;OLF3
OMIM Description
The mammalian olfactory receptor gene family is made up of hundreds of
genes that encode an immense variety of membrane-bound G protein-coupled
receptors. The receptors share several hallmark sequence motifs, yet are
quite variable in the region of the protein thought to be responsible
for binding odorants (Issel-Tarver and Rine, 1997). See also 164342.
CLONING
By using dog Or2f1 as probe to screen a Southern blot, followed by
subcloning the appropriate genomic fragment, Issel-Tarver and Rine
(1997) cloned OR2F1, which they called OLF3. The deduced 317-amino acid
protein contains an extracellular N-terminal domain with a potential
N-glycosylation site, 7 predicted transmembrane segments, and potential
C-terminal phosphorylation sites. Human and canine OR2F1 share 86%
identity.
MAPPING
By Southern hybridization and PCR analysis, Issel-Tarver and Rine (1997)
mapped the OR2F1 gene to chromosome 7q35.
OR6B1
| dbSNP name | rs7787378(C,T); rs728275(C,T) |
| ccdsGene name | CCDS43667.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 135946 |
| EntrezGene Description | olfactory receptor, family 6, subfamily B, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6B1:NM_001005281:exon1:c.C427T:p.R143C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95007 |
| dbNSFP Uniprot ID | OR6B1_HUMAN |
| dbNSFP KGp1 AF | 0.163919413919 |
| dbNSFP KGp1 Afr AF | 0.0772357723577 |
| dbNSFP KGp1 Amr AF | 0.306629834254 |
| dbNSFP KGp1 Asn AF | 0.246503496503 |
| dbNSFP KGp1 Eur AF | 0.089709762533 |
| dbSNP GMAF | 0.163 |
| ESP Afr MAF | 0.070662 |
| ESP All MAF | 0.085512 |
| ESP Eur/Amr MAF | 0.092947 |
| ExAC AF | 0.14 |
OR2A5
| dbSNP name | rs2961144(A,G); rs6464573(G,T); rs4407791(T,C) |
| ccdsGene name | CCDS43668.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 393046 |
| EntrezGene Description | olfactory receptor, family 2, subfamily A, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2A5:NM_012365:exon1:c.A376G:p.I126V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96R48 |
| dbNSFP Uniprot ID | OR2A5_HUMAN |
| dbNSFP KGp1 AF | 0.246336996337 |
| dbNSFP KGp1 Afr AF | 0.471544715447 |
| dbNSFP KGp1 Amr AF | 0.279005524862 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.270448548813 |
| dbSNP GMAF | 0.2466 |
| ESP Afr MAF | 0.463748 |
| ESP All MAF | 0.365557 |
| ESP Eur/Amr MAF | 0.316403 |
| ExAC AF | 0.292 |
OR2A25
| dbSNP name | rs59319753(G,C); rs6951485(G,A); rs61731397(T,C); rs2961135(G,C) |
| ccdsGene name | CCDS43669.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 392138 |
| EntrezGene Description | olfactory receptor, family 2, subfamily A, member 25 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2A25:NM_001004488:exon1:c.G96C:p.L32L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3687 |
| ESP Afr MAF | 0.20404 |
| ESP All MAF | 0.207058 |
| ESP Eur/Amr MAF | 0.208605 |
| ExAC AF | 0.289 |
OR2A12
| dbSNP name | rs34947817(G,A) |
| ccdsGene name | CCDS43670.1 |
| CosmicCodingMuts gene | OR2A12 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 346525 |
| EntrezGene Description | olfactory receptor, family 2, subfamily A, member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2A12:NM_001004135:exon1:c.G791A:p.S264N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGT7 |
| dbNSFP Uniprot ID | O2A12_HUMAN |
| dbNSFP KGp1 AF | 0.127747252747 |
| dbNSFP KGp1 Afr AF | 0.231707317073 |
| dbNSFP KGp1 Amr AF | 0.127071823204 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.156992084433 |
| dbSNP GMAF | 0.1276 |
| ESP Afr MAF | 0.23913 |
| ESP All MAF | 0.212101 |
| ESP Eur/Amr MAF | 0.199638 |
| ExAC AF | 0.149 |
OR2A2
| dbSNP name | rs10230228(C,A); rs10252253(T,C); rs2961149(T,G); rs2951315(T,C) |
| ccdsGene name | CCDS43671.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 442361 |
| EntrezGene Description | olfactory receptor, family 2, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2A2:NM_001005480:exon1:c.C13A:p.Q5K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IF42 |
| dbNSFP Uniprot ID | OR2A2_HUMAN |
| dbNSFP KGp1 AF | 0.166666666667 |
| dbNSFP KGp1 Afr AF | 0.392276422764 |
| dbNSFP KGp1 Amr AF | 0.140883977901 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.158311345646 |
| dbSNP GMAF | 0.1662 |
| ESP Afr MAF | 0.358034 |
| ESP All MAF | 0.251616 |
| ESP Eur/Amr MAF | 0.200669 |
| ExAC AF | 0.161 |
OR2A14
| dbSNP name | rs2961160(G,T); rs2961161(C,G) |
| ccdsGene name | CCDS43672.1 |
| cytoBand name | 7q35 |
| EntrezGene GeneID | 135941 |
| EntrezGene Description | olfactory receptor, family 2, subfamily A, member 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2A14:NM_001001659:exon1:c.G398T:p.S133I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96R47 |
| dbNSFP Uniprot ID | O2A14_HUMAN |
| dbNSFP KGp1 AF | 0.644688644689 |
| dbNSFP KGp1 Afr AF | 0.747967479675 |
| dbNSFP KGp1 Amr AF | 0.726519337017 |
| dbNSFP KGp1 Asn AF | 0.746503496503 |
| dbNSFP KGp1 Eur AF | 0.461741424802 |
| dbSNP GMAF | 0.3558 |
| ESP Afr MAF | 0.253472 |
| ESP All MAF | 0.394364 |
| ESP Eur/Amr MAF | 0.465752 |
| ExAC AF | 0.594,2.445e-05 |
ZBED6CL
| dbSNP name | rs3800780(C,A); rs3800781(T,A); rs73474332(C,T); rs3800782(A,G); rs79275116(C,T); rs76490935(A,G); rs11978222(G,A); rs3800783(A,G); rs114973325(G,A); rs74334311(G,A); rs3735172(A,G); rs12671192(G,A) |
| cytoBand name | 7q36.1 |
| EntrezGene GeneID | 113763 |
| snpEff Gene Name | LRRC61 |
| EntrezGene Description | ZBED6 C-terminal like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2539 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, progressive (1 patient);
Poor head control;
[Ears];
Sensorineural hearing loss (1 family);
[Eyes];
Microphthalmia;
Large eyes;
Decreased visual acuity;
Cataract;
Coloboma
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
ABDOMEN:
[Gastrointestinal];
Feeding problems
SKELETAL:
Joint contractures;
[Spine];
Scoliosis
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Muscle weakness and atrophy, progressive;
Muscle biopsy shows defective glycosylation of alpha-dystroglycan;
Secondary loss of merosin and desmin
NEUROLOGIC:
[Central nervous system];
Psychomotor retardation, severe;
Loss of ambulation;
Poor speech;
Hydrocephalus (1 patient);
Cerebellar hypoplasia (1 patient);
Brainstem hypoplasia (1 patient);
Agyria (1 patient);
Brain hypomyelination
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset at birth;
Clinical variability;
Two unrelated families have been reported (last curated June 2014)
MOLECULAR BASIS:
Caused by mutation in the protein-O-mannose kinase gene (POMK, 615247.0001)
OMIM Title
*615252 ZBED6 C TERMINUS-LIKE PROTEIN; ZBED6CL
;;CHROMOSOME 7 OPEN READING FRAME 29; C7ORF29
OMIM Description
CLONING
By searching databases for ZBED genes (see ZBED1; 300178), Hayward et
al. (2013) identified ZBED6CL. The deduced 296-amino acid protein is
made up primarily of a catalytic domain like that found at the C termini
of most ZBED proteins, but it lacks the N-terminal zinc finger BED
domain. The catalytic domain of ZBED6CL contains a DDE motif similar to
that found in the catalytic pockets of integrases of retroviruses and
long terminal repeat retrotransposons.
MAPPING
By genomic sequence analysis, Hayward et al. (2013) mapped the ZBED6CL
gene to chromosome 7q36.1.
PRKAG2
| dbSNP name | rs7429(C,T); rs1051956(C,A); rs184932311(A,G); rs8961(T,C); rs764801(T,C); rs764800(G,A); rs6945103(T,C); rs6963427(C,T); rs6945637(T,C); rs13246715(A,C); rs5016446(A,C); rs5016447(C,T); rs5017429(C,T); rs73727848(T,C); rs5017426(A,G); rs5017425(G,A); rs13237561(T,C); rs36022838(G,A); rs4726047(A,G); rs4726048(C,T); rs4725410(A,T); rs4726049(T,C); rs4726050(C,T); rs79133627(C,T); rs6464147(T,C); rs80248081(G,A); rs7806619(C,G); rs73475407(A,G); rs28763998(A,G); rs17173189(G,A); rs78551428(A,G); rs7782888(T,C); rs77954112(C,T); rs57276651(G,C); rs9942590(A,G); rs149858008(T,G); rs112791672(C,T); rs11982878(C,T); rs7793338(T,C); rs7793517(T,A); rs186114650(A,T); rs2302533(A,T); rs2302532(A,C); rs73475418(T,C); rs59202589(C,T); rs139261798(G,C); rs141541040(A,C); rs73156280(C,T); rs2241053(C,T); rs2241052(C,T); rs2302531(G,A); rs2302530(G,A); rs2302529(G,T); rs149268507(C,T); rs113260584(T,A); rs7787908(C,T); rs7807134(T,C); rs7788234(A,C); rs79994029(A,G); rs17715460(G,A); rs17173197(C,T); rs74378494(G,A); rs79901758(A,G); rs76331945(C,T); rs75217350(G,A); rs6955903(C,G); rs76747376(T,C); rs28764001(C,G); rs112864625(T,C); rs111720710(T,C); rs113731249(A,C); rs79720560(G,A); rs75785240(G,A); rs56394887(G,A); rs139040172(G,T); rs59266280(G,A); rs2302528(A,G); rs7791529(T,C); rs17715595(C,T); rs73475429(G,A); rs4726052(A,G); rs3762014(T,C); rs148814057(C,T); rs74303070(T,C); rs73475434(A,G); rs17173198(T,C); rs2727544(G,A); rs75666789(C,T); rs78195204(G,A); rs1029947(T,C); rs1029946(A,G); rs1029945(C,T); rs181024199(C,G); rs4726053(G,A); rs113781976(G,T); rs139187111(G,C); rs61666170(T,A); rs11765101(C,G); rs4726054(G,A); rs11765815(G,A); rs75885547(T,C); rs73475440(A,G); rs73156296(T,C); rs73156298(C,A); rs73156300(G,A); rs17173199(G,A); rs73156302(G,C); rs2538041(G,A); rs17643028(C,A); rs6953318(A,G); rs6953900(G,A); rs76148215(C,T); rs60935035(G,T); rs73475446(A,C); rs2538040(C,G); rs3789815(G,A); rs2538039(A,G); rs2538038(T,G); rs2538037(A,C); rs75360367(C,G); rs73158109(C,T); rs66711554(A,G); rs142537708(C,T); rs56935576(A,G); rs6974777(G,T); rs57471262(G,A); rs6974841(C,T); rs17173202(T,C); rs375368467(G,A); rs6464148(C,A); rs7811398(G,A); rs7811537(G,A); rs7811554(G,A); rs113868349(G,C); rs4726055(T,C); rs35050553(G,T); rs34353342(C,T); rs4726056(A,G); rs1971030(T,C); rs12164128(T,G); rs1541538(T,C); rs373090106(A,G); rs377557430(C,T); rs9640292(G,A); rs4726057(C,T); rs4726058(C,T); rs11979989(C,T); rs368631452(A,G); rs118035196(C,T); rs11983751(T,C); rs11980127(G,A); rs12056287(T,C); rs4725411(A,G); rs4725412(G,C); rs6949110(T,G); rs6967274(G,A); rs3789813(A,G); rs3789812(T,C); rs3789811(G,A); rs148055692(C,G); rs3789810(G,A); rs3789809(T,C); rs78915859(T,C); rs2538036(G,C); rs113845641(C,T); rs111589757(C,T); rs7810070(A,T); rs73727866(C,G); rs55957357(C,T); rs113642894(C,A); rs4725413(C,A); rs4726059(G,A); rs60032544(A,G); rs111699856(G,A); rs74498648(T,A); rs7794071(A,G); rs7794333(C,A); rs730226(A,C); rs79153965(A,C); rs73158121(G,A); rs12111653(G,A); rs2727572(C,T); rs28451523(C,A); rs371833177(C,T); rs55807670(G,A); rs76550327(G,A); rs60819347(G,C); rs59950752(T,C); rs142158548(C,T); rs76520307(T,C); rs73730209(C,T); rs73730212(A,G); rs371132392(C,T); rs59262765(T,G); rs112842575(C,T); rs73158123(G,C); rs12668489(C,T); rs73158124(C,T); rs73730214(G,A); rs2058497(T,A); rs6976650(C,T); rs6959337(T,C); rs6977131(C,T); rs75070518(C,G); rs77356942(C,T); rs12112591(T,C); rs79456594(G,T); rs6949815(C,A); rs6464151(T,C); rs6464152(G,A); rs2727567(T,C); rs79079718(T,C); rs7792920(C,G); rs55668852(C,A); rs370214947(G,A); rs55993398(G,A); rs6942626(T,G); rs73479354(G,A); rs117957560(C,T); rs12112462(C,T); rs368337543(C,T); rs10952314(T,C); rs7807386(C,G); rs66794877(G,T); rs6464153(G,A); rs117440434(G,T); rs4726060(T,C); rs374031113(C,T); rs1558538(C,T); rs1558537(T,C); rs7776671(A,T); rs7795789(T,C); rs7795957(T,C); rs9640297(T,C); rs9640298(C,T); rs116483973(C,T); rs76409819(C,T); rs11771537(T,C); rs2374229(A,G); rs374494745(G,A); rs79227891(T,C); rs80078116(C,T); rs2538045(A,G); rs2538044(T,A); rs2538043(C,A); rs2538042(T,G); rs139870649(C,T); rs76611932(C,T); rs148109439(T,G); rs369486075(T,C); rs2538034(A,G); rs4726061(T,C); rs4726062(G,A); rs4726063(G,A); rs77329718(C,T); rs7799942(C,A); rs6967519(C,T); rs6967946(G,A); rs6967822(C,G); rs375446218(C,T); rs4725415(G,A); rs2536059(G,A); rs6954706(T,C); rs6464156(A,G); rs12667222(T,C); rs12673539(G,A); rs2727565(C,A); rs6965024(T,A); rs9801653(C,A); rs2536058(T,C); rs78248188(A,G); rs73478069(A,C); rs141166159(C,T); rs79937579(A,G); rs76175335(A,G); rs1362237(G,C); rs4725416(G,A); rs4726067(T,C); rs2727566(C,A); rs2536057(C,G); rs1860739(G,A); rs73478086(T,C); rs73478092(C,T); rs375293464(G,A); rs145676501(G,C); rs190653282(C,T); rs369585358(G,A); rs58461640(G,A); rs113129955(C,T); rs4725418(C,T); rs4725419(T,G); rs61364355(C,G); rs4726069(G,A); rs4726070(G,A); rs6964957(C,T); rs61556956(C,T); rs57240667(A,G); rs58212083(G,A); rs112404544(A,G); rs143423253(G,A); rs7803854(A,G); rs7807886(G,C); rs7807681(A,G); rs7807997(A,T); rs7791544(T,C); rs7791563(T,C); rs73480014(A,C); rs141987598(A,G); rs145763290(C,T); rs73480015(T,C); rs112675802(A,G); rs58343831(C,T); rs59580177(C,T); rs58079278(T,G); rs111782443(C,A); rs146299971(A,G); rs192029847(T,A); rs73480022(T,C); rs4726075(A,G); rs4726076(A,G); rs4725420(C,G); rs4725421(A,G); rs73479887(A,G); rs59152884(A,G); rs369165875(T,C); rs113736539(A,G); rs377387025(T,A); rs78527342(C,A); rs370813672(C,A); rs73479899(T,G); rs6464158(A,G); rs3109944(A,G); rs73479902(C,A); rs17173208(T,C); rs17173210(G,A); rs75319230(T,C); rs147198533(A,T); rs147438765(A,G); rs116642669(T,G); rs75953658(T,A); rs115072584(A,G); rs2079987(C,G); rs7796163(A,T); rs55862840(T,A); rs1592443(G,A); rs1345278(T,C); rs6956765(T,G); rs141075604(A,T); rs368873805(T,G); rs376801042(C,T); rs2727527(A,C); rs75324463(G,A); rs73728219(T,C); rs6949829(T,G); rs147035740(G,T); rs6968004(C,T); rs10251264(C,T); rs185984577(A,G); rs4726080(G,A); rs4726081(A,G); rs2727528(C,A); rs6964824(T,C); rs2058394(T,C); rs954228(T,C); rs1986813(A,G); rs2017491(C,T); rs66576954(T,C); rs6950281(A,C); rs148318551(G,A); rs868766(T,A); rs1860735(T,C); rs2727529(C,T); rs2254644(G,T); rs2536055(G,A); rs6464160(G,T); rs1860734(C,T); rs1860733(G,A); rs1860732(A,G); rs1860731(C,A); rs1362236(A,G); rs953221(C,T); rs954025(C,T); rs2727531(G,A); rs73481949(G,A); rs6954399(A,G); rs1105842(C,A); rs1105843(A,G); rs73481959(G,A); rs1362235(T,C); rs954482(C,T); rs114941110(G,A); rs146045806(G,A); rs114395733(C,T); rs2466996(T,C); rs2727533(T,C); rs2536054(C,T); rs2244852(G,A); rs2727535(G,A); rs73158145(C,G); rs75006832(G,C); rs112113536(G,C); rs2727536(G,C); rs78053178(C,T); rs73481972(C,T); rs140001300(G,A); rs116226629(A,G); rs114604087(T,C); rs367777291(G,A); rs867668(G,A); rs4726082(G,C); rs62478165(G,A); rs2536095(A,C); rs2727538(G,A); rs10046471(G,A); rs62478166(G,A); rs2727539(G,A); rs2727540(G,A); rs2727541(T,C); rs79685349(G,A); rs62478167(A,G); rs2727542(T,C); rs73158148(C,T); rs7791800(A,G); rs7791936(C,A); rs75225558(G,C); rs141310865(C,A); rs6955918(T,C); rs2536092(A,G); rs6973948(C,T); rs6956272(T,C); rs6978523(G,T); rs6978142(A,G); rs6960581(T,C); rs2536091(A,C); rs12535248(C,G); rs73158151(T,C); rs7780035(C,A); rs6464161(T,C); rs6464162(G,A); rs6951177(C,T); rs2536090(A,G); rs116796297(G,A); rs7790408(C,A); rs2727560(G,A); rs1894813(A,G); rs2727557(A,G); rs2536089(C,T); rs2727554(A,C); rs2727553(A,G); rs869033(C,T); rs880915(T,C); rs180704693(C,T); rs73481985(T,C); rs75066733(A,G); rs2536088(G,C); rs4726084(G,A); rs75164001(C,T); rs2727549(G,A); rs1860746(C,A); rs10269870(T,G); rs2536086(T,C); rs10274589(T,A); rs10258842(C,T); rs10277859(T,C); rs141515716(G,T); rs6980380(T,C); rs2536085(C,T); rs2024266(C,T); rs10266158(C,T); rs7797944(C,T); rs78423035(G,T); rs2727550(G,A); rs3095359(C,T); rs6970368(A,G); rs6970728(G,C); rs79495718(T,C); rs6970666(A,C); rs6953809(T,A); rs1860745(C,T); rs78853345(C,A); rs1860744(C,G); rs2536084(C,T); rs10275386(C,T); rs10232066(T,A); rs10278860(G,C); rs75440011(T,G); rs2727551(G,A); rs61023859(C,T); rs150122851(G,C); rs2536083(G,T); rs2536082(A,G); rs7778356(C,T); rs10046458(C,T); rs6949482(G,C); rs73484108(T,A); rs112810819(G,A); rs2727552(T,C); rs75411036(G,A); rs10269404(C,G); rs117045205(C,T); rs10269789(C,T); rs114089433(T,A); rs56765232(A,G); rs111465750(G,A); rs74892167(C,G); rs7780804(T,C); rs141185912(C,A); rs112312977(T,C); rs9648723(A,C); rs56145758(T,A); rs144656974(C,T); rs12673708(G,T); rs6952398(T,C); rs12673766(G,A); rs11983465(C,G); rs6947064(A,G); rs6967507(T,C); rs6947912(G,C); rs6967838(T,C); rs6947707(A,T); rs6968460(T,C); rs6948449(C,T); rs2888788(A,G); rs1105946(G,A); rs73158176(C,G); rs12669379(T,C); rs1476871(G,A); rs10235478(C,T); rs140756197(C,T); rs10235949(G,A); rs10251362(T,C); rs2727564(A,G); rs111781205(C,T); rs2374270(C,A); rs73158180(A,C); rs66497154(T,C); rs4725423(C,T); rs2727563(T,C); rs116781443(T,C); rs57807319(T,C); rs59558034(T,C); rs10263707(T,G); rs60815793(C,T); rs12534878(C,T); rs114166988(T,C); rs148643895(C,A); rs2727562(A,G); rs74495775(G,A); rs2536080(G,A); rs7781082(C,T); rs7781347(C,T); rs2727561(A,C); rs10480299(T,C); rs7786673(G,T); rs10480300(C,T); rs7786603(A,T); rs74857152(G,T); rs12668733(C,T); rs78257587(T,G); rs7805747(G,A); rs2536078(A,T); rs146595726(G,A); rs2727556(G,T); rs7810463(A,G); rs2536077(T,C); rs6945073(C,T); rs28533208(C,T); rs7778862(A,G); rs114700279(C,T); rs7798168(T,C); rs7779111(C,G); rs115185349(C,T); rs6945264(A,G); rs116225253(C,G); rs77990866(C,T); rs76582033(T,C); rs80344643(C,G); rs79685042(C,T); rs139214999(A,G); rs73484136(A,T); rs73484138(G,A); rs143797013(C,G); rs78794442(T,C); rs57482629(T,C); rs76056009(G,A); rs76770821(G,A); rs6464165(T,C); rs10224210(T,C); rs79728668(T,C); rs79913076(C,A); rs78256949(G,A); rs149314921(G,A); rs116431701(A,G); rs139423736(A,G); rs10265221(T,C); rs10224002(A,G); rs73158188(C,T); rs10253736(C,T); rs2727547(G,T); rs10952316(A,G); rs10254101(C,T); rs10952317(C,T); rs12670430(G,C); rs140271651(G,C); rs7792937(C,T); rs62478182(A,C); rs73484149(C,T); rs2536075(C,T); rs78308051(C,T); rs1860743(T,C); rs62478183(C,T); rs2079988(C,A); rs2536073(G,A); rs7808855(A,G); rs4726086(C,T); rs7777428(G,A); rs2536072(G,T); rs10279256(C,T); rs146520273(C,T); rs2536071(C,T); rs7782653(C,A); rs2536069(T,C); rs2727548(G,A); rs6954688(C,T); rs116088319(C,T); rs4726087(G,A); rs115387651(G,A); rs9640176(C,G); rs9640177(C,T); rs2536067(A,G); rs7797773(C,T); rs115196288(G,A); rs2536066(A,G); rs11760870(C,T); rs2536065(C,A); rs10807989(C,T); rs11979282(A,G); rs2270212(G,C); rs373680604(G,A); rs2256079(A,G); rs7810345(T,C); rs2429833(C,T); rs62478184(G,A); rs2429832(A,G); rs111235981(G,A); rs185110294(G,A); rs4726088(G,A); rs6464166(T,C); rs112363688(C,T); rs1108722(A,G); rs115241520(A,G); rs1104897(C,T); rs60791946(T,C); rs34078741(T,C); rs1547470(T,C); rs58772035(G,A); rs11767633(G,A); rs2536063(G,C); rs10237555(C,T); rs76846458(C,G); rs6952517(C,T); rs146839228(T,A); rs28416498(C,T); rs885273(A,G); rs147022618(C,A); rs28413026(C,A); rs6464167(G,A); rs116310546(G,A); rs6464168(A,G); rs7810022(A,C); rs7797862(T,C); rs6464169(G,T); rs11761557(A,T); rs11768438(G,A); rs10278273(T,C); rs1001116(C,T); rs138097685(T,C); rs4546566(T,C); rs59875794(C,T); rs1001117(G,A); rs61350941(T,C); rs6957149(A,T); rs115257026(T,A); rs11771330(C,T); rs11771414(G,A); rs11771445(G,A); rs35969034(G,T); rs7799353(C,T); rs7800351(G,C); rs1860741(A,C); rs1860740(G,A); rs7788160(T,G); rs17173258(T,C); rs6978479(G,A); rs6960717(T,C); rs75644100(C,T); rs147696101(C,T); rs145257988(T,C); rs7779158(G,A); rs7779376(A,G); rs140148824(A,G); rs4725426(T,G); rs4725427(T,C); rs147238792(C,T); rs142140010(A,T); rs6970522(A,G); rs6970962(A,G); rs7807769(A,C); rs112187745(T,C); rs62478209(T,A); rs79215320(G,A); rs7801616(T,C); rs12537154(A,T); rs35937356(C,T); rs35798852(C,T); rs34593075(C,T); rs2109782(C,A); rs34563855(C,T); rs34598471(G,A); rs6965926(C,A); rs12668627(T,A); rs114388622(C,T); rs12703152(T,A); rs868624(T,C); rs57157172(T,C); rs1104840(T,C); rs1104838(G,C); rs6946043(C,A); rs7780008(C,T); rs7799154(T,C); rs7780421(G,A); rs7800069(T,C); rs73485923(T,C); rs7784818(A,G); rs78095788(T,C); rs35346765(C,T); rs148659355(T,C); rs10271360(A,G); rs3934596(C,A); rs79816892(T,C); rs77461458(C,A); rs190993085(A,G); rs6965834(A,G); rs4726091(A,G); rs4725431(T,C); rs4725432(C,A); rs12539660(G,C); rs12534382(A,G); rs7809018(A,G); rs7809589(G,T); rs7809503(A,G); rs76412828(C,A); rs3935852(G,C); rs4418266(C,T); rs55964814(G,A); rs4726092(C,G); rs112149356(G,A); rs145912906(G,A); rs138951522(C,T); rs75804896(C,T); rs9632641(A,C); rs78667038(T,C); rs11773541(T,A); rs6955023(A,G); rs6464170(C,G); rs80039831(T,C); rs181430461(G,A); rs4726093(C,T); rs181575483(C,T); rs12374732(T,C); rs12375159(C,T); rs112201244(G,A); rs12375163(C,T); rs112931845(C,T); rs78291918(G,A); rs74303077(C,T); rs187194388(A,T); rs58368463(G,A); rs7782177(G,T); rs116106177(T,C); rs62478216(C,G); rs73728291(T,C); rs7782702(C,T); rs12703157(C,T); rs62478217(T,C); rs6953882(G,A); rs11761317(G,A); rs11975504(T,C); rs77060504(C,G); rs73728293(C,T); rs73485953(C,T); rs12669420(T,C); rs6979356(T,C); rs6959849(C,T); rs12671980(A,G); rs77505659(A,G); rs11763144(C,G); rs137958238(G,C); rs4425665(C,T); rs61520245(A,T); rs56859244(G,A); rs143522881(C,T); rs4726094(C,T); rs7796138(C,A); rs11770585(A,C); rs34735358(T,C); rs6972910(C,G); rs80211409(G,A); rs372535972(G,T); rs79918575(G,C); rs149030887(C,A); rs7789699(T,C); rs6978628(C,T); rs34659848(T,A); rs80240081(T,C); rs10252278(G,T); rs117762008(T,A); rs4236431(G,A); rs146234867(C,T); rs4726095(T,A); rs149161832(C,T); rs118118867(C,T); rs147729121(A,G); rs75243518(G,T); rs10253833(T,C); rs76727675(G,A); rs58498831(A,G); rs60146500(T,C); rs11768953(T,G); rs58943536(C,T); rs4726096(A,G); rs12112702(G,A); rs112023402(G,A); rs11766272(G,A); rs56361293(A,C); rs79269598(C,T); rs4726097(G,C); rs4726098(A,G); rs4128396(A,C); rs4128397(A,G); rs4128398(A,G); rs4128399(T,C); rs76923703(G,T); rs115835528(A,C); rs79313741(G,T); rs145055825(C,T); rs75799992(C,T); rs56131024(C,T); rs114492692(A,G); rs79012079(A,C); rs4725434(C,T); rs115031629(G,C); rs142805533(G,A); rs78751861(T,C); rs9648724(G,A); rs115813192(G,A); rs34802637(A,G); rs4570063(A,C); rs148560689(C,T); rs6976245(C,T); rs140166603(G,A); rs4442045(T,C); rs58825093(C,T); rs55845365(C,G); rs4726099(C,T); rs56158745(T,C); rs4726100(T,C); rs4236432(A,G); rs9648725(T,C); rs146975187(A,G); rs62478243(C,T); rs78150542(C,T); rs13224758(G,A); rs12703159(C,T); rs10257529(G,A); rs56729506(C,T); rs7797865(T,C); rs62478244(T,C); rs55793576(G,A); rs62478245(C,T); rs6464171(G,C); rs6464172(G,A); rs6464173(A,G); rs4530949(T,C); rs114917317(G,A); rs12539356(G,T); rs62478246(G,A); rs1881638(A,G); rs1881637(C,T); rs62478247(G,A); rs4236433(G,C); rs4582468(A,G); rs4593442(C,T); rs11773011(C,G); rs7455163(G,A); rs1881636(C,T); rs4595037(C,T); rs4631369(A,G); rs4632971(A,C); rs74535090(G,A); rs77134166(A,G); rs7800856(T,C); rs10952318(T,C); rs7782161(G,A); rs184502355(A,G); rs56129741(C,G); rs6954429(C,T); rs11768925(A,G); rs78938416(C,G); rs62478250(G,A); rs4726101(G,A); rs1881633(C,A); rs34244587(T,G); rs6975104(C,G); rs35604617(G,C); rs6975614(C,T); rs114008100(G,T); rs34388354(T,G); rs2374299(A,T); rs1881632(G,A); rs6979926(C,T); rs1881631(A,G); rs1881630(A,G); rs2374300(C,T); rs1881629(C,T); rs1881628(T,G); rs192151184(A,G); rs12703160(T,C); rs12703161(C,T); rs1528974(C,T); rs1528975(C,T); rs11769593(A,T); rs1528976(A,G); rs12532553(C,T); rs10952319(A,G); rs6464174(T,C); rs11767132(T,G); rs11763613(G,A); rs76549296(A,G); rs11770376(A,C); rs34498984(A,C); rs9969184(G,C); rs11763717(G,A); rs11763700(C,G); rs75379928(G,T); rs35279162(C,T); rs199533997(C,A); rs73487739(A,G); rs12703162(C,T); rs78776830(G,A); rs13225852(T,C); rs75808206(G,C); rs7805942(A,C); rs56922253(C,T); rs6978617(C,T); rs6960931(T,C); rs1108845(C,T); rs1881626(T,C); rs76737291(C,T); rs17567084(C,A); rs2374307(T,G); rs17567098(A,C); rs79725612(A,G); rs78734226(T,G); rs75252123(G,A); rs76357939(C,T); rs11773373(G,A); rs11760502(C,T); rs4726102(A,G); rs79311137(T,A); rs7800364(G,A); rs139040938(C,T); rs78708917(G,A); rs113371527(G,T); rs187934772(G,A); rs73160032(C,T); rs73160033(C,T); rs73160034(A,C); rs75080685(T,C); rs75521567(C,T); rs73160035(C,T); rs73160037(T,A); rs73160038(C,T); rs73160039(G,C); rs77326977(G,C); rs116346767(G,T); rs56138260(T,C); rs140942657(G,C); rs56204560(G,A); rs55783946(A,G); rs56259653(G,C); rs142077126(A,G); rs7783677(A,G); rs77466830(C,A); rs13233587(C,T); rs13233608(C,T); rs7788721(G,A); rs10238094(C,T); rs7788502(C,T); rs73728405(G,A); rs79645059(C,T); rs11771216(A,C); rs13238117(G,A); rs11764602(G,A); rs11765309(C,A); rs1881624(C,T); rs74782537(T,C); rs75243283(G,C); rs75697045(T,G); rs79707330(G,C); rs79459893(G,A); rs58038944(C,T); rs10276092(A,G); rs77041940(A,C); rs12535957(C,T); rs56998446(A,G); rs6943343(A,G); rs151099541(T,C); rs58953739(C,T); rs56932207(G,T); rs75331245(A,G); rs80103672(T,C); rs6950343(C,T); rs6950351(C,T); rs55858267(A,G); rs9648726(C,T); rs9648727(T,C); rs9648728(T,C); rs9648729(G,C); rs9648730(G,A); rs75532717(G,A); rs2374309(T,C); rs11773761(A,G); rs11773789(A,G); rs79183491(C,T); rs75116588(G,A); rs57486649(T,C); rs10277544(T,C); rs10261999(G,T); rs62480473(A,G); rs10277655(T,C); rs1109277(G,C); rs73160047(A,T); rs10236110(A,G); rs6953357(G,A); rs6953067(C,G); rs73160048(G,T); rs62480474(C,G); rs2178305(G,C); rs56331005(A,G); rs59157287(A,T); rs60814812(T,C); rs56308233(C,A); rs74504814(C,T); rs1969558(C,A); rs59218083(A,G); rs116255223(C,T); rs58351370(C,T); rs73728418(G,A); rs34460571(A,G); rs76175884(G,A); rs11772236(T,G); rs75930806(G,T); rs10260657(G,A); rs79695519(C,T); rs6957050(T,C); rs6975127(C,T); rs34784704(C,T); rs7807430(C,T); rs7807749(C,T); rs7811285(A,G); rs79671766(G,A); rs113285624(G,A); rs7795096(T,C); rs7776488(G,A); rs7812239(C,G); rs7776530(C,A); rs34243711(C,G); rs57194047(G,A); rs10952322(C,T); rs10952323(C,T); rs11772588(C,A); rs1881639(A,C); rs6464176(T,C); rs116720275(A,T); rs4726103(C,T); rs67760509(C,G); rs67976709(T,A); rs3813852(T,C); rs11971588(C,A); rs11762585(C,G); rs11762640(G,A); rs7803846(T,A); rs6464178(A,G); rs67647043(C,T); rs12703163(T,C); rs67190377(C,T); rs1569222(G,A); rs2178304(C,T); rs6464179(G,A); rs6962064(G,C); rs6961830(C,T); rs6962881(G,A); rs6967007(G,T); rs11767361(A,G); rs11760640(C,T); rs60745002(G,A); rs6955784(G,T); rs7789674(G,A); rs35721560(G,A); rs34867733(C,T); rs7808590(T,A); rs11766003(T,A); rs12669703(T,A); rs9640300(A,G); rs6961971(A,G); rs12703164(G,C); rs4726104(T,C); rs9640179(G,A); rs11771399(A,G); rs9640302(A,G); rs59404899(A,G); rs116257392(A,G); rs73160061(G,A); rs73160063(C,T); rs56118280(T,C); rs146149087(A,T); rs12703165(C,T); rs74745704(C,T); rs12669153(G,A); rs13240743(C,G); rs13235096(T,A); rs76218710(T,C); rs11767806(C,G); rs10257323(G,A); rs56377426(G,A); rs4726105(A,T); rs4725435(C,T); rs114278629(A,G); rs34047758(A,G); rs36113661(G,A); rs35599550(G,A); rs35697533(G,T); rs150114208(G,A); rs11971304(T,C); rs35503973(C,A); rs78881925(T,C) |
| ccdsGene name | CCDS5928.1 |
| cytoBand name | 7q36.1 |
| EntrezGene GeneID | 51422 |
| EntrezGene Description | protein kinase, AMP-activated, gamma 2 non-catalytic subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRKAG2:NM_024429:exon10:c.T752A:p.I251N,PRKAG2:NM_016203:exon14:c.T1475A:p.I492N,PRKAG2:NM_001040633:exon14:c.T1343A:p.I448N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7979 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B7Z6X8 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 3.253e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
OMIM Title
*602743 PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-2; PRKAG2
;;AMP-ACTIVATED PROTEIN KINASE, NONCATALYTIC, GAMMA-2;;
AMPK-GAMMA-2
OMIM Description
DESCRIPTION
The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to act
as a metabolic stress-sensing protein kinase. AMPK is a heterotrimeric
protein composed of a catalytic alpha subunit, a noncatalytic beta
subunit, and a noncatalytic gamma subunit. See PRKAA1 (602739) for
background.
CLONING
By searching an EST database with PRKAG1 (602742) as the probe, followed
by PCR screening of cDNA libraries, Lang et al. (2000) identified a cDNA
encoding PRKAG2. Sequence analysis predicted that the 328-amino acid
protein, which is 76% identical to PRKAG1, contains 4 conserved
cystathionine-beta-synthase domains but lacks N-linked glycosylation
sites. Lang et al. (2000) noted that the entire PRKAG2 amino acid
sequence is identical to a part of the 569-amino acid PRKAG2 sequence
reported by Cheung et al. (2000), suggesting the existence of different
promoters. They designated the long and short PRKAG2 isoforms PRKAG2a
and PRKAG2b, respectively. Genomic sequence analysis determined that
PRKAG2b spans 80 kb and contains 12 exons. Northern blot analysis
detected a specific 2.4-kb PRKAG2b transcript that was most abundantly
expressed in heart, followed by testis and placenta; it was not
expressed in liver and thymus. A 3.8-kb PRKAG2a transcript was expressed
in liver, but not in heart, placenta, or thymus, and a 3.0-kb PRKAG2a
transcript was expressed at extremely high levels in heart and at lower
levels in skeletal muscle, kidney, spleen, and testis.
MAPPING
Stapleton et al. (1997) identified human ESTs encoding human
AMPK-gamma-2. They noted that the AMPK-gamma-2 gene was mapped to
7q35-q36 by Genethon. By radiation hybrid analysis, Lang et al. (2000)
mapped the PRKAG2 gene to 7q36.
MOLECULAR GENETICS
In 2 apparently unrelated families with autosomal dominant
Wolff-Parkinson-White syndrome (WPW; 194200), Gollob et al. (2001)
identified a mutation in the PRKAG2 gene (R302Q; 602743.0001).
Blair et al. (2001) identified heterozygous mutations in the PRKAG2 gene
in 2 families with severe hypertrophic cardiomyopathy (CMH6; 600858), in
which some affected individuals also displayed Wolff-Parkinson-White
ventricular preexcitation. Both mutations, H142A (602743.0002) and a
3-bp insertion (602743.0003), occur in highly conserved regions. Because
AMPK provides a central sensing mechanism that protects cells from
exhaustion of ATP supplies, Blair et al. (2001) proposed that energy
compromise may provide a unifying pathogenic mechanism in all forms of
CMH.
Sinha et al. (2000) reported a family in which 12 persons had
ventricular preexcitation, 6 of whom also had cardiac hypertrophy. Three
patients underwent successful ablation of typical accessory
atrioventricular bundles, with subsequent loss of preexcitation. Gollob
et al. (2001) demonstrated the presence of the R302Q mutation of PRKAG2
in this kindred.
Reports that dominant mutations in PRKAG2, an enzyme that modulates
glucose uptake and glycolysis, can cause hypertrophic cardiomyopathy
challenged the hypothesis that hypertrophic cardiomyopathy is a disease
of the sarcomere. In addition to cardiac hypertrophy, individuals with
PRKAG2 mutations frequently manifest electrophysiologic abnormalities,
particularly Wolff-Parkinson-White syndrome (Gollob et al., 2001),
atrial fibrillation, and progressive development of atrioventricular
conduction block. Although atrial fibrillation is common in CMH patients
and becomes increasingly prevalent with disease duration, neither
accessory pathway nor conduction system diseases are typical features of
CMH. To understand the mechanisms by which PRKAG2 defects cause disease,
Arad et al. (2002) defined additional novel mutations (T400N,
602743.0004; N488I, 602743.0005) and examined the clinical
manifestations found in affected individuals. A previously unrecognized
and unusual histopathology was identified in hearts with PRKAG2 defects,
which prompted biochemical analyses of the functional consequences of
human PRKAG2 mutations on Snf4, the yeast homolog of the gamma-2 protein
kinase subunit. Arad et al. (2002) concluded that their data indicated
that PRKAG2 defects do not cause CMH, but rather a novel glycogen
storage disease of the heart. They found that although the cardiac
pathology caused by the PRKAG2 mutations R302Q, T400N, and N488I
included myocyte enlargement and minimal interstitial fibrosis, these
mutations were not associated with myocyte and myofibrillar disarray,
the pathognomonic features of hypertrophic cardiomyopathy caused by
sarcomere protein mutations. Instead, PRKAG2 mutations caused pronounced
vacuole formation within myocytes. Several lines of evidence indicated
that these vacuoles are filled with glycogen-associated granules.
Analyses of the effects of human PRKAG2 mutations on Snf1/Snf4 kinase
function demonstrated constitutive activity, which could foster glycogen
accumulation. Thus, this disorder is a metabolic storage disease in
which hypertrophy, ventricular preexcitation, and conduction system
defects coexist. Support for the hypothesis that human PRKAG2 missense
mutations cause an increase in AMP kinase activity and stimulate
carbohydrate accumulation also comes from analyses of RN- pigs (Milan et
al., 2000; Hamilton et al., 2001). RN- pigs produce 'acid meat' that is
of inferior quality due to increased muscle glycogen content. The
porcine RN- mutation is analogous to the human PRKAG2 mutation
arg302-to-gln (602743.0001).
In 3 of 5 patients with fatal congenital heart glycogenosis (261740), 1
of whom had previously been reported by Regalado et al. (1999),
Burwinkel et al. (2005) identified heterozygosity for an arg531-to-gln
mutation in the PRKAG2 gene (R531Q; 602743.0007). The patients died of
hemodynamic and respiratory failure secondary to hypertrophic
nonobstructive cardiomyopathy but also had Wolff-Parkinson-White
syndrome-like conduction anomalies. Biochemical characterization of the
mutant protein showed a greater than 100-fold reduction of binding
affinities for the regulatory nucleotides AMP and ATP but an enhanced
basal activity and increased phosphorylation of the alpha subunit.
Burwinkel et al. (2005) noted that the molecular abnormalities of the
R531Q mutant protein are more pronounced than those of other PRKAG2
mutants, which likely accounts for the more severe phenotype with fetal
onset, extreme cardiomegaly, and a fatal outcome in infancy.
Arad et al. (2005) analyzed the PRKAG2 gene in 35 patients with
hypertrophic cardiomyopathy who were negative for mutations in known
sarcomere-protein genes, and identified a heterozygous missense mutation
(Y487H; 602743.0008) in 1 proband with moderate hypertrophy and an
extremely short PR interval.
In a 38-year-old man with hypertrophic cardiomyopathy, severe conduction
system abnormalities, and mild skeletal muscle glycogenosis, who was
negative for mutation in the LMNA gene (150330), Laforet et al. (2006)
identified heterozygosity for a mutation in the PRKAG2 gene
(602743.0011). The authors suggested that PRKAG2 could be a candidate
for unexplained skeletal muscle glycogenosis associated with cardiac
abnormalities.
In a child with idiopathic cardiac hypertrophy and presumed sporadic
cardiomyopathy, who was negative for mutations in 9 of the known CMH
genes, Morita et al. (2008) identified heterozygosity for a missense
mutation in the PRKAG2 gene (H530R; 602743.0009).
Kelly et al. (2009) reported a father, son, and daughter with
hypertrophic cardiomyopathy in whom they identified heterozygosity for a
missense mutation in the PRKAG2 gene (E506Q; 602743.0010).
Endomyocardial tissue from the son showed a normal amount of glycogen
present in the myocytes by staining and electron microscopy. Kelly et
al. (2009) stated that 8 affected members of a family reported by Bayrak
et al. (2006) with a PRKAG2 mutation at the same codon (E506K) had
ventricular preexcitation and mild left ventricular hypertrophy;
endomyocardial biopsy of the adult proband showed profound intracellular
vacuolization and marked interstitial fibrosis. Noting that in the
patients reported by Burwinkel et al. (2005), the approximately 4- to
6-fold increase in cardiac mass was associated with only a 3-fold
increase in glycogen content and an absence of more organized cellular
aggregations of glycogen, Kelly et al. (2009) concluded that CMH due to
PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that
expected from observed amounts of glycogen deposition.
ANIMAL MODEL
Arad et al. (2003) constructed transgenic mice overexpressing the PRKAG2
cDNA with or without a missense N488I human mutation (602743.0005). The
transgenic mice showed elevated AMP-activated protein kinase activity,
accumulated large amounts of cardiac glycogen, developed dramatic left
ventricular hypertrophy, and exhibited ventricular preexcitation and
sinus node dysfunction. Electrophysiologic testing demonstrated
alternative atrioventricular conduction pathways consistent with
Wolff-Parkinson-White syndrome. Cardiac histopathology revealed that the
annulus fibrosis, which normally insulates the ventricles from
inappropriate excitation by the atria, was disrupted by glycogen-filled
myocytes. Arad et al. (2003) concluded that these data establish that
PRKAG2 mutations cause a glycogen storage cardiomyopathy, provide an
anatomic explanation for electrophysiologic findings, and implicate
disruption of the annulus fibrosis by glycogen-engorged myocytes as the
cause of preexcitation in Pompe (232300), Danon (300257), and other
glycogen storage diseases.
Sidhu et al. (2005) generated transgenic mice expressing the human
PRKAG2 gene containing the arg302-to-gln (R302Q; 602743.0001) mutation
and observed a phenotype identical to that of Wolff-Parkinson-White
syndrome, including preexcitation, inducible orthodromic AV reentrant
tachycardia, cardiac hypertrophy, and excessive cardiac glycogen. The
primary molecular defect was loss of cardiac AMPK activity, which
appeared to be due to disruption of the gamma-2 subunit binding site for
AMP.
KMT2C
| dbSNP name | rs9969322(T,C); rs12333958(A,C); rs12333453(G,A); rs6954722(T,C); rs116067017(C,T); rs10248540(T,C); rs12703197(T,C); rs6944296(G,A); rs10240771(C,T); rs28393197(T,G); rs6952130(T,C); rs6952768(T,C); rs59925177(G,A); rs78034305(A,C); rs28477116(G,C); rs6942743(G,A); rs10257775(C,T); rs3778920(G,T); rs3778919(A,G); rs2240819(C,T); rs6973417(T,C); rs10266387(G,A); rs10236914(A,G); rs10282254(T,C); rs6954362(C,T); rs7779859(T,C); rs55924535(G,A); rs62481488(C,T); rs10231138(A,G); rs3800836(C,T); rs6952380(C,T); rs3757421(C,T); rs28540667(C,T); rs56753294(C,T); rs56394236(G,C); rs7810535(A,G); rs114308820(T,C); rs10228222(T,A); rs17173352(C,T); rs10216286(C,T); rs10214963(C,A); rs7789338(C,A); rs140626076(T,C); rs76084910(T,C); rs7787732(T,C); rs17173357(G,A); rs10233184(G,A); rs10260957(T,C); rs111410971(G,A); rs10269449(T,C); rs6464210(A,G); rs59934980(T,A); rs28588581(A,G); rs6464211(C,T); rs10252263(C,T); rs17173367(T,C); rs7778804(T,C); rs17173370(G,C); rs6951159(T,C); rs61730538(T,C); rs139195228(C,A); rs113365136(G,A); rs4726138(C,T); rs10246450(T,C); rs3800835(T,A); rs111734304(T,C); rs61730536(C,T); rs3800834(C,T); rs6963460(A,G); rs6963742(C,T); rs6972835(C,T); rs28711411(G,C); rs6464212(T,C); rs6464213(A,G); rs112349462(C,T); rs4725444(C,G); rs6975587(T,A); rs10237419(C,T); rs28418446(T,A); rs112924423(T,C); rs17173373(T,C); rs34580279(C,T); rs28720800(C,T); rs10487891(A,G); rs10487890(A,C); rs10245041(G,A); rs370416539(T,C); rs6943984(G,A); rs6948202(C,T); rs7787859(A,G); rs7791915(A,G); rs10265729(G,A); rs10269962(G,A); rs2885115(T,A); rs182246937(G,C); rs4024336(G,A); rs3058648(T,A); rs7457414(A,T); rs147786840(A,G); rs111308548(A,G); rs7806131(A,G); rs10273600(G,A); rs188774504(A,T); rs13438774(G,A); rs10242004(T,C); rs10242296(T,C); rs71534910(C,T); rs62481495(A,G); rs7806351(A,G); rs376283661(G,A); rs372873576(T,C); rs10261659(T,C); rs7810089(G,A); rs1138664(A,G); rs1138663(A,C); rs10279439(G,A); rs10046464(G,A); rs10232190(G,A); rs139465763(C,T); rs62481508(A,G); rs9886160(C,T); rs140116675(A,G); rs10231616(G,A); rs10268076(T,C); rs2360891(G,C); rs192780723(T,C); rs10238690(A,C); rs144509369(T,C); rs6978008(T,C); rs73728795(G,C); rs10085791(G,A); rs187080406(A,T); rs3735156(C,G); rs6948919(T,C); rs111534987(T,C); rs28582564(T,C); rs113993829(A,G); rs12333593(A,G); rs6464215(G,A); rs6975229(T,C); rs6464216(A,G); rs12333748(A,G); rs13228319(A,T); rs7793081(A,G); rs6970056(G,A); rs10231758(G,A); rs10235761(C,G); rs370828365(A,C); rs184223721(T,A); rs112259176(T,C); rs114900241(G,A); rs4618614(A,G); rs76153768(C,T); rs10252437(C,T); rs75339372(T,A); rs28691267(T,C); rs10237008(C,T); rs28571742(G,A); rs111532174(A,G); rs10273957(A,G); rs10249375(G,A); rs7796107(T,C); rs369342058(T,C); rs78717543(A,G); rs9655615(A,C); rs6955778(T,A); rs1137721(C,T); rs372578547(G,A); rs6979744(C,T); rs28640225(C,T); rs113982022(T,C); rs6953012(A,G); rs112803179(A,G); rs1986375(G,A); rs12533279(A,G); rs2360217(A,C); rs73730039(A,G); rs6979566(A,T); rs142923466(T,A); rs7787666(T,C); rs7810349(G,C); rs10236400(T,G); rs10250870(A,C); rs10237153(T,C); rs9690245(G,T); rs4726150(G,T); rs10226539(T,C); rs10270901(C,T); rs10248857(A,G); rs141813262(G,A); rs186548222(T,C); rs6953419(A,C); rs10232439(G,A); rs10252255(T,C); rs55695505(T,G); rs111250506(T,G); rs9632623(T,C); rs28361895(C,T); rs28642936(C,T); rs4266556(A,G); rs73730041(C,A); rs7786732(A,G); rs10244604(A,G); rs116330323(G,A); rs7806141(G,C); rs7789818(T,C); rs28575926(G,A); rs192092093(A,C); rs10239761(G,A); rs10239783(C,T); rs116338747(A,G); rs371092778(G,T); rs138502404(C,T); rs56031431(T,C); rs10259904(A,T); rs10249694(T,C); rs7799662(T,C); rs2360874(C,T); rs10271992(A,C); rs10279901(A,G); rs73730044(A,G); rs73730045(G,C); rs13226101(C,T); rs115456355(C,T); rs78196990(G,A); rs10263545(G,A); rs6464221(T,C); rs113505076(G,A); rs10228402(A,G); rs113014775(G,A); rs117641613(T,C); rs10262621(C,T); rs191016652(C,T); rs10266844(G,A); rs10240607(A,G); rs10274359(G,A); rs147222850(G,A); rs116089370(G,A); rs7781309(T,C); rs115746359(A,C); rs115526878(A,G); rs73730048(T,C); rs4570064(G,A); rs10224334(C,A); rs10480303(T,C); rs7791121(T,C); rs7812203(A,G); rs9655616(A,G); rs141905306(A,C); rs181776330(G,A); rs117093508(G,A); rs9655617(A,G); rs111826855(T,C); rs111732880(C,T); rs188276343(C,T); rs10226650(C,T); rs7786170(G,A); rs9690324(G,A); rs17173407(T,G); rs115588365(T,C); rs141605058(C,T); rs138070192(C,T); rs142378413(G,A); rs10243401(C,A); rs10244291(C,T); rs10230761(G,A); rs10230762(G,A); rs10249801(T,C); rs1055978(A,T); rs10258150(T,A); rs6977645(C,T); rs6978146(C,T); rs6978172(A,T); rs10266257(T,C); rs6966258(T,C); rs6949854(A,C); rs10225914(A,G); rs10274209(T,C); rs116118690(A,G); rs143071114(C,G); rs10257703(C,G); rs10262700(G,A); rs112954529(A,G); rs75524872(G,A); rs12333496(C,T); rs56910218(T,A); rs11763960(G,A); rs10258897(T,C); rs151299344(G,A); rs17173424(C,G); rs115451587(C,G); rs6951817(G,T); rs7791144(G,A); rs10242533(C,T); rs115315851(T,C); rs7802366(G,A); rs7802778(G,A); rs10281573(G,A); rs4726158(G,A); rs13223888(G,T); rs113239759(G,A); rs7796615(A,C); rs6974154(C,T); rs55922504(A,C); rs73164558(C,T); rs10267990(G,A); rs6951870(A,G); rs7790805(A,G); rs11764314(T,C); rs35581269(C,G) |
| ccdsGene name | CCDS5931.1 |
| cytoBand name | 7q36.1 |
| EntrezGene GeneID | 58508 |
| snpEff Gene Name | MLL3 |
| EntrezGene Description | lysine (K)-specific methyltransferase 2C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KMT2C:NM_170606:exon43:c.A10513G:p.N3505D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5036 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NEZ4 |
| dbNSFP Uniprot ID | MLL3_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0001382 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
ABDOMEN:
Distended abdomen;
[Gastrointestinal];
Diarrhea, severe, chronic;
Increased bowel sounds
METABOLIC FEATURES:
Hyperosmolar dehydration;
Metabolic acidosis
LABORATORY ABNORMALITIES:
Glucosuria, mild, intermittent;
Abnormal glucose oral tolerance test;
Glucose breath hydrogen test shows malabsorption of glucose and galactose
MISCELLANEOUS:
Onset in first days of life;
Diarrhea persists even with vigorous nursing;
May be lethal if untreated;
Patients gradually develop tolerance to carbohydrates over time;
Dramatic improvement with proper treatment;
High incidence among Old Order Amish
MOLECULAR BASIS:
Caused by mutation in the intestinal sodium/glucose transporter gene
(SLC5A1, 182380.0001)
OMIM Title
*606833 LYSINE-SPECIFIC METHYLTRANSFERASE 2C; KMT2C
;;MYELOID/LYMPHOID OR MIXED-LINEAGE LEUKEMIA 3; MLL3;;
KIAA1506
OMIM Description
CLONING
By searching for cDNA sequences with the potential to encode large
proteins expressed in brain, Nagase et al. (2000) identified a partial
cDNA encoding MLL3, which they termed KIAA1506. RT-PCR analysis detected
ubiquitous expression that was highest in testis and ovary, followed by
brain and liver. Within brain, expression was highest in hippocampus,
caudate nucleus, and substantia nigra.
By genomic sequence analysis combined with RACE and PCR on a fetal
thymus cDNA library, Ruault et al. (2002) isolated 3 partial overlapping
cDNAs that they assembled to identify MLL3. The deduced 4,911-amino acid
protein is more closely related to MLL2 (602113) than to MLL1 (159555)
or MLL4 (606834). The authors identified a shorter isoform (isoform II)
in the databases that has 4,026 predicted residues due to an alternative
5-prime region. MLL3 has 6 plant homeodomain (PHD) fingers preceded by a
cys-rich ZNF1 domain in its N terminus; a high mobility group (HMG) box,
an ATPase alpha-beta signature, and a leucine zipper motif in its
central region; and 2 C-terminal FY (phe-tyr) motifs and a SET
(suppressor of variegation, enhancer of zeste, and trithorax) domain
preceded by a ZNF2 domain in its C terminus. The predicted protein also
contains several putative nuclear localization motifs. Isoform II lacks
ZNF1 and the PHD. Northern blot analysis revealed weak expression of a
15-kb transcript. PCR analysis of a cDNA panel detected expression in
all tissues tested except skeletal muscle and fetal liver.
GENE STRUCTURE
Ruault et al. (2002) determined that the MLL3 gene contains 60 exons and
spans more than 216 kb. It is preceded in the 5-prime region by a 1.8-kb
CpG island. Isoform II of MLL3 lacks the first 14 exons. The authors
found that the 5-prime untranslated region of MLL3 possesses a
nonpolymorphic CGG repeat.
MAPPING
Using FISH, Ruault et al. (2002) mapped the MLL3 gene to chromosome
7q36, a region commonly deleted in malignant myeloid disorders. They
also identified signals in the juxtacentromeric regions of chromosomes
1, 2, 13, and 21, which probably contain paralogous regions duplicated
during primate evolution.
GENE FUNCTION
Daniel et al. (2010) showed that activated B cells deficient in the PTIP
(608254) component of the MLL3-MLL4 complex display impaired
trimethylation of histone H3 (see 602810) at lysine-4 (H3K4me3) and
transcription initiation of downstream switch regions at the
immunoglobulin heavy chain (Igh; 147100) locus, leading to defective
immunoglobulin class switching. Daniel et al. (2010) also showed that
PTIP accumulation at double-strand breakpoints contributes to class
switch recombination and genome stability independent of Igh switch
transcription. Daniel et al. (2010) concluded that their results
demonstrated that PTIP promotes specific chromatin changes that control
the accessibility of the Igh locus to class switch recombination and
suggested a nonredundant role for the MLL3-MLL4 complex in altering
antibody effector function.
MOLECULAR GENETICS
In 4 of 9 EHMT1 (607001) mutation-negative patients with core features
of Kleefstra syndrome (610253) but otherwise heterogeneous phenotypes,
Kleefstra et al. (2012) identified mutations in 4 functionally related
genes, MLL3, MBD5 (611472), SMARCB1 (601607), and NR1I3 (603881). All
these genes encode epigenetic regulators.
LINC01003
| dbSNP name | rs3087586(A,C); rs114971361(A,T) |
| cytoBand name | 7q36.1 |
| EntrezGene GeneID | 100128822 |
| EntrezGene Description | long intergenic non-protein coding RNA 1003 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3021 |
PAXIP1-AS1
| dbSNP name | rs517881(G,A); rs73171087(A,G); rs431085(T,C); rs28412080(A,G); rs377850(A,G); rs1718(T,C) |
| cytoBand name | 7q36.2 |
| EntrezGene GeneID | 202781 |
| snpEff Gene Name | PAXIP1 |
| EntrezGene Description | PAXIP1 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08035 |
C7orf13
| dbSNP name | rs3735189(T,C); rs7805578(C,T) |
| cytoBand name | 7q36.3 |
| EntrezGene GeneID | 129790 |
| snpEff Gene Name | RNF32 |
| EntrezGene Description | chromosome 7 open reading frame 13 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1244 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Impaired smooth pursuit;
Abnormal saccades;
Nystagmus;
Optic atrophy (67%)
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Feeding difficulties
SKELETAL:
[Feet];
Pes calcaneovarus
NEUROLOGIC:
[Central nervous system];
Gait ataxia;
Cerebellar ataxia;
Dysmetria;
Dysdiadochokinesia;
Intention tremor;
Extrapyramidal features;
Chorea of all limbs;
Progressive loss of movement control;
Dystonia;
Dysarthria;
Bradykinesia;
Hypertonia;
Spasticity;
Loss of independent ambulation within a few years;
Extensor plantar responses;
Speech delay;
Seizures;
Cognitive decline;
Cerebellar atrophy;
Increased iron deposition in the basal ganglia;
Cerebral atrophy;
'Eye of the tiger' sign on MRI;
Axonal swellings or spheroids;
Lewy bodies in the substantia nigra;
Lewy bodies throughout the brain;
Neurofibrillary tangles;
[Behavioral/psychiatric manifestations];
Diminished social interaction;
Autistic features;
Impulsivity;
Poor attention span;
Hyperactivity;
Emotional lability
MISCELLANEOUS:
Childhood onset (average 4 to 6 years);
Progressive disorder;
Variable phenotype;
Allelic disorder to infantile neuroaxonal dystrophy (256600)
MOLECULAR BASIS:
Caused by mutation in the phospholipase A2, group VI gene (PLA2G6,
603604.0002)
OMIM Title
*610242 CHROMOSOME 7 OPEN READING FRAME 13; C7ORF13
OMIM Description
CLONING
By sequence analysis and PCR of a lymphocyte cDNA library, van Baren et
al. (2002) cloned C7ORF13. The deduced protein contains 216 amino acids.
Northern blot analysis detected a transcript of 2.3 kb in testis only.
Expression was not detected in developing mouse, and van Baren et al.
(2002) found no homologs of the intronless C7ORF13 gene in other
species, suggesting it was derived from a retroposon.
GENE STRUCTURE
Van Baren et al. (2002) determined that C7ORF13 is an intronless gene.
MAPPING
By genomic sequence analysis, van Baren et al. (2002) mapped the C7ORF13
gene to chromosome 7q36, where it partially overlaps the RNF32 gene
(610241) on the opposite strand.
MIR595
| dbSNP name | rs4909237(C,T) |
| ccdsGene name | CCDS5947.1 |
| cytoBand name | 7q36.3 |
| EntrezGene GeneID | 693180 |
| snpEff Gene Name | PTPRN2 |
| EntrezGene Description | microRNA 595 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1841 |
| ESP Afr MAF | 0.06824 |
| ESP All MAF | 0.124466 |
| ESP Eur/Amr MAF | 0.149079 |
| ExAC AF | 0.183 |
DEFA11P
| dbSNP name | rs7821152(A,T); rs4403430(G,A) |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 724068 |
| EntrezGene Description | defensin, alpha 11 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0 |
CLDN23
| dbSNP name | rs2280560(C,T); rs12153(G,C); rs77145835(G,C); rs114865749(G,T); rs1060107(G,T); rs4840350(A,G); rs1060106(A,G); rs11249882(T,C); rs11249883(G,A); rs11249884(T,C) |
| ccdsGene name | CCDS55195.1 |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 137075 |
| EntrezGene Description | claudin 23 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN23:NM_194284:exon1:c.C694T:p.P232S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96B33 |
| dbNSFP Uniprot ID | CLD23_HUMAN |
| dbNSFP KGp1 AF | 0.266941391941 |
| dbNSFP KGp1 Afr AF | 0.158536585366 |
| dbNSFP KGp1 Amr AF | 0.273480662983 |
| dbNSFP KGp1 Asn AF | 0.43006993007 |
| dbNSFP KGp1 Eur AF | 0.211081794195 |
| dbSNP GMAF | 0.2668 |
| ESP Afr MAF | 0.139253 |
| ESP All MAF | 0.193711 |
| ESP Eur/Amr MAF | 0.220191 |
| ExAC AF | 0.241 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Cardiomyopathy
SKELETAL:
[Feet];
Achilles tendon contractures
MUSCLE, SOFT TISSUE:
Muscle weakness, distal, progressive;
Muscle atrophy, distal;
Proximal muscle involvement may occur;
Muscle stiffness or aching;
EMG shows myopathic and neurogenic changes;
Muscle biopsy shows myofibrillar myopathy;
Abnormal muscle fibers with amorphous, granular, or hyaline deposits;
Congophilic staining;
Increased staining for myotilin, dystrophin, desmin;
Electron microscopy shows dense material emanating from the Z-disk;
Phagocytic vacuoles with degraded membranous material
NEUROLOGIC:
[Peripheral nervous system];
Peripheral neuropathy;
Hyporeflexia/areflexia in lower limbs
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset (mean 60 years);
Slowly progressive disorder;
Limb-girdle muscular dystrophy 1A (LGMD1A, 159000) is an allelic
disorder with overlapping clinical features
MOLECULAR BASIS:
Caused by mutations in the titin immunoglobulin domain protein gene
(TTID, 604103.0002).
OMIM Title
*609203 CLAUDIN 23; CLDN23
OMIM Description
CLONING
By microarray analysis and laser-capture microdissection to identify
transcripts downregulated in intestinal gastric cancer, followed by
database analysis, Katoh and Katoh (2003) identified CLDN23. The deduced
292-amino acid protein has 4 transmembrane domains and cytoplasmic N and
C termini. It has a WWCC motif in the first extracellular loop. Katoh
and Katoh (2003) also identified mouse Cldn23, which shares 79.5% amino
acid identity with human CLDN23.
MAPPING
By genomic sequence analysis, Katoh and Katoh (2003) determined that the
CLDN23 gene is linked to the MFHAS1 (605352) and PPP1R3B genes on
chromosome 8p23.1.
LINC00599
| dbSNP name | rs2272026(C,T); rs491364(G,A); rs370712938(T,G); rs118190748(T,G); rs2670893(T,G); rs1962430(G,T); rs1708879(G,A); rs73530415(A,T); rs592420(A,G); rs531564(G,C); rs73662598(G,A) |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 157627 |
| snpEff Gene Name | MIR124-1 |
| EntrezGene Description | long intergenic non-protein coding RNA 599 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3567 |
SLC35G5
| dbSNP name | rs74495029(A,C) |
| ccdsGene name | CCDS5980.1 |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 83650 |
| EntrezGene Description | solute carrier family 35, member G5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC35G5:NM_054028:exon1:c.A918C:p.A306A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1107 |
| ESP Afr MAF | 0.026101 |
| ESP All MAF | 0.034708 |
| ESP Eur/Amr MAF | 0.039124 |
| ExAC AF | 0.079,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
less than 3rd centile (in one patient)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Osteosclerosis of the anterior and posterior ribs;
Osteosclerosis of the clavicles;
Osteosclerosis of the scapulae
SKELETAL:
[Skull];
No osteosclerosis;
[Spine];
Osteosclerosis of vertebrae;
[Pelvis];
Osteosclerosis of the iliac crests;
Osteosclerosis of the ischium;
Osteosclerosis of the pubic bone;
[Limbs];
Osteosclerosis of the metaphyses of the long bones of the upper and
lower extremities;
Osteopenic shafts of long bones;
[Hands];
Osteosclerosis in short tubular bones of the hands [Feet];
Osteosclerosis of the talus;
Osteosclerosis of the calcaneus
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation (in one patient);
Hypotonia;
Seizures (in one patient);
Spastic paraplegia, later onset (in one patient)
LABORATORY ABNORMALITIES:
Elevated alkaline phosphatase (in one patient);
Elevated AST (aspartate aminotransferase) and CPK (creatine phosphokinase);
Elevated urinary pyridinoline and deoxypyridinoline
MISCELLANEOUS:
Four patients reported (last curated April 2013)
OMIM Title
*615199 SOLUTE CARRIER FAMILY 35, MEMBER G5; SLC35G5
;;ACYL-MALONYL-CONDENSING ENZYME; AMAC;;
ACYL-MALONYL-CONDENSING ENZYME 1-LIKE 2; AMAC1L2
OMIM Description
CLONING
Using a cDNA selection strategy to identify genes in the critical region
for keratolytic winter erythema (KWE; 148370) on chromosome 8, followed
by sequence analysis and RT-PCR, Appel et al. (2002) cloned SLC35G5,
which they called AMAC. RT-PCR detected AMAC expression in all human
tissues examined except liver. AMAC was also expressed in skin, primary
human keratinocytes, and HeLa cells. Comparison with the mouse Amac gene
suggested that human AMAC may be a transcribed pseudogene.
GENE STRUCTURE
Appel et al. (2002) determined that the SLC35G5 gene contains 1 exon.
MAPPING
By constructing a physical and transcriptional map of the KWE critical
region on chromosome 8, Appel et al. (2002) mapped the SLC35G5 gene to
chromosome 8p23-p22. They noted that highly similar sequences are also
located on chromosomes 17p13.1, 17q11.2, and 18p11.2.
EVOLUTION
Xing et al. (2006) determined that the AMAC1L2 gene arose by
SINE-VNTR-Alu (SVA) retrotransposon-mediated sequence transduction,
which happened before the divergence of humans and African great apes.
C8orf49
| dbSNP name | rs804285(G,C); rs56213203(A,T); rs809204(A,G); rs13281294(C,G); rs2740431(T,A); rs811966(C,T); rs36018280(G,A); rs809203(T,A); rs2645455(T,A); rs17153776(C,A); rs17810696(C,G); rs7015453(C,T); rs111566513(C,G); rs2686206(T,C); rs17810775(T,A); rs66510044(G,A) |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 606553 |
| EntrezGene Description | chromosome 8 open reading frame 49 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PQH1 |
| dbNSFP KGp1 AF | 0.981227106227 |
| dbNSFP KGp1 Afr AF | 0.920731707317 |
| dbNSFP KGp1 Amr AF | 0.994475138122 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.01882 |
| ExAC AF | 0.992 |
CTSB
| dbSNP name | rs6731(T,C); rs1142957(A,C); rs1736077(G,C); rs77145771(A,G); rs8005(A,C); rs12898(G,A); rs2740592(A,G); rs2645425(G,A); rs11786618(G,A); rs1736078(A,C); rs4839(T,C); rs9009(A,T); rs1065712(G,C); rs6730(G,A); rs3088244(C,G); rs709822(C,G); rs3947(G,A); rs8898(T,C); rs709821(G,C); rs142249463(C,A); rs28460683(G,A); rs1736081(T,G); rs10107851(T,C); rs187694088(C,T); rs1692811(C,G); rs1736082(C,T); rs1736083(G,T); rs1692812(T,G); rs73663021(T,C); rs73663022(T,G); rs191156018(G,A); rs1692813(G,T); rs1692814(T,C); rs1692815(G,C); rs1692816(A,C); rs17573(C,T); rs1692817(C,A); rs1692818(C,G); rs1736086(C,T); rs2294138(C,T); rs2294140(C,G); rs1736089(G,A); rs113628575(G,A); rs1736090(T,C); rs28592650(C,G); rs35581201(T,C); rs13280858(C,T); rs13254438(T,C); rs13278902(G,C); rs2645423(C,A); rs2645422(G,C); rs146628196(T,G); rs62495696(A,G); rs74639061(G,C); rs2645420(G,A); rs2645419(T,C); rs11548596(G,A); rs28577034(A,T); rs2645417(T,G); rs2740595(C,G); rs62495697(G,A); rs1293289(G,A); rs1293290(T,C); rs1803250(T,C); rs1293291(A,G); rs1293292(G,A); rs1122182(T,A); rs12338(G,C); rs2272767(C,T); rs148523722(C,A); rs1293295(C,A); rs1293296(A,C); rs58164566(G,A); rs1293297(G,C); rs1293298(A,C); rs117700846(G,A); rs1736103(C,T); rs17814360(G,A); rs78107889(C,T); rs17154027(A,G); rs17814426(C,T); rs73209040(A,G); rs73209041(T,G); rs6980952(G,C); rs73209042(G,C); rs1293288(T,C); rs114143730(T,C); rs1293303(G,C); rs1293304(A,G); rs1293305(C,A); rs1293306(C,T); rs73534709(G,A); rs2645415(A,G); rs1299525(C,T); rs145958781(C,T); rs113448138(C,G); rs139221783(G,C); rs1293307(A,G); rs1293309(G,A); rs141111503(T,C) |
| ccdsGene name | CCDS5986.1 |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 1508 |
| EntrezGene Description | cathepsin B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CTSB:NM_147781:exon5:c.C272T:p.P91L,CTSB:NM_001908:exon4:c.C272T:p.P91L,CTSB:NM_147783:exon5:c.C272T:p.P91L,CTSB:NM_147780:exon6:c.C272T:p.P91L,CTSB:NM_147782:exon5:c.C272T:p.P91L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7279 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.009532 |
| ESP All MAF | 0.00346 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.001049 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Zonular cataract;
Pulverulent cataract;
Stellate cataract;
Nuclear cataract;
Anterior polar cataract;
Perinuclear cataract;
Lamellar cataract
MISCELLANEOUS:
Variable cataract phenotypes within a family;
Cataracts are progressive but may vary between eyes of an individual;
Cataracts variably present at birth
MOLECULAR BASIS:
Caused by mutation in the heat-shock transcription factor 4 (HSF4,
602438.0001)
OMIM Title
*116810 CATHEPSIN B; CTSB
;;CATB;;
AMYLOID PRECURSOR PROTEIN SECRETASE;;
APP SECRETASE; APPS
OMIM Description
CLONING
Murnane (1985) pointed out amino acid sequence homology between HRAS p21
(190020) and cathepsin B.
Chan et al. (1986) cloned preprocathepsin B from hepatoma and kidney
cDNA libraries. The deduced 339-amino acid preprocathepsin B contains a
17-residue N-terminal prepeptide followed by a 62-residue propeptide,
254 residues that are in the mature (single-chain) cathepsin B, and a
6-residue C-terminal extension. Human, mouse, and rat procathepsin B
share at least 68% sequence identity.
Moin et al. (1992) purified 3 forms of cathepsin B from normal human
liver and several human tumor tissues. SDS-PAGE detected 2 forms of 25
and 26 kD that appeared as a doublet and a third form of about 30 kD.
The doublet was associated with the highest cathepsin B activity.
N-terminal sequencing revealed that the 25- and 26-kD forms represent
the heavy chain of the mature double-chain form of cathepsin B.
Endoglycosidase treatment converted the 26-kD form into the 25-kD form,
suggesting that cathepsin B exists as both glycosylated and
unglycosylated forms. N-terminal sequencing indicated that the 30-kD
protein was the single-chain form. Using several biochemical and
immunologic criteria, Moin et al. (1992) determined that the tumor and
normal liver forms of cathepsin B were similar in all characteristics
examined.
Tam et al. (1994) isolated 2 CTSB cDNAs from a normal human embryonic
fibroblast cDNA library. These clones have a 10-bp insertion in the
3-prime untranslated region (UTR) compared with the CTSB sequence
reported by Chan et al. (1986). The insertion may allow the formation of
a stable stem-loop structure. One of the clones reported by Tam et al.
(1994) also has an extension of about 1 kb in the 3-prime UTR. Northern
blot analysis using probes unique to the 3-prime UTR extension detected
4.0- and 1.7-kb CTSB transcripts, but not the major 2.2-kb transcript.
GENE STRUCTURE
Berquin et al. (1995) stated that the CTSB gene contains 12 exons. They
identified 2 additional alternatively splices exons, which they
designated 2a and 2b, between exons 2 and 3 in the 5-prime UTR of the
CTSB gene. All of the exons of the 5-prime UTR could be alternatively
spliced to produce several transcript species. In addition, there are at
least 3 upstream translation initiation codons. Berquin et al. (1995)
determined that the CTSB gene spans nearly 27 kb, although they
suggested that it may be larger.
MAPPING
Wang et al. (1987) assigned the CTSB gene to chromosome 8p22 by means of
a cDNA probe used in Southern blot analysis of somatic cell hybrids and
in situ hybridization. Fong et al. (1992) mapped CTSB to 8p23.1-p22 by 3
independent methods: analysis of human-hamster somatic cell hybrid DNA
by PCR, comparison of hybridization signals to cathepsin B in interphase
nuclei of normal fibroblasts and fibroblasts with a chromosome 8
deletion, and fluorescence in situ hybridization.
Deussing et al. (1997) mapped the Ctsb gene to mouse chromosome 14 and
localized a related sequence to chromosome 2.
GENE FUNCTION
Esch et al. (1990) demonstrated cleavage of the amyloid beta peptide
during constitutive processing of its precursor (APP; 104760). Cleavage
occurs in the interior of the amyloid peptide sequence, thereby
precluding formation and deposition of the APP protein. Esch et al.
(1990) suggested that a genetic defect in this processing mechanism
might be a basis of Alzheimer disease (104300). Tagawa et al. (1991)
demonstrated that APP secretase is identical to cathepsin B.
By RT-PCR and primer extension assays, Berquin et al. (1995) found that
CTSB mRNA species differed among tissues and between a glioblastoma
sample and a cell line derived from it. Two alternative exons, exons 2a
and 2b, were detected more frequently in tumor samples than in matched
normal tissues.
Antigen presentation by major histocompatibility complex (MHC) class II
molecules requires the participation of different proteases in the
endocytic route to degrade endocytosed antigens as well as the MHC class
II-associated invariant chain. Only cathepsin S (116845) appears to be
essential for complete destruction of the invariant chain. Degradation
of antigens themselves in vitro and experiments using protease
inhibitors suggested that cathepsin B and cathepsin D (116840), 2 major
cysteine and aspartyl proteases, respectively, are involved in antigen
degradation. Deussing et al. (1998) analyzed the antigen-presenting
properties of cells derived from mice deficient in either cathepsin B or
cathepsin D and found that the overall capacity of the
antigen-presenting cells deficient in either cathepsin was unaffected.
Degradation of the invariant chain proceeded normally in both classes of
cells. Deussing et al. (1998) concluded that neither cathepsin B nor
cathepsin D is essential for MHC class II-mediated antigen presentation.
CTSB is overexpressed in tumors of the lung, prostate, colon, breast,
and stomach. Hughes et al. (1998) found an amplicon at 8p23-p22 that
resulted in CTSB overexpression in esophageal adenocarcinoma. Of the
potentially coamplified genes that are known to map to this region, they
found that Southern blot analysis of 66 esophageal adenocarcinomas
demonstrated only CTSB and the gene for farnesyldiphosphate
farnesyltransferase (FDFT1; 184420) to be the only ones consistently
amplified in 8 (12.1%) of the tumors. Northern blot analysis showed
overexpression of CTSB and FDFT1 mRNA in all 6 of the amplified
esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was
present in 2 of 6 nonamplified tumors analyzed. However, FDFT1 mRNA
overexpression without amplification was not observed. Abundant
extracellular expression of CTSB protein was found in 29 of 40 (72.5%)
of esophageal adenocarcinoma specimens by use of immunohistochemical
analysis. The findings were thought to support an important role for
CTSB in esophageal adenocarcinoma and possibly in other tumors.
Guicciardi et al. (2000) determined that Ctsb accumulated in the cytosol
of mouse hepatocytes and rat hepatoma cells exposed to TNFA (191160) and
that it contributed to TNFA-induced apoptosis. Using cell-free systems,
they showed that caspase-8 (601763) caused release of active Ctsb from
purified lysosomes and that Ctsb, in turn, increased cytosol-induced
release of cytochrome c from mitochondria. TNFA-induced apoptosis was
markedly diminished in hepatocytes isolated from Ctsb null mice.
By immunogold electron microscopy, Kukor et al. (2002) determined that
CTSB is abundant in the secretory compartment of the exocrine pancreas.
Pro-CTSB and mature CTSB were secreted together with trypsinogen
(276000) and active trypsin into the pancreatic juice of patients with
sporadic or hereditary pancreatitis (167800). CTSB activated trypsinogen
in vitro, but it appeared unlikely that CTSB contributes to hereditary
pancreatitis.
Using selective protease inhibitors in African green monkey kidney cells
and protease-deficient mouse cell lines, Chandran et al. (2005)
identified an essential role for Catb and an accessory role for Catl
(CTSL; 116880) in the entry of vesicular stomatitis virus particles
pseudotyped with Ebola virus glycoprotein. They proposed that CATB and
CATL are part of a multistep mechanism contributing to Ebola virus
infection and that cathepsin inhibitors that diminish viral
multiplication may have a role in antiviral therapy.
MOLECULAR GENETICS
Mahurkar et al. (2006) found an association between the val26 allele of
a leu26-to-val polymorphism (dbSNP rs12338) in the CTSB gene in patients
with tropical calcific pancreatitis (608189); the association appeared
to be independent of SPINK1 (167790) mutation status, suggesting that
val26 may act as a susceptibility allele in the pathogenesis of TCP.
USP17L7
| dbSNP name | rs28594743(C,G); rs9721012(T,G); rs9720197(G,A); rs2698968(A,G); rs75826165(G,A); rs115444041(G,A) |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 100132923 |
| EntrezGene Symbol | FAM66D |
| snpEff Gene Name | USP17L2 |
| EntrezGene Description | family with sequence similarity 66, member D |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | USP17L7:NM_001256869:exon1:c.G464C:p.R155T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1024 |
| ExAC AF | 0.053,2.659e-05 |
LOC649352
| dbSNP name | rs13273613(C,A); rs145707011(C,T); rs3959004(G,A) |
| cytoBand name | 8p23.1 |
| EntrezGene GeneID | 100133172 |
| EntrezGene Symbol | FAM66A |
| snpEff Gene Name | AC087203.1 |
| EntrezGene Description | family with sequence similarity 66, member A |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4793 |
C8orf48
| dbSNP name | rs13273355(C,T); rs10096353(C,G); rs11203497(T,A); rs71522356(A,G) |
| ccdsGene name | CCDS47809.1 |
| cytoBand name | 8p22 |
| EntrezGene GeneID | 157773 |
| EntrezGene Description | chromosome 8 open reading frame 48 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C8orf48:NM_001007090:exon1:c.C83T:p.S28F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96LL4 |
| dbNSFP Uniprot ID | CH048_HUMAN |
| dbNSFP KGp1 AF | 0.835622710623 |
| dbNSFP KGp1 Afr AF | 0.691056910569 |
| dbNSFP KGp1 Amr AF | 0.825966850829 |
| dbNSFP KGp1 Asn AF | 0.979020979021 |
| dbNSFP KGp1 Eur AF | 0.825857519789 |
| dbSNP GMAF | 0.1644 |
| ESP Afr MAF | 0.272399 |
| ESP All MAF | 0.208936 |
| ESP Eur/Amr MAF | 0.181332 |
| ExAC AF | 0.786 |
SGCZ
| dbSNP name | rs17118615(A,G); rs77245943(A,G); rs73213896(A,T); rs73520324(G,A); rs13250137(C,T); rs117141833(G,C); rs138997485(G,C); rs148572704(A,G); rs115936070(G,C); rs115383936(A,G); rs12543031(G,A); rs1841912(C,A); rs17118622(T,C); rs11775245(T,C); rs148887242(C,G); rs60953291(T,C); rs59064758(T,C); rs1478042(G,A); rs74444465(T,C); rs1478041(T,A); rs73213899(A,G); rs113753209(C,T); rs13263748(C,T); rs6994825(A,T); rs56106017(C,T); rs6999123(T,C); rs6999144(T,C); rs4831530(A,T); rs7013460(G,C); rs6996097(A,G); rs10112987(C,G); rs13280472(G,T); rs6984849(G,T); rs114720825(A,C); rs117525471(T,G); rs146829173(C,T); rs6986663(C,T); rs73215903(T,A); rs1478040(G,A); rs12155874(A,G); rs12156096(G,T); rs12678173(T,C); rs1478039(G,A); rs10086561(T,C); rs6997103(G,A); rs13251453(A,G); rs75069120(A,G); rs7007582(G,C); rs6530723(G,A); rs35204627(C,T); rs1973167(A,G); rs12546928(G,A); rs12544741(A,C); rs10503484(G,T); rs114104214(G,T); rs13276095(A,C); rs13248520(T,C); rs959118(T,A); rs6987032(T,C); rs6530724(G,T); rs78005520(A,G); rs13266182(T,C); rs2220205(G,A); rs2220204(G,A); rs35065526(G,A); rs55853834(A,C); rs111356123(A,G); rs183050551(C,A); rs190598778(C,A); rs9643971(T,A); rs61594930(T,C); rs10503485(T,C); rs7815761(G,A); rs7820727(C,A); rs9643910(G,T); rs9643972(G,A); rs11993263(C,A); rs17118667(T,C); rs9643911(T,G); rs10503486(A,G); rs10503487(A,C); rs12682628(T,C); rs1382150(A,G); rs7010173(C,T); rs10106579(G,T); rs73217929(C,T); rs73217932(A,G); rs13275402(T,C); rs114717381(G,T); rs114851939(A,G); rs13257715(T,C); rs73520378(C,G); rs12546153(C,T); rs13259591(T,C); rs10104893(T,G); rs13252664(A,G); rs59398265(G,A); rs11203576(T,C); rs6988641(C,T); rs73520383(A,G); rs79257607(G,T); rs10109252(A,G); rs55709146(G,A); rs73217933(G,C); rs73520387(G,A); rs73217934(G,A); rs11203577(T,A); rs17211024(T,C); rs4831531(A,G); rs115003794(C,T); rs140429746(A,G); rs144069404(G,C); rs116953108(A,T); rs10096675(A,T); rs141458196(T,C); rs77924777(T,C); rs73520399(G,T); rs73520400(T,C); rs13249760(A,G); rs73522403(A,G); rs115568375(A,G); rs73665765(C,T); rs13248079(G,A); rs59376398(T,A); rs11203578(G,A); rs17118702(C,T); rs141675180(T,C); rs10098108(C,A); rs34389480(C,A); rs17276956(A,C); rs11988202(G,C); rs34078873(A,G); rs17118706(A,C); rs73522414(A,G); rs73522417(T,C); rs10888080(C,T); rs12675733(T,G); rs12681431(C,G); rs13270757(T,C); rs35054571(G,A); rs4492379(T,G); rs17118710(A,G); rs77851342(C,T); rs113379505(C,T); rs10888081(G,C); rs73522423(T,C); rs10888082(G,A); rs73522424(T,C); rs6996119(A,C); rs56121790(A,G); rs73217948(C,G); rs73217949(C,T); rs7005452(T,A); rs60146348(T,A); rs10106930(T,C); rs13265667(T,C); rs56404733(T,C); rs55701072(A,T); rs10888083(T,C); rs1824743(C,T); rs1824744(A,T); rs11993274(G,C); rs73217951(G,A); rs12678130(T,C); rs115307439(G,C); rs10888084(A,G); rs79148607(G,C); rs36067918(A,C); rs73217958(T,A); rs73664106(T,C); rs6994093(T,A); rs117411570(T,A); rs1478044(T,C); rs73522453(G,T); rs12675921(G,A); rs55742062(A,C); rs10111643(A,G); rs1478045(C,T); rs73664115(G,C); rs78613823(G,A); rs73664116(A,G); rs73522460(G,C); rs73217962(T,A); rs13269831(C,T); rs73522461(T,C); rs60431949(G,C); rs765493(C,A); rs183230503(G,T); rs7816298(C,G); rs13251936(G,T); rs1824730(T,C); rs13254246(C,T); rs13263774(T,A); rs1824731(G,A); rs79809877(T,C); rs2169698(C,T); rs191339601(G,A); rs4487768(C,T); rs72496284(A,T); rs73522472(C,T); rs13272092(G,C); rs6982075(T,C); rs7001172(C,G); rs11780908(A,C); rs4458875(C,T); rs144360796(T,C); rs147836026(C,G); rs11778510(T,A); rs58935582(G,C); rs59895693(C,T); rs56085427(A,T); rs114120141(C,A); rs4377964(A,G); rs73522479(C,G); rs1601428(G,A); rs13270472(T,A); rs1586295(T,C); rs73217971(G,C); rs7820730(C,T); rs12677899(A,G); rs77714551(G,C); rs73522487(G,A); rs56017210(A,G); rs56751844(C,G); rs13253386(T,G); rs73213547(A,G); rs2126809(T,C); rs12545891(A,T); rs1824732(T,G); rs80323480(A,C); rs67730760(T,C); rs7823636(A,C); rs73522501(C,T); rs13276610(A,T); rs73213553(A,T); rs73524103(T,A); rs7002189(T,A); rs76438853(A,C); rs73213555(A,G); rs73213556(G,A); rs10089871(G,A); rs10108456(T,C); rs73213558(T,C); rs73213559(A,C); rs11775065(G,C); rs55829066(A,G); rs67022821(G,A); rs7825381(T,C); rs190835913(A,G); rs78572316(A,G); rs73213562(A,G); rs73213563(T,C); rs73213564(G,A); rs73213565(G,T); rs60246208(C,G); rs12548892(T,C); rs10086068(C,T); rs1809341(G,C); rs1809340(A,G); rs34278155(C,T); rs4415315(T,G); rs3888260(A,G); rs115014171(C,A); rs116685938(G,A); rs7817792(G,A); rs74524620(T,C); rs73213574(T,G); rs57407844(A,C); rs73213575(T,C); rs1382147(G,T); rs1382146(G,A); rs1382145(G,A); rs1382144(T,C); rs113684328(G,A); rs79820044(G,A); rs13269652(T,G); rs34107329(G,A); rs12549321(C,T); rs12542569(T,A); rs12542572(T,C); rs6994473(T,G); rs79084523(A,G); rs9325688(A,C); rs7841810(G,A); rs981657(C,T); rs2014581(C,T); rs11987917(A,G); rs1478028(C,G); rs965859(C,G); rs10112523(G,C); rs12545743(G,A); rs73524132(T,G); rs7826581(C,T); rs12547822(C,T); rs12542755(G,A); rs1841906(A,T); rs56215061(G,A); rs183330095(T,C); rs56145133(G,A); rs6992644(T,C); rs1038031(G,A); rs6993740(A,T); rs7011198(G,T); rs185480134(A,G); rs1841905(C,T); rs2290969(C,T); rs2290968(T,C); rs9325689(C,G); rs13253277(T,C); rs1841904(A,C); rs1382141(C,A); rs10102785(A,G); rs56123472(C,A); rs73524148(T,C); rs76998428(G,A); rs1478026(C,T); rs7839595(A,G); rs6989768(G,A); rs1841903(C,T); rs73524156(C,G); rs10095643(G,A); rs1478024(A,C); rs10099355(G,C); rs34218938(C,T); rs1871100(G,C); rs10100006(G,C); rs1478023(T,C); rs13260343(A,G); rs28416952(C,T); rs10481430(T,G); rs1824742(C,T); rs4240168(T,C); rs11985639(C,T); rs4831541(G,C); rs7838241(A,G); rs76896931(C,T); rs76581516(T,C); rs4831543(C,A); rs4551355(C,A); rs13282100(A,G); rs13282109(A,T); rs1020930(A,T); rs1551917(T,G); rs1973166(A,G); rs76044928(G,A); rs148919986(A,G); rs11781453(A,T); rs17212259(A,G); rs79819168(A,G); rs1382139(C,G); rs1382138(C,A); rs11203580(A,G); rs7840084(C,G); rs12156365(G,A); rs67735428(C,G); rs57818049(G,A); rs12680272(A,G); rs4831279(T,C); rs1871099(G,C); rs10888085(T,C); rs11203581(T,C); rs73217576(C,T); rs68184191(C,T); rs77175663(T,A); rs11203582(A,G); rs34678271(C,A); rs11992888(C,T); rs11985495(G,T); rs77698785(C,G); rs10441664(C,T); rs140922107(G,A); rs12679768(C,G); rs66915985(G,C); rs66476614(C,T); rs2054426(A,G); rs11986613(G,C); rs11997673(A,G); rs76294354(G,A); rs10109838(A,G); rs4145610(A,G); rs10095080(T,C); rs73664163(G,A); rs7008062(G,C); rs74379818(G,C); rs11989616(C,G); rs10095928(T,C); rs7013907(C,T); rs10108958(G,T); rs7017724(G,C); rs7018108(G,C); rs189913453(A,G); rs1979382(T,A); rs2169702(T,G); rs76050700(T,A); rs34803352(T,C); rs73664164(G,C); rs148064979(G,A); rs2035202(T,C); rs62492285(G,C); rs1904078(G,T); rs6530728(T,A); rs7016314(T,C); rs56040119(G,T); rs146297226(C,G); rs1478022(C,G); rs11987143(G,C); rs7828061(C,A); rs13251919(T,G); rs10112456(A,G); rs7002511(C,T); rs34102125(G,C); rs7002801(C,G); rs28831762(G,C); rs7002819(C,T); rs6984467(A,C); rs13250239(G,A); rs1871098(G,T); rs1871097(A,T); rs1871096(T,C); rs1871095(T,G); rs13258694(G,A); rs11990112(G,C); rs1478020(T,C); rs62492286(T,C); rs7829937(T,C); rs35108680(G,A); rs7842239(G,A); rs6530729(G,C); rs2169701(C,T); rs56078739(T,G); rs28595774(A,G); rs114067324(A,G); rs147787559(T,C); rs2126811(A,G); rs11203583(C,T); rs4524791(T,A); rs12680596(C,A); rs143445163(T,C); rs4831282(G,A); rs13248243(G,C); rs7819363(A,T); rs7819489(A,G); rs35736129(T,C); rs28693799(G,A); rs111681482(A,G); rs7840997(C,T); rs35846575(T,C); rs1824733(G,C); rs12678124(G,C); rs1478014(C,T); rs77800113(C,A); rs1478015(G,A); rs1478016(T,C); rs79103488(A,G); rs35956897(G,C); rs34394024(A,T); rs7816129(G,C); rs7842299(T,G); rs78335187(A,G); rs7821005(C,T); rs7821247(C,A); rs11993032(G,A); rs75541800(T,C); rs77550874(T,C); rs10091847(G,A); rs59105600(G,C); rs10113003(T,C); rs148313249(T,G); rs57609697(T,G); rs34600686(C,T); rs138332533(A,G); rs28504110(A,T); rs113444781(G,C); rs143996956(C,A); rs1824735(T,C); rs35399891(G,C); rs12156028(T,A); rs1158606(G,T); rs1304567(T,C); rs1593628(C,T); rs116049899(C,T); rs6530730(G,A); rs28847673(G,A); rs13259319(C,A); rs28417690(A,C); rs12155959(G,C); rs12155763(A,G); rs7814090(G,A); rs78525725(T,C); rs75566310(C,A); rs74575792(A,G); rs76801568(A,G); rs2059675(C,A); rs11990101(T,A); rs10090772(C,A); rs74585141(G,A); rs1824739(C,T); rs115041433(T,C); rs2054422(T,C); rs76634469(T,A); rs73528708(C,T); rs7842004(A,C); rs1478017(A,C); rs66881719(T,C); rs74982119(G,A); rs35359659(G,A); rs35513683(T,C); rs73528709(T,C); rs11991371(A,G); rs77758351(T,C); rs9325690(A,G); rs13281547(A,G); rs9987243(C,T); rs185057728(G,A); rs77072190(A,T); rs78252715(A,G); rs79798510(A,C); rs114460371(C,A); rs10102365(G,A); rs140797636(T,C); rs10089915(A,T); rs17278157(C,T); rs17278178(T,C); rs12679992(T,G); rs11996588(G,A); rs7008958(G,C); rs112835262(A,T); rs10096956(T,C); rs10096854(A,T); rs10099889(T,C); rs11203584(G,T); rs113136480(A,G); rs10503488(G,C); rs6997719(A,T); rs1824740(A,T); rs73219219(G,A); rs2217124(G,C); rs6981772(G,A); rs7002641(A,G); rs79933063(A,G); rs10101540(A,C); rs10087090(C,T); rs10104772(T,G); rs10104800(T,C); rs10104923(T,C); rs10086513(G,A); rs192631097(T,A); rs7007996(A,C); rs7008726(A,G); rs7016734(T,A); rs6993061(C,T); rs34604718(G,C); rs7012997(A,G); rs1382136(C,T); rs2195049(A,G); rs1382137(C,T); rs62492296(C,T); rs1351068(T,C); rs141412741(C,T); rs76716768(C,T); rs17278416(T,G); rs17212661(C,T); rs1351069(T,G); rs113480132(T,C); rs10092002(A,C); rs34972118(A,G); rs77962715(T,G); rs62492298(C,T); rs74585687(G,A); rs62492299(G,A); rs10105439(G,A); rs13261526(G,C); rs6530731(A,T); rs13279634(T,G); rs13271166(C,T); rs13271414(C,T); rs76376050(T,G); rs28684538(G,A); rs2126810(T,C); rs2169699(A,G); rs2169700(C,T); rs62492321(G,C); rs62492322(A,G); rs66864079(A,T); rs7830850(A,C); rs62492323(G,C); rs62492325(C,G); rs7813447(C,T); rs62492326(C,T); rs7812587(G,T); rs146949357(C,A); rs4831551(T,C); rs13254982(G,C); rs4831552(A,G); rs7007237(A,C); rs62492328(T,C); rs116282736(C,A); rs7015375(T,C); rs62492329(C,T); rs115801807(C,G); rs62492330(C,A); rs62492331(T,C); rs13266345(G,C); rs7016966(A,G); rs75711601(A,T); rs78352106(A,G); rs4571734(A,C); rs35789757(C,T); rs2410165(C,G); rs34114926(T,C); rs34103514(A,T); rs35897666(T,C); rs35582170(C,A); rs28511571(G,A); rs4477022(C,T); rs13252153(C,T); rs13252423(C,A); rs181246732(T,C); rs34223868(C,T); rs5014265(A,C); rs5014264(T,G); rs5014263(G,T); rs34633072(G,A); rs4831554(C,G); rs4831555(C,G); rs4831556(T,A); rs4831283(A,G); rs28782928(C,G); rs7013519(C,G); rs75987392(T,C); rs2410166(G,A); rs4313160(T,C); rs13270134(G,A); rs2054431(A,G); rs80004533(T,C); rs2054430(T,C); rs7830245(T,C); rs2054429(A,G); rs13278543(G,A); rs13279102(G,A); rs11780410(G,C); rs11777317(A,T); rs28410303(A,C); rs79453938(G,A); rs78662029(G,C); rs2054428(T,G); rs1871102(G,T); rs1871101(G,C); rs34227627(G,A); rs138223891(G,C); rs2054427(T,C); rs62492335(G,C); rs28698754(C,A); rs114825850(C,G); rs34473759(C,G); rs7844811(A,C); rs13256202(T,C); rs13256764(T,C); rs7831309(C,T); rs67397260(G,A); rs184609023(A,C); rs66963659(G,C); rs67237408(T,C); rs6530733(T,A); rs62492336(G,A); rs62492337(A,C); rs116074306(C,T); rs189118555(A,G); rs34516872(C,G); rs33976552(C,G); rs35672783(A,G); rs13266987(T,G); rs7835210(G,C); rs12334437(T,C); rs4831557(A,C); rs4831558(G,A); rs115706913(T,C); rs7835818(G,A); rs115017926(C,T); rs28684895(A,G); rs77738224(C,G); rs981904(T,A); rs981905(G,A); rs2054423(A,T); rs2054424(A,C); rs114655455(T,C); rs115862699(C,T); rs2054425(C,T); rs10107810(G,A); rs35393067(T,C); rs11776860(A,G); rs2059673(T,C); rs2059674(C,G); rs2410167(G,A); rs2054421(G,A); rs2054420(C,T); rs77174468(C,T); rs2054419(A,G); rs60307406(T,G); rs2410168(A,C); rs2054418(T,G); rs4480121(T,C); rs12678209(G,A); rs12676819(T,C); rs7846533(C,T); rs12676820(A,G); rs7815847(C,T); rs12334829(G,T); rs7815140(G,C); rs116625085(A,G); rs10087349(G,A); rs7816456(C,G); rs10087468(G,A); rs7816719(C,T); rs7834539(A,G); rs7834540(A,C); rs7838226(T,G); rs11992106(G,T); rs11992831(G,C); rs34711557(G,C); rs6989764(C,G); rs6530734(A,T); rs34586769(G,A); rs28415820(C,T); rs12675362(C,G); rs35482427(T,C); rs34899486(G,A); rs13262425(G,A); rs13265580(A,T); rs13262491(G,A); rs13264808(C,G); rs13280543(T,C); rs71524112(C,T); rs79523145(G,A); rs7014808(A,G); rs6981010(T,A); rs977228(G,T); rs12547581(G,A); rs6530735(C,G); rs7844145(A,G); rs1478038(A,G); rs1478037(T,A); rs1478036(A,G); rs9657230(A,G); rs1478035(A,G); rs79917832(C,T); rs9657231(G,T); rs34635812(G,C); rs75501055(T,C); rs7830988(C,T); rs7830259(G,C); rs11988115(C,A); rs10216716(G,A); rs10216748(C,T); rs56656905(C,T); rs4490826(A,G); rs1365638(A,C); rs1365639(T,C); rs4442149(C,T); rs4637829(A,G); rs73219289(A,C); rs13255607(G,A); rs73219291(C,A); rs35755862(G,C); rs969552(A,G); rs34293153(T,C); rs10112420(T,A); rs9657201(G,A); rs7825435(C,T); rs13272080(C,T); rs13273446(A,C); rs4831559(G,C); rs1841911(A,G); rs183616005(T,C); rs1841910(G,T); rs4831560(G,C); rs1478034(C,A); rs7829353(G,C); rs17118829(T,G); rs3903317(T,A); rs3903318(C,T); rs143019761(A,T); rs13254655(G,C); rs17118836(G,A); rs74715282(A,T); rs17292180(G,A); rs11203585(G,C); rs11203586(G,A); rs13275341(T,G); rs13266960(C,T); rs17213822(C,A); rs1382140(G,T); rs76663305(C,G); rs1382142(C,T); rs1382143(A,G); rs13250197(C,G); rs13251264(A,G); rs1382148(C,A); rs187314999(A,C); rs28422064(T,C); rs76137354(T,C); rs17118852(A,G); rs6530736(A,C); rs77870833(T,C); rs13269000(T,C); rs182184376(G,A); rs17118855(G,C); rs6530737(A,G); rs4831561(T,C); rs13263601(A,C); rs4831562(C,G); rs6993798(C,T); rs4831563(T,A); rs9942836(T,A); rs5016286(C,T); rs187540883(G,C); rs2042760(C,G); rs2410169(G,C); rs13255876(T,G); rs9942785(G,T); rs17118860(G,A); rs75567645(T,A); rs17118863(G,A); rs9657233(T,C); rs78346209(C,T); rs1351071(T,G); rs1351070(C,T); rs2410170(A,C); rs11988897(T,C); rs73667116(A,G); rs13249458(C,G); rs76312406(C,T); rs6530738(T,C); rs7836055(A,T); rs12675035(C,G); rs12677612(T,C); rs7840280(T,C); rs77533350(A,G); rs7818174(G,A); rs7819289(C,T); rs7822826(C,T); rs34513984(G,A); rs73664003(T,G); rs34953040(T,C); rs35443490(T,G); rs11782510(G,C); rs57674106(C,A); rs11782538(G,T); rs13269547(C,T); rs13269611(C,A); rs9325695(G,C); rs75771652(T,C); rs75523422(G,T); rs77082892(G,A); rs7008422(C,G); rs4440633(C,T); rs4332133(T,G); rs4275225(G,T); rs4521757(A,G); rs7013623(C,G); rs35154599(G,A); rs2410185(G,A); rs1346276(C,G); rs62500200(G,A); rs62500201(G,C); rs1346275(A,G); rs1346274(C,T); rs7842522(G,A); rs1346273(T,C); rs1365649(G,T); rs13281312(C,A); rs1365648(A,T); rs3988435(A,G); rs7831589(A,G); rs7812895(G,A); rs7839024(T,C); rs1365647(G,T); rs17293289(A,G); rs12542082(G,A); rs77611893(T,A); rs79230920(A,C); rs9325698(G,A); rs9325699(G,A); rs9325700(C,T); rs148881837(C,A); rs9325701(C,T); rs9325702(G,A); rs76983255(C,T); rs13267451(T,C); rs73519405(A,G); rs55755261(T,G); rs55783571(G,A); rs10105044(C,T); rs10091434(A,G); rs35524191(T,C); rs13269878(T,C); rs1365646(T,C); rs1365645(A,G); rs1365644(C,T); rs76904877(C,A); rs1427002(C,T); rs1365642(A,G); rs1427001(A,G); rs1427000(C,T); rs6530739(A,G); rs6530740(T,C); rs6530741(C,T); rs6530743(A,T); rs5005958(C,T); rs148169767(C,T); rs5005957(G,A); rs201737973(C,T); rs7833701(T,C); rs17293820(T,G); rs10112775(C,G); rs10112034(G,C); rs116167166(G,A); rs10099360(A,C); rs10113000(C,G); rs1541771(G,A); rs6530744(G,C); rs1541770(A,T); rs73519429(G,C); rs78143304(G,A); rs73519430(T,C); rs56933999(C,T); rs62500205(C,T); rs4360295(G,A); rs60685224(T,C); rs35258736(G,C); rs10088988(C,G); rs7816517(G,C); rs7817555(C,T); rs7838797(A,T); rs7821673(C,A); rs35789646(T,G); rs35212565(G,T); rs7839860(A,G); rs9886428(G,A); rs34307156(A,G); rs35823436(C,G); rs1427003(T,C); rs13273128(G,T); rs73222825(G,A); rs28677841(A,G); rs7000067(G,C); rs114096293(A,G); rs34786320(G,C); rs10087038(A,G); rs10099853(G,C); rs34062482(A,C); rs11985534(A,G); rs2059672(C,T); rs4831288(G,T); rs11203588(T,A); rs7835815(G,A); rs1427025(T,C); rs1427024(G,A); rs17228471(C,T); rs75772572(A,C); rs34992346(T,C); rs35969875(A,G); rs139785791(C,T); rs13270554(G,C); rs7014940(A,G); rs6980825(A,G); rs11203589(A,G); rs12541432(T,C); rs12548310(C,T); rs7813566(A,T); rs55976608(C,T); rs13256008(T,C); rs34284931(T,A); rs35070002(T,C); rs34653417(A,G); rs56304123(G,T); rs28406919(C,T); rs13256717(C,G); rs34471517(C,A); rs1427023(G,A); rs13257104(C,G); rs1427022(C,G); rs4831569(C,A); rs4831289(A,C); rs78008005(C,A); rs7009679(G,A); rs12542368(A,G); rs12549721(C,T); rs62500223(G,A); rs11203590(A,G); rs28769717(G,C); rs11990597(G,A); rs28890207(G,T); rs6997468(A,T); rs75963807(A,G); rs34734828(A,G); rs725946(C,T); rs725944(T,C); rs725945(A,G); rs17118885(A,G); rs12676792(A,G); rs17294565(A,C); rs17228833(T,C); rs17228952(T,G); rs1427021(C,T); rs10088009(T,C); rs62500225(G,C); rs62500226(T,C); rs80350989(T,C); rs77202275(G,C); rs79211951(A,T); rs11203591(T,C); rs10088952(A,G); rs115897802(C,G); rs148616045(G,C); rs4317567(C,G); rs34778087(G,A); rs7463570(C,T); rs34346379(G,A); rs73664086(C,T); rs10089918(A,T); rs28493219(C,T); rs78547413(T,C); rs7835276(T,A); rs112184389(A,G); rs1896210(T,C); rs77809087(T,A); rs10107379(T,C); rs10107626(T,A); rs10089234(G,C); rs7818984(C,T); rs28476483(C,T); rs74407237(C,A); rs183038661(G,C); rs17229197(C,T); rs6651379(C,A); rs28449644(T,G); rs17229260(C,T); rs28434461(G,A); rs17229309(C,G); rs10094530(C,T); rs17295102(T,C); rs17229371(A,T); rs4269545(G,A); rs1426999(C,T); rs12545677(A,G); rs17118923(A,G); rs13275676(G,A); rs10087192(T,A); rs10098101(C,T); rs1426998(C,T); rs10097490(G,A); rs10112651(A,G); rs12679233(T,C); rs12676735(C,T); rs12548611(G,A); rs7833414(C,T); rs1365641(C,G); rs7832483(G,C); rs7833688(C,T); rs1426997(A,G); rs10091656(A,T); rs10094757(T,C); rs10091806(A,G); rs10105467(C,T); rs10094880(T,G); rs10105570(C,T); rs57437378(C,T); rs56082469(T,C); rs59590361(T,C); rs57102609(A,G); rs28470200(G,A); rs7825535(T,C); rs59418389(T,C); rs192310033(G,T); rs6530745(A,G); rs6530746(A,C); rs113433477(T,C); rs7000456(T,C); rs77232858(G,A); rs75188653(C,T); rs185808788(G,C); rs7004662(T,A); rs62500229(T,G); rs1426996(G,A); rs61683100(C,T); rs13257014(T,C); rs113183453(C,G); rs76831599(G,T); rs78255114(C,T); rs17118926(G,C); rs74664960(G,A); rs13255615(G,C); rs17118928(T,C); rs12549205(A,C); rs17118931(G,A); rs181075676(A,C); rs80325606(G,A); rs12550264(T,C); rs17229834(G,A); rs13264883(G,C); rs10108151(A,T); rs1427005(C,G); rs13258631(C,T); rs1427006(A,G); rs1427007(A,C); rs6530747(C,A); rs73664089(C,A); rs6988694(A,G); rs6530748(T,C); rs12679793(T,C); rs4831570(C,T); rs59285818(C,A); rs17118956(T,C); rs72603992(T,C); rs72603993(T,C); rs4831292(G,T); rs17118964(C,T); rs13251658(T,A); rs13276161(G,A); rs79975060(T,A); rs58355257(T,C); rs35790742(G,A); rs6999172(A,G); rs6999312(A,G); rs73664090(T,C); rs7003889(T,G); rs7018350(C,G); rs7000113(A,C); rs34354815(G,C); rs7000301(A,G); rs7004371(T,C); rs13278809(G,C); rs35372448(T,A); rs890535(T,A); rs10503490(T,C); rs11774327(G,T); rs10503491(C,T); rs10503492(G,C); rs890537(C,T); rs11775244(G,A); rs1365650(G,T); rs890538(C,T); rs3889733(A,G); rs752095(T,A); rs890539(A,G); rs6980964(T,G); rs17118994(C,G); rs2410172(C,T); rs890540(C,T); rs890541(C,G); rs890542(C,A); rs1160738(C,T); rs1160739(C,T); rs10089704(T,C); rs9657203(G,T); rs12548539(C,T); rs9657234(T,C); rs9657204(T,C); rs12541704(A,T); rs9643913(C,T); rs9643914(T,G); rs9643915(C,T); rs13257327(G,A); rs73666513(G,C); rs9643973(G,T); rs9643916(G,A); rs9643917(C,G); rs9643918(C,T); rs6530749(C,G); rs6530750(G,A); rs6419066(T,A); rs6530751(C,G); rs6530752(G,C); rs6530753(G,T); rs6530754(A,G); rs6530755(T,C); rs34372654(A,T); rs34148827(T,C); rs6998391(A,G); rs11203592(C,G); rs59074197(C,T); rs10101326(T,C); rs11203593(G,C); rs7002850(T,A); rs7829139(A,G); rs6530757(T,C); rs7829315(A,G); rs6530758(A,G); rs6530759(A,T); rs6530760(A,G); rs28667425(T,C); rs7845236(G,A); rs35753840(A,C); rs13269970(C,G); rs13269981(C,T); rs73207775(G,C); rs13271892(A,G); rs13271921(A,G); rs13279352(T,C); rs13279599(T,C); rs13269013(G,C); rs35521161(T,C); rs13272581(A,G); rs12115156(T,C); rs12115157(T,C); rs12114751(C,G); rs12114752(C,T); rs11203594(G,A); rs12114757(C,T); rs11203595(A,C); rs12114761(C,A); rs11774450(T,C); rs79234072(T,A); rs78229904(T,C); rs1427008(A,G); rs1427004(T,C); rs28439931(G,C); rs10441665(G,A); rs12674914(A,C); rs35897399(C,T); rs150345316(G,A); rs74515329(A,G); rs1991345(G,A); rs28639817(A,G); rs60814120(T,C); rs1991346(A,G); rs1427011(A,G); rs1427012(C,A); rs114613314(T,G); rs1427013(C,T); rs10441656(G,A); rs7826631(T,A); rs72603994(A,G); rs7840296(C,T); rs12677537(G,C); rs72603995(T,C); rs12676502(T,C); rs7831081(T,G); rs10110418(G,C); rs10097743(A,C); rs183062405(G,T); rs10086111(G,A); rs7814925(C,G); rs7813850(G,A); rs34388208(C,T); rs7836552(T,C); rs7832800(A,C); rs2410173(G,T); rs11774187(C,T); rs1593627(G,A); rs10089596(G,C); rs1427015(G,A); rs149889866(T,C); rs1427016(C,T); rs2410174(T,G); rs111252435(T,A); rs115548936(T,C); rs7465499(T,C); rs10109318(A,G); rs2410175(G,A); rs2162437(T,C); rs2162438(C,A); rs11203596(T,A); rs12678379(A,G); rs1319570(G,A); rs1157967(G,A); rs10098497(G,C); rs115903795(G,A); rs34614527(T,C); rs17230838(C,A); rs115053422(T,G); rs139821452(A,T); rs1427018(T,G); rs17119018(A,G); rs7004879(T,C); rs6981590(C,T); rs115531664(T,G); rs1346277(A,G); rs10089267(C,T); rs28414733(G,A); rs2217126(C,T); rs114267994(G,A); rs17231005(A,C); rs17231019(A,G); rs137974357(C,G); rs17119030(A,C); rs1346278(T,C); rs1559901(A,C); rs7461181(G,A); rs72603997(T,A); rs1559902(C,G); rs10096683(G,A); rs187536116(A,C); rs1427019(T,G); rs35492010(C,T); rs1346279(C,T); rs1346280(A,G); rs12548475(G,T); rs75461288(C,T); rs1427020(A,G); rs115372237(C,T); rs72603998(T,G); rs113420878(T,G); rs74989082(T,C); rs13261420(T,C); rs72603999(T,G); rs72604000(T,G); rs72604001(A,G); rs12547474(T,C); rs1030423(G,A); rs12544484(C,A); rs12546979(A,T); rs6993950(T,C); rs1365655(A,C); rs13263851(A,C); rs1365656(A,C); rs12681877(G,A); rs73207793(T,C); rs11995832(T,C); rs12156331(T,G); rs11203597(C,G); rs17095085(G,C); rs1896211(A,C); rs13255247(G,C); rs111809317(A,G); rs56738802(A,C); rs1820528(A,G); rs1820529(G,A); rs2217125(T,G); rs13266057(G,A); rs6530761(T,A); rs7007516(C,T); rs73207798(A,C); rs17119045(A,T); rs73207799(T,C); rs17297046(C,T); rs17231348(G,T); rs13277849(G,A); rs12549343(T,A); rs77601072(T,C); rs12541209(G,T); rs12546389(C,T); rs77153027(T,C); rs13254837(C,T); rs13263675(T,A); rs73207801(G,C); rs13271573(T,C); rs1896212(C,T); rs12056706(C,T); rs6990042(G,T); rs6994152(G,A); rs73666525(C,T); rs11994216(C,T); rs34201730(G,A); rs7015616(A,T); rs6995965(C,T); rs6981825(T,C); rs73209862(C,T); rs35491924(A,G); rs17231453(G,C); rs979950(A,G); rs979951(G,A); rs73209866(T,C); rs979952(G,T); rs2059670(A,C); rs62497788(T,C); rs146150156(C,A); rs9643919(C,T); rs73209868(C,A); rs72604002(G,C); rs7017763(C,T); rs35400537(T,C); rs1365651(G,T); rs1365652(T,G); rs9694843(T,C); rs10109396(A,G); rs1365653(C,G); rs12550172(A,G); rs12235018(C,T); rs7828313(G,C); rs62497792(A,C); rs7357477(C,T); rs73209873(T,G); rs17119066(T,C); rs1427009(T,A); rs12234915(T,A); rs62497793(T,C); rs62497794(T,A); rs35689103(C,T); rs12544242(T,C); rs12543686(A,G); rs12543702(A,G); rs7814772(C,T); rs7814935(C,T); rs7814468(G,A); rs7814480(G,A); rs13269646(T,C); rs10090427(G,C); rs66502804(A,G); rs4831574(C,T); rs4831575(T,C); rs4831576(A,G); rs9650352(T,C); rs9650353(T,G); rs11203598(C,T); rs10097709(G,A); rs61395816(A,C); rs11203600(T,C); rs6530764(A,G); rs6530765(T,C); rs13256807(A,G); rs57193041(A,T); rs7826826(C,T); rs10086477(T,C); rs10096346(G,A); rs17231904(A,G); rs17119072(G,A); rs7003304(C,T); rs144624036(A,G); rs10104508(G,A); rs10104654(G,C); rs6994149(T,C); rs76275570(G,A); rs890533(A,C); rs3988437(T,C); rs34450162(T,C); rs2081666(T,C); rs145125332(G,A); rs1834710(A,G); rs1593626(T,C); rs12386975(G,C); rs17232265(T,A); rs11991427(C,G); rs7000497(A,C); rs2081667(C,G); rs147486197(G,A); rs2081668(C,G); rs7816210(G,C); rs13264899(T,C); rs12550119(T,G); rs2410186(T,C); rs1072579(G,C); rs11985371(T,C); rs2898389(T,C); rs9643974(T,C); rs13252122(T,G); rs13251296(G,C); rs13251298(G,T); rs62497814(C,G); rs191784742(A,G); rs13259741(G,C); rs6989762(C,T); rs6989905(C,G); rs11997612(T,C); rs117550199(G,A); rs7826347(C,T); rs10503493(C,A); rs17119119(T,C); rs7000337(C,T); rs11987787(G,T); rs11995124(C,A); rs62497815(T,C); rs11995226(C,A); rs1426994(G,A); rs150202401(T,C); rs17119124(G,A); rs28653646(T,C); rs13249475(T,C); rs2059676(A,G); rs1559900(C,T); rs17119141(T,G); rs189412724(G,A); rs79837218(G,A); rs17119150(C,G); rs72607303(C,T); rs62497816(T,C); rs76016430(T,C); rs140555578(T,G); rs142619229(C,T); rs723087(G,C); rs17119184(C,G); rs989870(C,A); rs1426995(G,T); rs137861904(A,G); rs62497817(T,C); rs11992179(T,C); rs4831577(G,A); rs115739416(C,T); rs35588736(A,C); rs28764827(T,C); rs10092992(A,G); rs28897173(T,C); rs7841764(G,T); rs4330692(G,A); rs34269011(C,T); rs6997359(C,T); rs78507543(T,A); rs13252836(A,C); rs12681201(G,T); rs75987387(A,G); rs7824519(T,G); rs12548010(T,G); rs76264531(G,C); rs34067440(T,C); rs186512439(T,G); rs7829344(T,C); rs117317667(G,T); rs1896209(C,T); rs150907938(C,T); rs62497818(G,C); rs9325704(G,A); rs13253560(G,C); rs116561355(G,C); rs7821664(C,G); rs114844881(T,C); rs72607304(T,C); rs115166358(C,G); rs114459188(A,G); rs10090668(T,G); rs11990924(C,G); rs62497839(C,G); rs145847588(C,T); rs72607305(C,G); rs78542207(T,G); rs116347970(A,C); rs146024891(C,T); rs77323560(T,G); rs7842578(T,A); rs4512382(T,C); rs78022630(A,G); rs12550757(T,C); rs4372004(C,A); rs111542400(A,T); rs4305903(T,A); rs115730281(G,A); rs150636622(C,T); rs34421020(T,G); rs28456326(C,A); rs75255574(T,C); rs76012863(A,C); rs117566865(C,A); rs13263674(A,G); rs10101058(G,T); rs28459298(A,C); rs10088445(A,G); rs10102093(C,G); rs189195863(A,T); rs10101982(G,A); rs9325705(G,C); rs10102919(C,A); rs10092829(A,G); rs17299443(G,A); rs28728193(C,T); rs28637881(G,A); rs17119221(A,T); rs17119223(C,G); rs12676434(T,C); rs12155793(T,C); rs7463769(A,G); rs1551817(G,C); rs28688159(G,A); rs60296458(A,C); rs3860043(G,A); rs4621808(G,T); rs10888087(T,C); rs10100855(G,A); rs11203601(C,A); rs10092634(A,C); rs75907074(A,G); rs10503495(T,C); rs13271858(G,C); rs17119239(A,G); rs10156368(T,A); rs10503496(C,T); rs10110337(T,C); rs9693228(C,T); rs9693161(G,A); rs10093316(C,T); rs7826553(C,G); rs10110923(A,G); rs7844447(A,T); rs7813887(T,C); rs7827012(C,A); rs7813921(T,C); rs17119251(T,C); rs17119252(C,T); rs7845179(A,G); rs7814677(T,G); rs7830532(G,A); rs13258546(T,C); rs7831148(G,T); rs10100553(G,A); rs10093905(T,C); rs10093942(T,C); rs10090856(A,G); rs11992900(A,C); rs11993691(T,A); rs11993692(T,C); rs6988872(A,G); rs7006178(G,C); rs11989288(C,T); rs11992991(A,G); rs11993756(T,C); rs11989327(C,G); rs10097762(T,G); rs73219736(A,G); rs10095027(A,G); rs10098106(T,C); rs2054356(A,G); rs13267926(G,A); rs10098233(T,C); rs28570369(T,A); rs28686962(T,C); rs11997300(G,A); rs11994112(A,G); rs11994823(A,T); rs11994850(A,G); rs11991189(C,T); rs11995667(T,C); rs11994871(A,G); rs13277345(G,A); rs7833562(T,C); rs7830092(A,T); rs7845705(G,A); rs1461884(G,C); rs7834044(T,C); rs7812660(C,T); rs7834185(T,C); rs7830640(A,G); rs7815329(G,C); rs7816387(C,T); rs11992185(C,T); rs77493743(A,G); rs73664342(T,C); rs11984827(G,A); rs11984851(G,C); rs11996725(T,C); rs11992296(C,T); rs4831579(C,G); rs11996049(A,G); rs73664343(A,T); rs73664345(C,G); rs36002179(G,C); rs79440426(G,T); rs73664346(G,A); rs73664348(T,C); rs78618668(T,A); rs1037934(G,A); rs1037936(T,C); rs11993428(C,A); rs72607307(C,A); rs2410189(A,G); rs78702283(G,T); rs2410190(T,C); rs7813981(T,C); rs7813984(T,C); rs1551813(A,G); rs4831580(T,C); rs4831581(A,G); rs147963705(G,C); rs1551814(T,C); rs1551815(C,T); rs4831582(C,T); rs4831583(A,G); rs1551816(G,C); rs67199088(T,A); rs971619(A,C); rs4831585(A,C); rs28418768(T,A); rs73664350(T,A); rs73664351(G,C); rs73664352(C,T); rs973298(G,C); rs7465081(A,C); rs11997843(A,G); rs12550735(T,C); rs11998565(T,C); rs11985101(T,G); rs9657235(G,A); rs11998615(A,G); rs11994979(C,T); rs6530767(C,A); rs6530768(A,G); rs6530769(C,T); rs6530770(A,G); rs7003898(G,A); rs142668150(G,A); rs6990914(T,C); rs6991066(T,C); rs2199416(G,A); rs11996087(C,T); rs11985519(A,G); rs11986327(T,C); rs11996180(C,T); rs11987103(T,C); rs11987111(T,G); rs75708753(A,G); rs6991871(A,G); rs6992042(A,T); rs9325706(G,T); rs7827220(T,C); rs7823565(A,G); rs7823570(A,G); rs7840450(C,A); rs7840593(C,T); rs189942146(C,T); rs117829516(T,C); rs11988167(T,C); rs1461843(G,C); rs11998102(C,T); rs11990736(G,A); rs1461844(G,A); rs73664354(C,T); rs150752443(T,C); rs10441658(C,A); rs10441660(G,A); rs6981852(G,A); rs6530771(G,A); rs75121167(A,G); rs6419067(G,T); rs6530772(G,A); rs1947705(G,T); rs35884913(G,A); rs11984849(C,T); rs11988587(A,C); rs6530773(A,C); rs4831586(C,G); rs10105361(A,G); rs4831587(C,G); rs7008279(A,C); rs28483126(T,C); rs73664360(T,C); rs28739301(C,T); rs73219744(G,A); rs28713271(T,C); rs4428672(C,T); rs4269546(C,A); rs189436748(C,T); rs7460217(A,T); rs4342592(T,C); rs13254879(A,G); rs35194896(A,G); rs13255213(A,C); rs11203603(A,C); rs13263388(T,C); rs13252747(G,C); rs28433112(A,T); rs28539573(A,G); rs6990241(A,G); rs28593702(C,T); rs67483193(A,G); rs67565539(T,G); rs67667816(C,G); rs34735562(G,A); rs12542645(T,G); rs12549464(C,G); rs7461141(A,G); rs115307422(G,C); rs7461169(A,G); rs10888088(T,C); rs12544546(G,A); rs12542764(T,C); rs182465808(C,A); rs10109761(C,T); rs10109185(G,A); rs10096480(A,G); rs10110085(C,T); rs1471336(G,A); rs1471337(T,C); rs12056483(T,A); rs7462836(T,G); rs2169423(C,T); rs10100028(A,T); rs78638015(G,A); rs12543569(A,C); rs12545852(G,C); rs12544195(T,G); rs67208007(T,A); rs9918924(G,A); rs9918847(T,C); rs9918734(C,T); rs1471338(A,G); rs9918835(A,T); rs9918752(G,A); rs1471339(T,C); rs1471340(C,G); rs1471341(G,T); rs1381416(G,T); rs1381417(C,G); rs1381418(A,G); rs1461881(C,T); rs1461882(T,C); rs4410905(G,A); rs3887200(G,A); rs4484699(A,C); rs3887199(C,T); rs13264759(G,C); rs11990060(A,G); rs4455828(T,G); rs11990907(T,C); rs35487723(T,C); rs11782514(G,A); rs56033452(A,T); rs11782596(G,T); rs183232066(G,C); rs11203604(G,A); rs11987419(C,T); rs57354962(C,T); rs11776795(C,G); rs11776823(C,A); rs11781105(T,C); rs11203605(T,C); rs11203606(G,A); rs11776984(C,T); rs12545811(A,G); rs11203607(G,A); rs11782022(T,C); rs11992292(A,T); rs17119275(T,C); rs17119276(G,A); rs62499663(G,A); rs13263288(A,G); rs17301803(C,G); rs17301830(G,C); rs11997381(G,C); rs11203608(G,A); rs10096208(A,G); rs10099205(T,C); rs11995020(T,C); rs80287092(A,T); rs35757344(T,C); rs75466603(A,G); rs72607308(G,T); rs11986178(C,T); rs73219758(G,A); rs181764320(G,A); rs17301935(T,A); rs17301963(G,A); rs17301991(C,T); rs73534057(T,C); rs12542288(C,T); rs1074927(C,T); rs10097077(C,A); rs112754577(G,C); rs73534064(C,T); rs28691256(G,A); rs34536602(C,T); rs147717735(T,C); rs73534069(T,C); rs111620179(C,G); rs10503497(A,C); rs13268716(T,A); rs13258084(G,A); rs77278710(G,A); rs13261862(A,C); rs7837188(C,T); rs13262171(A,G); rs373990829(C,T); rs6989578(A,C); rs13268559(C,T); rs7840953(C,T); rs7828138(T,A); rs7841248(C,T); rs10503498(C,G); rs78848478(G,C); rs13270590(A,C); rs13271129(A,C); rs10098344(T,C); rs138095527(G,C); rs11995597(T,C); rs34805259(C,T); rs2898391(G,A); rs191283190(A,T); rs4375000(T,A); rs149853503(A,C); rs58760181(G,C); rs7815232(G,A); rs9657238(C,T); rs200690033(C,T); rs67240866(A,T); rs150178380(A,G); rs17242772(A,G); rs1903600(A,G); rs1903601(T,A); rs1903602(A,G); rs728845(A,G); rs17242877(A,G); rs898830(C,A); rs898831(A,G); rs6994805(G,T); rs898832(G,T); rs62499686(T,C); rs62499687(C,A); rs56182559(C,G); rs10086450(T,A); rs35716509(C,T); rs62499689(G,A); rs73188350(G,A); rs75822410(C,A); rs7013302(T,C); rs7013916(T,C); rs182039410(G,A); rs13263532(C,G); rs7009959(A,T); rs13272449(T,C); rs117297642(T,C); rs10095571(C,T); rs113923660(C,T); rs10095706(C,T); rs62499690(A,G); rs10095822(C,A); rs62499691(T,C); rs28743113(T,G); rs73188352(G,T); rs62499692(G,A); rs62499693(A,G); rs28660686(G,A); rs13282800(T,C); rs6986126(T,G); rs10099187(G,C); rs67934334(G,A); rs73188359(C,G); rs10092714(T,C); rs10103337(C,T); rs13265496(T,C); rs13266385(T,A); rs73188360(A,G); rs10090509(A,G); rs62499696(G,C); rs62499697(T,C); rs6530776(C,T); rs7827191(T,C); rs34470669(T,C); rs55862954(G,C); rs75745560(G,A); rs28700027(A,T); rs115617038(T,A); rs28710257(A,T); rs2035140(G,C); rs2035141(A,T); rs2035142(A,C); rs74438849(A,C); rs11786651(A,T); rs4644256(G,A); rs4588854(T,C); rs201347641(G,A); rs199911877(T,C); rs191375099(G,A); rs184843773(G,A); rs188163772(C,T); rs34875064(T,C); rs10098701(G,A); rs79343197(G,A); rs10086381(A,C); rs111772564(C,T); rs12155579(T,C); rs144639824(G,A); rs190554682(T,C); rs115225945(C,G); rs11990724(C,T); rs7831470(T,C); rs35891990(G,C); rs62499702(G,T); rs10113331(G,A); rs13266701(G,A); rs78003005(T,G); rs74747242(C,T); rs34430367(T,C); rs11787310(A,C); rs11774367(T,C); rs11776773(G,A); rs75474223(C,T); rs11203610(C,T); rs11774440(T,C); rs7812923(A,G); rs78723968(A,G); rs11784763(C,T); rs75459547(T,A); rs55739808(G,A); rs28491021(T,C); rs13261193(G,T); rs77254648(A,G); rs55704353(T,C); rs10105771(G,C); rs1551810(A,G); rs1551811(G,C); rs1551812(C,T); rs56340810(G,C); rs75312958(G,C); rs1037931(G,A); rs79955214(C,T); rs1020876(T,C); rs1037932(T,C); rs2169424(A,C); rs7813614(C,T); rs1461883(C,G); rs11984635(C,T); rs11989070(T,G); rs75417688(A,G); rs1870817(G,A); rs10089641(G,T); rs80020387(C,A); rs7830759(G,A); rs7830888(G,C); rs77719852(A,C); rs10094152(T,G); rs10104220(G,C); rs111544068(G,C); rs73519306(A,C); rs11775369(A,T); rs11775370(A,C); rs60025935(G,C); rs75891256(G,A); rs60285615(C,T); rs73519321(G,C); rs6651380(T,C); rs6530778(A,G); rs6651381(G,A); rs113133714(C,T); rs112293197(G,T); rs140895985(G,C); rs59490599(A,G); rs11779847(T,C); rs34946059(A,G); rs76186723(T,C); rs4831589(C,G); rs146224118(C,A); rs4831590(G,A); rs184140419(A,C); rs112536386(C,T); rs1841647(T,C); rs1461874(G,A); rs11203611(C,T); rs62499708(C,T); rs12548390(G,T); rs67433011(A,G); rs76156361(A,G); rs62499710(C,G); rs115033025(T,G); rs1903597(A,C); rs78608265(G,C); rs10109051(C,T); rs73188273(A,G); rs114799977(C,T); rs80213888(A,C); rs56954908(T,C); rs10113093(T,G); rs55981406(T,C); rs150457727(T,C); rs115834425(A,G); rs60315311(T,C); rs143728551(T,C); rs11996820(G,C); rs10097226(T,A); rs7016159(C,T); rs7016319(C,A); rs10110727(G,A); rs76065829(T,G); rs28624787(T,C); rs59918016(T,C); rs13251391(C,T); rs60987655(G,C); rs7815726(C,A); rs7815841(C,G); rs7816029(C,T); rs58633223(T,C); rs10108848(T,C); rs11203612(T,C); rs4831596(G,A); rs56162446(A,T); rs28714234(T,C); rs139403226(A,G); rs112964481(A,T); rs77745730(G,C); rs142580724(A,G); rs4831597(A,G); rs6982219(A,C); rs73525341(A,G); rs4831598(G,T); rs79483783(T,G); rs74641376(A,T); rs62499724(C,A); rs10100614(A,G); rs10086326(C,T); rs11996163(T,C); rs75377847(T,G); rs10107476(T,A); rs143449136(G,A); rs138079978(G,A); rs112022642(C,G); rs10107802(T,C); rs7819092(C,T); rs7836965(A,C); rs56945239(T,C); rs10108297(T,C); rs7841037(T,C); rs7841326(A,G); rs76947118(T,A); rs58641124(G,T); rs79873583(T,C); rs62499725(T,C); rs75019460(G,A); rs2126320(G,A); rs78765458(C,T); rs144932231(T,A); rs11988285(G,A); rs11985809(T,A); rs67293780(A,G); rs11995726(C,A); rs7003662(G,A); rs80087557(T,G); rs76342559(T,A); rs7008372(G,A); rs76205407(T,C); rs28499026(T,C); rs79339612(G,A); rs115430684(C,T); rs62499726(A,C); rs62499727(A,C); rs73188287(A,C); rs62499728(G,A); rs62499729(C,T); rs67918892(T,C); rs28654784(G,T); rs7842935(G,A); rs7834728(T,C); rs7813756(C,G); rs7831561(A,G); rs7831696(A,C); rs10089540(C,G); rs6530780(A,T); rs2035144(C,G); rs12677673(T,C); rs2169422(A,G); rs28538505(T,C); rs6983449(A,G); rs3985616(A,G); rs4270967(C,T); rs3848990(G,A); rs3848991(G,A); rs3848992(G,A); rs3848993(G,A); rs12543647(G,T); rs77375689(A,G); rs5023504(G,T); rs5023503(A,G); rs142448858(T,C); rs5023502(C,G); rs12549206(C,T); rs12544228(G,C); rs12549209(C,T); rs11203613(G,A); rs181514113(A,G); rs11203614(A,T); rs11203615(C,T); rs1531424(C,T); rs114972820(G,C); rs13267243(G,A); rs13267537(G,A); rs13267830(G,A); rs13271051(A,G); rs36077823(T,G); rs11986904(A,G); rs13270616(C,T); rs11986930(A,G); rs11987681(T,A); rs150982954(T,C); rs11987708(T,C); rs13279691(T,C); rs11990163(G,T); rs13269368(G,A); rs145972868(T,C); rs13280185(T,C); rs13272869(A,T); rs28568420(C,T); rs13272164(C,G); rs7841626(G,A); rs7833207(T,C); rs7829742(A,G); rs7845380(G,A); rs7846404(C,T); rs7830173(A,C); rs1531423(A,T); rs7812596(C,A); rs60322664(C,T); rs76580857(G,A); rs13254391(C,A); rs17119369(G,A); rs59354220(C,T); rs62498361(G,T); rs6989351(G,A); rs11779752(T,C); rs78306142(C,G); rs28742279(C,T); rs73190212(C,G); rs34382583(A,G); rs62498371(C,T); rs6988078(T,C); rs17303140(T,G); rs7006747(C,T); rs7005685(G,A); rs11203616(G,A); rs7836622(C,T); rs11785159(G,A); rs115023733(T,C); rs7823803(T,G); rs1158040(G,A); rs17119389(A,G); rs17119392(A,T); rs62498372(T,C); rs1542503(T,C); rs36088270(A,G); rs62498374(A,C); rs13259013(G,A); rs17119404(C,T); rs7009025(A,G); rs12677421(A,G); rs10091423(G,C); rs73190226(G,C); rs17119415(C,G); rs9694622(A,G); rs7018156(T,C); rs6994616(C,G); rs11993846(G,A); rs1381411(T,G); rs6994436(G,T); rs112420755(A,T); rs11203617(C,T); rs13280856(G,T); rs76167677(T,G); rs75068931(G,A); rs12679497(T,A); rs77837450(A,C); rs13257456(A,G); rs7834116(G,A); rs73664365(C,G); rs77378117(G,C); rs1947709(C,A); rs75013314(G,A); rs7010413(C,T); rs7009793(G,A); rs4831296(C,T); rs72607311(G,A); rs75852792(A,T); rs768339(G,A); rs1350871(G,T); rs1381415(A,T); rs7016332(C,G); rs7015187(G,A); rs76109831(T,C); rs6530781(T,C); rs6530782(C,T); rs7016826(C,T); rs11991116(C,T); rs183347240(C,T); rs7836501(T,A); rs80040115(A,T); rs7815009(C,T); rs13251062(C,T); rs1350872(A,G); rs36037695(T,C); rs13252317(C,T); rs73664366(A,T); rs13262626(A,G); rs56272865(T,C); rs13259825(G,A); rs79226016(T,C); rs56038915(A,C); rs1461875(T,C); rs1947706(G,C); rs1947707(A,G); rs7829560(C,A); rs79498921(T,C); rs7829721(C,T); rs7828975(G,A); rs73190240(G,A); rs1531422(A,T); rs75359920(G,A); rs55677382(C,G); rs2126323(A,G); rs2126324(C,T); rs2126325(T,C); rs73190244(C,T); rs11787319(G,C); rs62498387(C,T); rs28858073(T,C); rs116496261(C,T); rs10113798(G,A); rs10088958(G,A); rs192499302(G,C); rs75443063(T,C); rs62498388(G,T); rs74973474(T,G); rs76870448(C,A); rs12675036(G,C); rs75831670(C,G); rs12679716(C,A); rs12682277(T,C); rs12675509(G,A); rs17119486(T,C); rs140381664(G,A); rs10094764(C,T); rs13270111(C,T); rs10098266(C,T); rs6984208(T,A); rs62498389(C,T); rs12386824(G,C); rs62498390(G,C); rs12386790(T,G); rs12386825(G,A); rs12386937(C,T); rs10216405(A,G); rs75789045(C,A); rs10216809(C,T); rs79669739(G,A); rs10095577(T,C); rs10105424(G,C); rs143732270(T,C); rs4831600(T,C); rs4831297(T,C); rs114375747(G,A); rs4831298(C,G); rs898829(C,T); rs10216705(T,C); rs1461880(A,T); rs1461879(A,T); rs28608857(A,G); rs28493084(A,G); rs1461878(G,A); rs1461877(G,T); rs1461876(C,T); rs28387675(G,C); rs28449970(G,C); rs28654177(C,T); rs9657239(C,T); rs744032(A,G); rs9657240(G,A); rs17119516(T,C); rs73664368(T,A); rs1993762(T,C); rs10088928(G,C); rs28558178(T,C); rs11989301(A,G); rs78991522(A,G); rs28572496(A,G); rs62498392(A,C); rs6530783(T,C); rs2054359(G,T); rs2054358(C,A); rs76432031(C,T); rs2054357(T,C); rs7823243(T,C); rs10094262(T,C); rs12677133(G,A); rs12681441(C,G); rs12056456(T,C); rs1350874(T,C); rs75846721(G,C); rs10046684(T,G); rs10046658(A,G); rs1350873(G,A); rs10046763(C,T); rs35069741(T,C); rs12386977(C,T); rs113564123(T,C); rs201297551(G,A); rs67519813(C,T); rs17119525(C,T); rs12676913(T,A); rs10448133(A,G); rs76146348(A,G); rs9657207(T,G); rs116412276(A,G); rs28687904(G,T); rs79199957(A,G); rs56368848(T,G); rs17119539(G,A); rs76903114(T,C); rs185486652(A,G); rs10106919(A,T); rs12545261(T,C); rs17305130(A,G); rs10110025(T,G); rs7839802(A,G); rs13273898(T,A); rs75540040(G,T); rs2169425(C,T); rs2126326(G,A); rs12678069(A,T); rs10113541(T,G); rs17334533(A,G); rs34305869(G,A); rs4831601(T,C); rs145311325(C,T); rs73190265(T,A); rs80036626(C,T); rs4517122(G,C); rs17119601(G,T); rs145735515(C,G); rs75241959(A,C); rs182522715(G,C); rs9325711(T,A); rs116193443(T,C); rs7836262(C,T); rs17119609(A,G); rs10091251(A,G); rs10094460(T,A); rs78677914(T,C); rs13259015(G,A); rs116370483(A,G); rs17119616(G,A); rs73531020(A,C); rs10091067(C,T); rs150775396(T,C); rs11990349(T,C); rs62498398(C,G); rs62498399(T,A); rs11203618(G,C); rs10888089(C,G); rs7846308(T,A); rs11203619(A,G); rs150022599(T,C); rs7812643(T,G); rs75205927(C,T); rs74938468(T,C); rs76637760(A,G); rs2169421(A,C); rs114879225(C,T); rs10098871(G,T); rs74379819(A,G); rs28759255(T,C); rs1461867(G,A); rs17119628(G,A); rs7827204(T,C); rs10106807(G,C); rs1461866(A,C); rs9325712(C,A); rs7011834(C,A); rs75361355(T,A); rs17119646(T,A); rs74699803(T,C); rs150073279(T,G); rs17119648(C,G); rs17119650(G,C); rs1461865(T,C); rs77968902(T,C); rs115743119(C,G); rs1461863(C,G); rs76880293(C,T); rs1461861(T,C); rs1461860(T,A); rs10104474(T,A); rs1381410(G,A); rs10503499(G,C); rs34599245(A,G); rs17119661(A,G); rs988891(C,T); rs17119664(A,T); rs988890(C,T); rs139556173(G,A); rs1461859(C,A); rs1461858(C,A); rs17119669(T,C); rs147800566(C,G); rs143458541(C,G); rs10112934(T,A); rs11786628(A,T); rs10113046(T,G); rs13272775(C,T); rs11987549(G,T); rs11987553(G,C); rs1461857(T,A); rs1461856(G,A); rs1461855(T,A); rs10098953(G,C); rs11203620(C,T); rs11203621(T,C); rs10089289(G,C); rs12546558(G,A); rs11203622(T,C); rs12541731(C,T); rs989268(T,C); rs12544457(A,T); rs1461854(G,A); rs1903592(T,C); rs72607312(A,C); rs56107133(C,T); rs72607313(T,A); rs17119700(T,C); rs72607314(G,C); rs6993084(C,A); rs17119705(T,C); rs34094260(C,T); rs10111879(T,C); rs12542477(C,T); rs12545663(T,C); rs12545131(A,G); rs1461852(C,T); rs1461851(A,T); rs1461850(G,T); rs1381409(G,T); rs1381408(C,T); rs186739375(G,T); rs13280583(A,G); rs11987722(C,G); rs17119710(T,C); rs13279780(C,A); rs10097996(G,A); rs13254243(T,G); rs1461849(C,T); rs17247795(A,G); rs17119718(T,G); rs79058779(A,G); rs13254052(C,T); rs17119719(C,T); rs10101640(G,C); rs17119727(A,G); rs6986539(A,C); rs1461848(G,A); rs1461847(G,A); rs1461846(A,G); rs56161219(G,A); rs13272979(T,C); rs12335007(T,C); rs17119749(A,C); rs111909026(A,G); rs56779973(G,A); rs186000680(G,A); rs1461845(C,T); rs73531097(C,T); rs1350870(C,T); rs10888090(C,T); rs112734902(T,C); rs73531101(G,C); rs12547357(C,G); rs11203623(A,T); rs17119762(A,G); rs17119767(C,A); rs17119771(A,G); rs13271560(A,C); rs1037938(T,A); rs13275871(G,T); rs141685909(G,A); rs138344094(A,G); rs57557941(T,A); rs12680412(C,A); rs12676207(G,T); rs12155884(C,T); rs142158291(G,T); rs3988434(C,T); rs13280750(T,G); rs13281019(A,C); rs115457069(T,A); rs2410192(C,T); rs2410193(G,A); rs4831602(C,T); rs74707948(T,A); rs73533119(G,C); rs115455678(A,G); rs112621410(T,C); rs7010645(A,C); rs12547156(C,T); rs6990393(G,A); rs7822573(C,T); rs145236051(T,C); rs3848994(C,T); rs111338641(G,A); rs112008611(A,G); rs150493493(A,C); rs113888457(A,G); rs146638260(C,A); rs13249395(T,C); rs6982795(T,A); rs143027088(T,A); rs75166602(G,T); rs61111321(A,G); rs3848995(C,G); rs35321922(T,G); rs141463266(G,A); rs9325715(A,G); rs35648707(T,A); rs9657242(A,G); rs115317198(T,G); rs73533129(C,A); rs12542568(T,C); rs73533132(T,C); rs12542565(A,G); rs2614934(A,T); rs2614935(A,C); rs2665614(C,T); rs2665613(C,G); rs13253156(T,G); rs13281154(A,G); rs56367836(T,A); rs114013212(T,G); rs144566947(C,T); rs2614936(C,G); rs67971905(C,A); rs825905(C,A); rs825906(G,T); rs35473337(T,C); rs12549054(C,T); rs10090479(A,G); rs113213706(A,C); rs58744692(G,C); rs861141(G,A); rs825907(C,A); rs77248333(T,C); rs825908(C,T); rs76856373(A,G); rs825909(G,A); rs825910(C,T); rs825911(G,C); rs28461743(A,G); rs825912(G,A); rs1903596(T,C); rs76569920(T,G); rs6989884(C,T); rs78281298(G,C); rs1848884(C,A); rs34910548(A,G); rs1095402(C,T); rs12375353(A,G); rs1095403(A,G); rs2410194(A,G); rs2410195(G,A); rs79422815(T,C); rs77143007(T,G); rs17119785(G,A); rs2175280(T,A); rs59299000(T,G); rs12680094(T,C); rs1510428(A,G); rs1510429(C,T); rs114334761(T,C); rs17308752(G,A); rs146392029(T,A); rs13266948(G,A); rs11990300(A,G); rs7824260(C,T); rs10503500(T,G); rs4831605(G,A); rs6998355(G,A); rs12546390(T,C); rs10046619(A,C); rs1510430(G,A); rs79709195(A,T); rs13265072(A,C); rs1510431(A,G); rs6996623(A,G); rs7001161(T,A); rs12682064(G,A); rs116915092(T,G); rs67473342(C,G); rs7001373(A,G); rs6981895(C,T); rs7831516(A,T); rs72496289(A,T); rs10100882(A,T); rs114159126(A,C); rs7832223(A,G); rs111971316(A,C); rs142150711(T,G); rs62498432(C,T); rs140016928(C,A); rs1553831(C,T); rs1510432(G,A); rs11203629(G,C); rs10503501(G,A); rs10503502(C,T); rs4484700(C,T); rs10109655(C,A); rs1912470(C,T); rs78504150(G,A); rs78706969(G,A); rs10089396(C,G); rs62498435(C,T); rs62498436(G,C); rs75965441(G,A); rs28406832(A,C); rs17249839(G,A); rs67307558(G,A); rs13274454(G,T); rs7831506(C,G); rs74340342(C,A); rs76290120(A,G); rs68069632(T,C); rs62498437(C,T); rs13267760(T,C); rs78401410(G,C); rs181075043(A,G); rs76173729(T,G); rs146143059(C,T); rs1463994(C,G); rs1463995(A,C); rs1463996(G,A); rs4831607(G,T); rs35636760(G,A); rs10102862(T,C); rs112653332(A,G); rs76676156(T,G); rs62498440(G,C); rs7009623(T,C); rs4240169(A,C); rs62498441(C,A); rs6985599(T,G); rs13256433(T,C); rs35543636(G,A); rs75793564(T,C); rs10086627(A,C); rs10100338(C,T); rs17250357(A,G); rs55942432(T,G); rs6984291(C,T); rs10086949(G,T); rs73192366(T,A); rs9325716(A,G); rs7013654(T,G); rs28415920(G,A); rs188989966(C,G); rs10094685(G,T); rs10109950(A,G); rs10109958(A,G); rs10095644(C,T); rs10110210(A,C); rs73192369(A,C); rs117475932(G,A); rs28538641(T,A); rs11203633(G,T); rs10092607(T,C); rs80353218(A,T); rs74512756(T,C); rs59619928(T,C); rs10104442(A,T); rs79929956(A,G); rs2036825(G,A); rs938013(C,T); rs146517568(C,A); rs2036826(T,C); rs10108368(A,G); rs10094091(C,T); rs1510424(A,G); rs7845451(T,G); rs10093701(G,C); rs7845609(T,A); rs28655364(C,T); rs28415925(A,T); rs7842466(A,C); rs79846716(A,G); rs17250457(T,C); rs28508512(G,A); rs17119866(C,T); rs1510425(A,T); rs28537565(A,G); rs7829099(C,T); rs7815975(T,C); rs1912469(T,C); rs6530789(T,G); rs10101170(G,A); rs146215452(G,A); rs11781336(A,C); rs73517251(A,G); rs67116586(C,A); rs2175277(G,A); rs10101639(G,A); rs13263619(T,G); rs10453158(A,G); rs9325717(C,T); rs192740375(G,A); rs142156070(A,G); rs17250568(A,G); rs870615(T,C); rs870616(C,G); rs10093170(A,G); rs10106070(G,A); rs34194674(G,T); rs17119873(C,G); rs73517264(G,A); rs10096569(A,G); rs73517271(A,T); rs870792(T,C); rs35868129(C,A); rs35876910(C,T); rs28540285(A,G); rs28453712(T,C); rs78347530(G,T); rs28758487(T,A); rs68194488(A,G); rs2410198(C,A); rs2410199(C,A); rs71524131(G,A); rs76210955(T,C); rs7007355(A,G); rs2898392(T,A); rs7007954(A,G); rs62494839(C,T); rs9657243(C,G); rs28729891(C,G); rs28626237(C,T); rs73664404(C,G); rs28712813(G,C); rs35277779(C,T); rs56654885(G,A); rs58232618(G,T); rs75106626(C,G); rs73664405(T,C); rs112691980(A,G); rs13253002(T,A); rs1510426(A,T); rs7005072(T,C); rs2175278(G,T); rs17250763(A,G); rs2136727(G,C); rs62494842(C,T); rs2175279(C,G); rs79903542(A,G); rs10092408(C,G); rs17310163(A,G); rs11997822(T,C); rs17310177(T,C); rs62494843(C,T); rs73194110(G,A); rs117693694(C,T); rs62494844(T,A); rs73664406(T,C); rs1355300(C,G); rs1355301(G,T); rs1355302(T,A); rs1355303(G,A); rs7465427(A,T); rs10096433(G,T); rs1397279(T,C); rs56163244(T,C); rs10096729(G,A); rs12675018(T,C); rs79683061(T,C); rs11203635(A,C); rs17251054(A,T); rs7815367(A,G); rs12675129(T,C); rs114046115(T,C); rs4831609(C,T); rs4240170(T,G); rs4240171(T,C); rs4831610(C,T); rs4240172(G,A); rs4240173(T,C); rs4289812(G,T); rs12542406(T,C); rs4623425(A,G); rs34925040(T,C); rs7837164(C,T); rs4831611(G,A); rs4831612(C,T); rs4831613(A,T); rs4831614(C,T); rs4831615(G,T); rs4831616(T,C); rs73664408(A,T); rs144871056(C,T); rs11203636(C,G); rs11203637(T,C); rs72607315(G,C); rs11203638(G,A); rs11203642(G,C); rs1510448(A,T); rs1510447(C,G); rs10088391(C,T); rs13254180(C,T); rs62493061(T,A); rs10103217(A,G); rs10088748(C,A); rs4831299(T,C); rs112625828(G,T); rs10088409(G,A); rs11203643(T,C); rs11203644(G,A); rs8180890(A,T); rs12676368(G,T); rs2136729(G,T); rs8180903(A,G); rs8180904(A,G); rs7010545(C,G); rs73194127(G,T); rs7009853(G,T); rs7011191(C,T); rs1355305(C,T); rs1355304(A,G); rs12056560(G,T); rs6997714(T,C); rs10888091(G,T); rs12056497(T,C); rs12155755(T,C); rs35885558(G,T); rs11203645(A,G); rs13277667(C,T); rs13277681(C,T); rs2221763(G,C); rs192280017(C,T); rs13278587(C,T); rs2202989(G,T); rs4831618(C,T); rs4831619(G,A); rs4831620(G,A); rs4831621(C,G); rs73194137(G,A); rs4831622(A,G); rs1397296(C,T); rs13260601(C,T); rs1397295(C,T); rs1397294(G,C); rs10109020(T,C); rs13260069(G,A); rs12216725(C,T); rs10091736(C,A); rs12547358(G,A); rs12547411(G,C); rs13280211(T,C); rs9643920(C,T); rs6995144(C,T); rs11203646(G,C); rs6981363(A,C); rs6981703(A,T); rs2202988(G,T); rs140389667(G,A); rs2202986(C,G); rs139009551(A,G); rs151111285(A,G); rs113889210(G,A); rs79842900(G,A); rs79387194(T,C); rs13257952(C,G); rs10283268(T,G); rs13258861(C,T); rs115101487(G,C); rs376293864(G,C); rs1397280(C,T); rs1397281(A,C); rs11993407(G,A); rs28660541(T,A); rs7461463(C,T); rs114424387(C,A); rs1397282(G,A); rs13269454(C,T); rs115035614(A,T); rs1397283(A,C); rs1397284(G,A); rs1397285(T,C); rs1397286(T,C); rs36102325(C,A); rs117658421(A,G); rs7004259(C,T); rs6989771(T,C); rs73188107(C,A); rs17251320(G,T); rs28535487(T,G); rs1397287(T,C); rs28624754(G,A); rs73188109(G,A); rs28649806(C,T); rs35853761(A,G); rs115334197(G,T); rs73664410(G,A); rs10108935(G,A); rs55868415(C,T); rs2410200(T,G); rs12680631(T,A); rs1510434(G,C); rs1510435(C,T); rs1877012(C,A); rs201571031(A,C); rs75607907(T,C); rs28571982(G,A); rs28673941(A,T); rs10092760(G,A); rs79142914(T,C); rs10108196(A,G); rs73664414(T,C); rs117638587(A,T); rs115927932(G,A); rs146196002(C,T); rs1912471(G,A); rs1912472(G,A); rs7845268(T,G); rs7823106(G,C); rs190213053(A,T); rs181762735(T,C); rs1510436(A,T); rs6530791(G,T); rs112536033(C,T); rs73664415(T,C); rs28375265(A,T); rs1877014(A,T); rs1877015(A,T); rs7814453(T,G); rs1877016(G,A); rs1877017(C,G); rs1877018(G,A); rs73664416(T,G); rs4831300(C,G); rs4831624(A,G); rs4831301(C,A); rs56783085(C,A); rs7831034(G,C); rs73664417(T,C); rs1877019(T,G); rs1877020(A,T); rs1877021(A,T); rs7816052(A,G); rs78300015(C,T); rs12544441(C,T); rs12544458(C,A); rs12547518(T,C); rs13270975(A,T); rs10503503(A,G); rs13268099(G,A); rs1510437(C,T); rs116759360(T,G); rs1588436(A,C); rs56083306(T,C); rs1588437(G,T); rs143604103(T,C); rs1397288(T,C); rs148322463(C,A); rs113829350(A,G); rs117176474(G,A); rs13280296(G,A); rs113114360(T,C); rs184544147(T,C); rs12681609(T,C); rs112924295(A,T); rs11985140(G,T); rs12176636(A,G); rs115127205(T,C); rs73521683(C,A); rs2175281(T,C); rs1463997(G,T); rs1510440(G,C); rs1510441(T,A); rs72607317(T,A); rs4495427(T,C); rs1397289(C,T); rs1397290(T,C); rs117842264(A,G); rs60943198(C,T); rs78883306(T,C); rs1397291(T,C); rs72607319(C,A); rs148123133(T,C); rs10107731(G,C); rs17119934(A,G); rs72607320(A,G); rs142205004(A,G); rs58491597(G,T); rs13276038(G,C); rs75113740(C,T); rs78992693(C,A); rs57490436(C,A); rs964338(C,T); rs964337(A,G); rs964336(C,T); rs964335(C,G); rs10087408(C,A); rs6651373(A,G); rs60911465(C,A); rs11781218(C,A); rs78039495(C,A); rs72607321(T,C); rs72607322(G,C); rs72607323(G,C); rs72607324(A,T); rs2202985(C,A); rs150040272(C,T); rs72607325(C,T); rs79252636(C,G); rs28493981(C,T); rs72607326(A,G); rs61423120(G,A); rs4831628(A,G); rs74566451(A,G); rs190907807(G,C); rs17317521(C,G); rs74872035(T,G); rs1510442(T,C); rs1510443(C,T); rs7812889(T,C); rs7843671(A,G); rs1031051(T,C); rs12334464(G,A); rs118053402(T,G); rs1031050(C,T); rs1031049(T,C); rs1473002(C,T); rs1553828(A,C); rs35931805(T,G); rs1858247(C,T); rs13257353(A,G); rs12675449(T,C); rs12681143(C,T); rs73664421(C,T); rs1397292(A,C); rs190614929(G,A); rs28722739(T,C); rs12155595(A,C); rs12542237(T,G); rs12549061(C,T); rs12541692(A,G); rs1397293(G,C); rs78174770(G,A); rs75517618(A,G); rs118000576(T,A); rs141015346(C,A); rs56686309(G,C); rs1470201(T,C); rs113708118(A,C); rs1470200(G,C); rs1470199(A,G); rs1470198(C,A); rs4831630(A,G); rs60153070(G,C); rs10111399(C,T); rs17119939(T,A); rs56126103(G,C); rs72607330(G,A); rs7017407(C,A); rs57739051(C,G); rs117728786(A,C); rs13259984(T,G); rs7003341(A,G); rs117475070(G,A); rs7814372(G,A); rs7836928(T,C); rs34040031(G,C); rs35377854(G,A); rs17252297(G,T); rs7815663(C,A); rs7814658(G,A); rs12546155(G,A); rs6530792(A,G); rs6530793(A,C); rs6530794(T,C); rs10503504(A,G); rs73188152(C,T); rs10097358(G,C); rs77614214(C,A); rs13278643(C,T); rs13252442(T,A); rs118026587(T,G); rs10098420(C,G); rs7816089(T,C); rs115746105(A,G); rs7812485(A,T); rs115130842(A,G); rs7828429(G,C); rs7816496(T,C); rs114744523(A,C); rs36005535(C,A); rs35461573(G,T); rs143713422(T,G); rs56198876(A,G); rs10503505(T,C); rs34638324(A,T); rs33977854(G,A); rs1020227(C,T); rs117580985(G,A); rs7003856(G,A); rs60496611(G,A); rs1020226(G,T); rs147100812(T,G); rs11776399(T,C); rs13265711(C,T); rs10503506(A,G); rs4831631(C,G); rs73664427(A,G); rs147116869(G,A); rs73200885(T,C); rs58947477(A,G); rs10113307(G,C); rs11778242(T,C); rs6982610(C,A); rs10113669(G,C); rs13249873(C,T); rs9987304(T,C); rs77872389(C,A); rs11984711(C,T); rs73200887(G,A); rs12544938(T,A); rs11203647(C,T); rs17119940(A,C); rs987387(T,C); rs7012607(A,G); rs2083657(G,T); rs6994067(C,T); rs28545354(A,G); rs10087225(T,G); rs10097072(G,C); rs7828659(C,T); rs2053491(G,A); rs2053489(T,C); rs17119954(C,T); rs116557237(T,C); rs11203648(C,G); rs11203649(T,C); rs11203650(T,G); rs11988683(C,T); rs1899368(A,T); rs1510444(G,A); rs4831632(A,T); rs12216821(T,G); rs11996622(G,A); rs7008625(G,A); rs17119956(T,A); rs11203651(G,A); rs11989735(T,C); rs10503507(C,A); rs12541555(C,A); rs10503508(G,C); rs12544291(A,C); rs11203652(T,C); rs7014730(T,C); rs985348(A,G); rs113246647(G,A); rs12216811(G,A); rs7826031(G,C); rs11203653(T,C); rs17119972(C,A); rs2053493(T,G); rs7827059(G,T); rs13439026(C,T); rs7815018(A,G); rs148717494(A,G); rs7815426(A,G); rs17119984(C,T); rs7819355(T,A); rs7832622(C,T); rs6984678(A,G); rs6988773(T,A); rs17119987(A,T); rs1510445(G,C); rs1510446(T,C); rs115978622(T,C); rs73664428(T,G); rs10503509(T,A); rs13270646(T,C); rs183863578(T,C); rs10503510(C,T); rs10503511(G,A); rs11990504(C,T); rs7846232(C,T); rs7846360(C,T); rs113307447(A,G); rs11991331(C,T); rs11991362(C,T); rs11995787(T,G); rs111990185(G,A); rs7830848(A,T); rs17120008(C,T); rs7817298(C,T); rs12549522(T,A); rs113766316(G,A); rs7838778(T,C); rs7835796(A,G); rs10104062(A,T); rs76447560(C,T); rs56127547(T,A); rs200075542(C,T); rs9325721(T,C); rs143280260(T,G); rs11203654(A,G); rs11203655(G,C); rs11203656(A,G); rs11203657(G,A); rs13273014(G,C); rs11203658(C,A); rs10097067(C,G); rs9325722(T,G); rs9325723(G,A); rs9325724(G,C); rs9325725(C,T); rs6996024(G,A); rs6992692(A,T); rs6992725(A,G); rs370743992(C,A); rs4144411(C,T); rs4144410(C,T); rs9325726(T,C); rs10097849(T,G); rs1877010(A,C); rs1877009(A,G); rs9657244(T,A); rs9657208(A,C); rs9657209(A,G); rs9657210(T,G); rs11203659(T,C); rs11203660(G,A); rs12681397(T,C); rs10087537(C,A); rs12674587(G,T); rs12674600(G,C); rs58191109(T,G); rs12680975(A,T); rs61694075(T,C); rs11203661(C,T); rs111409717(A,C); rs11203662(G,A); rs1441942(G,A); rs1441941(G,A); rs113227685(C,T); rs113626658(G,A); rs68073858(G,A); rs113844443(A,C); rs10109111(T,C); rs73202814(C,A); rs59271374(C,T); rs1546485(A,T); rs111418175(A,G); rs1510449(G,C); rs113446682(C,G); rs111690474(C,T); rs12550695(T,C); rs62493126(A,G); rs35194664(C,T); rs112819867(C,T); rs9325727(A,G); rs113187935(A,C); rs371793207(A,G); rs10099551(C,G); rs187392023(A,G); rs10098745(G,A); rs112884020(T,C); rs113429368(T,C); rs10888093(A,G); rs12675427(T,C); rs150498574(A,G); rs111931323(A,G); rs113902160(G,A); rs111689988(T,C); rs112280765(G,A); rs113145579(G,A); rs9643983(A,C); rs4831302(A,G); rs7005439(G,A); rs6988258(A,G); rs36070845(C,G); rs1441937(C,A); rs112528418(C,T); rs117855017(G,A); rs112278082(A,G); rs6992810(A,C); rs28788561(T,C); rs11203663(G,A); rs185031639(T,C); rs138567716(T,C); rs72607333(C,A); rs72607334(T,C); rs76262215(T,C); rs79447451(G,C); rs11988305(T,C); rs11988333(T,C); rs28813190(A,C); rs28812503(T,C); rs7844337(G,A); rs28433505(C,T); rs28437397(G,A); rs28413745(C,T); rs148184345(G,A); rs28417805(A,G); rs60496793(C,G); rs28478773(A,G); rs188498081(C,T); rs28462260(G,A); rs7836644(T,C); rs28536746(C,T); rs28433283(T,A); rs28583952(G,A); rs12546111(G,A); rs11777809(A,G); rs966334(G,T); rs74659712(A,G); rs147742417(A,T); rs966335(C,G); rs10098099(C,A); rs4831633(T,C); rs4831634(G,A); rs9325728(T,C); rs9325729(C,T); rs4831635(A,T); rs4831636(C,T); rs9918824(C,T); rs9918743(T,C); rs11987535(G,A); rs1814140(C,T); rs1814141(G,C); rs11988376(G,A); rs1814142(T,C); rs11203665(G,A); rs12548883(C,G); rs17120041(T,C); rs373250871(C,A); rs118049437(T,C); rs142353335(A,T); rs993234(C,G); rs1510450(A,G); rs4831637(T,C); rs148218172(C,T); rs17320272(C,T); rs62493145(C,T); rs117018240(G,A); rs62493147(G,T); rs1899366(T,G); rs2197106(A,G); rs144868748(T,C); rs35685176(A,G); rs10113182(G,T); rs920613(C,T); rs2898396(A,G); rs920614(C,T); rs147276611(C,T); rs920615(C,T); rs920616(A,C); rs74721669(G,A); rs28654876(C,A); rs6987164(C,T); rs139868043(T,C); rs2410208(A,C); rs6984821(A,G); rs79808100(A,G); rs6989198(T,G); rs10088482(A,G); rs6985612(A,G); rs73664431(A,G); rs1510453(A,G); rs10101674(G,C); rs6985928(A,G); rs10503512(T,C); rs17267649(A,G); rs2119737(G,C); rs183539154(G,A); rs7009785(T,C); rs11986159(C,T); rs11989868(A,C); rs11990657(T,A); rs17120076(T,G); rs2197107(T,G); rs1397297(A,G); rs62493149(T,C); rs62493150(A,G); rs73527548(G,C); rs80265466(T,G); rs13282394(G,T); rs4831639(T,G); rs17268076(C,G); rs1510454(A,T); rs17268124(C,T); rs1510455(T,C); rs369026163(T,A); rs12544512(C,G); rs7836693(G,A); rs7837805(C,T); rs10503513(T,C); rs2055856(G,C); rs6999260(T,C); rs6999437(T,C); rs6995277(A,C); rs7017742(C,T); rs17321361(A,T); rs113980056(C,T); rs17268361(G,A); rs1348212(A,G); rs6991474(C,T); rs6991947(C,G); rs66752930(A,C); rs142692563(C,A); rs67200850(C,G); rs17340230(T,C); rs140837291(C,T); rs11998116(A,G); rs13266683(C,T); rs13266896(C,T); rs13275951(T,A); rs111371354(C,A); rs62495168(G,T); rs138224478(G,C); rs73527568(G,C); rs148342386(A,C); rs79440045(A,G); rs4548184(C,T); rs4831304(C,T); rs4831305(G,A); rs150267368(T,C); rs17321556(T,C); rs17321597(G,A); rs7009140(A,G); rs12675184(G,T); rs12681568(A,C); rs12681603(A,G); rs2119738(A,G); rs17321715(G,C); rs376423589(T,G); rs17116185(C,T); rs17116188(T,C); rs17116192(C,G); rs150319934(A,T); rs11987712(G,C); rs143847315(C,A); rs148196225(T,A); rs76547270(C,A); rs149798593(G,C); rs7010702(C,T); rs7009889(G,A); rs138513900(A,G); rs141560714(T,G); rs17322000(C,G); rs17322021(C,G); rs17120120(G,C); rs957607(C,T); rs957608(A,G); rs17322098(C,T); rs9643987(G,A); rs150859394(A,G); rs17322154(A,C); rs147744880(T,C); rs17120128(A,G); rs11990812(G,T); rs11987651(A,C); rs6983514(C,G); rs61030627(C,T); rs17120133(G,C); rs58111790(T,C); rs6984334(C,T); rs7018001(A,G); rs62495172(A,G); rs6980658(A,C); rs78322704(T,C); rs73527598(C,T); rs2246384(G,C); rs73527602(G,T); rs73529204(A,G); rs7833574(C,T); rs73664438(T,G); rs34835594(G,A); rs12681041(C,T); rs35730989(T,C); rs73529214(G,T); rs10106269(C,T); rs2036818(T,C); rs13262767(G,A); rs1031057(T,G); rs35976922(T,A); rs1031058(T,C); rs1031059(A,G); rs73664441(C,T); rs374864136(A,T); rs1972916(C,G); rs2036829(A,G); rs2036828(A,G); rs7814607(C,T); rs7007098(A,G); rs6987475(C,T); rs2249645(A,G); rs2249655(T,C); rs10105080(A,T); rs117806798(T,G); rs7822045(G,A); rs60432380(G,A); rs2249788(A,T); rs7822179(G,A); rs2249793(A,G); rs2249806(G,C); rs11991086(T,C); rs920617(G,A); rs920618(G,C); rs920620(G,A); rs13277639(C,A); rs13439643(G,A); rs7821142(A,T); rs2250166(T,C); rs62495175(C,T); rs34998243(G,A); rs2264525(C,T); rs2264040(G,A); rs2089750(T,C); rs2089749(G,C); rs2102516(T,A); rs2264044(G,A); rs2264526(A,T); rs2264045(G,A); rs4831307(A,G); rs58971793(C,T); rs61471953(A,T); rs2250285(C,T); rs75139979(G,A); rs58207973(C,A); rs76079150(T,G); rs73529243(A,G); rs2250371(C,G); rs7461133(C,G); rs148078641(A,G); rs1010894(G,A); rs1553829(T,G); rs2136728(G,C); rs186942155(G,T); rs2175282(A,G); rs28633118(A,G); rs2250506(G,A); rs1441938(G,A); rs1441939(A,G); rs2250521(T,C); rs2250532(G,A); rs111351188(T,C); rs79495215(T,C); rs2250542(C,T); rs2250650(C,A); rs187695738(C,G); rs1828389(G,A); rs191460903(T,C); rs1588438(C,A); rs2165591(C,T); rs2250782(G,C); rs77458824(A,T); rs1397299(T,C); rs73529254(C,T); rs73529256(G,A); rs73529257(C,A); rs115510494(A,G); rs35083121(G,A); rs34706549(G,C); rs78843535(T,G); rs34436652(T,C); rs113213971(G,C); rs2466921(G,T); rs35459555(T,C); rs2253890(C,A); rs60182964(T,C); rs73529264(C,G); rs13252608(G,A); rs150478892(A,G); rs6984341(G,C); rs77386634(G,C); rs2036819(G,C); rs2036820(C,A); rs60185304(C,T); rs2254052(G,C); rs13266207(A,G); rs73529270(G,A); rs13274423(T,G); rs80099998(G,A); rs6981585(T,C); rs73529273(T,G); rs2254162(A,T); rs370984467(C,G); rs2264855(A,C); rs9772730(C,T); rs2254183(G,A); rs60167334(C,T); rs61591110(A,T); rs2254300(C,A); rs11989568(T,C); rs2254310(T,A); rs1899365(A,G); rs10092386(C,T); rs73529286(T,G); rs61173547(A,G); rs894258(G,T); rs2036822(T,C); rs2036823(T,A); rs57852034(C,T); rs2036824(A,T); rs11203666(C,T); rs1510457(A,G); rs73529288(G,A); rs7004874(G,A); rs34542853(A,G); rs12544246(C,T); rs2254763(C,T); rs115523554(G,A); rs117367934(A,G); rs2254776(T,C); rs12216762(C,T); rs2175283(T,C); rs2243766(T,C); rs12216774(C,G); rs2136730(C,T); rs2136731(C,T); rs2264047(C,G); rs2264530(C,G); rs57365315(T,C); rs144658409(A,C); rs17120165(A,C); rs1073067(C,T); rs1073066(G,A); rs1073068(T,G); rs1073065(G,A); rs73529298(C,T); rs17120170(G,T); rs2243910(C,T); rs2243992(C,T); rs10105105(T,C); rs10087547(C,A); rs17120176(G,C); rs17120181(A,G); rs2244009(A,G); rs17120187(T,A); rs1858248(C,T); rs2244118(A,G); rs2244122(G,T); rs372880940(C,G); rs56370032(G,T); rs1510458(G,T); rs10503514(A,G); rs2244210(C,G); rs2244211(A,T); rs2244212(G,A); rs2244220(G,A); rs2244222(G,A); rs149573336(A,C); rs2244329(T,C); rs2055857(A,G); rs7010682(C,T); rs2244348(T,G); rs7010845(C,T); rs2244354(G,T); rs78663980(T,A); rs2244469(C,T); rs2244476(G,A); rs7001226(T,A); rs1397300(C,T); rs2165592(A,G); rs2053492(C,T); rs2244607(T,A); rs77569414(T,C); rs1510459(T,C); rs6988344(C,T); rs17120202(A,C); rs2244851(C,T); rs17120204(C,T); rs2119739(A,C); rs60874873(C,T); rs2247664(A,G); rs13252304(G,A); rs2247676(A,G); rs2247686(T,G); rs17120210(C,A); rs56306350(T,A); rs62493261(T,G); rs113003120(A,G); rs972017(C,T); rs972018(C,T); rs1000803(C,T); rs1000804(T,A); rs4403410(T,C); rs61041816(A,C); rs145158782(G,A); rs1965816(T,C); rs4282(T,A); rs73531142(G,C); rs969771(A,G); rs76357584(T,A); rs117497141(A,G); rs2248499(G,A); rs2248500(C,T); rs73531145(A,G); rs1866976(T,A); rs2248529(A,C); rs2251475(A,T); rs73531149(T,A); rs894259(C,A); rs1441943(T,C); rs6530802(C,T); rs2410210(A,G); rs2251590(A,C); rs56841247(G,T); rs59284518(C,T); rs2165593(C,T); rs2251610(T,C); rs2251611(T,C); rs7016109(T,G); rs1837874(G,A); rs62493272(T,C); rs1031048(G,A); rs73531158(G,C); rs73531159(C,T); rs2119741(T,C); rs2119742(T,C); rs181357827(A,T); rs726907(A,T); rs2252093(G,C); rs1441944(T,G); rs56106741(G,C); rs55962508(A,C); rs2165594(G,T); rs147236262(T,C); rs28367223(C,A); rs971383(G,A); rs971384(G,A); rs2252329(T,C); rs2252332(G,A); rs2252336(A,G); rs11781481(T,C); rs7822116(T,C); rs73531166(A,C); rs2252598(A,T); rs2439723(C,G); rs11783419(T,C); rs11779138(C,T); rs58675287(T,A); rs149635517(A,C); rs79284146(T,A); rs11994604(T,C); rs117408641(C,G); rs10110420(G,A); rs76163207(G,A); rs34665037(A,T); rs36049498(G,A); rs2255678(A,C); rs55782183(T,A); rs2255685(T,C); rs73531169(C,G); rs7836714(T,C); rs77368190(A,G); rs2255785(G,C); rs6530803(G,C); rs2255788(G,C); rs10105135(T,A); rs10105241(T,C); rs2255802(G,A); rs118020871(T,C); rs3860044(T,A); rs28408280(T,A); rs112139940(C,T); rs113552728(G,A); rs2255912(G,C); rs13272204(A,T); rs6980965(T,C); rs1031052(T,G); rs2256035(A,G); rs79852460(C,T); rs2256127(C,T); rs2256138(C,G); rs73531185(T,G); rs73664474(T,C); rs73531188(T,C); rs116378946(C,A); rs4831647(A,G); rs2256304(A,G); rs2256311(G,A); rs73531189(A,G); rs7831691(A,T); rs7835470(T,C); rs73531190(C,G); rs35582257(C,T); rs28533144(T,G); rs2256538(C,T); rs13257044(G,C); rs2256560(T,C); rs201938297(T,A); rs10046649(G,T); rs7841817(A,G); rs73531195(A,G); rs1031053(A,G); rs2256689(G,C); rs2256690(T,C); rs73531196(G,T); rs1899369(A,G); rs73201219(C,T); rs11994701(C,G); rs28566978(T,G); rs1992448(C,T); rs117274732(T,C); rs11987475(G,T); rs2252460(T,C); rs2252461(A,T); rs73201225(C,T); rs2252570(A,G); rs78650896(T,C); rs142724938(G,A); rs17343750(C,A); rs73531197(G,C); rs11989414(G,T); rs73531200(A,G); rs1441945(G,A); rs1441946(C,G); rs73531201(G,A); rs1441947(T,G); rs2252835(A,G); rs7843005(G,T); rs7846701(G,A); rs7812481(G,A); rs2252948(G,T); rs2197108(G,C); rs2253078(G,T); rs10788688(C,A); rs141774013(A,G); rs150597307(T,C); rs2253102(T,A); rs2253103(G,A); rs2253107(G,A); rs2253225(C,T); rs146243835(G,A); rs2253245(A,G); rs2253251(G,A); rs115551166(T,C); rs73533003(A,G); rs2253339(T,C); rs2253458(G,A); rs7829979(T,C); rs7826254(A,T); rs2253544(C,G); rs56137925(T,C); rs11991254(G,A); rs73533009(A,T); rs2253573(C,T); rs12155570(C,G); rs73533012(C,T); rs35077634(T,C); rs73533015(G,C); rs28526652(A,T); rs6990399(G,T); rs13275534(T,C); rs13272315(G,A); rs138535050(G,A); rs2256810(T,C); rs13276431(A,G); rs1899370(G,A); rs1899371(G,A); rs56337529(T,C); rs13257852(T,C); rs35922301(G,C); rs35646042(A,T); rs55915306(T,A); rs76826572(G,C); rs55780655(A,T); rs58210537(T,C); rs11989386(C,G); rs2257068(A,C); rs17120281(C,T); rs17120283(T,C); rs73664478(T,C); rs2251058(A,G); rs2255923(A,T); rs73533019(A,T); rs1441933(G,A); rs2726603(G,A); rs1441934(A,G); rs1441935(C,G); rs2243689(A,G); rs2243692(C,T); rs2264854(A,T); rs2264039(A,C); rs2243733(C,T); rs17120286(T,C); rs2246433(T,C); rs73533026(C,T); rs7010659(G,C); rs2264856(C,T); rs2119736(T,C); rs4831310(G,A); rs7845724(C,G); rs74366260(A,G); rs28690756(G,C); rs2246639(G,C); rs2246651(G,T); rs147618731(T,G); rs1441936(C,T); rs6984901(C,T); rs60624996(C,T); rs1372419(T,A); rs2246779(A,C); rs73533031(G,T); rs11785642(A,G); rs10090706(G,A); rs2246792(C,T); rs2246794(A,G); rs2246811(C,T); rs73533035(T,C); rs73533037(T,C); rs2246822(G,C); rs73533038(G,A); rs727387(T,C); rs727386(A,T); rs2246916(C,T); rs1899363(C,T); rs1899364(C,T); rs147609144(A,G); rs7822325(A,G); rs2247039(C,G); rs7826379(T,C); rs73664479(C,G); rs28470908(T,C); rs2247142(A,G); rs35770515(T,C); rs2466923(T,G); rs149274956(C,T); rs2439724(C,T); rs13270931(G,C); rs6995984(A,G); rs73533049(A,G); rs190331764(A,G); rs77779210(G,A); rs146790986(C,G); rs1031054(C,T); rs1031055(A,G); rs73533051(A,C); rs58296507(C,T); rs2250879(G,C); rs7002469(A,G); rs62493296(A,G); rs2250963(T,A); rs2165590(T,C); rs28370274(T,C); rs17120295(C,G); rs2251091(T,C); rs17120304(C,G); rs17120307(C,T); rs28539611(G,T); rs2034005(C,G); rs7341577(T,C); rs2251199(A,G); rs76024875(T,C); rs7007236(G,A); rs76529817(T,C); rs62493308(T,C); rs2251303(C,T); rs28625037(C,G); rs79634395(G,C); rs76864278(T,G); rs17120311(A,G); rs6530805(A,G); rs12676853(T,C); rs114519199(T,C); rs60192631(A,T); rs73664482(C,T); rs78566306(C,T); rs17278826(C,T); rs17120323(A,G); rs6985587(G,A); rs59473859(A,G); rs4348490(G,A); rs6530806(T,G); rs6530807(C,G); rs11779930(T,C); rs7840345(A,C); rs56356224(G,C); rs4831651(T,C); rs4831653(A,T); rs11988237(C,T); rs60924482(C,T); rs78042325(A,G); rs58644303(G,A); rs55747174(G,A); rs73533076(C,G); rs4538885(C,A); rs7835573(G,A); rs75506949(A,C); rs7823866(T,C); rs7008090(C,G); rs73533083(C,T); rs75892915(A,G); rs62493310(T,C); rs80147781(G,C); rs56273003(C,A); rs12543926(A,G); rs59868775(C,T); rs62493311(C,G); rs4831655(T,C); rs116122756(G,A); rs56875527(G,A); rs58363693(C,A); rs73533093(G,A); rs79608085(A,G); rs7824413(G,A); rs7824430(G,A); rs12678018(A,G); rs7826089(C,T); rs7826396(C,T); rs4587337(C,T); rs78171643(C,A); rs73664483(T,A); rs58732674(C,T); rs6982705(A,C); rs58636797(C,A); rs184591491(A,C); rs73535008(A,G); rs7824061(A,G); rs76781251(C,T); rs146358026(G,C); rs11991885(C,G); rs11996319(T,C); rs10086345(G,C); rs4515548(T,C); rs77358713(G,C); rs115961748(G,A); rs17120353(C,T); rs12681897(T,C); rs17120356(G,C); rs57853405(G,T); rs7013356(T,A); rs11997535(T,G); rs7013782(T,A); rs74469529(A,G); rs6990064(C,G); rs17120385(C,G); rs7824647(G,T); rs7824677(G,T); rs76314409(T,C); rs7832178(A,G); rs9650381(G,A); rs192043488(G,C); rs7836869(A,G); rs73535020(T,C); rs62493314(T,A); rs73535024(G,A); rs73535027(T,C); rs4623423(C,G); rs62493315(T,C); rs73535030(T,A); rs116125711(T,G); rs73535031(A,T); rs17120394(T,C); rs12677960(A,C); rs73535033(A,C); rs6999273(C,A); rs4368979(A,C); rs17120403(T,A); rs7462449(G,A); rs4422772(G,A); rs6530809(A,T); rs7830186(C,T); rs28529465(T,C); rs11988778(C,A); rs11988822(C,G); rs7818282(A,C); rs79412231(C,T); rs74763640(G,A); rs4831656(T,C); rs4240174(G,A); rs4240175(T,G); rs10093567(A,G); rs76497791(C,T); rs4596659(G,T); rs78049241(T,C); rs4615568(G,C); rs11780862(C,T); rs185104278(T,C); rs4262322(G,T); rs11997069(T,C); rs10107666(T,C); rs10089288(G,A); rs10104703(A,C); rs10107786(T,C); rs10089784(G,T); rs74303178(C,T); rs62493317(A,G); rs62493318(G,A); rs28520260(A,G); rs62493319(A,T); rs17463290(C,T); rs10503515(C,G); rs4831658(A,C); rs74494894(G,A); rs17573100(A,C); rs377379474(C,T); rs4345555(T,C); rs78319879(G,A); rs77653017(C,A); rs75212789(T,C); rs114307529(G,C); rs73201276(T,G); rs74711947(T,C); rs141093216(G,C); rs62493320(T,A); rs139079360(A,G); rs35160940(T,G); rs6530810(G,A); rs73664488(A,G); rs58258770(G,A); rs28886380(T,C); rs368288638(T,G); rs73666905(C,T); rs56260930(T,C); rs4645558(A,G); rs4602887(A,C); rs4645559(A,T); rs28546205(G,C); rs79375029(G,A); rs114847653(A,T); rs73201281(C,G); rs11785355(G,A); rs28698884(A,C); rs4463427(A,G); rs59027009(G,A); rs12680572(A,T); rs56161037(C,T); rs117366179(C,G); rs139356781(A,G); rs114621964(C,A); rs118075315(C,T); rs6530811(T,A); rs59641559(C,A); rs10095307(A,G); rs10098711(T,A); rs76102375(A,G); rs145706865(G,A); rs73666912(G,A); rs115354498(C,A); rs17120468(C,T); rs62493334(T,C); rs28631700(A,G); rs34447150(T,C); rs76133581(T,C); rs2726605(C,T); rs1480696(G,A); rs2726606(C,T); rs114712867(C,T); rs2726607(T,G); rs34895619(C,A); rs2622332(T,C); rs184282386(T,G); rs2726608(A,G); rs79331662(C,T); rs2622331(G,A); rs76901793(C,G); rs76728147(T,A); rs142073008(T,C); rs188205442(A,T); rs1871700(C,G); rs17120473(G,T); rs144350711(A,G); rs11995684(G,A); rs9643990(C,G); rs9643991(A,G); rs150353764(A,C); rs17601783(G,C); rs17120501(A,C); rs13258031(C,G); rs4831660(C,T); rs10100097(A,G); rs4831314(C,T); rs13256990(A,G); rs142172488(T,A); rs7386446(C,T); rs4831661(G,T); rs4831315(C,G); rs1480691(T,C); rs10111809(A,G); rs61500087(G,A); rs146180279(G,A); rs17120564(A,T); rs75605176(T,C); rs182079121(G,C); rs62493335(A,G); rs4831662(C,G); rs1351413(A,G); rs11997438(C,T); rs13253015(T,A); rs77742736(T,C); rs17601874(A,G); rs11988018(A,G); rs1904849(T,G); rs192493720(G,A); rs75060297(G,A); rs28404894(A,T); rs17601881(C,T); rs17470219(C,A); rs12156344(C,A); rs4831663(G,A); rs17120597(G,C); rs10108332(C,T); rs1564450(C,T); rs1564449(A,G); rs1564448(A,T); rs1564447(T,A); rs10503522(G,A); rs4285493(C,T); rs146936430(G,A); rs57512518(T,A); rs10108956(T,G); rs28541908(G,C); rs7838524(A,C); rs28562741(C,T); rs28490015(T,A); rs996896(T,C); rs10099062(C,T); rs12677033(C,G); rs150356226(C,A); rs4645560(G,A); rs922657(G,A); rs17120609(C,A); rs6986321(G,C); rs7836729(A,G); rs28626277(G,T); rs73201292(C,T); rs28562848(A,T); rs73666945(T,C); rs2061980(T,A); rs4831316(C,T); rs4831317(A,G); rs117456041(C,A); rs114139741(C,T); rs17601930(C,T); rs4265186(G,A); rs10105197(G,T); rs28652841(C,T); rs28704701(G,T); rs111305833(G,A); rs2410228(A,G); rs28394437(G,C); rs28608986(G,A); rs28617181(C,G); rs28546385(G,A); rs28605449(C,G); rs28741049(A,C); rs17120612(A,C); rs17120614(A,G); rs17654710(A,T); rs6982108(C,A); rs7001918(A,G); rs28410253(T,C); rs7002234(A,C); rs7006359(T,C); rs10113659(G,T); rs12546671(C,A); rs62493340(G,A); rs7841147(A,C); rs7830408(A,T); rs12682545(C,G); rs73201298(C,T); rs73201299(C,G); rs4401862(T,C); rs2199910(T,C); rs78317767(T,A); rs11992231(G,A); rs9643992(G,T); rs7844008(T,A); rs11203669(A,G); rs1480698(T,A); rs57073614(A,T); rs75877405(A,G); rs7002314(G,A); rs75876054(G,A); rs13261449(A,G); rs10094773(T,C); rs57199859(T,A); rs12679928(T,C); rs1383408(T,C); rs1480695(A,G); rs7014300(C,A); rs6995976(A,T); rs7004153(T,C); rs4322009(A,T); rs1351415(C,T); rs1351414(G,C); rs58685458(T,C); rs58903685(T,A); rs61504408(A,G); rs7813529(C,T); rs116766845(T,C); rs11781498(C,T); rs1471550(T,G); rs61071537(C,T); rs6991016(G,A); rs77341445(T,C); rs11785078(G,A); rs76619931(G,A); rs6530814(C,G); rs6530815(A,G); rs4831318(A,G); rs4831664(A,T); rs56742353(A,G); rs7838487(T,G); rs11787321(T,C); rs79907272(G,A); rs35891839(C,G); rs1963534(G,T); rs11776177(G,C); rs2046097(C,T); rs2046096(A,G); rs10096700(C,T); rs182074755(T,A); rs1383412(G,T); rs4831665(G,A); rs17470444(A,G); rs4831666(A,T); rs4636208(T,A); rs4607611(T,G); rs931148(C,T); rs931147(C,A); rs1871703(C,T); rs962727(C,T); rs1871702(G,A); rs1383411(C,T); rs17654787(C,G); rs4582563(G,C); rs7387381(C,G); rs28631042(G,A); rs7387638(C,G); rs7833907(C,G); rs17608413(C,T); rs13439657(C,T); rs77995518(G,C); rs60906550(A,C); rs74521572(G,A); rs10096113(T,C); rs7839009(C,G); rs11988988(T,C); rs10101010(A,G); rs79381624(T,A); rs11777723(A,C); rs9643993(T,A); rs9643994(C,T); rs61107981(T,C); rs78261553(T,C); rs7824031(C,T); rs28715428(A,T); rs55662092(G,T); rs76792450(G,A); rs10098188(C,G); rs10112644(A,G); rs10087777(T,C); rs10112732(A,T); rs17654841(G,A); rs10503524(A,G); rs17608468(T,A); rs56148585(C,A); rs6530816(C,T); rs10112336(G,A); rs10099668(A,G); rs1026821(T,C); rs11985226(C,A); rs7817131(G,A); rs9694404(T,C); rs28413642(C,T); rs28659185(G,A); rs2061983(G,A); rs6990433(G,A); rs17573960(C,G); rs6990445(G,T); rs4455829(C,T); rs4549773(C,A); rs78708641(G,A); rs10081602(A,G); rs7827121(G,A); rs12546303(A,C); rs78862428(A,G); rs6530817(C,T); rs7008305(C,A); rs75301248(T,G); rs7008737(C,T); rs73203309(G,A); rs7008905(C,A); rs144595903(C,A); rs4562327(C,T); rs77687438(G,A); rs79986506(A,G); rs11780537(C,G); rs11784231(A,G); rs6530818(C,T); rs76522180(A,C); rs75366609(A,G); rs74416791(C,A); rs79676688(T,C); rs73666954(G,T); rs185164919(C,T); rs11993525(C,A); rs7388469(T,C); rs116653077(T,C); rs6987734(A,G); rs7006724(C,T); rs79335168(T,C); rs6992946(T,C); rs28631771(G,C); rs11993796(A,G); rs13267348(G,T); rs188294176(T,C); rs7016812(C,G); rs13276196(G,T); rs77806235(T,A); rs5028286(A,G); rs13261120(T,C); rs10503525(T,C); rs17654901(C,G); rs28408309(G,A); rs75409224(T,C); rs9650382(G,A); rs9325741(T,C); rs13340563(G,A); rs78440783(C,T); rs7000841(C,T); rs11987866(G,A); rs113197027(G,T); rs113534208(G,A); rs28376071(T,C); rs7834329(G,A); rs7834663(G,A); rs10093265(T,A); rs10090436(A,T); rs7835110(G,T); rs7835159(G,A); rs17654931(C,T); rs7012024(C,T); rs7012038(C,A); rs7010925(G,A); rs12545463(G,A); rs7016798(T,C); rs148578264(G,A); rs111959012(C,T); rs79352122(T,C); rs7018087(T,C); rs79887401(G,T); rs10109779(A,G); rs10097898(G,A); rs78231597(T,C); rs112290544(T,A); rs79182432(G,T); rs78297434(C,T); rs12681103(C,A); rs58250466(G,A); rs10092923(A,G); rs117514553(A,G); rs17574078(T,C); rs76435708(G,A); rs6530821(G,A); rs10100668(A,G); rs117306691(C,T); rs2046098(G,A); rs10089619(G,A); rs10108343(T,C); rs2046099(T,C); rs13268706(C,T); rs17574120(T,G); rs76446791(T,C); rs11991997(T,C); rs11994486(G,C); rs78148189(G,A); rs73665352(T,C); rs11992089(T,C); rs11992114(T,A); rs73665353(A,G); rs13254449(A,T); rs28398777(T,C); rs1480694(T,C); rs79106214(T,C); rs35249522(C,T); rs59074729(C,T); rs139735388(T,C); rs6651384(A,G); rs11989104(A,G); rs9657247(T,C); rs192273428(G,A); rs4831320(A,C); rs4831321(C,T); rs12547159(G,C); rs138546537(G,A); rs7826655(G,C); rs13278000(A,G); rs17608642(C,T); rs17120686(C,T); rs17608649(C,G); rs13251088(C,T); rs13249325(G,T); rs12680718(G,C); rs4427170(A,T); rs4626602(G,C); rs77054540(C,T); rs59298322(C,T); rs2061976(A,G); rs7836895(G,T); rs13278622(T,C); rs13271146(A,T); rs74382655(C,T); rs141813169(C,T); rs17120703(G,T); rs13270347(G,A); rs13270373(G,A); rs7845713(G,T); rs12545896(C,T); rs12548400(A,G); rs10088046(G,C); rs10088159(G,A); rs10088171(G,C); rs10088999(C,T); rs13256266(C,T); rs13265692(T,C); rs7010473(T,A); rs9693111(G,C); rs9693204(C,T); rs7820939(G,A); rs6530822(G,C); rs9693225(C,G); rs7840310(A,G); rs73665355(T,A); rs7005721(C,G); rs6991950(T,C); rs7005262(G,A); rs73665356(A,C); rs73665357(G,A); rs60072986(G,A); rs115280093(G,A); rs117904911(A,T); rs17608712(G,C); rs73665358(T,C); rs13265890(G,A); rs13266158(G,A); rs56263802(A,C); rs11203670(T,C); rs184419712(A,G); rs11203671(A,T); rs11203672(C,T); rs372639581(A,T); rs62495392(C,A); rs6530823(G,C); rs6530824(T,G); rs6530825(C,A); rs7016297(G,C); rs9694829(C,T); rs7003157(T,A); rs143773972(T,A); rs7846072(C,A); rs9694784(G,T); rs62495393(G,C); rs7814519(G,C); rs7837047(T,G); rs7815541(C,T); rs10888094(G,A); rs10888095(C,A); rs6984132(G,A); rs2012994(G,A); rs1125265(C,T); rs2061978(G,T); rs6530826(T,C); rs6995148(C,T); rs6530827(C,G); rs7812667(T,C); rs17120731(T,C); rs13271765(G,A); rs13271780(G,A); rs13282338(T,C); rs62493666(T,C); rs73665364(T,C); rs12680576(C,T); rs12674502(A,G); rs12676340(G,A); rs12674940(T,G); rs12680588(C,T); rs13266339(C,G); rs11203673(C,T); rs11203674(G,A); rs13266087(G,C); rs11786914(C,A); rs2127774(G,A); rs79226497(A,G); rs13251017(T,C); rs73665366(C,T); rs10111834(C,T); rs13251628(T,A); rs13278210(C,T); rs13251961(T,C); rs62493667(G,A); rs11203675(C,A); rs12550462(T,C); rs63324763(A,G); rs7013075(A,C); rs6992296(G,C); rs6992611(G,A); rs6992613(G,T); rs10283038(G,A); rs4831667(G,T); rs7817295(A,T); rs7817470(A,C); rs7817481(A,C); rs6990730(T,A); rs7004077(G,C); rs6530828(G,C); rs4831668(T,C); rs4831670(G,A); rs7387135(A,C); rs34632821(A,T); rs7015648(C,A); rs7015829(C,G); rs4585750(C,G); rs2170239(C,T); rs13257934(C,T); rs67597983(T,C); rs7007836(A,C); rs1480699(T,C); rs13267486(G,A); rs7815606(T,G); rs4582565(T,C); rs10088985(A,G); rs147999649(A,C); rs12550664(C,A); rs79895607(G,C); rs7830454(A,G); rs7846057(G,C); rs55726353(T,C); rs7830861(A,T); rs7830867(A,G); rs79983157(T,C); rs28473524(C,T); rs28514431(C,T); rs936631(G,A); rs2898406(T,C); rs57332249(C,T); rs7388371(T,C); rs12678080(T,C); rs11780017(T,C); rs144045102(C,T); rs7388537(A,T); rs4598251(G,A); rs73205405(C,T); rs10087569(A,G); rs116798945(G,C); rs4348491(A,G); rs4631466(C,T); rs4631467(C,T); rs4348492(A,T); rs34866426(A,G); rs4304329(G,T); rs4323471(G,A); rs11783107(A,G); rs62493673(G,A); rs73205408(G,T); rs117831553(G,A); rs746836(C,T); rs192594961(T,C); rs76749663(C,T); rs77357652(C,T); rs79600420(C,T); rs4503099(A,C); rs72607335(C,A); rs73665372(C,T); rs73521075(G,A); rs75334471(C,G); rs80159918(A,G); rs7009631(A,G); rs12545310(A,C); rs28840533(C,T); rs73205411(T,G); rs9650354(G,A); rs9650355(A,G); rs9650384(G,A); rs9650385(G,A); rs78735084(G,C); rs11994889(G,A); rs73205415(T,C); rs74786756(G,A); rs10888100(T,C); rs56338556(T,C); rs114590597(T,C); rs4831671(T,C); rs4831672(T,C); rs4831673(A,G); rs78327029(C,G); rs141198547(G,C); rs4831674(T,G); rs73205418(T,G); rs79916430(C,A); rs115394260(A,T); rs114834249(G,A); rs1598188(G,C); rs1598190(A,C); rs7007999(T,C); rs6983207(G,A); rs12546359(C,G); rs145586653(G,C); rs73521092(T,C); rs7005301(C,A); rs7005497(C,T); rs7004485(G,A); rs6995750(T,C); rs7838801(G,C); rs13248550(T,C); rs10100240(T,C); rs10109935(G,A); rs7002722(A,G); rs2219139(A,G); rs10888101(C,T); rs1378034(G,A); rs17574523(A,C); rs12156052(C,T); rs7822784(G,A); rs146025201(T,G); rs1454595(G,C); rs2054064(A,T); rs59504482(G,A); rs57771945(A,T); rs2054065(T,C); rs7829147(G,A); rs28529162(C,T); rs10105780(G,C); rs58881962(T,C); rs13273301(T,C); rs7822323(A,T); rs7822327(A,C); rs62493714(A,T); rs12542871(T,C); rs142974837(T,G); rs79133295(A,C); rs73665376(C,T); rs985314(G,A); rs78325445(C,T); rs7844246(T,G); rs1869578(G,A); rs1454596(C,G); rs921715(A,C); rs1454597(T,C); rs921716(T,C); rs6530829(T,C); rs10087013(T,A); rs17608908(G,A); rs75510063(G,A); rs78325849(T,C); rs17120803(T,C); rs17120804(T,C); rs68164455(T,C); rs17120805(G,T); rs13258778(G,C); rs112403913(G,A); rs7008233(C,G); rs1454598(C,T); rs56864313(A,G); rs12056421(T,C); rs10095579(A,G); rs75311469(T,C); rs10108640(G,C); rs79011801(T,C); rs17120815(C,G); rs17608929(T,C); rs74539135(G,T); rs10089919(C,T); rs11779853(T,C); rs4831323(C,A); rs76047512(C,A); rs17655231(T,C); rs4831675(T,C); rs6996197(G,A); rs12678686(T,A); rs138593062(A,G); rs10100576(G,T); rs112511180(A,C); rs182842603(C,G); rs10101583(T,C); rs10111470(G,A); rs10111568(G,C); rs13254178(C,G); rs76964425(C,A); rs12679312(G,A); rs17608964(T,C); rs17120823(G,A); rs75408224(C,A); rs17655279(A,G); rs7464441(A,T); rs72607336(T,C); rs13273423(C,T); rs13273444(C,T); rs13281953(T,C); rs62493717(C,A); rs77436368(T,C); rs28721284(T,A); rs59394803(C,T); rs17120832(A,T); rs1840359(T,C); rs1840358(G,T); rs74905932(G,C); rs10888102(C,A); rs10888103(A,G); rs79680889(A,G); rs28591461(G,T); rs7844909(G,T); rs10503526(G,C); rs28571715(T,A); rs28605251(G,A); rs28750235(C,T); rs10503528(G,C); rs77739461(G,A); rs11203676(A,G); rs77312632(G,A); rs7819346(G,A); rs79054952(T,G); rs7842276(T,C); rs2898407(C,A); rs17120838(C,T); rs112064775(G,A); rs1378037(G,T); rs1378036(G,A); rs1378035(A,G); rs7822541(A,G); rs1454594(A,G); rs11203677(A,G); rs12678133(C,A); rs58177496(G,C); rs17609053(T,C); rs17609060(T,C); rs17609074(T,C); rs7011953(T,C); rs79786870(A,C); rs73665380(T,G); rs67876485(A,G); rs1454593(A,G); rs66851234(G,A); rs17120855(C,A); rs17120860(C,A); rs6994086(C,T); rs35206708(T,C); rs1454592(C,T); rs17120868(G,C); rs1454591(G,C); rs17120872(T,A); rs73665382(C,T); rs62494573(G,C); rs78160555(C,G); rs7813027(A,G); rs17655367(T,C); rs59906071(C,A); rs62494574(C,T); rs58774726(G,C); rs1454590(G,A); rs2124028(G,A); rs55793257(A,T); rs7842315(G,A); rs113991941(G,C); rs2410229(G,T); rs6530831(C,G); rs10093133(C,T); rs181228816(T,G); rs10107753(A,G); rs10093615(C,T); rs9325742(A,G); rs57745242(A,G); rs1378033(T,G); rs17609124(T,C); rs2410230(G,C); rs17120884(G,C); rs2168126(G,A); rs2124027(C,G); rs1454589(C,G); rs1454588(C,T); rs141243263(C,G); rs72607337(T,A); rs184223947(A,G); rs76412265(C,G); rs1840354(G,C); rs1454587(A,G); rs7824948(T,C); rs75889457(G,A); rs145599722(G,A); rs28586947(A,T); rs10503530(T,C); rs10503531(T,C); rs17655425(G,A); rs66513835(T,C); rs28660118(A,C); rs4831676(G,A); rs4831677(T,G); rs11990043(A,T); rs6530832(A,T); rs13439373(A,C); rs17120898(T,C); rs1031495(G,A); rs7015642(G,A); rs75029343(A,T); rs1026353(A,G); rs17655443(T,C); rs1031494(T,C); rs4831678(A,G); rs4831679(C,T); rs7838267(A,C); rs7820754(C,T); rs17120908(T,G); rs73665383(G,C); rs7821053(C,T); rs28516917(A,T); rs6989374(G,C); rs6530833(A,C); rs7825260(G,A); rs2124026(T,C); rs7001781(C,T); rs181721230(C,A); rs2124024(T,G); rs2124023(T,C); rs2168124(C,T); rs10093338(T,C); rs2410231(C,T); rs2410232(C,G); rs117941548(A,T); rs9918868(G,T); rs9918800(A,G); rs9918870(G,A); rs17120915(C,G); rs116891980(C,G); rs75125425(C,T); rs6530834(T,C); rs6530835(A,G); rs2054063(G,C); rs2054062(G,C); rs1598187(G,A); rs67149782(T,A); rs1598186(A,T); rs1598185(G,A); rs61693777(C,T); rs76386137(G,A); rs76732308(C,T); rs7003571(G,A); rs150841871(G,A); rs1454586(A,G); rs62501012(T,C); rs7822084(A,G); rs1840353(A,C); rs1840352(A,G); rs1026352(T,C); rs1026351(A,G); rs201595836(A,T); rs73665384(A,G); rs1026350(G,C); rs1026349(C,T); rs6651385(A,G); rs1031492(C,T); rs6530836(C,T); rs10503532(G,A); rs11203678(T,C); rs148546151(G,A); rs76324354(C,T); rs188719876(A,G); rs7822641(G,A); rs6530837(C,T); rs2168123(G,A); rs7812772(A,G); rs7828874(G,C); rs73525061(T,C); rs4383970(A,T); rs117695893(T,G); rs77465940(G,T); rs7009607(C,T); rs62499772(A,T); rs7842009(G,A); rs12682086(C,G); rs11777265(T,C); rs7830724(T,C); rs62499773(C,A); rs7827568(A,C); rs13265356(C,A); rs75966265(G,A); rs148039403(A,G); rs7840326(A,G); rs7821558(G,C); rs74493711(G,A); rs73525069(G,A); rs17120932(G,A); rs78089174(G,C); rs4294182(C,A); rs6982470(T,C); rs4351419(C,G); rs13274370(G,C); rs146673068(C,T); rs9325743(G,A); rs56259177(C,T); rs56136887(G,T); rs55763341(C,T); rs10217070(A,G); rs17655533(A,G); rs59388035(T,A); rs17655539(G,A); rs75697213(T,C); rs921714(G,C); rs73525072(T,C); rs115143766(G,T); rs78757657(C,A); rs74961508(C,T); rs4142660(G,T); rs4142661(C,G); rs17574959(T,C); rs1993315(C,T); rs4451316(C,T); rs78856608(T,C); rs62499780(C,T); rs1993314(G,A); rs1454585(A,T); rs17471523(C,G); rs12335331(C,G); rs11991092(G,C); rs57080216(C,T); rs7462844(A,G); rs1454584(T,G); rs1454583(G,A); rs112080169(T,C); rs117487616(A,C); rs17471544(T,A); rs28647749(A,G); rs2054061(C,G); rs2054060(A,G); rs1902081(G,A); rs62499782(G,C); rs113026159(A,G); rs76443537(G,C); rs1454582(C,G); rs62499783(G,A); rs1454581(C,G); rs1378031(T,C); rs62499784(G,A); rs10111663(A,G); rs7844593(G,A); rs7832820(T,C); rs7846146(C,A); rs11780948(G,C); rs118066204(C,T); rs76656751(T,G); rs1378030(A,G); rs17575042(T,C); rs1454580(A,G); rs17575063(G,C); rs1378029(C,A); rs11783872(G,C); rs147351112(T,G); rs268438(A,G); rs268437(T,C); rs268436(T,G); rs17655587(G,T); rs10503533(G,A); rs116298489(G,A); rs143085372(C,T); rs6998750(A,G); rs2034758(G,T); rs7814258(G,C); rs17609395(C,A); rs58862799(T,C); rs12056855(T,C); rs2045402(T,C); rs60680158(C,T); rs6997205(A,T); rs62499788(A,C); rs17120983(G,C); rs4831684(G,A); rs4831685(G,A); rs13249540(C,A); rs268433(C,T); rs17120994(T,C); rs62499829(C,T); rs17471747(T,C); rs141341081(T,C); rs10091599(C,G); rs77141010(A,G); rs75649404(T,C); rs6984881(T,C); rs4831324(G,A); rs113941523(T,C); rs112846765(T,G); rs115687784(G,A); rs116191663(A,T); rs115145158(A,G); rs268429(A,G); rs11779924(C,A); rs62499830(G,A); rs1379338(G,C); rs78489119(G,A); rs268428(G,A); rs268427(A,G); rs12114925(T,G); rs268426(G,T); rs268425(T,C); rs268424(C,A); rs268423(T,C); rs185744366(C,T); rs268422(C,T); rs1869577(C,A); rs142663470(G,A); rs62499831(T,C); rs113304466(T,A); rs114326028(C,T); rs12056694(C,T); rs75617462(T,A); rs268421(G,T); rs79269650(C,A); rs7832745(C,T); rs7833187(C,T); rs76682527(G,A); rs17609514(T,C); rs268420(G,T); rs4831325(A,T); rs79932342(C,T); rs17575278(T,C); rs174852(A,G); rs2198596(G,C); rs114168107(A,G); rs478019(A,C); rs28408982(C,T); rs561900(T,C); rs561432(A,G); rs560546(C,A); rs560877(T,C); rs560332(A,G); rs535352(A,G); rs554891(T,C); rs17575313(G,A); rs76188958(A,T); rs79885653(G,A); rs198529(T,C); rs268443(T,A); rs80331635(T,C); rs60561765(A,C); rs11776351(G,C); rs268442(G,C); rs268441(G,C); rs11776413(G,A); rs268440(G,T); rs6530838(C,A); rs17471917(G,A); rs139055301(G,T); rs13250784(C,T); rs78754485(A,G); rs142471431(G,T); rs7007630(C,G); rs268439(T,G); rs79727036(C,T); rs147891182(C,T); rs36065000(A,C); rs10108992(C,T); rs73527025(G,C); rs268380(C,T); rs61488093(G,A); rs73527028(T,G); rs73527029(G,C); rs268379(T,C); rs58374201(G,A); rs11997676(T,C); rs58184795(G,A); rs60770393(C,T); rs9643996(A,G); rs1902620(C,G); rs268377(A,G); rs1902619(G,C); rs268376(G,A); rs1457217(A,G); rs268375(C,T); rs12541013(A,G); rs77041357(T,C); rs147413133(C,T); rs73527035(T,C); rs12548485(C,T); rs12548503(C,T); rs12541163(A,C); rs12549055(C,T); rs12544054(G,T); rs17655886(G,A); rs76943743(G,C); rs60404729(A,G); rs72607338(C,A); rs174851(G,C); rs1869576(A,G); rs77161904(C,T); rs75345317(C,T); rs57686171(G,A); rs147149795(G,A); rs58872898(T,C); rs75722882(C,T); rs73527041(T,C); rs17609705(T,C); rs35761763(A,C); rs35782581(A,C); rs35621254(T,G); rs13276040(T,C); rs10503535(G,A); rs80134031(C,T); rs10503536(A,G); rs268418(A,G); rs17121054(C,G); rs268417(G,T); rs368933233(G,A); rs56369360(T,C); rs56033232(C,T); rs55760582(C,A); rs56052534(A,C); rs73527049(A,G); rs73527052(T,A); rs17121056(T,C); rs73527054(G,A); rs17434807(C,T); rs80168267(A,G); rs73527060(G,A); rs138678920(T,C); rs268416(G,T); rs10503537(G,A); rs28546546(T,G); rs12674795(C,G); rs75434762(A,G); rs12674797(C,G); rs12678727(G,A); rs268415(G,C); rs150569729(G,A); rs58282951(C,T); rs183850(C,A); rs61469568(G,C); rs59481272(T,C); rs73529333(G,A); rs371971883(C,G); rs72607339(G,A); rs113911502(T,C); rs72607340(G,A); rs73529345(C,A); rs62499835(A,C); rs58642726(G,C); rs76934454(T,C); rs76088492(T,C); rs61152810(C,T); rs57293507(C,T); rs138680335(T,G); rs76267920(C,A); rs6987011(T,A); rs73529356(A,C); rs73529359(G,A); rs115358535(A,T); rs145596263(C,T); rs73529363(C,A); rs73529365(T,C); rs62499836(T,C); rs73529366(G,C); rs12682273(C,T); rs7828345(A,C); rs268414(G,C); rs113432411(G,C); rs268413(T,G); rs74433511(T,C); rs1457212(C,A); rs12546024(G,C); rs268412(G,T); rs73531493(G,C); rs73665391(A,T); rs268411(G,T); rs268410(A,G); rs268409(C,T); rs268408(A,G); rs11782714(G,C); rs73533408(T,G); rs114413839(A,G); rs10097670(G,A); rs12548016(G,A); rs12546353(T,A); rs371533769(G,A); rs12543358(C,T); rs183909733(G,A); rs7829209(G,A); rs2085122(G,A); rs7832844(G,A); rs268407(G,A); rs73533417(T,C); rs2410233(C,A); rs268406(C,A); rs12056742(T,A); rs1598745(G,A); rs268404(C,G); rs1598182(T,C); rs73665392(C,A); rs9886582(G,A); rs268403(A,C); rs166533(T,C); rs268402(A,G); rs517123(C,T); rs187903(T,C); rs10097372(A,G); rs268401(C,T); rs268400(G,C); rs7001802(A,T); rs268399(C,G); rs268398(C,T); rs268397(T,A); rs268396(A,C); rs4831687(T,C); rs60134023(T,C); rs58993070(A,G); rs4831688(C,T); rs145572322(G,C); rs475281(A,G); rs482004(A,C); rs17472085(C,G); rs6986649(G,T); rs77361440(G,C); rs114511151(C,T); rs138278314(G,A); rs13249659(G,A); rs13250542(G,A); rs268391(T,C); rs116531275(C,G); rs1471119(G,A); rs268390(G,C); rs7840960(G,A); rs268389(G,C); rs268388(C,A); rs268387(G,A); rs79564220(A,G); rs4831326(C,A); rs268386(T,C); rs268385(A,T); rs268384(C,A); rs268383(C,T); rs146539677(C,A); rs268382(C,G); rs268381(A,G); rs6530841(C,T); rs150306149(C,T); rs6992257(C,T); rs2603520(C,T); rs750895(C,T); rs115954699(A,G); rs12674622(T,G); rs967411(C,A); rs1077593(G,A); rs1077592(G,C); rs268352(T,G); rs187902(G,A); rs268353(T,C); rs268354(A,G); rs1457222(G,A); rs1457223(C,A); rs67205345(G,A); rs268355(A,T); rs28459068(G,C); rs268356(A,G); rs6989730(A,C); rs17121108(G,A); rs549468(C,A); rs17609949(T,C); rs268357(C,G); rs148284660(G,A); rs2898409(G,C); rs13269086(G,C); rs268359(C,T); rs13271509(C,T); rs268360(A,G); rs13260980(G,A); rs268361(G,A); rs2603521(A,G); rs498857(C,A); rs1457224(C,A); rs7820870(G,A); rs268362(G,A); rs147598880(G,T); rs185585(A,T); rs268363(G,A); rs268364(C,G); rs13274267(C,A); rs268365(C,A); rs3988426(C,G); rs534681(G,A); rs557523(G,A); rs77574116(A,T); rs115064770(T,C); rs62501988(G,A); rs11785338(C,A); rs1563572(G,A); rs2168127(T,C); rs13250842(T,C); rs141860891(A,G); rs13252931(A,C); rs141047911(G,A); rs268348(C,T); rs268349(C,T); rs268350(G,C); rs147513720(T,C); rs80112206(G,T); rs144319625(T,C); rs268351(C,A); rs11779569(T,A); rs2061287(G,T); rs13272751(A,T); rs9325744(A,G); rs74426913(G,C); rs530122(C,G); rs552993(C,T); rs10503540(C,G); rs554064(T,C); rs482244(G,A); rs558425(A,G); rs507053(C,T); rs559324(T,C); rs76022831(C,A); rs509852(T,G); rs11777315(C,T); rs514205(T,C); rs1869579(T,A); rs543631(T,C); rs13257462(T,G); rs7814553(C,G); rs7006889(T,G); rs7836517(T,C); rs77634078(T,C); rs13251047(C,G); rs573856(C,T); rs146768202(G,C); rs11989265(T,C); rs7840505(T,C); rs487505(C,G); rs17472351(A,G); rs2168128(C,T); rs79958707(C,T); rs2603525(T,C); rs6992134(G,A); rs28406446(C,T); rs2410239(A,G); rs17575783(T,C); rs62501991(C,T); rs268367(G,A); rs12680924(G,A); rs7008311(G,A); rs268368(G,C); rs268369(A,T); rs4831328(G,A); rs4831690(C,T); rs4831691(G,A); rs1457226(T,C); rs17656261(C,T); rs7832338(A,C); rs959358(T,C); rs268370(T,C); rs268371(C,T); rs113874437(T,C); rs12155592(G,A); rs17575818(T,C); rs12678763(A,C); rs75733548(T,C); rs17472386(T,A); rs11782036(T,C); rs10105174(C,T); rs78464409(A,T); rs77472787(C,G); rs75587175(C,A); rs268372(A,G); rs268373(T,C); rs78834380(A,C); rs74772683(T,C); rs76317806(A,G); rs75237456(C,T); rs78526575(G,C); rs6990575(A,C); rs17121136(A,G); rs268374(A,G); rs7013214(C,T); rs1457227(G,C); rs78924517(G,T); rs17610165(T,C); rs75863076(C,G); rs116132652(G,A); rs115217550(G,A); rs114340042(A,G); rs76530994(T,G); rs79692696(C,T); rs9918843(T,C); rs9918926(C,T); rs9918915(G,C); rs9918930(C,G); rs9918754(C,T); rs9918755(C,G); rs9918745(G,T); rs111760346(T,C); rs1840892(T,A); rs111631642(C,A); rs113541410(A,T); rs76411800(T,C); rs2054055(A,G); rs182423546(T,C); rs2054056(G,T); rs141406631(A,T); rs9918793(C,T); rs9918783(G,A); rs2054057(G,A); rs2054058(C,T); rs2054059(T,A); rs7844721(T,G); rs7841105(A,G); rs11203680(A,G); rs12542763(G,C); rs11203681(A,G); rs11203682(T,C); rs11203683(C,T); rs10096451(G,T); rs10097637(C,G); rs10096927(G,A); rs1457225(G,C); rs10096949(G,C); rs11203684(A,T); rs11203685(G,A); rs11203686(G,T); rs11988045(G,A); rs11985550(T,C); rs6988637(T,G); rs7003284(C,T); rs10088184(A,G); rs13269588(T,C); rs10104775(G,A); rs2061286(T,G); rs9325747(A,C); rs73207327(T,G); rs10107974(G,A); rs10108070(G,C); rs12386861(G,A); rs10098315(T,C); rs1902621(C,A); rs4102391(C,A); rs118098596(A,G); rs75958629(A,T); rs75743138(T,C); rs75969571(G,A); rs6990291(C,T); rs77003297(C,G); rs28450200(C,T); rs62502013(C,A); rs9643997(T,A); rs56035660(A,C); rs11203688(C,T); rs13258669(C,A); rs10093802(T,C); rs13257140(G,A); rs7827254(T,A); rs58785635(T,C); rs268334(C,G); rs268335(G,A); rs73535895(C,T); rs73535898(C,G); rs75464138(G,A); rs268336(C,A); rs28428905(G,T); rs268337(C,T); rs268338(T,A); rs268339(T,A); rs268340(G,A); rs117924223(A,C); rs117491400(T,C); rs268341(A,T); rs268342(G,A); rs73537905(G,A); rs268343(G,C); rs268344(T,C); rs268345(C,T); rs268346(T,G); rs28702478(C,T); rs116673153(G,A); rs77449096(C,G); rs17121150(T,A); rs74853354(G,A); rs79577405(T,C); rs139376775(A,G); rs80321631(G,A); rs13257860(T,C); rs76420472(G,C); rs78428260(A,C); rs59828775(A,C); rs17575958(T,G); rs17472540(A,T); rs76357861(T,C); rs77132535(C,T); rs78740152(G,A); rs17472547(C,G); rs117658139(T,C); rs73524825(G,A); rs11996692(G,C); rs17121154(A,T); rs73524829(C,T); rs4415316(C,A); rs17121158(C,A); rs143529481(T,G); rs113459080(C,T); rs73524833(A,C); rs17121159(A,T); rs1473391(G,A); rs1457228(A,G); rs79825276(C,A); rs77567987(G,C); rs117565482(T,G); rs75279377(T,A); rs77527687(G,T); rs148005441(G,C); rs4831692(A,G); rs74840204(C,G); rs7010086(T,C); rs78338628(T,C); rs75783116(C,T); rs1457230(C,T); rs78480621(C,G); rs77881086(A,C); rs73524837(G,T); rs34956190(T,A); rs76898713(A,G); rs75944454(C,G); rs79737642(C,T); rs73667931(A,G); rs7820168(T,C); rs4831330(G,A); rs4831331(C,G); rs11782187(A,G); rs11782191(A,G) |
| ccdsGene name | CCDS5992.2 |
| cytoBand name | 8p22 |
| EntrezGene GeneID | 137868 |
| EntrezGene Description | sarcoglycan, zeta |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SGCZ:NM_139167:exon6:c.G613T:p.D205Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9059 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q08AT0 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 1.545e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
RESPIRATORY:
Recurrent upper and lower respiratory tract infections
GENITOURINARY:
[Internal genitalia, male];
Chronic epididymitis
IMMUNOLOGY:
Lymph node hyperplasia;
Elevated IgM;
Low IgG and IgA;
Impaired Ig class switch recombination (CSR);
Normal B-cell (CD19+) count
MISCELLANEOUS:
Recurrent bacterial infections
MOLECULAR BASIS:
Caused by mutation in the uracil-DNA glycosylase gene (UNG, 191525.0001)
OMIM Title
*608113 SARCOGLYCAN, ZETA; SGCZ
;;ZSG1;;
ZETA-SARCOGLYCAN
OMIM Description
CLONING
By searching electronic databases and by RT-PCR experiments, Wheeler et
al. (2002) identified the murine zeta-sarcoglycan (SGCZ) gene. The gene
shares 56% identity and 74% similarity in amino acid sequence both to
gamma-sarcoglycan (SGCG; 608896) and delta-sarcoglycan (SGCD; 601411).
It is also 89% identical to human SGCZ on the nucleotide level.
GENE STRUCTURE
Wheeler et al. (2002) determined that human SGCZ shares the same
intron-exon organization as the gamma- and delta-sarcoglycan genes.
ANIMAL MODEL
Wheeler et al. (2002) generated a zeta-sarcoglycan-specific antibody and
found that zeta-sarcoglycan associated with other members of the
sarcoglycan complex at the murine plasma membrane. Additionally,
zeta-sarcoglycan was reduced at the membrane in 2 mouse models of
muscular dystrophy, gsg -/- (LGMD2C) and dsg -/- (SGCD).
Zeta-sarcoglycan was also found as a component of the vascular smooth
muscle sarcoglycan complex. The authors proposed that zeta-sarcoglycan
is an integral component of the sarcoglycan complex and, as such, may be
important in the pathogenesis of muscular dystrophy.
MAPPING
Based on homology to the murine gene, Wheeler et al. (2002) localized
the human gene to chromosome 8p22 by searching electronic databases.
MIR6841
| dbSNP name | rs76347846(A,G) |
| cytoBand name | 8p21.2 |
| EntrezGene GeneID | 4747 |
| EntrezGene Symbol | NEFL |
| snpEff Gene Name | NEFL |
| EntrezGene Description | neurofilament, light polypeptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06474 |
| ESP Afr MAF | 0.110507 |
| ESP All MAF | 0.087877 |
| ESP Eur/Amr MAF | 0.077313 |
| ExAC AF | 0.064 |
ELP3
| dbSNP name | rs11779927(A,G); rs34247390(T,G); rs28507020(G,C); rs28533132(G,A); rs2305452(G,A); rs11786004(G,A); rs73226770(T,C); rs2123472(C,A); rs59497557(C,T); rs2167768(T,C); rs6558036(G,A); rs13261052(G,A); rs1563055(C,T); rs10282902(C,T); rs113629737(C,T); rs56306964(C,T); rs4732818(C,A); rs10110868(C,G); rs2290371(A,G); rs11544370(C,A); rs2290370(C,T); rs2290369(G,A); rs4732819(A,G); rs6558037(G,C); rs35385733(G,A); rs12716544(C,G); rs13439880(A,G); rs6558038(T,A); rs28402837(G,A); rs6558039(C,T); rs7832075(A,G); rs115597464(T,G); rs4732820(C,T); rs6996985(G,C); rs111577308(A,G); rs59949871(A,C); rs185821971(G,A); rs2874904(T,C); rs9314358(G,A); rs3213997(A,G); rs13282722(T,A); rs9886599(A,T); rs4732622(A,T); rs13277221(T,C); rs4732823(A,G); rs7012681(G,C); rs4732623(C,G); rs4732624(C,G); rs11781887(T,C); rs189635725(G,A); rs113532514(A,G); rs147462079(G,A); rs4732824(G,A); rs111452898(T,G); rs79771130(C,T); rs28869580(T,A); rs6998039(A,T); rs7002651(T,C); rs4732627(G,T); rs9987220(T,C); rs9987184(A,C); rs34460067(A,G); rs11136032(C,T); rs12541153(G,A); rs12548838(A,G); rs1530929(C,A); rs1000275(A,G); rs114201834(G,A); rs1000274(A,G); rs13248070(T,C); rs4510811(C,T); rs142583374(G,A); rs35133929(A,G); rs7812540(A,G); rs7829704(C,T); rs55759364(C,T); rs10098763(C,T); rs28653620(C,T); rs59321770(C,A); rs4732826(G,T); rs10103080(C,G); rs4732827(A,G); rs55865355(G,C); rs375761791(G,A); rs9314359(T,C); rs9285028(C,T); rs4732828(T,G); rs4732628(C,G); rs13250007(T,G); rs3757895(G,A); rs3757894(G,C); rs3757893(C,T); rs7830851(A,G); rs7341664(T,A); rs4732830(A,G); rs76043038(A,G); rs7017268(A,G); rs7000894(G,A); rs12544289(A,G); rs10104739(A,G); rs12542344(C,T); rs11136033(A,G); rs7003418(T,C); rs17058631(T,G); rs6999490(A,G); rs4377920(A,G); rs10095097(T,A); rs10095192(T,A); rs78817492(T,G); rs10216910(A,G); rs10092376(C,T); rs74916475(G,C); rs765326(T,C); rs79519536(C,A); rs117698037(C,A); rs10111096(A,G); rs10093221(T,C); rs10093756(T,A); rs10090926(A,G); rs9644138(C,T); rs59061949(C,T); rs55850635(A,G); rs12548074(A,G); rs73226797(G,A); rs12548106(A,T); rs28455649(T,C); rs4732832(A,C); rs2322899(G,T); rs12541966(G,A); rs368244055(G,A); rs6986312(G,T); rs75111346(A,G); rs7841594(A,G); rs73226800(A,G); rs10086494(C,T); rs190129217(G,A); rs78507622(A,G); rs10087429(C,T); rs7002379(G,A); rs10091449(C,T); rs1982441(G,T); rs7812704(G,A); rs6985761(G,A); rs28529628(G,A); rs2015443(C,T); rs718343(T,C); rs351766(G,A); rs10106658(G,T); rs351765(C,T); rs2045694(C,T); rs181974988(C,T); rs4732629(A,G); rs351762(T,C); rs351761(T,A); rs79147362(T,C); rs2061587(A,C); rs11784168(T,C); rs76392385(C,G); rs12335090(A,G); rs17058684(G,T); rs113133661(G,A); rs73228804(T,C); rs351758(C,T); rs143025496(C,T); rs6558041(T,C); rs12543689(G,T); rs1599406(T,C); rs35393937(G,A); rs4295614(C,T); rs4317529(T,G); rs4732833(G,T); rs4570112(G,C); rs17058685(C,T); rs2322974(A,G); rs3857877(G,C); rs3857878(T,C); rs6982543(T,A); rs4732835(A,G); rs7845797(A,G); rs1350801(T,C); rs34762662(G,A); rs2126157(G,C); rs10090868(A,G); rs10104690(C,A); rs1381116(C,T); rs4732836(A,G); rs11786174(C,A); rs7838796(A,G); rs17058696(G,A); rs186925788(G,A); rs10088666(C,T); rs55737949(G,A); rs6558044(T,C); rs4732838(A,G); rs13275530(A,G); rs4266606(C,T); rs116651197(G,A); rs10087458(A,G); rs34685539(C,A); rs10104271(G,A); rs10104987(T,C); rs936473(A,G); rs6558045(T,A); rs201167042(C,T); rs28759287(G,A); rs6992370(A,C) |
| ccdsGene name | CCDS6065.1 |
| CosmicCodingMuts gene | ELP3 |
| cytoBand name | 8p21.1 |
| EntrezGene GeneID | 55140 |
| EntrezGene Description | elongator acetyltransferase complex subunit 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ELP3:NM_001284222:exon13:c.G1343A:p.R448H,ELP3:NM_001284226:exon12:c.G1109A:p.R370H,ELP3:NM_001284220:exon12:c.G1169A:p.R390H,ELP3:NM_001284224:exon11:c.G1028A:p.R343H,ELP3:NM_001284225:exon11:c.G1028A:p.R343H,ELP3:NM_018091:exon13:c.G1385A:p.R462H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6821 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DE19 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 6.506e-05,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
MUSCLE, SOFT TISSUE:
Muscle weakness, predominantly proximal (in some patients);
Gowers sign (in some patients);
Muscle biopsy shows fiber type variation (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, mild to moderate;
Speech delay;
Brain MRS shows decreased creatine content;
[Behavioral/psychiatric manifestations];
Autistic behavior
LABORATORY ABNORMALITIES:
Decreased plasma and urinary guanidinoacetate (GAA);
Organic aciduria
MISCELLANEOUS:
Onset in infancy;
Favorable response to oral creatine treatment
MOLECULAR BASIS:
Caused by mutation in the L-arginine:glycine amidinotransferase gene
(GATM, 602360.0001)
OMIM Title
*612722 ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 3; ELP3
;;ELONGATION PROTEIN 3, S. CEREVISIAE, HOMOLOG OF;;
KAT9
OMIM Description
DESCRIPTION
ELP3 is the catalytic subunit of the histone acetyltransferase elongator
complex, which contributes to transcript elongation and also regulates
the maturation of projection neurons (Creppe et al., 2009).
GENE FUNCTION
Wittschieben et al. (1999) showed that in yeast Elp3 is a histone
acetyltransferase (HAT) capable of acetylating core histones in vitro
and is essential to elongator complex function.
By examining the elongator complex purified from HeLa cells, Hawkes et
al. (2002) found that the complex existed in 2 forms, the
holo-elongator, which had histone acetyltransferase activity directed
against histones H3 (see 602810) and H4 (see 602822), and a 3-subunit
core form, which did not have histone acetyltransferase activity despite
containing the catalytic subunit ELP3. ELP2 (616054) and IKAP (IKBKAP;
603722) were also detected in the core elongator complex. ELP4 (606985),
ELP5 (615019), and ELP6 (615020) were detected in the active
holo-elongator complex. Hawkes et al. (2002) proposed that the elongator
complex serves a role in RNA polymerase II (see 180660)-associated
chromatin remodeling during transcriptional elongation.
Creppe et al. (2009) found that ELP3 interacted with endogenous ELP1
(IKBKAP), the scaffold subunit of the elongator complex, in all human
cell types examined. Depletion of Elp3 reduced the branching of
projection mouse neurons in vitro and in vivo, and Elp3-silenced
projection neurons displayed defects in radial migration. In human cell
lines, both ELP1 and ELP3 associated with microtubules, and depletion of
either ELP1 or ELP3 resulted in reduced acetylation of alpha-tubulin
(see TUBA1A; 602529). In HEK293 cells, ELP3 expression counteracted
HDAC6 (300272)-mediated alpha-tubulin deacetylation in a dose-dependent
manner, and this effect required the histone acetyltransferase domain of
ELP3.
Simpson et al. (2009) showed that knockdown of Elp3 by antisense
morpholinos in zebrafish embryos resulted in dose-dependent shortening
and abnormal branching of motor neurons with no concomitant morphologic
abnormalities.
To search for factors responsible for paternal DNA demethylation, Okada
et al. (2010) developed a live cell imaging system that allows the
monitoring of paternal DNA methylation state in zygotes. Through short
interfering RNA-mediated knockdown in mouse zygotes, Okada et al. (2010)
identified Elp3, a component of the elongator complex, to be important
for paternal DNA demethylation. Okada et al. (2010) demonstrated that
knockdown of Elp3 impairs paternal DNA demethylation as indicated by
reporter binding, immunostaining, and bisulfite sequencing. Similar
results were also obtained when other elongator components, Elp1 and
Elp4, were knocked down. Injection of mRNA encoding the Elp3 radical SAM
domain mutant, but not the HAT domain mutant, into MII oocytes before
fertilization also impaired paternal DNA demethylation, indicating that
the SAM radical domain is involved in the demethylation process. Okada
et al. (2010) concluded that their study not only established a critical
role for the elongator complex in zygotic paternal genome demethylation,
but also indicates that the demethylation process may be mediated
through a reaction that requires an intact radical SAM domain.
Using RNA interference, Close et al. (2012) found that depletion of any
of the elongator complex components Elp1, Elp3, Elp5, or Elp6 in B16-F10
mouse melanoma cells reduced cell motility in a wound-healing assay and
reduced the capacity of cells to form colonies in soft agar.
MAPPING
Hartz (2009) mapped the ELP3 gene to chromosome 8p21.1 based on an
alignment of the ELP3 sequence (GenBank GENBANK BC001240) with the
genomic sequence (build 36.1).
MOLECULAR GENETICS
Simpson et al. (2009) performed a multistage association study using
1,884 microsatellite markers in 3 populations totaling 781 ALS (105400)
patients and 702 control individuals. They identified a significant
association (p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in
intron 10 of the ELP3 gene. Fine mapping with SNPs in and around the
ELP3 gene identified a haplotype consisting of allele 6 of D8S1820 and
dbSNP rs12682496 strongly associated with ALS (p = 1.05 x 10(-6)).
LOC728024
| dbSNP name | rs150448924(G,A); rs77587080(T,G) |
| ccdsGene name | CCDS6095.1 |
| cytoBand name | 8p11.23 |
| EntrezGene GeneID | 728024 |
| snpEff Gene Name | ERLIN2 |
| EntrezGene Description | chromosome X open reading frame 56 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
ADRB3
| dbSNP name | rs4998(C,G) |
| cytoBand name | 8p11.23 |
| EntrezGene GeneID | 155 |
| EntrezGene Description | adrenoceptor beta 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09917 |
OMIM Clinical Significance
Mouth:
Mouth ulcerations
GU:
Genital ulcerations;
Epididymitis
Skin:
Erythema nodosum-like eruptions;
Superficial thrombophlebitis;
Pustular skin lesions;
Hyperirritability;
Raynaud phenomenon
Hair:
Alopecia areata
Neuro:
Brainstem syndrome;
Meningoencephalomyelitic syndrome;
Organic confusional state;
Schizoaffective disorder
Joints:
Arthritis
Eyes:
Uveitis;
Hypopyon;
Iritis;
Iridocyclitis;
Choreoretinitis
Inheritance:
Familial cases reported, but probably not Mendelian
OMIM Title
*109691 BETA-3-ADRENERGIC RECEPTOR; ADRB3
OMIM Description
CLONING
Emorine et al. (1989) isolated a third beta-adrenergic receptor,
beta-3-adrenergic receptor (ADRB3). (See ADRB1 (109630) and ADRB2
(109690).) Exposure of eukaryotic cells transfected with this gene to
adrenaline or noradrenaline promoted the accumulation of adenosine
3-prime,5-prime-monophosphate. The potency of beta-AR agonists and
inhibitors was described.
Van Spronsen et al. (1993) demonstrated that the transcription start
sites of the mouse and human ADRB3 mRNA are located in a region
comprised between 150 and 200 nucleotides 5-prime from the ATG
translation start codon. Motifs potentially implicated in heterologous
regulation of ADRB3 expression by glucocorticoids and by beta-adrenergic
agonists were identified upstream from these cap sites.
GENE STRUCTURE
Van Spronsen et al. (1993) described the exon/intron structure of the
mouse and human ADRB3 genes. Their results suggested that utilization of
alternate promoters and/or 3-prime untranslated regions may allow
tissue-specific regulation of the expression of ADRB3.
MAPPING
Wilkie et al. (1993) presented a list of G protein-coupled receptor
genes (their Table 3), indicating that the ADRB3 gene had been mapped to
8p12-p11.2 and the homologous gene to mouse chromosome 8.
MOLECULAR GENETICS
The beta-3-adrenergic receptor, located mainly in adipose tissue, is
involved in the regulation of lipolysis and thermogenesis. The potential
relevance of this receptor to obesity (see 601665) in humans led Clement
et al. (1995) to screen obese patients for the mutation in the ADRB3
gene that results in replacement of tryptophan by arginine at position
64 (W64R; 109691.0001). They studied DNA extracted from leukocytes of 94
normal subjects and 185 unrelated patients with morbid obesity, as
defined by a body-mass index (BMI; the weight in kilograms divided by
the square of the height in meters) greater than 40. The mutation was
detected by analysis of RFLPs with the restriction enzyme BstNI, which
discriminates between the normal and mutant sequences. The frequency of
the W64R variant was similar in the morbidly obese patients and the
normal subjects: 0.08 and 0.10, respectively. However, patients with
morbid obesity who were heterozygous for the allele had an increased
capacity to gain weight: the mean weight in the 14 heterozygous patients
was 140 kg, as compared with 126 kg in the 171 patients without the
mutation (P = 0.03). There were no homozygotes in this sample. The
cumulative 25-year change in weight (from the age of 20 years) was 67 kg
in W64R heterozygotes, as compared with 51 kg in those without the
mutation. The maximum weight differential (the maximal lifetime weight
minus the weight at 20 years of age) in the heterozygotes was 74 kg, as
compared with 59 kg in the patients without the mutation (P = 0.02).
Clement et al. (1995) interpreted the findings as indicating that the
ADRB3 gene mutation W64R increases the capacity to gain weight.
EVOLUTION
Cagliani et al. (2009) analyzed the recent evolutionary history of the
ADRB genes in humans, with particular concern to selective patterns.
Although their data suggested neutral selection for the ADRB1 gene, most
tests rejected neutral evolution for the ADRB2 and ADRB3 genes. The
ADRB3 gene appeared to be subject to a selective sweep in African
populations. Haplotype analysis indicated that of the 27 inferred ADRB3
haplotypes, those carrying the W64 allele occurred significantly less
frequently than expected under neutrality in the Nigerian Yoruba sample.
A similar but nonsignificant trend was also observed in the European
sample. Cagliani et al. (2009) concluded that there is directional
selection at the ADRB3 gene in African populations.
ANIMAL MODEL
To determine whether the sympathetic nervous system is the efferent arm
of diet-induced thermogenesis, Bachman et al. (2002) created mice that
lacked the beta-adrenergic receptors ADRB1, ADRB2, and ADRB3. Beta-less
mice on a chow diet had a reduced metabolic rate and were slightly
obese. On a high-fat diet, beta-less mice, in contrast to wildtype mice,
developed massive obesity that was due entirely to a failure of
diet-induced thermogenesis. Bachman et al. (2002) concluded that the
beta-adrenergic receptors are necessary for diet-induced thermogenesis
and that this efferent pathway plays a critical role in the body's
defense against diet-induced obesity.
RNF5P1
| dbSNP name | rs15078(G,A); rs327933(C,A); rs327934(C,T); rs7812668(T,C) |
| cytoBand name | 8p11.22 |
| EntrezGene GeneID | 286140 |
| EntrezGene Description | ring finger protein 5, E3 ubiquitin protein ligase pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4807 |
C8orf4
| dbSNP name | rs6474226(G,A); rs10199(A,G); rs73606287(A,G); rs28672910(C,G) |
| ccdsGene name | CCDS6115.1 |
| cytoBand name | 8p11.21 |
| EntrezGene GeneID | 56892 |
| EntrezGene Description | chromosome 8 open reading frame 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C8orf4:NM_020130:exon1:c.G28A:p.V10I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NR00 |
| dbNSFP Uniprot ID | CH004_HUMAN |
| dbNSFP KGp1 AF | 0.994505494505 |
| dbNSFP KGp1 Afr AF | 0.975609756098 |
| dbNSFP KGp1 Amr AF | 1.0 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.032229 |
| ESP All MAF | 0.011072 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.997 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Abnormal smooth pursuit;
Vertical gaze limitation;
Nystagmus (rare);
Optic atrophy (rare);
[Mouth];
Drooling (in some patients);
[Teeth];
Hypodontia (in some patients);
Oligodontia (in some patients)
ABDOMEN:
[Gastrointestinal];
Dysphagia (in some patients)
GENITOURINARY:
[Bladder];
Bladder dysfunction (rare)
NEUROLOGIC:
[Central nervous system];
Spasticity;
Ataxia;
Extensor plantar responses;
Hyperreflexia;
Motor regression;
Upper motor neuron signs;
Postural tremor;
Cerebellar signs;
Dysmetria;
Dysarthria;
Seizures, partial complex (rare);
Developmental delay, mild (in some);
Cognitive regression, mild;
Leukodystrophy;
Hypomyelination;
Thinning of the corpus callosum;
Cortical atrophy;
Cerebellar atrophy;
[Peripheral nervous system];
Peripheral neuropathy (some patients);
Decreased vibratory and positional sense (some patients)
ENDOCRINE FEATURES:
Hypogonadotropic hypogonadism (in some patients)
MISCELLANEOUS:
Onset in childhood (range 1 to 12 years);
Variable phenotype;
Progressive disorder;
Many patients become wheelchair-bound by second or third decade
MOLECULAR BASIS:
Caused by mutation in the RNA polymerase III, subunit A gene (POLR3A,
614258.0001)
OMIM Title
*607702 CHROMOSOME 8 OPEN READING FRAME 4; C8ORF4
;;THYROID CANCER 1; TC1
OMIM Description
CLONING
By subtractive hybridization between papillary thyroid carcinomas and
surrounding normal thyroid tissue, Chua et al. (2000) obtained a partial
cDNA, which they designated TC1. By 5-prime RACE and primer extension
analysis, they obtained the full-length TC1 cDNA, which encodes a
deduced 106-amino acid protein with a calculated molecular mass of about
12 kD. Northern blot analysis detected a 1.4-kb transcript in several
thyroid cancers. RNA dot-blot analysis revealed expression in all
tissues examined, with relatively lower levels in brain, thymus, and
leukocytes.
GENE FUNCTION
By Northern blot analysis and RT-PCR, Chua et al. (2000) found that TC1
was upregulated in 15 of 16 thyroid cancers.
By array CGH, Yang et al. (2006) analyzed the copy number and expression
level of genes in the 8p12-p11 amplicon in 22 human breast cancer
(114480) specimens and 7 breast cancer cell lines. Of the 21 potential
genes identified, PCR analysis and functional analysis indicated that 3
genes, LSM1 (607281), BAG4 (603884), and C8ORF4 are breast cancer
oncogenes that can work in combination to influence a transformed
phenotype in human mammary epithelial cells.
Kim et al. (2009) demonstrated TC1 expression in endothelial cells but
not monocyte lines. Transient expression results in upregulation of
cytokines, e.g., IL1A (147760) and IL6 (147620); chemokines, such as
CCL5 (187011), CXCL1 (155730), and IL8 (146930); and adhesion molecules
VCAM1 (192225) and ICAM1 (147840). Knockdown of TC1 results in
downregulation of these genes. TC1 expression enhances
monocyte-endothelial cell adhesion and increases endothelial cell
permeability. Expression of TC1 is NFKB (164011)-dependent and enhances
NFKB nuclear translocation and DNA binding. Kim et al. (2009) concluded
that TC1 is an endothelial inflammatory regulator that may be involved
in inflammatory vascular diseases.
GENE STRUCTURE
Chua et al. (2000) determined that the TC1 gene contains a single exon.
The promoter region contains a TATA box-like sequence and binding sites
for nuclear transcription factor Y (see 189903) and
CCAAT/enhancer-binding protein (see 116897).
MAPPING
By FISH, Chua et al. (2000) mapped the TC1 gene to chromosome 8p11.2.
ANIMAL MODEL
Kim et al. (2009) showed that the well-conserved TC1 protein is
expressed in the angio-hematopoietic system in zebrafish and, when
overexpressed, results in edema.
NKX6-3
| dbSNP name | rs58895504(C,A) |
| cytoBand name | 8p11.21 |
| EntrezGene GeneID | 157848 |
| EntrezGene Description | NK6 homeobox 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06382 |
| ESP Afr MAF | 0.114325 |
| ESP All MAF | 0.061334 |
| ESP Eur/Amr MAF | 0.034203 |
| ExAC AF | 0.033 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Normal birth length;
[Weight];
Normal birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Normal birth head circumference;
Microcephaly, acquired;
[Eyes];
Sparse eyebrows;
Sparse eyelashes
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy
SKIN, NAILS, HAIR:
[Skin];
Ichthyosis;
[Hair];
Sparse eyebrows;
Sparse eyelashes;
Minimal hair growth
NEUROLOGIC:
[Central nervous system];
Hypotonia, profound muscular (in some patients);
Seizures (in some patients);
Hypsarrhythmia (in some patients)
METABOLIC FEATURES:
Hypoketotic hypoglycemia (in some patients)
LABORATORY ABNORMALITIES:
Abnormal transferrin isoelectric focusing (IEF);
Increased disialo- and asialotransferrin;
Decreased lipid-linked oligosaccharides (LLO)
MISCELLANEOUS:
Death in early infancy (in some patients);
Some patients present with apparent nonsyndromic dilated cardiomyopathy
in early childhood
MOLECULAR BASIS:
Caused by mutation in the transmembrane protein 15 gene (TMEM15, 610746.0001)
OMIM Title
*610772 NK6 HOMEOBOX 3; NKX6-3
;;NK6, DROSOPHILA, HOMOLOG OF, 3;;
NKX6.3
OMIM Description
DESCRIPTION
The NKX family of homeodomain proteins controls numerous developmental
processes. Members of the NKX6 subfamily, including NKX6-3, are involved
in development of the central nervous system (CNS), gastrointestinal
tract, and pancreas (Alanentalo et al., 2006).
CLONING
By database analysis, Alanentalo et al. (2006) identified NKX6-3, which
is predicted to encode a 266-amino acid protein and shares 93.6% amino
acid identity with mouse Nkx6.3. The authors cloned mouse Nkx6.3, which
encodes a 262-amino acid protein with a calculated molecular mass of
28.7 kD. Similar to Nkx6.1 (602563) and Nkx6.2 (605955), mouse Nkx6.3
contains an N-terminal TN domain, which is involved in formation of
transcriptional repression complexes, a 60-amino acid homeodomain, and a
C-terminal 20-amino acid region.
GENE FUNCTION
Alanentalo et al. (2006) performed in situ hybridization studies on
mouse embryos. In contrast to Nkx6.1 and Nkx6.2 that are broadly
expressed in ventral positions of the developing CNS, expression of
Nkx6.3 was selective to a subpopulation of differentiating V2 neurons at
caudal hindbrain levels. Nkx6.3 expression was also detected in stomach
duodenal regions, limited to a more caudal region of the developing
stomach. Expression of Nkx6.3 shifted to overlap with Nkx6.2 in the
stomach between E10.5 and E12.5 and duodenal Nkx6.3 expression was
dramatically reduced between E16.5 and birth.
MAPPING
By genomic sequence analysis, Alanentalo et al. (2006) mapped the NKX6-3
gene to chromosome 8. The mouse Nkx6-3 gene mapped to mouse chromosome
8.
LOC100287846
| dbSNP name | rs6990363(T,G); rs149764146(T,C); rs13259872(C,T); rs11779308(A,G); rs185166292(C,T) |
| cytoBand name | 8q11.21 |
| EntrezGene GeneID | 100287846 |
| snpEff Gene Name | RP11-1134I14.8 |
| EntrezGene Description | patched 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2438 |
SBF1P1
| dbSNP name | rs2622585(A,T); rs6473987(C,T); rs2929052(T,A); rs2975987(G,A); rs2939632(C,T); rs2975986(G,C); rs2975985(G,A); rs2929050(G,C); rs2939633(A,G); rs2939634(A,G); rs2929049(T,C); rs2939635(C,G); rs867532(A,G); rs147358665(G,T); rs2929048(G,T); rs2975982(G,A); rs2929047(T,A); rs867531(T,C); rs867530(C,G); rs2929046(C,T); rs2975981(C,T); rs2929045(T,A); rs2939637(C,T); rs2975980(T,C); rs2929044(G,A); rs2939638(A,T); rs2929043(G,A); rs146965995(G,C); rs2939639(A,T); rs6473988(A,C); rs6473989(A,T); rs2929042(A,T) |
| ccdsGene name | CCDS34893.1 |
| cytoBand name | 8q12.1 |
| EntrezGene GeneID | 100133234 |
| snpEff Gene Name | XKR4 |
| EntrezGene Description | SET binding factor 1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2176 |
UG0898H09
| dbSNP name | rs57802569(G,A); rs78910069(G,C); rs5007413(A,C); rs60280139(G,A); rs16930023(G,A); rs16930025(T,C); rs16918945(A,G); rs16918948(A,G); rs4739032(G,A); rs16930036(T,C) |
| ccdsGene name | CCDS55239.1 |
| cytoBand name | 8q12.3 |
| EntrezGene GeneID | 643763 |
| snpEff Gene Name | NKAIN3 |
| EntrezGene Description | uncharacterized LOC643763 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1364 |
LOC401463
| dbSNP name | rs62519833(A,G); rs73689545(G,A) |
| cytoBand name | 8q12.3 |
| EntrezGene GeneID | 401463 |
| snpEff Gene Name | BHLHE22 |
| EntrezGene Description | uncharacterized LOC401463 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.107 |
BHLHE22
| dbSNP name | rs9650210(C,A) |
| cytoBand name | 8q12.3 |
| EntrezGene GeneID | 27319 |
| snpEff Gene Name | CYP7B1 |
| EntrezGene Description | basic helix-loop-helix family, member e22 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07622 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Recurrent skin infections;
Cellulitis
MUSCLE, SOFT TISSUE:
Lymphedema of the lower limbs;
Lymphedema of the hands (in some patients)
MISCELLANEOUS:
Onset in first or second decades;
Females tend to have earlier onset;
Reduced penetrance
MOLECULAR BASIS:
Caused by mutation in the Gap junction protein, gamma-2 gene (GJC2,
608803.0009)
OMIM Title
*613483 BASIC HELIX-LOOP-HELIX FAMILY, MEMBER E22; BHLHE22
;;BASIC HELIX-LOOP-HELIX DOMAIN-CONTAINING PROTEIN, CLASS B, 5; BHLHB5;;
BETA3
OMIM Description
DESCRIPTION
BHLHE22 belongs to the basic helix-loop-helix (bHLH) family of
transcription factors that regulate cell fate determination,
proliferation, and differentiation. These proteins function as dimers
and bind to an E-box DNA sequence (CANNTG). BHLHE22 is expressed
exclusively in the central nervous system and retina (Xu et al., 2002).
CLONING
By EST database analysis and screening a BAC library, Xu et al. (2002)
cloned human BHLHE22, which they called BHLHB5. The deduced 381-amino
acid protein has a calculated molecular mass of 37 kD and shares 94%
identity with the 355-amino acid mouse protein. BHLHB5 has an N-terminal
proline-rich domain, followed by a glycine-rich domain, a
polyglycine-serine region, a bHLH domain, and a C-terminal alanine-rich
region. The polyglycine-serine region of human BHLHB5 has a serine
stretch encoded by a 27-bp trinucleotide repeat (CAG)9 that is absent in
mouse and hamster Bhlhb5. The C-terminal 149 amino acids, including the
60-amino acid bHLH domain, is identical in human, mouse, and hamster
BHLHB5. Northern blot analysis of mouse tissues detected Bhlhb5
expression only in brain. RT-PCR analysis also revealed Bhlhb5
expression in mouse eye and in whole mouse embryo at 9.5 days
postcoitum. Northern blot analysis of human brain regions detected
BHLHB5 transcripts of 3.0 and 3.8 kb. Highest expression was in
cerebellum, followed by occipital pole and cerebral cortex, with lower
expression in frontal lobe, medulla, temporal lobe, and putamen. No
expression was detected in adult human spinal cord. In situ
hybridization showed Bhlhb5 expression in distinct regions of the
forebrain, hindbrain, and spinal cord in mouse embryos.
By immunohistochemical analysis of developing mouse retina, Feng et al.
(2006) found that Bhlhb5 was expressed in postmitotic cells in the early
mouse neuroblast layer and in select groups of cells of the inner
nuclear layer and ganglion cell layer at later stages. Coimmunolabeling
of Bhlhb5 and cell type-specific markers in adult mouse retina revealed
that expression of Bhlhb5 was restricted to GABAergic (see 137140)
amacrine cells and OFF-type cone bipolar cells.
Ross et al. (2010) observed Bhlhb5 in a subpopulation of late-born
neurons that migrated to the superficial layers of the dorsal horn of
the spinal cord in embryonic mice.
GENE FUNCTION
Xu et al. (2002) showed that mouse Bhlhb5 could repress expression of a
reporter gene driven by the human PAX6 (607108) promoter following
expression in several mammalian cell lines. Mutation of the DNA-binding
basic domain of Bhlhb5 had little effect on its repressive activity.
Bhlhb5 coimmunoprecipitated with the ubiquitous bHLH protein E12 (TCF3;
147141), suggesting that repression is mediated, at least in part, by
sequestration.
GENE STRUCTURE
Xu et al. (2002) determined that the mouse and human BHLHE22 genes
contain no introns. The human BHLHB5 gene contains 2 promoter regions.
MAPPING
Using FISH, Xu et al. (2002) mapped the BHLHE22 gene to chromosome 8q13.
They mapped the mouse Bhlhe22 gene to a region of chromosome 3A3 that
shares homology of synteny with human chromosome 8q13.
ANIMAL MODEL
Feng et al. (2006) found that Bhlhb5 -/- mice were born at a normal
mendelian ratio and were fertile, but they displayed slow weight gain
and developed skin lesions between 1 and 2 months of age. Examination of
Bhlhb5 -/- retinas showed reduced generation of specific retinal cell
subtypes, particularly cone bipolar cells and GABAergic amacrine cells
that normally express Bhlhb5.
Joshi et al. (2008) observed a highly stereotypical disruption of gene
expression patterns in the neocortex of Bhlhb5 -/- mice, with ectopic,
absent, or reduced expression of multiple area-specific genes in the
somatosensory and caudal motor cortices. There was significant
disruption of somatosensory cortical barrels and aberrant
differentiation of caudal corticospinal motor neurons, accompanied by
failure of corticospinal tract formation. Joshi et al. (2008) concluded
that Bhlhb5 is required for acquisition of area-specific properties by
postmitotic neurons of the somatosensory and caudal motor cortices.
Using electron microscopy, Ross et al. (2010) found no neuropathology in
the dorsal roots of Bhlhb5 -/- mice. However, they found that Bhlhb5 was
required for the continued survival of specific inhibitory neurons in
the superficial laminae of the dorsal horn. Loss of Bhlhb5 resulted in
loss of inhibitory neurons due to programmed cell death and led to the
development of pathologic skin lesions caused by enhanced scratching
responses to pruritic agents. Bhlhb5 -/- mice showed normal responses to
noxious mechanical, thermal, and chemical stimuli.
CRH
| dbSNP name | rs6159(T,G) |
| ccdsGene name | CCDS6188.1 |
| cytoBand name | 8q13.1 |
| EntrezGene GeneID | 1392 |
| EntrezGene Description | corticotropin releasing hormone |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CRH:NM_000756:exon2:c.A288C:p.G96G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3567 |
| ESP Afr MAF | 0.347662 |
| ESP All MAF | 0.158235 |
| ESP Eur/Amr MAF | 0.08102 |
| ExAC AF | 0.133 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Prenatal growth retardation;
Short stature;
Specific growth curves are available
HEAD AND NECK:
[Head];
Microcephaly;
Brachycephaly;
[Face];
Long philtrum;
Micrognathia;
[Ears];
Low-set ears;
Sensorineural hearing loss;
Conductive hearing loss to due otitis media;
[Eyes];
Synophrys;
Myopia;
Long curly eyelashes;
Ptosis;
[Nose];
Anteverted nostrils;
Depressed nasal bridge;
[Mouth];
Thin upper lip;
Downturned corners of the mouth;
High arched palate;
Cleft lip/palate;
[Teeth];
Widely spaced teeth;
Late-erupting teeth;
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Congenital heart defect
RESPIRATORY:
[Lung];
Pneumonia;
Congenital diaphragmatic hernia
CHEST:
[Breasts];
Small nipples
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux;
Pyloric stenosis
GENITOURINARY:
[External genitalia, male];
Hypoplastic male genitalia;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Structural anomalies of the renal tract;
Absent/poor corticomedullary differentiation (some patients);
Pelvic dilation (some patients);
Vesicoureteral reflux (rare);
Small kidney (rare);
Isolated renal cyst (rare);
Renal ectopia (rare);
Reduced renal function (in some patients with structural anomalies);
Proteinuria (rare)
SKELETAL:
[Limbs];
Limited elbow extension;
Dislocation of the radial head;
Phocomelia;
[Hands];
Single transverse palmar crease;
Proximally placed thumbs;
Fifth finger clinodactyly;
Oligodactyly;
[Feet];
Syndactyly of toes 2 and 3
SKIN, NAILS, HAIR:
[Skin];
Cutis marmorata;
Single transverse palmar crease;
[Hair];
Hirsutism;
Low posterior hair line
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Language delay;
Hypertonicity;
[Behavioral/psychiatric manifestations];
Self-injurious behavior
VOICE:
Low-pitched, growling cry in infancy
MISCELLANEOUS:
Highly variable phenotype;
Many cases due to de novo mutation or chromosome aberration;
Empiric risk for a sib of an affected child between 2 and 5%;
Prevalence of 0.6 to 10 per 100,000 individuals
MOLECULAR BASIS:
Caused by mutation in the Nipped-B-like gene (NIPBL, 608667.0001)
OMIM Title
*122560 CORTICOTROPIN-RELEASING HORMONE; CRH
;;CORTICOTROPIN-RELEASING FACTOR; CRF
OMIM Description
CLONING
Response to stress in mammals requires an intact
hypothalamic-pituitary-adrenal axis. The proximal part of the response
is mediated by secretion of corticotropin-releasing hormone (CRH) by the
paraventricular nucleus of the hypothalamus. CRH is a 41-amino acid
peptide derived by enzymatic cleavage from a 191-amino acid
preprohormone. Shibahara et al. (1983) cloned and sequenced the human
CRH gene.
MAPPING
Arbiser et al. (1988) assigned the gene for CRH to 8q13 by somatic cell
hybrid and in situ hybridization studies. The absence of secondary
hybridization strongly suggested that hypothalamic and placental CRH are
transcribed from the same gene. Kellogg et al. (1989) corroborated the
assignment to 8q13 by in situ hybridization. Knapp et al. (1993) showed
that the homologous gene is located on mouse chromosome 3.
GENE FUNCTION
Sasaki et al. (1987) measured plasma CRH levels during pregnancy, labor,
and delivery, and at 1 and 2 hours postpartum in 97 pregnant women.
Plasma CRH concentrations progressively increased during pregnancy,
correlated well with the weeks of pregnancy, and declined rapidly after
delivery. Umbilical cord CRH levels were much lower than those in
corresponding maternal plasma, suggesting that CRH is preferentially
secreted into the maternal circulation. Maternal plasma CRH-sized
material, obtained by affinity chromatography and gel filtration,
stimulated ACTH release from anterior pituitary tissue in a
dose-dependent manner and was equipotent with rat CRH. Sasaki et al.
(1987) suggested that placental CRH might be an important stimulator of
the maternal pituitary-adrenal axis during pregnancy, labor, and
delivery.
Campbell et al. (1987) measured plasma CRH levels throughout the third
trimester of pregnancy, during labor, and postpartum in 80 normal
pregnant women and 49 women with pregnancy-induced hypertension (PIH;
see PEE1, 189800). In normal pregnant women, plasma CRH levels increased
markedly at 40 weeks and remained so during labor. Women with PIH had
plasma CRH levels significantly elevated above that normal range, as did
11 women from the 'normal' group who subsequently went into premature
labor. After delivery, plasma CRH returned to normal within 15 hours.
Total plasma cortisol levels varied little throughout the third
trimester, but increased during labor and remained elevated for 2 to 3
days postpartum. There was, therefore, no correlation between plasma
cortisol and CRH, implying that placental CRH is not primarily involved
in the control of the maternal hypothalamopituitary adrenal axis during
pregnancy. Campbell et al. (1987) also noted that concentrations of CRH
in umbilical cord plasma samples were considerably lower than those in
the maternal circulation and were close to those in normal nonpregnant
adults.
Robinson et al. (1988) established primary cultures of purified human
cytotrophoblasts to examine the effect of glucocorticoids on the
expression of the CRH gene in placenta. The authors found that
glucocorticoids stimulate synthesis of placental CRH, as demonstrated by
slot blot hybridization of RNA prepared from cytotrophoblasts. In
addition, using the technique of RNase H digestion of a heteroduplex
between CRH mRNA and a synthetic oligonucleotide complementary to the
5-prime CRH mRNA, the authors demonstrated the transcriptional
initiation site of the CRH gene. The authors speculated on the role of
this regulatory mechanism on the levels of fetal glucocorticoids in the
pre- and postparturition periods.
CRH is made not only in the hypothalamus but also in peripheral tissues,
such as T lymphocytes, and is expressed in very large amounts in the
human placenta (Robinson et al., 1988).
McLean et al. (1995) presented evidence that placental secretion of CRH
is a marker of the 'placental clock' that is active from an early stage
in human pregnancy and determines the length of gestation and the timing
of parturition and delivery. Using a prospective, longitudinal cohort
study of 485 pregnant women, McLean et al. (1995) demonstrated that
placental secretion of CRH, measured as maternal plasma CRH
concentration as early as 16 to 20 weeks of gestation, identified groups
of women destined to experience normal term, preterm, or post-term
delivery. An exponential rise in maternal plasma CRH concentrations with
advancing pregnancy is associated with a concomitant fall in
concentrations of the specific CRH-binding protein (CRHBP; 122559) in
late pregnancy, leading to a rapid increase in circulating levels of
bioavailable CRH at the onset of parturition, suggesting that CRH may
act directly as a trigger for parturition in humans.
Behan et al. (1995) observed that the marked reduction in CRF found in
Alzheimer disease (AD; e.g., 104300) is due to CRFBP (CRHBP; 122559), a
high-affinity binding protein that inactivates CRF. The authors showed
that ligands which interfere with this process in AD raise free CRF
levels to that of controls. Behan et al. (1995) also studied the
learning and memory effects of a CRF-receptor agonist and a CRFBP ligand
in rats.
Asakura et al. (1997) localized immunoreactive corticotropin-releasing
factor (IrCRF) and its mRNA to the thecal cells of small antral and
mature follicles of the human ovary. A low abundance of IrCRF and mRNA
was also detected in stromal cells of both stages of follicles. Greater
CRF gene expression was seen in mature than in small antral follicles.
CRF receptor (CRFR1; 122561) mRNA signal was found exclusively in thecal
cells of mature follicles and moderately in small antral follicles.
Granulosa cells were devoid of CRF and CRFR1 mRNAs and proteins. The
authors concluded that the thecal compartment of the human ovary
contains a CRF system endowed with CRF, CRFR1, and the CRFBP protein
while granulosa cells are devoid of this system.
In choriocarcinoma cell lines, activation of cAMP-dependent pathways
increases human CRH reporter gene expression. Scatena and Adler (1998)
identified a cAMP-responsive region between -200 and -99 bp of the CRH
promoter, distinct from the cAMP response element (CRE) at -220 bp, and
also identified a candidate transcription factor present in nuclear
extracts of human, but not rodent, choriocarcinoma cell lines. This
region, which does not contain a canonical CRE, transfers protein kinase
A (EC 2.7.1.37; see 176911) responsiveness to a heterologous promoter.
Using electromobility shift assays and methylation and uracil
interference studies, Scatena and Adler (1998) localized factor binding
to a 20-bp region from -128 to -109 bp of the CRH promoter. This 20-bp
fragment exhibited a similar shift in nuclear extracts from both human
term placenta and from human JEG-3 cells. Although this factor
participates in cAMP-regulated gene expression, competition
electrophoretic mobility assays demonstrated that the factor does not
bind to a CRE. Furthermore, neither anti-CREB (123810) nor anti-ATF2
(123811) antibodies altered factor binding. The authors concluded that
this 58-kD protein is the human-specific CRH activator previously
identified (Scatena and Adler, 1996) as contributing to the
species-specific expression of CRH in human placenta.
Xu et al. (2000) investigated the effects of CRH expression in human
pituitary corticotroph adenomas (PCAs). CRH mRNA transcripts were
demonstrated on paraffin sections using the quantitative in situ
hybridization method in 37 of 43 PCAs, including 17 of 22 microadenomas,
15 of 15 macroadenomas, and 5 of 6 locally invasive adenomas according
to Hardy's classification of pituitary adenomas. The more important
findings were that CRH mRNA signal intensity in pituitary corticotroph
adenoma cells was linearly correlated with Ki-67 (176741) tumor growth
fractions, and in macroadenoma and locally invasive adenoma cells it was
significantly higher than in microadenoma cells. On the other hand, CRH
mRNA transcript accumulation was absent or negligible in 10 normal
pituitary glands. The authors concluded that CRH from a local source of
corticotroph adenoma cells not only has autocrine/paracrine functions in
corticotroph adenomatous tissue, but also is an important factor
associated with a proliferative potential of PCAs.
Cheng et al. (2000) explored the effect of cAMP on CRH promoter activity
in primary cultures of human placental cells. Both forskolin and
8-bromo-cAMP, activators of protein kinase A, can increase CRH promoter
activity 5-fold in transiently transfected human primary placental
cells, in a manner that parallels the increase in endogenous CRH
peptide. Electrophoretic mobility shift assay and mutation analysis
combined with transient transfection demonstrated that in placental
cells cAMP stimulates CRH gene expression through a cAMP regulatory
element in the proximal CRH promoter region and involves a placental
nuclear protein interacting specifically with the cAMP regulatory
element.
It has been suggested that CRH is a placental clock that controls the
duration of pregnancy and that the timing of the rise in CRH may permit
prediction of the onset of labor. Inder et al. (2001) performed a
prospective longitudinal study, in 297 women, to examine the utility of
a single second-trimester plasma CRH measurement to predict preterm
delivery. Sampling for plasma CRH at 26 weeks' gestation seemed the
optimal time point to maximize sensitivity and specificity of the test.
The mean (+/- SD) plasma CRH in women at this gestation who eventually
delivered after spontaneous labor within 1 week of their due date (39 to
41 weeks, n = 127) was 34.7 +/- 27.0 pM. A plasma CRH of more than 90 pM
at 26 weeks' gestation had a sensitivity of 45% and a specificity of 94%
for prediction of preterm delivery. The authors concluded that a single
measurement of plasma CRH, toward the end of the second trimester, may
identify a group at risk for preterm delivery, but over 50% of such
deliveries will be unpredicted. These data do not support the routine
clinical use of plasma CRH as a predictor of preterm labor.
Makrigiannakis et al. (2001) observed decreased FASL expression in human
extravillous trophoblasts and choriocarcinoma cell lines following
treatment with the CRHR1 antagonist antalarmin. In contrast, CRH
increased FASL expression and induced apoptosis of activated T cells,
and antalarmin inhibited this effect. Treatment of female rats with
antalarmin resulted in a marked decrease in implantation sites and live
embryos, as well as diminished endometrial Fasl expression. Embryos from
T cell-deficient mothers or from syngeneic matings were not rejected
when mothers were given antalarmin. Makrigiannakis et al. (2001)
proposed that locally produced CRH promotes implantation and the
maintenance of early pregnancy by killing activated T cells.
Sebaceous glands may be involved in a pathway conceptually similar to
that of the hypothalamic-pituitary-adrenal (HPA) axis. CRH is the most
proximal element of the HPA axis, and it acts as a central coordinator
for neuroendocrine and behavioral responses to stress. To examine the
probability of an HPA equivalent pathway in sebaceous glands, Zouboulis
et al. (2002) investigated the expression of CRH, CRH-binding protein,
CRHBP (122559), and CRH receptors (CRHR1, 122561 and CRHR2, 602034) in
sebocytes in vitro and their regulation by CRH and several other
hormones. CRHR1 was the predominant type, being twice as abundant as
CRHR2. CRH was biologically active on human sebocytes; it induced
biphasic increase in synthesis of sebaceous lipids, although it did not
affect cell viability, cell proliferation, or IL1B (147720)-induced IL8
(146930) release. Zouboulis et al. (2002) interpreted these and other
findings as indicating that CRH may be an autocrine hormone for human
sebocytes that exerts homeostatic lipogenic activity, whereas
testosterone and growth hormone induced CRH negative feedback. The
findings implicated CRH in the clinical development of acne, seborrhea,
androgenetic alopecia, skin aging, xerosis, and other skin disorders
associated with alterations in lipid formation of sebaceous origin.
Maji et al. (2009) found that peptide and protein hormones, including
CRF, in secretory granules of the endocrine system are stored in an
amyloid-like cross-beta-sheet-rich conformation, and concluded that
functional amyloids in the pituitary and other organs can contribute to
normal cell and tissue physiology.
Lemos et al. (2012) reported that CRF, a neuropeptide released in
response to acute stressors and other arousing environmental stimuli,
acts in the nucleus accumbens of naive mice to increase dopamine release
through coactivation of the receptors CRFR1 and CRFR2. Remarkably,
severe-stress exposure completely abolished this effect without recovery
for at least 90 days. This loss of CRF's capacity to regulate dopamine
release in the nucleus accumbens is accompanied by a switch in the
reaction to CRF from appetitive to aversive, indicating a diametric
change in the emotional response to acute stressors. Lemos et al. (2012)
concluded that their results offer a biologic substrate for the switch
in affect which is central to stress-induced depressive disorders.
ANIMAL MODEL
To find the importance of CRH in the response of the
hypothalamic-pituitary-adrenal axis to stress and its role in fetal
development, Muglia et al. (1995) constructed a mouse model of CRH
deficiency by targeted mutation in embryonic stem cells. They reported
that CRH-deficient mice reveal a fetal glucocorticoid requirement for
lung maturation. Postnatally, however, despite marked glucocorticoid
deficiency, the mice exhibited normal growth, fertility, and longevity,
suggesting that the major role of glucocorticoid occurs during fetal,
rather than postnatal, life.
In adult male rhesus macaques, Habib et al. (2000) evaluated the effects
of a lipophilic nonpeptide antagonist to CRH type 1 receptor,
antalarmin, on the behavioral, neuroendocrine, and autonomic components
of the stress response. After oral administration, significant
antalarmin concentrations were detected in the systemic circulation and
the cerebrospinal fluid. The monkeys were exposed to an intense social
stressor, namely, placement of 2 unfamiliar males in adjacent cages
separated only by a transparent Plexiglas screen. Antalarmin
significantly inhibited a repertoire of behaviors associated with
anxiety and fear, such as body tremors, grimacing, teeth gnashing,
urination, and defecation. In contrast, antalarmin increased exploratory
and sexual behaviors that are normally suppressed during stress.
Moreover, antalarmin significantly diminished the increases in
cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic,
and adrenal medullary responses to stress. Habib et al. (2000) suggested
that a CRH type 1 receptor antagonist may be of therapeutic value in
human psychiatric, reproductive, and cardiovascular disorders associated
with CRH system hyperactivity.
Using a turpentine-induced model of subacute inflammation in Crh -/-
mice, Venihaki et al. (2001) demonstrated that during inflammation Crh
is required for a normal adrenocorticotropin hormone (ACTH) increase but
not for adrenal corticosterone rise. A paradoxical increase of plasma
interleukin-6 (IL6; 147620) associated with Crh deficiency suggested
that regulation of Il6 release during inflammation is Crh dependent.
Venihaki et al. (2001) also demonstrated that adrenal Il6 expression is
Crh dependent, as its basal and inflammation-induced expression was
blocked by Crh deficiency. Mice deficient in both Crh and Il6 had a flat
hypothalamic-pituitary-adrenal response to inflammation.
Donelan et al. (2006) used intradermal injection of various peptides to
assess vascular permeability, as measured by Evans blue extravasation,
in rat skin. They found that Crh and neurotensin (NTS; 162650) potently
induced vascular permeability. The effect of Crh and Nts was blocked by
a neurotensin receptor (see NTSR1; 162651) antagonist and did not occur
in Nts -/- mice. RT-PCR analysis showed that Crh and Nts were present in
dorsal root ganglia and that Crhr was expressed on mouse skin mast
cells. Donelan et al. (2006) concluded that NTS is involved in the
action of CRH. They suggested that mast cell-neuron interactions and
mast cell activation may be involved in the pathophysiology of skin
conditions such as atopic dermatitis, urticaria, and psoriasis.
HISTORY
In a consanguineous kindred in Israel, Mandel et al. (1990) identified
11 children with autosomal recessive hypothalamic corticotropin
deficiency. Death without diagnosis occurred in 7. The affected children
studied extensively numbered 4; 2 were diagnosed prenatally. The first
diagnosed patient presented at age 2 months with hypoglycemia,
hepatitis, facial dysmorphism, convulsions, and agenesis of the corpus
callosum. The prenatal diagnosis was suggested by low maternal urinary
estriol and confirmed at birth by undetectable levels of cortisol and
ACTH (176830). Treatment with cortisol resulted in normal development.
Growth hormone deficiency and a thyroid organification defect were
secondary to adrenal insufficiency. The disorder was clearly an
autosomal recessive. Majzoub (1995) stated that the findings in this
Bedouin family had not been reported in full. Linkage was being used to
determine whether CRH deficiency was indeed present.
LOC101241902
| dbSNP name | rs1483572(A,C); rs3739330(G,A); rs2046338(C,A); rs2046339(T,C); rs2717544(G,T) |
| cytoBand name | 8q21.12 |
| EntrezGene GeneID | 101241902 |
| snpEff Gene Name | IL7 |
| EntrezGene Description | chromosome 4 open reading frame 46 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4495 |
SLC10A5
| dbSNP name | rs6995098(T,C); rs2955006(A,G); rs75101336(C,T) |
| ccdsGene name | CCDS34915.1 |
| cytoBand name | 8q21.13 |
| EntrezGene GeneID | 347051 |
| EntrezGene Description | solute carrier family 10, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC10A5:NM_001010893:exon1:c.A792G:p.S264S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0753 |
| ESP Afr MAF | 0.111666 |
| ESP All MAF | 0.058204 |
| ESP Eur/Amr MAF | 0.030814 |
| ExAC AF | 0.049 |
DCAF4L2
| dbSNP name | rs147877561(G,A); rs113061626(G,A); rs139114827(G,T); rs149447989(G,C) |
| cytoBand name | 8q21.3 |
| EntrezGene GeneID | 138009 |
| EntrezGene Description | DDB1 and CUL4 associated factor 4-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005969 |
MIR8084
| dbSNP name | rs404337(G,A) |
| cytoBand name | 8q22.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3714 |
| ExAC AF | 0.445 |
RBM12B-AS1
| dbSNP name | rs3813853(G,A) |
| cytoBand name | 8q22.1 |
| EntrezGene GeneID | 389677 |
| EntrezGene Symbol | RBM12B |
| snpEff Gene Name | C8orf39 |
| EntrezGene Description | RNA binding motif protein 12B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.426282051282 |
| dbNSFP KGp1 Afr AF | 0.563008130081 |
| dbNSFP KGp1 Amr AF | 0.397790055249 |
| dbNSFP KGp1 Asn AF | 0.454545454545 |
| dbNSFP KGp1 Eur AF | 0.32981530343 |
| dbSNP GMAF | 0.4265 |
| ExAC AF | 0.282 |
LOC100288748
| dbSNP name | rs62523408(C,T); rs13266676(C,T); rs7824334(T,G); rs12679585(G,A); rs13268847(C,G); rs2162237(A,C) |
| cytoBand name | 8q22.1 |
| EntrezGene GeneID | 100288748 |
| snpEff Gene Name | ESRP1 |
| EntrezGene Description | uncharacterized LOC100288748 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2502 |
LOC100500773
| dbSNP name | rs75325762(A,G); rs75309483(G,A); rs74327923(G,T); rs10504957(C,A); rs116472792(C,T); rs10504958(T,C); rs17769268(C,T); rs75346548(C,T); rs76409586(G,A); rs74657812(C,T) |
| cytoBand name | 8q22.1 |
| EntrezGene GeneID | 100500773 |
| snpEff Gene Name | RP11-31K23.1 |
| EntrezGene Description | serine/arginine-rich splicing factor 3 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03535 |
TSPYL5
| dbSNP name | rs2583501(A,G); rs2635163(A,G) |
| cytoBand name | 8q22.1 |
| EntrezGene GeneID | 101927066 |
| EntrezGene Symbol | LOC101927066 |
| EntrezGene Description | uncharacterized LOC101927066 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2094 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Porokeratosis;
Small conically shaped papules (1 to 3 mm in diameter) located on
face, neck, trunk, and limbs;
Papules enlarge centrifugally to form central atrophic area with an
irregular keratotic ridge;
Linear porokeratosis (1 patient);
HISTOLOGY:;
Invagination of the epidermis;
Column of parakeratotic cells overlying absent granular layer
MISCELLANEOUS:
Onset in young adulthood;
Lesions become more prominent with sun exposure;
Intrafamilial variability;
One Chinese family has been reported (last curated July 2012)
OMIM Title
*614721 TSPY-LIKE 5; TSPYL5
;;KIAA1750
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated adult hippocampus
cDNA library, Nagase et al. (2000) cloned TSPYL5, which they designated
KIAA1750. The transcript contains a repetitive element in its 3-prime
end, and the deduced protein contains 431 amino acids. RT-PCR ELISA
detected low TSPYL5 expression in all adult and fetal tissues and
specific adult brain regions examined.
GENE FUNCTION
Jung et al. (2008) found that expression of TSPYL5 was downregulated in
7 of 9 gastric cancer cell lines and that downregulation correlated with
hypermethylation of the TSPYL5 CpG island. Methylation-specific PCR
revealed a high frequency of TSPYL5 hypermethylation in primary gastric
tumors compared with normal tissues. Transfection of TSPYL5 suppressed
the ability of gastric cancer cell lines to form colonies in soft agar.
Kim et al. (2010) observed hypomethylation of TSPYL5 in A549 lung
adenocarcinoma cells, which are relatively resistant to gamma radiation,
compared with H460 lung cancer cells, which are more sensitive to gamma
radiation. Knockdown of TSPYL5 expression via small interfering RNA in
A549 cells inhibited cell growth and colony formation. Knockdown of
TSPYL5 also elevated PTEN (601728) and p21 (CDKN1A; 116899) cellular
levels and inhibited AKT (see 164730) activation, but it did not alter
the EGFR (131550)/AKT pathway. Conversely, overexpression of TSYPL5
protected H460 cells from gamma radiation-induced damage, concomitant
with p21 and PTEN downregulation and AKT activation.
Using expression analysis, Epping et al. (2011) identified TSPYL5
expression as a marker for poor prognosis in breast cancers, with
highest TSPYL5 expression in basal-like breast cancers. Affinity
purification and mass spectrometric analysis of MCF7 and primary human
fibroblasts revealed that TSPYL5 interacted with ubiquitin-specific
protease-7 (USP7; 602519) and reduced USP7 activity toward p53 (TP53;
191170). Consequently, interaction of TSPYL5 with USP7 increased the
rate of p53 ubiquitination and degradation and reversed p53-dependent
cell proliferation arrest and senescence.
GENE STRUCTURE
Jung et al. (2008) determined that the 5-prime end of the TSPYL5 gene,
including exon 1, is contained within a CpG island. The first exon
contains the translational start site.
MAPPING
Epping et al. (2011) stated that the TSPYL5 gene maps to chromosome
8q22.
KCNS2
| dbSNP name | rs3802197(G,T) |
| cytoBand name | 8q22.2 |
| EntrezGene GeneID | 3788 |
| snpEff Gene Name | STK3 |
| EntrezGene Description | potassium voltage-gated channel, delayed-rectifier, subfamily S, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3136 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602906 POTASSIUM CHANNEL, VOLTAGE-GATED, DELAYED-RECTIFIER, SUBFAMILY S,
MEMBER 2; KCNS2
;;VOLTAGE-GATED POTASSIUM CHANNEL 9.2; KV9.2
OMIM Description
DESCRIPTION
Voltage-gated potassium channels (Kv) form the largest and most
diversified class of ion channels. These proteins are present in both
excitable and nonexcitable cells. Their main functions are associated
with the regulation of the resting membrane potential and the control of
the shape and frequency of action potentials. The KCNS2 gene encodes a
neuronal modulatory alpha subunit, Kv9.2 (summary by Salinas et al.,
1997).
CLONING
By searching an expressed sequence tag (EST) database with the peptide
sequence of the silent Kv8.1 alpha subunit (KCNV1; 608164), Salinas et
al. (1997) identified human cDNAs encoding KCNS2, which they called
Kv9.2. Using these ESTs, the authors isolated a mouse Kcns2 cDNA from a
brain cDNA library. The predicted 477-amino acid Kcns2 protein has all
of the structural characteristics of an outward rectifier Kv alpha
subunit, namely 6 transmembrane domains, a transmembrane region with 5
positively charged amino acids, and a conserved pore-forming region.
Several putative phosphorylation sites are located in the cytoplasmic
regions. Northern blot analysis showed that Kcns2 is expressed only in
the brain. In situ hybridization detected high levels of Kcns2 mRNA in
the olfactory bulb, cerebral cortex, hippocampal formation, habenula,
basolateral amygdaloid nuclei, and cerebellum; expression was also found
in the retina and spinal cord.
GENE FUNCTION
Salinas et al. (1997) demonstrated that mouse Kcns2 does not have
potassium channel activity by itself but can modulate the activities of
the Kv2.1 (see KCNB1, 600397) and Kv2.2 alpha subunits.
MAPPING
By fluorescence in situ hybridization and radiation hybrid mapping,
Banfi et al. (1996) mapped an EST (GenBank GENBANK R19352) corresponding
to the human KCNS2 gene (Salinas et al., 1997) to chromosome 8q22.
Gross (2012) mapped the KCNS2 gene to chromosome 8q22.2 based on an
alignment of the KCNS2 sequence (GenBank GENBANK BC027932) with the
genomic sequence (GRCh37).
NACAP1
| dbSNP name | rs112132843(G,A); rs10108277(C,T); rs113137949(T,C); rs10095458(T,C) |
| cytoBand name | 8q22.3 |
| EntrezGene GeneID | 83955 |
| EntrezGene Description | nascent-polypeptide-associated complex alpha polypeptide pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01194 |
| ExAC AF | 0.003887 |
MIR5680
| dbSNP name | rs12549434(T,C); rs487571(T,C) |
| cytoBand name | 8q22.3 |
| EntrezGene GeneID | 100847001 |
| snpEff Gene Name | NCALD |
| EntrezGene Description | microRNA 5680 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07025 |
| ExAC AF | 0.02 |
COL14A1
| dbSNP name | rs140034015(G,A); rs61037895(C,T); rs4369033(C,A); rs4588897(A,G); rs60830936(T,C); rs74488171(G,A); rs7820004(C,T); rs7838551(T,C); rs4407920(G,A); rs73317770(G,A); rs113907438(C,G); rs35529075(C,G); rs4871042(C,G); rs73704239(A,T); rs4271006(T,G); rs73317779(C,T); rs77939324(T,C); rs77678583(T,G); rs36107869(G,A); rs147378102(G,A); rs10086829(G,A); rs73317783(G,C); rs4376529(A,G); rs7827802(A,T); rs76315210(T,C); rs4364673(A,C); rs12546625(G,A); rs73704241(A,G); rs112797635(A,G); rs4407921(C,T); rs73704242(A,C); rs7846067(C,T); rs7846510(C,A); rs7816925(A,T); rs7818027(G,C); rs4871044(C,T); rs6995843(C,T); rs60298200(G,A); rs59742638(G,A); rs6469901(A,C); rs7828948(T,A); rs79597068(A,G); rs371046461(C,T); rs10101000(C,G); rs7460965(C,T); rs6996015(G,A); rs7000103(A,C); rs10808507(G,A); rs6983133(T,G); rs4133251(A,G); rs4541974(T,C); rs4871045(T,C); rs10738134(T,C); rs7840217(C,G); rs4398968(G,T); rs35420329(G,A); rs141537506(C,T); rs74556922(A,C); rs6469902(A,T); rs117068860(C,T); rs10087151(G,A); rs77314077(T,C); rs73319711(A,C); rs114319871(T,G); rs58517661(T,C); rs112953380(T,C); rs7459829(C,T); rs12543460(G,A); rs188477279(C,T); rs140010778(C,T); rs115698005(A,T); rs4478617(G,A); rs4871046(T,C); rs4601361(A,G); rs7824436(C,T); rs75073234(T,C); rs10110722(G,A); rs115427781(C,T); rs13276675(C,T); rs1869830(A,G); rs16893621(G,A); rs1563387(G,T); rs2124471(C,A); rs56122736(G,A); rs2198751(C,T); rs147202135(G,A); rs7015331(C,T); rs7002691(A,G); rs72675779(T,C); rs16893630(C,A); rs12541735(C,T); rs12545031(T,C); rs961223(G,C); rs113040845(A,G); rs62526993(C,T); rs6980706(A,G); rs67893286(A,G); rs2326481(T,C); rs12543951(G,A); rs148283759(C,G); rs189870098(T,C); rs113117932(T,C); rs2198755(T,C); rs138171534(G,T); rs4870721(C,G); rs13257307(A,C); rs7386673(T,G); rs11997372(T,C); rs145668905(G,A); rs11993652(C,T); rs7842537(A,G); rs150017323(A,G); rs62527009(G,C); rs187358530(A,G); rs2198749(A,G); rs2219244(T,C); rs7005932(G,A); rs10955958(A,G); rs11992259(C,G); rs4421388(C,A); rs7829249(T,C); rs35439635(T,G); rs12547879(C,G); rs62527010(C,T); rs149263552(T,A); rs7834184(T,G); rs34368129(G,A); rs34706724(T,C); rs74634507(A,T); rs12549898(G,A); rs10955959(A,G); rs7814963(T,A); rs13275053(A,C); rs13275595(C,T); rs113322584(C,T); rs6998988(A,G); rs7004406(A,T); rs112711816(C,T); rs13261812(T,A); rs16893639(A,G); rs2305597(A,C); rs61729463(G,C); rs7015242(C,T); rs2305598(T,C); rs2305599(C,T); rs72675793(C,T); rs73327330(G,A); rs2326483(C,T); rs72675794(G,A); rs7013781(G,A); rs7013555(A,G); rs7018328(C,G); rs6980799(G,A); rs61754508(C,T); rs2305600(T,C); rs2054148(C,T); rs116135978(T,A); rs115108697(A,G); rs113153517(C,G); rs10955961(T,C); rs111359440(T,C); rs10955962(A,T); rs143476114(G,A); rs957694(T,C); rs957696(A,G); rs3765062(G,A); rs7841837(G,A); rs2875940(C,T); rs921861(A,C); rs10505377(C,G); rs6994973(G,T); rs11786178(A,G); rs114014347(T,C); rs76103299(A,G); rs2034841(T,C); rs2034842(T,C); rs116527668(A,G); rs114701864(G,A); rs2219246(A,C); rs74818061(A,G); rs12547117(C,T); rs12542144(A,G); rs10808508(C,T); rs10808509(C,T); rs139902428(G,A); rs114751580(T,C); rs4870722(T,C); rs4870723(A,C); rs112022680(T,C); rs4870724(T,G); rs4870725(G,A); rs7387373(C,T); rs56159702(T,C); rs58829748(C,T); rs12543412(T,C); rs6996780(T,C); rs79137215(C,T); rs148875457(T,G); rs75432165(T,G); rs11773991(T,C); rs6988293(G,A); rs6989074(G,A); rs10110806(C,T); rs13277399(T,C); rs4871047(C,T); rs12550446(G,A); rs7833313(A,G); rs75357595(C,A); rs61753754(G,A); rs1993392(G,A); rs10100745(T,C); rs10086059(C,T); rs11991690(A,G); rs10089433(A,T); rs2290519(C,T); rs7842055(G,T); rs12679689(A,G); rs10093861(A,G); rs10094424(G,A); rs144534520(G,A); rs4871048(C,T); rs4871049(G,A); rs145372708(T,C); rs7813202(G,T); rs117754724(T,C); rs116298813(T,G); rs6469903(T,C); rs142337564(G,A); rs139142451(T,C); rs7017267(T,C); rs147478089(C,T); rs2198752(T,C); rs79043846(G,A); rs7832461(G,A); rs28889138(C,G); rs7832647(C,T); rs79806422(G,T); rs10955963(T,C); rs35688244(G,A); rs12546577(C,G); rs144679815(T,C); rs60791395(C,T); rs4871050(C,G); rs7013077(G,A); rs10505378(T,G); rs76030368(C,T); rs35932543(T,A); rs959537(T,G); rs16893710(T,C); rs10955964(T,C); rs16893712(G,A); rs11781442(G,A); rs116964119(C,T); rs112449017(G,T); rs77101749(C,T); rs2305603(T,C); rs57278901(C,A); rs1010830(T,G); rs114908989(G,A); rs1010831(A,C); rs12542829(A,G); rs12547847(G,A); rs112795888(A,G); rs16893725(G,A); rs16893728(A,C); rs13258857(G,C); rs76461739(G,A); rs13258640(C,A); rs4871051(A,C); rs2305604(T,C); rs2305605(G,A); rs61738288(C,T); rs4307383(T,C); rs111953360(G,A); rs113252138(A,G); rs75089118(A,G); rs4871052(G,T); rs2305607(A,G); rs7813903(A,C); rs116380802(C,T); rs7823333(A,T); rs17827510(A,G); rs2198754(C,T); rs10481069(C,T); rs113703593(C,T); rs10111291(A,G); rs1006203(A,G); rs993823(C,T); rs78572620(A,G); rs3750255(A,G); rs7008903(A,G); rs1563400(C,T); rs1006657(A,T); rs10955966(G,T); rs11990441(T,A); rs11990470(T,C); rs7813088(A,C); rs7813506(A,G); rs7814222(G,A); rs78063722(T,C); rs79029535(A,G); rs17236463(T,A); rs146907278(T,C); rs17833361(G,A); rs2290520(A,C); rs201060029(A,G); rs149149415(G,A); rs959370(T,C); rs17833457(T,G); rs79283227(A,G); rs1158471(C,T); rs7827901(G,C); rs76200748(A,G); rs147115453(C,T); rs200486928(T,C); rs11781559(G,T); rs11781561(G,A); rs75590937(A,G); rs77599611(G,A); rs144746094(A,G); rs149833457(C,G); rs4279641(G,A); rs62527048(A,G); rs11783320(A,G); rs79432425(G,A); rs2219240(T,A); rs4871053(T,A); rs10088126(A,T); rs28529014(T,C); rs2305609(T,A); rs10107257(T,C); rs10092516(G,A); rs114236859(G,A); rs1869831(G,A); rs1869832(G,C); rs1563388(G,A); rs10107534(A,G); rs10110786(A,C); rs28465286(A,G); rs181930979(A,G); rs118115561(A,G); rs7817682(T,C); rs7834446(A,T); rs17237080(T,C); rs16893819(A,G); rs7839121(G,A); rs78488878(A,C); rs11775222(A,T); rs10106845(T,G); rs2100540(A,T); rs111582508(C,T); rs62527051(T,C); rs73329045(C,A); rs17833992(G,C); rs367845714(G,A); rs1993390(A,G); rs7818861(C,A); rs79096816(A,G); rs6993434(A,G); rs1563389(C,T); rs186267860(A,C); rs1993391(C,A); rs57553886(T,C); rs1968737(A,G); rs7817097(A,G); rs7835757(T,A); rs1073523(T,C); rs144769935(G,T); rs11785760(G,A); rs1319578(C,T); rs1158849(A,T); rs2124470(A,G); rs144290957(A,T); rs12676121(T,C); rs117201965(C,T); rs2219241(A,T); rs2198747(C,T); rs139246329(T,A); rs1531131(C,T); rs150334764(A,G); rs73329067(T,G); rs62527054(T,C); rs117911641(G,A); rs114657503(C,A); rs149992280(G,A); rs7841201(A,G); rs7844938(C,A); rs7829213(T,C); rs7845246(C,T); rs7341620(T,C); rs7341686(G,A); rs116951709(A,G); rs7017945(C,T); rs7004015(T,C); rs182132230(A,G); rs6983911(A,C); rs10100841(C,T); rs6469905(A,G); rs7839367(T,C); rs7821139(C,T); rs144923012(C,T); rs6469909(T,C); rs6994888(C,T); rs6469910(C,T); rs6469911(T,A); rs7830625(G,A); rs12678374(C,A); rs10103136(T,A); rs7006048(A,G); rs7006555(A,G); rs7010688(A,G); rs114018352(T,C); rs10955968(T,C); rs2198748(T,A); rs2219242(G,C); rs6469913(G,C); rs6469914(G,A); rs12678188(C,T); rs7003797(C,T); rs7004099(C,A); rs7004292(C,T); rs73329094(A,C); rs6469915(A,G); rs10505379(G,T); rs10505380(A,G); rs4871056(T,G); rs28377018(T,G); rs4871057(A,C); rs79386207(G,T); rs7844334(C,T); rs79931707(T,C); rs16893907(C,T); rs7819160(G,A); rs141456366(A,G); rs114226075(C,T); rs150689264(A,C); rs79522313(C,T); rs6469916(G,A); rs16893916(A,G); rs34104524(C,A); rs11988416(A,G); rs9650079(C,T); rs9650080(G,A); rs75461686(T,C); rs7001798(A,C); rs7001937(A,G); rs11774731(C,T); rs79965261(A,G); rs28526109(T,G); rs58378319(C,A); rs6987036(G,C); rs73706434(T,G); rs4871058(A,C); rs36071361(G,C); rs2034843(A,G); rs2034844(A,G); rs73706435(T,G); rs2168406(T,C); rs10096828(A,T); rs7017523(A,G); rs116393019(T,G); rs78854445(T,C); rs7821701(G,T); rs10955969(T,C); rs79017620(A,C); rs75297917(A,T); rs76512821(G,A); rs79502910(G,A); rs2054149(C,T); rs79778042(A,G); rs13255609(A,G); rs7838078(T,C); rs7823806(G,A); rs7823977(G,T); rs2290521(T,G); rs1563390(G,A); rs1563391(A,G); rs1563392(A,T); rs2198750(G,C); rs4143484(T,C); rs63246862(G,A); rs3816523(G,A); rs2290523(G,A); rs2290524(G,A); rs6469917(C,T); rs4871059(C,A); rs4871060(C,T); rs2168407(T,G); rs78483611(A,G); rs1563393(C,T); rs1563394(C,A); rs1563395(A,C); rs141373635(A,G); rs78150086(A,G); rs7003062(T,C); rs6982921(A,G); rs114687825(A,G); rs930852(A,G); rs1563396(G,A); rs1563397(C,T); rs1563398(G,C); rs980825(A,G); rs7824821(G,A); rs62528266(A,C); rs7828729(G,A); rs4870726(G,A); rs7846160(T,C); rs7832817(G,T); rs13438950(C,T); rs35248031(G,T); rs116414295(G,C); rs11782639(A,G); rs1031576(A,G); rs144361831(T,C); rs1031577(T,C); rs11776868(C,A); rs16893954(A,G); rs80242932(C,T); rs6469918(C,A); rs77777296(A,G); rs1563399(T,A); rs16893962(C,A); rs7011270(C,G); rs6469920(A,G); rs6469921(C,A); rs10955971(G,A); rs7834496(T,A); rs16893976(G,A); rs7821312(C,T); rs16893983(A,G); rs7015443(T,A); rs76640271(C,T); rs7835198(C,T); rs7835363(A,G); rs7819405(T,G); rs4590476(G,C); rs4463470(T,C); rs6469922(A,T); rs1129353(G,A); rs2429(G,T); rs9402(C,T) |
| ccdsGene name | CCDS34938.1 |
| cytoBand name | 8q24.12 |
| EntrezGene GeneID | 7373 |
| EntrezGene Description | collagen, type XIV, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL14A1:NM_021110:exon29:c.G3565A:p.V1189I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6011 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q05707 |
| dbNSFP Uniprot ID | COEA1_HUMAN |
| dbNSFP KGp1 AF | 0.00457875457875 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.004591 |
| ESP Afr MAF | 0.014299 |
| ESP All MAF | 0.006074 |
| ESP Eur/Amr MAF | 0.00186 |
| ExAC AF | 0.004229 |
OMIM Clinical Significance
Eyes:
Agenesis of macula;
Coloboma of macula
Inheritance:
Autosomal dominant
OMIM Title
*120324 COLLAGEN, TYPE XIV, ALPHA-1; COL14A1
;;UNDULIN; UND
OMIM Description
DESCRIPTION
Type XIV collagen is a fibril-associated collagen with an interrupted
triple helix. It interacts with the fibril surface and regulates
fibrillogenesis (Ansorge et al., 2009).
CLONING
Schuppan et al. (1990) isolated undulin, a large glycoprotein of the
interstitial extracellular matrix, from skin and placenta. In
SDS-polyacrylamide gels, undulin had a molecular mass above 1,000 kD;
under reducing conditions, it migrated as 270-, 190-, and 180-kD
polypeptides. Undulin was restricted to dense and soft connective
tissues and was associated with mature collagen fibrils.
Dublet and van der Rest (1991) extracted a homotrimeric collagen
molecule, type XIV collagen, from fetal bovine skin and tendon. They
demonstrated that collagen XIV has a triple helical disulfide-bonded
domain homologous to type IX (e.g., 120210) and type XII (e.g., 120320)
collagens.
By immunoscreening a human placenta cDNA expression library with
antibodies against monkey undulin, Just et al. (1991) isolated 2 partial
cDNAs, called UN1 and UN2, which encode the C-terminal portions of 2
undulin isoforms. The sequences of UN1 and UN2 are partly identical, and
the authors suggested that they represent differentially spliced undulin
transcripts. Northern blot analysis of human rhabdomyosarcoma cell
poly(A) RNA using a probe specific for UN1 detected approximately 4.2-,
6.5-, and 8.5-kb transcripts; a probe specific for UN2 detected a
single, approximately 5-kb transcript. The deduced polypeptides contain
a differentially spliced von Willebrand factor (VWF; 613160) A domain
and the type III homology domains found in fibronectin (135600) and
tenascin (187380). Whereas UN1 has 7 complete and 1 truncated type III
homology domains followed by a short proline-rich C-terminal segment,
UN2 has 2 complete and 1 incomplete type III homologies followed by a
unique acidic C-terminal domain. The authors stated that the mRNAs
related to UN1 likely encode the major chains of the undulin molecule.
To complete the partial human undulin cDNA sequences determined by Just
et al. (1991), Bauer et al. (1997) isolated additional undulin cDNAs by
5-prime RACE, 3-prime RACE, and library screenings (GenBank GENBANK
Y11709, GENBANK Y11710, GENBANK Y11711). Beginning at the N terminus,
the predicted 1,780-amino acid undulin protein contains a putative
signal peptide, followed immediately by a fibronectin type III domain, a
VWF A domain, 7 fibronectin type III domains, a second VWF A domain, and
several collagenous and noncollagenous domains in the C-terminal region.
The authors identified 2 additional 3-prime cDNAs; one of these may
represent usage of an alternative polyadenylation signal, and the other
encodes a variant C-terminal noncollagenous domain. Bauer et al. (1997)
stated that undulin is identical to collagen XIV. The human undulin
proteins are 75% identical to chicken collagen XIV.
MAPPING
By fluorescence in situ hybridization, Schnittger et al. (1995) assigned
the UND gene to chromosome 8q23.
MOLECULAR GENETICS
In 8 affected and 2 unaffected members of a 4-generation Chinese family
with autosomal dominant punctate palmoplantar keratoderma (PPKP) mapping
to chromosome 8q24.13-q24.21 (PPKP1B; 614936), Guo et al. (2012)
identified a possibly causative heterozygous missense mutation in the
COL14A1 gene (P1502L; 120324.0001).
ANIMAL MODEL
Ansorge et al. (2009) found that Col14a1 -/- mice were born at the
expected mendelian ratio and developed normally. Newborn wildtype mice
expressed high levels of Col14a1 mRNA and protein in skin and tendon,
and expression of Col14a1 in flexor digitorum longus tendon correlated
with the formation of mature fibrils from fibril intermediates.
Expression of Col14a1 in both skin and tendon decreased with maturity
and was not detected in adult wildtype tendon. Skin of both newborn and
adult Col14a1 -/- mice appeared normal, but mutant skin showed altered
biomechanical properties, with reduced maximum stress tolerance and
decreased modulus of elasticity. Tendons of newborn Col14a1 -/- mice
appeared disorganized with abnormal fibril and fiber assembly, and
biomechanical analysis showed reduced maximum load, stiffness, and
modulus of elasticity compared with wildtype tendon. However, tendons of
adult Col14a1 -/- mice appeared and functioned normally. Ansorge et al.
(2009) concluded that COL14A1 has a regulatory role in the early stages
of collagen fibrillogenesis.
TRMT12
| dbSNP name | rs3812473(G,T); rs77055381(T,C); rs3812474(A,T); rs3812475(T,C); rs61752958(C,T); rs111369177(G,A); rs11556913(T,C); rs11986208(T,A) |
| cytoBand name | 8q24.13 |
| EntrezGene GeneID | 55039 |
| EntrezGene Description | tRNA methyltransferase 12 homolog (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1042 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Limbs];
Ankle contractures
MUSCLE, SOFT TISSUE:
Muscle amyotrophy
NEUROLOGIC:
[Central nervous system];
Delayed motor development (in some patients);
[Peripheral nervous system];
Proximal and distal asymmetric muscle weakness of the upper and lower
limbs;
Gait difficulties;
Frequent falls;
Areflexia;
Decreased motor nerve conduction velocities;
Decreased nerve amplitudes;
Sural nerve biopsy shows axonal loss;
Thinly myelinated nerve fibers;
Onion bulb formation;
De- and remyelination;
Distal sensory impairment
MISCELLANEOUS:
Onset usually in early childhood;
Adult onset may occur;
Variable severity;
Motor impairment more significant than sensory impairment;
Progressive disorder;
Some patients may become wheelchair-bound;
Trauma may accelerate symptoms
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae Fig4 gene (FIG4,
609390.0001)
OMIM Title
*611244 tRNA METHYLTRANSFERASE 12, S. CEREVISIAE, HOMOLOG OF; TRMT12
;;TRM12;;
tRNA-WYBUTOSINE-SYNTHESIZING PROTEIN 2, S. CEREVISIAE, HOMOLOG OF;
TYW2;;
tRNA-YW-SYNTHESIZING PROTEIN 2, S. CEREVISIAE, HOMOLOG OF
OMIM Description
DESCRIPTION
Wybutosine (yW) is a hypermodified guanosine at the 3-prime position
adjacent to the anticodon of phenylalanine tRNA that stabilizes
codon-anticodon interactions during decoding on the ribosome. TRMT12 is
the human homolog of a yeast gene essential for yW synthesis (Noma and
Suzuki, 2006).
CLONING
By searching databases for homologs of yeast Trm12, Kalhor et al. (2005)
identified human TRMT12.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the TRMT12
gene to chromosome 8 (TMAP D8S1919).
FAM84B
| dbSNP name | rs189365099(T,C); rs11539702(A,G); rs142690541(G,A); rs77693027(G,C) |
| cytoBand name | 8q24.21 |
| EntrezGene GeneID | 157638 |
| EntrezGene Description | family with sequence similarity 84, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Short philtrum;
Thick philtrum;
Maxillary hypoplasia;
[Ears];
Low-set ears;
Thick earlobes;
[Eyes];
Telecanthus;
Megalocornea;
Blue sclerae;
Corneal ulcer;
Downslanting palpebral fissures;
Ptosis;
High-arched, dense eyebrows;
Curled eyelashes;
Synophrys;
[Nose];
Prominent nasal bridge;
Broad nasal bridge;
Bulbous nasal tip;
[Mouth];
Full lips;
Everted lower lip;
[Neck];
Short neck
CHEST:
[Breasts];
Widely spaced nipples
ABDOMEN:
[Gastrointestinal];
Hirschsprung disease (in most patients)
SKELETAL:
[Hands];
Tapered fingers;
Clinodactyly;
Small hands
SKIN, NAILS, HAIR:
[Hair];
Sparse hair
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Pachygyria;
Polymicrogyria;
Thin corpus callosum;
Brainstem hypoplasia
MISCELLANEOUS:
Prenatal onset;
Additional developmental abnormalities may be seen in some patients
MOLECULAR BASIS:
Caused by mutation in the KIAA1279 gene (KIAA1279, 609367.0001)
OMIM Title
*609483 FAMILY WITH SEQUENCE SIMILARITY 84, MEMBER B; FAM84B
;;BREAST CANCER MEMBRANE PROTEIN 101; BCMP101
OMIM Description
CLONING
Using a proteomics approach to identify genes upregulated in breast
cancer cell membranes, followed by database analysis and PCR of a pooled
testis, fetal lung, and B-cell cDNA library, Adam et al. (2003) cloned
BCMP101. The deduced protein contains 310 amino acids. RT-PCR and
immunohistochemical analyses demonstrated low BCMP101 expression in
multiple normal tissues. However, high levels of BCMP101 mRNA were
detected in breast carcinoma cells, with expression upregulated more
than 2-fold in 6 of 7 breast carcinomas tested compared with adjacent
normal tissue. Fluorescence-tagged BCMP101 showed widespread
intracellular localization and significant expression on the plasma
membrane, particularly in areas of cell-cell contact.
GENE FUNCTION
By yeast 2-hybrid analysis of breast cancer-derived cDNA, Adam et al.
(2003) found that BCMP101 interacted with alpha-1 catenin (CTNNA1;
116805).
GENE STRUCTURE
Adam et al. (2003) determined that 1 exon contains the coding region of
the BCMP101 gene.
MAPPING
By genomic sequence analysis, Adam et al. (2003) mapped the BCMP101 gene
to chromosome 8q24.21.
PRNCR1
| dbSNP name | rs7001504(T,G); rs72725872(G,A); rs13252298(A,G); rs73705712(A,G); rs7841060(T,G); rs6997559(C,T); rs56311652(T,A); rs55905282(G,A); rs7007694(C,T); rs13257371(C,A); rs4571699(A,G); rs59765225(A,G); rs11993508(C,T); rs17832021(A,T); rs56006726(G,C); rs1456316(A,T); rs9656813(A,G); rs9656814(C,T); rs9656815(C,T); rs10505484(G,A); rs62529913(A,G); rs11994653(G,A); rs62529914(C,T); rs6470496(A,T); rs192806516(A,T); rs6470497(T,C); rs7844454(T,C); rs7826322(A,G); rs7000321(A,C); rs7000967(A,G); rs72725876(C,T); rs7001895(G,C); rs72725879(C,T); rs5013678(T,C); rs13254738(C,A); rs7006390(C,T) |
| cytoBand name | 8q24.21 |
| snpEff Gene Name | RP11-255B23.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4008 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Sinusitis, recurrent;
[Ears];
Otitis media, recurrent;
[Nose];
Rhinitis
RESPIRATORY:
Respiratory insufficiency due to defective ciliary clearance;
Respiratory infections, recurrent;
[Airways];
Chronic bronchitis;
[Lungs];
Bronchiectasis
ABDOMEN:
Situs inversus (in about 50% of patients)
LABORATORY ABNORMALITIES:
Electron microscopy of patient respiratory cells shows defects of
outer dynein arms;
Decreased or absent ciliary motility;
Decreased nasal nitric oxide
MISCELLANEOUS:
Onset in early childhood
MOLECULAR BASIS:
Caused by mutation in the armadillo repeat-containing protein 4 gene
(ARMC4, 615408.0001)
OMIM Title
*615452 PROSTATE CANCER-ASSOCIATED NONCODING RNA 1; PRNCR1
;;PROSTATE CANCER-ASSOCIATED TRANSCRIPT 8; PCAT8
OMIM Description
CLONING
By fine mapping and sequencing of a region of chromosome 8 linked with
prostate cancer (see HPC10, 611100), Chung et al. (2011) identified
PRNCR1. The transcript was approximately 13 kb long and was
polyadenylated. PRNCR1 shares sequence similarity with the SRRM1
(605975) transcript from chromosome 1.
GENE FUNCTION
Using real-time quantitative RT-PCR, Chung et al. (2011) found that
expression of PRNCR1 was upregulated in 5 of 10 microdissected prostate
cancer cell populations and 2 of 4 prostate intraepithelial neoplasias
compared with normal prostate epithelial cells microdissected from the
same prostate cancer tissues. Knockdown of PRNCR1 via small interfering
RNA duplexes reduced cell viability in androgen-sensitive LNCaP prostate
cancer cells and reduced growth in an androgen receptor (AR;
313700)-negative prostate cancer cell line. Knockdown of PRNCR1 reduced
expression of a cotransfected AR reporter gene following androgen
stimulation.
Yang et al. (2013) reported that 2 long noncoding RNAs (lncRNAs) highly
overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1 (605443),
bind successively to the AR and strongly enhance both ligand-dependent
and ligand-independent AR-mediated gene activation programs and
proliferation in prostate cancer cells. Binding of PRNCR1 to the
carboxy-terminally acetylated AR on enhancers and its association with
DOT1L (607375) appear to be required for recruitment of the second
lncRNA, PCGEM1, to the AR amino terminus, which is methylated by DOT1L.
Unexpectedly, recognition of specific protein marks by PCGEM1-recruited
pygopus-2 (PYGO2; 606903) PHD domain enhances selective looping of
AR-bound enhancers to target gene promoters in these cells. In resistant
prostate cancer cells, these overexpressed lncRNAs can interact with,
and are required for, the robust activation of both truncated and
full-length AR, causing ligand-independent activation of the AR
transcriptional program and cell proliferation. Conditionally expressed
short hairpin RNA targeting these lncRNAs in castration-resistant
prostate cancer cell lines strongly suppressed tumor xenograft growth in
vivo. Yang et al. (2013) concluded that these overexpressed lncRNAs can
potentially serve as a required component of castration resistance in
prostatic tumors.
GENE STRUCTURE
Chung et al. (2011) observed that the PRNCR1 transcript contains no
introns.
MAPPING
By genomic sequence analysis, Chung et al. (2011) mapped the PRNCR1 gene
to chromosome 8q24.
MOLECULAR GENETICS
Chung et al. (2011) identified a 4-SNP haplotype within the PRNCR1 gene
that was associated with prostate cancer susceptibility (p = 2.00 x
10(-24), OR = 1.74, 95% confidence interval = 1.56-1.93). For discussion
of multiple independent variants on chromosome 8q24 associated with
prostate cancer, see HPC10 (611100).
MIR1206
| dbSNP name | rs2114358(G,A) |
| cytoBand name | 8q24.21 |
| EntrezGene GeneID | 100302170 |
| snpEff Gene Name | U4 |
| EntrezGene Description | microRNA 1206 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2998 |
| ESP Afr MAF | 0.276148 |
| ESP All MAF | 0.364854 |
| ESP Eur/Amr MAF | 0.403685 |
| ExAC AF | 0.625 |
MIR1208
| dbSNP name | rs2648841(G,T) |
| cytoBand name | 8q24.21 |
| EntrezGene GeneID | 100302281 |
| EntrezGene Description | microRNA 1208 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1919 |
| ESP Afr MAF | 0.082589 |
| ESP All MAF | 0.087087 |
| ESP Eur/Amr MAF | 0.089056 |
| ExAC AF | 0.137,0.042 |
ASAP1-IT2
| dbSNP name | rs16904200(T,C); rs7816255(A,G); rs16904201(G,A) |
| ccdsGene name | CCDS6362.1 |
| cytoBand name | 8q24.21 |
| EntrezGene GeneID | 100507117 |
| snpEff Gene Name | ASAP1 |
| EntrezGene Description | ASAP1 intronic transcript 2 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
ASAP1-IT1
| dbSNP name | rs79291630(T,C); rs79790211(T,G); rs73409328(T,C); rs16893272(A,T) |
| ccdsGene name | CCDS6362.1 |
| cytoBand name | 8q24.21 |
| EntrezGene GeneID | 50807 |
| EntrezGene Symbol | ASAP1 |
| snpEff Gene Name | ASAP1 |
| EntrezGene Description | ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0225 |
KCNQ3
| dbSNP name | rs1437822(C,T); rs138128512(A,T); rs11785257(G,A); rs2436124(G,A); rs2436125(T,C); rs75865310(C,T); rs2436126(G,A); rs2436127(T,C); rs143422118(A,G); rs2469630(T,C); rs2436129(G,C); rs113866948(A,G); rs7815106(T,C); rs9297840(A,G); rs2469629(C,T); rs10095295(T,A); rs10108362(A,G); rs2436130(T,G); rs11786417(G,A); rs145396746(G,A); rs1437824(T,C); rs2436131(T,A); rs2469628(C,T); rs148887203(C,A); rs1025436(C,T); rs2469627(T,C); rs2469626(T,C); rs150703936(G,A); rs2272679(G,A); rs977939(G,A); rs76720699(T,G); rs10956640(G,C); rs10956641(G,T); rs78243592(T,C); rs114095081(G,T); rs2469625(G,C); rs2436132(G,A); rs112894691(T,C); rs16904603(C,T); rs2436133(A,G); rs2436134(A,G); rs76014624(T,C); rs2469622(C,G); rs2436135(T,C); rs2469621(G,T); rs2469510(T,G); rs114677566(G,A); rs2469511(A,G); rs7819259(C,A); rs77693956(A,G); rs2469620(C,T); rs2436136(G,A); rs112165512(G,C); rs34719956(C,T); rs2469512(G,A); rs111823144(C,T); rs79653924(C,A); rs2469618(G,A); rs10110659(C,A); rs2469513(C,G); rs13275557(A,G); rs141453721(G,C); rs7839133(G,T); rs17652451(T,C); rs2469617(A,G); rs2469514(C,T); rs116312785(A,G); rs6991482(G,A); rs115701859(T,C); rs2469616(C,G); rs2469615(T,C); rs74475609(C,G); rs2469516(C,T); rs114510315(T,G); rs2436137(G,C); rs17652604(G,A); rs77010329(C,T); rs78352720(T,C); rs1549849(T,C); rs17574375(T,A); rs1864769(T,C); rs62519560(T,C); rs2436138(G,A); rs16904606(A,G); rs2436139(C,T); rs2436140(G,A); rs2436141(G,A); rs2436142(C,T); rs2469614(G,A); rs2469517(A,G); rs2469518(G,A); rs2469519(T,C); rs1864770(C,G); rs1864771(A,C); rs1864772(T,C); rs2469520(G,A); rs1432029(T,C); rs117237831(T,C); rs79063232(A,T); rs1864773(A,G); rs115146242(T,C); rs1437818(C,T); rs62519562(C,A); rs114176940(A,G); rs2469612(G,A); rs1595411(G,A); rs2436144(C,T); rs112284679(G,A); rs1595412(T,G); rs2436146(C,T); rs1864768(A,T); rs930370(T,C); rs930371(T,C); rs747849(G,A); rs747850(A,T); rs1991718(C,T); rs747893(C,G); rs747892(G,A); rs2004248(G,A); rs2469522(G,A); rs115446513(A,G); rs2469523(G,C); rs77934842(G,A); rs62519563(C,T); rs2469524(G,A); rs62519564(G,A); rs2469610(G,A); rs116556486(A,G); rs62519565(T,G); rs2915574(C,T); rs2957031(G,A); rs2957033(G,T); rs2957034(A,T); rs1816375(G,A); rs1816646(T,C); rs4736554(G,C); rs142576865(A,C); rs2082311(G,A); rs11780224(A,G); rs6471044(T,C); rs115873312(G,A); rs2118436(G,A); rs62519567(G,A); rs1579644(T,C); rs1347696(G,C); rs6651173(G,A); rs6415550(T,A); rs6651259(G,A); rs77414466(C,T); rs78768113(C,G); rs79170832(C,T); rs1007215(G,A); rs78132307(G,A); rs73355074(T,C); rs79834123(C,T); rs7003955(G,A); rs16904607(C,T); rs16904608(T,C); rs115536052(C,T); rs9693071(T,G); rs73355078(C,T); rs11993002(A,G); rs7007544(T,G); rs6471046(G,A); rs7008160(T,C); rs6471047(A,C); rs11991537(T,G); rs1437819(C,G); rs1432030(A,G); rs17653354(G,A); rs73355088(G,A); rs893391(G,C); rs16904609(G,A); rs16904610(G,A); rs16904611(C,G); rs16904612(C,T); rs116692616(A,T); rs16904613(C,T); rs116797380(A,G); rs16904614(T,C); rs16904615(C,A); rs78190433(T,A); rs56692991(G,A); rs190071719(C,G); rs181384540(T,C); rs62519568(G,C); rs78673097(A,T); rs78771083(T,C); rs17575389(A,G); rs76211677(G,A); rs7833027(C,G); rs7008599(C,T); rs114449154(T,A); rs10283399(C,T); rs3779973(G,A); rs62519569(G,A); rs62519570(T,C); rs117462843(C,T); rs17575663(A,C); rs3779972(C,T); rs16904619(C,T); rs78320361(G,A); rs17575754(G,C); rs115115273(C,T); rs6991887(C,T); rs61080577(C,T); rs62519571(T,C); rs62519572(G,A); rs62519573(C,T); rs2075728(G,A); rs62519574(T,C); rs17653902(C,T); rs41272377(C,G); rs10505590(G,A); rs77494140(T,G); rs75870584(T,A); rs16904620(C,T); rs17575971(A,G); rs10505591(A,C); rs16904621(G,A); rs62519578(C,T); rs77241890(T,C); rs17654072(A,G); rs62519579(C,T); rs62519580(C,T); rs17576083(C,T); rs78007482(T,A); rs79066881(T,G); rs62519581(T,G); rs62519582(C,T); rs77070227(T,C); rs73355102(T,C); rs62519583(T,C); rs16904622(C,T); rs6996455(G,C); rs62519584(C,T); rs17576188(C,G); rs58663515(T,C); rs62519585(C,T); rs62519586(T,C); rs76215494(C,G); rs41272379(C,G); rs41272381(C,G); rs41272383(T,C); rs41272385(G,A); rs41272387(A,G); rs41272389(A,G); rs76474027(G,A); rs4736408(T,A); rs10505592(C,T); rs62519591(T,C); rs62519592(A,G); rs7011183(C,T); rs111326274(G,A); rs62519593(G,A); rs111853174(G,A); rs144195907(A,T); rs10956645(C,T); rs62519594(A,T); rs11984956(A,G); rs72719103(C,T); rs62519597(C,A); rs62519598(C,A); rs62519599(T,C); rs10092250(G,T); rs55646550(T,C); rs11987318(A,G); rs62519602(T,C); rs62519603(A,G); rs143834189(G,A); rs58750092(T,G); rs59081807(G,C); rs58417923(G,T); rs62519605(C,T); rs62519606(C,A); rs17654304(A,T); rs62519615(G,A); rs62519616(G,A); rs10956646(C,T); rs28584332(C,T); rs62519619(A,T); rs62519620(T,G); rs62519621(T,A); rs62519622(T,C); rs28624784(C,T); rs2019008(G,C); rs28522410(C,T); rs16904623(G,C); rs73356943(G,A); rs73356945(T,C); rs62519625(C,T); rs62519626(A,G); rs62519627(T,A); rs11984759(C,T); rs1109396(G,A); rs62519628(C,T); rs79608833(G,A); rs58443180(G,T); rs62519630(C,G); rs58333423(A,G); rs713148(C,T); rs4610724(T,A); rs4266630(C,T); rs4282550(T,G); rs4266631(C,G); rs4388439(A,G); rs62519632(A,C); rs62519633(T,C); rs17654436(C,G); rs16904624(T,C); rs62519636(T,C); rs72719107(G,T); rs74823893(T,A); rs62519637(G,A); rs62519638(T,G); rs56664029(T,C); rs16904625(G,A); rs62519639(A,G); rs79322911(G,A); rs73356971(T,A); rs73356972(T,C); rs76981334(G,A); rs7005923(T,G); rs13277622(C,T); rs62519641(A,G); rs7016820(T,C); rs6984507(T,C); rs16904626(A,G); rs17595739(T,C); rs17595767(A,G); rs62519643(T,A); rs9643288(G,A); rs62519644(A,T); rs62519645(C,T); rs16904627(C,T); rs7357525(G,A); rs9650111(T,C); rs11779500(C,A); rs60877482(C,T); rs115105103(T,A); rs36088495(A,G); rs11997060(T,C); rs34543882(C,A); rs16904628(G,C); rs17654749(C,T); rs17595945(A,C); rs4736557(C,G); rs80018466(C,T); rs16904629(C,T); rs139710570(C,T); rs117444551(T,C); rs7464877(T,C); rs1437811(T,A); rs7014083(T,C); rs139556619(G,C); rs62519655(T,C); rs1437812(A,C); rs11990962(A,G); rs2163607(T,C); rs6987299(G,A); rs137948602(G,A); rs113800208(C,T); rs148623943(C,T); rs80321343(T,C); rs76824501(G,A); rs149249038(C,T); rs140136624(A,G); rs1549848(G,A); rs1036539(A,T); rs112419684(G,A); rs1025435(C,T); rs1036540(G,A); rs7001287(T,C); rs10090173(C,T); rs12541725(C,T); rs16904631(T,C); rs16904632(A,G); rs112168708(T,C); rs16904633(C,G); rs76407614(C,T); rs113096270(C,G); rs1350383(A,G); rs10092367(T,C); rs60916568(G,A); rs4736558(A,T); rs4736559(A,G); rs1379584(C,T); rs930894(G,A); rs35587315(A,G); rs35771927(G,A); rs36024812(T,C); rs17596360(T,G); rs12681383(T,A); rs12681384(T,C); rs7825358(C,T); rs4736560(A,G); rs4736561(C,G); rs4736562(A,G); rs1031635(G,A); rs4639491(T,C); rs6471048(C,T); rs76113791(G,A); rs78602332(C,T); rs7839935(A,G); rs13278425(A,G); rs145851731(C,T); rs138399223(C,T); rs11995895(T,C); rs13253490(C,T); rs7017664(G,C); rs17596711(A,G); rs115649285(G,A); rs2403737(T,C); rs2403738(T,G); rs897904(T,G); rs73708599(C,T); rs7820812(A,G); rs11787044(T,G); rs16904635(C,T); rs78938039(G,A); rs6999946(C,T); rs16904637(G,T); rs2005160(G,C); rs2005161(A,G); rs7844150(G,T); rs755140(G,A); rs1078332(G,A); rs13278301(C,T); rs13281112(T,C); rs7814576(A,G); rs7819270(G,A); rs12056417(A,G); rs6988160(G,T); rs140570038(T,C); rs142816075(C,A); rs13280878(A,G); rs4736564(C,T); rs12056823(C,A); rs1563630(T,G); rs4346976(G,A); rs77952973(G,T); rs113069600(A,G); rs111828820(G,A); rs2403739(T,G); rs1379583(C,G); rs2403740(T,C); rs11785134(G,A); rs2085519(T,C); rs2085518(G,C); rs2085517(G,A); rs4736565(C,A); rs4736410(T,G); rs6986817(T,G); rs11776658(T,A); rs7009148(G,A); rs4736411(T,A); rs13251709(T,G); rs1585205(A,C); rs147698033(G,A); rs4428655(G,A); rs10808599(A,C); rs13273969(T,C); rs13279891(A,C); rs6985058(T,C); rs7007269(A,C); rs13255301(C,G); rs6471049(C,T); rs73710504(C,T); rs77108681(G,T); rs4736566(G,T); rs4736567(A,G); rs1457777(G,T); rs10505594(G,A); rs13257492(C,A); rs7835382(T,C); rs4736568(G,A); rs12675635(C,T); rs1902820(G,A); rs6991520(G,A); rs2896654(C,G); rs4736570(T,A); rs16904639(T,C); rs56044290(C,G); rs7832589(A,G); rs79487262(T,A); rs12550771(A,G); rs726576(C,T); rs79858896(T,C); rs7001804(C,T); rs7002013(C,T); rs151062596(T,G); rs2168779(C,T); rs2168780(T,C); rs2125153(G,T); rs7836596(A,G); rs7840315(A,G); rs16904642(G,A); rs16904643(A,G); rs79960530(C,T); rs1379582(G,A); rs7845250(A,T); rs74738576(T,C); rs13258436(T,C); rs55961250(T,G); rs150902665(G,C); rs2896655(G,A); rs13276897(T,C); rs7840021(T,C); rs13249851(C,T); rs140833391(G,T); rs4736412(T,C); rs10808600(C,A); rs10956650(A,G); rs10956651(A,G); rs17597858(T,C); rs55652259(T,A); rs148683177(G,A); rs1457778(G,A); rs73710507(T,C); rs138985123(C,T); rs11782396(G,A); rs13264960(C,T); rs13265691(G,A); rs145194201(C,T); rs142104348(T,C); rs964168(C,T); rs1870232(C,T); rs11779291(G,A); rs13276075(G,A); rs12550408(A,T); rs1457779(G,A); rs1457780(C,T); rs1457781(C,T); rs4642625(T,A); rs73710510(C,A); rs6992659(A,G); rs13282321(G,A); rs73358986(T,A); rs13249479(T,C); rs139808097(G,A); rs12547484(C,G); rs75964532(G,T); rs1457782(T,C); rs73710512(C,A); rs139959117(T,C); rs1026450(T,C); rs28706399(T,C); rs7838196(G,C); rs2100644(T,C); rs7846364(C,T); rs7818112(A,C); rs7814194(T,C); rs6471052(G,A); rs114379121(C,T); rs7814862(T,C); rs6471053(C,G); rs2403773(A,G); rs2016777(A,G); rs13280318(A,G); rs1457784(C,A); rs4736571(T,C); rs55881075(C,T); rs73360818(A,G); rs10956653(C,T); rs990111(A,G); rs10956654(G,C); rs75202805(C,T); rs1471144(C,G); rs114698163(T,C); rs11780080(T,G); rs62520369(G,A); rs992938(C,T); rs1157281(C,T); rs6471055(T,G); rs6471056(T,C); rs6471057(C,T); rs6471058(C,A); rs6471059(G,A); rs11778399(G,A); rs11778434(C,T); rs11996426(A,G); rs10108720(G,A); rs11990218(C,A); rs10095678(T,C); rs7010949(G,T); rs77927141(T,C); rs78607181(G,A); rs7837201(T,C); rs7819670(G,C); rs7837646(T,C); rs58498752(G,A); rs1457788(T,C); rs1457787(A,G); rs1457786(T,A); rs182441594(G,C); rs4736572(C,A); rs77300278(T,A); rs10094383(T,C); rs10094856(T,C); rs13275782(G,C); rs7010053(G,A); rs1379585(G,C); rs185793275(T,G); rs114635870(G,A); rs4736413(T,C); rs989014(T,G); rs989013(A,G); rs9297842(T,C); rs73360856(G,C); rs114587083(C,T); rs142555210(C,T); rs4736573(C,A); rs12541666(T,C); rs116604199(C,G); rs16904656(G,C); rs2034913(A,G); rs11786788(G,A); rs11776665(T,C); rs62520372(T,G); rs73710537(C,T); rs17599131(T,A); rs147012843(C,T); rs9649969(T,G); rs62520375(G,C); rs76289342(C,T); rs13267466(A,C); rs876111(C,T); rs2896656(T,C); rs897905(C,G); rs139892151(G,A); rs13255429(C,A); rs6471060(C,T); rs76288385(G,A); rs1902819(T,C); rs11779326(G,A); rs7006568(A,C); rs1004349(T,A); rs75198725(A,G); rs138481724(G,C); rs6471061(C,G); rs6471062(A,G); rs76330119(C,T); rs7819140(C,A); rs144174585(T,C); rs1020740(T,C); rs7824311(G,A); rs7824424(G,T); rs117607124(C,T); rs4319073(C,T); rs149378321(A,C); rs62520379(G,A); rs6999714(G,A); rs142748284(C,G); rs6999857(G,A); rs112969495(G,A); rs7004085(G,C); rs73343817(G,A); rs141991707(T,C); rs148363207(T,A); rs118116614(G,A); rs13276777(C,T); rs138296426(C,G); rs10956658(C,T); rs10087382(G,C); rs10102127(T,C); rs16904661(A,G); rs7813775(G,C); rs112480314(G,A); rs113145054(C,A); rs185393981(T,C); rs145818753(T,C); rs16904662(G,A); rs16904663(G,T); rs16904664(G,C); rs11993966(G,A); rs6988110(C,T); rs6988532(G,C); rs10505595(A,G); rs16904665(A,C); rs1379581(A,G); rs16904666(T,C); rs58087658(G,A); rs16904667(G,A); rs897902(G,T); rs147195693(C,T); rs60824366(C,T); rs16904668(T,C); rs4339620(C,T); rs111741650(C,T); rs112872936(G,A); rs76667352(A,G); rs73343846(G,C); rs12681708(G,T); rs1457776(C,T); rs12115116(C,T); rs116884047(G,A); rs62520380(C,T); rs73343851(G,T); rs73343853(G,A); rs80042040(G,A); rs1466313(G,A); rs60684301(G,A); rs10097662(A,G); rs10098077(G,A); rs11995561(G,A); rs189732440(A,G); rs140146409(T,C); rs9297846(T,G); rs9297847(G,T); rs9297848(G,A); rs9297849(G,A); rs9297850(C,T); rs143558642(C,G); rs186681695(G,A); rs59542153(C,T); rs11785651(C,T); rs60002601(G,A); rs930897(A,G); rs930896(C,T); rs930895(G,A); rs12682536(C,T); rs1870234(G,A); rs73710552(G,A); rs60042093(C,T); rs117472991(T,C); rs10956659(T,C); rs73710554(A,C); rs16904671(T,C); rs28401651(C,G); rs16904672(C,T); rs12679098(A,G); rs12679129(A,T); rs978152(C,G); rs79907269(G,A); rs73710557(C,T); rs187682355(T,C); rs141602180(A,T); rs111241297(T,C); rs76677278(A,T); rs4576409(A,G); rs1457789(C,T); rs6982899(T,A); rs73343890(T,C); rs148927863(A,G); rs1533402(C,G); rs73343896(A,G); rs117281570(T,C); rs16904673(G,A); rs73343901(G,A); rs1350384(G,A); rs16904674(A,G); rs73708405(T,C); rs60405929(T,C); rs59292953(C,T); rs2896657(C,G); rs4736574(C,A); rs4458854(C,A); rs7016984(G,A); rs2403774(T,A); rs4527849(C,A); rs57443470(G,A); rs4736414(G,A); rs4736575(A,G); rs73708407(C,A); rs4736576(A,G); rs6984395(C,A); rs76499550(C,A); rs7820317(G,A); rs73345917(A,G); rs73345919(A,C); rs112215366(G,T); rs117534398(G,C); rs11776533(G,A); rs7821360(C,T); rs7843765(T,A); rs4351399(C,T); rs2100648(C,T); rs2100647(A,G); rs2100646(C,T); rs2100645(G,A); rs55752255(C,A); rs4736577(A,T); rs118025649(T,G); rs11990186(G,T); rs11990162(C,T); rs10095671(T,C); rs6415551(C,T); rs9656994(A,G); rs112882599(T,A); rs16904675(A,G); rs59526505(G,A); rs73708413(G,A); rs113250352(G,A); rs76740736(C,T); rs57953382(C,T); rs6471063(G,A); rs182435144(T,G); rs7005360(G,T); rs7834752(A,G); rs7835039(C,T); rs6471064(T,A); rs1350381(C,T); rs1350382(G,A); rs6992843(T,C); rs11998311(G,A); rs118023919(C,T); rs16904676(G,T); rs73345946(T,A); rs72721036(G,A); rs141037205(C,A); rs112120734(G,A); rs73345951(C,T); rs72721038(A,C); rs59083631(C,T); rs2608208(T,C); rs75455830(T,C); rs2673610(C,T); rs2673609(C,G); rs76917904(C,T); rs2673608(T,C); rs2721917(A,G); rs117078390(C,T); rs2673613(T,G); rs117041271(C,A); rs7822712(G,A); rs73345971(C,T); rs2673612(C,T); rs148619848(G,A); rs2198985(C,T); rs60348297(C,A); rs74412504(G,A); rs77768566(C,G); rs73708437(C,T); rs2608210(C,G); rs1457785(G,A); rs72721042(A,G); rs2608211(C,G); rs2673567(G,T); rs2608212(A,T); rs2395493(G,A); rs59221182(C,T); rs2258309(C,G); rs2721916(T,C); rs75635413(C,G); rs79542845(T,G); rs73708444(C,G); rs4095732(C,G); rs58394541(T,G); rs148234247(G,A); rs3957207(G,T); rs56086541(A,C); rs2721912(G,A); rs112125308(G,A); rs2597357(A,G); rs58290366(T,C); rs142419622(C,T); rs3857926(C,T); rs2673588(A,G); rs2673589(A,G); rs2721911(G,A); rs113418070(G,A); rs6471065(C,T); rs2673590(G,T); rs6471066(C,G); rs7000365(C,T); rs114545876(C,T); rs2597356(C,T); rs56727289(G,C); rs2673592(G,C); rs13271444(T,C); rs373264686(G,A); rs58076975(T,C); rs76276113(C,T); rs72721049(A,G); rs116417229(G,A); rs6471067(G,A); rs16904679(A,G); rs76556271(C,T); rs2597355(A,G); rs2673607(G,T); rs11986253(G,C); rs2673606(C,T); rs11987131(G,A); rs2597353(C,T); rs7004250(C,T); rs2673605(C,T); rs7004654(A,G); rs55918229(T,A); rs2673604(C,A); rs2673603(G,A); rs2673602(C,T); rs72721053(A,G); rs58912154(G,C); rs2597351(A,G); rs2721903(T,G); rs2721902(C,T); rs2167170(G,A); rs112699850(G,A); rs2673601(G,A); rs202201226(G,T); rs113691696(C,T); rs2673600(C,G); rs2721900(C,T); rs2721899(A,G); rs2466352(C,G); rs2442975(T,A); rs2721898(G,A); rs2721897(A,G); rs2673562(G,T); rs72721054(T,C); rs117796932(G,T); rs17601112(T,C); rs2597339(G,C); rs56857507(A,C); rs2673561(C,G); rs2721895(T,C); rs2597338(G,A); rs144596697(G,C); rs79269059(C,T); rs17659416(A,G); rs2597337(G,C); rs77495581(G,A); rs55910321(T,C); rs78206643(G,A); rs10111396(A,G); rs2721894(A,C); rs72721057(G,A); rs72721058(G,C); rs79061711(C,G); rs62520387(C,T); rs2597336(G,A); rs72721059(G,A); rs111975634(C,T); rs72721060(G,A); rs17659499(G,A); rs16904682(G,T); rs72721061(G,A); rs72721062(C,T); rs115571885(C,G); rs116351467(A,G); rs2597335(A,G); rs2721885(C,G); rs112386275(G,T); rs55726911(G,A); rs73708454(C,A); rs117555927(C,G); rs77211549(A,G); rs2597334(A,C); rs2597333(G,A); rs2597332(T,C); rs117192471(A,G); rs145215392(A,C); rs2597331(G,A); rs2597330(G,A); rs12548732(G,A); rs55641670(A,G); rs55659230(G,A); rs77219701(A,G); rs7012444(C,T); rs57016900(T,C); rs1913724(G,T); rs57189643(G,A); rs2673614(T,C); rs1962131(C,T); rs145334304(C,T); rs2597328(G,A); rs192273842(C,T); rs2597327(T,C); rs16904684(G,A); rs4736580(T,C); rs1515517(C,T); rs869710(T,C); rs4736582(C,T); rs4736583(C,A); rs1515520(G,C); rs113278721(G,A); rs78785240(G,A); rs2673593(T,G); rs28637511(A,C); rs7841732(T,C); rs13281459(A,T); rs7834336(A,C); rs56280859(C,T); rs7827302(C,T); rs11988569(G,A); rs11992343(T,C); rs12544635(G,A); rs2466351(G,A); rs7837397(G,A); rs61324127(C,T); rs56187070(A,G); rs10086366(G,A); rs1878017(C,T); rs1878016(T,G); rs12549298(T,A); rs72721072(T,C); rs112593560(C,T); rs10956661(A,G); rs2721905(A,C); rs2673573(G,A); rs2721906(G,C); rs2673574(A,G); rs72721077(A,G); rs1464122(T,C); rs938426(T,C); rs58613338(T,C); rs2597350(T,C); rs2597349(G,A); rs2673568(C,T); rs2721907(G,A); rs55876503(C,T); rs12542971(A,G); rs12543579(A,C); rs142773321(C,T); rs55808349(A,C); rs10216765(G,A); rs2673566(A,G); rs2721908(T,C); rs144505269(A,G); rs111248619(G,A); rs112037451(G,C); rs4520143(C,T); rs114954179(C,T); rs72721085(T,G); rs2673565(A,G); rs116572380(C,T); rs2721909(A,C); rs3857927(G,T); rs77300876(C,T); rs77668408(T,C); rs143098646(C,T); rs146147159(A,T); rs140168672(G,A); rs144763054(T,G); rs35126611(C,T); rs142868286(G,A); rs60920622(T,C); rs140697222(G,A); rs72721094(T,C); rs4736584(G,T); rs2597348(C,T); rs2673587(A,C); rs2403775(A,G); rs2597346(T,A); rs2673586(A,G); rs7843409(G,A); rs7843653(C,T); rs2597345(C,T); rs10956662(C,A); rs10808601(G,A); rs10956663(G,T); rs12547451(A,G); rs2597371(C,A); rs12114194(C,A); rs144014740(C,T); rs2721924(C,T); rs11780826(T,C); rs11777255(G,A); rs11777243(C,T); rs2673555(T,C); rs2673556(G,C); rs4736585(G,A); rs2721886(C,T); rs72723109(T,C); rs2673559(G,T); rs2673558(C,A); rs113293031(A,G); rs72723110(G,A); rs6997998(C,T); rs2721887(A,G); rs2721888(A,G); rs2597372(C,T); rs72723113(A,T); rs2673557(T,C); rs10217015(C,T); rs191223456(C,G); rs72723116(T,C); rs13258052(G,A); rs60823325(A,G); rs2673563(T,C); rs112258418(T,C); rs13279695(T,C); rs72723117(G,A); rs2597365(T,C); rs72723121(G,C); rs9987406(T,A); rs72723124(T,C); rs72723127(C,G); rs72723128(C,T); rs9643290(G,A); rs2167171(C,A); rs115858949(G,A); rs2403788(G,A); rs112756134(T,C); rs1913723(A,G); rs193200211(A,G); rs2721910(A,C); rs113930804(C,T); rs113806459(G,A); rs150214488(C,T); rs72723133(G,C); rs77687990(T,C); rs1464120(G,T); rs72723134(T,C); rs1464121(T,C); rs35155387(C,T); rs2721889(A,G); rs2673560(T,C) |
| ccdsGene name | CCDS34943.1 |
| cytoBand name | 8q24.22 |
| EntrezGene GeneID | 3786 |
| EntrezGene Description | potassium voltage-gated channel, KQT-like subfamily, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNQ3:NM_004519:exon15:c.C2306A:p.P769H,KCNQ3:NM_001204824:exon15:c.C1946A:p.P649H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8244 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7ET42 |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.026328 |
| ESP All MAF | 0.009534 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 0.002716 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Horseshoe kidney;
Ectopic kidney;
Absent kidney;
Dilated Bowman capsules;
Cystic tubular dilatation in the cortex and medulla;
[Ureters];
Double ureter
SKELETAL:
[Limbs];
Short, curved forearms;
Absence of the radii;
[Hands];
Medial flexion of the hands;
Absence of the thumbs
NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Ventriculomegaly;
Dilated ventricles
MISCELLANEOUS:
One family with 2 affected fetuses has been reported (as of August
2011)
OMIM Title
*602232 POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 3; KCNQ3
;;POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY Q, MEMBER 3
OMIM Description
DESCRIPTION
KCNQ3 is a member of a family of voltage-gated potassium channels. The
first human genes identified in this family were KCNQ1 (607542) and
KCNQ2 (602235). KCNQ1 is expressed in the heart and inner ear; KCNQ2 and
KCNQ3 are expressed in the brain.
CLONING
By conducting a BLAST search with the KCNQ2 full-length cDNA against the
EST database, Charlier et al. (1998) identified KCNQ3, a member of the
voltage-gated potassium channel family.
By screening a human fetal brain cDNA library, Yang et al. (1998)
identified a full-length cDNA corresponding to the KCNQ3 gene. The cDNA
encodes a deduced 854-amino acid protein with structural features
related to KCNQ1. Northern blot analysis detected restricted expression
of a 10.5-kb KCNQ3 mRNA transcript in brain, including the cerebral
cortex, hippocampus, caudate, amygdala, and thalamus.
MAPPING
By analysis of a somatic cell hybrid panel, Charlier et al. (1998)
mapped the KCNQ3 gene to chromosome 8. Analysis of radiation hybrids
showed tight linkage of KCNQ3 to markers previously mapped to 8q24.
GENE FUNCTION
The M-channel is a slowly activating and deactivating potassium
conductance that plays a critical role in determining the subthreshold
electroexcitability of neurons as well as the responsiveness to synaptic
inputs. The M-current was first described in peripheral sympathetic
neurons, and differential expression of this conductance produces
subtypes of sympathetic neurons with distinct firing patterns. The
M-channel is also expressed in many neurons in the central nervous
system. Wang et al. (1998) showed that the KCNQ2 and KCNQ3 channel
subunits can coassemble to form a channel with essentially identical
biophysical properties and pharmacologic sensitivities to the native
M-channel and that the pattern of KCNQ2 and KCNQ3 gene expression is
consistent with these genes encoding the native M-channel.
By in vitro functional analysis, Yang et al. (1998) demonstrated that
the KCNQ3 channel is a voltage-gated, rapidly activating K(+)-selective
channel similar to KCNQ1. Coexpression of KCNQ2 and KCNQ3 resulted in a
substantial synergistic increase in current amplitude, indicating
functional interaction between the 2 channels. KCNQ2 and KCNQ3 were also
found to interact with KCNE1 (176261).
Cooper et al. (2000) found that the KCNQ2 and KCNQ3 proteins were
colocalized in a somatodendritic pattern on pyramidal and polymorphic
neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2,
but not KCNQ3, was also prominent in some terminal fields, suggesting a
presynaptic role for a distinct subgroup of M-channels in the regulation
of action potential propagation and neurotransmitter release. KCNQ2 and
KCNQ3 could be coimmunoprecipitated from brain lysates. Further, both
proteins were coassociated with tubulin (see 602529) and protein kinase
A (see 176911) within a triton X-100-insoluble protein complex. Cooper
et al. (2000) suggested that these studies provided a view of a
signaling complex that may be important for cognitive function as well
as epilepsy, and that analysis of this complex may shed light on the
transduction pathway linking muscarinic acetylcholine receptor (see
118510) activation to M-channel inhibition.
By recording channel currents produced in cRNA-injected Xenopus oocytes,
Zhang et al. (2003) found that phosphatidylinositol (4,5)-bisphosphate
(PIP2) activated all members of the KCNQ channel family analyzed,
including human KCNQ2 and heterodimers of human KCNQ2 and rat Kcnq3.
Similar results were obtained with mammalian cells expressing KCNQ2 and
Kcnq3. Mutation of his328-to-cys in KCNQ2 and his330-to-cys in Kcnq3
reduced or eliminated PIP2-mediated channel activation. Wortmannin, a
pharmacologic inhibitor of PIP2 regeneration, slowed the recovery from
PIP2 hydrolysis and decreased the sensitivity of the KCNQ2/Kcnq3 channel
to PIP2. Zhang et al. (2003) concluded that PIP2 acts as a
membrane-diffusible second messenger to regulate the activity of KCNQ
currents.
In cellular studies, Zhou et al. (2013) found that the antiepileptic
agent retigabine was more effective on KCNQ3 than KCNQ2, whereas zinc
pyrithome (ZnPy) was more effective on KCNQ2 with no detectable effect
on KCNQ3. In neurons, activation of muscarinic receptor signaling
desensitized effects by retigabine but not ZnPy. Reduction of PIP2
caused KCNQ3 to become sensitive to ZnPy and to lose sensitivity to
retigabine. This dynamic shift of pharmacologic selectivity caused by
PIP2 could be induced by voltage-sensitive phosphatase and abolished by
mutating a PIP2 site within the S4-S5 linker of KCNQ3. The findings
suggested that drug-channel binding and selectivity is a dynamic process
and may be regulated by receptor signaling pathways via PIP2.
MOLECULAR GENETICS
In an affected member of a Mexican American family with benign familial
neonatal seizures 2 (BFNS2; 121201) reported by Ryan et al. (1991),
Charlier et al. (1998) identified a single heterozygous missense
mutation in the KCNQ3 gene (G263V; 602232.0001).
In affected members of a Japanese family with BFNS2, Hirose et al.
(2000) identified a heterozygous missense mutation in the KCNQ3 gene
(W309R; 602232.0002).
Li et al. (2008) and Fister et al. (2013) identified a heterozygous
missense mutation in the KCNQ3 gene (R330C; 602232.0003) in affected
members of Chinese and Slovenian families, respectively, with benign
neonatal seizures-2.
HPYR1
| dbSNP name | rs6471080(T,G); rs13249785(T,C); rs4736596(T,A) |
| cytoBand name | 8q24.22 |
| EntrezGene GeneID | 93668 |
| EntrezGene Description | Helicobacter pylori responsive 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2319 |
COL22A1
| dbSNP name | rs73442789(C,T); rs60639203(C,T); rs140270238(G,A); rs10106999(A,G); rs4607616(T,C); rs10096258(C,T); rs7009499(G,A); rs10110076(G,A); rs10097485(A,G); rs10097507(A,G); rs55658588(C,T); rs11991611(G,A); rs57128052(A,G); rs72727816(A,G); rs7832390(G,A); rs10087521(T,A); rs149366411(G,A); rs4074721(C,T); rs146334338(C,T); rs6981391(C,T); rs4074877(C,T); rs142746543(C,A); rs116201201(C,T); rs11166828(C,T); rs4394401(G,A); rs6993225(C,T); rs7017350(A,G); rs7017353(A,G); rs4076063(T,C); rs58592409(A,G); rs4442151(C,T); rs4446747(C,T); rs12546923(A,C); rs12549170(G,A); rs4909809(C,G); rs74819433(G,A); rs9657454(A,G); rs4471041(T,C); rs7842890(T,C); rs28458209(T,C); rs7839636(A,G); rs7822001(C,A); rs4909810(G,A); rs12681582(T,G); rs11166829(G,A); rs4076439(C,T); rs4076438(A,G); rs77886009(C,T); rs7006875(C,T); rs28507972(G,T); rs28464630(C,T); rs4073697(C,A); rs116941057(T,C); rs4341165(C,T); rs4311658(G,T); rs13251371(A,G); rs191064476(T,C); rs182256359(G,T); rs61085818(A,G); rs7012042(G,A); rs9650562(A,G); rs28605314(C,T); rs4243896(C,T); rs4243897(C,G); rs7000261(C,G); rs13263938(C,A); rs10094887(G,A); rs10094993(G,A); rs79392014(C,T); rs118099873(G,T); rs10089840(T,C); rs4076991(A,G); rs7016969(C,T); rs4909811(A,G); rs7009396(A,G); rs13252946(C,A); rs13252948(C,G); rs10088251(C,T); rs10105805(T,G); rs10091242(C,T); rs4581056(A,G); rs75740390(G,A); rs4623432(T,C); rs4576426(T,G); rs4260898(G,A); rs7836250(A,C); rs7839790(T,A); rs57299725(C,T); rs7818269(G,C); rs10100776(A,G); rs6996538(G,A); rs6983378(T,C); rs3924860(T,C); rs10094167(G,A); rs10094272(G,C); rs6577935(T,C); rs6991254(A,T); rs7012573(G,C); rs11782113(T,A); rs13255044(A,G); rs10088864(A,G); rs10101810(G,A); rs62527861(G,A); rs56369943(C,T); rs4301456(A,C); rs74640390(C,T); rs79787008(T,C); rs188341085(C,T); rs4458882(G,A); rs4634647(C,G); rs4131277(T,C); rs373870013(A,G); rs6990723(G,A); rs62527863(T,C); rs62527864(A,G); rs4636211(C,T); rs138856665(A,G); rs7462154(G,C); rs4909812(G,A); rs4909434(C,T); rs4909813(T,A); rs4909814(T,C); rs375535691(T,C); rs369579220(G,A); rs4909815(C,T); rs7003632(T,C); rs10091563(A,G); rs117102790(G,A); rs7464337(T,G); rs11166830(G,A); rs80196025(T,C); rs12678385(C,T); rs4909816(C,T); rs4909817(T,C); rs375153899(T,A); rs115293451(G,A); rs4909818(A,G); rs7006342(C,A); rs13248687(T,A); rs10097597(C,T); rs4909436(C,T); rs145785262(G,C); rs11166831(C,T); rs182328367(T,G); rs145335529(A,C); rs115734379(A,G); rs148212068(T,G); rs4074064(A,G); rs190402848(A,T); rs142400190(C,T); rs7460256(C,T); rs377124609(C,T); rs12546338(C,T); rs11786621(T,C); rs6990757(T,C); rs375959893(C,T); rs7006043(C,T); rs56028525(G,C); rs59323567(G,C); rs9324491(C,T); rs60872158(C,G); rs9324492(C,T); rs4909439(C,T); rs6577938(T,G); rs28650009(G,A); rs4909440(T,C); rs57777291(G,A); rs4909441(T,C); rs6982714(G,T); rs6984002(C,G); rs6982882(G,C); rs111509839(T,C); rs6988358(G,C); rs372891677(C,A); rs4909825(C,A); rs6577939(C,T); rs72727847(G,C); rs3923549(A,G); rs72727851(C,T); rs7460457(A,G); rs3924863(G,A); rs3924862(G,A); rs3903033(C,T); rs143910537(C,T); rs6985495(G,C); rs4073447(A,T); rs4073446(A,G); rs74431349(G,A); rs72727853(G,A); rs4909826(T,C); rs11166832(T,C); rs12675091(C,T); rs13268481(T,C); rs6421014(G,A); rs7002247(G,T); rs6989017(T,C); rs75422933(G,A); rs7460303(A,G); rs12547337(G,A); rs148595495(G,C); rs11993715(G,A); rs73445470(G,A); rs11166833(C,T); rs10087668(T,C); rs11784469(G,C); rs11781324(A,G); rs10102532(C,T); rs7462741(T,A); rs138907820(G,A); rs4072881(C,T); rs3935702(C,T); rs3935703(C,G); rs150410981(C,T); rs58343081(G,A); rs4072506(T,C); rs3935045(T,C); rs55721420(A,G); rs147162075(G,A); rs72727872(C,T); rs73445491(C,T); rs11780703(C,T); rs11780732(C,T); rs10875431(T,C); rs10875432(G,A); rs73445496(G,A); rs11166834(T,G); rs4344118(C,A); rs4549820(T,C); rs181691243(C,G); rs4545145(G,A); rs114733093(C,T); rs13271565(T,C); rs11775437(A,G); rs13272198(T,C); rs11166835(G,T); rs4410946(A,G); rs4269582(C,T); rs4607662(G,C); rs72727876(G,A); rs73449681(G,A); rs73449683(C,T); rs183136772(C,T); rs189556823(C,T); rs73449686(T,C); rs4279644(T,C); rs72727879(T,C); rs73449692(C,T); rs187725104(C,T); rs73721920(A,T); rs11987510(C,T); rs7840408(G,A); rs4380981(A,G); rs4527924(T,C); rs72727885(T,A); rs72727886(T,C); rs72727889(A,G); rs9657455(C,A); rs11988391(C,T); rs180863939(G,A); rs112116668(G,A); rs4909828(G,C); rs13250220(G,A); rs67432052(C,T); rs377363221(G,A); rs13260810(C,T); rs9657456(C,G); rs72727898(A,G); rs67017256(C,A); rs4369035(A,G); rs11989534(C,A); rs11989535(C,G); rs4520206(T,C); rs138525438(C,T); rs185975345(G,A); rs11990354(C,A); rs13268861(G,T); rs13272110(A,C); rs66644529(G,A); rs11994143(A,G); rs11990481(C,G); rs11784024(T,C); rs73449701(C,T); rs11997487(G,A); rs148050986(C,T); rs4909829(G,C); rs180851606(C,T); rs4909830(T,C); rs28704583(C,T); rs6997633(A,G); rs7844565(C,T); rs115673127(G,T); rs10090396(A,G); rs10081530(G,A); rs11785186(G,A); rs368557035(T,A); rs62527900(A,G); rs4545144(G,T); rs7842696(A,C); rs111843463(G,A); rs28576317(T,C); rs4361792(T,C); rs111621914(G,T); rs13264997(A,G); rs60597602(C,A); rs4243903(T,C); rs9942790(C,T); rs11777130(G,A); rs11777150(G,A); rs4493946(G,A); rs4540440(G,A); rs7839680(G,A); rs186297442(A,T); rs7843796(G,C); rs76685238(T,C); rs7828523(A,C); rs7844188(G,A); rs191356823(T,A); rs7006910(T,C); rs6983531(C,T); rs6982588(G,C); rs6982858(G,A); rs6998293(C,T); rs76940729(T,C); rs115271692(C,T); rs4506262(T,C); rs11787079(T,C); rs10111891(T,C); rs10093704(G,A); rs7817095(A,C); rs11787153(T,C); rs9644500(T,C); rs10097897(G,A); rs77838335(C,T); rs7813511(C,G); rs7831458(A,C); rs7812770(G,A); rs4909443(A,G); rs4909444(G,T); rs72729624(A,C); rs149606658(G,A); rs62527922(G,A); rs60078568(T,C); rs10104531(T,C); rs10089224(G,A); rs112948163(A,G); rs35026609(G,A); rs62527936(C,T); rs11785534(C,G); rs4909832(A,G); rs4909833(G,A); rs72729635(C,T); rs3936181(G,T); rs62527937(C,T); rs10109299(G,A); rs62527938(G,A); rs10112470(G,A); rs76816909(C,A); rs4593591(C,G); rs4514025(C,T); rs4073002(C,A); rs79859461(T,C); rs12674962(C,T); rs77960932(G,C); rs10107433(T,C); rs62527939(G,A); rs10107678(A,C); rs7835385(G,T); rs79206227(C,T); rs13249448(T,C); rs62527943(C,T); rs142440702(A,C); rs192977235(G,T); rs74528502(G,A); rs62527944(T,C); rs4545143(T,A); rs76734214(G,A); rs4560831(G,A); rs4454319(A,G); rs34505054(C,T); rs4909835(A,G); rs4909836(A,G); rs77613350(G,A); rs4909837(G,A); rs62527945(C,T); rs62527949(G,A); rs5025363(C,T); rs72729644(A,T); rs75799801(C,A); rs9650563(A,G); rs79739380(G,A); rs11780480(C,T); rs4243904(A,T); rs4243905(C,T); rs77669297(T,G); rs184782729(C,T); rs76731699(T,C); rs74886030(T,C); rs4074052(A,G); rs141577779(A,G); rs13248775(C,G); rs12546630(T,C); rs150926652(A,G); rs4463471(T,C); rs141361043(G,A); rs144590377(G,A); rs145390502(A,G); rs4265224(A,C); rs4263812(A,G); rs143592896(G,A); rs11166837(T,C); rs117227693(C,T); rs11776127(G,A); rs7388083(C,A); rs112928940(A,G); rs117837680(G,T); rs76441066(A,G); rs10089734(A,G); rs79511148(G,T); rs12544002(G,C); rs9657459(A,G); rs9657460(T,C); rs13255858(G,C); rs76788768(G,A); rs74897681(C,T); rs77773632(G,T); rs5008927(G,C); rs28613696(C,T); rs78522569(C,T); rs78308175(T,C); rs13259719(T,C); rs12681358(T,C); rs12674545(G,A); rs4282617(C,G); rs79787108(C,T); rs9969589(A,G); rs4436164(A,G); rs77951297(C,T); rs4255177(T,C); rs111939745(C,G); rs9324493(A,G); rs9969523(C,A); rs10103039(C,T); rs11778635(G,A); rs62527954(G,A); rs62527955(G,A); rs10110090(C,T); rs62527956(T,A); rs11166838(G,A); rs62527957(C,A); rs7007617(A,T); rs73443079(G,A); rs5023000(C,T); rs7841761(A,G); rs34822982(C,T); rs11774914(C,T); rs138454217(T,G); rs4319142(G,A); rs12678237(T,C); rs13260589(C,T); rs11166839(A,G); rs11775339(A,C); rs77253387(A,C); rs76700047(T,C); rs73443086(C,A); rs76119666(T,G); rs28726333(C,A); rs117434912(G,A); rs62527958(T,C); rs62527959(A,G); rs149082060(C,G); rs10112806(C,A); rs12550730(C,T); rs12545759(G,A); rs73443093(C,T); rs140961270(C,T); rs4074457(G,A); rs4075073(G,T); rs4075072(C,T); rs6577942(C,T); rs73719097(C,T); rs115920102(A,C); rs10096974(G,A); rs73443094(C,A); rs9324495(T,C); rs10101051(C,T); rs10087596(A,G); rs28695380(C,T); rs10091350(A,G); rs183389464(A,G); rs143874937(T,C); rs11994119(A,T); rs12680005(A,G); rs3862310(C,T); rs10112907(C,G); rs10099502(A,G); rs10102641(T,C); rs10099637(A,G); rs10112521(G,T); rs11991552(C,T); rs10113301(T,C); rs10110621(A,G); rs10096277(C,T); rs73445003(C,A); rs10096388(C,T); rs151054020(C,T); rs4588898(C,T); rs4567084(G,A); rs10093066(T,C); rs7357589(G,C); rs150124900(G,A); rs4582606(C,G); rs73722205(T,C); rs10098259(A,G); rs10111881(C,T); rs10111882(C,G); rs4409435(T,C); rs4481653(C,T); rs4302884(G,T); rs10105280(T,A); rs73445011(C,A); rs183064946(A,C); rs10090839(G,C); rs10106218(A,G); rs73445014(T,C); rs10109866(T,C); rs7835533(C,T); rs7839333(C,T); rs7838405(G,A); rs7386845(A,G); rs79298560(A,G); rs7387178(T,C); rs55734613(T,A); rs183133537(T,A); rs72729671(G,A); rs62530663(G,T); rs55688039(T,C); rs2318341(G,A); rs10088210(T,C); rs149637922(G,A); rs74372914(C,A); rs13255079(C,T); rs12543947(G,C); rs11166840(C,A); rs74751313(A,C); rs10093176(A,G); rs372148378(G,A); rs77209119(G,A); rs78634247(A,G); rs10505705(G,A); rs7461196(G,A); rs112312397(G,A); rs112027670(T,C); rs17676060(C,T); rs76911068(A,G); rs115807088(C,T); rs77081234(A,G); rs111407804(A,C); rs9324496(T,C); rs76586230(C,T); rs4736187(T,C); rs7837487(C,A); rs2318340(A,G); rs113563588(A,G); rs7009274(C,T); rs16909553(A,T); rs2873683(G,C); rs4736186(T,C); rs7839138(A,G); rs73437366(C,T); rs2318339(C,G); rs2318338(T,C); rs7825723(G,A); rs112861200(G,A); rs11989847(T,C); rs7831232(C,T); rs7002313(C,T); rs35756813(C,T); rs4736040(A,G); rs4736185(C,T); rs4736039(A,G); rs7824025(A,C); rs7824190(A,G); rs9644503(A,G); rs4060123(C,A); rs2873682(T,C); rs7012142(G,A); rs112305490(C,T); rs7845811(G,T); rs76107190(G,A); rs1320275(T,A); rs1320274(G,A); rs1320273(T,C); rs2318337(C,T); rs13280699(T,C); rs2318336(T,C); rs73719363(C,T); rs13279646(C,T); rs6577944(C,T); rs6577945(G,A); rs6577946(C,A); rs6577947(C,A); rs4236875(C,T); rs6981476(T,C); rs372526285(T,C); rs6981648(T,G); rs10103379(G,A); rs4255166(C,G); rs75903722(G,A); rs4387007(C,T); rs2318362(G,A); rs6995563(G,A); rs34284837(C,T); rs12155713(T,C); rs73361011(G,A); rs16909580(C,T); rs370281443(G,A); rs7821140(C,T); rs35186067(C,T); rs11166842(C,A); rs28715167(C,T); rs4736038(C,T); rs11774530(C,T); rs11166843(C,G); rs10088847(C,T); rs11166844(C,T); rs10090903(G,T); rs12546880(G,C); rs4736184(A,G); rs56662818(T,C); rs188914793(G,A); rs75364771(G,C); rs62530720(A,G); rs73361020(G,A); rs10086220(T,C); rs10086222(A,G); rs73719985(A,G); rs7843456(G,C); rs7843580(G,A); rs7831669(T,C); rs62530721(C,T); rs7844608(C,T); rs7832107(T,C); rs7828786(A,G); rs4736037(A,G); rs4736183(T,C); rs7836442(T,C); rs2318333(C,A); rs1320270(A,G); rs117332745(G,A); rs11990130(C,T); rs10108719(C,T); rs1320271(G,A); rs1879042(A,G); rs11780307(C,G); rs73361027(T,C); rs111382930(C,T); rs5019355(T,C); rs58099005(G,A); rs13277717(G,C); rs28461252(C,T); rs11781300(T,C); rs143244357(C,T); rs146704850(C,T); rs371422217(G,A); rs34370046(T,C); rs374132809(G,A); rs73719989(C,T); rs16909594(A,G); rs73361030(G,A); rs115635834(A,G); rs10092896(T,C); rs370272197(C,T); rs373706579(G,A); rs10107255(C,A); rs150618280(G,T); rs10100867(A,G); rs73361031(T,C); rs2318334(T,C); rs73361032(C,T); rs6998209(C,T); rs149163176(C,T); rs73362852(A,G); rs6989719(T,G); rs16909606(C,G); rs115134376(G,A); rs61702452(G,T); rs187303936(C,T); rs36048514(A,T); rs181990604(T,G); rs35102924(C,A); rs10282799(G,A); rs10283245(T,C); rs11781634(C,T); rs1574370(C,T); rs7460631(T,G); rs11786910(T,C); rs7836628(C,T); rs6577948(G,A); rs6577949(G,A); rs1573833(A,G); rs115320052(C,T); rs148467766(A,G); rs144991819(A,G); rs73362874(T,C); rs183935554(G,A); rs6991720(C,G); rs62530723(C,T); rs12544238(A,T); rs115042232(T,C); rs16909635(T,C); rs73362877(T,C); rs16909637(T,C); rs116342849(G,A); rs139287518(C,T); rs78110007(A,C); rs77261544(T,C); rs72729700(G,A); rs7837787(A,G); rs4281141(G,C); rs16909640(C,T); rs142518225(C,T); rs1317115(C,A); rs1317114(A,G); rs7465128(A,G); rs13262305(C,A); rs11992887(G,T); rs149989819(T,C); rs11987216(C,A); rs11166845(C,T); rs11992506(T,C); rs137904412(C,T); rs6998177(A,G); rs7016754(C,T); rs139340666(G,A); rs148848140(C,T); rs1343978(A,G); rs374867067(T,C); rs143016589(A,G); rs12547982(G,T); rs12155960(A,G); rs13255090(A,G); rs13255736(A,G); rs11779129(C,A); rs7818881(C,T); rs4991003(C,A); rs10086199(G,A); rs16893541(G,C); rs10107709(T,G); rs10090299(C,T); rs10107843(T,C); rs11786131(T,A); rs10108522(T,C); rs1879051(G,A); rs7838300(C,T); rs7838450(C,T); rs62528781(C,T); rs2318332(C,G); rs10101430(G,A); rs13256774(A,G); rs6577951(A,G); rs7015755(A,G); rs6995061(G,T); rs142240462(G,A); rs145909041(G,A); rs10481408(A,G); rs10481409(A,G); rs9324497(G,A); rs11166848(C,G); rs4736127(A,G); rs73366836(C,T); rs73366838(A,C); rs140263027(A,G); rs1320279(C,T); rs1316523(C,T); rs6990065(G,A); rs13279213(G,A); rs34939101(A,C); rs10113304(C,T); rs73366848(G,A); rs2873680(C,T); rs6988322(A,G); rs10093925(T,C); rs79217844(G,A); rs6987627(G,C); rs144337224(A,C); rs11989324(T,C); rs116435947(C,T); rs2292927(T,C); rs3750282(C,T); rs3750283(G,C); rs112516466(T,C); rs1320272(C,G); rs72731620(C,T); rs111932762(G,T); rs2873681(C,T); rs76458145(A,G); rs4736009(C,T); rs59176636(A,C); rs369829879(C,T); rs35835134(T,C); rs59757202(A,G); rs7013177(T,C); rs7009213(A,T); rs55940901(C,T); rs6577952(T,C); rs6577953(C,G); rs73366869(T,C); rs371733485(C,G); rs112995035(G,C); rs73366872(G,A); rs16909676(C,T); rs6993839(G,A); rs6994373(T,C); rs11780454(T,G); rs9692785(T,C); rs7821789(A,G); rs7825663(T,C); rs73366877(T,C); rs6995718(A,G); rs6995886(A,G); rs6996369(A,G); rs138614897(A,T); rs6996386(A,G); rs7001094(T,C); rs4736001(G,A); rs4736000(C,A); rs4735999(C,G); rs9650564(C,T); rs9650565(C,T); rs13275321(A,G); rs73366890(G,C); rs72731625(T,C); rs72731626(C,A); rs6993598(C,T); rs9692908(G,A); rs112088912(C,T); rs113294618(G,A); rs112735897(A,G); rs62528785(C,T); rs7001894(G,A); rs73366894(C,T); rs11787056(T,C); rs73720617(G,A); rs138153250(T,C); rs11775793(G,T); rs146611704(G,A); rs141423529(C,G); rs4736298(G,T); rs34689984(C,A); rs4736297(C,A); rs4736296(G,C); rs7014497(C,T); rs371826415(C,T); rs9650566(G,A); rs114892664(C,G); rs16909681(G,A); rs7001558(C,T); rs139521491(G,A); rs144441145(A,T); rs6577954(G,T); rs77680508(A,C); rs6577955(C,T); rs4060121(G,C); rs1573809(C,T); rs2318331(G,A); rs16909685(C,G); rs56691429(A,G); rs28550986(C,T); rs16909687(A,G); rs74542712(T,C); rs73368810(G,A); rs6984777(G,A); rs6988991(G,T); rs73368817(G,A); rs9644504(C,T); rs73720622(G,A); rs111307194(A,T); rs117285666(G,A); rs6577956(C,T); rs16909696(G,C); rs9644505(G,A); rs78850480(C,A); rs7837088(T,A); rs7833411(A,G); rs75461529(A,G); rs62528786(C,T); rs35339221(T,C); rs34547194(T,C); rs11777748(T,C); rs10105701(T,C); rs10105721(T,C); rs72731634(A,T); rs28398038(T,C); rs6985916(T,C); rs7000416(C,T); rs73368830(T,C); rs12675384(C,T); rs76465136(C,G); rs56220053(C,T); rs10113464(T,C); rs73368835(C,G); rs57279391(G,C); rs12114311(C,T); rs11166849(T,C); rs118056130(C,T); rs17678562(T,C); rs73368837(A,C); rs1574172(A,G); rs17740495(T,C); rs114074304(C,T); rs10104373(C,T); rs73351923(C,A); rs10505706(G,C); rs11990049(C,T); rs12547472(A,G); rs11166850(A,G); rs187191675(G,A); rs7819724(G,A); rs190005282(A,G); rs4736078(G,A); rs4736268(C,T); rs116628013(C,T); rs73351938(G,C); rs11166851(T,C); rs11166852(A,G); rs11166853(A,G); rs12549623(C,T); rs11775756(A,C); rs11989698(G,A); rs112321148(G,A); rs11986555(A,G); rs77814417(G,A); rs73351950(G,A); rs79662522(G,T); rs76649478(C,T); rs73351953(T,C); rs79132951(T,C); rs78317185(T,G); rs17689724(T,C); rs16893545(A,C); rs28417366(T,C); rs16893548(C,T); rs16909722(C,T); rs16909726(G,A); rs11782663(G,A); rs11776018(C,T); rs57158334(A,T); rs2008339(C,T); rs11776125(C,G); rs11991356(T,C); rs11994766(G,A); rs62528812(T,C); rs115945995(G,A); rs62635348(T,C); rs62528814(G,A); rs13265526(C,T); rs62528815(C,T); rs4736258(T,A); rs6988229(C,T); rs77377108(A,T); rs72731640(C,T); rs111918508(C,T); rs7823737(T,C); rs6998323(T,C); rs7011683(G,A); rs144080309(A,T); rs12549200(G,A); rs12677866(C,T); rs17740982(C,T); rs115893591(C,T); rs11990492(C,T); rs62528816(A,G); rs4736255(A,G); rs76486895(G,A); rs16909740(G,A); rs62528818(A,G); rs115063052(G,A); rs12541806(T,G); rs11166854(T,C); rs1962444(C,T); rs1316978(A,G); rs74891792(G,A); rs2318342(C,T); rs7814168(A,G); rs2318343(C,T); rs16909746(C,T); rs28680346(C,T); rs6577957(T,C); rs9324498(A,G); rs7845402(C,T); rs4736229(A,G); rs2318344(G,A); rs7013126(T,C); rs7013414(T,C); rs7013605(T,C); rs11998363(C,A); rs62528820(G,T); rs4736221(G,A); rs4736220(G,A); rs6999051(G,C); rs7000425(C,T); rs28363936(T,C); rs73353926(C,T); rs28489084(G,A); rs7006103(T,C); rs7002792(A,G); rs1879046(A,G); rs1879047(C,T); rs4595154(A,T); rs4736060(C,T); rs10110632(G,A); rs10098048(A,G); rs4736216(G,A); rs4736215(G,T); rs4736214(G,A); rs9644439(G,C); rs10156259(C,T); rs7812653(A,G); rs10105755(A,G); rs11992725(G,A); rs7820219(T,G); rs7820239(T,C); rs10094560(C,T); rs62528845(G,C); rs28750143(C,T); rs28531929(C,T); rs2318346(C,T); rs2318347(T,C); rs2318348(G,A); rs7827058(A,G); rs142564871(G,A); rs72731664(G,T); rs7819077(C,T); rs7819375(C,T); rs7007907(A,G); rs4599849(C,T); rs7836870(C,T); rs6577958(T,C); rs4736207(G,A); rs7828568(T,C); rs7828583(T,A); rs7824825(A,G); rs11780422(A,G); rs78010861(G,T); rs6577959(C,T); rs6577960(A,G); rs6577961(C,T); rs6577963(C,T); rs74390643(G,T); rs6986041(C,T); rs28560401(T,C); rs7839358(T,A); rs2873684(T,C); rs12681025(T,C); rs4736056(G,A); rs4736055(C,A); rs4736054(C,T); rs11784270(A,C); rs16909799(G,T); rs56885010(A,G); rs4736205(G,A); rs4736204(C,T); rs7016566(A,G); rs4736053(G,T); rs4736052(T,C); rs4736051(T,C); rs6983081(T,C); rs6987124(T,A); rs6983070(A,T); rs6987338(T,C); rs6577964(A,G); rs80095588(C,T); rs7001988(C,T); rs2873685(G,T); rs4736050(C,G); rs4236882(C,A); rs1320280(T,C); rs1316335(G,A); rs4480153(T,C); rs10100280(G,A); rs1316448(G,A); rs72731675(G,T); rs9324500(C,A); rs9657434(G,T); rs9657435(A,G); rs12550374(G,A); rs12545655(C,T); rs12545692(C,T); rs1317975(C,G) |
| ccdsGene name | CCDS6376.1 |
| cytoBand name | 8q24.23 |
| EntrezGene GeneID | 169044 |
| EntrezGene Description | collagen, type XXII, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL22A1:NM_152888:exon14:c.G1703A:p.R568Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6629 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.008398 |
| ESP All MAF | 0.002999 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.001 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Progressive cone degeneration (in some patients);
Photophobia;
Nyctalopia;
Decreased central vision;
Dyschromatopsia;
Macular granularity (in some patients);
Central macular atrophy (in some patients);
Central scotoma on Goldmann visual field (in some patients);
Supernormal and delayed scotopic rod electroretinogram (in some patients);
Cone degeneration, stationary (in some patients);
Nystagmus (in some patients);
Normal scotopic responses on rod electroretinogram (in some patients);
Severely reduced cone and absent 30Hz flicker responses on cone electroretinogram
(in some patients)
MISCELLANEOUS:
Onset in first to second decade
MOLECULAR BASIS:
Caused by mutation in the phosphodiesterase 6H, cGMP-specific, cone,
gamma gene (PDE6H, 601190.0001)
OMIM Title
*610026 COLLAGEN, TYPE XXII, ALPHA-1; COL22A1
OMIM Description
DESCRIPTION
COL22A1, a member of the FACIT (fibrillar-associated collagens with
interrupted triple helices) subgroup of the collagen protein family,
specifically localizes to tissue junctions (Koch et al., 2004).
CLONING
By EST database searching, Koch et al. (2004) identified a sequence with
homology to the C-terminal amino acid sequence of type XII collagen
(COL12A1; 120320). Using PCR-based strategies, they isolated the
full-length cDNA of a novel collagen, designated COL22A1, from placenta
and hip cartilage/bone cDNA libraries. The deduced 1,626-amino acid
protein contains a putative 27-amino acid signal peptide. It has the
typical structure of a FACIT collagen, with an N-terminal globular
domain and a short C-terminal collagenous stretch. The N terminus has a
VWA (von Willebrand factor A-like) domain, followed by a TSPN
(N-terminal thrombospondin-like domain) containing N-glycosylation
sites. The C-terminal 105 amino acids contain interruptions in Gly-X-Y
triplets followed by 2 cysteine residues. It shares the greatest overall
homology with COL21A1 (610002), but its VWA domain also has similarity
to the VWA domains of COL12A1 and matrilin-1 (MATN1; 115437). Northern
blot analysis of human tisuses detected a 6.4-kb transcript in skeletal
muscle and heart. RT-PCR on mouse tissues revealed additional signals in
cartilage, skin and keratinocytes, and eye. In situ hybridization
detected mouse Col22a1 mRNA exclusively in muscle cells at the muscle
attachment sites to tendon elements and ribs. Immunofluorescence studies
demonstrated that mouse Col22a1 protein distribution is specific to
tissue junctions, including the myotendinous junction in skeletal and
heart muscle, the articular cartilage-synovial fluid junctions, and the
border between the anagen hair follicle and the dermis in skin.
Immunoelectron microscopy localized Col22a1 to basement membranes
outlining the myotendinous junction.
GENE FUNCTION
Using cell adhesion assays, Koch et al. (2004) demonstrated that COL22A1
acts as a cell adhesion ligand for lung fibroblasts expressing
alpha-1/beta-1 and alpha-2/beta-1 integrins, and for keratinocytes
expressing alpha-2/beta-1 integrins (Koch et al., 2004).
GENE STRUCTURE
Koch et al. (2004) determined that the COL22A1 gene contains 66 exons
and spans 326 kb. The signal peptide coding sequence is located in the
second exon.
MAPPING
By genomic sequence analysis, Koch et al. (2004) mapped the COL22A1 gene
to chromosome 8q24.2 and the mouse homolog to chromosome 15D2-D3.
MIR4472-1
| dbSNP name | rs28655823(G,C) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 100616268 |
| EntrezGene Description | microRNA 4472-1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2172 |
| ExAC AF | 0.033 |
CDC42P3
| dbSNP name | rs12547761(T,C); rs6993581(G,A) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 100133669 |
| EntrezGene Symbol | LOC100133669 |
| snpEff Gene Name | RP11-273G15.2 |
| EntrezGene Description | uncharacterized LOC100133669 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4761 |
LY6H
| dbSNP name | rs56924527(C,A); rs7007949(G,A); rs10109061(A,G); rs9694368(C,G) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 4062 |
| EntrezGene Description | lymphocyte antigen 6 complex, locus H |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04086 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, high-frequency (onset in childhood-adolescence);
Deafness, moderate-severe (onset in third decade);
Cochleosaccular dysplasia;
Organ of Corti degeneration
MISCELLANEOUS:
Onset of hearing loss in late childhood or adolescence;
Allelic to Fechtner syndrome (153640), May-Hegglin anomaly (155100),
Sebastian syndrome (605249), and Epstein syndrome (153650)
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy chain 9, nonmuscle gene (MYH9,
160775.0008)
OMIM Title
*603625 LYMPHOCYTE ANTIGEN 6 COMPLEX, LOCUS H; LY6H
OMIM Description
CLONING
The LY6 antigens are a family of glycosylphosphatidylinositol-anchored
cell surface glycoproteins. Horie et al. (1998) identified LY6H, a novel
member of the LY6 family, among random sequences from a human fetal
brain cDNA library. The full-length cDNA encodes a 161-amino acid
polypeptide which is 23 to 33% identical to other known family members.
Northern blot analysis revealed that a 1-kb LY6H transcript was
expressed at a high level in brain and at a lower level in testis, small
intestine, and colon.
MAPPING
Horie et al. (1998) used FISH to map LY6H to human chromosome 8q24.3, a
localization that is shared with other LY6 family members including LY6D
(606204), LY6E (601384), and GML (602370).
RHPN1-AS1
| dbSNP name | rs2467950(A,G); rs2450764(A,C); rs4874104(G,A); rs114661767(C,T) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 78998 |
| snpEff Gene Name | RHPN1 |
| EntrezGene Description | RHPN1 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1419 |
MAFA
| dbSNP name | rs1466622(T,C); rs1466621(T,A) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 389692 |
| EntrezGene Description | v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Venous thrombosis;
Portal hypertension
ABDOMEN:
[Liver];
Hepatic venous thrombosis;
Portal vein thrombosis;
Portal hypertension;
Hepatomegaly;
[Spleen];
Splenomegaly
NEUROLOGIC:
[Central nervous system];
Seizures, absence;
Seizures, atonic
HEMATOLOGY:
No hemolysis;
No bone marrow abnormalities
LABORATORY ABNORMALITIES:
Decreased expression of glycosylphosphatidylinositol-linked proteins
(e.g., CD59 107271 and CD24 600274) on hematopoietic cells
MISCELLANEOUS:
Two unrelated families have been reported (last curated May 2014);
Onset of thrombosis by age 2 years
MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol glycan, class M gene
(PIGM, 610273.0001)
OMIM Title
*610303 V-MAF AVIAN MUSCULOAPONEUROTIC FIBROSARCOMA ONCOGENE HOMOLOG A; MAFA
;;RIPE3B1
OMIM Description
DESCRIPTION
MAFA is a transcription factor that binds RIPE3b, a conserved enhancer
element that regulates pancreatic beta cell-specific expression of the
insulin gene (INS; 176730) (Olbrot et al., 2002).
CLONING
By searching a genomic database for sequences similar to hamster Mafa,
followed by PCR of genomic DNA, Olbrot et al. (2002) cloned human MAFA.
The deduced 352-amino acid protein contains an N-terminal activation
domain rich in serine, proline, and threonine, followed by 2
glycine-rich regions separated by a histidine-rich region, and a
C-terminal DNA-binding and dimerization domain containing a basic
leucine zipper. Northern blot analysis detected Mafa in mouse and
hamster insulinoma cells, in mouse thymus, and in mouse embryos at
embryonic day 14, and there was evidence of alternative splicing. No
expression was detected in other mouse tissues examined or in a
glucagon-producing cell line.
GENE FUNCTION
Using EMSA, Olbrot et al. (2002) found that full-length and N-terminally
truncated MAFA bound a RIPE3b probe, and it appeared to bind as a
homodimer. Following transfection in HeLa cells, only the full-length
protein activated insulin gene expression from the RIPE3b element,
although the N-terminally truncated form localized to the nucleus.
Expression of MAFA, as well as PDX1 (600733) and BETA2 (NEUROD1;
601724), 2 other transcription factors that bind enhancer elements in
the insulin gene, is enriched in beta cells. Following their
transfection into non-beta cell lines, Zhao et al. (2005) found that
rodent Pdx1 and Beta2 showed little or no activation of a reporter
construct driven by the insulin promoter in the absence of Mafa. Mafa
together with Pdx1 or Beta2 produced synergistic activation, and insulin
promoter activity was even higher when all 3 proteins were present.
Stimulation was attenuated upon compromising either Mafa transactivation
or DNA-binding activity. Coimmunoprecipitation and in vitro pull-down
assays showed that Mafa directly bound endogenous rodent Pdx1 and Beta2.
Dominant-negative and small interfering RNAs of Mafa profoundly reduced
insulin promoter activity in rodent beta cell lines. Mafa was induced in
parallel with insulin mRNA in glucose-stimulated rat islets, and insulin
mRNA levels were elevated in rat islets by adenovirus-mediated Mafa
expression. Zhao et al. (2005) concluded that MAFA plays a key role in
coordinating and controlling the level of insulin gene expression in
islet beta cells.
GENE STRUCTURE
Olbrot et al. (2002) determined that the coding region of the MAFA gene
is intronless.
MAPPING
By genomic sequence analysis, Olbrot et al. (2002) mapped the MAFA gene
to chromosome 8q24.
ANIMAL MODEL
Zhang et al. (2005) found that Mafa-null mice were born at the expected
frequency and survived until adulthood. Mafa-null mice displayed
intolerance to glucose and developed diabetes mellitus. Glucose-,
arginine-, or KCl-stimulated insulin secretion from pancreatic beta
cells was severely impaired, although insulin content per se was not
significantly affected. Mafa-null mice also showed age-dependent
pancreatic islet abnormalities. Molecular analysis revealed that Ins1,
Ins2, Pdx1, Beta2, and Glut2 (SLC2A2; 138160) transcripts were
diminished in Mafa-deficient mice.
Zhou et al. (2008) used a strategy of reexpressing key developmental
regulators in vivo to identify a specific combination of 3 transcription
factors, Neurog3 (604882), Pdx1 (600733), and Mafa, that reprogrammed
differentiated pancreatic exocrine cells in adult mice into cells that
closely resembled beta cells. Induced beta cells were indistinguishable
from endogenous islet beta cells in size, shape, and ultrastructure.
They expressed genes essential for beta cell function and could
ameliorate hyperglycemia by remodeling local vasculature and secreting
insulin. Zhou et al. (2008) concluded that their study provided an
example of cellular reprogramming using defined factors in an adult
organ and suggested a general paradigm for directing cell reprogramming
without reversion to a pluripotent stem cell state.
TIGD5
| dbSNP name | rs146036086(G,A) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 84948 |
| snpEff Gene Name | PYCRL |
| EntrezGene Description | tigger transposable element derived 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
PYCRL
| dbSNP name | rs755217(G,A); rs896962(T,C); rs35955574(G,A); rs78780542(C,T); rs2242090(C,G); rs61735421(C,T); rs2242088(C,G); rs7818082(G,A); rs4874169(A,G); rs28405113(C,A); rs11136305(C,T); rs34892354(G,C); rs62522171(C,A) |
| ccdsGene name | CCDS6407.2 |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 65263 |
| EntrezGene Description | pyrroline-5-carboxylate reductase-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PYCRL:NM_023078:exon6:c.C835T:p.R279W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8135 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | D3DWK4 |
| dbSNP GMAF | 0.002296 |
| ExAC AF | 1.426e-03,2.689e-04 |
BREA2
| dbSNP name | rs56207585(A,G); rs13269487(T,C); rs1141722(A,T) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 286076 |
| snpEff Gene Name | ZNF707 |
| EntrezGene Description | breast cancer estrogen-induced apoptosis 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04637 |
NRBP2
| dbSNP name | rs7465214(G,A); rs72693365(G,A) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 340371 |
| EntrezGene Description | nuclear receptor binding protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2773 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Microretrognathia;
[Ears];
Simple cup-shaped ears;
Low-set ears;
Preauricular fistulas, bilateral;
Hearing loss, mixed conductive-sensorineural;
[Eyes];
Alacrima;
Nasolacrimal duct stenosis;
Blue sclerae (in some patients);
[Nose];
Nasolacrimal duct stenosis;
[Teeth];
Dental caries;
Malocclusion (in some patients)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Protruding shoulders;
Winged scapulae
SKELETAL:
[Skull];
Mastoiditis, bilateral (in some patients);
[Spine];
Anterior scalloping, lower thoracic and lumbar vertebral bodies (in
some patients);
Fusion defect at L5/S1 (in some patients);
[Hands];
Tapering fingers (in some patients);
Clinodactyly (in some patients);
[Feet];
Cutaneous syndactyly, second and third toes (in some patients)
NEUROLOGIC:
[Central nervous system];
Intellectual disability, moderate (in some patients);
Developmental delay, moderate (in some patients);
Periventricular white matter gliosis (in some patients)
MISCELLANEOUS:
Based on 1 reported family (last curated December 2013)
MOLECULAR BASIS:
Caused by mutation in paired box gene-1 (PAX1, 167411.0001)
OMIM Title
*615563 NUCLEAR RECEPTOR-BINDING PROTEIN 2; NRBP2
OMIM Description
CLONING
By database analysis, Larsson et al. (2008) identified human NRBP2,
which encodes a deduced 507-amino acid protein. In situ hybridization of
developing mouse brain revealed Nrbp2 expression in the walls of the
third and fourth ventricles and in hippocampus. In adult mouse brain,
Nrbp2 was expressed in neurons of the CA3 region of hippocampus and in
Purkinje cells of cerebellum. Immunohistochemical analysis localized
Nrbp2 to the cytoplasm of mouse neural stem/progenitor cells. NRBP2 was
expressed in a subset of rounded tumor cells in nodular-type pediatric
medulloblastomas. Endogenous HEK293 cell NRBP2 had an apparent molecular
mass of 55 to 60 kD by SDS-PAGE.
MAPPING
By genomic sequence analysis, Dauber et al. (2013) mapped the NRBP2 gene
to chromosome 8q24.3.
GENE FUNCTION
Demoulin et al. (2006) found that expression of Nrbp2 was upregulated
following differentiation in rodent neural stem/progenitor cells.
Larsson et al. (2008) found that knockdown of Nrbp2 during neural
differentiation of mouse embryonic stem cells did not change the
proportion of neurons and astrocytes formed, but increased cell
sensitivity to apoptotic stimuli.
ANIMAL MODEL
Dauber et al. (2013) found that knockdown of either of the 2 zebrafish
Nrbp2 orthologs resulted in no phenotype. However, suppression of both
orthologs led to global delay and embryonic lethality with no
organ-specific phenotype.
FOXH1
| dbSNP name | rs2721176(T,C); rs750472(A,C) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 8928 |
| EntrezGene Description | forkhead box H1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07163 |
| ESP Afr MAF | 0.010426 |
| ESP All MAF | 0.004225 |
| ESP Eur/Amr MAF | 0.001063 |
| ExAC AF | 0.97 |
LRRC24
| dbSNP name | rs2620651(A,C); rs150586326(C,T); rs2721137(T,C); rs2721138(T,C); rs9071(G,A); rs67557810(C,T) |
| ccdsGene name | CCDS34969.1 |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 441381 |
| EntrezGene Description | leucine rich repeat containing 24 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LRRC24:NM_001024678:exon5:c.T648G:p.G216G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1667 |
| ESP Afr MAF | 0.332258 |
| ESP All MAF | 0.119853 |
| ESP Eur/Amr MAF | 0.011198 |
| ExAC AF | 0.036 |
TMED10P1
| dbSNP name | rs4489360(G,A); rs61740502(T,G); rs2978409(A,T); rs4302882(A,G); rs114489000(C,A); rs2978441(C,T); rs6599551(T,C); rs6981609(C,T); rs61505616(G,A); rs147956221(T,C) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 286102 |
| snpEff Gene Name | RP5-1047A19.4 |
| EntrezGene Description | transmembrane emp24-like trafficking protein 10 (yeast) pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2994 |
| ExAC AF | 0.199 |
ZNF252P-AS1
| dbSNP name | rs2294042(C,T); rs6989348(C,T); rs2294043(C,A); rs77308683(T,A); rs142727110(G,A); rs2979285(T,A); rs7832026(A,G); rs2294044(G,C) |
| cytoBand name | 8q24.3 |
| EntrezGene GeneID | 286103 |
| snpEff Gene Name | C8orf77 |
| EntrezGene Description | ZNF252P antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3361 |
| ExAC AF | 0.157 |
C9orf66
| dbSNP name | rs680654(G,A); rs680144(G,A); rs10964550(G,C); rs7850051(G,C); rs140428543(C,T); rs77382222(T,A); rs636922(A,C); rs2023402(C,T); rs635615(C,T) |
| cytoBand name | 9p24.3 |
| EntrezGene GeneID | 157983 |
| snpEff Gene Name | DOCK8 |
| EntrezGene Description | chromosome 9 open reading frame 66 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2911 |
LINC01230
| dbSNP name | rs2279985(G,A); rs2279984(T,A) |
| cytoBand name | 9p24.3 |
| snpEff Gene Name | DMRT2 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4913 |
RANBP6
| dbSNP name | rs41281759(G,A); rs73389044(T,C); rs7425(T,C); rs10758736(G,A); rs106033(A,C); rs1411949(A,G); rs114777314(T,C); rs343500(T,C) |
| cytoBand name | 9p24.1 |
| EntrezGene GeneID | 26953 |
| EntrezGene Description | RAN binding protein 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01331 |
TPD52L3
| dbSNP name | rs3847262(T,C); rs7033960(C,G); rs898673(A,G); rs1052335(A,C); rs1037885(G,A); rs2890707(A,G); rs10491836(C,A); rs16924356(G,A); rs16924360(T,G) |
| ccdsGene name | CCDS34984.1 |
| cytoBand name | 9p24.1 |
| EntrezGene GeneID | 89882 |
| EntrezGene Description | tumor protein D52-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TPD52L3:NM_001001874:exon1:c.T352C:p.F118L,TPD52L3:NM_033516:exon1:c.T352C:p.F118L,TPD52L3:NM_001001875:exon1:c.T352C:p.F118L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96J77-2 |
| dbNSFP KGp1 AF | 0.936355311355 |
| dbNSFP KGp1 Afr AF | 0.80081300813 |
| dbNSFP KGp1 Amr AF | 0.947513812155 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.970976253298 |
| dbSNP GMAF | 0.06382 |
| ESP Afr MAF | 0.175443 |
| ESP All MAF | 0.094649 |
| ESP Eur/Amr MAF | 0.053256 |
| ExAC AF | 0.95 |
GLDC
| dbSNP name | rs7848919(G,A); rs35834773(C,G); rs111326356(C,T); rs2228098(C,G); rs142004524(C,T); rs10975630(T,C); rs12000020(A,G); rs10975631(G,A); rs4742210(T,A); rs55933544(C,T); rs148291521(G,A); rs3818705(A,T); rs2282162(G,A); rs2282161(G,A); rs2282160(T,C); rs2282159(C,T); rs2282158(C,T); rs11999004(C,T); rs12001457(T,C); rs4742211(C,T); rs75645738(A,G); rs3765556(G,C); rs3765555(G,T); rs149860035(G,C); rs10465093(C,T); rs139060600(G,C); rs12346479(G,A); rs12343253(A,T); rs12347465(G,A); rs142157077(G,T); rs2026973(G,A); rs2026972(G,C); rs12348822(G,A); rs6477088(G,A); rs12345729(T,C); rs4742212(A,G); rs4742213(G,T); rs2013966(T,C); rs1811943(C,G); rs12341267(C,T); rs2297443(T,C); rs74709676(T,C); rs2297442(T,C); rs10815441(T,G); rs2026971(T,G); rs72693601(T,A); rs59699173(C,A); rs62566159(C,G); rs7858290(T,G); rs928393(C,T); rs115409809(A,G); rs4518719(T,C); rs3902970(G,A); rs4419859(T,C); rs117563512(T,G); rs117199224(G,A); rs6477089(A,G); rs75636497(C,G); rs4415375(T,C); rs114883150(C,T); rs55736048(G,C); rs76537482(A,T); rs4742214(G,C); rs7863638(G,A); rs12685035(C,T); rs10441734(C,T); rs10975638(C,G); rs16924678(T,C); rs11792185(C,A); rs7854679(A,G); rs34750106(G,C); rs74627428(T,C); rs12347456(C,T); rs12347506(C,T); rs72695504(C,T); rs17591030(C,T); rs12347488(T,C); rs28499127(A,G); rs145062104(G,A); rs34948145(G,T); rs41281769(A,C); rs3739653(G,C); rs77995862(G,A); rs77358755(T,C); rs16924682(T,G); rs4512434(T,C); rs4740848(G,A); rs12683164(G,C); rs2274874(G,C); rs1929933(A,G); rs17499965(G,C); rs10815443(T,C); rs114667156(A,G); rs10125618(A,G); rs10975640(T,G); rs16924687(G,C); rs77765174(G,A); rs147275962(C,T); rs4333664(C,T); rs7041988(T,C); rs7021790(G,T); rs7021944(G,A); rs78216226(G,A); rs79760729(C,T); rs76741478(A,G); rs7863696(T,A); rs7860596(A,G); rs58097455(G,A); rs61682033(C,T); rs116228264(C,G); rs58845338(C,A); rs78348469(A,G); rs7853386(G,C); rs60256554(C,T); rs57195296(A,G); rs78982505(A,C); rs4237166(G,C); rs16924691(C,T); rs142842728(A,G); rs76901780(C,G); rs7039182(C,A); rs75477221(C,T); rs7027507(T,C); rs6477091(T,A); rs7870809(C,A); rs7859893(A,G); rs147218239(T,G); rs141112147(C,T); rs13288399(G,C); rs7849131(G,T); rs7846856(A,G); rs143620205(C,T); rs116217159(T,C); rs10975649(G,A); rs10975650(A,G); rs10815445(T,A); rs116527304(G,A); rs10815446(C,G); rs10815447(G,A); rs56301407(C,A); rs10815448(T,C); rs7030133(T,G); rs62568987(A,G); rs7027289(A,G); rs2026974(A,T); rs182212536(A,T); rs74938436(C,G); rs7862900(A,C); rs80094923(C,G); rs62568993(T,G); rs35972094(T,C); rs10975654(A,T); rs10975655(A,T); rs116690999(A,C); rs10511461(G,A); rs62568994(G,A); rs4742218(C,T); rs77780233(G,A); rs7049229(A,T); rs12378606(C,T); rs187680622(C,A); rs13296487(A,T); rs16924709(T,G); rs116471380(G,A); rs59060834(C,T); rs10815450(A,G); rs144828680(C,T); rs12004478(T,C); rs72695519(A,G); rs12004647(A,G); rs10975660(C,T); rs186647001(T,C); rs7036639(C,T); rs7036653(C,A); rs60251520(G,C); rs10975662(T,C); rs12683179(G,C); rs1929930(A,G); rs1929931(G,A); rs60798439(T,C); rs16924717(A,G); rs2150915(A,G); rs7037383(T,C); rs11789593(G,A); rs968196(C,G); rs968197(A,T); rs55875652(G,C); rs74461075(G,A); rs7021684(G,A); rs7022724(C,T); rs10975665(A,T); rs12683100(A,G); rs4387027(C,T); rs4602948(T,G); rs4543594(C,T); rs11790612(G,A); rs75713620(C,G); rs77712643(C,A); rs78650694(C,T); rs60874990(G,A); rs13297203(C,G); rs11788881(G,A); rs16924727(A,G); rs72695533(A,G); rs56038827(T,C); rs76610829(C,T); rs1974189(G,A); rs4504696(A,G); rs113326675(A,G); rs78073049(C,T); rs79114789(A,G); rs76153763(C,T); rs77756489(T,G); rs80185476(A,G); rs77808781(C,G); rs79260957(A,G); rs115292710(G,A); rs10975668(G,A); rs10975669(G,A); rs6477094(C,T); rs11789777(T,C); rs189572490(T,A); rs192870343(A,G); rs112438601(T,C); rs57964364(T,A); rs59998046(G,A); rs57793935(T,G); rs376269386(C,T); rs11999044(C,T); rs7864644(G,A); rs116136434(C,G); rs115265158(C,A); rs60064949(T,C); rs79643203(C,T); rs115816937(C,T); rs140031377(A,C); rs35372321(A,G); rs188489263(C,G); rs7863517(T,C); rs10975671(G,A); rs7863777(A,G); rs114533814(G,A); rs150658600(G,A); rs7867577(T,C); rs113037912(C,A); rs7849728(C,G); rs6477096(C,T); rs16924731(G,A); rs35287966(C,G); rs138157427(G,C); rs7040427(G,A); rs7026782(A,G); rs12683330(C,T); rs7030760(T,C); rs145535829(C,T); rs111713542(C,G); rs7030910(T,C); rs141080861(C,T); rs7034260(T,C); rs7873092(C,T); rs7872165(G,C); rs7862146(T,A); rs7862147(T,A); rs7046575(C,A); rs7035481(A,G); rs7019525(C,T); rs62569040(A,T); rs41303229(T,A); rs113067442(G,C); rs183237661(A,G); rs7019384(G,C); rs7020315(C,A); rs7019544(G,T); rs7023971(C,T); rs7043546(T,C); rs7027957(C,T); rs13296893(G,A); rs73402952(A,C); rs2228095(G,A); rs78949122(A,T); rs10975681(T,C); rs28833481(G,T); rs13295349(C,T); rs10125015(A,G); rs112429519(C,A); rs35374927(C,T); rs116286048(A,G); rs12341084(T,G); rs7020909(T,C); rs6477097(A,C); rs4629927(C,G); rs73639330(T,C); rs6477098(G,A); rs6477099(G,A); rs10117821(A,G); rs7021520(A,G); rs138785706(T,A); rs3925456(C,T); rs7035933(G,T); rs73402958(C,A); rs73402959(T,C); rs10815452(T,A); rs11788649(C,T); rs10815453(G,A); rs78747164(C,T); rs78292560(G,C); rs7044487(G,T); rs7045613(C,T); rs149528835(T,C); rs7049056(C,G); rs7034327(A,C); rs10117232(C,G); rs7876003(G,C); rs10975691(A,C); rs113918964(C,T); rs2578282(C,G); rs1821892(C,G); rs73402968(T,A); rs10975694(A,T); rs10123810(T,C); rs10120677(C,A); rs10124449(T,C); rs10123971(A,G); rs373352371(A,C); rs10124675(A,G); rs10815454(G,C); rs35872509(T,G); rs10124861(A,C); rs2578264(G,A); rs2118653(A,G); rs111576097(C,T); rs144146088(G,A); rs2164953(G,C); rs149453350(C,T); rs190750727(T,C); rs10758800(A,G); rs112544005(C,T); rs112645470(C,G); rs10481602(G,A); rs12005123(A,C); rs111315930(A,G); rs2578267(C,T); rs2773502(A,G); rs11999501(G,A); rs2578268(T,C); rs2578269(C,T); rs2578270(T,C); rs2578271(G,A); rs2773503(A,G); rs2773504(C,T); rs12352496(A,G); rs12353462(T,C); rs59759266(C,G); rs2578272(C,T); rs10975705(C,A); rs2773505(A,G); rs2773506(A,C); rs2578273(G,A); rs10481603(A,T); rs7860255(A,G); rs34247224(A,G); rs72695571(G,A); rs72695572(G,A); rs34298851(C,T); rs35870984(G,A); rs35376178(A,G); rs141032280(C,G); rs4742230(A,G); rs13294720(T,A); rs77234082(C,G); rs1972847(T,C); rs12001793(G,A); rs2773507(C,T); rs7858498(T,A); rs116217696(C,G); rs115292896(C,T); rs34891903(C,T); rs1260460(A,G); rs934854(A,G); rs934855(G,T); rs2578274(A,G); rs1269167(C,T); rs1260463(G,A); rs1260464(G,C); rs72695579(G,T); rs1025720(G,A); rs1025721(C,T); rs72695580(C,G); rs1025722(T,G); rs111875513(G,T); rs7853194(C,G); rs10117019(T,A); rs7029245(C,A); rs2578279(C,T); rs7031908(G,A); rs2773511(T,C); rs2118656(A,G); rs2918176(C,G); rs2438409(A,G); rs2438410(T,C); rs2890722(T,C); rs113915069(G,A); rs10115774(C,T); rs2918177(A,G); rs141083030(G,A); rs11788879(C,T); rs7872937(C,T); rs4742231(G,A); rs4742232(A,G); rs2918183(G,A); rs2578290(C,T); rs372971948(G,A); rs1755600(A,C); rs1629134(C,T); rs1755603(G,A); rs181216580(C,G); rs1658977(T,C); rs1658978(T,C); rs1755604(G,A); rs185877198(A,T); rs10815458(C,G); rs1755605(C,T); rs1755606(A,G); rs1755607(T,C); rs1755608(A,G); rs1755609(G,A); rs373932876(A,G); rs2773508(A,T); rs2578292(A,G); rs4742234(A,G); rs13300114(C,T); rs1755615(T,C); rs1755616(C,G); rs1658953(T,G); rs10975711(C,G); rs1755617(C,T) |
| ccdsGene name | CCDS34987.1 |
| cytoBand name | 9p24.1 |
| EntrezGene GeneID | 2731 |
| EntrezGene Description | glycine dehydrogenase (decarboxylating) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GLDC:NM_000170:exon18:c.G2113A:p.V705M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7765 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P23378 |
| dbNSFP Uniprot ID | GCSP_HUMAN |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00923482849604 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.002307 |
| ESP Eur/Amr MAF | 0.003256 |
| ExAC AF | 0.003684 |
OMIM Clinical Significance
Skin:
Jaundice
Neuro:
Kernicterus;
Cerebral palsy
Lab:
Neonatal unconjugated hyperbilirubinemia
Inheritance:
Autosomal recessive
OMIM Title
*238300 GLYCINE DECARBOXYLASE; GLDC
;;GLYCINE CLEAVAGE SYSTEM P PROTEIN; GCSP;;
GLYCINE DEHYDROGENASE
OMIM Description
DESCRIPTION
The enzyme system for cleavage of glycine (glycine cleavage system; GCS;
EC 2.1.2.10), which is confined to the mitochondria, is composed of 4
protein components: P protein (a pyridoxal phosphate-dependent glycine
decarboxylase), H protein (a lipoic acid-containing protein, 238330), T
protein (a tetrahydrofolate-requiring enzyme, 238310), and L protein (a
lipoamide dehydrogenase, 238331).
Mutations in the P, T, and H proteins have been found to cause glycine
encephalopathy (GCE; 605899).
CLONING
Kume et al. (1990) cloned the cDNA encoding human glycine decarboxylase,
P protein. The deduced protein contains 1,020 amino acids. By RNA blot
analysis, Takayanagi et al. (2000) demonstrated that GLDC is expressed
in human liver, kidney, brain, and placenta. By dot-blot analysis, Kure
et al. (2001) detected expression of GLDC in a limited number of tissues
with strong expression in liver, placenta, and kidney; moderate
expression in brain, small intestine, thyroid gland, and pituitary
gland; and weak expression in colon, bladder, and lung.
GENE STRUCTURE
Takayanagi et al. (2000) determined the structure of the GLDC gene and
its pseudogene. The GLDC gene spans at least 135 kb and contains 25
exons. All donor and acceptor sites adhered to the canonical GT-AG rule,
except for the donor site of intron 21, where a variant form GC is used
instead of GT. By primer extension analysis, the transcription
initiation site was assigned to a residue 163 bp upstream from the
translation initiation triplet. The GLDC pseudogene has no introns and
shares 97.5% homology with the coding region of functional GLDC,
suggesting that it is a processed pseudogene that arose from the GLDC
transcript about 4 to 8 million years ago.
MOLECULAR GENETICS
Using the GCSP cDNA as a probe in Southern blot analysis of genomic DNA
from 2 patients with nonketotic hyperglycinemia, Tada et al. (1990)
showed that they had a specific defect in P protein, namely, a partial
deletion.
A high frequency of glycine encephalopathy has been found in some
counties of Finland (von Wendt and Simila, 1980). In 13 heterozygotes in
Finland, von Wendt et al. (1981) found minor dysfunctions of the central
nervous system which they suggested may be due to a slightly abnormal
degradation of glycine (which has a neurotransmitter role). Kure et al.
(1992) found that 14 of 20 P protein alleles in Finnish patients carried
a single nucleotide substitution from G to T in the protein coding
region, which resulted in an amino acid alteration from serine-564 to
isoleucine (238300.0001).
Toone et al. (2000) identified a recurrent mutation in the P protein,
R515S (238300.0004), in heterozygosity in 2 unrelated patients with
glycine encephalopathy.
Applegarth and Toone (2001) reviewed the laboratory diagnosis of glycine
encephalopathy and confirmed 9 mutations in the T protein (AMT; 238310)
and 8 mutations in the P protein. They also reviewed 7 cases of
transient NKH.
Nonketotic hyperglycinemia, or glycine encephalopathy (605899), is
caused by deficiency of the glycine cleavage multienzyme system with 3
specific components encoded by GLDC, AMT, and GCSH (238330). Kure et al.
(2006) undertook a comprehensive screening for mutations in these 3
enzymes in 69 families (56, 6, and 7 families with neonatal, infantile,
and late-onset type NKH, respectively). GLDC or AMT mutations were
identified in 75% of neonatal and 83% of infantile families, but not in
late-onset type NKH. No GCSH mutation was identified in this study. GLDC
mutations were identified in 36 families, and AMT mutations were
detected in 11 families. In 16 of the 36 families with GLDC mutations,
mutations were identified in only 1 allele despite sequencing of the
entire coding regions. The GLDC gene consists of 25 exons. Seven of the
32 GLDC missense mutations were clustered in exon 19, which encodes the
cofactor-binding site lys754. A large deletion involving exon 1 of the
GLDC gene was found in Caucasian, Oriental, and black families. Multiple
origins of the exon 1 deletion were suggested by haplotype analysis with
4 GLDC polymorphisms.
MAPPING
Burton et al. (1989) observed nonketotic glycinemia in an infant with
the metabolic and chromosomal features of the 9p- syndrome, leading them
to suggest that a gene for nonketotic glycinemia may be located on the
short arm of chromosome 9. By fluorescence in situ hybridization using
genomic clones, Isobe et al. (1994) assigned the functional GCSP gene to
9p24-p23 and a processed pseudogene to 4q12. Sakakibara et al. (1990)
had found deletion of the 5-prime region of the GCSP gene in a patient
with glycine encephalopathy.
ANIMAL MODEL
Sakata et al. (2001) reported the structure and expression of the
glycine cleavage system in the rat central nervous system.
RRAGA
| dbSNP name | rs2233802(C,A) |
| cytoBand name | 9p22.1 |
| EntrezGene GeneID | 10670 |
| snpEff Gene Name | HAUS6 |
| EntrezGene Description | Ras-related GTP binding A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1878 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Constricted visual fields by age 20 years;
Night blindness by age 20 years;
Loss of central vision between ages 25-30 years;
Complete blindness between ages 40-50 years;
Fundus pigment lumps, bone-corpuscle/bone-spicule pattern;
Attenuation of retinal blood vessels;
Obliteration of peripheral retinal blood vessels (in some patients);
Pallid optic disc
MISCELLANEOUS:
One family reported (last curated July 2008)
OMIM Title
*612194 RAS-RELATED GTP-BINDING PROTEIN A; RRAGA
;;RAGA;;
FIP1
OMIM Description
CLONING
Using mouse Raga to screen a fetal brain cDNA library, followed by RACE,
Schurmann et al. (1995) cloned human RAGA. The deduced 313-amino acid
protein shares similarity with RAS (HRAS; 190020) and contains
phosphate/magnesium-binding motifs PM1, PM2, and PM3, and the guanine
nucleotide-binding motif G1. An additional guanine nucleotide-binding
motif, G2, is strikingly different from those found in all other RAS
homologs. The C-terminal domain contains a putative transmembrane
region. Northern blot analysis of rat tissues detected highest
expression in adrenal gland.
Using adenovirus E3-14.7K protein in a yeast 2-hybrid screen of a HeLa
cell cDNA library, Li et al. (1997) cloned RRAGA, which they called
FIP1. They noted that the protein contains 2 putative myristoylation
sites, several putative phosphorylation sites, and 2 domains homologous
to bacterial metalloproteases. In transfected mouse fibroblasts, FIP1
colocalized with adenovirus E3-4.7K in the cytoplasm, especially near
the nuclear membrane and in discrete foci on or near the plasma
membrane; FIP1 also localized without E3-4.7K in the nucleus. Northern
blot analysis detected FIP1 in all human tissues examined, with highest
expression in skeletal muscle.
GENE FUNCTION
Schurmann et al. (1995) found that recombinant RAGA bound a
nonhydrolyzable analog of GTP, but that it lacked intrinsic GTPase
activity.
Using a protein pull-down assay with recombinant proteins, Li et al.
(1997) confirmed the interaction between FIP1 and adenovirus E3-14.7K.
Mutation analysis revealed N- and C-terminal domains of FIP1 that were
required for the interaction. In human embryonic kidney cells, TNF-alpha
(TNF; 191160), a proinflammatory cytokine with antiviral activity,
promoted the transient association of FIP1 with phosphoproteins. In
mouse fibroblasts, antisense FIP1 RNA inhibited TNF-alpha-induced
cytolysis.
The multiprotein mTORC1 protein kinase complex (see 601231) is the
central component of a pathway that promotes growth in response to
insulin, energy levels, and amino acids and is deregulated in common
cancers. Sancak et al. (2008) found that the Rag proteins, a family of 4
related small guanosine triphosphatases (GTPases) (RAGA, RAGB (300725),
RAGC (608267), and RAGD (608268)) interact with mTORC1 in an amino
acid-sensitive manner and are necessary for the activation of the mTORC1
pathway by amino acids. A Rag mutant that was constitutively bound to
guanosine triphosphate interacted strongly with mTORC1, and its
expression within cells made the mTORC1 pathway resistant to amino acid
deprivation. Conversely, expression of a guanosine diphosphate-bound Rag
mutant prevented stimulation of mTORC1 by amino acids. Sancak et al.
(2008) concluded that the Rag proteins do not directly stimulate the
kinase activity of mTORC1, but, like amino acids, promote the
intracellular localization of mTOR to a compartment that also contains
its activator RHEB (601293).
Bar-Peled et al. (2013) identified the octameric GATOR
(GTPase-activating protein (GAP) activity toward RAGs) complex as a
critical regulator of the pathway that signals amino acid sufficiency to
mTORC1. GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2.
Inhibition of the GATOR1 subunits DEPDC5 (614191), NPRL2 (607072), and
NPRL3 (600928) makes mTORC1 signaling resistant to amino acid
deprivation. In contrast, inhibition of the GATOR2 subunits MIOS
(615359), WDR24, WDR59, SEH1L (609263), and SEC13 (600152) suppresses
mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively
regulates DEPDC5. GATOR1 has GAP activity for RAGA and RAGB, and its
components are mutated in human cancer. In cancer cells with
inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive
to amino acid starvation, and such cells are hypersensitive to
rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded
that they had identified a key negative regulator of the RAG GTPases and
revealed that, like other mTORC1 regulators, RAG function can be
deregulated in cancer.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RRAGA
gene to chromosome 9 (TMAP A001X42).
ANIMAL MODEL
Efeyan et al. (2013) generated knock-in mice that express a
constitutively active form of RagA, RagA(GTP), from its endogenous
promoter. RagA(GTP/GTP) homozygous mice developed normally but failed to
survive postnatal day 1. When delivered by cesarean section, fasted
RagA(GTP/GTP) neonates die almost twice as rapidly as wildtype
littermates. Within an hour of birth wildtype neonates strongly inhibit
mTORC1 (601231), which coincides with profound hypoglycemia and a
decrease in plasma amino acid concentrations. In contrast, mTORC1
inhibition does not occur in RagA(GTP/GTP) neonates, despite identical
reductions in blood nutrient amounts. With prolonged fasting, wildtype
neonates recover their plasma glucose concentrations, but RagA(GTP/GTP)
mice remain hypoglycemic until death, despite using glycogen at a faster
rate. The glucose homeostasis defect correlates with the inability of
fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino
acids for de novo glucose production. Because profound hypoglycemia does
not inhibit mTORC1 in RagA(GTP/GTP) neonates, Efeyan et al. (2013)
considered the possibility that the Rag pathway signals glucose as well
as amino acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to
glucose deprivation in RagA(GTP/GTP) fibroblasts, and glucose, like
amino acids, controls its recruitment to the lysosomal surface, the site
of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino
acid concentrations to mTORC1, and have an unexpectedly key role in
neonates in autophagy induction and thus nutrient homeostasis and
viability.
IFNB1
| dbSNP name | rs143678442(C,G); rs1051922(G,A); rs41309794(G,A) |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3456 |
| EntrezGene Description | interferon, beta 1, fibroblast |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
OMIM Clinical Significance
Endocrine:
Multiple pancreatic beta-cell adenomas;
Diabetes mellitus
Inheritance:
Autosomal dominant
OMIM Title
*147640 INTERFERON, BETA-1; IFNB1
;;INTERFERON, FIBROBLAST; IFF;;
IFN, FIBROBLAST;;
BETA-INTERFERON; IFB; IFNB
OMIM Description
CLONING
From the nucleotide sequence of the gene for fibroblast interferon,
cloned by recombinant DNA technology, Derynck et al. (1980) deduced the
complete amino acid sequence of the protein, which contains 166 amino
acids.
Cavalieri et al. (1977) showed that leukocyte and fibroblast interferon
are encoded by different species of mRNA. That these arise from separate
genes was demonstrated by Taniguchi et al. (1980). Between leukocyte
interferon, or interferon-alpha (IFNA; 147660), and fibroblast
interferon, or interferon-beta, they also found 45% homology at the
nucleotide level and 29% at the amino acid level.
GENE FUNCTION
Diaz et al. (1988) demonstrated homozygous deletion of both the beta and
alpha interferon genes in neoplastic hematopoietic cells, some of which
had gross chromosomal deletions of chromosome 9p22-p21. The cell lines
also demonstrated deficiency of the enzyme 5-prime-methylthioadenosine
phosphorylase. The authors speculated that the homozygous deletions may
be associated with the loss of a tumor-suppressor gene involved in
neoplastic development; an alternative hypothesis was that the
interferon genes themselves act as tumor-suppressor genes, and their
deletion or inactivation may be associated with the development of
neoplastic growth.
Siegal et al. (1999) demonstrated that purified interferon-producing
cells were the CD4(+)CD11c(-) type-2 dendritic cell precursors, which
produce 200 to 1,000 times more interferon than other blood cells after
microbial challenge. Dendritic cell precursors are thus an effector cell
type of the immune system, critical for antiviral and antitumor immune
responses.
Takayanagi et al. (2002) demonstrated that RANKL (602642) induces the
IFN-beta gene in osteoclast precursor cells, and that IFN-beta inhibits
the differentiation of osteoclasts by interfering with the RANKL-induced
expression of c-Fos (164810), an essential transcription factor for the
formation of osteoclasts. This IFN-beta gene induction mechanism is
distinct from that induced by virus, and is dependent on c-Fos itself.
Thus an autoregulatory mechanism operates--the RANKL-induced c-Fos
induces its own inhibitor. The importance of this regulatory mechanism
for bone homeostasis is emphasized by the observation that mice
deficient in IFN-beta signaling exhibit severe osteopenia accompanied by
enhanced osteoclastogenesis.
Takaoka et al. (2003) demonstrated that transcription of the p53 gene
(191170) is induced by IFNA/IFNB, accompanied by an increase in p53
protein level. IFNA/B signaling itself does not activate p53, but
contributes to boosting p53 responses to stress signals. Takaoka et al.
(2003) showed examples in which p53 gene induction by IFNA/B indeed
contributed to tumor suppression. Furthermore, they showed that p53 is
activated in virally infected cells to evoke an apoptotic response and
that p53 is critical for antiviral defense of the host. Takaoka et al.
(2003) showed that the p53 gene is transcriptionally induced by IFNA/B
through ISGF3 (147574), demonstrating p53 gene induction by its
cytokine. Whereas IFNA/B induce p53 mRNA and increase its protein level,
p53-mediated responses such as cell cycle arrest or apoptosis were not
observed in cells treated with IFNA/B alone.
Because type I IFNs are critical for regulation of osteoclastogenesis in
mice, Coelho et al. (2005) compared the effects of IFNA2 (147562) and
IFNB on differentiation of human monocytes into osteoclasts. Although
primary monocytes undergoing osteoclastic differentiation were highly
and equally sensitive to both proteins, IFNB was 100-fold more potent
than IFNA2 at inhibiting osteoclastogenesis. Microarray and RT-PCR
analyses showed that CXCL11 (604852) was the only gene differentially
upregulated in this cellular system by IFNB compared with IFNA2.
Treatment of monocytes with CXCL11 inhibited osteoclastic
differentiation, and CXCL11 acted through a receptor distinct from CXCR3
(300574) and not through antagonism of CCR5 (601373). Coelho et al.
(2005) proposed that IFNB may have clinical relevance in preventing
osteolysis.
Using microarray, PCR, and complementarity analyses, Pedersen et al.
(2007) identified 8 miRNAs that were rapidly upregulated in
IFNB-stimulated mouse and human liver cell lines that showed sequence
complementarity to hepatitis C virus (HCV; see 609532), an RNA virus,
but not to hepatitis B virus (HBV; see 610424), a DNA virus. Of the 8
upregulated miRNAs, miR196 (MIRN196; 608632), miR296 (MIRN296; 610945),
miR351 (MIRN351), miR431 (MIRN431; 611708), and miR448 (MIRN448; 300686)
had anti-HCV activity, and miR196 and miR448 directly targeted HCV
genomic RNA. IFNB stimulation downregulated miR122 (MIRN122A; 609582), a
liver-specific miRNA essential for HCV replication. Pedersen et al.
(2007) concluded that IFNA and IFNB, a common treatment regimen for HCV
infection, use cellular miRNA, at least in part, to combat viral
infections.
Wilson et al. (2013) demonstrated in mice infected with lymphocytic
choriomeningitis virus (LCMV) that blockade of type I interferon (IFN-I)
signaling diminished chronic immune activation and immune suppression,
restored lymphoid tissue architecture, and increased immune parameters
associated with control of virus replication, ultimately facilitating
clearance of the persistent infection. The accelerated control of
persistent infection induced by blocking IFN-I signaling required CD4 T
cells and was associated with enhanced IFN-gamma (IFNG; 147570)
production. Wilson et al. (2013) concluded that interfering with chronic
IFN-I signaling during persistent infection redirects the immune
environment to enable control of infection. Wilson et al. (2013) noted
that human HIV and HCV infections are also associated with immune
activation driven by chronic IFN-I signaling and suggested that a
similar blockade of IFN-I may improve control of these infections.
Using RT-PCR and immunohistochemistry, Teles et al. (2013) demonstrated
increased expression of the type I interferon IFNB in lesions of
lepromatous leprosy (i.e., multibacillary, or L-lep) patients compared
with tuberculoid leprosy (i.e., paucibacillary, or T-lep) patients (see
609888). Expression of an IFNB receptor, IFNAR1 (107450), was also
increased in L-lep lesions. Increased expression of IFNB was associated
with increased expression of IL10 (124092), and IFNB alone induced IL10
expression in mononuclear cells in vitro. There was an inverse
correlation between IL10 expression and expression of the antimicrobial
peptides CAMP (600474) and DEFB4 (DEFB4A; 602215). Measurement of
uncultivable Mycobacterium leprae viability based on the ratio of M.
leprae 16S rRNA to M. leprae repetitive element DNA indicated that IFNG
induced antimicrobial activity against M. leprae in monocytes by about
35%, which was abrogated by the addition of either IFNB or IL10. Teles
et al. (2013) concluded that the type I interferon gene expression
program prominently expressed in L-lep lesions inhibits the IFNG-induced
antimicrobial response against M. leprae through an intermediary, IL10.
MAPPING
By study of human-mouse cell hybrids, Meager et al. (1979) concluded
that chromosome 5 is not involved in production of interferon. Instead
they found correlation between interferon production and chromosome 9,
and the interferon produced by the hybrids was predominantly of the
fibroblast type. Chany et al. (1980) likewise concluded that chromosome
9 carries a locus for an interferon, which they referred to as beta.
Chromosome 13 also appeared to be involved. Chany et al. (1980)
suggested that the locus on chromosome 13 might have something to do
with IFNA synthesis.
Tavernier et al. (1981) presented evidence for a single fibroblast
interferon gene. As in the case of IFN-alpha, no intervening sequences
were discovered. Houghton et al. (1981) independently arrived at the
same findings. Using radioactive probes from purified cDNA clones of
interferons, Owerbach et al. (1981) located at least 8 leukocyte
interferon genes and a fibroblast interferon gene on chromosome 9. Ohno
and Taniguchi (1981) also showed that the beta-interferon gene(s), like
the alpha-interferon genes, lacks intervening sequences. Comparison of
the cDNA sequence of alpha and beta interferons showed apparent homology
in amino acid sequence and in nucleotide sequence, indicating that they
were presumably derived from a common ancestor. The fact that they are
syntenic supports that conclusion.
By in situ hybridization, Trent et al. (1982) confirmed the location of
IFF and IFL on chromosome 9p and concluded that IFF is distal to IFL.
They mapped IFB to chromosome 9pter-p21. Studying 2 patients with
unbalanced rearrangements of 9p, Henry et al. (1984) used a genomic
clone for IFNB1 and concluded that the gene is located on chromosome
9p21.
Sagar et al. (1984) concluded that IFN-beta-related DNA is dispersed in
the human genome. The data from study of human-rodent somatic cell
hybrids induced with poly(I)poly(C) or with viral inducers were
consistent with assignment of IFB mRNA species of different lengths to
chromosomes 9, 5, and 2 (reviewed by Sagar et al., 1984). Another
IFN-beta had been assigned to chromosome 4 (Sehgal et al., 1983).
Ohlsson et al. (1985) identified 5 RFLPs associated with the alpha- and
beta-interferon gene cluster. Heterozygosities made them excellent
markers for the short arm of chromosome 9. In a study of 25 Caucasian
families, no recombination was found between the alpha and beta markers.
Furthermore, 12 of 32 possible haplotypes were found, indicating linkage
disequilibrium which was of similar magnitude between various alpha
markers as it was between alpha and beta markers. Thus, the alpha and
beta genes must be clustered within a few hundred kilobases. Duplication
of the beta gene, apparently of recent origin, was found in some persons
and segregated regularly.
By studying an acute monocytic leukemia (AMoL)-associated translocation
t(9;11)(p22;q23), Diaz et al. (1986) concluded that the IFNB1 gene is
located in chromosome 9p22, distal to alpha-interferon.
CYTOGENETICS
In 3 patients with AMoL and t(9;11)(p22;q23), Diaz et al. (1986) showed
that the breakpoint on 9p split the interferon genes and that IFNB1 gene
was translocated to chromosome 11. The ETS1 gene (164720) was
translocated from chromosome 11 to 9p adjacent to the interferon genes.
They suggested that juxtaposition of interferon and ETS1 genes may be
involved in the pathogenesis of AMoL.
IFNW1
| dbSNP name | rs10964859(C,G) |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3467 |
| EntrezGene Description | interferon, omega 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2718 |
OMIM Clinical Significance
Skin:
Hypersensitivity to insect stings
Inheritance:
Autosomal dominant
OMIM Title
*147553 INTERFERON, OMEGA-1; IFNW1
;;IFN-ALPHA-LIKE
INTERFERON, OMEGA-2, PSEUDOGENE; IFNWP2, INCLUDED
OMIM Description
MAPPING
Henco et al. (1985) compiled partial maps of the interferon gene cluster
located on 9p21. These maps showed that members of the 2 main families
of genes in the IFN superfamily, interferon-alpha (147660) and
interferon-omega (IFNW), are interspersed. Olopade et al. (1992) studied
the deletions of the short arm of chromosome 9 frequently observed in
acute lymphoblastic leukemia and in gliomas. These deletions often
include the entire interferon gene cluster, which comprises about 26
IFNA, IFNW, and IFNB1 (147640) genes, as well as the gene for
methylthioadenosine phosphorylase (MTAP; 156540). By comparing
microscopic deletions with the genes lost at the molecular level,
Olopade et al. (1992) determined the order of these genes on 9p to be
tel--IFNB1--IFNA/IFNW cluster--MTAP--cen. In a few cell lines and in
primary leukemia cells, they observed deletions that had breakpoints
within the IFN gene cluster and resulted in partial loss of the IFN
genes. These partial deletions allowed them to determine the order of
some genes or groups of genes in the IFNA/IFNW gene cluster. From their
deletion analysis, Olopade et al. (1992) deduced the following order of
the IFN gene on 9p: pter--IFNB1--(IFNW1,
IFNA21)--IFNWP15--IFNA4--IFNW9--IFNA7--IFNA10--IFNWP18--IFNAP16--IFNA17--IFNA14--(IFNA22,
IFNA5, IFNAP20, IFNA6, IFNA13, IFNA2)--(IFNA8, IFNW2, IFNWP19,
IFNA1)--MTAP--cen. The genes within the large linkage group are arranged
in tandem with their 3-prime end pointing toward the telomere of the
short arm. Thus, at least 2 functional interferon-omega genes, IFNW1 and
IFNW2, were mapped and several IFNW pseudogenes, e.g., IFNWP15, were
localized.
- Pseudogenes
Diaz and Bohlander (1993) provided a tabulation of the nomenclature of
the human interferon genes and listed IFNWP2 as a pseudogene. The only
functional interferon-omega gene is presumably IFNW1.
IFNA10
| dbSNP name | rs28368148(C,G) |
| ccdsGene name | CCDS6499.1 |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3446 |
| EntrezGene Description | interferon, alpha 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IFNA10:NM_002171:exon1:c.G492C:p.W164C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.2601 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P01566 |
| dbNSFP Uniprot ID | IFN10_HUMAN |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0105540897098 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.001816 |
| ESP All MAF | 0.009765 |
| ESP Eur/Amr MAF | 0.013837 |
| ExAC AF | 0.007904 |
OMIM Clinical Significance
Skin:
Hypersensitivity to insect stings
Inheritance:
Autosomal dominant
OMIM Title
*147577 INTERFERON, ALPHA-10; IFNA10
OMIM Description
MAPPING
The IFNA10 gene was positioned in the cluster of interferon genes on
chromosome 9p22 by deletion mapping (Olopade et al., 1992).
IFNA22P
| dbSNP name | rs10757210(A,G); rs10113879(G,T); rs10120675(A,G) |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3453 |
| EntrezGene Description | interferon, alpha 22, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3953 |
IFNA2
| dbSNP name | rs77047588(C,T); rs35971916(G,T) |
| ccdsGene name | CCDS6506.1 |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3440 |
| EntrezGene Description | interferon, alpha 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IFNA2:NM_000605:exon1:c.G513A:p.M171I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0134 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6DJX8 |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.014072 |
| ESP All MAF | 0.004767 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001423 |
OMIM Clinical Significance
Skin:
Hypersensitivity to insect stings
Inheritance:
Autosomal dominant
OMIM Title
*147562 INTERFERON, ALPHA-2; IFNA2
OMIM Description
GENE FUNCTION
The successful use of intranasal alpha-2-interferon produced by
recombinant DNA technology in the prophylaxis of the common cold was
reported by Douglas et al. (1986) and Hayden et al. (1986).
Ezekowitz et al. (1992) demonstrated the usefulness of recombinant
alpha-interferon (interferon alfa-2a) for inducing regression of
life-threatening corticosteroid-resistant hemangiomas in infancy. The
hemangiomas treated were those that impair the function of vital
structures or cause life-endangering complications such as
thrombocytopenic coagulopathy with giant hemangioma (Kasabach-Merritt
syndrome; 141000). The authors published 2 detailed errata clarifying
and correcting numerous ambiguities and errors.
Dithmar et al. (2000) showed the usefulness of recombinant
alpha-interferon (IFN alfa-2b) for decreasing hepatic metastases from
intraocular melanoma in a murine model. The authors concluded that
adjuvant recombinant IFN alfa-2b treatment given before or at the time
of enucleation might be a treatment option for patients with uveal
melanoma (155720) with high-risk factors for developing metastatic
disease.
IFN alfa-2b is used to treat high-risk cutaneous melanomas (155600),
although IFN alfa therapy is associated with a number of systemic side
effects, including a flu-like syndrome, fatigue, malaise, weight loss,
depression, nausea, anorexia, diarrhea, neutropenia, and
thrombocytopenia. Hejny et al. (2001) reported 7 patients who developed
retinopathy while receiving high-dose IFN alfa-2b therapy for adjuvant
treatment of high-risk cutaneous melanoma. The risk of retinopathy
appeared to be greater with higher dosage therapy and caused severe
vision loss in 2 patients. The authors concluded that patients receiving
high-dose IFN alfa-2b therapy need to be monitored for sequelae,
including retinal neovascularization, until the retinopathy has
resolved.
MAPPING
The IFNA2 gene was positioned in the cluster of interferon genes on
chromosome 9p22 by deletion mapping (Olopade et al., 1992).
IFNA8
| dbSNP name | rs3739630(G,A); rs10964982(G,A); rs16938396(T,C) |
| ccdsGene name | CCDS6507.1 |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 3445 |
| EntrezGene Description | interferon, alpha 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IFNA8:NM_002170:exon1:c.G409A:p.E137K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P32881 |
| dbNSFP Uniprot ID | IFNA8_HUMAN |
| dbNSFP KGp1 AF | 0.0503663003663 |
| dbNSFP KGp1 Afr AF | 0.176829268293 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0314685314685 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.05051 |
| ESP Afr MAF | 0.132547 |
| ESP All MAF | 0.045364 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.016 |
OMIM Clinical Significance
Skin:
Hypersensitivity to insect stings
Inheritance:
Autosomal dominant
OMIM Title
*147568 INTERFERON, ALPHA-8; IFNA8
OMIM Description
MAPPING
The IFNA8 gene was positioned in the cluster of interferon genes on 9p22
by deletion mapping (Olopade et al., 1992).
IFNE
| dbSNP name | rs1125488(T,G); rs10125074(G,A); rs2039380(C,G) |
| ccdsGene name | CCDS34997.1 |
| cytoBand name | 9p21.3 |
| EntrezGene GeneID | 554202 |
| EntrezGene Symbol | MIR31HG |
| EntrezGene Description | MIR31 host gene (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | IFNE:NM_176891:exon1:c.A138C:p.Q46H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86WN2 |
| dbNSFP Uniprot ID | IFNE_HUMAN |
| dbNSFP KGp1 AF | 0.0462454212454 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.0966850828729 |
| dbNSFP KGp1 Asn AF | 0.0227272727273 |
| dbNSFP KGp1 Eur AF | 0.0580474934037 |
| dbSNP GMAF | 0.04591 |
| ESP Afr MAF | 0.03813 |
| ESP All MAF | 0.059434 |
| ESP Eur/Amr MAF | 0.070349 |
| ExAC AF | 0.07 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low weight
HEAD AND NECK:
[Neck];
Short neck
CHEST:
[External features];
Short trunk;
Barrel-shaped chest;
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum
SKELETAL:
[Spine];
Exaggerated lordosis;
Platyspondyly;
Posterior double humps of vertebral body;
Irregular surface of iliac spine;
Odontoid hypoplasia, mild;
[Limbs];
Elevated shoulder joints;
Limited extension of elbow joints;
Genu valgum;
Flattened femoral heads;
Broad femoral neck, mild;
Reduced trochanter and femur head distance ratio;
Irregular shallow acetabular roofs;
Metaphyseal irregularity of the upper tibia;
Flattened epiphysis of the lower tibia;
Flattened humeral head;
[Hands];
Short metacarpal bones;
Broad metacarpal bones;
Short phalanges;
Broad phalanges;
Broad interphalangeal joints;
[Feet];
Flat feet;
Prominent heels;
Short metatarsal bones;
Broad metatarsal bones;
Short phalanges;
Broad phalanges
MOLECULAR BASIS:
Caused by mutation in the Ras-associated protein RAB33B gene (RAB33B,
605950.0001)
OMIM Title
*615223 INTERFERON, EPSILON; IFNE
;;IFNE1;;
INTERFERON, TAU-1; IFNT1
OMIM Description
DESCRIPTION
Type I interferons, like INFE, are cytokines with pleiotropic activities
that include inhibition of viral replication and cell proliferation and
activation of the immune system (summary by Hardy et al., 2004).
CLONING
By sequence analysis, Hardy et al. (2004) identified IFNE1 within an
interferon gene cluster on human chromosome 9p and mouse chromosome 4,
and they amplified the human and mouse genes from WISH and embryonic
fibroblast cDNA libraries, respectively. The deduced human protein
contains 208 amino acids, including a 23-amino leader sequence. Like
other type I interferons, IFNE was predicted to assume a 5-alpha helix
barrel-shaped tertiary structure. Human IFNE also includes a predicted
sixth alpha helix not found in mouse Ifne or other type I interferons.
Both mouse and human IFNE1 share highest similarity with the type I
interferons IFNB (IFNB1; 147640) and IFNK (615326). RT-PCR detected
IFNE1 expression in several human cancer cell lines and adult mouse
tissues. Among adult mouse tissues, expression was highest in ovary and
uterus. Northern blot analysis of whole mouse embryos detected a 1.5-kb
transcript at all stages of development examined. At embryonic day 14,
the 1.5-kb transcript was detected in brain, liver, lung, kidney, large
intestine, and thymus. An additional transcript of 0.9 kb was detected
in whole mouse embryos from embryonic day 8 to 12. Both transcripts were
detected in placentas of gestating mice, with the 0.9-kb transcript
showing particularly high expression at embryonic day 10.
GENE FUNCTION
Using Northern blot analysis, Hardy et al. (2004) found that Ifne
expression was upregulated about 3-fold in mouse L929 cells treated with
Semliki Forest virus.
Fung et al. (2013) characterized IFNE as a type 1 interferon because it
signals via the IFNAR1 (107450) and IFNAR2 (602376) receptors to induce
IFN-regulated genes. In contrast to other type 1 interferons, IFNE was
not induced by known pattern recognition receptor pathways; instead,
IFNE was constitutively expressed by epithelial cells of the female
reproductive tract and was hormonally regulated. Ifne-deficient mice had
increased susceptibility to infection of the female reproductive tract
by the common sexually transmitted infections herpes simplex virus 2 and
Chlamydia muridarum. Fung et al. (2013) concluded that IFNE is a potent
antipathogen and immunoregulatory cytokine.
GENE STRUCTURE
Hardy et al. (2004) determined that IFNE is an intronless gene.
MAPPING
By genomic sequence analysis, Hardy et al. (2004) mapped the IFNE gene
to a interferon gene cluster on chromosome 9p21. They mapped the mouse
Ifne gene to a region of chromosome 4C4 that shares homology of synteny
with human chromosome 9p21.
TUSC1
| dbSNP name | rs4592123(C,A); rs10812298(A,C); rs10812299(T,C); rs7044566(T,A); rs7028310(C,G); rs143160482(A,C); rs12348(T,C); rs1128957(C,G); rs1128953(A,C); rs61483294(G,A); rs10967034(T,A); rs34772164(G,A) |
| cytoBand name | 9p21.2 |
| EntrezGene GeneID | 286319 |
| EntrezGene Description | tumor suppressor candidate 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09045 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Eyes];
Optic neuropathy;
Optic atrophy;
Visual impairment
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy (in some patients);
Concentric hypertrophic cardiomyopathy (in some patients);
Patent ductus arteriosus (in some patients);
Patent foramen ovale (in some patients)
RESPIRATORY:
Respiratory failure
ABDOMEN:
[Liver];
Hepatomegaly (in some patients);
[Gastrointestinal];
Poor feeding
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness;
Rhabdomyolysis;
Ragged red fibers seen on muscle biopsy;
COX-deficient fibers
NEUROLOGIC:
[Central nervous system];
Global developmental delay;
Encephalopathy;
Seizures;
Dystonia;
Cognitive impairment;
Tremor;
Ataxia;
Hypotonia, neonatal;
Reduced brain gyri;
Enlarged ventricles;
Abnormal signals in the thalami seen on MRI;
[Peripheral nervous system];
Axonal sensorimotor neuropathy (in some patients)
METABOLIC FEATURES:
Lactic acidosis
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased serum creatine kinase;
Increased serum ketones;
Increased serum ammonia;
Decreased activity of mitochondrial respiratory complexes I, III,
and IV
MISCELLANEOUS:
Highly variable phenotype
MOLECULAR BASIS:
Caused by mutation in the mitochondrial Ts translation elongation
factor gene (TSFM, 604723.0001)
OMIM Title
*610529 TUMOR SUPPRESSOR CANDIDATE 1; TUSC1
;;TSG9
OMIM Description
CLONING
Using analysis of loss of heterozygosity (LOH) in nonsmall cell lung
carcinomas (NSCLC) and SCLC cell lines, database searching, and PCR
analysis to identify potential lung cancer tumor suppressor genes in a
region of LOH on chromosome 9p, Shan et al. (2004) isolated TUSC1. The
deduced 209-amino acid TUSC1 protein shares 79% sequence similarity with
mouse Tusc1. Northern blot analysis detected 2.0-kb and 1.5-kb
transcripts, most likely generated by alternative polyadenylation
signals, in most tissues examined, with highest expression in testis,
weak expression of the 2.0-kb transcript in muscle, and weak expression
of the 1.5-kb transcript in colon, lung, and spleen. An additional
1.1-kb transcript was detected exclusively in testis. Using RT-PCR
analysis, Shan et al. (2004) detected no TUSC1 transcripts in 3 nonsmall
cell lung carcinoma cell lines with homozygous deletion of the 9p region
and showed decreased TUSC1 expression in 3 other tumor cell lines.
GENE STRUCTURE
Shan et al. (2004) determined that the TUSC1 gene is intronless.
MAPPING
By genomic sequence analysis, Shan et al. (2004) mapped the TUSC1 gene
near D9S126, in a region that is frequently deleted in lung carcinomas,
on chromosome 9p21. They mapped the mouse Tusc1 gene to chromosome 4.
TAF1L
| dbSNP name | rs139721916(T,A); rs16918393(T,C); rs10758145(T,C); rs45559233(G,A); rs17219559(T,C); rs56351932(A,G) |
| cytoBand name | 9p21.1 |
| EntrezGene GeneID | 138474 |
| EntrezGene Description | TAF1 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 210kDa-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007346 |
TMEM215
| dbSNP name | rs1810807(T,C); rs644337(C,T); rs167280(G,C); rs300639(T,C); rs300638(G,T); rs300637(G,T); rs214130(C,T); rs10813876(T,C); rs300636(A,T) |
| ccdsGene name | CCDS6530.1 |
| cytoBand name | 9p21.1 |
| EntrezGene GeneID | 401498 |
| EntrezGene Description | transmembrane protein 215 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM215:NM_212558:exon2:c.T657C:p.C219C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2213 |
| ESP Afr MAF | 0.094922 |
| ESP All MAF | 0.210865 |
| ESP Eur/Amr MAF | 0.270277 |
| ExAC AF | 0.236 |
ANXA2P2
| dbSNP name | rs855523(A,C); rs10758216(G,C); rs36079164(C,T); rs10971607(T,C); rs855524(C,T) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 304 |
| EntrezGene Description | annexin A2 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1093 |
| ExAC AF | 0.104 |
PTENP1
| dbSNP name | rs7043915(A,G); rs7044016(C,A); rs114679179(C,T); rs10971638(C,T); rs10814025(T,A); rs10814026(A,C); rs12000677(A,C); rs7849845(A,C); rs855465(C,A); rs7853346(C,G); rs111298584(C,T) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 11191 |
| EntrezGene Description | phosphatase and tensin homolog pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06749 |
CCL27
| dbSNP name | rs34352067(C,T) |
| ccdsGene name | CCDS6569.1 |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 10850 |
| EntrezGene Description | chemokine (C-C motif) ligand 27 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCL27:NM_006664:exon3:c.G300A:p.L100L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.064458 |
| ESP All MAF | 0.043365 |
| ESP Eur/Amr MAF | 0.032558 |
| ExAC AF | 0.043 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
NEUROLOGIC:
[Central nervous system];
See juvenile myoclonic epilepsy (606904)
OMIM Title
*604833 CHEMOKINE, CC MOTIF, LIGAND 27; CCL27
;;SMALL INDUCIBLE CYTOKINE SUBFAMILY A, MEMBER 27; SCYA27;;
IL11RA-LOCUS CHEMOKINE; ILC;;
CUTANEOUS T CELL-ATTRACTING CHEMOKINE; CTACK;;
ESKINE
OMIM Description
DESCRIPTION
Chemokines are a group of small (approximately 8-14 kD), mostly basic,
structurally related molecules that regulate cell trafficking of various
types of leukocytes through interactions with a subset of
7-transmembrane, G protein-coupled receptors. Chemokines also play
fundamental roles in the development, homeostasis, and function of the
immune system, and they have effects on cells of the central nervous
system as well as on endothelial cells involved in angiogenesis or
angiostasis. Chemokines are divided into 2 major subfamilies, CXC and
CC, based on the arrangement of the first 2 of the 4 conserved cysteine
residues; the 2 cysteines are separated by a single amino acid in CXC
chemokines and are adjacent in CC chemokines (summary by Zlotnik and
Yoshie, 2000). The skin-associated chemokine CCL27 has a role in T
cell-mediated skin inflammation (Homey et al., 2002).
CLONING
Molluscum contagiosum virus (MCV) is a poxvirus that infects young
children and sexually active adults, causing long-lasting benign
proliferative lesions of the skin with little or no inflammatory
response. Sequence analysis of the MCV-1 genome revealed a CC-like open
reading frame (Senkevich et al., 1996). By searching a public EST
database using the MCV-1 sequence as the probe, Ishikawa-Mochizuki et
al. (1999) identified mouse ESTs encoding a novel CC chemokine. Sequence
analysis of the mouse cDNAs indicated that the gene is located close to
the Il11ra gene (600939) in a tail-to-tail orientation. By searching the
human genomic sequence containing the IL11RA gene, Ishikawa-Mochizuki et
al. (1999) identified exons encoding a novel CC sequence in the same
arrangement with IL11RA as that seen in the mouse. They isolated a
full-length cDNA encoding SCYA27, which they called IL11RA-locus
chemokine (ILC), by 5-prime and 3-prime RACE using a human thymus cDNA
library. The SCYA27 gene encodes a deduced 112-amino acid protein
containing a 24-amino acid signal peptide. Northern blot analysis
detected weak expression of a 0.8-kb SCYA27 transcript in thymus and
placenta, and PCR analysis detected SCYA27 expression in thymus,
placenta, testis, and ovary. RT-PCR analysis detected SCYA27 expression
in normal skin.
GENE FUNCTION
By searching a private EST database, Morales et al. (1999) identified a
human EST encoding SCYA27, which they termed cutaneous T cell-attracting
chemokine (CTACK). Southern blot analysis detected SCYA27 expression in
cDNA libraries derived from normal or psoriatic skin but not those
derived from other tissues. RT-PCR analysis detected SCYA27 expression
that was upregulated after incubation with the proinflammatory cytokines
TNF (191160) and IL1B (147720) in cultured keratinocytes but not in
dermal fibroblasts, melanocytes, or gamma-delta T cells. Morales et al.
(1999) found that SCYA27 attracts a subset of cutaneous
lymphocyte-associated antigen (CLA)-positive CD4 (186940)-positive and
CD8 (186910)-positive memory (i.e., CD45RO-positive) T cells; the
CLA-positive cells migrated only in the presence of an SCYA27 gradient.
Jarmin et al. (2000) and Homey et al. (2000) determined that the
receptor for SCYA27 is GPR2 (CCR10; 600240).
Using immunohistochemical analysis, Homey et al. (2002) demonstrated
expression of CCL27 in normal keratinocytes and its strong upregulation
in skin lesions of atopic dermatitis, contact dermatitis, and psoriasis
patients. CCR10+ T lymphocytes were detected in lesional but not normal
skin of these patients. Flow cytometric analysis showed that CCL27 binds
extracellular matrix components and dermal microvascular endothelial
cells and fibroblasts and mediates adhesion and transendothelial
migration of CCR10+ circulating leukocytes. CCR10 is predominantly
expressed on CD4+CLA+ (cutaneous lymphocyte antigen), rather than CD8+,
circulating T cells. RT-PCR, confocal microscopy, and ELISA analysis
indicated that keratinocytes exposed to TNF or IL1B but not to IL4
(147780) or IFNG (147570) in vitro express increased CCL27.
Using quantitative PCR and immunohistochemical analysis, Pivarcsi et al.
(2007) found decreased expression of CCL27 in actinic keratosis (AK),
basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) lesions
compared with healthy skin and nonlesional tissue. Immunoblot analysis,
RT-PCR, and ELISA showed that oncogenic RAS (HRAS; 190020) and EGFR
(131550) activation suppressed CCL27 expression in primary keratinocytes
and in a keratinocyte cell line. Tumor patients treated with EGFR
inhibitors frequently develop inflammation, and Pivarcsi et al. (2007)
found that these inflamed lesions showed increased CCL27 expression.
Immunohistochemistry and image analysis showed that the ratio of
phosphorylated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) to total
ERK1/ERK2 increased somewhat in AK and markedly in BCC and SCC.
Neutralization of Ccl27 in a mouse skin tumor model significantly
enhanced tumor growth, impaired Ifng production, and inhibited
recruitment of Cd4- and Cd8-positive T lymphocytes expressing Ccr10.
Pivarcsi et al. (2007) concluded that transformed keratinocytes may
evade host immune responses by progressively downregulating homeostatic
expression of CCL27 and reducing T-cell trafficking.
MAPPING
The IL11RA gene maps to 9p13. By genomic sequence analysis,
Ishikawa-Mochizuki et al. (1999) mapped the SCYA27 gene to the same
location. They noted that the SCYA19 (602227) and SCYA21 (602737) genes
also map to 9p13. By interspecific backcross analysis, Morales et al.
(1999) mapped the mouse Scya27 gene to the proximal region of chromosome
4.
ANIMAL MODEL
Homey et al. (2002) injected mice with human CCL27 intradermally. RT-PCR
analysis revealed dose-dependent expression of IL2, CCR10, and LFA1A
(153370). Immunohistochemical analysis demonstrated that treatment with
glucocorticosteroid or anti-Ccl27 markedly reduced skin thickness and
leukocyte recruitment in contact hypersensitivity and atopic dermatitis
mouse models. Homey et al. (2002) concluded that neutralization of
CCL27-CCR10 interactions impairs lymphocyte recruitment and inhibits
allergen-induced skin inflammation. They suggested that these molecules
could be targets for selective therapy of inflammatory and autoimmune
skin diseases.
CCL21
| dbSNP name | rs11574916(G,A); rs11574915(A,C) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 101929739 |
| EntrezGene Symbol | LOC101929739 |
| EntrezGene Description | uncharacterized LOC101929739 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01515 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
OMIM Title
*602737 CHEMOKINE, CC MOTIF, LIGAND 21; CCL21
;;SMALL INDUCIBLE CYTOKINE SUBFAMILY A, MEMBER 21; SCYA21;;
SECONDARY LYMPHOID TISSUE CHEMOKINE; SLC;;
EXODUS 2
OMIM Description
DESCRIPTION
CCL21 is a ligand for CCR7 (600242) and guides the interactions between
CCR7+ T cells and antigen-presenting cells (APCs) needed for T cell
education and priming. These events are involved both in triggering
adaptive immunity and maintaining peripheral tolerance (summary by
Shields et al., 2010).
CLONING
Chemokines are a family of proteins that direct leukocyte migration and
activation to inflammatory stimuli. In the C-C, or beta, subfamily, the
first 2 conserved cysteines are adjacent to each other (see SCYA20;
601960). Hedrick and Zlotnik (1997), Hromas et al. (1997), and Nagira et
al. (1997) identified human ESTs encoding the C-C chemokine SCYA21,
which they designated 6CKINE, EXODUS2, and secondary lymphoid tissue
chemokine (SLC), respectively. By Northern blot analysis, Hromas et al.
(1997) showed that the 0.9-kb SCYA21 mRNA is expressed preferentially in
lymph node tissue. Nagira et al. (1997) reported that the predicted
134-amino acid SCYA21 protein has a 23-amino acid signal sequence and a
unique, approximately 30-amino acid C-terminal extension which contains
2 extra cysteines. Unlike other C-C chemokines, SCYA21 was specifically
chemotactic for lymphocytes. Hedrick and Zlotnik (1997) cloned a mouse
Scya21 cDNA and reported that the predicted amino acid sequences of
mouse and human SCYA21 are 86% similar.
GENE FUNCTION
B lymphocytes recirculate between B cell-rich compartments (follicles or
B zones) in secondary lymphoid organs, surveying for antigen. After
antigen binding, B cells move to the boundary of B and T zones to
interact with T-helper cells. Reif et al. (2002) demonstrated that
antigen-engaged B cells have increased expression of CCR7 (600242), the
receptor for the T-zone chemokines CCL19 (also known as SCYA19) and
CCL21, and that they exhibit increased responsiveness to both
chemoattractants. In mice lacking lymphoid CCL19 and CCL21 chemokines,
or with B cells that lack CCR7, antigen engagement fails to cause
movement to the T zone. Using retroviral-mediated gene transfer, the
authors demonstrated that increased expression of CCR7 is sufficient to
direct B cells to the T zone. Reciprocally, overexpression of CXCR5
(601613), the receptor for the B-zone chemokine CXCL13 (605149), is
sufficient to overcome antigen-induced B-cell movement to the T zone.
Reif et al. (2002) concluded that their findings defined the mechanism
of B-cell relocalization in response to antigen, and established that
cell position in vivo can be determined by the balance of responsiveness
to chemoattractants made in separate but adjacent zones.
Although chemokine signaling is often promiscuous, signaling events
between members of the distinct chemokine classes (CXC, CC, CX3C, and C)
are almost never observed. Dijkstra et al. (2004) showed that human
CCL21, in the absence of its primary receptor, CCR7, is a functional
ligand for CXCR3 (300574), inducing chemotaxis in adult microglial
cells, but not in kidney epithelial cells. CCL21-induced chemotaxis
could be inhibited by the CXCR3 ligand, CXCL10 (147310), whereas CXCL10
had no effect on CX3CL1 (601880) chemotactic activity. Fluorescence
microscopy demonstrated that CXCR3 was expressed predominantly in
microglial cytoplasm. Dijkstra et al. (2004) concluded that CCL21
signaling through CXCR3 depends on the cellular background in which
CXCR3 is expressed.
Moyron-Quiroz et al. (2004) showed that mice lacking spleen, lymph
nodes, and Peyer patches generated robust B- and T-cell responses to
influenza at sites of induced bronchus-associated lymphoid tissue
(iBALT). Cxcl13 and Ccl21 were expressed at sites of iBALT formation.
These mice cleared influenza infection and survived higher challenge
doses than did normal mice. Moyron-Quiroz et al. (2004) proposed that
the immune responses of these mice are not only more protective, but
also less pathologic, than systemic immune responses.
Rangel-Moreno et al. (2007) found that, in the absence of spleen and
lymph nodes, pulmonary expression of the Ccr7 ligands Ccl19 and Ccl21
was critical for local immune responses to influenza virus infection in
mice. The Ccr7 ligands and Cxcl13 were essential for iBALT formation.
Fluorescence microscopy demonstrated expression of these homeostatic
chemokines in nonhematopoietic cells in high endothelial venules in
lungs of influenza-infected mice. Rangel-Moreno et al. (2007) concluded
that CCL19, CCL21, and CXCL13 are expressed at sites of inflammation and
contribute to development of local lymphoid tissue, as well as to
initiation and expansion of adaptive immune responses.
Mueller et al. (2007) showed that CCL21 and CXCL13 are transiently
downregulated within lymphoid tissues during immune responses by a
mechanism controlled by the cytokine interferon-gamma (147570). This
modulation altered the localization of lymphocytes and dendritic cells
within responding lymphoid tissues. As a consequence, priming of T cell
responses to a second distinct pathogen after chemokine modulation
became impaired. Mueller et al. (2007) proposed that this transient
chemokine modulation may help orchestrate local cellularity, thus
minimizing competition for space and resources in activated lymphoid
tissues.
In mice, Shields et al. (2010) found that Ccl21 expression by melanoma
tumors was associated with an immunotolerant microenvironment, which
included the induction of lymphoid-like reticular stromal networks, an
altered cytokine milieu, and the recruitment of regulatory leukocyte
populations. In contrast, Ccl21-deficient tumors induced
antigen-specific immunity. Ccl21-mediated immune tolerance was dependent
on host rather than tumor expression of the Ccl21 receptor Ccr7
(600242), and could protect distant, coimplanted Ccl21-deficient tumors
and even nonsyngeneic allografts from rejection. Shields et al. (2010)
concluded that by altering the tumor microenvironment, Ccl21-secreting
tumors shift the host immune response from immunogenic to tolerogenic,
which facilitates tumor progression.
Using global expression analysis, Harhausen et al. (2010) showed that
Cd93 (120577) mRNA was highly induced in endothelial cells, selected
macrophages, and microglia of mice after transient focal cerebral
ischemia. Occlusion of the middle cerebral artery followed by
reperfusion in Cd93 -/- mice resulted in increased leukocyte
infiltration into brain. Infarct volumes were greater in Cd93 -/- mice
than wildtype mice after short occlusion and long reperfusion times, but
not after long occlusion and short reperfusion times. Transcription
profiles of Cd93 -/- mice and wildtype mice, with confirmation by PCR
and immunohistochemistry, detected significant upregulation of Ccl21 in
untreated and treated Cd93 -/- mice at all time points. Harhausen et al.
(2010) concluded that CCL21 contributes to neurodegeneration and that
the neuroprotective effect of CD93 is mediated via suppression of the
neuroinflammatory response through downregulation of CCL21.
Weber et al. (2013) identified endogenous gradients of the chemokine
CCL21 within mouse skin and showed that they guide dendritic cells
toward lymphatic vessels. Quantitative imaging revealed depots of CCL21
within lymphatic endothelial cells and steeply decaying gradients within
the perilymphatic interstitium. These gradients matched the migratory
patterns of the dendritic cells, which directionally approach vessels
from a distance of up to 90 microns. Interstitial CCL21 is immobilized
to heparan sulfates, and its experimental delocalization or swamping the
endogenous gradients abolished directed migration. Weber et al. (2013)
concluded that their findings functionally established the concept of
haptotaxis, directed migration along immobilized gradients, in tissues.
MAPPING
By somatic cell hybrid and radiation hybrid analyses, Nagira et al.
(1997) mapped the SCYA21 gene to 9p13. Using a YAC contig and BAC clones
from this region, they found that the SCYA21 and SCYA19 (602227) genes
are located within 120 kb of each other.
ANIMAL MODEL
Using transgenic mice, adoptive transfer, and flow cytometric analysis,
Ploix et al. (2001) showed that expression of a CCR7 ligand, CCL21, is
necessary for CD4+ but not CD8+ T cells to reach their steady state 'set
point,' even in lymphopenic recipients. In addition, adoptive transfer
of antigen-specific T cells into nonlymphopenic mice overexpressing
CCL21 caused autoimmune diabetes. The authors proposed that
perturbations in the expression of CCR7 ligands, such as CCL21 or CCL19,
may alter susceptibility to autoimmunity.
Using global expression analysis, Harhausen et al. (2010) showed that
Cd93 (120577) mRNA was highly induced in endothelial cells, selected
macrophages, and microglia of mice after transient focal cerebral
ischemia. Occlusion of the middle cerebral artery followed by
reperfusion in Cd93 -/- mice resulted in increased leukocyte
infiltration into brain. Infarct volumes were greater in Cd93 -/- mice
than wildtype mice after short occlusion and long reperfusion times, but
not after long occlusion and short reperfusion times. Transcription
profiles of Cd93 -/- mice and wildtype mice, with confirmation by PCR
and immunohistochemistry, detected significant upregulation of Ccl21 in
untreated and treated Cd93 -/- mice at all time points. Harhausen et al.
(2010) concluded that CCL21 contributes to neurodegeneration and that
the neuroprotective effect of CD93 is mediated via suppression of the
neuroinflammatory response through downregulation of CCL21.
UNC13B
| dbSNP name | rs60707010(G,A); rs138217685(A,G); rs72722992(C,G); rs4878606(G,C); rs147191390(C,T); rs13293564(G,T); rs113127097(T,A); rs10972363(G,C); rs10972365(T,C); rs10972366(G,A); rs7855972(T,C); rs11788308(C,G); rs4879875(G,A); rs4879876(G,A); rs7020771(C,T); rs10972367(C,T); rs10972368(G,T); rs10738937(A,G); rs10738938(C,G); rs7042070(T,C); rs7033763(G,A); rs10465081(G,C); rs10738939(C,T); rs7865406(G,A); rs10465027(G,A); rs7852108(T,C); rs10814210(G,A); rs118093579(C,T); rs10814211(C,T); rs10738940(T,G); rs1332607(A,G); rs4879877(G,A); rs4879878(C,G); rs4879879(A,G); rs3904436(C,T); rs7035888(T,A); rs72722998(C,T); rs62543164(G,A); rs75031461(C,A); rs2381221(C,T); rs2381222(C,T); rs4111861(T,C); rs4111860(A,C); rs4111859(A,T); rs7048427(C,T); rs183093514(A,T); rs62543165(A,G); rs3904435(C,T); rs3904434(T,C); rs7031461(G,A); rs10814213(G,A); rs375495634(C,T); rs6476476(G,A); rs6476477(G,A); rs73497380(A,T); rs373488568(T,C); rs7043259(A,T); rs7044080(G,A); rs4111904(G,T); rs144203104(T,C); rs148485449(T,C); rs79310976(C,G); rs73497383(A,G); rs62543166(A,G); rs146935356(T,C); rs10972380(G,T); rs11496461(A,G); rs11496462(A,G); rs7873985(G,A); rs7849264(C,T); rs370451580(A,G); rs117814993(G,T); rs73497387(A,G); rs10972381(T,C); rs12346113(C,T); rs3849918(A,G); rs7032682(T,G); rs80279878(G,A); rs116004755(A,C); rs372464194(T,C); rs376516087(T,G); rs3849919(T,C); rs12344190(T,C); rs7036061(T,C); rs60137160(G,A); rs10972383(A,C); rs139523417(G,T); rs3849920(T,G); rs3849921(A,G); rs10972384(A,G); rs6476478(G,C); rs12685290(G,A); rs10283768(C,A); rs10118007(C,T); rs28887496(C,T); rs11792838(T,C); rs7874133(T,C); rs7858966(C,T); rs117271690(C,T); rs2381301(A,C); rs377022554(A,G); rs12380271(T,C); rs377642320(C,T); rs113276784(A,G); rs115425035(A,G); rs10972388(T,C); rs370030731(G,A); rs7025711(G,A); rs376863655(C,T); rs2381302(A,C); rs10814215(G,A); rs73499312(A,G); rs10972393(A,G); rs10972395(C,T); rs373243697(T,G); rs376224811(G,A); rs376508702(T,G); rs2381303(C,A); rs7851161(A,T); rs73499316(A,G); rs7040615(T,C); rs10118130(G,A); rs113986819(C,T); rs10972404(T,A); rs10972405(G,A); rs10972406(T,A); rs117668005(A,G); rs74792484(A,T); rs6476481(G,A); rs148442906(A,G); rs112891863(T,C); rs10814217(A,G); rs1930357(C,T); rs12350361(C,T); rs7025623(C,T); rs10972414(C,T); rs10758301(G,T); rs62543194(A,C); rs375173598(C,G); rs1930361(T,A); rs1022943(G,T); rs10121009(T,C); rs113792864(C,T); rs147507456(G,A); rs117496937(T,G); rs2151200(T,C); rs80224878(A,G); rs10114937(C,T); rs7868818(A,G); rs73499332(A,G); rs80163148(T,G); rs10972415(A,G); rs150190999(A,G); rs10972416(C,G); rs76413522(C,A); rs4879887(T,A); rs183288100(A,G); rs10511919(C,T); rs72725027(G,A); rs10758302(A,G); rs2031666(A,G); rs7031549(G,A); rs76663680(G,A); rs75097672(A,G); rs10972418(G,T); rs7866794(C,T); rs10814220(C,G); rs77276191(T,C); rs10972422(A,T); rs17361235(T,G); rs12352096(G,A); rs10758303(G,A); rs10972425(T,A); rs4419897(A,G); rs10814221(T,C); rs10738941(T,C); rs10217739(C,T); rs4879889(G,A); rs661712(T,C); rs12337082(C,T); rs12376433(G,T); rs579461(C,A); rs494831(A,G); rs3780727(C,A); rs2025722(G,A); rs555244(T,C); rs10814222(G,A); rs642223(A,G); rs11790683(T,C); rs16932326(A,G); rs10972428(C,T); rs10814223(G,A); rs618950(T,A); rs3780729(T,C); rs11794854(A,G); rs2770151(C,G); rs75279559(A,G); rs572527(C,A); rs78304930(C,A); rs117602095(G,A); rs1930358(G,A); rs630255(C,A); rs17361814(G,A); rs580376(C,T); rs73499354(A,C); rs62543215(G,A); rs575102(T,C); rs944752(A,G); rs117362213(G,T); rs10814225(T,C); rs10972429(C,T); rs654977(A,G); rs513002(G,T); rs76807069(T,G); rs671875(G,A); rs62543216(T,C); rs10972430(A,G); rs10814226(T,C); rs74891674(C,T); rs1927954(T,C); rs10758305(A,G); rs12350457(C,A); rs10972431(A,G); rs10972432(T,C); rs7847331(T,C); rs10972434(G,A); rs10814227(G,A); rs10972437(A,G); rs12376673(A,G); rs7019496(A,G); rs10814228(A,G); rs7852335(C,T); rs7855761(C,A); rs6476482(G,C); rs115946747(C,G); rs59138324(A,C); rs80168359(T,C); rs1927955(C,T); rs17296428(C,G); rs2069008(A,C); rs12350669(A,G); rs10814229(T,C); rs77383680(C,G); rs716359(T,A); rs1927957(C,T); rs6476483(A,G); rs78207612(G,T); rs34502395(G,T); rs7467018(C,T); rs12351465(A,C); rs73499383(A,G); rs77338432(C,T); rs73499384(C,T); rs115606297(C,G); rs10511920(C,T); rs75735943(A,G); rs1927959(T,C); rs115793873(C,T); rs10972444(T,G); rs10814230(A,C); rs186328301(G,A); rs146713343(C,T); rs4352935(G,A); rs12342455(A,G); rs12353066(G,A); rs7046041(A,G); rs10814231(A,G); rs16932371(C,T); rs12348768(C,T); rs4879891(G,C); rs7024042(G,A); rs1927960(C,T); rs1927961(G,C); rs10972446(A,G); rs10972447(T,C); rs7028867(C,A); rs73499399(C,A); rs12336687(G,A); rs10814232(T,C); rs4610835(G,A); rs12235806(C,T); rs7019659(G,A); rs10972448(G,C); rs7020051(G,A); rs12684897(T,C); rs7039948(T,C); rs60744888(C,G); rs7866864(C,T); rs2149368(G,A); rs3780730(A,G); rs17849230(C,T); rs72725035(C,T); rs2282001(G,C); rs12553623(C,T); rs12551074(A,G); rs57640488(A,G); rs73501716(G,T); rs4879892(T,G); rs4879893(A,G); rs2282000(C,T); rs76792055(T,C); rs2281999(C,T); rs115948126(C,A); rs4879894(A,G); rs7024134(T,C); rs114807268(C,T); rs750548(T,C); rs7032865(T,C); rs4143933(A,G); rs1927962(A,G); rs10511921(C,G); rs79238767(A,G); rs7851661(G,C); rs7851900(G,A); rs59695598(G,T); rs2015513(A,G); rs9987526(T,C); rs943842(C,T); rs73501731(C,G); rs41276043(C,G); rs2274593(C,T); rs4878613(G,A); rs74979010(G,A); rs115805584(A,G); rs12726(G,A); rs3802423(G,A) |
| ccdsGene name | CCDS6579.1 |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 10497 |
| EntrezGene Description | unc-13 homolog B (C. elegans) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNC13B:NM_006377:exon28:c.C3288G:p.F1096L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.606 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F8W8M9 |
| dbNSFP KGp1 AF | 0.00869963369963 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0197889182058 |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.002497 |
| ESP All MAF | 0.00592 |
| ESP Eur/Amr MAF | 0.007674 |
| ExAC AF | 0.009181 |
RMRP
| dbSNP name | rs7021642(G,A); rs7021463(C,G) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 6023 |
| snpEff Gene Name | C9orf100 |
| EntrezGene Description | RNA component of mitochondrial RNA processing endoribonuclease |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1488 |
| ExAC AF | 0.092 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Sensorineural hearing loss;
[Eyes];
External ophthalmoplegia, progressive (PEO);
Ptosis;
Cataracts (later onset)
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Gastroparesis;
Gastrointestinal pseudoobstruction
GENITOURINARY:
[External genitalia, male];
Testicular atrophy (in a subset of patients);
[Internal genitalia, female];
Premature ovarian failure (in a subset of patients)
SKELETAL:
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Exercise intolerance;
Muscle weakness, progressive;
Muscle atrophy;
Facial muscle weakness;
Limb muscle weakness;
EMG shows myopathic changes;
Muscle biopsy shows ragged red fibers;
Muscle biopsy shows increased variation in fiber size;
Muscle biopsy shows necrotic and atrophic fibers with centralized
nuclei;
Muscle biopsy shows multiple mitochondrial DNA (mtDNA) deletions;
Muscle biopsy shows decreased activity of cytochrome c oxidase;
Electron microscopy shows subsarcolemmal accumulations of abnormally
shaped mitochondria
NEUROLOGIC:
[Central nervous system];
Ataxia;
Parkinsonism (later onset);
Dysarthria;
Resting tremor;
Rigidity;
Bradykinesia;
Cerebellar ataxia;
Favorable response to levodopa;
Loss of pigmented neurons in the substantia nigra;
No Lewy bodies;
[Peripheral nervous system];
Gait ataxia;
Hyporeflexia;
Distal sensory loss of proprioception and vibration sense;
Sensory axonal neuropathy;
[Behavioral/psychiatric manifestations];
Depression
ENDOCRINE FEATURES:
Primary amenorrhea (in a subset of patients);
Secondary amenorrhea (in a subset of patients);
Premature menopause (in a subset of patients);
Hypergonadotropic hypogonadism (in a subset of patients);
Decreased secondary sexual characteristics (in a subset of patients)
LABORATORY ABNORMALITIES:
Increased serum lactate;
Rhabdomyolysis in response to alcohol
MISCELLANEOUS:
Highly variable phenotype;
Adult onset;
Progressive disorder;
Incidence of 1/100,000 in Italy and Finland;
Patients often have a more severe and complicated phenotype in addition
to PEO;
Hypogonadism reported in a large Swedish kindred;
See also autosomal recessive PEOB (258450);
Genetic heterogeneity (see PEOA2 609283, PEOA3 609286, and PEOA4
610131);
POLG mutations account for approximately 45% of all PEO cases
MOLECULAR BASIS:
Caused by mutations in the DNA polymerase gamma gene (POLG, 174763.0001)
OMIM Title
*157660 MITOCHONDRIAL RNA-PROCESSING ENDORIBONUCLEASE, RNA COMPONENT OF; RMRP
;;RMRPR
OMIM Description
DESCRIPTION
Mitochondrial RNA-processing endoribonuclease (RNase MRP) cleaves
mitochondrial RNA complementary to the light chain of the displacement
loop (D loop) at a unique site (Chang and Clayton, 1987). The enzyme is
a ribonucleoprotein whose RNA component is a nuclear gene product. The
RNA component is the first known RNA encoded by a single-copy gene in
the nucleus and imported into mitochondria. The RMRP gene is
untranslated, i.e., it encodes an RNA, not a protein (summary by Hsieh
et al., 1990).
MAPPING
By study of interspecific somatic cell hybrids and by in situ
hybridization, Hsieh et al. (1989, 1990) located the RMRP gene to
9p21-p12. By interspecific hybrids, the corresponding gene was assigned
to mouse chromosome 4.
GENE FUNCTION
Clayton (2001) discussed the probable function of RMRP.
To provide a physiologic demonstration of a function for RNase MRP in
mammalian cells, Thiel et al. (2005) performed functional studies in
yeast and humans. They showed that different RMRP gene mutations lead to
decreased cell growth by impairing ribosomal assembly and by altering
cyclin-dependent cell cycle regulation. Clinical heterogeneity was
explained by a correlation between the level and type of functional
impairment in vitro and the severity of short stature or predisposition
to cancer. Whereas the cartilage-hair hypoplasia (250250) founder 70A-G
mutation (157660.0001) affected both pathways intermediately, mutations
resulting in anauxetic dysplasia (607095) did not affect B-cyclin
(123836) mRNA levels but did severely incapacitate ribosomal assembly
via defective endonucleolytic cleavage. Anauxetic dysplasia mutations
thus lead to poor processing of ribosomal RNA while allowing normal mRNA
processing and, therefore, genetically separate the different functions
of RNase MRP.
Maida et al. (2009) demonstrated that TERT (187270) interacts with RMRP,
which is mutated in cartilage-hair hypoplasia. Human TERT and RMRP form
a distinct ribonucleoprotein complex that has RNA-dependent RNA
polymerase activity and produces double-stranded RNAs (dsRNAs) that can
be processed into small interfering RNA (siRNA) in a Dicer
(606241)-dependent manner. Maida et al. (2009) showed that the human
TERT-RMRP RNA-dependent RNA polymerase (RdRP) shows a strong preference
for RNA templates that can form 3-prime fold-back structures. Using RMRP
as a template, the TERT-RMRP RdRP produces dsRNAs that are processed by
Dicer into 22-nucleotide dsRNAs that contain 5-prime monophosphate and
3-prime hydroxyl groups that are loaded into AGO2 (606229), confirming
that these short RNAs represent endogenous siRNAs. The involvement of
human TERT in 2 syndromes characterized by stem cell failure
(cartilage-hair hypoplasia and dyskeratosis congenita, 127550) suggested
to Maida et al. (2009) that ribonucleoprotein complexes containing TERT
have a critical role in stem cell biology.
MOLECULAR GENETICS
Using a positional cloning strategy and mutation analysis, Ridanpaa et
al. (2001) showed that homozygous or compound heterozygous mutations in
the RMRP gene (157660.0001-157660.0008) are responsible for
cartilage-hair hypoplasia (CHH; 250250), an autosomal recessive disorder
characterized by disproportionate short stature, hypoplastic hair,
ligamentous laxity, defective immunity, hypoplastic anemia, and neuronal
dysplasia of the intestine. The mutations identified in patients with
CHH were of 2 distinct types. The first category consisted of insertions
or duplications between 6 and 30 nucleotides long residing in the region
between the TATA box and the transcription initiation site. These
mutations interfered with the transcription of the RMRP gene. The second
category consisted of single-nucleotide substitutions and other changes
involving at most 2 nucleotides. These resided in highly conserved
residues of the transcribed sequence.
Ridanpaa et al. (2002) described 36 different mutations in the RMRP gene
in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and
localization, these mutations could be classified into 3 categories:
mutations affecting the promoter region, small changes of conserved
nucleotides in the transcript, and insertions and duplications in the
5-prime end of the transcript. The only region of known function that
seemed to avoid mutations was the nucleolar localization signal region
between nucleotides 23 and 62. Eight different mutations in the promoter
region and 28 mutations in the RNA coding region of 267 nucleotides were
reported. The most common mutation in CHH patients was the 70A-G
transition (157600.0001). This mutation represented 92% of the mutations
in Finnish CHH patients. Studies of linkage disequilibrium based on
maximum likelihood estimates with close markers, genealogic studies, and
haplotype data suggested that the mutation was introduced to Finland
some 3,900 to 4,800 years ago and before the expansion of the
population. The same major mutation accounted for 48% of the mutations
among CHH patients from other parts of Europe, North and South America,
the Near East, and Australia. In the non-Finnish CHH families, the 70A-G
mutation segregated with the same major haplotype, although shorter, as
in most of the Finnish families. In 23 of these 27 chromosomes, the
common region extended over 60 kb; therefore, all the chromosomes most
likely arose from a solitary event many thousands of years ago.
Among the sporadic cases of CHH in which Ridanpaa et al. (2002)
identified mutations in the RMRP gene were 1 from China, 2 from Israel,
and 1 from Turkey. Families with more than 1 affected member affected by
CHH and found to have RMRP mutations were from Saudi Arabia and Poland.
Nakashima et al. (2003) identified novel mutations in the RMRP gene in
Japanese patients, but did not find the 70A-G common founder mutation in
any of the 12 patients studied.
Sequencing 120 RMRP alleles from a control group, Bonafe et al. (2002)
found an unusually high density of single-nucleotide polymorphisms
(SNPs) in and around the RMRP gene. The biologic significance of this
finding was unclear.
Upon finding causative mutations in the RMRP gene, Bonafe et al. (2002)
concluded that recessive metaphyseal dysplasia without hypotrichosis
(250460) is a variant of CHH, manifesting only as short stature and
metaphyseal dysplasia. Ridanpaa et al. (2003) studied the RMRP gene and
the H1RNA gene (608513) in 20 patients with the diagnosis of Schmid-type
metaphyseal chondrodysplasia (156500) in whom no mutations were
detectable in the COL10A1 gene (120110). Two patients were found to be
homozygous for a 70A-G transition in the RMRP gene, which is the major
mutation causing CHH. The description suggests the metaphyseal dysplasia
without hypotrichosis described by Bonafe et al. (2002); the affected
individuals reported by Bonafe et al. (2002) were compound heterozygous
for the common Finnish mutation (157660.0001) and a duplication mutation
(157660.0005) in the RMRP gene.
Kuijpers et al. (2003) described a female patient in whom the diagnosis
of kyphomelic dysplasia (211350) was made in infancy because of her
short-limb dwarfism and kyphomelia, especially of the femurs. She
developed a combined aplastic anemia and immunodeficiency by the age of
2 years. These responded well to allogeneic bone marrow transplantation
from her HLA-identical brother at the age of 3 years. Growth remained
extremely retarded, however. Clinical and radiologic features reported
up to the age of 8 years gradually changed and became more typical for
CHH, as was confirmed by the finding of compound heterozygosity for 2
novel mutations in the RMRP gene: 195insT (157660.0016) and 63C-T
(157660.0017). The 63C-T mutation was said to have previously been found
in an Australian CHH patient. Both mutations resided in evolutionarily
conserved nucleotides and were not found in healthy controls. Molecular
studies in the parents showed the father to have the 195insT and the
mother to have the 63C-T mutation.
Thiel et al. (2005) performed positional cloning at the locus for
anauxetic dysplasia (607095), a rare autosomal recessive
spondylometaepiphyseal dysplasia characterized by the prenatal onset of
extreme short stature, an adult height of less than 85 cm, hypodontia,
and mild mental retardation. Homozygosity mapping led to the
identification of novel mutations in the RMRP gene
(157660.0018-157660.0021), indicating that the disorder is allelic to
cartilage-hair hypoplasia (250250) as well as to metaphyseal dysplasia
without hypotrichosis.
Hermanns et al. (2005) studied the effects of mutations in both the
promoter and the transcribed region of RMRP. While mutations in the
promoter abolished transcription in vitro, RMRP RNA levels in patients
with transcribed mutations were also decreased, suggesting an unstable
RNA. RMRP mutations introduced into the yeast ortholog nuclear
mitochondrial endonuclease-1 (Nme1) exhibited normal mitochondrial
function, chromosomal segregation, and cell cycle progression, while a
CHH fibroblast cell line exhibited normal mitochondrial content.
However, the most commonly found mutation in CHH patients, 70A-G
(157660.0001), caused an alteration in ribosomal processing by altering
the ratio of the short versus the long form of the 5.8S rRNA in yeast.
Transcriptional profiling of CHH patient RNAs showed upregulation of
several cytokines and cell cycle regulatory genes, 1 of which has been
implicated in chondrocyte hypertrophy. Hermanns et al. (2005) suggested
that alteration of ribosomal processing in CHH may be associated with
altered cytokine signaling and cell cycle progression in terminally
differentiating cells in the lymphocytic and chondrocytic cell lineages.
Hirose et al. (2006) screened 9 Japanese patients for mutations in the
RMRP gene and identified homozygous or compound heterozygous mutations
in 6 patients. The authors noted that the 70A-G founder mutation
prevalent in Western populations had not been found in Japanese
patients, whereas 2 mutations common in Japanese patients, 218A-G
(157660.0013) and a 17-bp duplication at nucleotide +3 (157660.0014),
had not been reported in other populations. Haplotype analysis revealed
that the 2 latter mutations were contained within rare distinct
haplotypes, indicating the presence of unique founders among Japanese
CHH patients. Hirose et al. (2006) observed that none of the Japanese
patients they evaluated exhibited all of the skeletal, hair, and
immunologic features characteristic of classic CHH.
In 27 CHH patients referred for molecular evaluation of the clinical
diagnosis, Hermanns et al. (2006) found RMRP mutations in 22. The
phenotype in 1 of the 5 mutation-negative patients was fully congruent
with the adopted case definition of CHH. In a second of these patients,
the diagnosis of Schmid type metaphyseal chondrodysplasia (156500) was
made and confirmed by the detection of a mutation in the COL10A1 gene.
The remaining patients most likely represented one or more metaphyseal
chondrodysplasias not hitherto delineated. The pattern of cumulative
growth in infancy and early childhood in the latter 4 patients was the
single feature with greatest negative predictive power for CHH. Fourteen
of the mutations reported by Hermanns et al. (2006) had not been
reported previously. Only 4 of 22 CHH patients were homozygous for the
70A-G mutation. Ridanpaa et al. (2002) postulated that the 70A-G
mutation was of ancient founder origin.
Thiel et al. (2007) stated that in addition to the founder mutation
70A-G, which is present in 92% of Finnish and 48% of non-Finnish
patients with CHH, a total of 25 insertions or duplications between the
TATA box and the transcription start site and more than 62 other
mutations within the RMRP gene had been identified in patients with
phenotypes in the cartilage hair hypoplasia-anauxetic dysplasia (CHH-AD)
spectrum. That spectrum, ranging from the milder phenotypes metaphyseal
dysplasia without hypotrichosis (250460) and CHH to the severe anauxetic
dysplasia, includes different degrees of short stature, hair hypoplasia,
defective erythrogenesis, and immunodeficiency. To investigate the
genotype-phenotype correlation, Thiel et al. (2007) analyzed the
position and the functional effect of 13 mutations in patients with
variable features of the CHH-AD spectrum. Those at the severe end of the
spectrum included a patient with anauxetic dysplasia who was compound
heterozygous for a null deletion mutation (157660.0022) and the 195C-T
mutation (see 157660.0009), which had been described in patients with
milder phenotypes. Mapping of nucleotide conservation to the
2-dimensional structure of the RMRP transcript showed that
disease-causing mutations either affect evolutionarily conserved
nucleotides or are likely to alter secondary structure through
mispairing in stem regions. In vitro testing of mitochondrial
RNA-processing ribonuclease multiprotein-specific mRNA and rRNA cleavage
of different mutations showed a strong correlation between the decrease
in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia,
whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicted
the presence of hair hypoplasia, immunodeficiency, and hematologic
abnormalities and thus increased cancer risk.
Nakashima et al. (2007) performed RT-PCR analysis of cDNA from CHH
patients carrying RMRP mutations, including 2 promoter mutations, a
16-bp duplication at +1 and a 17-bp duplication at +3 (157660.0014), and
2 transcribed mutations, 168G-A and 218A-G (157660.0013), and confirmed
lower expression levels of RMRP for all mutations. By 5-prime RACE
analysis, they showed that reduced transcription in the promoter mutants
was accompanied by shifting of the transcription initiation sites to
nucleotides 5-prime upstream of the authentic site. By RT-PCR analysis
of mouse fibroblasts transfected with transcribed mutant RMRP, they
confirmed reduced RMRP expression. Reduced transcription correlated with
greater instability of mutant RMRP transcripts compared to controls. A
comparable reduction of transcription was seen when the major CHH
mutation 70A-G was introduced into mouse ES cells, and low expression
level of the 70A-G Rmrp RNA was confirmed by expression assays in
cultured cells, and again correlated with RNA instability. Nakashima et
al. (2007) concluded that loss of mutant RNA transcripts is a critical
feature of pathogenesis of CHH.
LINC00950
| dbSNP name | rs4879932(T,C); rs10814287(T,C); rs112570874(G,A); rs11791889(G,A); rs141949057(A,G); rs4879933(G,A); rs12552435(A,G); rs112506275(T,C); rs146312447(A,G); rs79359632(G,A); rs148445007(C,T); rs9525(A,C); rs77291929(T,A) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 92973 |
| snpEff Gene Name | OR13E1P |
| EntrezGene Description | long intergenic non-protein coding RNA 950 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1804 |
OR13J1
| dbSNP name | rs150584050(G,A); rs7044405(T,C); rs72727089(G,A) |
| ccdsGene name | CCDS35011.1 |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 392309 |
| EntrezGene Description | olfactory receptor, family 13, subfamily J, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13J1:NM_001004487:exon1:c.C598T:p.L200L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.004229 |
| ESP Eur/Amr MAF | 0.005814 |
| ExAC AF | 0.004611 |
HRCT1
| dbSNP name | rs112212538(C,A); rs144123850(T,C) |
| ccdsGene name | CCDS35012.1 |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 646962 |
| EntrezGene Description | histidine rich carboxyl terminus 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HRCT1:NM_001039792:exon1:c.C317A:p.P106H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6UXD1 |
| dbNSFP Uniprot ID | HRCT1_HUMAN |
| dbNSFP KGp1 AF | 0.154304029304 |
| dbNSFP KGp1 Afr AF | 0.166666666667 |
| dbNSFP KGp1 Amr AF | 0.129834254144 |
| dbNSFP KGp1 Asn AF | 0.0786713286713 |
| dbNSFP KGp1 Eur AF | 0.215039577836 |
| dbSNP GMAF | 0.1543 |
OR2S2
| dbSNP name | rs2233568(G,A); rs2233566(A,G); rs2233565(T,C); rs2233564(T,C); rs2233563(C,T); rs2233560(G,A); rs2233558(T,C); rs2233557(C,T) |
| ccdsGene name | CCDS6596.2 |
| CosmicCodingMuts gene | OR2S2 |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 56656 |
| EntrezGene Description | olfactory receptor, family 2, subfamily S, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2S2:NM_019897:exon1:c.C741T:p.T247T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3457 |
| ESP Afr MAF | 0.460735 |
| ESP All MAF | 0.374135 |
| ESP Eur/Amr MAF | 0.329767 |
| ExAC AF | 0.315 |
CCIN
| dbSNP name | rs3739610(G,A); rs3739609(T,C); rs61735202(G,A); rs113222879(A,G) |
| cytoBand name | 9p13.3 |
| EntrezGene GeneID | 881 |
| EntrezGene Description | calicin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3434 |
| ESP Afr MAF | 0.408761 |
| ESP All MAF | 0.336306 |
| ESP Eur/Amr MAF | 0.299186 |
| ExAC AF | 0.31 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Nephritis;
Membranous glomerulonephropathy
SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash;
Malar rash
HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia
IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of B cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells
LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Antiribonuclear protein positive;
Anti-SSB positive;
Anti-factor VIII positive
MISCELLANEOUS:
Onset in infancy or childhood
MOLECULAR BASIS:
Caused by mutations in the caspase 10 gene (CASP10, 601762.0001)
OMIM Title
*603960 CALICIN; CCIN
OMIM Description
DESCRIPTION
In mammalian sperm, the dense cytoplasmic webs surrounding the nuclei
contain a complex structure called the perinuclear theca. Longo et al.
(1987) determined that 2 kinds of basic proteins are the major
constituents of the thecal structure: calicin, a 60-kD protein localized
almost exclusively to the calyx, and a group of multiple-band
polypeptides (MBPs or cylicins; see 300768) that are found both in the
calyx and the subacrosomal layer.
CLONING
Von Bulow et al. (1995) purified calicin from bull sperm and determined
a partial protein sequence. By PCR analysis of testis cDNA with
oligonucleotide primers based on the calicin protein sequence, they
isolated bovine and human cDNAs encoding calicin. The predicted bovine
protein contains 588 amino acids and has a calculated pI of 8.1. The
partial human cDNA encodes a protein that starts at a position
corresponding to the fourth amino acid of bovine calicin. Overall, the 2
calicins are 91% identical. There are 3 consecutive repeats in the
middle of the calicin protein. Sequence comparisons revealed that
calicin shares homology with the Drosophila kelch protein, which is
associated with the actin-rich intercellular bridges (ring canals) in
the egg chamber that connect the oocyte and the nurse cells. Von Bulow
et al. (1995) noted that calicin is missing or is arranged in a
dramatically different pattern in the heads of malformed human
spermatozoa such as teratozoospermias with 'round-headed' sperm or with
other 'postacrosomal sheath defects.'
MAPPING
Gross (2014) mapped the CCIN gene to chromosome 9p13.3 based on an
alignment of the CCIN sequence (GenBank GENBANK AF333334) with the
genomic sequence (GRCh37).
FAM201A
| dbSNP name | rs1815549(G,A); rs7046879(G,C) |
| cytoBand name | 9p13.1 |
| EntrezGene GeneID | 158228 |
| EntrezGene Description | family with sequence similarity 201, member A |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5SY85 |
| dbNSFP Uniprot ID | F201A_HUMAN |
| dbNSFP KGp1 AF | 0.316391941392 |
| dbNSFP KGp1 Afr AF | 0.126016260163 |
| dbNSFP KGp1 Amr AF | 0.406077348066 |
| dbNSFP KGp1 Asn AF | 0.412587412587 |
| dbNSFP KGp1 Eur AF | 0.324538258575 |
| dbSNP GMAF | 0.3173 |
| ExAC AF | 0.252 |
PRKACG
| dbSNP name | rs12345886(G,T); rs3812538(G,C); rs3730386(G,C); rs41288749(G,A) |
| cytoBand name | 9q21.11 |
| EntrezGene GeneID | 5568 |
| snpEff Gene Name | PIP5K1B |
| EntrezGene Description | protein kinase, cAMP-dependent, catalytic, gamma |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2227 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Superficial thrombophlebitis;
Deep venous thrombosis
RESPIRATORY:
[Lung];
Pulmonary embolism
SKIN, NAILS, HAIR:
[Skin];
Warfarin-induced skin necrosis
NEUROLOGIC:
[Central nervous system];
Cerebral thrombosis (e.g. 612283.0014 protein C deficiency)
LABORATORY ABNORMALITIES:
Plasma protein C deficiency
MISCELLANEOUS:
Vast majority of heterozygotes are asymptomatic;
Protein C deficiency is found in 3-4% of patients with venous thromboembolism;
Acquired protein C deficiency seen in liver disease, DIC, and following
surgery;
See also autosomal recessive form (612304)
MOLECULAR BASIS:
Caused by mutation in the protein C gene (PROC, 612283.0001)
OMIM Title
*176893 PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, GAMMA; PRKACG
OMIM Description
CLONING
Beebe et al. (1990) reported the molecular cloning of a third isoform of
the catalytic subunit of cAMP-dependent protein kinase (C-alpha (PRKACA;
601639) and C-beta (PRKACB; 176892) had previously been characterized).
The third form, isolated from a human testis cDNA library and designated
C-gamma, was clearly derived from a gene distinct from C-alpha and
C-beta and showed tissue-specific expression. Whereas at the amino acid
level C-alpha and C-beta showed 93% homology, C-gamma showed only about
80% homology to both C-alpha and C-beta.
Reinton et al. (1998) isolated the entire human PRKACG genomic sequence.
The PRKACG gene is intronless, contains remnants of a poly(A) tail, is
flanked by direct repeats, and is colinear with the PRKACA gene. Thus,
the authors concluded that the PRKACG gene is a PRKACA-derived
retroposon. Northern blot analysis detected PRKACG expression in
fractionated germ cells of human testes.
MAPPING
Foss et al. (1991, 1992) mapped the gene for the subunit C-gamma to
chromosome 9 by study of somatic cell hybrids. By in situ hybridization,
they confirmed the assignment and regionalized the gene to chromosome
9q13.
GENE FUNCTION
Among 304 Swiss individuals tested and genotyped, de Quervain and
Papassotiropoulos (2006) found a significant association (p = 0.00008)
between short-term episodic memory performance and genetic variations in
a 7-gene cluster consisting of the ADCY8 (103070), PRKACG, CAMK2G
(602123), GRIN2A (138253), GRIN2B (138252), GRM3 (601115), and PRKCA
(176960) genes, all of which have well-established molecular and
biologic functions in animal memory. Functional MRI studies in an
independent set of 32 individuals with similar memory performance showed
a correlation between activation in memory-related brain regions,
including the hippocampus and parahippocampal gyrus, and genetic
variability in the 7-gene cluster. De Quervain and Papassotiropoulos
(2006) concluded that these 7 genes encode proteins of the memory
formation signaling cascade that are important for human memory
function.
MOLECULAR GENETICS
For discussion of a possible association between duplication of the
PRKACG gene and 46,XY gonadal dysgenesis, see SRXY1 (400044).
RPSAP9
| dbSNP name | rs7036849(T,C); rs7033581(A,G) |
| cytoBand name | 9q21.13 |
| EntrezGene GeneID | 653162 |
| snpEff Gene Name | RFK |
| EntrezGene Description | ribosomal protein SA pseudogene 9 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.118 |
| ExAC AF | 0.934,8.693e-04,8.279e-06 |
FRMD3
| dbSNP name | rs6559715(C,G); rs7874181(T,G); rs11139995(C,T); rs1048228(T,G); rs73475665(A,G); rs1048223(A,G); rs77494496(T,G); rs1408105(T,A); rs4877741(A,G); rs4877742(C,G); rs4877743(T,G); rs4877744(T,A); rs4877745(T,C); rs4877746(T,C); rs1056476(G,A); rs10114696(A,G); rs10115475(A,G); rs1535747(C,T); rs4877249(G,A); rs73475670(G,A); rs75661208(G,A); rs7041467(A,G); rs4877748(C,T); rs7869662(A,G); rs12553212(C,T); rs75972927(C,G); rs2209191(G,A); rs58583068(A,G); rs6559716(A,C); rs7036410(T,A); rs34975489(C,T); rs112198313(T,C); rs7028221(A,G); rs2224820(G,C); rs2378656(G,T); rs13302766(C,A); rs7029645(G,A); rs116434007(A,T); rs144143910(A,G); rs115713922(C,A); rs115779777(A,G); rs113114323(T,C); rs7030958(T,C); rs4877750(T,C); rs13294854(C,T); rs7035425(T,G); rs7019268(A,T); rs2378657(T,C); rs2889953(G,A); rs58579431(T,C); rs1924241(C,T); rs1924242(G,A); rs4395967(G,A); rs1323785(T,C); rs139953501(C,T); rs11139998(C,G); rs12339855(A,G); rs10867967(G,A); rs11139999(C,T); rs1544064(A,C); rs1323784(A,G); rs1323782(A,G); rs11795001(C,T); rs72743036(C,T); rs11791029(A,T); rs1544063(T,C); rs11795034(C,T); rs113895408(G,T); rs11795096(C,G); rs11140001(G,T); rs13283875(A,G); rs4418413(A,T); rs9695210(G,A); rs10867968(C,T); rs13296597(C,T); rs12376739(G,T); rs1547628(T,G); rs1535746(T,G); rs13302331(G,A); rs56128787(T,C); rs10512138(T,C); rs7857494(T,C); rs4877751(G,A); rs12345712(A,G); rs12336693(C,G); rs11788630(G,A); rs7034639(C,T); rs7034898(C,A); rs12003055(T,C); rs12005318(A,C); rs1359169(A,G); rs148043670(T,C); rs13298532(T,C); rs10780583(C,T); rs12353330(A,C); rs118043070(T,C); rs115773509(C,T); rs10780584(T,C); rs13288171(C,T); rs13294469(A,G); rs35471874(G,C); rs35921929(G,A); rs11140004(C,G); rs10780586(T,C); rs10867971(G,A); rs113821675(G,A); rs17086124(G,A); rs10867972(G,A); rs11792963(G,C); rs10867973(A,G); rs7856762(A,C); rs55707933(C,T); rs10735562(A,G); rs10867974(G,A); rs7872136(G,A); rs3739658(C,T); rs1323780(A,C); rs2209186(A,C); rs2209187(T,G); rs2209188(G,C); rs2378658(A,G); rs1535753(A,C); rs1535752(G,A); rs372201657(C,T); rs942283(A,G); rs942282(C,G); rs942281(G,A); rs942280(C,T); rs942279(A,T); rs149870127(T,C); rs942278(T,C); rs10867975(C,T); rs1323779(T,A); rs1323778(C,G); rs1323777(A,G); rs10867976(G,C); rs11793977(C,T); rs10867977(A,G); rs375775213(T,A); rs2889954(G,A); rs2378659(G,A); rs10118491(A,G); rs115772558(G,A); rs1886125(G,T); rs1886126(C,T); rs77159835(G,C); rs1323776(T,C); rs11140007(G,C); rs6559718(A,G); rs116267244(G,A); rs10867978(T,C); rs4877250(C,T); rs10867979(C,G); rs10117251(T,C); rs78077374(C,T); rs148787397(C,T); rs1535751(T,C); rs1570582(C,A); rs11140009(T,C); rs1323775(T,A); rs1535750(A,C); rs1408107(C,T); rs4877251(C,A); rs11140010(C,T); rs10780587(A,G); rs34913088(A,G); rs75478948(T,G); rs11140011(A,G); rs1359168(A,C); rs1359167(G,C); rs10867980(A,G); rs10867981(A,G); rs10867982(C,G); rs10867983(C,A); rs10867984(C,G); rs11140013(G,A); rs6559719(T,C); rs11140014(T,A); rs11140015(A,G); rs4877752(T,C); rs79879138(G,T); rs1359166(C,T); rs73481838(A,G); rs4877753(T,C); rs62563596(C,G); rs12380047(A,G); rs79788257(G,C); rs112471968(C,T); rs75970005(G,A); rs62563597(T,C); rs11140017(C,T); rs141657619(A,G); rs1535749(T,A); rs78504091(A,T); rs11140018(T,C); rs13295597(G,C); rs7869062(A,C); rs76992231(G,A); rs2031261(A,G); rs10867985(C,T); rs11787795(A,G); rs11140019(G,C); rs13286515(G,A); rs12378433(C,G); rs57251635(T,A); rs12375992(A,G); rs11794508(T,C); rs11140020(A,T); rs13284867(T,C); rs13284048(G,A); rs112251807(G,C); rs1323774(C,G); rs11140022(T,C); rs76732333(G,C); rs17086147(C,T); rs73463609(C,T); rs61572195(C,A); rs2025387(C,A); rs10115905(T,C); rs11140023(A,C); rs10867986(T,G); rs146288231(T,A); rs2889231(T,C); rs115795434(T,G); rs4111395(T,C); rs12377587(G,A); rs12379032(T,C); rs4877754(G,A); rs72743061(T,A); rs112118843(C,A); rs4361831(G,A); rs4468012(G,A); rs3903845(A,G); rs11140024(C,A); rs10121282(G,A); rs10121898(C,A); rs10780590(C,T); rs72618131(G,A); rs10780591(A,G); rs3903843(G,A); rs10780592(A,C); rs11140027(C,A); rs151158485(C,G); rs140211524(T,C); rs183415233(C,T); rs7030025(C,T); rs12000548(A,G); rs7858141(G,C); rs72618132(T,A); rs7858312(G,A); rs56079822(T,A); rs61226190(C,T); rs7847871(T,C); rs7861920(C,T); rs12115226(T,A); rs3903842(A,C); rs13293256(G,T); rs10124534(C,T); rs72618133(A,G); rs10124608(G,A); rs10115612(T,A); rs11140028(G,A); rs11140029(G,T); rs10867988(G,A); rs146118037(C,T); rs10867989(G,A); rs10867990(T,A); rs3849863(T,G); rs78782685(T,C); rs7029260(T,G); rs11140030(C,T); rs10114054(G,A); rs10867991(C,T); rs10867992(T,C); rs11140032(G,A); rs7860626(T,C); rs55679485(G,T); rs10867993(A,C); rs10780593(A,T); rs17086156(C,T); rs10780594(C,T); rs11793310(G,A); rs17402202(C,T); rs12555197(G,A); rs72618134(C,T); rs62563600(C,T); rs11140033(G,C); rs17311062(C,T); rs12006006(G,A); rs7861973(C,A); rs2375926(C,T); rs11140034(G,A); rs3860899(G,A); rs10512139(G,C); rs72618135(C,T); rs7029388(G,T); rs11140035(T,C); rs12375872(G,A); rs10780595(T,C); rs7033063(A,C); rs3860900(T,C); rs139172134(T,A); rs7865708(C,A); rs12000902(G,A); rs2889243(T,C); rs7032234(T,C); rs12001540(G,A); rs4242620(G,A); rs4242621(A,G); rs4877755(C,A); rs74976073(C,G); rs60628722(G,A); rs143516540(T,C); rs62563651(G,T); rs62563652(C,T); rs10120343(T,C); rs3860902(T,C); rs10780596(T,C); rs10780597(T,C); rs147736311(C,T); rs1536889(T,C); rs1536888(A,C); rs4877252(A,T); rs10746700(T,A); rs10746701(A,T); rs10746702(C,T); rs10746703(A,T); rs10867995(C,G); rs10120527(C,T); rs57018246(G,A); rs2375885(G,T); rs3860903(A,G); rs2375886(G,A); rs4877253(A,G); rs2277175(C,A); rs9314712(G,A); rs10125561(T,G); rs10867997(A,G); rs11140040(G,A); rs10119376(G,A); rs148045308(C,T); rs73463650(C,A); rs11140041(C,T); rs72743079(T,C); rs10867998(T,C); rs12346118(C,T); rs2375924(T,C); rs2889245(G,A); rs2375925(A,T); rs146676701(A,G); rs3889596(G,A); rs10441792(C,G); rs11140045(G,A); rs11140046(A,G); rs3915916(G,T); rs113621593(C,G); rs4085854(A,G); rs146665489(C,T); rs7048102(C,A); rs73463659(C,A); rs11140051(A,C); rs11140052(G,A); rs7034503(A,G); rs7035160(A,G); rs72743082(G,T); rs72743083(T,C); rs182939728(T,C); rs7869978(A,G); rs11140054(A,G); rs11140055(T,G); rs7856526(T,C); rs10119054(A,T); rs10125280(C,T); rs189578655(T,C); rs77546747(T,C); rs10868000(T,C); rs55825433(G,A); rs149110028(T,G); rs12550900(G,A); rs138290445(C,T); rs10868001(A,G); rs11140056(A,G); rs7847924(T,C); rs35498149(G,A); rs7851145(T,A); rs4297106(G,A); rs72743091(C,G); rs2375922(C,T); rs375962990(T,C); rs3928783(G,A); rs3928782(C,T); rs1556150(C,A); rs2183260(T,G); rs1556149(A,G); rs12337462(C,T); rs145743315(T,C); rs72743096(C,T); rs72743099(T,A); rs3739657(T,C); rs143750551(G,A); rs3739656(C,T); rs62563655(A,G); rs3860905(T,C); rs3849865(A,G); rs3860907(G,A); rs4877757(G,A); rs7847162(T,A); rs3860908(A,C); rs3860909(C,A); rs7037541(C,G); rs28585601(C,T); rs7037795(A,G); rs7037928(A,C); rs12342540(C,T); rs34267732(T,C); rs11140060(G,C); rs11792767(T,C); rs76171721(G,A); rs62560269(A,C); rs150019904(G,A); rs11140061(T,C); rs7019165(G,A); rs3904189(T,G); rs140194983(T,C); rs13300839(A,G); rs75995839(A,C); rs10780599(C,T); rs74400239(T,C); rs78308497(A,G); rs115243996(T,A); rs7021336(T,C); rs115969960(G,A); rs34767126(G,A); rs12348065(G,C); rs4097499(G,C); rs148812940(T,C); rs186150212(C,T); rs368509013(G,A); rs3860910(C,G); rs3904188(T,C); rs13299648(C,G); rs10512140(T,C); rs72745014(C,T); rs4084066(G,A); rs3860911(C,T); rs114796609(G,T); rs10780600(G,A); rs72745016(T,G); rs10780601(C,T); rs79203970(C,T); rs11140064(G,A); rs189071712(G,C); rs3860912(T,G); rs4145728(A,G); rs3849866(A,T); rs72745020(C,T); rs12350022(G,A); rs7870557(A,C); rs7870804(C,G); rs3860913(G,C); rs3860914(G,T); rs181863483(C,T); rs12337675(T,C); rs10868003(G,C); rs375026438(G,A); rs17086209(G,A); rs7021167(A,G); rs146421448(A,G); rs3906148(A,G); rs72745024(C,A); rs3739655(T,C); rs59288178(C,T); rs7853850(C,T); rs7854453(G,A); rs4478644(G,T); rs10117284(A,G); rs12349789(C,T); rs11140065(T,C); rs10125072(G,T); rs78785315(C,T); rs12115799(C,A); rs3904187(T,C); rs74948054(A,G); rs115560880(T,C); rs72745036(A,C); rs79539259(G,C); rs10746705(C,A); rs6559722(G,A); rs4111394(T,C); rs3860915(C,A); rs7868589(C,A); rs12340422(C,T); rs4145729(C,T); rs4877758(G,T); rs11140066(A,G); rs11140067(T,C); rs10868004(G,T); rs183823293(T,A); rs116458965(T,C); rs112724819(G,A); rs12000173(G,A); rs3933281(T,C); rs12339003(G,C); rs140609234(C,T); rs73465724(C,T); rs4242622(A,C); rs76127157(G,A); rs17086219(G,A); rs17086223(T,C); rs17086225(T,C); rs7035287(T,C); rs12347584(T,C); rs3860916(C,T); rs12343915(G,A); rs373562992(T,A); rs10119608(G,A); rs9314713(A,G); rs55938439(G,C); rs10481759(A,G); rs9314714(C,T); rs10115207(A,G); rs370922537(G,A); rs4097498(A,C); rs72745047(C,T); rs9314715(G,C); rs28399912(A,G); rs10122474(T,C); rs11140068(G,A); rs78962107(T,G); rs115805304(C,T); rs10119379(C,T); rs12343805(G,A); rs12343806(G,A); rs17086234(G,A); rs116655283(C,T); rs4877759(G,A); rs11998876(A,T); rs76801658(C,T); rs13440164(C,T); rs13440167(G,T); rs3904186(T,C); rs373952913(G,A); rs7039438(T,C); rs60152061(G,A); rs3904185(G,A); rs7027592(A,G); rs7039388(G,C); rs12551179(T,C); rs114880559(T,G); rs3860917(A,C); rs17086247(C,A); rs12553050(A,G); rs12352587(C,T); rs114406014(T,C); rs55816152(T,C); rs17086251(G,T); rs6559723(A,C); rs871790(C,T); rs74487472(T,C); rs113106932(G,T); rs4634740(C,T); rs4014038(T,C); rs3889637(C,T); rs12003254(C,T); rs12337733(A,G); rs10868005(C,G); rs10868006(A,G); rs11140078(T,C); rs10217746(T,C); rs10217752(T,G); rs4537377(T,G); rs4636280(A,C); rs72745059(G,A); rs10116367(A,G); rs114598445(C,T); rs11140080(G,A); rs72745060(T,G); rs11140081(C,T); rs11140082(T,C); rs10217271(A,G); rs11140083(A,G); rs78699537(G,A); rs10217669(C,T); rs7019130(T,C); rs114512118(T,C); rs7037659(G,A); rs4877761(C,T); rs3860919(C,T); rs11140085(C,G); rs114400933(A,C); rs116457102(T,G); rs11140087(C,T); rs3893398(G,C); rs3849867(A,G); rs3893399(G,A); rs3849868(G,C); rs3860921(T,A); rs72745080(A,G); rs369652969(G,A); rs11140088(G,A); rs114945660(T,A); rs12005884(C,T); rs72745084(C,T); rs10868007(A,G); rs7037923(C,T); rs7023415(T,C); rs4877762(G,A); rs4877763(G,A); rs56658338(T,C); rs73465767(C,T); rs60329197(A,G); rs8181122(G,A); rs10217435(T,C); rs3860924(T,C); rs7037329(G,A); rs72745087(T,G); rs58623804(G,A); rs59092131(G,A); rs61424289(T,C); rs77646161(T,C); rs12346296(T,C); rs12350642(A,G); rs2375919(T,C); rs3860925(A,G); rs3915532(G,A); rs28512300(G,A); rs72745090(T,G); rs10481736(T,C); rs10780602(A,G); rs11999447(C,T); rs117172755(G,A); rs7022758(C,G); rs7023220(G,A); rs7023140(C,T); rs7023259(C,T); rs11140090(G,T); rs376695938(C,A); rs10119045(T,C); rs72745092(T,C); rs373859389(T,C); rs10780603(T,C); rs10780604(C,T); rs4145727(T,C); rs72745096(C,T); rs3860926(C,T); rs72745099(C,G); rs10868009(A,G); rs10868010(G,A); rs74570629(G,A); rs7866062(T,G); rs3860927(A,G); rs3860928(T,A); rs76455438(C,A); rs117505011(C,A); rs12685326(C,A); rs12685342(G,A); rs11140094(T,A); rs11140095(G,A); rs28719707(T,C); rs138693370(A,C); rs11140096(A,G); rs114689272(C,T); rs11140097(C,G); rs10868011(T,C); rs10868012(T,G); rs10868013(C,T); rs10868014(T,G); rs10123326(T,C); rs56073325(A,C); rs12682903(A,G); rs1999398(G,A); rs10868015(G,T); rs11140101(A,G); rs10868016(A,G); rs7865303(T,G); rs4877767(C,T); rs77379514(A,G); rs78927555(G,A); rs4877255(T,C); rs115018603(A,G); rs6559726(T,C); rs6559727(T,C); rs11140102(C,A); rs74871174(G,T); rs75596574(T,C); rs72746815(G,C); rs4520248(G,A); rs11140103(T,C); rs12555500(G,A); rs4877768(C,A); rs11140104(T,C); rs11140105(T,C); rs4877769(A,G); rs4877770(A,G); rs4014024(C,T); rs3860929(T,A); rs10868017(G,A); rs7851397(T,C); rs11140109(T,C); rs4877773(T,C); rs4877774(T,C); rs4877775(G,C); rs4877776(T,C); rs4877777(A,C); rs76537381(T,C); rs7869397(A,G); rs76367398(C,T); rs35161622(C,A); rs7872891(C,T); rs17086293(A,T); rs7873016(C,G); rs76488807(G,A); rs116083862(G,A); rs76362252(G,A); rs60254558(G,A); rs13301580(C,G); rs13301440(A,T); rs61213861(T,A); rs7855304(G,T); rs7855690(G,T); rs115223749(C,T); rs35928246(G,C); rs2375927(T,C); rs4877256(A,G); rs17086295(C,T); rs77311851(C,T); rs2375928(C,G); rs372520636(G,A); rs3860930(G,A); rs7045466(A,C); rs7034871(T,G); rs2375929(T,C); rs7019064(G,A); rs7850633(C,T); rs374418269(G,A); rs375947039(G,A); rs370476420(G,A); rs12000033(G,A); rs12551710(C,T); rs150201096(G,A); rs10746709(C,T); rs7032181(G,C); rs7032223(C,A); rs10120060(T,C); rs76517428(C,T); rs369021213(A,G); rs4425838(A,G); rs7048137(G,A); rs10118508(C,T); rs55730336(G,A); rs12343511(C,T); rs12348445(T,C); rs12343646(C,T); rs75182668(G,A); rs11787686(A,G); rs17086317(A,G); rs17086319(T,C); rs7026481(C,T); rs7026525(A,C); rs5014090(A,G); rs5014091(T,C); rs5014092(C,T); rs5014093(G,A); rs5014094(A,G); rs4877778(A,T); rs5014095(C,G); rs5014096(C,A); rs4877779(C,T); rs2375931(G,A); rs11140112(T,C); rs7020613(T,A); rs7021023(T,C); rs7035629(C,T); rs7039039(G,A); rs12554044(T,C); rs62560308(T,C); rs35580298(A,C); rs28595483(G,A); rs74836821(A,G); rs10868018(A,G); rs12349480(T,C); rs137861113(C,T); rs11140113(G,A); rs75105063(G,A); rs10868019(T,C); rs370233761(C,A); rs4120051(T,A); rs369201537(C,T); rs7025284(C,G); rs3860931(A,G); rs10746710(G,A); rs10746711(T,C); rs3860932(C,T); rs10746712(G,T); rs10746713(T,C); rs3860933(A,G); rs75852895(T,C); rs10780605(G,A); rs150844934(G,A); rs11140115(G,A); rs11140116(C,T); rs12350888(G,A); rs10868020(C,T); rs11140117(A,G); rs7873385(A,G); rs75361735(T,C); rs3860934(T,A); rs12380450(C,T); rs73468237(A,T); rs6559728(A,G); rs35561467(A,T); rs12352296(C,G); rs12352407(G,A); rs4097648(G,C); rs12380849(G,A); rs144888150(A,C); rs9314717(C,T); rs9314718(G,C); rs9314719(T,C); rs9314720(C,T); rs3860935(T,C); rs11140118(G,T); rs3860936(T,C); rs11140119(C,T); rs4097647(C,A); rs12376872(A,T); rs9314721(G,C); rs76601238(T,A); rs10780606(A,G); rs3860937(A,G); rs3860938(G,T); rs12350750(G,A); rs3860939(G,A); rs3860940(A,G); rs3860941(G,A); rs11140121(C,A); rs11794693(C,T); rs376052954(T,A); rs11140122(T,C); rs4097644(G,A); rs4097643(T,A); rs4111744(G,A); rs9942844(C,T); rs9987431(C,T); rs11140123(C,A); rs12551103(C,T); rs6559729(T,C); rs11140124(C,A); rs9695864(T,C); rs140945703(T,G); rs10780607(G,A); rs11140125(C,T); rs11140126(G,A); rs7863524(G,T); rs6559730(A,G); rs28595736(G,A); rs6559731(C,A); rs3860942(T,C); rs11140128(T,A); rs3860943(A,G); rs143159844(G,A); rs4877782(A,G); rs4877783(A,G); rs11140130(T,C); rs75472417(C,T); rs7045457(A,T); rs77134228(A,T); rs77930150(T,A); rs2889244(C,T); rs4317655(T,C); rs17086386(A,T); rs75858517(G,A); rs12552693(T,C); rs114637678(T,C); rs147864663(A,T); rs4877257(T,G); rs17405770(C,T); rs79503383(C,A); rs61190275(T,C); rs4877785(G,T); rs115993663(G,A); rs74911558(C,T); rs77860388(C,T); rs62560353(G,T); rs60961568(G,A); rs11793207(T,C); rs62560354(C,A); rs12551334(A,T); rs28493568(G,A); rs7862471(G,C); rs77964188(T,G); rs7043389(G,T); rs7043391(G,C); rs7043575(A,G); rs78292390(G,C); rs75761566(G,A); rs78636141(T,C); rs7043959(A,G); rs368176526(T,G); rs10868022(T,C); rs10780608(T,C); rs10780609(G,A); rs77458987(A,G); rs149027628(A,G); rs138719737(C,T); rs7041666(T,C); rs117547912(C,T); rs7042568(T,C); rs11795151(T,C); rs7037655(C,A); rs11789184(A,G); rs7038103(A,G); rs4363276(T,A); rs4263845(A,C); rs7869714(A,G); rs4877786(C,T); rs7046729(C,T); rs139241505(G,A); rs143592793(A,G); rs7019435(A,G); rs17086403(T,G); rs5028328(A,G); rs192159435(C,T); rs4424349(T,A); rs11140137(T,C); rs7037642(A,G); rs145492595(A,G); rs141065289(A,C); rs17086413(C,G); rs10868023(T,A); rs77633233(A,T); rs368494537(C,T); rs375463345(G,A); rs12349143(C,T); rs17086428(C,T); rs147311118(A,T); rs79009998(A,G); rs12551989(T,A); rs4877787(C,T); rs11140139(G,A); rs10868024(T,G); rs4877788(T,C); rs11140140(T,G); rs79370211(A,G); rs375832018(C,T); rs7855679(C,T); rs116872662(G,A); rs11140141(T,G); rs7858885(G,A); rs11140142(C,T); rs11140143(T,C); rs7849075(T,C); rs79191314(C,T); rs7863215(G,A); rs143603561(T,C); rs12343731(A,G); rs11795139(C,T); rs77773760(T,C); rs57882958(A,G); rs62559801(C,T); rs73468296(G,A) |
| ccdsGene name | CCDS43840.1 |
| CosmicCodingMuts gene | FRMD3 |
| cytoBand name | 9q21.32 |
| EntrezGene GeneID | 257019 |
| EntrezGene Description | FERM domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FRMD3:NM_001244959:exon13:c.G1091A:p.R364H,FRMD3:NM_001244960:exon13:c.G959A:p.R320H,FRMD3:NM_174938:exon13:c.G1091A:p.R364H,FRMD3:NM_001244961:exon8:c.G509A:p.R170H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6911 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A2A2Y4 |
| dbNSFP Uniprot ID | FRMD3_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 8.1e-05 |
| ESP Eur/Amr MAF | 0.00012 |
| ExAC AF | 4.083e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature (less common)
HEAD AND NECK:
[Eyes];
Cherry-red maculae (less common)
RESPIRATORY:
[Lung];
Dyspnea;
Frequent respiratory infections;
Decreased pulmonary diffusion secondary to alveolar infiltration;
Diffuse reticular or finely nodular infiltrations
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
NEUROLOGIC:
[Central nervous system];
Absence of neurologic manifestations
HEMATOLOGY:
Large vacuolated foam cells ('NP cells') on bone marrow biopsy;
'Sea blue' histiocytes;
Decreased platelets
LABORATORY ABNORMALITIES:
Decreased acid sphingomyelinase activity;
Multiple visceral organs (lung, liver, spleen, kidney) contain foamy
resident cells and histiocytes;
Electron microscopy of foam cells shows lamellar inclusions;
Increased LDL cholesterol;
Increased triglycerides;
Decreased HDL cholesterol
MISCELLANEOUS:
Onset in infancy or childhood;
Variable phenotype;
More common in Ashkenazi Jews;
Allelic disorder to Niemann-Pick disease type A (257200)
MOLECULAR BASIS:
Caused by mutations in the acid lysosomal sphingomyelin phosphodiesterase-1
gene (SMPD1, 607608.0002)
OMIM Title
*607619 FERM DOMAIN-CONTAINING PROTEIN 3; FRMD3
;;NONERYTHROID PROTEIN 4.1, OVARY TYPE;;
PROTEIN 4.1O;;
EPB41LO
OMIM Description
DESCRIPTION
Protein 4.1 of red blood cells, or 4.1R (EPB41; 130500), is a
multifunctional protein essential for maintaining erythrocyte shape and
membrane mechanical properties. The protein 4.1 family comprises a group
of structural proteins that includes, in addition to 4.1R, 4.1G (general
type; 603237), 4.1B (brain type; 605331), 4.1N (neuron type; 602879),
and 4.1O (ovary type).
CLONING
During large-scale sequence analysis of a fetal brain cDNA library, Ni
et al. (2003) cloned a cDNA encoding 4.1O. The 553-amino acid 4.1O
protein shares 38% identity with the 4.1B protein and contains a FERM
domain. PCR analysis of 16 human tissues showed expression of 4.1O only
in ovary. In 8 human fetal tissues, expression could be detected in
skeletal muscle, with lower levels in thymus and brain.
GENE FUNCTION
Haase et al. (2007) found that FRMD3 was expressed in normal human lung
tissue, but it was silenced in 54 of 58 primary nonsmall cell lung
carcinomas. Loss of FRMD3 expression did not correlate with specific
tumor stage, and FRMD3 was not downregulated in other tumor types
examined. FRMD3 overexpression in human epithelial cells reduced
clonogenicity by inducing apoptosis.
GENE STRUCTURE
By genomic sequence analysis, Ni et al. (2003) determined that the 4.1O
gene contains 14 exons.
MAPPING
By genomic sequence analysis, Ni et al. (2003) mapped the 4.1O gene to
chromosome 9q21-q22.
LOC494127
| dbSNP name | rs11141676(C,T); rs111680953(G,C); rs11141677(C,G); rs73654958(G,A); rs12552232(G,C); rs368788501(A,G) |
| cytoBand name | 9q21.33 |
| EntrezGene GeneID | 494127 |
| snpEff Gene Name | RP11-276H19.4 |
| EntrezGene Description | NFYC pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3411 |
LOC392364
| dbSNP name | rs199594257(C,G); rs56723878(T,C); rs7873960(G,A); rs7873972(G,A); rs144493906(G,A); rs7860068(T,C); rs34415878(G,C); rs7874019(A,C) |
| cytoBand name | 9q22.1 |
| EntrezGene GeneID | 392364 |
| snpEff Gene Name | XXyac-YM21GA2.7 |
| EntrezGene Description | nuclear pore associated protein 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| ExAC AF | 0.001339 |
SPATA31C2
| dbSNP name | rs116797903(C,T) |
| cytoBand name | 9q22.1 |
| EntrezGene GeneID | 645961 |
| snpEff Gene Name | FAM75C2 |
| EntrezGene Description | SPATA31 subfamily C, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SPATA31C2:NM_001166137:exon4:c.G444A:p.T148T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.043353 |
| ESP All MAF | 0.014236 |
| ESP Eur/Amr MAF | 0.001571 |
| ExAC AF | 0.005037 |
C9orf47
| dbSNP name | rs73654718(A,G); rs6559331(C,T); rs188446033(T,C); rs79303380(T,A); rs10867149(T,C); rs41304228(C,T); rs12336695(C,G); rs3934594(G,A); rs190054669(G,A); rs7045576(A,G) |
| cytoBand name | 9q22.1 |
| EntrezGene GeneID | 286223 |
| EntrezGene Description | chromosome 9 open reading frame 47 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07117 |
MIR3910-2
| dbSNP name | rs67339585(T,C) |
| cytoBand name | 9q22.31 |
| EntrezGene GeneID | 100500902 |
| snpEff Gene Name | ROR2 |
| EntrezGene Description | microRNA 3910-2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1722 |
| ExAC AF | 0.1 |
LOC100128361
| dbSNP name | rs2148537(G,A); rs10119539(G,A); rs6479426(G,A) |
| ccdsGene name | CCDS6699.1 |
| cytoBand name | 9q22.31 |
| EntrezGene GeneID | 100128361 |
| snpEff Gene Name | CENPP |
| EntrezGene Description | uncharacterized LOC100128361 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3159 |
| ExAC AF | 0.221 |
LINC00092
| dbSNP name | rs112088490(C,G); rs12686457(T,G) |
| cytoBand name | 9q22.32 |
| EntrezGene GeneID | 100188953 |
| snpEff Gene Name | NCRNA00092 |
| EntrezGene Description | long intergenic non-protein coding RNA 92 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | non_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02801 |
HSD17B3
| dbSNP name | rs62557536(C,T); rs2256618(G,C); rs62557537(T,C); rs73543262(G,A); rs6479179(T,A); rs77770507(G,A); rs75139562(T,C); rs4269659(C,T); rs8190566(T,C); rs280662(C,A); rs1927883(G,A); rs1927882(C,G); rs2066485(C,T); rs2476920(T,C); rs140216363(C,T); rs2066486(T,C); rs2066477(G,A); rs913580(T,C); rs373197999(T,C); rs7022826(C,T); rs8190551(C,T); rs2147252(C,G); rs2243595(G,A); rs1807197(T,C); rs7873481(G,T); rs2253502(G,A); rs1810711(T,G); rs116276256(G,A); rs2476921(T,C); rs912461(C,T); rs912462(G,A); rs371119(T,C); rs407179(C,T); rs441402(C,T); rs912463(G,C); rs1886260(A,G); rs8190544(G,A); rs867807(T,C); rs8190541(C,T); rs408876(A,G); rs371906721(G,A); rs114767009(A,G); rs35920604(G,A); rs2066475(C,T); rs2479825(A,G); rs2026001(T,G); rs379734(C,T); rs392312(G,A); rs370438(A,C); rs8190536(C,G); rs8190535(G,C); rs7863067(G,T); rs2479824(C,T); rs8190534(C,G); rs2257157(A,G); rs2476922(G,C); rs4401999(A,G); rs7039978(A,G); rs116133172(G,T); rs2476923(A,G); rs7040523(A,G); rs10125001(G,A); rs10117181(T,C); rs2770143(G,A); rs394243(T,A); rs2479823(G,C); rs166819(A,G); rs73545327(A,C); rs7042971(T,C); rs7043341(T,A); rs10739847(T,A); rs8190531(A,G); rs2479822(C,T); rs280654(A,G); rs181597201(C,G); rs8190530(C,T); rs7037932(G,T); rs280655(C,T); rs183903759(G,A); rs11788785(G,A); rs11791650(T,A); rs280656(C,G); rs7043452(G,C); rs9299363(G,C); rs35427805(G,C); rs11789467(G,A); rs11789867(G,T); rs2479821(T,A); rs999269(G,C); rs12553488(C,T); rs13302476(T,A); rs60854707(T,C); rs13289967(C,T); rs11791540(G,A); rs280657(T,A); rs10733725(T,G); rs2476927(G,A); rs8190527(A,G); rs10820205(G,A); rs2476926(C,T); rs4551481(A,G); rs8190522(C,T); rs2987357(T,C); rs2985281(A,G); rs10820208(G,A); rs280658(G,T); rs1983828(T,G); rs12682944(G,A); rs113942592(C,A); rs145163858(G,A); rs10990201(C,T); rs10990202(T,C); rs189516593(C,T); rs10990203(A,G); rs7852386(A,G); rs4743685(T,G); rs280665(C,T); rs2476925(A,G); rs10990208(T,C); rs10820220(C,T); rs6479221(A,G); rs77868769(C,T); rs9657644(G,A); rs280664(A,C); rs12686518(T,C); rs2181820(G,A); rs2147253(A,G); rs10820228(A,G); rs139148540(G,A); rs2987356(C,A); rs280663(T,C); rs8190513(A,G); rs8190512(C,A); rs2479828(A,G); rs2987360(C,T); rs10990251(G,C); rs10820242(A,T); rs10820243(T,C); rs10820245(C,T); rs59260289(G,A); rs10820247(G,A); rs34051033(G,A); rs7022250(G,C); rs72621420(T,C); rs416699(C,T); rs72621421(C,G); rs10990258(C,T); rs1119864(T,C); rs10990269(C,T); rs74408558(C,T); rs13284535(G,A); rs375944(A,C); rs11788083(A,G); rs375411(C,T); rs114636743(C,T); rs12683472(A,G); rs400851(T,A); rs1225274(G,T); rs58939415(G,A); rs115563361(A,C); rs112824929(G,A); rs8190508(G,A); rs8190505(C,T); rs7029101(T,C); rs3925451(G,A); rs8190498(C,A); rs8190496(A,G); rs8190495(A,G); rs2183009(A,G); rs8190492(C,G); rs61508499(G,A); rs28623339(T,C); rs10820289(A,C); rs77241360(T,C); rs76407913(A,G); rs74639959(T,C); rs8190490(C,T); rs8190489(G,A); rs8190486(G,A); rs2066474(T,C) |
| ccdsGene name | CCDS6716.1 |
| cytoBand name | 9q22.32 |
| EntrezGene GeneID | 3293 |
| EntrezGene Description | hydroxysteroid (17-beta) dehydrogenase 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HSD17B3:NM_000197:exon5:c.C440T:p.P147L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5943 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5U0Q6 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Initial loss of central visual acuity and color vision;
Photophobia and epiphora in day light;
Eventual loss of peripheral vision and night blindness;
Marked macular degeneration;
Mild retinal arteriolar constriction;
Mild temporal optic nerve pallor;
Mild peripheral retinal pigmentary changes
LABORATORY ABNORMALITIES:
Electroretinogram is abnormal--rod responses are mildly abnormal and
cone responses are markedly diminished
OMIM Title
*605573 17-@BETA HYDROXYSTEROID DEHYDROGENASE III; HSD17B3
;;17-@BETA-HSD III;;
ESTRADIOL 17-BETA-DEHYDROGENASE; EDH17B3;;
TESTICULAR 17-@BETA-HYDROXYSTEROID DEHYDROGENASE III
OMIM Description
The enzyme 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD; EC
1.1.1.62) converts androstenedione to testosterone in the fetal testes.
Defects in this conversion lead to a form of male pseudohermaphroditism
with gynecomastia (264300).
CLONING
Geissler et al. (1994) used expression cloning to isolate cDNAs encoding
a microsomal 17-beta-HSD type 3 isozyme that shares 23% sequence
identity with other 17-beta-HSD enzymes, uses NADPH as a cofactor, and
is expressed predominantly in the testes.
GENE STRUCTURE
Geissler et al. (1994) determined that the HSD17B3 gene spans at least
60 kb and consists of 11 exons, ranging in size from more than 264 bp to
as small as 35 bp.
MAPPING
By study of somatic cell hybrids and by fluorescence in situ
hybridization, Geissler et al. (1994) localized the HSD17B3 gene to
9q22.
MOLECULAR GENETICS
In a study of 5 unrelated male pseudohermaphrodites, Geissler et al.
(1994) identified 4 substitution and 2 splice junction mutations in the
HSD17B3 gene. To confirm that the substitution mutations impair enzyme
activity, the lesions were introduced into an expressible cDNA by
site-directed mutagenesis and analyzed by transfection into cultured
mammalian cells. These studies demonstrated that the mutations severely
compromised the activity of the isozyme.
Andersson et al. (1996) stated that the 17-beta-HSD3 mutations
characterized to that time included 10 missense mutations, 3 splice
junction mutations, and 1 small deletion that results in a frameshift.
Three of these mutations occurred in more than 1 family. Complementary
DNAs incorporating 9 of the 10 missense mutations had been constructed
and expressed in reporter cells; 8 of these 9 mutations cause almost
complete loss of enzymatic activity. In 2 subjects with loss of function
due to missense mutations, Andersson et al. (1996) found that
testosterone levels were very low in testicular venous blood. These data
suggested that the common mechanism for testosterone formation in
postpubertal subjects with this disorder is the conversion of
circulating androstenedione to testosterone by one or more of the
unaffected 17-beta-HSD isoenzymes.
At the time of the study of Lindqvist et al. (2001), 19 mutations in the
HSD17B3 gene that impair testosterone biosynthesis and cause male
undermasculinization had been found. Fifteen of these molecular lesions
were missense mutations, 3 were splice junction abnormalities, and 1 was
a frameshift mutation. Lindqvist et al. (2001) detected a novel
cys268-to-tyr substitution mutation in exon 10 of the HSD17B3 gene
(605573.0010) in a subject with 17-beta-hydroxysteroid dehydrogenase 3
deficiency, bringing the total of mutations to 20.
LOC441455
| dbSNP name | rs16911482(T,C); rs55881303(A,C); rs56940826(T,C); rs16911483(G,A); rs7871612(T,C) |
| cytoBand name | 9q22.33 |
| EntrezGene GeneID | 441455 |
| snpEff Gene Name | RP11-535M15.2 |
| EntrezGene Description | makorin ring finger protein 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1143 |
FOXE1
| dbSNP name | rs7046645(T,C); rs1443434(G,T); rs1443435(T,C); rs10984009(G,A) |
| cytoBand name | 9q22.33 |
| EntrezGene GeneID | 2304 |
| EntrezGene Description | forkhead box E1 (thyroid transcription factor 2) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1253 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
Micrognathia;
[Ears];
Stenotic external auditory canal;
[Eyes];
Prominent eyes;
[Nose];
Depressed nasal bridge;
Short, upturned nose;
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Ventricular hypertrophy;
Patent foramen ovale
RESPIRATORY:
Apnea
CHEST:
[External features];
Small chest;
[Ribs, sternum, clavicles, and scapulae];
Elongated clavicles
ABDOMEN:
[Gastrointestinal];
Meckel diverticulum
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
[Spine];
Wafer-thin platyspondyly;
[Pelvis];
Wide sacrosciatic notch;
Hypoplastic pelvis;
Trident configuration of acetabular roof;
[Limbs];
Radial hypoplasia;
Ulnar hypoplasia;
Rhizomelic limb shortening;
Irregular proximal humeral metaphyses;
Gracile long bones;
[Hands];
Transverse palmar creases;
Prominent palmar flexion creases;
Brachydactyly;
Ulnar deviation of the hands
SKIN, NAILS, HAIR:
[Skin];
Transverse palmar creases;
Prominent palmar flexion creases;
Cutis marmorata;
[Hair];
Fragile scalp hair;
Sparse hair
NEUROLOGIC:
[Central nervous system];
Progressive CNS degeneration;
Seizure;
Progressive ventriculomegaly;
Small cerebellum;
Brain atrophy;
Encephalomyelopathy;
Thin corpus callosum;
Diffuse, severe neuronal loss;
Gliosis;
Generalized myelin loss
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios
MISCELLANEOUS:
Death in early infancy
OMIM Title
*602617 FORKHEAD BOX E1; FOXE1
;;FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 15; FKHL15;;
THYROID TRANSCRIPTION FACTOR 2; TTF2;;
TITF2
OMIM Description
DESCRIPTION
FOXE1 belongs to a large family of forkhead box (FOX) transcription
factors with a conserved winged-helix DNA-binding domain (Venza et al.,
2011).
CLONING
The 'forkhead' gene family, originally identified in Drosophila, encodes
transcription factors with a conserved 100-amino acid DNA-binding motif
called the 'forkhead domain'. Chadwick et al. (1997) isolated FKHL15
cDNAs from a cDNA library enriched for transcripts from 9q22. The
predicted 376-amino acid FKHL15 protein contains a 19-residue
polyalanine tract and 2 putative nuclear localization signals which
flank the forkhead domain. Northern blot analysis detected a single
4.5-kb FKHL15 mRNA in a variety of tissues and multiple FKHL15
transcripts in others.
Clifton-Bligh et al. (1998) found by a database search against the rat
TTF2 gene more than 90% homology with FKHL15. A probe specific to the
3-prime UTR of FKHL15 detected a 5.3-kb transcript that was highly
expressed in thyroid tissues, and a second 3.2-kb transcript seen in
both thyroid and testis.
GENE STRUCTURE
Clifton-Bligh et al. (1998) found that the FKHL15 gene consists of a
single exon.
MAPPING
Chadwick et al. (1997) localized the FKHL15 gene to 9q22 by somatic cell
hybrid analysis and by its inclusion in cosmids that map to that region.
GENE FUNCTION
Thyroid gland organogenesis involves the dorso-caudal migration of a
median endodermal bud that originates from the posterior region of the
pharyngeal floor. The thyroid primordium migrates to the area located
between the fourth pharyngeal pouches and eventually fuses with them.
The adult thyroid gland is composed of cells derived from all 3 germ
layers, but thyroid follicular cells (TFCs), which are responsible for
thyroid hormone biosynthesis, appear to derive primarily from the median
primordium, though a contribution from the endoderm of the pharyngeal
pouches has also been proposed (Manley and Capecchi, 1998). Functional
differentiation, as shown by the expression of thyroglobulin, occurs in
TFCs following migration, suggesting that migration and functional
differentiation may be mutually exclusive. Three transcription factors,
TTF1 (NKX2-1; 600635), TTF2, and PAX8 (167415), are present from the
start of thyroid morphogenesis. TTF2, which is also expressed in most of
the foregut endoderm, in the craniopharyngeal ectoderm involved in
palate formation and in the Rathke pouch, is transiently expressed at
these sites from embryonic day (E) 8-8.5 to E13.5. The mRNA encoding
TTF2 is downregulated in TFC precursors following their migration and
just before their differentiation (summary by De Felice et al., 1998).
De Felice et al. (1998) reported that Zannini et al. (1997) suggested
that TTF2 is involved either in promoting the migration process or in
repressing differentiation of the TFCs until migration has occurred.
Thus, De Felice et al. (1998) predicted that the absence of TTF2 would
result in alteration of thyroid primordium migration and/or precocious
functional differentiation.
Brancaccio et al. (2004) reported that Foxe1 was specifically expressed
in the lower undifferentiated compartment of hair follicles in mouse
skin, at a time and site that parallel activation of the Shh (600725)
signaling pathway. Foxe1 protein was also expressed in human and mouse
basal cell carcinoma in which hedgehog signaling is constitutively
activated, whereas it was undetectable in normal epidermis and squamous
cell carcinoma. Expression of a dominant-negative form of Gli2 (165230)
in mouse skin resulted in complete suppression of Foxe1 expression in
hair follicles, whereas transcriptionally active Gli2 stimulated
activity of the Foxe1 promoter. Foxe1-null skin that was grafted to
immunodeficient mice displayed thin and curly pelage hairs, as well as
disoriented, misaligned, and aberrantly shaped hair follicles.
Brancaccio et al. (2004) concluded that the defect in Bamforth-Lazarus
syndrome is due to altered FOXE1 function in the hair follicle and is
independent of systemic defects present in affected individuals. They
further hypothesized that Foxe1 is a downstream target of the Shh/Gli
pathway in hair follicle morphogenesis and plays a crucial role in
correct hair follicle orientation into the dermis and subcutis.
To gain insight into human thyroid development and thyroid
dysgenesis-associated malformations, Trueba et al. (2005) studied the
expression patterns of the PAX8, TITF1, and FOXE1 genes during human
development. PAX8 and TITF1 were first expressed in the median thyroid
primordium. Interestingly, PAX8 was also expressed in the thyroglossal
duct and the ultimobranchial bodies. Human FOXE1 expression was detected
later than in the mouse. PAX8 was also expressed in the developing
central nervous system and kidney, including the ureteric bud and the
main collecting ducts. TITF1 was expressed in the ventral forebrain and
lung. FOXE1 expression was detected in the oropharyngeal epithelium and
thymus. The expression patterns of these genes in human show some
differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are
expressed in the mouse thyroid bud as soon as it differentiates on the
pharyngeal floor. The authors concluded that the expression patterns of
these 3 genes correlate well with the phenotypes observed in patients
carrying mutations of the corresponding gene.
Venza et al. (2011) identified human MSX1 (142983) and TGFB3 (190230),
which are required for proper palate formation, as direct FOXE1 target
genes. Wildtype FOXE1, but not FOXE1 with forkhead domain mutations,
directly bound FOXE1-binding motifs in the MSX1 and TGFB3 promoters and
drove expression of MSX1 and TGFB3 reporter genes.
MOLECULAR GENETICS
- Hypothyroidism, Athyroidal, with Spiky Hair and Cleft Palate
Clifton-Bligh et al. (1998) demonstrated that the FKHL15 gene, which is
the human homolog of the mouse Titf2 gene, was homozygously mutated
(A65V; 602617.0001) in 2 sibs with thyroid agenesis, cleft palate, and
choanal atresia, previously reported by Bamforth et al. (1989); see
Bamforth-Lazarus syndrome (241850). Spiky or curly hair was also a
feature, as was bifid epiglottis. Polyhydramnios, which was present in
the 2 pregnancies of the brothers and in another reported case of
Bamforth-Lazarus syndrome, may have been caused by the choanal atresia.
In 2 brothers with congenital hypothyroidism, athyreosis, and cleft
palate, Castanet et al. (2002) identified homozygosity for a missense
mutation in the FOXE1 gene (S57N; 602617.0002). The authors noted that
these patients had an incomplete clinical phenotype, lacking choanal
atresia and bifid epiglottis.
In a girl with Bamforth-Lazarus syndrome, Baris et al. (2006) identified
homozygosity for a missense mutation (R102C; 602617.0003) in the FOXE1
gene. The patient had congenital hypothyroidism, bilateral choanal
atresia, cleft palate, and spiky hair, but was not athyreotic.
Using transfected 293 EBNA cells, Venza et al. (2011) showed that
missense mutations within the FOXE1 forkhead domain associated with
Bamforth-Lazarus syndrome, including A65V, S57N, and R102C, reduced or
eliminated FOXE1-dependent upregulation of MSX1 (142983) and TGF-beta-3
(TGFB3; 190230), both of which are required for proper palate formation.
In contrast, reducing the length of the FOXE1 polyalanine stretch to
between 11 and 14 residues had no effect on its transcriptional
activity. FOXE1 with forkhead domain mutations failed to bind FOXE1
motifs in the MSX1 and TGFB3 promoters.
- Thyroid Dysgenesis
Carre et al. (2007) analyzed FOXE1 alanine tract length in 115 patients
with thyroid dysgenesis (see CHNG1, 275200) and 129 controls. They found
that 16/16 and 16/14 genotypes were inversely associated with thyroid
dysgenesis (OR, 0.39; p = 0.0005), suggesting that FOXE1 with 16
alanines protects against occurrence of thyroid dysgenesis; the
protective effect was confirmed by transmission disequilibrium analysis
in 39 parent-proband trios. Conversely, the 14/14 genotype was
associated with an increased risk of thyroid dysgenesis (OR, 2.59; p =
0.0005). Expression studies showed that transcription activity of FOXE1
with 16 alanines was 1.55-fold higher than FOXE1 with 14 alanines (p
less than 0.003); nuclear localization of FOXE1 was not affected. Carre
et al. (2007) suggested that FOXE1 alanine tract length modulates
genetic susceptibility to thyroid dysgenesis.
- Nonsyndromic Orofacial Clefting
Nonsyndromic orofacial clefts are a common complex birth defect caused
by genetic and environmental factors and/or their interactions. In a
cohort of cleft lip and palate (CL/P; see 119530) families from
Colombia, United States, and the Philippines, Moreno et al. (2009)
tested 397 SNPs spanning 9q22-q33 for association. Significant SNP and
haplotype association signals narrowed the interval to a 200-kb region
containing FOXE1, C9ORF156, and HEMGN (610715). Association results were
replicated in CL/P families of European descent; when all populations
were combined, the 2 most associated SNPs, dbSNP rs3758249 (P =
5.01E-13) and dbSNP rs4460498 (P = 6.51E-12), were located inside a
70-kb high linkage disequilibrium block containing FOXE1. Association
signals for Caucasians and Asians clustered 5-prime and 3-prime of
FOXE1, respectively. Isolated cleft palate (CP) was also associated,
indicating that FOXE1 may play a role in 2 phenotypes thought to be
genetically distinct. Foxe1 expression was found in the epithelium
undergoing fusion between the medial nasal and maxillary processes.
Mutation screens of FOXE1 identified 2 family-specific missense
mutations (ile59 to ser and pro208 to arg) at highly conserved amino
acids. Although predicted to be benign by a computer program, both
mutations are near previously identified deleterious mutations. The
authors concluded that FOXE1 may be a major gene for CL/P and CP.
- Association with Thyroid Cancer
For a discussion of a possible association between variation in the
FOXE1 gene and thyroid cancer, see 188550 and 188470.
ANIMAL MODEL
Many members of the forkhead/winged-helix transcription factor family
are key regulators of embryogenesis (summary by Kaufmann and Knochel,
1996). Thyroid transcription factor-2 (TTF2), a forkhead
domain-containing transcription factor, was cloned by Zannini et al.
(1997) and the mouse gene, designated Titf2, was mapped to chromosome 4.
De Felice et al. (1998) showed that Titf2-null mutant mice exhibit cleft
palate and either a sublingual or completely absent thyroid gland. Thus,
the Titf2-/- mutation results in neonatal hypothyroidism that showed
similarity to thyroid dysgenesis in humans. Among the 1 in 3,000 or
4,000 newborns in which congenital hypothyroidism is detected, 80% have
either an ectopic, small and sublingual thyroid, or have no thyroid
tissue (Toublanc, 1992). Most of these cases appear sporadically,
although a few cases of recurring familial thyroid dysgenesis (218700)
have been reported.
Venza et al. (2011) found that 14-day Foxe1 -/- mouse embryos nearly
lacked Msx1 and Tgfb3 expression in maxillary molar dental mesenchyme
and in epithelial cells of the anterior palate shelves, respectively,
compared with Foxe1 +/- embryos.
HISTORY
By screening a human fetal brain cDNA library with the forkhead domain
of rat HNF3A (602294) as probe, Wiese et al. (1997) identified what they
considered to be a novel member of the forkhead family of transcription
factors, which they called HFKL5 and was later designated FOXE2 by the
HUGO gene nomenclature committee. As described by Wiese et al. (1997),
the full-length cDNA encodes a deduced 500-amino acid protein with a
calculated molecular mass of approximately 55 kD. The protein shows
little homology in the forkhead domain with other members of the
forkhead family. Northern blot analysis detected a 4.4-kb transcript in
all fetal and adult tissues tested. In situ hybridization studies
detected expression in differentiated fetal and adult neurons but not in
undifferentiated neurons, such as those in the periventricular matrix.
Expression was also detected in neuron-derived cells in various tissues,
such as the parasympathetic ganglia of the intestine, and in a subset of
hepatocytes, lymphatic tissue cells, and kidney tubule cells. Although
Wiese et al. (1997) stated that the HFKL5 gene maps to chromosome 22,
Scott (2007) found that this mapping is not supported by the human
genome build 36.2.
COL15A1
| dbSNP name | rs1078205(C,G); rs1078206(T,G); rs911933(T,C); rs10819482(T,G); rs111543628(C,T); rs201056991(C,A); rs6478963(T,C); rs77652650(A,C); rs17710872(G,A); rs72737261(C,T); rs56119010(A,G); rs56227821(C,G); rs55677290(C,A); rs138661945(G,C); rs1333869(A,C); rs1333868(G,T); rs10120729(C,G); rs60433680(C,T); rs10988309(A,T); rs79221879(T,C); rs10116067(G,T); rs10114037(T,C); rs35082704(C,T); rs79094933(C,T); rs113936374(G,T); rs1333867(C,T); rs10760609(A,T); rs113415154(G,A); rs181273510(A,C); rs16918099(G,A); rs111882192(T,A); rs151204765(A,G); rs1855403(T,C); rs7045433(G,C); rs1855402(T,C); rs7038384(T,G); rs12341026(G,T); rs7874124(T,G); rs4743296(A,T); rs4743297(T,C); rs10988363(T,C); rs141150591(T,G); rs7032628(C,A); rs10118108(A,C); rs10819515(C,T); rs75720522(G,A); rs10819518(C,T); rs10988375(G,C); rs12237478(G,A); rs62561170(C,T); rs35994439(A,G); rs1889266(C,G); rs10512261(A,G); rs4743298(T,G); rs74332247(A,G); rs1413294(A,G); rs4407948(A,C); rs10120744(A,C); rs4742750(G,A); rs12005047(G,A); rs368515044(C,T); rs10819525(T,C); rs16918101(G,T); rs56933597(G,A); rs2050257(G,A); rs78014779(G,A); rs10988397(G,A); rs2416663(T,A); rs1889265(C,A); rs78895325(G,A); rs2151616(G,A); rs4743299(A,T); rs4743300(A,T); rs13300426(C,T); rs112759770(T,C); rs882728(A,G); rs188097933(T,A); rs882221(G,A); rs35706367(T,C); rs113293016(C,T); rs60355315(A,T); rs10819530(G,A); rs181491520(A,G); rs112501138(T,C); rs57336359(A,G); rs115290648(G,A); rs1473791(T,C); rs55870060(T,C); rs10819537(C,T); rs59544707(T,C); rs10819542(A,G); rs10988442(A,G); rs56150005(T,G); rs74998792(C,T); rs56997979(G,A); rs1572136(G,C); rs62561174(C,A); rs10988451(G,A); rs7027650(A,T); rs4743301(C,T); rs74824201(C,G); rs76181340(G,A); rs4743302(T,C); rs989392(G,A); rs989393(T,C); rs75008886(G,A); rs77710222(G,A); rs78523793(G,C); rs12005080(T,G); rs16918106(A,G); rs4743303(G,A); rs77736485(G,A); rs2075662(G,A); rs2075663(A,G); rs78492181(C,T); rs2075664(C,A); rs16918110(A,C); rs2075665(A,T); rs7023395(G,A); rs16918113(C,A); rs3780624(C,T); rs3780623(C,A); rs7859159(G,A); rs1543709(C,T); rs144070115(C,T); rs1543710(A,G); rs1023249(G,A); rs7035837(G,A); rs7021675(A,G); rs12554684(C,T); rs77302694(C,G); rs10988485(A,G); rs10988495(A,G); rs4327910(G,A); rs57803670(T,G); rs10988510(A,G); rs74337034(G,A); rs4743305(T,C); rs10988521(C,G); rs16918124(T,C); rs1413299(G,T); rs7867960(T,C); rs60048592(T,A); rs57410362(C,T); rs59112541(A,G); rs55773358(G,A); rs10819566(T,C); rs55687154(A,C); rs3780622(A,G); rs4743307(G,A); rs76753217(G,A); rs12378396(T,C); rs10988530(C,A); rs61462449(G,A); rs80173563(G,A); rs79820256(T,A); rs34138827(G,A); rs16918128(G,A); rs41305481(A,G); rs60062000(G,A); rs1889268(T,C); rs12380469(G,A); rs12377855(C,T); rs73503719(A,G); rs914993(C,A); rs2900148(A,G); rs112606431(A,G); rs73503720(G,A); rs7022881(A,T); rs11515534(C,G); rs11515536(C,T); rs75743382(G,A); rs12379014(T,C); rs73503727(G,A); rs7045794(G,A); rs55803862(T,G); rs60327679(A,G); rs79408118(T,G); rs73503730(T,A); rs77532138(G,A); rs78118674(G,A); rs7034847(T,C); rs6478966(G,A); rs73503733(T,C); rs7035399(T,C); rs7032060(A,T); rs7862968(A,G); rs76794723(G,T); rs874165(T,A); rs73503738(C,T); rs73655904(C,T); rs35250850(A,C); rs75709350(G,A); rs113347191(C,G); rs143128692(T,C); rs4743308(G,A); rs79782990(G,T); rs76096691(A,T); rs4743309(C,T); rs73503740(C,G); rs60021618(C,T); rs1041631(G,A); rs370687875(A,T); rs12335383(A,G); rs2274962(A,C); rs73503741(G,A); rs73503742(C,T); rs114594862(G,A); rs55810239(G,C); rs59877189(C,T); rs7043134(A,G); rs61478524(A,G); rs7046498(T,A); rs60878369(G,C); rs3739799(C,T); rs73503744(A,G); rs73503746(C,T); rs73503747(G,A); rs73503749(T,C); rs7848837(T,G); rs7861925(G,T); rs7851787(T,C); rs113131207(C,T); rs112955797(C,T); rs7028686(T,G); rs75962841(G,C); rs149281467(T,A); rs2297602(T,C); rs181480366(C,T); rs78858333(A,G); rs58180460(G,A); rs7022519(C,T); rs4743311(A,G); rs4742755(A,G); rs77593019(T,C); rs78829514(T,C); rs77152751(C,T); rs10988595(C,A); rs4743312(G,A); rs12684946(G,A); rs16918141(C,T); rs4743314(C,T); rs35820760(C,T); rs12684344(A,C); rs114581725(C,G); rs6478968(G,A); rs78733590(T,G); rs976240(G,A); rs976241(A,C); rs41308900(C,T); rs2075666(T,C); rs34154744(C,A); rs116990167(G,A); rs3780621(A,G); rs3780620(T,C); rs17711860(A,G); rs148714845(A,G); rs7874925(C,G); rs10988640(G,T); rs72737288(G,A); rs58805629(T,C); rs71501887(G,A); rs79977830(C,A); rs77348904(A,T); rs111610503(G,C); rs7854112(T,C); rs7851079(A,G); rs73503762(C,T); rs57927784(C,T); rs114302978(C,G); rs75226293(A,G); rs35413276(G,A); rs10512262(G,A); rs34749011(T,C); rs10988660(T,C); rs16918148(T,C); rs949802(G,A); rs114197824(C,T); rs16918154(T,C); rs34654420(C,T); rs77060722(C,T); rs60891605(A,T); rs928522(C,T); rs13302368(G,A); rs76420373(T,C); rs115980523(C,T); rs7855612(G,A); rs7874819(T,C); rs869776(T,C); rs117599390(A,G); rs10988690(G,C); rs7036916(G,C); rs7026229(A,G); rs113454924(G,A); rs13296166(G,A); rs79823899(C,G); rs74572497(A,G); rs12683611(G,A); rs113177990(G,A); rs12216916(C,T); rs16918163(A,G); rs4142986(C,G); rs7019613(T,C); rs79446785(G,A); rs16918167(G,T); rs12000479(A,C); rs2067986(C,T); rs3780617(T,C); rs3824511(C,T); rs10988691(G,A); rs16918174(A,C); rs35642150(A,G); rs79175563(A,G); rs77903571(T,A); rs11788317(T,C); rs11789689(G,A); rs13291453(T,G); rs6478969(G,T); rs7038068(A,G); rs12001981(G,A); rs11789439(T,G); rs34382379(A,T); rs112203357(C,A); rs4563947(G,A); rs1537506(C,T); rs4631520(G,A); rs1537505(A,C); rs112053546(A,C); rs7857774(G,A); rs7030799(G,A); rs1413298(A,G); rs77896999(T,A); rs75738969(C,T); rs73503789(C,G); rs78290795(C,G); rs114803848(G,T); rs143175172(G,T); rs150006088(G,A); rs16918198(G,A); rs1537504(G,A); rs4742756(G,A); rs115872058(A,C); rs4742758(G,A); rs4742759(A,G); rs115926721(A,G); rs112298774(A,G); rs34863444(G,A); rs10519(G,A); rs368606814(G,A); rs1051105(G,A) |
| ccdsGene name | CCDS35081.1 |
| cytoBand name | 9q22.33 |
| EntrezGene GeneID | 1306 |
| EntrezGene Description | collagen, type XV, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL15A1:NM_001855:exon18:c.C2114T:p.P705L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9047 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00824175824176 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0184696569921 |
| dbSNP GMAF | 0.008264 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.01507 |
| ESP Eur/Amr MAF | 0.021047 |
| ExAC AF | 0.016 |
OMIM Clinical Significance
Eyes:
Agenesis of macula;
Coloboma of macula
Inheritance:
Autosomal dominant
OMIM Title
*120325 COLLAGEN, TYPE XV, ALPHA-1; COL15A1
OMIM Description
CLONING
Myers et al. (1992) isolated a 2.1-kb cDNA clone containing a derived
gly-X-Y sequence very different from those of collagen types I through
XIV. The protein partially encoded by this clone was named the alpha-1
chain of type XV collagen. Kivirikko et al. (1994) and Muragaki et al.
(1994) obtained additional cDNA sequences and deduced the complete
primary structure of the polypeptide. The former group also partially
characterized the gene structure, while the latter noted strong amino
acid sequence similarity to mouse alpha-1(XVIII) collagen (COL18A1;
120328). The presence of a predicted signal peptide suggests that the
protein is secreted into the extracellular matrix. Muragaki et al.
(1994) also presented evidence for predominant expression in embryonic
internal organs such as the adrenal glands, kidney, and pancreas. Types
XV and XVIII collagen form a distinct subgroup among the collagens
(Muragaki et al., 1994; Rehn et al., 1994). Type XVIII collagen
(COL18A1; 120328) is the precursor of endostatin, which has a potent
antiangiogenic effect. The highest degree of homology between collagens
type XV and type XVIII involves the C-terminal endostatin sequence. The
corresponding fragment in type XV collagen has also been shown to have
antiangiogenic activity (Ramchandran et al., 1999; Sasaki et al., 2000).
Myers et al. (1996) stated that the collagen family of proteins consists
of 19 types encoded by 33 genes. Type XV collagen has a 577-amino acid,
highly interrupted, triple-helical region that is flanked by N- and
C-terminal noncollagenous domains of 555 and 256 residues, respectively.
Hagg et al. (1998) reported that the COL15A1 protein contains 1,388
amino acids.
GENE FUNCTION
Myers et al. (1996) produced a bacteria-expressed recombinant protein
representing the first half of the type XV collagen C-terminal domain in
order to generate highly specific polyclonal antisera. Northern blot
hybridization to human tissue RNAs indicated that type XV has a
widespread distribution. To determine the precise localization of type
XV collagen, immunohistochemical analyses were performed. A surprisingly
restricted and uniform presence was demonstrated in many tissues which
showed a strong association with vascular, neuronal, mesenchymal, and
some epithelial basement membrane zones. Myers et al. (1996) suggested
that type XV collagen may function in some manner to adhere basement
membrane to the underlying connective tissue stroma.
Using an antibody produced against the C-terminal noncollagenous domain
of human type XV collagen, Hagg et al. (1997) found conspicuous staining
of most capillaries and the staining of the basement membrane zones of
muscle cells. Differences in the expression of type XV collagen could be
observed during kidney development, and staining of fetal lung tissue
suggested that changes in its expression may also occur during the
formation of vascular structures. Pronounced renal interstitial type XV
collagen staining was observed in patients with kidney fibrosis
occurring as part of different pathologic processes. They suggested that
the accumulation of type XV collagen may accompany fibrotic processes.
To understand the biologic role of type XV collagen, Eklund et al.
(2001) introduced a null mutation in the Col15a1 gene into the germline
of mice. Despite the complete lack of type XV collagen, the mutant mice
developed and reproduced normally, and they were indistinguishable from
their wildtype littermates. However, Col15a1-deficient mice showed
progressive histologic changes characteristic for muscular disease after
3 months of age, and they were more vulnerable than controls to
exercise-induced muscle injury. Despite the antiangiogenic role of type
XV collagen-derived endostatin, the development of the vasculature
appeared normal in the null mice. Nevertheless, ultrastructural analyses
revealed collapsed capillaries and endothelial cell degeneration in
heart and skeletal muscle. Furthermore, perfused hearts showed a
diminished inotropic response, and exercise resulted in cardiac injury,
changes that mimic early or mild heart disease. Thus, type XV collagen
appears to function as a structural component needed to stabilize
skeletal muscle cells and microvessels.
Using normal human aortic smooth muscle cells (SMCs) in culture,
Connelly et al. (2013) identified 13 SmaI sites (CCCGGG) in the COL15A1
gene that lost methylation with replicative age. These sites clustered
in a region upstream of the transcription start site and at the 3-prime
end of the gene, within introns 30 and 31 and exon 35. Quantitative
real-time PCR of SMCs from a different source confirmed hypomethylation
at 2 of these sites with age in culture, concomitant with elevated
COL15A1 mRNA and protein. Knockdown of COL15A1 via small interfering RNA
reduced SMC proliferation and increased migration. In a mouse model of
diet-induced atherosclerosis, expression of Col15a1 was increased in
thoracic aorta, and a similar trend was found in human aorta.
GENE STRUCTURE
By genomic sequence analysis, Hagg et al. (1998) determined that the
COL15A1 gene has 42 coding exons spanning 145 kb. The promoter region
lacks a TATAA motif, has multiple apparently functional Sp1
(189906)-binding sites, and has several GC motifs similar to the
promoters of housekeeping genes. Comparative analysis between COL15A1
and mouse Col18a1 (120328) suggested that the 2 genes are derived from a
common ancestor.
MAPPING
By studying DNAs from rodent-human hybrid cells and by in situ
hybridization, Huebner et al. (1992) assigned the gene to 9q21-q22, a
region to which no other collagen genes had previously been assigned.
Huebner et al. (1992) stated that this was the twenty-first collagen
gene to be localized and that chromosome 9 was the twelfth of the human
chromosomes found to contain at least one member of this unusual gene
family. Hagg et al. (1997) cloned the mouse gene and mapped it to mouse
chromosome 4 in a region of conserved synteny with human chromosome
9q21-q22.
ANIMAL MODEL
Using light and electron microscopy, Rasi et al. (2010) found that
deletion of Col15a1 in mice resulted in disorganized fibrillar collagen
bundles in heart, with interstitial deposition of nonfibrillar protein
aggregates, abnormal capillary morphology, extravasated erythrocytes,
and ischemic damage in some cardiomyocytes. These changes correlated
with measurable microvascular and cardiac dysfunction and increased
myocardial stiffness. Echocardiograms indicated that the early changes
in cardiac performance and geometry in Col15a1 -/- mice varied with age
and showed some reversal with age.
LOC101928523
| dbSNP name | rs28856089(A,G) |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 101928523 |
| EntrezGene Description | uncharacterized LOC101928523 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1208 |
OR13F1
| dbSNP name | rs7049042(T,C); rs61748307(C,T); rs140274463(C,T); rs1949755(C,G); rs1403812(A,G); rs1403811(G,A); rs7030820(C,T); rs7847413(T,C) |
| ccdsGene name | CCDS35087.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 138805 |
| EntrezGene Description | olfactory receptor, family 13, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13F1:NM_001004485:exon1:c.T53C:p.F18S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS4 |
| dbNSFP Uniprot ID | O13F1_HUMAN |
| dbNSFP KGp1 AF | 0.782509157509 |
| dbNSFP KGp1 Afr AF | 0.886178861789 |
| dbNSFP KGp1 Amr AF | 0.734806629834 |
| dbNSFP KGp1 Asn AF | 0.772727272727 |
| dbNSFP KGp1 Eur AF | 0.745382585752 |
| dbSNP GMAF | 0.2181 |
| ESP Afr MAF | 0.13754 |
| ESP All MAF | 0.228433 |
| ESP Eur/Amr MAF | 0.275 |
| ExAC AF | 0.741 |
OR13C3
| dbSNP name | rs41312212(C,T); rs114632436(T,C); rs147753348(G,T); rs41305445(C,T); rs138480673(G,C); rs41304943(C,A) |
| ccdsGene name | CCDS35089.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 138803 |
| EntrezGene Description | olfactory receptor, family 13, subfamily C, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13C3:NM_001001961:exon1:c.G810A:p.T270T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0652 |
| ESP Afr MAF | 0.031094 |
| ESP All MAF | 0.027295 |
| ESP Eur/Amr MAF | 0.025349 |
| ExAC AF | 0.039 |
OR13C8
| dbSNP name | rs7026705(C,A); rs199669265(T,C) |
| ccdsGene name | CCDS35090.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 138802 |
| EntrezGene Description | olfactory receptor, family 13, subfamily C, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13C8:NM_001004483:exon1:c.C56A:p.A19D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS7 |
| dbNSFP Uniprot ID | O13C8_HUMAN |
| dbNSFP KGp1 AF | 0.641025641026 |
| dbNSFP KGp1 Afr AF | 0.644308943089 |
| dbNSFP KGp1 Amr AF | 0.569060773481 |
| dbNSFP KGp1 Asn AF | 0.947552447552 |
| dbNSFP KGp1 Eur AF | 0.441952506596 |
| dbSNP GMAF | 0.3586 |
| ESP Afr MAF | 0.379483 |
| ESP All MAF | 0.489928 |
| ESP Eur/Amr MAF | 0.423023 |
| ExAC AF | 0.525 |
OR13C5
| dbSNP name | rs1851725(A,G); rs1523678(T,C); rs7852858(G,A); rs1851724(A,G); rs75216399(G,A); rs73508187(C,G); rs6479259(T,C); rs4117966(C,T); rs1851723(T,C) |
| ccdsGene name | CCDS35091.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 138799 |
| EntrezGene Description | olfactory receptor, family 13, subfamily C, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13C5:NM_001004482:exon1:c.T869C:p.M290T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS8 |
| dbNSFP Uniprot ID | O13C5_HUMAN |
| dbNSFP KGp1 AF | 0.384157509158 |
| dbNSFP KGp1 Afr AF | 0.603658536585 |
| dbNSFP KGp1 Amr AF | 0.220994475138 |
| dbNSFP KGp1 Asn AF | 0.576923076923 |
| dbNSFP KGp1 Eur AF | 0.174142480211 |
| dbSNP GMAF | 0.3834 |
| ESP Afr MAF | 0.415116 |
| ESP All MAF | 0.326465 |
| ESP Eur/Amr MAF | 0.19407 |
| ExAC AF | 0.287 |
OR13C2
| dbSNP name | rs10156474(T,C); rs55706329(C,T) |
| ccdsGene name | CCDS35092.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 392376 |
| EntrezGene Description | olfactory receptor, family 13, subfamily C, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13C2:NM_001004481:exon1:c.A901G:p.K301E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS9 |
| dbNSFP Uniprot ID | O13C2_HUMAN |
| dbNSFP KGp1 AF | 0.378205128205 |
| dbNSFP KGp1 Afr AF | 0.577235772358 |
| dbNSFP KGp1 Amr AF | 0.218232044199 |
| dbNSFP KGp1 Asn AF | 0.578671328671 |
| dbNSFP KGp1 Eur AF | 0.174142480211 |
| dbSNP GMAF | 0.3774 |
| ESP Afr MAF | 0.430259 |
| ESP All MAF | 0.321181 |
| ESP Eur/Amr MAF | 0.193953 |
| ExAC AF | 0.286 |
OR13C9
| dbSNP name | rs10761054(G,T); rs77624771(G,A); rs993658(T,A); rs36091517(T,G); rs2900373(C,A) |
| ccdsGene name | CCDS35093.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 286362 |
| EntrezGene Description | olfactory receptor, family 13, subfamily C, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13C9:NM_001001956:exon1:c.C591A:p.F197L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGT0 |
| dbNSFP Uniprot ID | O13C9_HUMAN |
| dbNSFP KGp1 AF | 0.263278388278 |
| dbNSFP KGp1 Afr AF | 0.0589430894309 |
| dbNSFP KGp1 Amr AF | 0.345303867403 |
| dbNSFP KGp1 Asn AF | 0.384615384615 |
| dbNSFP KGp1 Eur AF | 0.265171503958 |
| dbSNP GMAF | 0.264 |
| ESP Afr MAF | 0.105538 |
| ESP All MAF | 0.187759 |
| ESP Eur/Amr MAF | 0.229884 |
| ExAC AF | 0.244 |
OR13D1
| dbSNP name | rs12347076(C,T); rs10820709(A,C); rs61742675(C,T); rs10761073(C,T); rs12338899(G,A) |
| ccdsGene name | CCDS35094.1 |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 286365 |
| EntrezGene Description | olfactory receptor, family 13, subfamily D, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13D1:NM_001004484:exon1:c.C231T:p.L77L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2672 |
| ESP Afr MAF | 0.179074 |
| ESP All MAF | 0.200907 |
| ESP Eur/Amr MAF | 0.212093 |
| ExAC AF | 0.238 |
LOC286367
| dbSNP name | rs2515606(A,G); rs10117535(C,T); rs57365304(C,A); rs2472473(G,A); rs78492621(A,G); rs75510317(A,G); rs79900774(T,C); rs2482430(T,C) |
| cytoBand name | 9q31.1 |
| EntrezGene GeneID | 286367 |
| snpEff Gene Name | NIPSNAP3B |
| EntrezGene Description | FP944 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.264 |
TAL2
| dbSNP name | rs45563635(C,T); rs7027450(A,G) |
| cytoBand name | 9q31.2 |
| EntrezGene GeneID | 6887 |
| EntrezGene Description | T-cell acute lymphocytic leukemia 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2181 |
OMIM Clinical Significance
Limbs:
Tarsal bone fusion;
No carpal fusion
Inheritance:
Autosomal dominant
OMIM Title
*186855 T-CELL ACUTE LYMPHOCYTIC LEUKEMIA 2; TAL2
OMIM Description
CLONING
Tumor-specific alteration of the TAL1 gene (187040) occurs in almost 25%
of patients with T-cell acute lymphoblastic leukemia (T-ALL). The TAL1
gene product is a helix-loop-helix (HLH) protein which shares 87% amino
acid sequence identity with LYL1 (151440), another HLH protein involved
in T-cell leukemogenesis. Xia et al. (1991) identified a distinct gene,
called TAL2, on the basis of its sequence homology with TAL1. They
demonstrated that TAL2 is located 33 kb from the chromosome 9 breakpoint
of t(7;9)(q34;q32), a recurring translocation specifically associated
with T-ALL. The translocation juxtaposes TAL2 with sequences from the
T-cell receptor beta-chain gene (TCRB; see 186930) on chromosome 7. The
TAL2 gene product includes an HLH protein dimerization domain and a
DNA-binding domain that are homologous to those encoded by the TAL1 and
LYL1 protooncogenes. Tycko et al. (1989) had characterized t(7;9) at the
molecular level in 3 patients with T-ALL and found that the chromosome 9
breakpoints were tightly clustered within a 31-bp sequence. Xia et al.
(1991) demonstrated direct linkage between TAL2 and the t(7;9)
breakpoint region by chromosome walking.
GENE FUNCTION
TAL2 is 1 of at least 9 different protooncogenes that are activated as a
consequence of translocation to 1 of the T-cell receptor loci in T-ALL.
Molecular and functional analysis of the breakpoints suggested a
unifying mechanistic model in which the translocation results from a
mistake occurring during V(D)J recombination. In most cases, oncogene
activation is a direct result of the juxtaposition of the protooncogene
and T-cell receptor regulatory elements on one of the derivative
chromosomes. Thus, chromosomal translocations are generally assumed to
be the initiating leukemogenic events and constitute important
diagnostic markers of neoplasia. The t(7;9)(q34;q32) translocation is
believed to be representative of this paradigm. The translocation is
mediated by V(D)J recombination using a fortuitous recombination site
located 3-prime of the TAL2 protooncogene, and the consequent
juxtaposition of TAL2 and the TCR-beta enhancer on the der(9) chromosome
results in TAL2 overexpression. A direct leukemogenic role of TAL2 is
supported by its structural and functional relationship to the
protooncogenes TAL1 and LYL1, which are similarly activated in
individuals with T-ALL and encode a specific class of bHLH proteins with
oncogenic features. To further define the role of TAL2 translocation in
the development of T-ALL, Marculescu et al. (2003) investigated the
occurrence of t(7;9)(q34;q32) in healthy individuals. PCR analysis of
thymus samples from 10 otherwise normal children undergoing thoracic
surgery revealed the presence of this translocation in 6 of 10 samples
at an estimated frequency of roughly 1 in 10 million thymic cells. They
then cloned and sequenced the PCR products. Notably, they found that the
der(9) breakpoints were distinct between individuals with T-ALL and
healthy individuals. In leukemic individuals, a fusion between the
fortuitous recombination site 3-prime of TAL2 and the J-beta-2 coding
segment was invariably observed. In contrast, breakpoints from healthy
individuals contained a fusion between the TAL2 recombination site and
the D-beta-1 recombination signal sequence in a signal-joint
configuration. The observation indicated that signal joints constitute
unstable genomic elements with potential oncogenic properties.
MAPPING
Xia et al. (1991) performed the chromosomal localization of TAL2 to
chromosome 9 by using a genomic DNA fragment as a probe in Southern
hybridization with DNAs from a panel of human/hamster somatic cell
hybrids. The regional localization to 9q31 was determined by
fluorescence in situ hybridization.
By interspecific backcross linkage analysis, Pilz et al. (1995) mapped
the Tal2 gene to mouse chromosome 4.
ACTL7B
| dbSNP name | rs11543179(G,A); rs3750468(G,A); rs17728850(A,G) |
| ccdsGene name | CCDS6771.1 |
| cytoBand name | 9q31.3 |
| EntrezGene GeneID | 10880 |
| EntrezGene Description | actin-like 7B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTL7B:NM_006686:exon1:c.C561T:p.Y187Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2199 |
| ESP Afr MAF | 0.218339 |
| ESP All MAF | 0.214923 |
| ESP Eur/Amr MAF | 0.213172 |
| ExAC AF | 0.222 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Maxillary hypoplasia;
Malar hypoplasia;
[Ears];
Hearing loss;
Small ears;
Malformed auricles;
[Eyes];
Blue irides;
Photophobia;
Blepharophimosis;
Blepharitis;
Dacryocystitis;
Lacrimal duct abnormalities;
[Nose];
Flat nasal tip;
[Mouth];
Cleft lip;
Cleft palate;
Xerostomia;
Absence of Stensen duct;
[Teeth];
Selective tooth agenesis;
Microdontia;
Caries
RESPIRATORY:
[Nasopharynx];
Choanal atresia
CHEST:
[Breasts];
Hypoplastic nipples
GENITOURINARY:
[External genitalia, male];
Micropenis;
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
Transverse vaginal septum;
[Kidneys];
Renal agenesis;
Renal dysplasia;
Hydronephrosis;
Duplicated collecting system;
[Ureters];
Megaureter;
Vesicoureteral reflux;
Ureterocele;
[Bladder];
Bladder diverticula
SKELETAL:
[Hands];
Syndactyly;
Ectrodactyly;
[Feet];
Syndactyly;
Ectrodactyly
SKIN, NAILS, HAIR:
[Skin];
Fair skin;
Hyperkeratosis;
[Nails];
Dystrophic nails;
Pitted nails;
[Hair];
Light colored hair;
Sparse, thin scalp hair;
Sparse pubic hair;
Sparse axillary hair;
Sparse eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Mental retardation (7%)
ENDOCRINE FEATURES:
Growth hormone deficiency;
Hypogonadotropic hypogonadism;
Central diabetes insipidus
MISCELLANEOUS:
Heterogeneous disorder;
Two loci described - EEC1 (129900) and EEC3 (604292);
Majority of EEC cases appear to be secondary to TP63 mutations (603273);
Allelic to ADULT syndrome (103285), split hand/foot malformation
4 (605289), Rapp-Hodgkin syndrome (129400), Hay-Wells syndrome
(106260), and limb-mammary syndrome (603543)
MOLECULAR BASIS:
Caused by mutation in the tumor protein p63 gene (TP63, 603273.0001)
OMIM Title
*604304 ACTIN-LIKE 7B; ACTL7B
OMIM Description
DESCRIPTION
Actins (e.g., 102610) and actin-related proteins (ARPs) are members of a
superfamily of proteins that have an actin fold, which is an ATP-binding
cleft, as the common feature. ARPs are significantly longer than
conventional actins, with the difference in length usually accounted for
by peptide insertions within the more divergent protein regions
surrounding the ATP-binding cleft Chadwick et al. (1999).
CLONING
By searching a DNA sequence database with a human genomic sequence from
the BAC 234B17, Chadwick et al. (1999) identified a gene encoding a
protein with sequence similarity to a variety of actin proteins. Since
this novel protein shared higher sequence similarity with ACTL7A
(604303) than with any other known actin-like protein, the authors named
it ACTL7B. The deduced 415-amino acid protein contains a single
conserved protein kinase C site and a single conserved
cAMP/cGMP-dependent phosphorylation site. As with other ARPs, ACTL7B is
significantly longer than conventional actins. However, unlike other
ARPs, the difference in size of ACTL7B is not due to insertions within
the protein regions surrounding the ATP-binding cleft, but rather is
caused by an extension of the N-terminal region. Human ACTL7B shares 88%
amino acid identity with mouse Actl7b, which the authors also
identified. Northern blot analysis of human adult tissues detected a
1.8-kb ACTL7B transcript that was strongly expressed in testis and
weakly expressed in prostate.
GENE STRUCTURE
Chadwick et al. (1999) determined that the ACTL7B gene is intronless.
The authors found that the ACTL7A and ACTL7B genes are located
approximately 4 kb apart in a head-to-head orientation within the
familial dysautonomia (DYS; 223900) candidate region in 9q31.
MAPPING
By genomic sequence analysis, Chadwick et al. (1999) determined that the
ACTL7B gene is located on chromosome 9q31. By linkage analysis using an
interspecific backcross, Chadwick et al. (1999) mapped the mouse Actl7b
gene to chromosome 4, in a region showing homology of synteny with human
9q31.
ACTL7A
| dbSNP name | rs35995497(G,C); rs3739693(G,A); rs7872077(G,A); rs56031956(C,G); rs4978370(A,G) |
| ccdsGene name | CCDS6772.1 |
| cytoBand name | 9q31.3 |
| EntrezGene GeneID | 10881 |
| EntrezGene Description | actin-like 7A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTL7A:NM_006687:exon1:c.C1027G:p.L343V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5576 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y615 |
| dbNSFP Uniprot ID | ACL7A_HUMAN |
| dbNSFP KGp1 AF | 0.0151098901099 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0331491712707 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0224274406332 |
| dbSNP GMAF | 0.01515 |
| ESP Afr MAF | 0.007036 |
| ESP All MAF | 0.025757 |
| ESP Eur/Amr MAF | 0.035349 |
| ExAC AF | 0.022 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Maxillary hypoplasia;
Malar hypoplasia;
[Ears];
Hearing loss;
Small ears;
Malformed auricles;
[Eyes];
Blue irides;
Photophobia;
Blepharophimosis;
Blepharitis;
Dacryocystitis;
Lacrimal duct abnormalities;
[Nose];
Flat nasal tip;
[Mouth];
Cleft lip;
Cleft palate;
Xerostomia;
Absence of Stensen duct;
[Teeth];
Selective tooth agenesis;
Microdontia;
Caries
RESPIRATORY:
[Nasopharynx];
Choanal atresia
CHEST:
[Breasts];
Hypoplastic nipples
GENITOURINARY:
[External genitalia, male];
Micropenis;
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
Transverse vaginal septum;
[Kidneys];
Renal agenesis;
Renal dysplasia;
Hydronephrosis;
Duplicated collecting system;
[Ureters];
Megaureter;
Vesicoureteral reflux;
Ureterocele;
[Bladder];
Bladder diverticula
SKELETAL:
[Hands];
Syndactyly;
Ectrodactyly;
[Feet];
Syndactyly;
Ectrodactyly
SKIN, NAILS, HAIR:
[Skin];
Fair skin;
Hyperkeratosis;
[Nails];
Dystrophic nails;
Pitted nails;
[Hair];
Light colored hair;
Sparse, thin scalp hair;
Sparse pubic hair;
Sparse axillary hair;
Sparse eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Mental retardation (7%)
ENDOCRINE FEATURES:
Growth hormone deficiency;
Hypogonadotropic hypogonadism;
Central diabetes insipidus
MISCELLANEOUS:
Heterogeneous disorder;
Two loci described - EEC1 (129900) and EEC3 (604292);
Majority of EEC cases appear to be secondary to TP63 mutations (603273);
Allelic to ADULT syndrome (103285), split hand/foot malformation
4 (605289), Rapp-Hodgkin syndrome (129400), Hay-Wells syndrome
(106260), and limb-mammary syndrome (603543)
MOLECULAR BASIS:
Caused by mutation in the tumor protein p63 gene (TP63, 603273.0001)
OMIM Title
*604303 ACTIN-LIKE 7A; ACTL7A
OMIM Description
DESCRIPTION
Actins (e.g., 102610) and actin-related proteins (ARPs) are members of a
superfamily of proteins that have an actin fold, which is an ATP-binding
cleft, as the common feature. ARPs are significantly longer than
conventional actins, with the difference in length usually accounted for
by peptide insertions within the more divergent protein regions
surrounding the ATP-binding cleft Chadwick et al. (1999).
CLONING
By cDNA selection and direct genomic sequencing from the familial
dysautonomia (DYS; 223900) candidate region in 9q31, Chadwick et al.
(1999) identified the ACTL7A gene. The authors found that the ACTL7A and
ACTL7B (604304) genes are intronless and are located approximately 4 kb
apart in a head-to-head orientation. The open reading frame of the
ACTL7A gene encodes a predicted 435-amino acid member of the ARP family.
As with other ARPs, ACTL7A is significantly longer than conventional
actins. However, unlike other ARPs, the difference in size of ACTL7A is
not due to insertions within the protein regions surrounding the
ATP-binding cleft, but rather is caused by an extension of the
N-terminal region. ACTL7A contains a single conserved
cAMP/cGMP-dependent phosphorylation site, several conserved protein
kinase C phosphorylation sites, and a leucine zipper consensus sequence.
Human ACTL7A shares greater than 86% amino acid identity with mouse
Actl7a, which the authors also identified. Northern blot analysis
detected a prominent 1.8-kb ACTL7A transcript in human adult testis and
a 1.2-kb ACTL7A transcript in all other human tissues, with the highest
expression in heart. Based on mutational analysis of the ACTL7A gene in
patients with dysautonomia, Chadwick et al. (1999) concluded that ACTL7A
is unlikely to be involved in the pathogenesis of this disorder.
MAPPING
Using a somatic cell hybrid mapping panel and genomic sequence analysis,
Chadwick et al. (1999) localized the ACTL7A cDNA to 9q within the region
for familial dysautonomia on 9q31. By linkage analysis using an
interspecific backcross, Chadwick et al. (1999) mapped the mouse Actl7a
gene to chromosome 4, in a region showing homology of synteny with human
9q31.
OR2K2
| dbSNP name | rs314452(A,G) |
| ccdsGene name | CCDS6778.1 |
| cytoBand name | 9q31.3 |
| EntrezGene GeneID | 26248 |
| EntrezGene Description | olfactory receptor, family 2, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2K2:NM_205859:exon1:c.T435C:p.A145A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4812 |
| ESP Afr MAF | 0.399909 |
| ESP All MAF | 0.442642 |
| ESP Eur/Amr MAF | 0.361977 |
| ExAC AF | 0.586 |
FAM225B
| dbSNP name | rs944301(C,T); rs41280203(T,A); rs2009977(G,A) |
| cytoBand name | 9q32 |
| EntrezGene GeneID | 100128385 |
| snpEff Gene Name | NCRNA00256B |
| EntrezGene Description | family with sequence similarity 225, member B (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3508 |
RNF183
| dbSNP name | rs3750535(A,T); rs3750534(T,C); rs3750532(T,C) |
| cytoBand name | 9q32 |
| EntrezGene GeneID | 138065 |
| snpEff Gene Name | PRPF4 |
| EntrezGene Description | ring finger protein 183 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4233 |
OR1J1
| dbSNP name | rs1962091(T,C); rs140334685(G,A) |
| ccdsGene name | CCDS35120.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 347168 |
| EntrezGene Description | olfactory receptor, family 1, subfamily J, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1J1:NM_001004451:exon1:c.A953G:p.N318S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS3 |
| dbNSFP Uniprot ID | OR1J1_HUMAN |
| dbNSFP KGp1 AF | 0.639652014652 |
| dbNSFP KGp1 Afr AF | 0.833333333333 |
| dbNSFP KGp1 Amr AF | 0.453038674033 |
| dbNSFP KGp1 Asn AF | 0.811188811189 |
| dbNSFP KGp1 Eur AF | 0.473614775726 |
| dbSNP GMAF | 0.3604 |
| ESP Afr MAF | 0.191417 |
| ESP All MAF | 0.436846 |
| ESP Eur/Amr MAF | 0.437413 |
| ExAC AF | 0.526 |
OR1J2
| dbSNP name | rs41277120(G,A); rs4836891(G,A); rs78611864(C,T) |
| ccdsGene name | CCDS35121.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 26740 |
| EntrezGene Description | olfactory receptor, family 1, subfamily J, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1J2:NM_054107:exon1:c.G355A:p.A119T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS2 |
| dbNSFP Uniprot ID | OR1J2_HUMAN |
| dbNSFP KGp1 AF | 0.111263736264 |
| dbNSFP KGp1 Afr AF | 0.0650406504065 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.340909090909 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.1116 |
| ESP Afr MAF | 0.061961 |
| ESP All MAF | 0.030371 |
| ESP Eur/Amr MAF | 0.014186 |
| ExAC AF | 0.046,8.183e-06 |
OR1N1
| dbSNP name | rs58226717(C,T); rs41277122(A,G); rs16911867(A,G); rs10818708(G,A) |
| ccdsGene name | CCDS6844.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 138883 |
| EntrezGene Description | olfactory receptor, family 1, subfamily N, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1N1:NM_012363:exon1:c.G680A:p.R227Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGS0 |
| dbNSFP Uniprot ID | OR1N1_HUMAN |
| dbNSFP KGp1 AF | 0.110347985348 |
| dbNSFP KGp1 Afr AF | 0.0650406504065 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.337412587413 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.1107 |
| ESP Afr MAF | 0.059691 |
| ESP All MAF | 0.028987 |
| ESP Eur/Amr MAF | 0.013256 |
| ExAC AF | 0.048 |
OR1N2
| dbSNP name | rs1831369(C,T); rs1831370(T,C); rs1411271(G,C); rs1341042(T,C); rs1341043(T,C); rs142516134(C,T); rs41316976(C,T); rs1341044(T,G); rs1411272(C,T) |
| ccdsGene name | CCDS35123.1 |
| CosmicCodingMuts gene | OR1N2 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 138882 |
| EntrezGene Description | olfactory receptor, family 1, subfamily N, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1N2:NM_001004457:exon1:c.C94T:p.L32L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3586 |
| ESP Afr MAF | 0.379709 |
| ESP All MAF | 0.284407 |
| ESP Eur/Amr MAF | 0.235581 |
| ExAC AF | 0.308 |
OR1L8
| dbSNP name | rs10739614(C,G); rs10985702(A,C); rs10985703(C,G); rs10985704(T,G); rs1999182(G,A) |
| ccdsGene name | CCDS35124.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 138881 |
| EntrezGene Description | olfactory receptor, family 1, subfamily L, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1L8:NM_001004454:exon1:c.G632C:p.R211P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGR8 |
| dbNSFP Uniprot ID | OR1L8_HUMAN |
| dbNSFP KGp1 AF | 0.737179487179 |
| dbNSFP KGp1 Afr AF | 0.715447154472 |
| dbNSFP KGp1 Amr AF | 0.651933701657 |
| dbNSFP KGp1 Asn AF | 0.993006993007 |
| dbNSFP KGp1 Eur AF | 0.598944591029 |
| dbSNP GMAF | 0.2617 |
| ESP Afr MAF | 0.30118 |
| ESP All MAF | 0.363909 |
| ESP Eur/Amr MAF | 0.396047 |
| ExAC AF | 0.645,8.132e-06 |
OR1Q1
| dbSNP name | rs972925(A,G); rs1329957(A,G) |
| ccdsGene name | CCDS35125.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 158131 |
| EntrezGene Description | olfactory receptor, family 1, subfamily Q, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1Q1:NM_012364:exon1:c.A71G:p.Q24R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q15612 |
| dbNSFP Uniprot ID | OR1Q1_HUMAN |
| dbNSFP KGp1 AF | 0.80815018315 |
| dbNSFP KGp1 Afr AF | 0.626016260163 |
| dbNSFP KGp1 Amr AF | 0.814917127072 |
| dbNSFP KGp1 Asn AF | 0.942307692308 |
| dbNSFP KGp1 Eur AF | 0.821899736148 |
| dbSNP GMAF | 0.1924 |
| ESP Afr MAF | 0.330232 |
| ESP All MAF | 0.231278 |
| ESP Eur/Amr MAF | 0.180581 |
| ExAC AF | 0.839 |
OR1B1
| dbSNP name | rs1556189(A,C); rs1476858(A,C); rs1476859(C,T); rs1476860(G,A); rs1536929(A,G); rs1536928(A,G); rs140947515(G,C); rs12347681(T,C) |
| ccdsGene name | CCDS35126.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 347169 |
| EntrezGene Description | olfactory receptor, family 1, subfamily B, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1B1:NM_001004450:exon1:c.T941G:p.V314G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGR6 |
| dbNSFP Uniprot ID | OR1B1_HUMAN |
| dbNSFP KGp1 AF | 0.805402930403 |
| dbNSFP KGp1 Afr AF | 0.642276422764 |
| dbNSFP KGp1 Amr AF | 0.812154696133 |
| dbNSFP KGp1 Asn AF | 0.954545454545 |
| dbNSFP KGp1 Eur AF | 0.795514511873 |
| dbSNP GMAF | 0.1947 |
| ESP Afr MAF | 0.324557 |
| ESP All MAF | 0.23789 |
| ESP Eur/Amr MAF | 0.193488 |
| ExAC AF | 0.828 |
OR1L1
| dbSNP name | rs73571128(C,G); rs70157(A,G); rs70156(A,C); rs237620(C,G) |
| ccdsGene name | CCDS35127.2 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 26737 |
| EntrezGene Description | olfactory receptor, family 1, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1L1:NM_001005236:exon1:c.C195G:p.I65M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH94 |
| dbNSFP Uniprot ID | OR1L1_HUMAN |
| dbNSFP KGp1 AF | 0.0567765567766 |
| dbNSFP KGp1 Afr AF | 0.144308943089 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.0786713286713 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.05693 |
| ESP Afr MAF | 0.133908 |
| ESP All MAF | 0.046056 |
| ESP Eur/Amr MAF | 0.001047 |
| ExAC AF | 0.022 |
OR1L3
| dbSNP name | rs16912096(T,C); rs16912099(A,G); rs74634130(T,C); rs79636164(C,T) |
| ccdsGene name | CCDS35128.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 26735 |
| EntrezGene Description | olfactory receptor, family 1, subfamily L, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1L3:NM_001005234:exon1:c.T317C:p.V106A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH93 |
| dbNSFP Uniprot ID | OR1L3_HUMAN |
| dbNSFP KGp1 AF | 0.0677655677656 |
| dbNSFP KGp1 Afr AF | 0.186991869919 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.0839160839161 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.06795 |
| ESP Afr MAF | 0.184294 |
| ESP All MAF | 0.063355 |
| ESP Eur/Amr MAF | 0.001395 |
| ExAC AF | 0.026 |
OR1L4
| dbSNP name | rs149895531(T,A) |
| ccdsGene name | CCDS35129.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 254973 |
| EntrezGene Description | olfactory receptor, family 1, subfamily L, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1L4:NM_001005235:exon1:c.T418A:p.W140R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0046 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGR5 |
| dbNSFP Uniprot ID | OR1L4_HUMAN |
| dbNSFP KGp1 AF | 0.0192307692308 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0448548812665 |
| dbSNP GMAF | 0.01928 |
| ESP Afr MAF | 0.006809 |
| ESP All MAF | 0.021836 |
| ESP Eur/Amr MAF | 0.029535 |
| ExAC AF | 0.026,2.358e-04 |
OR1L6
| dbSNP name | rs10760252(C,A); rs4838012(G,A) |
| ccdsGene name | CCDS35130.2 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 392390 |
| EntrezGene Description | olfactory receptor, family 1, subfamily L, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1L6:NM_001004453:exon1:c.C67A:p.Q23K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGR2 |
| dbNSFP Uniprot ID | OR1L6_HUMAN |
| dbNSFP KGp1 AF | 0.865842490842 |
| dbNSFP KGp1 Afr AF | 0.674796747967 |
| dbNSFP KGp1 Amr AF | 0.919889502762 |
| dbNSFP KGp1 Asn AF | 0.963286713287 |
| dbNSFP KGp1 Eur AF | 0.890501319261 |
| dbSNP GMAF | 0.1336 |
| ESP Afr MAF | 0.199501 |
| ESP All MAF | 0.090294 |
| ESP Eur/Amr MAF | 0.034318 |
| ExAC AF | 0.946 |
OR5C1
| dbSNP name | rs144163074(G,A) |
| ccdsGene name | CCDS35131.1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 392391 |
| EntrezGene Description | olfactory receptor, family 5, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5C1:NM_001001923:exon1:c.G521A:p.R174H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0485 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGR4 |
| dbNSFP Uniprot ID | OR5C1_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.000538 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0002927 |
OR1K1
| dbSNP name | rs10985782(T,C); rs7046603(T,C) |
| ccdsGene name | CCDS35132.1 |
| CosmicCodingMuts gene | OR1K1 |
| cytoBand name | 9q33.2 |
| EntrezGene GeneID | 392392 |
| EntrezGene Description | olfactory receptor, family 1, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1K1:NM_080859:exon1:c.T126C:p.G42G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1244 |
| ESP Afr MAF | 0.132773 |
| ESP All MAF | 0.129094 |
| ESP Eur/Amr MAF | 0.127209 |
| ExAC AF | 0.135 |
MIR600HG
| dbSNP name | rs75170643(G,A); rs700089(A,G) |
| cytoBand name | 9q33.3 |
| EntrezGene GeneID | 81571 |
| snpEff Gene Name | STRBP |
| EntrezGene Description | MIR600 host gene (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0427 |
MIR7150
| dbSNP name | rs58605477(A,G) |
| ccdsGene name | CCDS35134.1 |
| cytoBand name | 9q33.3 |
| EntrezGene GeneID | 57706 |
| EntrezGene Symbol | DENND1A |
| snpEff Gene Name | DENND1A |
| EntrezGene Description | DENN/MADD domain containing 1A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1841 |
| ExAC AF | 0.06 |
LOC100129034
| dbSNP name | rs10818946(T,G); rs72616651(A,G); rs1330811(G,A); rs7873147(T,C); rs7857897(G,A); rs115602550(T,C); rs10986323(C,T); rs912353(T,G); rs16927388(G,A); rs1139641(C,G); rs184376834(G,A); rs16927395(T,C) |
| ccdsGene name | CCDS6855.1 |
| cytoBand name | 9q33.3 |
| EntrezGene GeneID | 100129034 |
| snpEff Gene Name | NEK6 |
| EntrezGene Description | uncharacterized LOC100129034 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3246 |
NRON
| dbSNP name | rs56159772(C,T); rs16928980(T,C); rs13298216(G,A); rs77643931(T,G); rs10987270(C,T); rs112884871(T,G); rs74392245(C,T); rs4837079(A,G); rs75861091(G,T) |
| ccdsGene name | CCDS35142.1 |
| cytoBand name | 9q33.3 |
| EntrezGene GeneID | 641373 |
| snpEff Gene Name | FAM125B |
| EntrezGene Description | non-protein coding RNA, repressor of NFAT |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08815 |
PTGES2-AS1
| dbSNP name | rs1418421(T,C); rs10760541(G,A) |
| cytoBand name | 9q34.11 |
| EntrezGene GeneID | 389791 |
| snpEff Gene Name | AL590708.2 |
| EntrezGene Description | PTGES2 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03811 |
ENDOG
| dbSNP name | rs193141222(A,G); rs10819449(A,G); rs56778081(G,A); rs2977996(G,A); rs2280845(T,C); rs2997920(T,C); rs2977995(A,G); rs2280844(C,T) |
| ccdsGene name | CCDS6912.1 |
| cytoBand name | 9q34.11 |
| EntrezGene GeneID | 51490 |
| EntrezGene Symbol | C9orf114 |
| snpEff Gene Name | C9orf114 |
| EntrezGene Description | chromosome 9 open reading frame 114 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly
NEUROLOGIC:
[Central nervous system];
Megalencephaly;
Ataxia;
Spasticity;
Seizures;
Delay in motor development;
Mild mental retardation;
Diffuse swelling of cerebral white matter;
Large subcortical cysts in frontal and temporal lobes;
Diffuse spongiform leukoencephalopathy;
Vacuolizing myelinopathy
MISCELLANEOUS:
Onset in infancy;
Slow course of functional deterioration compared to severity of MRI
findings
MOLECULAR BASIS:
Caused by mutation in the MLC1 gene (MLC1, 605908.0001)
OMIM Title
*604051 ENDO/EXONUCLEASE, ENDOG-LIKE; EXOG
;;ENDONUCLEASE G-LIKE 1; ENDOGL1;;
ENGL
OMIM Description
DESCRIPTION
EXOG is an endonuclease G (ENDOG; 600440)-like mitochondrial
endo/exonuclease that has both endonuclease and 5-prime-to-3-prime
exonuclease activities (Cymerman et al., 2008).
CLONING
By analysis of a 515-kb cloned segment from 3p22-p21.3, a region that is
commonly deleted in various carcinomas, Daigo et al. (1999) identified
10 genes, 4 of which were novel. They designated one of the novel genes
ENGL (endonuclease G-like) because the predicted 368-amino acid ENGL
protein shares 38% identity with endonuclease G (ENDOG; 600440).
Northern blot analysis revealed that ENGL was expressed as a 1.7-kb mRNA
in all tissues tested. An additional 2.1-kb mRNA, designated ENGLb, was
detected in heart, liver, skeletal muscle, and testis. The ENGLb
transcript contained all or part of 4 of the 6 ENGL exons, as well as a
3-prime exon not present in the genomic clone analyzed.
Cymerman et al. (2008) reported that the 368-amino acid EXOG protein has
a calculated molecular mass of 41.1 kD. It contains an N-terminal
mitochondrial leader sequence (MLS), a central catalytic ser-arg-gly-his
(SRGH) motif, and a C-terminal coiled-coil domain. A predicted helical
transmembrane segment is located within the MLS. Confocal
immunohistochemical analysis revealed that EXOG localized to
mitochondria in HeLa cells. Mitochondrial subfractionation, immunogold
electron microscopy, and confocal laser scanning microscopy showed that
EXOG localized specifically to the inner mitochondrial membrane.
GENE FUNCTION
By assaying transfected HEK293 cells, Cymerman et al. (2008) showed that
EXOG had high endonuclease activity against circular single-stranded
DNA. Recombinant EXOG lacking the N-terminal MLS showed a similar
preference for circular single-stranded DNA, but it also cleaved
super-coiled and open circular DNA after prolonged incubation. EXOG
showed 5-prime-to-3-prime exonuclease activity toward single- and
double-stranded DNA and single-stranded RNA. It showed little to no
endonuclease activity on ribosomal RNA substrates. Mutation of the
conserved his140 within the SRGH catalytic motif or removal of the
C-terminal coiled-coil domain abolished EXOG activity. Cymerman et al.
(2008) also found that a naturally occurring SNP resulting in a
gly277-to-val (G277V) substitution inactivated EXOG. Mutation analysis
showed that the transmembrane segment within the N-terminal MLS of EXOG
was required for EXOG mitochondrial localization.
GENE STRUCTURE
Daigo et al. (1999) determined that the EXOG gene contains 6 exons.
Cymerman et al. (2008) found that it spans 28.35 kb.
MAPPING
Daigo et al. (1999) identified the EXOG gene within a 515-kb cloned
segment from 3p22-p21.3. EXOG was the most telomeric gene in the cloned
region and was located next to the ActRIIB (ACVR2B; 602730) gene.
Cymerman et al. (2008) stated that the EXOG gene maps to chromosome
3p21.3.
DOLK
| dbSNP name | rs147342916(G,C) |
| ccdsGene name | CCDS6915.1 |
| cytoBand name | 9q34.11 |
| EntrezGene GeneID | 22845 |
| EntrezGene Description | dolichol kinase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DOLK:NM_014908:exon1:c.C876G:p.F292L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.2395 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UPQ8 |
| dbNSFP Uniprot ID | DOLK_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ExAC AF | 4.066e-05 |
IER5L
| dbSNP name | rs1075650(T,C) |
| cytoBand name | 9q34.11 |
| EntrezGene GeneID | 389792 |
| EntrezGene Description | immediate early response 5-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2052 |
LOC100272217
| dbSNP name | rs4740196(C,A); rs4740197(G,A); rs12347401(A,C); rs12342072(G,A); rs4740350(G,A); rs11243867(C,T); rs4740351(G,A) |
| cytoBand name | 9q34.11 |
| EntrezGene GeneID | 100272217 |
| snpEff Gene Name | FUBP3 |
| EntrezGene Description | uncharacterized LOC100272217 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1607 |
QRFP
| dbSNP name | rs3847193(G,A) |
| ccdsGene name | CCDS6936.1 |
| cytoBand name | 9q34.12 |
| EntrezGene GeneID | 347148 |
| EntrezGene Description | pyroglutamylated RFamide peptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | QRFP:NM_198180:exon1:c.C57T:p.F19F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3118 |
| ESP Afr MAF | 0.346346 |
| ESP All MAF | 0.394356 |
| ESP Eur/Amr MAF | 0.261512 |
| ExAC AF | 0.277 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataract, congenital;
Cataract, nuclear (in some patients);
Cataract, posterior polar (in some patients);
Cataract, anterior polar (in some patients);
Cataract, cortical (in some patients);
Glaucoma (in some patients)
MISCELLANEOUS:
Two Pakistani families with a homozygous CRYBB3 mutation have been
reported (last curated August 2014);
One 4-generation Caucasian Italian family with a heterozygous CRYBB3
mutation has been reported (last curated August 2014)
MOLECULAR BASIS:
Caused by mutation in the beta-B3 crystallin gene (CRYBB3, 123630.0001)
OMIM Title
*609795 PYROGLUTAMYLATED RF-AMIDE PEPTIDE PRECURSOR PROTEIN; QRFP
;;QRFP PRECURSOR PROTEIN;;
NEUROPEPTIDE RF-AMIDE PEPTIDE PRECURSOR;;
P518 PRECURSOR PROTEIN
NEUROPEPTIDE RF-AMIDE PEPTIDE, INCLUDED;;
P518, INCLUDED;;
RF-AMIDE PEPTIDE, 26-AMINO ACID, INCLUDED; 26RFA, INCLUDED;;
PYROGLUTAMYLATED RF-AMIDE PEPTIDE, INCLUDED; QRFP, INCLUDED
OMIM Description
DESCRIPTION
The P518 precursor protein can be processed into several RF
(arg-phe)-amide peptides, including P518. RF-amide peptides share a
common C-terminal motif and are involved in cell signaling through G
protein-coupled receptors (Jiang et al., 2003).
CLONING
By searching a database for genes encoding RF-amide peptides, followed
by PCR of a kidney cDNA library, Jiang et al. (2003) cloned the P518
precursor gene. The deduced 126-amino acid protein contains a putative
N-terminal 22-amino acid signal peptide and no transmembrane domain,
suggesting that the protein or cleavage products can be secreted. The
26-amino acid P518 peptide sequence is located at the C terminus of the
precursor protein. Quantitative PCR detected significant expression of
P518 precursor mRNA in several specific brain regions, particularly in
cerebellum, medulla, retina, and vestibular nucleus. In peripheral
tissues, P518 precursor mRNA was detected in prostate, testis, colon,
thyroid, parathyroid, coronary artery, and bladder.
By searching for sequences similar to frog 26RFA, Chartrel et al. (2003)
identified human and rat cDNAs encoding prepro-26RFA. The deduced
136-amino acid human protein contains a 17-amino acid signal peptide,
followed by a dibasic processing site (arg-arg) and the 26RFA sequence,
which is identical to the P518 peptide sequence reported by Jiang et al.
(2003), at the C terminus. The human proprotein contains an additional
putative RF-amide peptide of 9 amino acids upstream of the 26RFA region
that is not found in rat.
By database analysis and RT-PCR of human brain RNA, Fukusumi et al.
(2003) isolated a cDNA encoding QRFP precursor protein. The 43-amino
acid QRFP peptide is located at the C terminus of the 136-amino acid
precursor protein.
Using in situ hybridization analysis in mouse brains, Takayasu et al.
(2006) demonstrated that QRFP is expressed exclusively in the
periventricular and lateral hypothalamus.
GENE FUNCTION
Jiang et al. (2003) found that the P518 peptide functioned as a
high-affinity ligand of GPR103 (606925) in GPR103-transfected human
embryonic kidney cells. The ability of P518 to mobilize intracellular
Ca(2+) via GPR103 appeared to be coupled to the G-alpha-q (GNAQ; 600998)
signaling pathway. In a human tissue RNA panel, both GPR103 and P518
precursor mRNA exhibited highest expression in brain, but their
expression in peripheral tissues was more divergent.
Chartrel et al. (2003) found that 26RFA induced a dose-dependent
stimulation of cAMP production by rat pituitary cells in vitro and
markedly increased food intake in mice.
In studies in CHO cells, Fukusumi et al. (2003) demonstrated that the
43-amino acid QRFP peptide was necessary to exhibit full agonistic
activity with GPR103. Intravenous administration of human QRFP into rats
caused release of aldosterone, suggesting that QRFP regulates adrenal
function.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the P518
precursor gene to chromosome 9 (TMAP RH48985).
ANIMAL MODEL
Takayasu et al. (2006) showed that QRFP administered centrally in mice
induced feeding behavior accompanied by increased general locomotor
activity and metabolic rate, as well as highly sustained elevations of
blood pressure and heart rate. QRFP-induced food intake was abolished by
preadministration of a specific antagonist for neuropeptide Y receptor
Y1 (162641). Hypothalamic prepro-QRFP mRNA expression was upregulated
upon fasting and in genetically obese ob/ob and db/db mice. Takayasu et
al. (2006) suggested that QRFP and GPR103 may regulate diverse
neuroendocrine and behavioral functions, and that this neuropeptide
system may be involved in metabolic syndrome (605552).
SARDH
| dbSNP name | rs129886(C,T); rs138313103(C,T); rs129887(C,T); rs129927(G,C); rs129922(C,A); rs10993952(C,T); rs10993953(C,T); rs7854480(G,C); rs2073836(A,T); rs2073835(G,A); rs183423716(G,T); rs10993956(C,T); rs9409877(C,A); rs2519127(T,C); rs7033395(C,T); rs129931(T,C); rs9409878(A,C); rs9409842(G,A); rs9409879(C,G); rs112397661(C,T); rs2797844(T,C); rs2797843(T,C); rs2073834(C,T); rs2797842(G,T); rs2797841(A,T); rs2797840(G,A); rs129932(G,A); rs2519123(C,G); rs2519122(C,G); rs2519121(A,G); rs2797839(C,T); rs2797838(T,C); rs129933(G,A); rs2797837(A,C); rs2797836(T,C); rs2797835(G,A); rs34508494(A,G); rs129935(C,T); rs2519119(A,G); rs2797834(G,A); rs10821578(C,T); rs129934(C,T); rs2519117(A,C); rs57370353(G,A); rs76413010(C,T); rs129938(T,C); rs129890(G,C); rs129936(C,T); rs129937(G,A); rs129889(G,A); rs113201781(G,A); rs2797832(T,C); rs2519131(C,G); rs2797831(C,T); rs129891(G,A); rs191859195(G,A); rs129895(A,G); rs129940(A,G); rs2797830(C,T); rs129893(T,C); rs129899(C,T); rs129894(A,G); rs129939(G,A); rs129898(C,T); rs129892(T,C); rs129948(A,G); rs129943(C,T); rs129896(A,G); rs129951(A,G); rs73564114(C,T); rs148329862(C,T); rs2797829(T,C); rs129897(A,G); rs146274167(C,A); rs113092824(G,C); rs756691(T,C); rs756690(C,T); rs111288338(C,T); rs1076149(T,A); rs756687(C,G); rs7859013(C,T); rs2519126(C,T); rs2502735(G,C); rs1548363(C,T); rs1548362(A,G); rs129900(T,C); rs129902(G,C); rs182265379(C,T); rs4744533(C,T); rs129903(C,T); rs730007(G,A); rs129905(T,C); rs129907(G,A); rs111314831(C,G); rs886016(T,C); rs756682(T,C); rs2797820(C,G); rs2502736(C,A); rs2073817(C,T); rs2502737(C,A); rs56355444(C,T); rs3003587(C,T); rs28472298(G,C); rs2502739(A,T); rs2427998(G,T); rs4744534(G,A); rs2502741(A,G); rs2502742(G,T); rs149278701(A,G); rs10993768(C,T); rs2502743(C,G); rs10993769(C,T); rs7852531(A,G); rs10993770(C,A); rs148204556(C,G); rs75175839(G,T); rs146114039(G,A); rs117102863(G,A); rs733347(C,T); rs2427995(A,C); rs2427994(T,C); rs2427993(C,T); rs2427991(T,C); rs2427990(T,C); rs2427989(C,T); rs2502745(C,G); rs113626931(C,T); rs2502746(G,A); rs2510248(G,A); rs694821(C,T); rs2510245(G,A); rs56169426(C,T); rs144218228(A,G); rs4979633(C,T); rs4979632(G,A); rs79105233(C,T); rs4979631(C,T); rs9409848(T,C); rs10821518(C,G); rs2073815(G,A); rs495464(A,T); rs2427987(A,G); rs2488550(A,G); rs489851(C,T); rs488013(C,A); rs675713(C,G); rs2797821(G,A); rs2849750(G,A); rs611111(A,G); rs537067(A,G); rs13285421(G,C); rs511293(G,A); rs2427985(A,G); rs7048777(C,T); rs756681(C,T); rs45581441(C,T); rs582326(G,C); rs9409819(A,G); rs525412(G,A); rs522676(G,A); rs522673(C,T); rs694357(T,G); rs116640041(C,T); rs12341880(T,A); rs2427984(C,G); rs2427983(G,A); rs2427982(C,G); rs77665633(C,T); rs2427981(C,A); rs10117852(C,T); rs2427979(A,G); rs28549806(G,A); rs28395318(A,G); rs113630982(T,A); rs1557648(A,G); rs2027963(T,G); rs2510240(T,C); rs113613980(C,T); rs7857468(C,A); rs7870095(T,C); rs2027962(C,A); rs10993775(G,A); rs7849946(G,A); rs76230435(C,T); rs7040170(A,G); rs10993776(G,A); rs2502757(C,T); rs4979628(T,C); rs2427999(A,T); rs2502758(C,A); rs7848155(C,T); rs4979630(G,A); rs10993778(A,C); rs2510234(T,C); rs2510235(T,C); rs2428103(T,C); rs73548055(G,A); rs2251217(T,G); rs2283125(C,A); rs2254109(A,G); rs2427996(C,T); rs2427988(A,G); rs137999690(C,T); rs12236251(G,A); rs72761174(G,A); rs10821521(C,G); rs2427978(T,A); rs916619(G,A); rs916620(C,T); rs2502759(A,G); rs3780804(T,G); rs593824(C,T); rs10993780(C,G); rs573904(C,T); rs2488553(G,A); rs2510263(A,G); rs579232(T,G); rs579236(G,A); rs491072(T,C); rs2502761(T,G); rs497622(T,C); rs2905214(C,T); rs12237736(G,A); rs62572818(C,G); rs2428102(A,T); rs7861063(G,T); rs111389997(C,T); rs12375833(C,T); rs12376409(A,T); rs476835(C,G) |
| ccdsGene name | CCDS6978.1 |
| cytoBand name | 9q34.2 |
| EntrezGene GeneID | 1757 |
| EntrezGene Description | sarcosine dehydrogenase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SARDH:NM_001134707:exon6:c.G889A:p.V297I,SARDH:NM_007101:exon6:c.G889A:p.V297I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5596 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.001816 |
| ESP All MAF | 0.001307 |
| ESP Eur/Amr MAF | 0.001047 |
| ExAC AF | 0.000862 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
MUSCLE, SOFT TISSUE:
Muscle atrophy, distal;
Muscle weakness, distal;
Weakness of the extensor muscles of the hands (initially);
Weakness of all intrinsic hand muscles (later);
Weakness of the anterior tibial muscle and toe extensors;
Steppage gait;
Walking difficulties;
Myopathic changes seen muscle biopsy;
Rimmed vacuoles
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Adult onset (range 40 to 60 years);
Slowly progressive;
High incidence in Sweden and Finland;
Incidence of 1 in 100 in some local Nordic areas;
Homozygotes have earlier onset and a more severe disorder
MOLECULAR BASIS:
Caused by mutation in the TIA1 cytotoxic granule-associated RNA-binding
protein gene (TIA1, 603518.0001)
OMIM Title
*604455 SARCOSINE DEHYDROGENASE; SARDH
;;SDH
OMIM Description
DESCRIPTION
Sarcosine dehydrogenase (SARDH; EC 1.5.99.1) is a liver mitochondrial
matrix flavoenzyme that catalyzes the oxidative demethylation of
sarcosine (summary by Eschenbrenner and Jorns, 1999).
CLONING
By homology searching, Eschenbrenner and Jorns (1999) identified a
partial human infant brain SARDH cDNA. Using this partial cDNA, they
isolated a full-length human liver cDNA. The predicted 918-amino acid
SARDH protein contains a putative 22-amino acid mitochondrial targeting
sequence, an ADP-binding site, and a stretch of 12 amino acids that
matches the covalent flavin-containing peptide from rat liver Sardh.
Human SARDH shares 89% amino acid sequence identity with rat liver Sardh
and 34% identity with rat liver dimethylglycine dehydrogenase. Northern
blot analysis of various human adult and fetal tissues detected a 4-kb
SARDH transcript at high levels in adult and fetal liver and at lower
levels in adult pancreas and kidney and fetal kidney. Eschenbrenner and
Jorns (1999) identified cDNAs corresponding to alternatively spliced and
polyadenylated SARDH transcripts.
GENE STRUCTURE
Eschenbrenner and Jorns (1999) determined that the SARDH gene spans at
least 75.3 kb and contains 21 exons.
MAPPING
Eschenbrenner and Jorns (1999) identified 3 genomic sequences from 9q34
that contain the SARDH gene. The localization of the human SARDH gene to
9q34 is consistent with genetic studies using a mouse model for
sarcosinemia that mapped the mouse Sardh gene to a region of chromosome
2 that shows homology of synteny with human 9q33-q34 (Harding et al.,
1992; Brunialti et al., 1996).
MOLECULAR GENETICS
In 4 individuals from 3 consanguineous Israeli Arab families and 3
individuals from 3 French families who had elevated levels of sarcosine
in blood and urine (SARCOS; 268900), Bar-joseph et al. (2012) sequenced
the SARDH gene and identified homozygous or compound heterozygous
mutations in 3 families (604455.0001-604455.0004). In 1 French family,
they found a uniparental disomy in the region of the SARDH gene. No
mutation in the SARDH gene was found in 2 of the Israeli Arab families,
suggesting genetic heterogeneity.
LINC00094
| dbSNP name | rs417142(G,T); rs71505267(T,C); rs408307(C,T); rs2520098(G,C); rs386770(G,C); rs410876(C,A); rs13296849(G,T); rs3739932(C,T) |
| cytoBand name | 9q34.2 |
| EntrezGene GeneID | 266655 |
| snpEff Gene Name | NCRNA00094 |
| EntrezGene Description | long intergenic non-protein coding RNA 94 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3522 |
COL5A1
| dbSNP name | rs4629950(C,T); rs11103455(C,T); rs7875570(C,T); rs28451948(A,T); rs57523855(C,T); rs12352462(T,A); rs10858265(T,C); rs66698367(C,T); rs73665730(T,C); rs11103456(A,G); rs4598327(G,A); rs11103457(C,T); rs57362508(C,T); rs4335205(A,G); rs11103460(G,C); rs4842138(A,G); rs10046876(G,C); rs73556983(T,C); rs147729163(A,G); rs112775512(G,A); rs7854299(A,G); rs60431532(C,T); rs6537939(C,T); rs6537940(C,T); rs6537941(C,A); rs6537942(A,G); rs7032486(C,T); rs7032489(C,G); rs7042369(T,G); rs12000599(C,A); rs80276821(C,T); rs76777016(T,C); rs80038646(G,A); rs75089903(C,T); rs4842139(T,C); rs73665731(A,G); rs12003552(A,T); rs10858266(T,C); rs77187500(T,C); rs58508630(A,G); rs6537943(A,G); rs4842140(G,C); rs76901301(G,A); rs7855673(G,A); rs4842141(G,A); rs4841922(T,C); rs7044151(C,T); rs7044529(C,T); rs74992333(C,A); rs188388623(C,A); rs10858267(A,C); rs118029018(T,C); rs72772536(C,T); rs75735676(C,T); rs145499971(G,C); rs10776897(G,A); rs7849852(T,C); rs138513412(G,A); rs59183620(A,G); rs13288677(A,G); rs56033447(C,T); rs12555085(G,C); rs72772543(G,C); rs4842142(A,G); rs4842143(T,G); rs10776898(G,A); rs10858268(C,T); rs16832(G,A); rs72772548(C,T); rs76345396(C,T); rs117266966(C,T); rs10858269(T,G); rs12338780(C,T); rs4077962(C,A); rs7866155(G,C); rs4076970(C,T); rs4076969(A,C); rs7861715(T,C); rs12346265(C,T); rs12346335(C,T); rs4598329(G,T); rs10858270(G,T); rs3922982(T,C); rs4596720(A,G); rs4841924(G,A); rs11103466(T,C); rs180735422(C,T); rs4072790(A,G); rs4401947(C,G); rs4401948(C,G); rs4607695(G,A); rs7466318(A,G); rs73665738(C,G); rs4341231(T,C); rs116715381(C,T); rs11103472(T,G); rs3922643(C,T); rs3922644(C,T); rs3124290(G,A); rs3128585(A,C); rs7038395(T,C); rs115666574(C,T); rs7028769(C,T); rs4842144(G,A); rs6537946(G,A); rs4381018(A,C); rs4529530(C,T); rs3109671(C,T); rs7028694(G,C); rs144353496(G,T); rs7860007(G,A); rs4240702(T,C); rs4240703(A,G); rs73560672(G,A); rs4240704(G,T); rs3935335(G,A); rs4319175(G,A); rs7848938(A,G); rs7872458(C,T); rs9409988(G,T); rs146114256(G,C); rs4842145(T,C); rs4842146(G,A); rs4842147(T,C); rs4842148(C,T); rs3109690(C,T); rs3128586(G,A); rs3124292(T,G); rs4461973(C,T); rs7468140(T,C); rs72772580(G,A); rs4552987(T,C); rs4400464(G,A); rs10858273(A,G); rs66635405(C,T); rs3922914(C,T); rs3922912(G,A); rs114098595(C,T); rs115279420(G,A); rs115089113(C,T); rs150288690(C,T); rs4548258(C,T); rs10858274(C,G); rs9409916(A,C); rs3109688(G,A); rs3109687(G,T); rs116312634(G,A); rs3128588(C,T); rs7869149(A,G); rs374334438(A,G); rs4841926(C,T); rs7852238(G,C); rs3128590(C,A); rs3128591(G,A); rs10858275(C,T); rs114406334(G,A); rs4841927(C,T); rs116275545(C,G); rs3124294(T,G); rs3124295(C,T); rs3128580(A,C); rs55645539(C,T); rs3128579(A,C); rs142948820(G,T); rs12683240(G,A); rs12684067(C,T); rs112498477(G,A); rs12684468(A,G); rs144146163(C,T); rs148136071(A,G); rs34980427(C,A); rs34326204(A,G); rs34529432(T,C); rs34991142(A,G); rs11103479(C,T); rs74422754(T,C); rs116826248(G,T); rs73564846(C,T); rs7035739(T,C); rs7044312(G,A); rs10776899(G,A); rs3109684(A,G); rs62571352(C,T); rs12004951(A,C); rs4075077(G,A); rs55655608(C,T); rs3128629(T,C); rs11103480(T,C); rs7875140(T,C); rs73564852(G,A); rs6537947(G,A); rs7854716(G,C); rs9409917(C,G); rs73568428(A,G); rs9409918(G,C); rs3124297(A,G); rs78421381(C,A); rs3128577(G,C); rs7869554(T,G); rs62571354(G,A); rs3124298(G,A); rs3124299(C,T); rs3109683(T,G); rs3128587(G,C); rs3128589(T,C); rs3124300(A,G); rs3124301(A,T); rs3128595(G,A); rs3124302(C,T); rs3128597(A,C); rs3124303(C,T); rs3124308(A,G); rs3128598(G,A); rs3128600(A,C); rs3128606(T,C); rs3124309(C,T); rs3109675(T,C); rs114388964(G,A); rs3124311(C,G); rs60665807(G,C); rs140978223(T,C); rs113038907(G,A); rs3128607(T,C); rs3124312(G,A); rs3124313(G,A); rs3128608(A,G); rs116961904(C,T); rs3109679(A,G); rs113903160(C,T); rs3109680(G,A); rs3128609(T,C); rs3128610(T,C); rs3128611(C,T); rs3109681(G,C); rs11103487(C,T); rs73568444(C,T); rs190590812(G,A); rs76479201(G,T); rs3109682(A,G); rs117846223(G,A); rs142166753(A,G); rs7855576(C,A); rs7041099(T,C); rs7031437(C,T); rs3109677(C,T); rs3128612(T,C); rs111753643(A,G); rs3109676(G,A); rs10115005(G,A); rs73568458(G,C); rs7019513(T,C); rs10120176(A,C); rs12684637(C,T); rs56122820(G,A); rs115335749(G,A); rs150238681(G,C); rs79288098(T,C); rs114550819(G,A); rs4842149(C,T); rs114938262(C,G); rs7858851(G,A); rs150853035(T,C); rs3128615(G,A); rs11103491(A,G); rs3128616(T,C); rs12347941(C,T); rs12685946(A,G); rs41299046(G,C); rs12686426(T,C); rs60008082(T,C); rs12345547(G,A); rs4842150(G,A); rs56669635(G,T); rs62574083(C,T); rs78665980(A,G); rs12685202(A,G); rs12685475(T,C); rs73558063(C,T); rs10123014(T,C); rs79679217(C,T); rs73558067(C,T); rs10121103(C,T); rs11103501(A,G); rs11103502(G,A); rs12685536(A,G); rs7030925(A,G); rs4842151(C,T); rs7046574(G,T); rs77827838(G,T); rs4842152(A,G); rs55696429(C,T); rs7028969(C,T); rs4842153(T,C); rs4841928(G,A); rs61566377(G,C); rs10122768(C,T); rs11103503(C,G); rs3128617(A,G); rs10124841(T,C); rs7849193(A,G); rs111467095(C,T); rs113699651(G,T); rs114543716(T,C); rs116509092(C,G); rs80342344(G,A); rs78963656(G,A); rs73558091(C,T); rs11103505(T,C); rs11103506(G,T); rs11103507(G,A); rs11103508(A,C); rs10858278(C,A); rs11103509(T,C); rs28391608(A,G); rs12552497(T,C); rs56054814(A,G); rs55903144(T,A); rs12555663(A,G); rs75229187(C,T); rs12555178(C,T); rs12555699(A,G); rs112254023(G,A); rs12379066(G,A); rs11103510(G,A); rs77581500(C,A); rs7040856(C,T); rs3128618(C,G); rs55933021(C,T); rs55724503(C,T); rs114140544(G,A); rs75872333(A,G); rs12338381(A,G); rs4842157(A,G); rs4842158(G,A); rs4842159(T,C); rs4842160(A,T); rs115126805(G,A); rs4842161(C,A); rs115093919(G,A); rs150289772(G,A); rs41302968(G,C); rs4842162(G,T); rs10776900(A,G); rs10776901(T,C); rs116267362(C,T); rs115384344(T,C); rs141853517(T,C); rs150610322(G,T); rs7866781(C,A); rs7855561(G,A); rs7855580(G,A); rs11103518(C,A); rs10745384(T,C); rs74343243(C,T); rs4842163(T,C); rs140802179(C,T); rs11103519(G,A); rs10120979(A,G); rs12685359(T,G); rs7470855(G,C); rs114706644(C,T); rs72774440(A,T); rs4842164(A,G); rs7870887(T,C); rs6537948(T,C); rs66460226(A,T); rs191444056(C,T); rs113864835(C,T); rs4842165(G,A); rs72774445(G,T); rs9409991(A,C); rs3124929(C,T); rs138425769(G,A); rs3124930(G,T); rs143203151(G,A); rs4563961(C,T); rs146662001(T,A); rs3124931(T,C); rs149905158(C,T); rs55774569(G,A); rs3128619(C,A); rs72774451(G,A); rs11103524(C,T); rs34589987(A,G); rs3124932(C,T); rs112797265(C,T); rs34226173(A,G); rs7849777(G,A); rs79631623(G,C); rs147928420(G,A); rs3128620(C,T); rs6537949(T,G); rs59126004(T,C); rs35361637(T,C); rs145522383(C,G); rs3124934(T,C); rs3128621(G,T); rs11998946(T,C); rs7874308(A,G); rs62571366(G,A); rs3128622(C,G); rs9409992(C,T); rs9409920(T,C); rs72774460(C,T); rs11103527(G,A); rs62571370(G,A); rs68123287(G,A); rs67553899(C,T); rs185558166(G,T); rs9308277(T,C); rs3124928(T,C); rs3128584(A,C); rs28577990(C,T); rs12346438(A,G); rs73560080(T,C); rs61326243(G,A); rs10120983(C,G); rs150081877(G,A); rs41306388(C,A); rs4072883(C,T); rs4072882(A,G); rs4842167(C,T); rs76703227(G,A); rs10858280(A,G); rs10776902(T,C); rs3811161(A,G); rs3811159(A,G); rs78511105(C,T); rs72774465(G,A); rs56013298(G,C); rs7873395(T,C); rs147682230(C,T); rs10776903(A,G); rs10776904(C,A); rs73560100(A,G); rs10745385(A,G); rs62571397(C,T); rs10776905(G,A); rs3811158(T,C); rs3811157(T,C); rs3811156(C,T); rs56334115(A,T); rs4842168(C,T); rs73561910(T,G); rs73561912(G,A); rs62571399(G,C); rs58421780(A,G); rs10776906(T,A); rs10776907(T,G); rs76332677(G,A); rs76291462(G,A); rs111612394(C,T); rs74942446(T,C); rs60738936(G,A); rs142496776(C,T); rs62571400(G,C); rs10858281(C,A); rs150486495(C,T); rs3827851(T,G); rs41311216(G,A); rs148666902(G,A); rs62571402(C,T); rs62571403(C,T); rs114607788(G,A); rs7851471(A,G); rs72774468(T,C); rs373157232(C,T); rs78743504(C,T); rs187929826(G,A); rs190674200(C,A); rs62571405(C,T); rs4842169(G,A); rs75894870(G,A); rs142490821(C,T); rs7863862(A,G); rs79635825(A,T); rs72502716(G,A); rs11103534(T,G); rs375510038(T,C); rs62571406(C,T); rs11103535(G,A); rs11103536(G,A); rs4531123(G,A); rs3811153(A,G); rs3811152(G,C); rs3827850(G,C); rs3827849(G,A); rs3811151(A,C); rs73664146(G,A); rs73664147(C,G); rs10776908(A,G); rs45629034(G,A); rs45556931(G,A); rs73664148(A,G); rs7874142(G,A); rs4842170(C,T); rs4841930(A,G); rs4841931(T,C); rs4841932(T,C); rs4841933(A,G); rs62571407(A,G); rs3827848(G,A); rs4841934(T,C); rs9942862(G,A); rs56356850(G,A); rs3811149(A,G); rs61739195(C,T); rs10858282(T,G); rs10776910(A,C); rs10858283(A,G); rs11103537(C,G); rs4373595(T,C); rs4372081(A,G); rs73664149(A,G); rs7854010(T,C); rs185363538(G,A); rs146381563(G,A); rs11792894(T,C); rs376721611(A,G); rs77174824(G,A); rs192041286(T,G); rs193107550(G,T); rs146189396(C,G); rs147842205(C,T); rs113451014(G,A); rs10745388(G,A); rs9696591(A,C) |
| ccdsGene name | CCDS6982.1 |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 1289 |
| EntrezGene Description | collagen, type V, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL5A1:NM_000093:exon53:c.C4135T:p.P1379S,COL5A1:NM_001278074:exon53:c.C4135T:p.P1379S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9386 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P20908 |
| dbNSFP Uniprot ID | CO5A1_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.007304 |
| ESP Eur/Amr MAF | 0.010349 |
| ExAC AF | 0.007392 |
OMIM Clinical Significance
Eyes:
Coloboma of iris, choroid and retina
Inheritance:
Autosomal dominant
OMIM Title
*120215 COLLAGEN, TYPE V, ALPHA-1; COL5A1
OMIM Description
CLONING
Type V collagen was first identified in human placenta and adult skin,
but later studies showed that it is present in many other tissues and
organs as a minor collagen component. Type V collagen occurs as
heterotrimers of 3 different polypeptide chains, alpha-1, alpha-2
(COL5A2, 120190), and alpha-3 (COL5A3, 120216), or 2 copies of alpha-1
and 1 copy of alpha-2; it also occurs as a homotrimer of alpha-1
polypeptides. Takahara et al. (1991) reported the sequence of cDNA
encoding the complete prepro-alpha-1(V) chain. The collagenous region
and COOH-terminal noncollagenous region closely resembled that of the
alpha-1(XI) (120280) chain; however, codon usage differed, suggesting
that the COL5A1 gene is evolutionarily distinct.
MAPPING
Using cDNA and genomic clones for the COL5A1 gene as probes, Greenspan
et al. (1992) determined in panels of human-mouse hybrid cell lines and
by in situ hybridization experiments that the COL5A1 gene is located in
the segment 9q34.2-q34.3. Caridi et al. (1992) likewise assigned the
COL5A1 gene to 9q34.3 by in situ hybridization. Mattei et al. (1993)
found that the homologous gene in the mouse is located in the A2-B
region of chromosome 2. They independently confirmed the localization of
the human gene to 9q34.
GENE STRUCTURE
Takahara et al. (1995) determined the complete genomic structure of
COL5A1 and showed that the gene is more complex than other fibrillar
collagen genes, having 66 exons compared to 52. The gene spans at least
750 kb.
GENE FUNCTION
Fichard et al. (1994) reviewed collagens V and XI and commented on their
fundamental role in the control of fibrillogenesis, probably by forming
a core within the fibrils. Another characteristic of these collagens is
the partial retention of their N-propeptide extensions in tissue forms,
which is unusual for known fibrillar collagens. The tissue locations of
collagen V and XI are different, but their structural and biologic
properties seem to be closely related. Their primary structures are
highly conserved at both the gene and the protein level, and this
conservation is the basis of their similar biologic properties. In
particular, they are both resistant to mammalian collagenases, and
surprisingly sensitive to trypsin. Although they have both cell adhesion
and heparin binding sites that could be crucial in physiologic processes
such as development and wound healing, the 2 collagens are usually
buried within the major collagen fibrils. It had become evident that
several collagen-type molecules are, in fact, heterotypic associations
of chains from both collagens V and XI, demonstrating that these 2
collagens are not distinct types but a single type that can be called
collagen V/XI.
MOLECULAR GENETICS
Nicholls et al. (1994) identified molecular abnormalities in type V
collagen in 2 patients with Ehlers-Danlos syndrome. The first patient,
with overlapping clinical features of both EDS I/II and EDS VII and
additional unusual corneal abnormalities, showed a G(+3)-to-T change in
the 5-prime splice site leading to deletion of the upstream exon
(120215.0001). The in-frame 54-bp deletion eliminated 6 Gly-X-Y triplets
from the triple helical domain. The second patient also showed clinical
features of EDS I/II and had, in addition, vascular weakness similar to
the EDS IV subtype. Both the alpha-1 and the alpha-2 chains of type V
collagen ran with lower mobility than normal on SDS-page gels,
indicative of excessive posttranslational modification of the protein
due to a point mutation in 1 of the protein chains.
Greenspan et al. (1995) used 3-prime untranslated region RFLPs to
exclude the COL5A1 gene as a candidate in families with tuberous
sclerosis-1 (191100), Ehlers-Danlos syndrome type II (EDS II; 130010),
and the nail-patella syndrome (161200). In addition, they described a
polymorphic simple sequence repeat (SSR) within a COL5A1 intron. They
used this SSR to exclude COL5A1 as a candidate gene also in hereditary
hemorrhagic telangiectasia (187300), and to add COL5A1 to the index
markers of chromosome 9 by evaluation of the COL5A1 locus on the CEPH
40-family reference pedigree set. This genetic mapping placed COL5A1
between markers D9S66 and D9S67.
Using an intragenic simple sequence repeat polymorphism of the COL5A1
gene as a linkage marker, Loughlin et al. (1995) showed linkage to
Ehlers-Danlos syndrome, type II; maximum lod = 8.3 at theta = 0.00 in a
single large pedigree. The inconsistency of these results with those of
Greenspan et al. (1995) may be explained by the fundamental
heterogeneity of EDS II.
Using a polymorphic intragenic simple sequence repeat at the COL5A1
locus, Burrows et al. (1996) demonstrated tight linkage to EDS I/II in a
3-generation family, giving a lod score of 4.07 at zero recombination.
The variation in expression in this family suggested that EDS types I
(EDS1; 130000) and II are allelic, and the linkage data supported the
hypothesis that mutation in COL5A1 can cause both phenotypes. That this
was indeed the case was demonstrated by Nicholls et al. (1996) who, in a
patient with clinical features of Ehlers-Danlos syndrome type I/II and
VII, demonstrated an exon-skipping mutation in the COL5A1 gene
(120215.0001).
Wenstrup et al. (1996) reported 2 families in which EDS I cosegregated
with the COL5A1 gene. In 2 other families with EDS I, linkage was
excluded from both the COL5A1 and the COL5A2 loci. Wenstrup et al.
(1996) demonstrated that affected individuals in one of the EDS I
COL5A1-linked families were heterozygous for a 4-bp deletion in intron
65 (120215.0002). This deletion led to a 234-bp deletion of exon 65 in
the processed mRNA for pro-alpha-1(V) collagen.
De Paepe et al. (1997) likewise identified a mutation in COL5A1
segregating with EDS I in a 4-generation family (120215.0003). In
addition, they detected splicing defects in the COL5A1 gene in a patient
with EDS I and in a family with EDS II (120215.0005). Thus they proved
that EDS I and II are allelic disorders.
To determine whether allele-product instability could explain failure to
identify some mutations in the COL5A1 gene in classic EDS, Schwarze et
al. (2000) analyzed polymorphic variants in the COL5A1 gene in 16
individuals and examined mRNA for the expression of both alleles and for
alterations in splicing. They found a splice site mutation in a single
individual and determined that, in 6 individuals, the mRNA from one
COL5A1 allele either was not expressed or was very unstable. They
identified small insertions or deletions in 5 of these cell strains, but
were unable to identify the mutation in the sixth individual. Thus,
although as many as half of the mutations that give rise to EDS types I
and II are likely to lie in the COL5A1 gene, a significant portion of
them result in very low levels of mRNA from the mutant allele, as a
consequence of nonsense-mediated mRNA decay.
Similarly, Wenstrup et al. (2000) found that 8 of 28 probands with
classic EDS, who were heterozygous for expressed polymorphisms in
COL5A1, showed complete or nearly complete loss of expression of 1
COL5A1 allele. Reduced levels of COL5A1 mRNA relative to levels of
COL5A2 mRNA were also observed in the cultured fibroblasts from EDS
probands. Products of the 2 COL5A1 alleles were approximately equal
after the addition of cycloheximide to the fibroblast cultures. After
harvesting of mRNAs from cycloheximide-treated cultured fibroblasts,
heteroduplex analysis of overlapping RT-PCR segments spanning the
complete COL5A1 cDNA showed anomalies in 4 of the 8 probands, leading to
identification of causative mutations; in the remaining 4 probands,
targeting of CGA-to-TGA mutations in genomic DNA revealed a premature
stop codon in one of them. Wenstrup et al. (2000) estimated that
one-third of persons with classic EDS have mutations of the COL5A1 gene
that result in haploinsufficiency. These findings indicated that normal
formation of the heterotypic collagen fibrils that contain types I, III,
and V collagen require the expression of both COL5A1 alleles.
Borck et al. (2010) reported a 42-year-old German man with EDS and
spontaneous rupture of his left common iliac artery, who was negative
for mutation in COL3A1 (120180) but was found instead to carry a de novo
heterozygous nonsense mutation (120215.0012) in the COL5A1 gene. The
authors stated that this was the first report of a patient with COL5A1
mutation-positive EDS and rupture of a large artery, suggesting that
arterial rupture might be a rare complication of classic EDS.
Symoens et al. (2012) analyzed COL5A1 and COL5A2 in 126 patients with a
diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen
defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2
mutations, and 7 were COL5A1 null-alleles with mutation unknown. The
majority of the 73 COL5A1 mutations generated a COL5A1 null-allele,
whereas one-third were structural mutations, scattered throughout
COL5A1. All COL5A2 mutations were structural mutations. Reduced
availability of type V collagen appeared to be the major disease-causing
mechanism, besides other intra- and extracellular contributing factors.
All type V collagen defects were identified within a group of 102
patients fulfilling all major clinical Villefranche criteria, that is,
skin hyperextensibility, dystrophic scarring, and joint hypermobility.
No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin
and joint hyperextensibility but lacked dystrophic scarring. Overall,
over 90% of patients fulfilling all major Villefranche criteria for
classic EDS were shown to harbor a type V collagen defect, indicating
that this is the major, if not the only, cause of classic EDS.
DKFZP434A062
| dbSNP name | rs57825369(C,T); rs28714232(C,T); rs28444490(C,T); rs28477913(A,G); rs28545822(T,C); rs115838471(G,A); rs28515716(A,G); rs62579954(G,T); rs78751002(C,T); rs35803302(G,C); rs141594878(C,T); rs28661870(A,G) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 26102 |
| snpEff Gene Name | GPSM1 |
| EntrezGene Description | uncharacterized LOC26102 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4132 |
C9orf163
| dbSNP name | rs34376913(T,C); rs60640016(C,T); rs1139057(C,T) |
| ccdsGene name | CCDS7001.1 |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 158055 |
| EntrezGene Description | chromosome 9 open reading frame 163 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C9orf163:NM_152571:exon1:c.T14C:p.L5P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N9P6 |
| dbNSFP Uniprot ID | CI163_HUMAN |
| dbNSFP KGp1 AF | 0.169413919414 |
| dbNSFP KGp1 Afr AF | 0.0934959349593 |
| dbNSFP KGp1 Amr AF | 0.237569060773 |
| dbNSFP KGp1 Asn AF | 0.0769230769231 |
| dbNSFP KGp1 Eur AF | 0.255936675462 |
| dbSNP GMAF | 0.1699 |
| ESP Afr MAF | 0.092688 |
| ESP All MAF | 0.160986 |
| ESP Eur/Amr MAF | 0.195022 |
| ExAC AF | 0.119 |
LOC100128593
| dbSNP name | rs2811728(G,A); rs111432548(G,A); rs1360879(G,A); rs1360880(G,T); rs1360881(C,T); rs10870118(C,T); rs945379(G,T); rs10283881(T,C); rs2784071(C,T); rs372214291(G,A) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 100128593 |
| snpEff Gene Name | LCN6 |
| EntrezGene Description | uncharacterized LOC100128593 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | low |
| dbSNP GMAF | 0.4844 |
| ESP Afr MAF | 0.271546 |
| ESP All MAF | 0.403283 |
| ESP Eur/Amr MAF | 0.470547 |
| ExAC AF | 0.471 |
MAN1B1-AS1
| dbSNP name | rs4880198(C,T); rs10118245(C,T); rs1018330(C,A); rs76441732(G,A); rs7466635(T,C) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 100289341 |
| snpEff Gene Name | UAP1L1 |
| EntrezGene Description | MAN1B1 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2309 |
LOC100129722
| dbSNP name | rs1133439(A,G); rs9696356(G,A); rs9695981(A,C); rs9695304(C,G) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 100129722 |
| snpEff Gene Name | C9orf173 |
| EntrezGene Description | uncharacterized LOC100129722 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1354 |
TOR4A
| dbSNP name | rs28455773(G,T); rs13301565(A,T) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 54863 |
| snpEff Gene Name | C9orf167 |
| EntrezGene Description | torsin family 4, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3976 |
NRARP
| dbSNP name | rs116113799(C,G) |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 441478 |
| EntrezGene Description | NOTCH-regulated ankyrin repeat protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009183 |
EHMT1-IT1
| dbSNP name | rs72766947(C,T); rs11137208(G,A); rs3125799(A,G) |
| ccdsGene name | CCDS7050.2 |
| cytoBand name | 9q34.3 |
| EntrezGene GeneID | 643210 |
| snpEff Gene Name | EHMT1 |
| EntrezGene Description | EHMT1 intronic transcript 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05831 |
TUBAL3
| dbSNP name | rs144656534(C,T); rs3255(C,T); rs192566368(G,A); rs151094531(G,A); rs7097775(G,A); rs34080891(G,A); rs115615637(C,T); rs7910290(A,G); rs6601957(A,G); rs7477292(T,C); rs11253155(G,A); rs191065100(A,C); rs148240710(C,T); rs11253156(A,G); rs77291689(C,A); rs113710649(G,T); rs148770466(A,C); rs79010590(G,A); rs7895912(T,A); rs78122058(A,G); rs6601958(C,G); rs150691235(G,T); rs11253158(T,C); rs3888366(A,C); rs115272133(C,T); rs192946149(G,A); rs78858303(T,C); rs74538105(A,G); rs74678426(C,T); rs79759440(C,T); rs35919465(G,C); rs10795272(G,A); rs76105533(C,A); rs7475717(A,G); rs7475746(A,T); rs10795273(C,T); rs10904489(G,A); rs11253160(G,A); rs7474730(C,A); rs7474645(G,A); rs7476136(G,A); rs7474717(T,C); rs10795274(C,T); rs10904490(A,C); rs113536055(A,G); rs7476837(C,T); rs8181389(C,T); rs74373056(G,T); rs9630122(G,C); rs10904491(G,A) |
| ccdsGene name | CCDS7066.2 |
| cytoBand name | 10p15.1 |
| EntrezGene GeneID | 79861 |
| EntrezGene Description | tubulin, alpha-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TUBAL3:NM_024803:exon4:c.C1097T:p.P366L,TUBAL3:NM_001171864:exon4:c.C977T:p.P326L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5746 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NHL2-2 |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.002724 |
| ESP All MAF | 0.000923 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0003822 |
CALML5
| dbSNP name | rs10904516(T,C); rs10904517(C,T) |
| ccdsGene name | CCDS7068.1 |
| CosmicCodingMuts gene | CALML5 |
| cytoBand name | 10p15.1 |
| EntrezGene GeneID | 51806 |
| EntrezGene Description | calmodulin-like 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CALML5:NM_017422:exon1:c.A221G:p.K74R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NZT1 |
| dbNSFP Uniprot ID | CALL5_HUMAN |
| dbNSFP KGp1 AF | 0.337912087912 |
| dbNSFP KGp1 Afr AF | 0.497967479675 |
| dbNSFP KGp1 Amr AF | 0.245856353591 |
| dbNSFP KGp1 Asn AF | 0.288461538462 |
| dbNSFP KGp1 Eur AF | 0.315303430079 |
| dbSNP GMAF | 0.3375 |
| ESP Afr MAF | 0.120291 |
| ESP All MAF | 0.076426 |
| ESP Eur/Amr MAF | 0.053953 |
| ExAC AF | 0.334 |
CALML3
| dbSNP name | rs1142825(G,A); rs4242797(G,A); rs4589189(G,C); rs4589188(G,A); rs1131482(G,T) |
| ccdsGene name | CCDS7069.1 |
| cytoBand name | 10p15.1 |
| EntrezGene GeneID | 810 |
| EntrezGene Description | calmodulin-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CALML3:NM_005185:exon1:c.G318A:p.L106L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3985 |
| ESP Afr MAF | 0.469133 |
| ESP All MAF | 0.321467 |
| ESP Eur/Amr MAF | 0.245814 |
| ExAC AF | 0.323 |
OMIM Clinical Significance
Limbs:
Brachydactyly of hands and feet;
Congenital finger flexion contractures;
Syndactyly;
Polydactyly
GU:
Septate vagina;
Urinary incontinence
Inheritance:
Autosomal dominant
OMIM Title
*114184 CALMODULIN-LIKE 3; CALML3
;;CALMODULIN-LIKE PROTEIN; CLP
OMIM Description
CLONING
Using calmodulin (CALM1; 114180) as probe, Koller and Strehler, (1988)
cloned CALML3, which they designated GH6, from a leukocyte genomic
library. The deduced 148-amino acid protein contains 4 helix-loop-helix
Ca(2+)-binding motifs and shares 85% identity with vertebrate
calmodulin. Northern blot analysis detected no expression in fibroblast,
teratoma, or erythroleukemia cell lines.
By immunohistochemical staining, Rogers et al. (2001) determined the
tissue distribution of CALML3, which they designated CLP. CLP was
expressed exclusively in the epithelium of the tissues surveyed and was
most abundant in thyroid, breast, prostate, kidney, and skin. CLP
expression appeared to increase in stratified epithelium during
differentiation, as illustrated in skin, where CLP staining intensified
from the basal through the spinous to the granular layers.
BIOCHEMICAL FEATURES
Qian et al. (1998) determined the secondary structure of CLP complexed
with Ca(2+) by multidimensional nuclear magnetic resonance spectroscopy.
Overall, CLP has a 2-domain structure similar to that of calmodulin.
Qian et al. (1998) identified differences between calmodulin and CLP in
the lengths of several helical elements and, most importantly, in the
central nonhelical flexible region. Their analysis suggested that the
sum of small differences in the central regions of calmodulin and CLP
plays a crucial role in target selectivity between these proteins.
Han et al. (2002) determined the 1.5-angstrom crystal structure of CLP
and compared it with that of calmodulin. They verified that CLP contains
2 globular domains connected by a central 7-turn alpha helix. Each
globular domain has 2 helix-loop-helix motifs that form the 4
Ca(2+)-binding sites. The central helix of CLP is less flexible than the
central helix of calmodulin, and the 2 proteins differ in the
orientation of the globular domains about the hinge region. Significant
differences between the electric surface potentials at the target
protein-binding regions of CLP and calmodulin suggested that the ranges
of CLP and calmodulin target proteins do not fully overlap.
GENE FUNCTION
Rogers et al. (2001) examined the expression of CLP in cultured normal
human keratinocytes in response to various agents known to affect
keratinocyte differentiation. They found that agents that inhibit
terminal differentiation, particularly epidermal growth factor (EGF;
131530), downregulate CLP expression. Using several other agents that
affect the growth and differentiation of keratinocytes, Rogers et al.
(2001) determined that upregulated expression of CLP mRNA is linked to
initiation of terminal differentiation.
Using gel overlays and yeast 2-hybrid screens, Rogers and Strehler
(2001) identified myosin X (MYO10; 601481) as a specific
Ca(2+)-dependent binding partner for CLP. CLP specifically bound to
motif 3 of the IQ domain of MYO10, and both proteins colocalized at the
cell periphery of mammary carcinoma cells. Rogers and Strehler (2001)
concluded that CLP is a specific light chain of MYO10 in vivo.
GENE STRUCTURE
Koller and Strehler (1988) determined that the CALML3 gene contains a
single exon. The upstream region has no obvious TATA box, but it does
have a putative CAAT box. The promoter region has several CGAGG and
CACCC repeat sequences and a putative cAMP responsive element.
MAPPING
Berchtold et al. (1993) mapped a functional intronless gene coding for
CLP to chromosome 10pter-p13. Chromosomal assignment was performed by
Southern blot analysis of DNA from human/rodent somatic cell hybrids and
amplification of a gene-specific 1,090-bp DNA fragment by PCR from DNA
of human/hamster cell hybrids. Chromosomal sublocalization was carried
out by in situ hybridization.
LOC283070
| dbSNP name | rs2431637(G,A); rs2431636(G,A); rs2431635(G,T); rs2431634(A,G); rs140557319(T,G); rs1047721(T,C); rs17152359(A,G); rs2482073(A,G); rs15980(G,A); rs13674(G,A); rs14563(T,C); rs7500(C,T) |
| cytoBand name | 10p13 |
| EntrezGene GeneID | 283070 |
| snpEff Gene Name | CAMK1D |
| EntrezGene Description | uncharacterized LOC283070 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3802 |
MIR1265
| dbSNP name | rs373578320(G,A); rs11259096(T,C) |
| cytoBand name | 10p13 |
| EntrezGene GeneID | 100302116 |
| snpEff Gene Name | FRMD4A |
| EntrezGene Description | microRNA 1265 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
C10orf111
| dbSNP name | rs73602470(G,C); rs6602811(C,T); rs6602812(T,A); rs7896053(C,T); rs7895698(G,A); rs3814172(T,C) |
| cytoBand name | 10p13 |
| EntrezGene GeneID | 221060 |
| snpEff Gene Name | RPP38 |
| EntrezGene Description | chromosome 10 open reading frame 111 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04132 |
STAM-AS1
| dbSNP name | rs7068027(G,A); rs11254698(C,T); rs17141450(G,T); rs118143549(T,G); rs72780790(T,C); rs2251596(C,T); rs11591804(A,C); rs2251710(T,A); rs2243617(A,G) |
| cytoBand name | 10p12.33 |
| snpEff Gene Name | STAM |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4986 |
NEBL-AS1
| dbSNP name | rs2279311(T,C) |
| cytoBand name | 10p12.31 |
| EntrezGene GeneID | 100128511 |
| snpEff Gene Name | NEBL |
| EntrezGene Description | NEBL antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.388 |
EBLN1
| dbSNP name | rs57562594(G,A); rs2243897(A,G); rs16922091(C,G); rs10466081(A,C); rs2478476(A,T) |
| cytoBand name | 10p12.31 |
| EntrezGene GeneID | 340900 |
| EntrezGene Description | endogenous Bornavirus-like nucleoprotein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EBLN1:NM_001199938:exon1:c.C1074T:p.R358R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06198 |
| ExAC AF | 0.028 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
SKIN, NAILS, HAIR:
[Hair];
Scalp hair appears banded, with alternating light and dark segments
(0.5 to 1.5 mm);
Hair may appear alternating shiny and dull;
Hairs have elliptical diameter with flattened surface;
Hair shaft shows partial twisting on its axis (periodicity of 1 to
2 mm);
Reflected light shows bright and dark bands;
Transmitted light shows no banding or inhomogeneities
MISCELLANEOUS:
Onset in infancy or early childhood;
No increased fragility of hair;
Considered a normal variant;
Distinct from pili annulati (180600)
OMIM Title
*613249 ENDOGENOUS BORNA-LIKE N ELEMENT-CONTAINING PROTEIN 1; EBLN1
OMIM Description
CLONING
Borna disease viruses (BDVs), a genus of nonsegmented negative-sense RNA
viruses, are unique among RNA viruses in that they establish persistent
infection in the cell nucleus. By searching human protein databases for
sequences similar to BDV proteins, Horie et al. (2010) identified a
hypothetical human protein, LOC340900, with significant sequence
similarity to the BDV nucleoprotein gene (BDV-N), which encodes a major
structural protein that tightly encapsidates the viral RNA to form the
nucleocapsid. The 366-residue LOC340900 sequence shares 41% sequence
identity and 58% similarity to the 370-residue BDV-N protein. Sequence
alignment of transcription regulatory elements demonstrated that the S
and T motifs in flanking sequences of the human protein were well
conserved with those of BDV. Homology of LOC340900 to BDV-N was also
confirmed by a permutation test. Because of findings indicating that
LOC340900 may represent an endogenous element related to the BDV-N gene,
Horie et al. (2010) designated the human gene EBLN1. The EBLN1 protein
shares 72% identity with the EBLN2 protein (613250). Horie et al. (2010)
showed that elements homologous to the BDV-N gene exist in the genomes
of several other mammalian species, including nonhuman primates,
rodents, and elephants. Horie et al. (2010) concluded that their results
provided the first evidence for endogenization of nonretroviral
virus-derived elements in mammalian genomes, and further suggested that
the L1 reverse transcriptase is used to promote the endogenization of
EBLN elements, which may still be occurring.
LOC100130992
| dbSNP name | rs73596588(A,G); rs76574603(A,G); rs79644468(C,G); rs115206025(C,T); rs74364268(A,G) |
| cytoBand name | 10p12.31 |
| EntrezGene GeneID | 100130992 |
| EntrezGene Description | uncharacterized LOC100130992 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1396 |
LOC100499489
| dbSNP name | rs3004(A,G); rs73598513(G,C); rs7918879(T,C); rs7073797(G,T); rs7899794(C,T); rs7898929(G,A); rs73598518(A,G); rs12268450(C,T); rs73598520(C,T); rs73598521(C,G) |
| cytoBand name | 10p12.2 |
| EntrezGene GeneID | 100499489 |
| snpEff Gene Name | SPAG6 |
| EntrezGene Description | uncharacterized LOC100499489 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1203 |
PTF1A
| dbSNP name | rs7918487(T,C) |
| ccdsGene name | CCDS7143.1 |
| cytoBand name | 10p12.2 |
| EntrezGene GeneID | 256297 |
| EntrezGene Description | pancreas specific transcription factor, 1a |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PTF1A:NM_178161:exon2:c.T787C:p.S263P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7RTS3 |
| dbNSFP Uniprot ID | PTF1A_HUMAN |
| dbNSFP KGp1 AF | 0.623626373626 |
| dbNSFP KGp1 Afr AF | 0.595528455285 |
| dbNSFP KGp1 Amr AF | 0.616022099448 |
| dbNSFP KGp1 Asn AF | 0.851398601399 |
| dbNSFP KGp1 Eur AF | 0.473614775726 |
| dbSNP GMAF | 0.376 |
| ESP Afr MAF | 0.441217 |
| ESP All MAF | 0.489236 |
| ESP Eur/Amr MAF | 0.486163 |
| ExAC AF | 0.546,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEOPLASIA:
Meningioma
MISCELLANEOUS:
Adult onset;
More common in women;
Frequency increases with advancing age;
High recurrence rate;
Incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the homolog of the Drosophila suppressor of
fused gene (SUFU, 607035.0007);
Caused by mutation in the SWI/SNF-related, matrix-associated, actin-dependent
regulator of chromatin, subfamily 1, member 1 gene (SMARCE1, 603111.0002).
OMIM Title
*607194 PANCREAS TRANSCRIPTION FACTOR 1, ALPHA SUBUNIT; PTF1A
;;PTF1-p48
OMIM Description
CLONING
The gene PTF1A encodes a basic helix-loop-helix protein of 48 kD that is
a sequence-specific DNA-binding subunit of the trimeric pancreas
transcription factor-1 (PTF1) (Krapp et al., 1996, 1998). Krapp et al.
(1996) cloned the PTF1A gene.
GENE FUNCTION
Pancreas development begins with the formation of buds at specific sites
in the embryonic foregut endoderm. Kawaguchi et al. (2002) used in vivo
recombination-based lineage tracing in mice to show that Ptf1a (also
known as PTF1-p48) is expressed at these early stages in the progenitors
of pancreatic ducts, exocrine and endocrine cells, rather than being an
exocrine-specific gene as previously described (Krapp et al., 1996;
Adell et al., 2000; Rose et al., 2001). Moreover, inactivation of Ptf1a
switches the character of pancreatic progenitors such that their progeny
proliferate in and adopt the normal fates of duodenal epithelium,
including its stem-cell compartment. Consistent with their proposal that
Ptf1a supports the specification of precursors of all 3 pancreatic cell
types, Kawaguchi et al. (2002) found that transgene-based expression of
Pdx1 (600733), a gene essential to pancreas formation, under the control
of Ptf1a cis-regulatory sequences restored pancreas tissue to Pdx1-null
mice that otherwise lacked mature exocrine and endocrine cells because
of an early arrest in organogenesis. The experiments of Kawaguchi et al.
(2002) provided evidence that Ptf1a expression is specifically connected
to the acquisition of pancreatic fate by undifferentiated foregut
endoderm.
Masui et al. (2007) found that Ptf1a interacted with Rbpj (RBPSUH;
147183) within a stable trimeric DNA-binding PTF1 complex during early
pancreatic development in mouse. As acinar cell development began, Rbpj
was swapped for Rbpjl, the constitutively active, pancreas-restricted
Rbpj paralog, and Rbpjl was a direct target of the PTF1 complex. At the
onset of acinar cell development, when the Rbpjl gene was first induced,
a PTF1 complex containing Rbpj bound to the Rbpjl promoter. As
development proceeded, Rbpjl gradually replaced Rbpj in the PTF1 complex
bound to the Rbpjl promoter and appeared on the PTF1 complex-binding
sites on the promoters of other acinar-specific genes, including those
for secretory digestive enzymes. Introduction of a Ptf1a mutant unable
to bind Rbpj truncated pancreatic development at an immature stage,
without the formation of acini or islets.
MOLECULAR GENETICS
- Pancreatic and Cerebellar Agenesis
Individuals with permanent neonatal diabetes mellitus (PNDM; 606176)
usually present within the first 3 months of life and require insulin
treatment. PNDM is both phenotypically and genetically heterogeneous. By
genomewide linkage search, Sellick et al. (2003) identified a locus on
10p13-p12.1 involved in PNDM associated with pancreatic and cerebellar
agenesis (PACA; 609069) in a consanguineous Pakistani family (Hoveyda et
al., 1999). The linkage to specific single-nucleotide polymorphism (SNP)
markers was confirmed with microsatellite markers and replicated in a
second family of northern European descent segregating an identical
phenotype. Sellick et al. (2004) selected 3 genes that mapped to the
region of linkage for candidate gene screening based on their expression
in human or mouse pancreatic and cerebellar tissue and implied biologic
function. These 3 genes were PIP5K2A (603140), PTF1A, and CACNB2
(600003). Sellick et al. (2004) identified the mutations 886C-T
(607194.0001) and 705insG (607194.0002) in the PTF1A gene as
disease-causing sequence changes. Both mutations caused truncation of
the expressed PTF1A protein C-terminal to the basic helix-loop-helix
domain. Reporter gene studies using a minimal PTF1A deletion mutant
indicated that the deleted region defines a new domain that is crucial
for the function of the protein. PTF1A was known to have a role in
mammalian pancreatic development; the clinical phenotype of the affected
individuals implicated the protein also as a key regulator of cerebellar
neurogenesis. Sellick et al. (2004) confirmed the essential role of
PTF1A in normal cerebellar development by detailed neuropathologic
analysis of Ptf1a -/- mice.
- Isolated Pancreatic Agenesis
By whole-genome sequencing of 2 probands from unrelated multiplex
consanguineous families with isolated pancreatic agenesis mapping to
chromosome 10p12 (PAGEN2; 615935), Weedon et al. (2014) identified
homozygosity in both patients for the same variant: an A-G transition on
chromosome 10 at g.23508437 (GRCh37), located about 25 kb downstream of
the PTF1A gene within an approximately 400-bp evolutionarily conserved
region. Sequencing of this putative pancreatic developmental enhancer in
19 additional probands with PAGEN revealed recessive mutations in 7 of
10 probands with isolated pancreatic agenesis as well as in 1 patient
who also had fatal cholestatic liver failure. Overall, 9 affected
individuals from 6 unrelated families of Syrian, Lebanese, Kurdish, and
Turkish ancestry were homozygous for the same chromosome 10 mutation,
g.23508437A-G, as part of a shared 1.2-Mb haplotype. In addition, a
sporadic patient from Pakistan was homozygous for g.23508363A-G; a
sporadic patient from Germany was compound heterozygous for
g.23508365A-G and g.23508446A-C; and 2 Arabian sibs were homozygous for
a 7.6-kb deletion that included the entire putative enhancer. Finally, a
sporadic Costa Rican patient who had pancreatic agenesis with fatal
cholestatic liver failure was homozygous for g.23508302A-G. Testing of
parents and sibs demonstrated cosegregation of the mutations with
diabetes and exocrine insufficiency, and none of the mutations were
found in 299 controls, in 1,092 individuals from the 1000 Genomes
Project database, or in the dbSNP (build 137) database. Functional
analysis demonstrated that the approximately 400-bp region acts as a
developmental enhancer of PTF1A in human embryonic pancreatic progenitor
cells and that the 6 mutations abolish enhancer activity: 3 of the
base-substitution mutations disrupt binding sites for FOXA2 (600288) and
1 disrupts a binding site for PDX1 (600733), whereas the remaining point
mutation disrupts the affinity of an uncharacterized sequence-specific
DNA-binding protein present in mouse pancreatic progenitors. Amberger
(2014) noted that the mutations identified by Weedon et al. (2014) are
located within C10ORF115, a long noncoding RNA.
OTUD1
| dbSNP name | rs148315007(A,T); rs1511822(G,A); rs4586049(C,T); rs200391921(G,T) |
| ccdsGene name | CCDS44366.1 |
| cytoBand name | 10p12.2 |
| EntrezGene GeneID | 220213 |
| EntrezGene Description | OTU domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OTUD1:NM_001145373:exon1:c.A1122T:p.A374A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.008264 |
| ESP Afr MAF | 0.038295 |
| ESP All MAF | 0.012484 |
| ESP Eur/Amr MAF | 0.001257 |
| ExAC AF | 0.004458 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Spastic paraplegia;
Upper limbs may be affected;
Abnormal gait;
Hyperreflexia;
Extensor plantar responses;
Ataxia (in some patients);
Cerebellar atrophy (in some patients);
Spinal cord atrophy (1 family);
[Peripheral nervous system];
Axonal motor neuropathy
MISCELLANEOUS:
Onset usually in the first decade;
Later onset has been reported
MOLECULAR BASIS:
Caused by mutation in the patatin-like phospholipase domain-containing
protein 6 (PNPLA6, 603197.0001)
OMIM Title
*612022 OTU DOMAIN-CONTAINING PROTEIN 1; OTUD1
;;DUBA7
OMIM Description
DESCRIPTION
Deubiquitinating enzymes (DUBs; see 603478) are proteases that
specifically cleave ubiquitin (191339) linkages, negating the action of
ubiquitin ligases. DUBA7 belongs to a DUB subfamily characterized by an
ovarian tumor (OTU) domain.
CLONING
Kayagaki et al. (2007) identified ovarian tumor domain (OTU)-containing
protein 1 (OTUD1) in a small interfering RNA (siRNA)-based screen for
OTU deubiquitinating enzyme (DUB) family members. The 3,389-basepair
mRNA contains an open reading frame (ORF) predicting a 638-amino acid
protein. OTUD1 contains, in addition to an OTU domain, a ubiquitin
interaction motif (UIM) at the carboxy terminus.
MAPPING
The OTUD1 gene maps to chromosome 10p12.2 (Kayagaki et al., 2007).
PRTFDC1
| dbSNP name | rs1045873(A,C); rs11627(T,A); rs7912596(A,T); rs112871867(T,C); rs56307671(G,T); rs113794505(G,A); rs1326192(G,C); rs112874002(T,C); rs6482448(A,G); rs10828708(G,T); rs10828709(G,T); rs73606579(C,T); rs3789922(T,C); rs7083870(A,G); rs10741068(C,T); rs10828710(G,A); rs9417400(G,A); rs141419404(T,C); rs1124120(C,T); rs112422336(T,G); rs113642883(C,G); rs11014268(C,A); rs2104488(G,T); rs12775525(G,A); rs10828712(G,A); rs16925091(A,G); rs10828713(C,T); rs10828714(G,A); rs16925092(C,T); rs112909134(T,C); rs11014269(C,T); rs4483484(C,T); rs4561108(C,T); rs112987257(T,C); rs2184645(G,C); rs6482449(C,T); rs2184644(C,T); rs2152434(A,G); rs2152433(C,T); rs150535911(G,A); rs149662543(T,A); rs7903234(G,A); rs9417401(T,C); rs57683413(C,T); rs142159647(G,T); rs78372835(G,C); rs75604132(T,C); rs10828715(C,G); rs9418462(C,T); rs114932206(A,G); rs74122885(A,G); rs2484650(G,A); rs1033960(T,C); rs4748990(G,A); rs148881852(T,C); rs72780347(C,A); rs1971470(G,T); rs141559224(G,A); rs115140396(T,C); rs78659823(C,T); rs11014271(C,T); rs111631022(T,G); rs112511699(G,T); rs7080425(A,G); rs35881420(A,G); rs10828716(A,G); rs12572362(T,C); rs72780349(T,C); rs55985845(T,A); rs12414663(A,T); rs35163095(C,T); rs56291772(C,A); rs1932422(C,T); rs61854266(C,T); rs7914909(C,T); rs77053920(A,C); rs11014279(C,T); rs7394259(G,A); rs146476887(C,T); rs2478093(G,A); rs6482450(C,G); rs57024130(G,A); rs146907874(C,G); rs113640001(G,T); rs6482451(G,A); rs2484651(C,A); rs913023(T,A); rs7920077(T,A); rs913024(T,C); rs963700(A,T); rs142778478(A,G); rs112910939(C,T); rs144877953(A,G); rs6482452(G,C); rs72780351(C,T); rs72780352(T,C); rs7096011(A,T); rs7078551(C,T); rs75927785(G,A); rs10741070(T,C); rs10764506(A,G); rs10828717(G,A); rs11014281(A,G); rs12255347(C,T); rs12262875(A,G); rs11812652(G,A); rs10764507(T,C); rs72780356(C,T); rs7904653(T,C); rs7916535(C,T); rs881486(C,T); rs881487(C,A); rs111380392(A,G); rs881488(A,G); rs881489(C,T); rs11014283(T,C); rs881501(T,C); rs76259199(A,G); rs11014285(G,A); rs16925127(G,A); rs12572969(C,G); rs12241855(A,G); rs60455981(C,T); rs1543576(T,C); rs1543575(A,C); rs117721347(C,A); rs10828718(G,A); rs11818757(C,T); rs59516951(A,G); rs10764508(T,C); rs12245984(T,C); rs12246114(A,T); rs16925138(A,G); rs61854283(C,T); rs139828915(A,G); rs56928079(C,G); rs2148270(A,G); rs74389407(C,A); rs2148269(A,G); rs112056314(G,A); rs73606586(A,G); rs61854284(G,C); rs181800191(C,T); rs7087994(C,T); rs112258897(A,T); rs113925216(C,G); rs77979359(C,T); rs112851138(A,G); rs111620982(C,A); rs112417073(T,C); rs10828719(C,G); rs112284842(C,T); rs7901000(T,G); rs113470043(G,A); rs79393717(A,T); rs113054213(G,A); rs1590563(G,C); rs1590562(T,C); rs146212243(C,T); rs61854286(C,A); rs61854287(A,G); rs61854288(T,C); rs144473863(G,A); rs61854289(G,A); rs61854290(C,A); rs75134611(T,C); rs113958377(C,T); rs115413824(G,A); rs61854291(C,T); rs61854292(T,C); rs7072126(G,A); rs61854293(C,A); rs74424565(G,A); rs61854294(C,T); rs61854295(A,G); rs61854296(C,T); rs61854297(G,T); rs76260409(A,G); rs1886995(G,T); rs927820(T,C); rs1886994(C,T); rs61854298(T,A); rs56836835(A,G); rs59130408(A,G); rs76975009(C,T); rs75509254(A,T); rs77622584(A,T); rs75936638(T,A); rs41408444(T,C); rs76690621(T,C); rs75736775(G,A); rs76381631(A,G); rs76510471(C,T); rs79485486(G,A); rs61854300(G,A); rs144250989(A,T); rs77117854(C,G); rs111847848(G,A); rs113768347(C,G); rs145306126(G,A); rs112394048(C,T); rs76749739(A,C); rs113555319(C,G); rs77052499(T,C); rs6482453(A,G); rs113957884(C,T); rs78516723(G,A); rs10764509(G,A); rs111493910(G,A); rs76128598(C,T); rs115930442(G,A); rs141510095(C,G); rs11014290(C,G); rs9971228(A,T); rs113062441(G,A); rs111819893(T,C); rs112694607(G,A); rs77902718(C,T); rs116633470(C,T); rs76845336(C,T); rs77428528(T,C); rs10828720(T,G); rs6482454(C,T); rs2148271(C,T); rs115827519(T,C); rs114458888(T,C); rs10828721(G,A); rs11014291(T,C); rs16925145(G,A); rs6482455(C,G); rs184254998(T,A); rs7905553(C,T); rs56739897(C,T); rs59837383(C,T); rs7084900(G,A); rs11014296(C,T); rs11014297(A,G); rs112952897(C,T); rs10828723(T,C); rs1409306(C,G); rs7896608(T,G); rs7908585(C,T); rs114718617(G,C); rs10828724(A,C); rs4504964(G,A); rs377540240(C,T); rs12415620(C,T); rs140800517(C,G); rs12266014(C,T); rs185192396(T,C); rs12412055(A,G); rs35261383(G,T); rs9804265(A,C); rs111822977(A,T); rs150747282(A,G); rs76146926(G,A); rs59409706(T,C); rs113988897(C,T); rs73606590(C,T); rs4319409(T,C); rs4237368(A,G); rs1964149(T,C); rs1964150(A,T); rs1033962(C,T); rs7918015(A,G); rs58709104(C,A); rs55891662(C,T); rs112955547(G,A); rs61854330(A,G); rs10828725(G,T); rs74122904(T,C); rs61854331(A,G); rs12256206(G,A); rs61854332(G,C); rs7910241(G,A); rs4748991(A,G); rs4748992(A,C); rs139146610(C,A); rs1409307(G,A); rs7078660(T,C); rs7914847(G,A); rs7903956(T,A); rs146771818(C,A); rs7080423(A,G); rs60111280(A,T); rs113531783(A,T); rs56037178(C,A); rs12255703(A,T); rs4747507(C,T); rs4747508(C,T); rs12571791(A,G); rs11818463(G,C); rs115588926(C,A); rs1078552(C,T); rs77807805(A,T); rs112553476(G,A); rs11014306(T,C); rs11014307(A,G); rs11014308(T,C); rs11014309(C,A); rs111806882(A,G); rs61854335(C,T); rs61854336(C,T); rs61854337(C,T); rs72780362(A,C); rs143395795(C,T); rs61854338(C,A); rs150710671(A,C); rs12246876(T,C); rs12246878(T,G); rs112107862(T,A); rs10764511(C,T); rs10828727(C,T); rs112908812(A,G); rs7068636(A,G); rs10828728(T,C); rs111989177(A,C); rs74340410(A,G); rs12250911(T,A); rs111575128(C,G); rs10828730(C,T); rs11014314(C,G); rs12218997(T,C); rs3748223(A,G); rs10828731(C,T); rs11014315(G,T); rs73606594(T,C); rs12767180(G,A); rs274299(A,G); rs274298(T,C); rs10764513(A,G); rs274297(G,A); rs2035888(C,T); rs11014318(A,G); rs10764514(G,A); rs111579828(A,G); rs113697625(C,T); rs11014319(A,C); rs274295(C,T); rs10741071(A,C); rs10741072(T,A); rs10828732(A,C); rs11014320(C,T); rs73606598(T,C); rs185669(C,T); rs113785246(A,T); rs73606599(A,G); rs2478091(C,A); rs3000491(T,G); rs113754760(C,T); rs274316(C,A); rs112078121(A,T); rs10828735(C,T); rs73606600(C,A); rs141442312(C,G); rs112526004(A,T); rs7083691(C,T); rs11014322(T,C); rs274315(A,G); rs274314(A,G) |
| ccdsGene name | CCDS7145.1 |
| cytoBand name | 10p12.1 |
| EntrezGene GeneID | 56952 |
| EntrezGene Description | phosphoribosyl transferase domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.8683 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0223577235772 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.024543 |
| ESP All MAF | 0.007499 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002029 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Abnormal saccades;
Abnormal smooth pursuit;
Nystagmus
NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia;
Gait ataxia;
Limb ataxia;
Dysarthria;
Dysmetria;
Brisk lower limb reflexes (in some patients);
Cerebellar atrophy
MISCELLANEOUS:
Adult onset (mean of 30 years);
Slowly progressive
MOLECULAR BASIS:
Caused by mutation in the synaptic nuclear envelope protein-1 gene
(SYNE1, 608441.0001)
OMIM Title
*610751 PHOSPHORIBOSYL TRANSFERASE DOMAIN-CONTAINING PROTEIN 1; PRTFDC1
OMIM Description
CLONING
By searching databases for hypoxanthine guanine
phosphoribosyltransferase-1 (HPRT1; 308000)-like genes, Keebaugh et al.
(2007) identified PRTFDC1. The predicted PRTFDC1 protein contains a
phosphoribosyl transferase domain, but it lacks conservation of 11 HPRT1
residues critical for HPRT function, suggesting that PRTFDC1 has lost
its ancestral HPRT activity. Database analysis revealed that Prtfdc1 is
present in several vertebrate species. However, in mouse, the Prtfdc1
gene appeared to be inactive due to 3 independent mutations.
Using real-time RT-PCR, Suzuki et al. (2007) detected PRTFDC1 expression
in a wide range of tissues. Expression was highest in brain, cervix, and
pancreas, and moderate to low in colon, spleen, testis, heart, kidney,
placenta, liver, and esophagus. PRTFDC1 was not detected in skeletal
muscle. High PRTFDC1 expression was also detected in a normal oral
epithelial cell line.
GENE FUNCTION
Suzuki et al. (2007) found that the PRTFDC1 gene was inactivated either
by deletion or hypermethylation in a significant subset of oral squamous
cell carcinomas. Restoration of PRTFDC1 expression in 1 of these lines
inhibited cell growth in colony formation assays, whereas knockdown of
PRTFDC1 expression in PRTFDC1-expressing cells promoted cell growth.
GENE STRUCTURE
Keebaugh et al. (2007) determined that the PRTFDC1 gene contains 9 exons
and spans more than 100 kb.
Suzuki et al. (2007) identified a functional CpG island around exon 1 of
the PRTFDC1 gene.
MAPPING
By genomic sequence analysis, Suzuki et al. (2007) mapped the PRTFDC1
gene to chromosome 10p12.
LRRC37A6P
| dbSNP name | rs1144509(C,A); rs1144510(T,C); rs3118890(G,C); rs3818962(G,A); rs12256490(C,T); rs640284(T,C); rs7913638(C,T); rs7914017(C,A); rs7898820(A,T); rs76326011(T,C); rs1144511(A,G); rs114346826(T,G); rs79307066(G,A); rs193053733(A,G); rs12258518(C,T); rs1148168(T,C); rs113927433(G,T); rs111867089(C,T); rs114580452(A,T); rs74902596(T,A); rs77584738(C,T); rs12245194(G,A); rs79988883(A,C); rs111833757(G,A); rs75591085(T,C); rs112425733(T,C); rs148958496(G,C); rs60813549(T,C); rs56710909(G,A); rs7087198(T,C); rs11015624(G,A); rs7069127(G,A); rs590142(T,C); rs7091897(T,C); rs7069761(G,A); rs7896532(C,T); rs7070377(G,A); rs7070508(G,C); rs7092591(T,C); rs7092612(T,C); rs61737928(C,T); rs61737707(G,A); rs75072404(C,T); rs11015625(C,T) |
| cytoBand name | 10p12.1 |
| EntrezGene GeneID | 387646 |
| snpEff Gene Name | ACBD5 |
| EntrezGene Description | leucine rich repeat containing 37, member A6, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2149 |
PTCHD3
| dbSNP name | rs2505323(A,G); rs1638630(T,C); rs2505327(A,G); rs2484173(A,G); rs199572862(A,G); rs2429485(T,C); rs2505328(T,G); rs2484175(G,A); rs12780383(G,A); rs3004203(A,G); rs2907595(T,C); rs2991998(G,A); rs2991999(C,T); rs541032(C,T); rs661945(G,A); rs662385(G,A); rs662886(A,G); rs2505296(A,T); rs2429486(C,T); rs35547423(C,T); rs4638210(C,T); rs2505298(A,G); rs2505299(T,G); rs2429488(T,C); rs2429489(T,C); rs2505301(T,A); rs2429490(C,T); rs2505303(A,G); rs2484178(T,C); rs2429491(T,C); rs2484179(A,G); rs11015742(G,A); rs2484180(A,C); rs2484181(T,G); rs2505307(C,A); rs2484182(G,T); rs2429492(C,T); rs2484183(G,T); rs1334893(G,A); rs7099798(C,T); rs11015743(C,T); rs2484185(A,C); rs2484186(G,A); rs2484188(G,A); rs2484189(G,A); rs2429495(T,C); rs2429496(T,C); rs2429497(T,C); rs79625684(A,C); rs2484190(C,T); rs2484191(T,C); rs2429498(C,T); rs2505311(A,G); rs2505312(A,G); rs11015745(A,G); rs982739(G,A); rs12572927(A,G); rs2484192(A,G); rs12359622(A,G); rs7076204(A,G); rs35686808(C,T); rs67973526(A,G); rs76159318(T,C); rs11015748(T,G); rs79385423(A,G); rs11812591(A,T); rs12265601(C,T); rs12265974(C,T); rs11015749(A,G); rs2429499(G,A); rs2429500(C,G); rs149388365(C,T); rs2429501(A,G); rs2429502(A,C); rs7082826(C,T); rs11015752(C,T); rs6482625(C,T); rs11015753(G,A); rs7071851(A,G) |
| ccdsGene name | CCDS31173.1 |
| cytoBand name | 10p12.1 |
| EntrezGene GeneID | 374308 |
| EntrezGene Description | patched domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PTCHD3:NM_001034842:exon4:c.T1438C:p.S480P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6585 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3KNS1 |
| dbNSFP Uniprot ID | PTHD3_HUMAN |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002765 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Retinal arteriolar tortuosity;
Retinal hemorrhage
CARDIOVASCULAR:
[Heart];
Arrhythmias, supraventricular;
[Vascular];
Aneurysms of right internal carotid artery, intracranial segment;
Aneurysm of right middle cerebral artery, horizontal segment;
Raynaud phenomenon
GENITOURINARY:
[Kidneys];
Hematuria, microscopic;
Hematuria, gross (in some patients);
Renal cysts;
Renal failure, mild;
Basement membrane alterations in Bowman capsule, tubules, and interstitial
capillaries, with irregular thickening, splitting into multiple layers,
and electron-lucent areas;
Glomerular basement membrane normal
SKIN, NAILS, HAIR:
[Skin];
ELECTRON MICROSCOPY:;
Basement membrane duplications at dermoepidermal junction;
Dermal arteriole dissociation in vascular smooth muscle cells;
Basement membrane abnormally spread in vascular smooth muscle cells
[Nails];
Capillary tortuosity in nail beds
MUSCLE, SOFT TISSUE:
Muscle cramps
NEUROLOGIC:
[Central nervous system];
Leukoencephalopathy, periventricular;
Microvascular spaces, dilated;
Cerebrovascular accident (in some patients)
LABORATORY ABNORMALITIES:
Creatine kinase, serum, elevated;
Glomerular filtration rate, decreased
MOLECULAR BASIS:
Caused by mutation in the collagen IV, alpha-1 polypeptide gene (COL4A1,
120130.0007)
OMIM Title
*611791 PATCHED DOMAIN-CONTAINING PROTEIN 3; PTCHD3
OMIM Description
CLONING
Fan et al. (2007) cloned 2 splice variants of mouse Ptchd3. The deduced
proteins contain 410 and 906 amino acids, of which the first 409
residues are identical. Northern blot analysis of mouse tissues detected
2 transcripts in testis only. RT-PCR showed Ptchd3 expression starting
around day 16 of mouse postnatal development, suggesting that Ptchd3 is
expressed around the pachytene stage of spermatogenesis. Expression of
Ptchd3 was not detected in mice lacking germ cells. Immunofluorescence
analysis localized PTCHD3 to the midpiece of human, mouse, and rat
sperm.
MAPPING
Fan et al. (2007) stated that the PTCHD3 gene maps to human chromosome
10p12.1 and to mouse chromosome 11E2.
ZEB1-AS1
| dbSNP name | rs11008457(A,G); rs3737178(A,G); rs3737179(T,G); rs3737180(G,C) |
| cytoBand name | 10p11.22 |
| EntrezGene GeneID | 220930 |
| snpEff Gene Name | ZEB1 |
| EntrezGene Description | ZEB1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.073 |
NRP1
| dbSNP name | rs1044274(T,C); rs1044268(C,T); rs189072579(T,C); rs1044222(T,C); rs10827206(C,T); rs1044210(G,T); rs189331586(A,T); rs2506140(A,G); rs13324(G,A); rs2506141(T,C); rs2474733(G,A); rs2506142(A,G); rs2506143(A,G); rs2506144(C,T); rs1048804(A,G); rs2474732(A,G); rs12771906(G,T); rs2506145(T,C); rs2474731(C,T); rs12415845(T,A); rs2474730(C,T); rs1010826(G,A); rs76711702(G,A); rs2474728(G,A); rs2474727(C,T); rs2224319(A,G); rs2506146(G,C); rs2228638(C,T); rs2383984(G,A); rs2506147(C,G); rs2073322(C,T); rs2070301(T,C); rs2070300(G,A); rs7910131(G,A); rs182067209(G,A); rs2073321(A,T); rs2506148(G,C); rs2253918(C,T); rs184906150(T,C); rs61856363(G,T); rs34217492(A,T); rs12572518(C,G); rs12572545(G,T); rs12573679(T,G); rs185777373(A,G); rs61760430(C,A); rs2506149(C,T); rs60607944(G,C); rs2243920(A,G); rs55913561(C,T); rs10827207(C,T); rs7077034(C,T); rs41511045(C,A); rs73257931(A,C); rs2506150(G,A); rs2474726(T,A); rs2506151(G,A); rs2506152(T,C); rs2474725(T,C); rs2474724(C,T); rs11009276(C,A); rs734187(G,A); rs60773850(C,T); rs734186(G,A); rs2247015(G,T); rs2474723(T,C); rs10827208(A,G); rs1139169(A,G); rs145490828(A,T); rs10827209(A,C); rs10827210(G,C); rs11009281(T,C); rs2247383(G,A); rs2247396(G,A); rs11009283(A,C); rs11009284(T,C); rs2247486(A,G); rs2247494(T,C); rs1555321(G,A); rs1555320(G,T); rs41306338(T,C); rs1555319(C,G); rs2284948(T,G); rs2284947(G,A); rs2284946(C,T); rs2284945(A,G); rs2284944(C,T); rs11009285(G,A); rs2474720(T,C); rs11009288(G,A); rs2247715(A,G); rs3818195(G,C); rs2474719(T,G); rs10827211(G,A); rs2474716(A,G); rs2269106(G,C); rs2269105(A,T); rs2269104(G,A); rs2284943(T,C); rs2284942(T,C); rs10218992(A,G); rs11812166(C,T); rs11815912(A,G); rs2474715(A,G); rs11812181(C,A); rs11815961(A,C); rs2474714(A,G); rs10827212(A,G); rs201423916(G,A); rs10827213(G,A); rs2891372(G,A); rs2506154(C,T); rs2474713(A,C); rs2383985(A,C); rs2474712(T,C); rs11009291(G,A); rs2038408(C,T); rs2038407(A,T); rs2269103(G,T); rs2070303(C,T); rs200458166(T,C); rs11009295(G,A); rs2506155(C,A); rs2300953(A,G); rs2300952(C,T); rs2254826(G,T); rs2300951(T,C); rs2300950(C,T); rs2300949(T,A); rs2300948(A,C); rs10827214(G,A); rs11594083(G,A); rs10763917(G,A); rs743168(G,A); rs11009298(A,G); rs11009299(C,T); rs11009301(T,C); rs2269102(T,C); rs2269101(C,T); rs2269100(T,G); rs2269099(T,C); rs2269098(G,A); rs1411923(G,A); rs1360456(C,T); rs4244999(C,T); rs12357399(C,T); rs12357439(G,C); rs12359014(T,C); rs11009302(G,A); rs2269096(C,T); rs10827215(G,A); rs4934836(G,A); rs11009305(G,A); rs10827216(G,A); rs10827217(C,T); rs10827218(T,C); rs4934837(G,A); rs2229935(G,A); rs2229934(G,A); rs149211451(A,G); rs2273466(T,C); rs11009306(A,G); rs112588537(A,T); rs2208174(C,T); rs2269095(T,C); rs3851076(T,C); rs186322816(C,T); rs61843160(C,G); rs10763918(C,T); rs145492424(G,T); rs17504012(G,C); rs57997960(C,T); rs56239610(G,A); rs12411679(T,A); rs11009308(A,G); rs2300947(C,T); rs116135909(C,T); rs11009309(C,A); rs1331317(A,G); rs1331316(C,T); rs150908749(A,G); rs16934232(C,G); rs3904032(G,A); rs11009311(C,A); rs72790215(G,C); rs78905792(C,T); rs141418090(G,A); rs61843204(G,A); rs77828306(C,T); rs1888691(C,T); rs78656993(A,G); rs1331315(A,G); rs1331314(C,G); rs2300944(C,T); rs927099(T,C); rs11009313(G,A); rs12765284(G,A); rs7915584(T,A); rs56242597(T,C); rs2269094(T,C); rs113734817(A,G); rs2269093(A,G); rs2269092(G,A); rs2269091(G,T); rs56291819(A,C); rs7893572(T,C); rs193216404(G,A); rs2269089(C,G); rs2269088(A,G); rs2269087(C,T); rs138998514(C,G); rs12762312(C,T); rs61843208(G,A); rs11009314(C,T); rs112807374(C,G); rs7920577(G,C); rs7920530(A,G); rs7920956(G,A); rs7920615(A,G); rs12570078(G,A); rs7920741(C,T); rs189645918(T,C); rs7921035(A,G); rs10827219(G,T); rs17413155(T,G); rs17413169(T,C); rs11009315(G,A); rs75432745(C,T); rs10490939(G,A); rs4934847(C,T); rs4934849(C,T); rs191779668(T,C); rs1888690(G,C); rs1888689(A,C); rs1888688(C,T); rs1888687(C,G); rs2077802(A,T); rs73251972(G,A); rs7915855(G,A); rs725328(C,T); rs75194564(G,T); rs12243943(G,A); rs139044889(C,T); rs2284941(T,C); rs35359173(G,T); rs2284940(T,A); rs6481840(T,C); rs6481841(G,A); rs11009318(T,C); rs11009319(G,A); rs11009320(G,A); rs148968281(G,T); rs61843210(T,A); rs16934266(T,C); rs12779935(A,G); rs12781701(T,C); rs41276086(C,A); rs11009323(C,T); rs2269085(T,C); rs2383987(T,C); rs2269084(G,C); rs1888686(T,C); rs1888685(C,T); rs11598565(A,G); rs73251978(A,G); rs11009324(G,A); rs146418754(C,T); rs10827220(G,C); rs10763919(T,A); rs143268815(G,A); rs7074620(T,C); rs4934851(T,C); rs4934583(G,A); rs1537174(G,A); rs1319014(G,A); rs1319013(T,G); rs7096016(C,A); rs1028548(T,A); rs11593943(C,T); rs10827221(G,C); rs139031410(G,A); rs12356872(C,T); rs11594606(G,A); rs7098579(T,C); rs17505094(G,C); rs3780869(C,T); rs3780868(T,A); rs3780867(G,A); rs193079169(C,T); rs10490938(C,T); rs10827222(T,A); rs4934852(A,T); rs16934292(G,A); rs11598845(T,C); rs11009326(C,T); rs11592642(A,G); rs150643258(C,A); rs58089461(C,T); rs2383988(A,G); rs7899851(C,T); rs2070299(G,A); rs2070298(A,C); rs2070297(G,A); rs2070296(C,T); rs7079053(A,G); rs2073320(A,G); rs143913547(G,A); rs11819374(C,T); rs112286543(G,A); rs2284939(G,A); rs151034550(C,G); rs2284938(A,G); rs11819443(C,T); rs7921144(G,T); rs6481842(T,G); rs10827223(A,T); rs1331312(G,C); rs1331311(T,C); rs7068390(C,A); rs141607577(A,G); rs73251998(C,T); rs10763920(G,T); rs73251999(T,C); rs73252000(T,C); rs10740868(G,A); rs10827224(A,C); rs1571781(A,G); rs7095842(T,C); rs7078603(C,T); rs10763921(C,T); rs7907256(G,A); rs7907166(A,G); rs10827225(T,A); rs59523886(G,A); rs10827226(T,C); rs4934584(A,G); rs12769036(T,A); rs2776927(C,T); rs12218572(T,C); rs11009328(C,A); rs17296436(A,G); rs17296443(C,T); rs10827227(C,T); rs9299707(T,A); rs74129647(G,A); rs150976370(C,A); rs2243668(G,A); rs79155924(C,T); rs148340929(C,T); rs34476541(A,G); rs139703403(T,C); rs181615327(T,C); rs9971191(A,G); rs10437419(T,C); rs76477097(A,T); rs183023693(C,T); rs9971215(A,G); rs61843219(T,C); rs10827228(T,G); rs10827229(C,A); rs2776925(G,A); rs2776924(G,C); rs1952983(G,T); rs61843220(C,A); rs10827230(C,T); rs11009333(A,T); rs2804460(T,C); rs2804461(A,G); rs869636(C,T); rs869637(T,C); rs74129648(C,T); rs870087(C,T); rs10763922(T,C); rs10763923(G,A); rs2804470(A,G); rs7079372(T,C); rs2776928(C,T); rs999965(T,C); rs139618249(T,C); rs999966(C,T); rs2804475(G,C); rs10763924(A,G); rs10763925(G,A); rs4934858(C,T); rs116570856(C,T); rs141408673(C,T); rs116082317(C,T); rs4934863(T,C); rs4934864(T,C); rs79137925(A,G); rs1331326(C,T); rs1331325(T,C); rs4934871(G,A); rs6481844(T,C); rs141382536(C,T); rs12358370(C,G); rs7910405(T,C); rs10827231(A,C); rs7894790(G,C); rs4277057(G,T); rs12573218(C,T); rs12573233(C,T); rs2776930(C,T); rs1331324(C,G); rs112595410(T,C); rs74129650(T,C); rs145835028(T,C); rs16934374(C,T); rs182469701(G,A); rs75290613(C,T); rs11009334(T,C); rs12252214(T,A); rs6481845(T,C); rs73252174(T,C); rs4934896(A,G); rs2065366(G,A); rs11597915(A,G); rs2065365(T,C); rs2065364(T,C); rs12573762(G,T); rs139998287(C,T); rs112118388(G,C); rs73252179(A,G); rs4934901(A,T); rs11009336(G,T); rs11595164(T,C); rs12358711(A,T); rs7896887(G,A); rs75135051(G,A); rs2776934(C,G); rs16934380(T,G); rs2776935(G,A); rs142040427(G,A); rs2776936(C,T); rs2804491(A,C); rs140100010(C,T); rs2804492(T,C); rs73252185(A,G); rs16934384(G,A); rs7086456(C,T); rs6481846(G,A); rs2768421(C,T); rs368974149(G,A); rs76932011(C,T); rs79206496(G,A); rs11009337(C,T); rs73252188(G,A); rs2768420(G,A); rs2804493(A,G); rs12259300(T,C); rs2776937(A,G); rs11009338(A,T); rs868609(T,C); rs112020602(C,T); rs11492493(G,A); rs9418057(T,C); rs10827232(G,A); rs11009339(C,G); rs2804494(G,C); rs11009340(G,T); rs73252200(C,T); rs60036686(C,A); rs146877442(C,T); rs2776923(C,A); rs4934914(G,A); rs7070290(G,A); rs7070426(G,T); rs2776922(A,G); rs2804495(G,T); rs10827234(T,C); rs10827235(C,G); rs10827236(A,G); rs113584938(C,A); rs2804496(T,C); rs11009343(A,T); rs74592913(C,T); rs4934597(C,T); rs75092248(C,A); rs1411926(T,A); rs12358796(C,T); rs11009344(G,A); rs78931693(G,C); rs34181815(T,C); rs1360457(A,G); rs74481906(C,G); rs61758245(A,G); rs61758241(A,G); rs1411924(C,T); rs61758240(T,C); rs2804498(C,T); rs1888684(A,G) |
| ccdsGene name | CCDS31179.1 |
| cytoBand name | 10p11.22 |
| EntrezGene GeneID | 8829 |
| EntrezGene Description | neuropilin 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.867 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 0.0002521 |
OMIM Clinical Significance
Skin:
Tegumentary leishmaniasis susceptibility
Inheritance:
Autosomal recessive;
Heterogeneity;
Age dependent penetrance
OMIM Title
*602069 NEUROPILIN 1; NRP1
;;NPN1; NP1;;
NRP;;
VASCULAR ENDOTHELIAL GROWTH FACTOR-165 RECEPTOR; VEGF165R;;
BLOOD DENDRITIC CELL ANTIGEN 4; BDCA4
OMIM Description
DESCRIPTION
NRP1 is a membrane-bound coreceptor to a tyrosine kinase receptor for
both vascular endothelial growth factor (VEGF; 192240) and semaphorin
(see SEMA3A; 603961) family members. NRP1 plays versatile roles in
angiogenesis, axon guidance, cell survival, migration, and invasion.
CLONING
Neuropilin is a type I transmembrane protein initially identified by
Takagi et al. (1987) and Fujisawa et al. (1989) as an epitope recognized
by a monoclonal antibody that labels specific subsets of axons in the
developing Xenopus nervous system. Neuropilin comprises in its
extracellular domain several distinctive motifs; its cytoplasmic domain
is short (40 amino acids) and is highly conserved among Xenopus, mouse,
and chick. He and Tessier-Lavigne (1997) cloned the gene encoding human
neuropilin and characterized the structure of the protein product.
Using VEGF165 to probe a breast carcinoma cell line expression library,
Soker et al. (1998) cloned NRP1. The deduced 923-amino acid protein
contains an N-terminal signal sequence, an ectodomain, a transmembrane
region, and a cytoplasmic domain, consistent with the structure of a
cell surface receptor. Northern blot analysis detected a 7.0-kb
transcript. Expression was high in heart and placenta, moderate in lung,
liver, skeletal muscle, kidney, and pancreas, and relatively low in
brain.
Gagnon et al. (2000) cloned a 2.2-kb truncated NRP1 cDNA from a prostate
carcinoma cell line cDNA library. The 3-prime end contains a unique
intron-derived sequence that is absent in full-length NRP1 cDNA. The
truncated cDNA encodes a deduced 664-amino acid soluble protein,
designated sNRP1, that contains only the N-terminal extracellular CUB
and coagulation factor homology domains. Western blot analysis detected
sNRP1 secreted by cells at an apparent molecular mass of 90 kD. In situ
hybridization of human tissues detected differential expression of
full-length NRP1 and sNRP1 mRNA in liver, kidney, skin, and breast.
Full-length NRP1, but not sNRP1, was detected in blood vessels.
Rossignol et al. (2000) identified another truncated soluble NRP1
isoform. The deduced 704-amino acid protein lacks the MAM homology,
transmembrane, and C-terminal cytoplasmic domains. RT-PCR analysis
detected full-length NRP1 and both soluble isoforms in all tissues
examined.
Cackowski et al. (2004) identified 2 novel splice variants that encode
soluble isoforms of NRP1. These isoforms, which contain 551 and 609
amino acids, are distinct from 2 previously characterized soluble
isoforms containing 644 and 704 amino acids (Gagnon et al., 2000;
Rossignol et al., 2000). All NRP1 soluble isoforms are identical to the
full-length 923-amino acid membrane-bound protein through the N-terminal
SEMA3A- and VEGF165-binding domains, but they lack the C-terminal MAM
domain, transmembrane region, and cytoplasmic domain of the full-length
protein.
GENE STRUCTURE
Rossignol et al. (2000) determined that the NRP1 gene contains 17 exons
and spans 120 kb. Cackowski et al. (2004) found that soluble NRP1
isoforms are derived from transcripts that are alternatively spliced
after exon 9.
MAPPING
By somatic cell hybrid analysis, Rossignol et al. (1999) mapped the NRP1
gene to chromosome 10. They localized the gene to 10p12 by radiation
hybrid mapping.
GENE FUNCTION
Extending axons in the developing nervous system are guided to their
targets through the coordinate actions of attractive and repulsive
guidance cues. The semaphorin family of guidance cues comprises several
members that can function as diffusible axonal chemorepellents. He and
Tessier-Lavigne (1997) set out to elucidate the mechanisms that mediate
the repulsive actions of collapsin-1/semaphorin III/D (SEMA3A), referred
to as 'Sema III'. By expression cloning they searched for sema
III-binding proteins in embryonic rat sensory neurons. They found that
sema III binds with high affinity to the transmembrane protein
neuropilin, and that antibodies to neuropilin blocks the ability of sema
III to repel sensory axons and to induce collapse of their growth cones.
He and Tessier-Lavigne (1997) concluded that neuropilin is a receptor or
a component of a receptor complex that mediates the effects of sema III
on these axons.
Kolodkin et al. (1997) likewise showed that neuropilin is a semaphorin
III receptor. They also identified rat neuropilin-2 (NRP2; 602070), a
related neuropilin family member, and showed that neuropilin and
neuropilin-2 are expressed in overlapping, yet distinct, populations of
neurons in the rat embryonic nervous system.
Soker et al. (1998) confirmed that NRP1 binds VEGF165 but not VEGF121.
They showed that when coexpressed in cells with KDR (VEGFR2; 191306),
neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated
chemotaxis. Conversely, inhibition of VEGF165 binding to neuropilin-1
inhibits its binding to KDR and its mitogenic activity for endothelial
cells. Soker et al. (1998) proposed that neuropilin-1 is a novel VEGF
receptor that modulates VEGF binding to KDR and subsequent bioactivity
and therefore may regulate VEGF-induced angiogenesis.
There are 3 isoforms of placenta growth factor (PGF; 601121), designated
PGF1, PGF2, and PGF3. Only PGF2 is able to bind heparin. Migdal et al.
(1998) found that PGF2 bound NRP1 in human umbilical vein endothelial
cells in a heparin-dependent fashion. Sulfation of the glucosamine-O-6
and iduronic acid-O-2 groups of heparin potentiated PGF2 binding to
NRP1. NRP1 also bound PGF1 with lower affinity.
Takahashi et al. (1999) found that the 2 semaphorin-binding proteins,
plexin-1 (PLXN1; 601055) and neuropilin-1 (NRP1), form a stable complex.
PLXN1 alone did not bind SEMA3A, but the NRP1/PLXN1 complex had a higher
affinity for SEMA3A than did NRP1 alone. While SEMA3A binding to NRP1
did not alter nonneuronal cell morphology, SEMA3A interaction with
NRP1/PLXN1 complexes induced adherent cells to round up. Expression of a
dominant-negative PLXN1 in sensory neurons blocked SEMA3A-induced growth
cone collapse. SEMA3A treatment led to the redistribution of growth cone
NRP1 and PLXN1 into clusters. Thus, the authors concluded that
physiologic SEMA3A receptors consist of NRP1/PLXN1 complexes.
Gagnon et al. (2000) determined that the 644-amino acid soluble NRP1
isoform (sNRP1) bound VEGF165, but not VEGF121. It inhibited VEGF165
binding to endothelial and tumor cells and VEGF165-induced tyrosine
phosphorylation of KDR in endothelial cells. Rat prostate carcinoma
cells expressing recombinant sNRP1 showed extensive hemorrhage, damaged
vessels, and apoptotic tumor cells. Gagnon et al. (2000) concluded that
sNRP1 appears to be a VEGF165 antagonist.
By raising monoclonal antibodies against immunomagnetically purified CD4
(186940)-positive blood dendritic cells (BDCs), Dzionek et al. (2000)
identified 3 BDC antigens: BDCA2 (CLEC4C; 606677), BDCA3, and BDCA4. In
fresh human blood, expression of BDCA2 and BDCA4 was strictly confined
to plasmacytoid CD123 (IL3RA; 308385)-bright/CD11C (ITGAX;
151510)-negative BDCs, whereas expression of BDCA3 was restricted to a
small population of CD123-negative/CD11C-positive BDCs. This small
population of BDCA3-positive BDCs shared many immunophenotypic features
with classical CD123-dim/CD11C-bright BDCs, but unlike those BDCs,
BDCA3-positive BDCs lacked expression of BDCA1 (CD1C; 188340), CD2
(186990), and several Fc receptors (see 146790).
Most striatal and cortical interneurons arise from the basal
telencephalon, later segregating to their respective targets. Marin et
al. (2001) demonstrated that migrating cortical interneurons avoid
entering the striatum because of a chemorepulsive signal composed at
least in part of semaphorin-3A (603961) and semaphorin-3F (601124).
Migrating interneurons expressing neuropilins, receptors for
semaphorins, are directed to the cortex; those lacking them go to the
striatum. Loss of neuropilin function increases the number of
interneurons that migrate into the striatum. Marin et al. (2001)
concluded that their observations reveal a mechanism by which
neuropilins mediate sorting of distinct neuronal populations into
different brain structures, and provide evidence that, in addition to
guiding axons, these receptors also control neuronal migration in the
central nervous system.
Primary immune responses require contact between dendritic cells (DC)
and resting naive T cells in secondary lymphoid organs. Noting that in
1868 Paul Langerhans described the analogy between DC (subsequently
termed Langerhans cells) and neurons in studies of the nerves in human
skin, Tordjman et al. (2002) proposed that NRP1 may be expressed by DC.
Using immunofluorescence microscopy, RT-PCR, and immunoblot analysis, as
well as flow cytometry, Tordjman et al. (2002) detected NRP1 on
dendritic cells and resting T lymphocytes. After T-cell contact with DC,
T-cell NRP1 colocalized with CD3 (see 186780) in the immunologic synapse
and, sometimes, also at the opposite pole of the T cell. Soluble NRP1
interacts in a homophilic fashion with NRP1 on both DC and T cells, and
this binding can be inhibited by blocking antibodies to NRP1. Ectopic
expression of NRP1 in COS cells induced cluster formation with resting T
cells. In the presence of blocking antibody to NRP1, cluster formation
between DC and resting, but not activated, T cells is partially
inhibited as is T cell proliferation, reflecting the presence of
numerous other adhesion or integrin molecules such as CD58 (LFA3;
153420) involved in the stabilization of DC-T cell contact. Tordjman et
al. (2002) concluded that NRP1-mediated interactions are a necessary
element in the initiation of the primary immune response and offer
another example, like that of agrin (103320), of a molecule shared by
neurologic and immunologic synapses.
Neuropilin-1, earlier identified as a neuronal receptor that mediates
repulsive growth cone guidance, functions also in endothelial cells as
an isoform-specific receptor for vascular endothelial growth factor
VEGF165 and as a coreceptor in vitro of VEGFR2. Oh et al. (2002) showed
that VEGF selectively upregulates NRP1 but not NRP2 via the VEGF
receptor 2-dependent pathway. In a murine model of VEGF-dependent
angioproliferative retinopathy, intense NRP1 mRNA expression was
observed in the newly formed vessels. Furthermore, selective NRP1
inhibition in this model suppressed neovascular formation substantially.
These results suggested that VEGF can not only activate endothelial
cells directly but also contribute to robust angiogenesis in vivo by a
mechanism that involves upregulation of its cognate receptor expression.
Cackowski et al. (2004) found that the 551- and 609-amino acid soluble
NRP1 isoforms showed binding capacities for SEMA3A and VEGF165 similar
to that of the 644-amino acid soluble NRP1 isoform. In addition, all 3
of these isoforms inhibited full-length NRP1-mediated migration in a
breast carcinoma cell line. Cackowski et al. (2004) concluded that the
soluble NRP1 isoforms antagonize NRP1-mediated cellular activities.
Using immunohistochemistry, Lepelletier et al. (2007) found that NP1 and
SEMA3A were expressed in thymic epithelial cells (TECs) and CD4/CD8 (see
186910) thymocytes. Both IL7 (146660), which is constitutively secreted
by TECs, and T-cell receptor (TCR) engagement upregulated NP1 expression
in thymocytes. SEMA3A blocked adhesion of NP1-positive thymocytes to
TECs and induced thymocyte repulsive migration, partially by inhibiting
binding of very late antigens (see ITGA4; 192975) to laminin (see LAMA1;
150320). Lepelletier et al. (2007) concluded that NP1 and SEMA3A
interactions are important in regulation of migration and adhesion of
thymocytes.
Sarris et al. (2008) found that mouse Nrp1, which is expressed by most
regulatory T cells (Tregs), but not by naive T-helper cells, promoted
prolonged interactions with immature dendritic cells, resulting in
higher sensitivity to limiting amounts of antigen. They proposed that
Treg cells have an advantage over naive Th cells, with the same
specificity leading to a default suppression of immune responses in the
absence of proinflammatory 'danger signals.'
Imai et al. (2009) analyzed the pre-target axon sorting for olfactory
map formation in mice. In olfactory sensory neurons, an axon guidance
receptor, neuropilin-1, and its repulsive ligand, semaphorin-3A (SEMA3A;
603961), are expressed in a complementary manner. Imai et al. (2009)
found that expression levels of neuropilin-1 determined both pre-target
sorting and projection sites of axons. Olfactory sensory neuron-specific
knockout of semaphorin-3A perturbed axon sorting and altered the
olfactory map topography. Thus, Imai et al. (2009) concluded that
pre-target axon sorting plays an important role in establishing the
topographic order based on the relative levels of guidance molecules
expressed by axons.
Tran et al. (2009) found that a Sema3A/Npn1/PlexA4 (604280) signaling
cascade controls basal dendritic arborization in layer V cortical
neurons, but does not influence spine morphogenesis or distribution. In
contrast, they demonstrated that the secreted semaphorin Sema3F (601124)
is a negative regulator of spine development and synaptic structure.
Mice with null mutations in genes encoding Sema3F and its holoreceptor
components Npn2 (602070) and plexin A3 (PLEXA3; 300022) exhibit
increased dentate gyrus granule cell and cortical layer V pyramidal
neuron spine number and size, and also aberrant spine distribution.
Moreover, Sema3F promotes loss of spines and excitatory synapses in
dissociated neurons in vitro, and in Npn2-null brain slices cortical
layer V and dentate gyrus granule cells exhibit increased miniature
excitatory postsynaptic current frequency. These disparate effects of
secreted semaphorins are reflected in the restricted dendritic
localization of Npn2 to apical dendrites and of Npn1 to all dendrites of
cortical pyramidal neurons.
Beck et al. (2011) used a mouse model of skin tumors to investigate the
impact of the vascular niche and VEGF (VEGFA; 192240) signaling on
controlling the stemness of squamous skin tumors during the early stages
of tumor progression. They showed that cancer stem cells of skin
papillomas are localized in a perivascular niche, in the immediate
vicinity of endothelial cells. Furthermore, blocking Vegfr2 (191306)
caused tumor regression not only by decreasing the microvascular
density, but also by reducing cancer stem cell pool size and impairing
cancer stem cell renewal properties. Conditional deletion of Vegfa in
tumor epithelial cells caused tumors to regress, whereas Vegf
overexpression by tumor epithelial cells accelerated tumor growth. In
addition to its well-known effect on angiogenesis, Vegf affected skin
tumor growth by promoting cancer stemness and symmetric cancer stem cell
division, leading to cancer stem cell expansion. Moreover, deletion of
Nrp1, a VEGF coreceptor expressed in cutaneous cancer stem cells,
blocked Vegf's ability to promote cancer stemness and renewal. Beck et
al. (2011) concluded that their results identified a dual role for tumor
cell-derived VEGF in promoting cancer stemness: by stimulating
angiogenesis in a paracrine manner, VEGF creates a perivascular niche
for cancer stem cells, and by directly affecting cancer stem cells
through NRP1 in an autocrine loop, VEGF stimulates cancer stemness and
renewal. Finally, deletion of NRP1 in normal epidermis prevents skin
tumor initiation.
Hayashi et al. (2012) showed that Sema3A exerts an osteoprotective
effect by both suppressing osteoclastic bone resorption and increasing
osteoblastic bone formation. The binding of Sema3A to Nrp1 inhibited
RANKL (602642)-induced osteoclast differentiation by inhibiting ITAM
(608740) and RhoA (165390) signaling pathways. In addition, Sema3A and
Nrp1 binding stimulated osteoblast and inhibited adipocyte
differentiation through the canonical Wnt/beta-catenin signaling pathway
(see 116806). The osteopenic phenotype in Sema3a-null mice was
recapitulated by mice in which the Sema3A-binding site of Nrp1 had been
genetically disrupted. Intravenous Sema3A administration in mice
increased bone volume and expedited bone regeneration.
Delgoffe et al. (2013) showed that the immune cell-expressed ligand
semaphorin 4A (SEMA4A; 607292) and the Treg cell-expressed receptor Nrp1
interact both in vitro, to potentiate Treg-cell function and survival,
and in vivo, at inflammatory sites. Using mice with a Treg
cell-restricted deletion of Nrp1, Delgoffe et al. (2013) showed that
Nrp1 is dispensable for suppression of autoimmunity and maintenance of
immune homeostasis, but is required by Treg cells to limit antitumor
immune responses and to cure established inflammatory colitis. Sema4a
ligation of Nrp1 restrained Akt (164730) phosphorylation cellularly and
at the immunologic synapse by Pten (601728), which increased nuclear
localization of the transcription factor Foxo3a (602681). The
Nrp1-induced transcriptome promoted Treg cell stability by enhancing
quiescence and survival factors while inhibiting programs that promote
differentiation. Importantly, this Nrp1-dependent molecular program is
evident in intratumoral Treg cells. Delgoffe et al. (2013) concluded
that their data supported a model in which Treg-cell stability can be
subverted in certain inflammatory sites, but is maintained by a
Sema4a-Nrp1 axis.
MOLECULAR GENETICS
Because mutant mice lacking a functional SEMA3A-binding domain in NRP1
have a Kallmann syndrome-like phenotype (see HH16, 614897), Hanchate et
al. (2012) analyzed the NRP1 gene in 24 patients with Kallmann syndrome
carrying heterozygous mutations in the SEMA3A gene and in 100 Kallmann
syndrome patients without SEMA3A mutations, but found no mutations. The
authors concluded that mutations in NRP1 are rare or not present in
patients with Kallmann syndrome.
ANIMAL MODEL
Takashima et al. (2002) showed that transgenic mice died in utero at
embryonic day 8.5 when both Nrp1 and Nrp2, which they called Np1 and
Np2, respectively, were knocked out. The yolk sacs of these mice were
totally avascular. Mice deficient for Nrp2 but heterozygous for Nrp1 or
deficient for Nrp1 but heterozygous for Nrp2 were also embryonic lethal
and survived to embryonic days 10 to 10.5. Other details of the abnormal
vascular phenotype resembled those of Vegf and Vefgr2 knockouts. The
results suggested that neuropilins are early genes in embryonic vessel
development and that both NRP1 and NRP2 are required.
NRP1 is a cell surface receptor for both VEGF and SEMA3A and is
expressed by both neurons and endothelial cells. Lee et al. (2002)
showed that in zebrafish the Nrp1 protein was a functional receptor for
human VEGF165. Whole-mount in situ hybridization showed that transcripts
of the zebrafish NRP1 gene during embryonic and early larval development
were detected mainly in neuronal and vascular tissues. A knockdown of
the gene in embryos resulted in vascular defects. Embryos treated with
VEGFR2 kinase inhibitor had a similar vessel defect, suggesting that
knockdown of zebrafish NRP1 reduces VEGF activity. To determine whether
NRP1 and VEGF activities are interdependent in vivo, zebrafish NRP1 and
VEGF morpholinos were coinjected into embryos at concentrations that
individually did not significantly inhibit blood vessel development. The
result was a potent inhibition of blood cell circulation via both
intersegmental and axial vessels, demonstrating that VEGF and NRP1 act
synergistically to promote a functional circulatory system. These
results provided the first physiologic demonstration that NRP1 regulated
angiogenesis through a VEGF-dependent pathway.
Gu et al. (2003) generated Npn1 knockin mice, which expressed a variant
of Npn1 with altered ligand binding, and conditional Npn1-null mice.
They determined that Vegf-Npn1 signaling in endothelial cells was
required for angiogenesis. Sema-Npn1 signaling was dispensable for
angiogenesis, but it was required for axonal pathfinding by several
populations of neurons in the central and peripheral nervous systems.
Both Vegf-Npn1 and Sema-Npn1 signaling were critical for heart
development.
Young et al. (2012) generated mice lacking a functional semaphorin (see
603961)-binding domain in Nrp1 and observed the development of a
Kallmann syndrome-like phenotype (see HH16, 614897). Pathohistologic
analysis of the mutant mice showed abnormal development of the
peripheral olfactory system and defective embryonic migration of the
neuroendocrine GnRH cells to the basal forebrain, which resulted in
increased mortality of newborn mice and reduced fertility in adults.
PARD3-AS1
| dbSNP name | rs1141026(G,C) |
| cytoBand name | 10p11.21 |
| snpEff Gene Name | PARD3 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08815 |
FZD8
| dbSNP name | rs1352(T,C); rs188557882(C,T) |
| cytoBand name | 10p11.21 |
| EntrezGene GeneID | 8325 |
| EntrezGene Description | frizzled family receptor 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps with exercise;
Muscle pain with exercise;
Muscle stiffness with exercise;
Muscle hyperirritability;
Muscle hypertrophy;
Muscle mounding;
Muscle activity is electrically silent on EMG;
Percussion-induced rapid rolling muscle contractions (PIRC);
Decreased caveolin-3 expression on muscle biopsy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Mean age of onset 22 years (range 5-54);
Genetic heterogeneity (see RMD1, 600332);
Autosomal recessive inheritance has been reported (see 601253.0010);
Allelic disorder to limb girdle muscular dystrophy type 1C (LGMD1C,
607801)
MOLECULAR BASIS:
Caused by mutations in the caveolin 3 gene (CAV3, 601253.0001)
OMIM Title
*606146 FRIZZLED, DROSOPHILA, HOMOLOG OF, 8; FZD8
OMIM Description
Drosophila cuticle hairs are arranged in a defined polarity that is
genetically controlled by 'frizzled,' a 7-transmembrane receptor with a
large extracellular N-terminal cysteine-rich domain (CRD). Members of
the FZD family are receptors for secreted WNT glycoproteins (see
602863), which are involved in developmental control. FZD proteins
transmit signals through the beta-catenin (CTNNB1; 116806) or JNK (e.g.,
JNK3; 602897) pathways. The selection of intracellular signaling cascade
may be determined by different C-terminal motifs in FZD proteins.
CLONING
By searching an EST database for sequences homologous to mouse Fzd8,
followed by PCR, screening genomic DNA, brain cDNA, and fetal cDNA
libraries, and RT-PCR on fetal kidney cDNA, Saitoh et al. (2001)
isolated a cDNA encoding human FZD8. Sequence analysis predicted that
the 694-amino acid protein, which is 69% identical to FZD5 (601723) and
95% identical to mouse Fzd8, contains an N-terminal signal peptide, a
CRD, 7 transmembrane domains, 3 N-linked glycosylation sites, and a
C-terminal ser/thr-X-val motif, which is a binding site for scaffold
proteins with multiple PDZ domains. Northern blot analysis revealed
expression of a 4.0-kb FZD8 transcript that was most abundant in fetal
kidney, followed by fetal brain and fetal lung. In adult tissue, FZD8
was expressed in kidney, heart, pancreas, and skeletal muscle. Based on
its high degree of identity to the mouse sequence, Saitoh et al. (2001)
predicted that FZD8 may also activate the CTNNB1-TCF signaling pathway,
like mouse Fzd8.
BIOCHEMICAL FEATURES
- Crystal Structure
Dann et al. (2001) determined the crystal structures of the CRDs from
mouse Fzd8 and secreted frizzled-related protein-3 (FRZB; 605083) after
eliminating their N-linked glycosylation sites by mutation. The CRD
structures were predominantly alpha helical, with all cysteines forming
disulfide bonds. They appeared to represent a novel fold distantly
related to 4-helix bundles. Using 3 mutagenesis strategies, Dann et al.
(2001) implicated a single region on the CRD surface as important for
WNT binding.
Janda et al. (2012) determined the crystal structure of Xenopus Wnt8
(606360) in complex with mouse Fzd8 CRD to a 3.25-angstrom resolution.
An unusual 2-domain Wnt structure, not obviously related to known
protein folds, resembled a hand with thumb and index fingers extended to
grasp the Fzd8 CRD at 2 distinct binding sites. One site is dominated by
a palmitoleic acid lipid group projecting from ser187 at the tip of
Wnt's 'thumb' into a deep groove in the Fzd8 CRD. In the second binding
site, the conserved tip of Wnt's 'index finger' forms hydrophobic amino
acid contacts with a depression on the opposite side of the Fzd8 CRD.
The conservation of amino acids in both interfaces appears to facilitate
ligand-receptor cross-reactivity.
GENE STRUCTURE
By genomic sequence analysis, Saitoh et al. (2001) determined that the
FZD8 gene has only 1 exon.
GENE FUNCTION
Interstitial cystitis, a chronic painful urinary bladder disorder
characterized by thinning or ulceration of the bladder epithelial
lining, affects approximately 1 million people in the United States.
Keay et al. (2000, 2001) identified a glycosylated frizzled-related
peptide inhibitor of cell proliferation that is secreted specifically by
bladder epithelial cells from patients with this disorder. This
antiproliferative factor (APF) profoundly inhibits bladder cell
proliferation by means of regulation of cell adhesion protein and growth
factor production (Keay et al., 2003). Keay et al. (2004) determined APF
to be an acidic, heat-stable sialoglycopeptide whose peptide chain has
100% homology to the putative sixth transmembrane domain of frizzled-8.
Both synthetic and native APF had identical biologic activity in normal
bladder epithelial cells and T24 bladder cancer cells. Northern blot
analysis indicated binding of a probe containing the sequence for the
frizzled-8 segment with mRNA extracted from cells of patients with
interstitial cystitis but not controls. Keay et al. (2004) concluded
that APF is a frizzled-related peptide growth inhibitor containing
exclusively a transmembrane segment of a frizzled protein and that it is
a potential biomarker for interstitial cystitis.
MAPPING
Using FISH, Saitoh et al. (2001) mapped the FZD8 gene to 10p11.2. Wang
et al. (1996) mapped the mouse Fzd8 gene to chromosome 18, between the
Tpl2 (191195) and Cdh2 (114020) genes.
MTRNR2L7
| dbSNP name | rs10827804(G,T); rs11011277(A,T); rs2180706(G,A); rs2208320(G,T); rs2224373(G,A) |
| cytoBand name | 10p11.21 |
| EntrezGene GeneID | 100288485 |
| EntrezGene Description | MT-RNR2-like 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3884 |
ZNF33BP1
| dbSNP name | rs79092117(G,T); rs12412402(G,A); rs11011370(G,A); rs11595684(T,C) |
| cytoBand name | 10p11.1 |
| EntrezGene GeneID | 100419868 |
| snpEff Gene Name | RP11-162G10.4 |
| EntrezGene Description | zinc finger protein 33B pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01928 |
ACTR3BP5
| dbSNP name | rs118025224(A,G) |
| cytoBand name | 10p11.1 |
| EntrezGene GeneID | 399746 |
| EntrezGene Description | ACTR3B pseudogene 5 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03903 |
HNRNPA3P1
| dbSNP name | rs10793493(G,A); rs10899905(C,T); rs7093194(T,G); rs7071189(G,A); rs115166560(G,T); rs1998748(T,C); rs1998749(G,C); rs3750724(T,C) |
| cytoBand name | 10q11.21 |
| EntrezGene GeneID | 10151 |
| EntrezGene Description | heterogeneous nuclear ribonucleoprotein A3 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3884 |
LOC100130539
| dbSNP name | rs809601(G,A); rs808972(T,A) |
| cytoBand name | 10q11.21 |
| EntrezGene GeneID | 100130539 |
| snpEff Gene Name | CXCL12 |
| EntrezGene Description | uncharacterized LOC100130539 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07897 |
C10orf25
| dbSNP name | rs76539446(G,T); rs78332143(A,T); rs12269028(A,T) |
| cytoBand name | 10q11.21 |
| EntrezGene GeneID | 220979 |
| snpEff Gene Name | RASSF4 |
| EntrezGene Description | chromosome 10 open reading frame 25 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03444 |
ERCC6
| dbSNP name | rs75139617(C,T); rs73297748(A,G); rs11101137(A,G); rs3750751(C,T); rs4253234(G,C); rs4253231(A,G); rs2228529(T,C); rs4253226(T,C); rs3810945(C,T); rs12221460(A,C); rs12220258(C,T); rs4838518(T,C); rs4838519(A,C); rs4253217(C,T); rs4253216(T,C); rs4253215(C,G); rs182151909(A,G); rs971026(C,A); rs78952611(C,A); rs3940160(C,T); rs2104346(A,G); rs2209281(C,T); rs7086144(T,C); rs75226363(C,G); rs12217467(C,A); rs28454254(A,G); rs932735(T,G); rs73305562(T,C); rs77729515(G,A); rs4240505(G,A); rs2228527(T,C); rs2228526(T,C); rs10437449(A,C); rs2228525(G,A); rs2229760(G,A); rs4253197(A,G); rs4253193(A,G); rs4253190(C,T); rs4838522(T,C); rs3750749(A,G); rs7909342(C,T); rs912470(A,C); rs142616577(A,C); rs4253166(T,G); rs138443493(A,T); rs4240506(C,T); rs4253165(C,T); rs4253164(T,G); rs4253162(T,C); rs113074110(A,G); rs10857497(A,G); rs11101140(A,G); rs7076173(C,T); rs73305578(G,A); rs4253160(T,A); rs4253151(C,T); rs185998785(A,G); rs17010116(A,C); rs17775180(C,A); rs7087700(G,A); rs58002245(C,T); rs7072383(A,C); rs4253146(T,C); rs4253145(A,G); rs4253144(A,G); rs4253143(T,C); rs4253138(C,T); rs4253133(A,G); rs4253132(G,A); rs4253128(C,G); rs4240507(G,T); rs4240508(T,C); rs4240509(C,T); rs4838523(G,A); rs7073830(G,A); rs7922756(T,G); rs10776576(G,A); rs7903930(C,G); rs72792895(C,G); rs7920256(A,G); rs1924488(G,A); rs10857499(G,A); rs971667(G,A); rs6537538(C,T); rs973808(G,A); rs4253121(G,A); rs4253120(A,G); rs116373975(C,A); rs4838524(C,T); rs73305599(T,C); rs72793793(C,T); rs958967(G,A); rs3793788(A,T); rs4240510(A,G); rs4253112(G,A); rs4253111(T,C); rs4253109(A,T); rs4253106(C,T); rs4253102(G,A); rs4253101(T,G); rs4253096(A,T); rs4253087(T,C); rs4253082(C,T); rs3763730(T,G); rs7092520(T,C); rs150405562(C,T); rs79347679(A,C); rs4253079(T,G); rs4253078(G,C); rs4253077(A,C) |
| ccdsGene name | CCDS7229.1 |
| cytoBand name | 10q11.23 |
| EntrezGene GeneID | 2074 |
| EntrezGene Description | excision repair cross-complementing rodent repair deficiency, complementation group 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ERCC6:NM_000124:exon7:c.G1659T:p.K553N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5631 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 0.0002196 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Face];
Facial dysmorphism;
[Eyes];
Microphthalmia;
Retinal dysplasia;
Coloboma;
Extinguished electroretinogram
GENITOURINARY:
[Kidneys];
Renal hypoplasia
SKELETAL:
[Feet];
Polydactyly, postaxial;
Syndactyly
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Molar tooth sign on brain imaging;
Stretched cerebellar peduncles
MISCELLANEOUS:
One family has been reported (last curated February 2014)
MOLECULAR BASIS:
Caused by mutation in the phosphodiesterase 6D, cGMP-specific, rod,
delta gene (PDE6D, 602676.0001)
OMIM Title
*615667 ERCC6-LIKE 2; ERCC6L2
;;RAD26-LIKE; RAD26L
OMIM Description
DESCRIPTION
ERCC6L2 belongs to a family of helicases related to yeast Snf2 (see
600014) that are involved in chromatin unwinding, transcription
regulation, and DNA recombination, translocation, and repair (Tummala et
al., 2014).
CLONING
Using exome sequencing to identify the gene mutated in patients with
bone marrow failure and neurologic dysfunction (615715), Tummala et al.
(2014) identified ERCC6L2. The deduced 712-amino acid protein has a
calculated molecular mass of 81 kD. It has a putative 13-amino acid
N-terminal mitochondrial localization signal, followed by a DEAH
ATP-helicase domain and a catalytic helicase C-terminal domain. ERCC6L2
shares highest sequence similarity with chromatin-remodeling and
DNA-repair proteins, including ERCC6 (609413). Database analysis
revealed ubiquitous ERCC6L2 expression. Western blot analysis of human
cell lines showed that ERCC6L2 had an apparent molecular mass of 72 kD.
Immunohistochemical analysis revealed that ERCC6L2 localized to both
cytoplasmic and nuclear compartments.
GENE FUNCTION
Tummala et al. (2014) found that ERCC6L2 translocated to mitochondria
and nuclei following exposure of human A549 cells to DNA-damaging agents
that elicit nucleotide excision repair. Knockdown of ERCC6L2 via small
interfering RNA caused formation of nuclear foci containing
phosphorylated H2AX (H2AFX; 601772), increased intracellular reactive
oxygen species (ROS), and sensitized cells to genotoxic stress.
Pretreatment of cells with an antioxidant that scavenges ROS inhibited
ERCC6L2 translocation to mitochondria and nucleus upon genotoxic stress
and reduced stress-induced cell death in ERCC6L2-knockdown cells.
Tummala et al. (2014) concluded that ERCC6L2 is an early DNA
damage-response protein that traffics to mitochondria and nucleus in an
ROS-dependent fashion.
GENE STRUCTURE
Tummala et al. (2014) determined that the ERCC6L2 gene contains 14
exons.
MAPPING
By genomic sequence analysis, Tummala et al. (2014) mapped the ERCC6L2
gene to chromosome 9q22.32.
MOLECULAR GENETICS
By exome sequencing of 2 unrelated patients with bone marrow failure
syndrome-2 (BMFS2; 615715), Tummala et al. (2014) identified 2 different
homozygous truncating mutations in the ERCC6L2 gene (615667.0001 and
615667.0002). The patients had trilineage bone marrow failure, learning
disabilities, and microcephaly. Cutaneous features and increased
chromosome breakage were not present, but 1 patient had short telomeres.
Fluorescence labeling of patient cells showed that the mutant truncated
proteins were mislocalized to the endoplasmic reticulum, autophagic
vacuoles, and lysosomes, suggesting that normal localization was
impaired by aggregation of the mutant protein and retention for
degradation. Tummala et al. (2014) noted that a DNA-damage response is
required during cell proliferation and tissue maintenance, and suggested
that the mutations resulted in an increase in ROS and the accumulation
of DNA damage, which underlie the disease manifestations observed in the
affected individuals.
ERCC6-PGBD3
| dbSNP name | rs4253075(C,T); rs4253074(A,T); rs4253073(G,A); rs4253072(C,T); rs11101144(A,T); rs111242827(A,C); rs57612136(A,G); rs2281792(T,C); rs2281793(C,T); rs4253061(T,C); rs4253060(C,T); rs75941022(C,A); rs4253055(A,G); rs1018603(C,A); rs2281794(T,C); rs3750748(C,T); rs59898389(C,T); rs12220085(T,C); rs76062895(T,C); rs11101147(C,T); rs4253050(C,G); rs4253049(G,A); rs2228528(C,T); rs150935953(G,A); rs4253043(C,A); rs4253042(T,C); rs76977396(C,T); rs79893651(A,G); rs58711755(T,C); rs7082895(G,A); rs74800786(A,G); rs73311017(G,A); rs73311019(A,G); rs61846612(G,A); rs7096755(C,A); rs75344111(G,A); rs4253040(A,T); rs4253038(A,G); rs4253037(C,T); rs4253029(T,C); rs4253028(G,A); rs4253026(A,G); rs4253025(G,A); rs4253024(G,A); rs4253023(C,G); rs1012554(C,T); rs4253017(C,T); rs4253016(G,A); rs1012553(A,G); rs4253013(C,T); rs2228524(G,C); rs4253011(G,A); rs4253010(T,C); rs4253009(T,C); rs10857501(A,G); rs10776577(T,C); rs10857502(A,G); rs76060723(G,T); rs61846615(A,G); rs4838527(G,A); rs3793786(G,A); rs76925204(G,A); rs1917802(T,C); rs1917801(G,A); rs79859389(T,C); rs200500364(T,C); rs61846616(C,G); rs12242851(T,C); rs3793784(G,C) |
| ccdsGene name | CCDS7229.1 |
| cytoBand name | 10q11.23 |
| EntrezGene GeneID | 101243544 |
| snpEff Gene Name | ERCC6 |
| EntrezGene Description | ERCC6-PGBD3 readthrough |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ERCC6-PGBD3:NM_001277059:exon5:c.C670T:p.L224F,ERCC6:NM_000124:exon5:c.C670T:p.L224F,ERCC6-PGBD3:NM_001277058:exon5:c.C670T:p.L224F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7325 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EV46 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0002604 |
SLC18A3
| dbSNP name | rs8187730(C,A); rs2269338(G,T) |
| ccdsGene name | CCDS7231.1 |
| cytoBand name | 10q11.23 |
| EntrezGene GeneID | 6572 |
| EntrezGene Description | solute carrier family 18 (vesicular acetylcholine transporter), member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC18A3:NM_003055:exon1:c.C1559A:p.A520E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q16572 |
| dbNSFP Uniprot ID | VACHT_HUMAN |
| dbNSFP KGp1 AF | 0.997252747253 |
| dbNSFP KGp1 Afr AF | 0.987804878049 |
| dbNSFP KGp1 Amr AF | 1.0 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.0125 |
| ESP All MAF | 0.004233 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.999 |
OMIM Clinical Significance
Metabolic:
Succinicacidemia;
Organic acidemia;
Lactic acidosis
Resp:
Respiratory distress
Lab:
Serum succinic acid levels greatly increased;
Low NADH-cytochrome c reductase activity;
Low NADH-ferricyanide reductase activity
Inheritance:
Autosomal recessive
OMIM Title
*600336 SOLUTE CARRIER FAMILY 18 (VESICULAR ACETYLCHOLINE), MEMBER 3; SLC18A3
;;VESICULAR ACETYLCHOLINE TRANSPORTER; VACHT
OMIM Description
CLONING
Erickson et al. (1994) cloned a vesicular acetylcholine transporter cDNA
from a human neuroblastoma cDNA library. The amino acid conservation
between rat and human VACHT is 94%. In situ hybridization studies
demonstrated high levels of expression of rat VACHT mRNA in all major
cholinergic cell groups examined. The distribution was virtually
identical to that previously reported for choline acetyltransferase
(CHAT; 118490) mRNA and protein and was consistent with the expression
of both VACHT and CHAT exclusively in the cholinergic nervous system.
Northern blot analysis of rat tissues detected a single, approximately
3-kb VACHT mRNA expressed in regions of the brain containing cholinergic
neurons and in PC12 cells.
MAPPING
By in situ hybridization, Erickson et al. (1994) mapped the human VACHT
gene to chromosome 10q11.2. They demonstrated that the VACHT gene is
encoded by a sequence contained uninterrupted within the first intron of
the CHAT gene (118490), the enzyme required for acetylcholine
biosynthesis in the peripheral and central cholinergic nervous systems.
Transcription of VACHT and CHAT mRNA from the same or contiguous
promoters within the single regulatory locus provides a previously
undescribed genetic mechanism for coordinate regulation of 2 proteins
whose expression is required to establish a mammalian neuronal
phenotype.
ANIMAL MODEL
Lara et al. (2010) noted that Vacht -/- mice are unable to release
acetylcholine (ACh) in response to depolarization and die shortly after
birth due to respiratory failure. Lara et al. (2010) studied a line of
mutant mice termed 'Vacht knockdown homozygous' (Vacht KD(HOM)) that
show reduced Vacht expression and altered ACh release. Young Vacht
KD(HOM) mice had normal cardiac function, but by 3 months of age they
exhibited reduced cardiac contractility and left ventricle fractional
shortening. These changes were alleviated by pharmacologic restoration
of ACh at synapses. Isolated Vacht KD(HOM) heart preparations had
reduced systolic tension with elevated expression of markers of
cardiomyocyte stress, and these changes were also alleviated by
restoration of ACh. Vacht KD(HOM) and Vacht -/- mice exhibited altered
autonomic control of heart rate, overexpression of the M2 muscarinic
receptor (CHRM2; 118493), and decreased expression of beta-1 adrenergic
receptors (ADRB1; 109630). Expression of the G-protein kinase Grk2
(ADRBK1; 109635) was also elevated in Vacht KD(HOM) hearts compared with
wildtype.
MIR605
| dbSNP name | rs2043556(T,C) |
| ccdsGene name | CCDS7244.1 |
| cytoBand name | 10q21.1 |
| EntrezGene GeneID | 693190 |
| snpEff Gene Name | PRKG1 |
| EntrezGene Description | microRNA 605 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2759 |
| ESP Afr MAF | 0.201149 |
| ESP All MAF | 0.18854 |
| ESP Eur/Amr MAF | 0.182938 |
| ExAC AF | 0.141 |
CSTF2T
| dbSNP name | rs1045767(A,G); rs14168(A,C); rs16921604(C,T); rs16921605(A,G); rs16921608(A,G); rs148650617(G,A); rs41305705(G,A); rs142914640(A,G); rs11601(G,A); rs3740228(A,G); rs3824686(C,T); rs2292828(A,G) |
| ccdsGene name | CCDS7244.1 |
| cytoBand name | 10q21.1 |
| EntrezGene GeneID | 23283 |
| snpEff Gene Name | PRKG1 |
| EntrezGene Description | cleavage stimulation factor, 3' pre-RNA, subunit 2, 64kDa, tau variant |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1506 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature, final adult height 150-160cm
HEAD AND NECK:
[Head];
Brachycephaly;
Large fontanelle;
Delayed closure of fontanelle;
[Face];
Tall forehead;
Bitemporal narrowing;
Short philtrum;
Midface hypoplasia;
[Ears];
Hearing loss, conductive;
Hearing loss, sensorineural;
[Eyes];
Myopia;
Upslanting palpebral fissures;
Ptosis;
Short palpebral fissures;
[Mouth];
Thin upper lip;
[Neck];
Long neck
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Mitral regurgitation;
Bicuspid aortic valve;
Aortic regurgitation;
[Vascular];
Patent ductus arteriosus;
Hypertension;
Vessel calcification (hands & feet)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum
ABDOMEN:
[External features];
Umbilical hernia
GENITOURINARY:
[External genitalia, male];
Hypospadias;
Inguinal hernia
SKELETAL:
Delayed bone age;
Epiphyseal dysplasia;
Premature osteoarthritis;
[Spine];
Scoliosis;
[Pelvis];
Decreased hip extension;
Degenerative hip disease;
[Limbs];
Decreased extension (elbows and knees);
Prominent deltoid insertion of humerus;
Small, flat epiphyses (distal radius);
Cubitus valgus;
Hyperextensible elbows;
[Hands];
Absent distal flexion creases;
Fifth finger clinodactyly;
Camptodactyly (progressive);
Pseudoepiphyses (middle phalanges);
Thumb subluxation;
Short forth metacarpal;
[Feet];
Severe metatarsus adductus;
2-3 toe syndactyly
SKIN, NAILS, HAIR:
[Skin];
Absent distal flexion creases (fingers)
NEUROLOGIC:
[Central nervous system];
cranial nerve palsy, intermittent, transient
NEOPLASIA:
Meningioma
MISCELLANEOUS:
Progressive degenerative hip disease requiring replacement in 2nd
to 4th decade
OMIM Title
*611968 CLEAVAGE STIMULATION FACTOR, 3-PRIME PRE-RNA, SUBUNIT 2, 64-KD, TAU
VARIANT; CSTF2T
;;CSTF2, TAU VARIANT;;
CSTF64, TAU VARIANT;;
TAU-CSTF64;;
KIAA0689
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Ishikawa et al. (1998) cloned CSTF2T, which they designated
KIAA0689. RT-PCR analysis detected moderate expression in all tissues
examined.
Using the RNA-binding domain of mouse Cstr2t as bait, Dass et al. (2002)
cloned human CSTF2T from a testis cDNA library. The deduced 616-amino
acid protein has a calculated molecular mass of 64.4 kD. It has an
N-terminal RNA-binding domain, 9 MEARA/G repeats, and a highly conserved
C-terminal domain. Human CSTF2T shares 89.8% amino acid identity with
mouse Cstf2t, which contains 630 amino acids and has 8 MEARA/G repeats.
Human CSTF2T and CSTF2 (300907) share 74.9% amino acid identity.
GENE FUNCTION
Dass et al. (2001) confirmed that the RNA-binding domain of mouse Cstf2t
bound RNA.
GENE STRUCTURE
Dass et al. (2002) determined that the CSTF2T gene is intronless.
MAPPING
By PCR of human/mouse hybrid cell lines and radiation hybrid analysis,
Dass et al. (2002) mapped the CSTF2T gene to chromosome 10q22-q23.
Dass et al. (2001) mapped the mouse Cstf2t gene to chromosome 19.
ANIMAL MODEL
Dass et al. (2007) found that Cstf2t -/- mice were born at the expected
mendelian frequency and showed no obvious abnormalities. However, Cstf2t
-/- males were infertile and displayed aberrant spermatogenesis,
resulting in male infertility that resembled
oligoasthenoteratozoospermia. Both Cstft +/- males and Cstft -/- females
were fertile. Microarray analysis showed no difference in testis mRNA
expression between wildtype and Cstf2t -/- mice at 17 days postpartum,
but there were significant differences at 22 and 25 days postpartum. The
differences at 22 days postpartum represented mRNAs encoding proteins
involved in basic cellular functions, whereas the differences at 25 days
postpartum represented mRNAs encoding proteins involved in
spermatogenesis functions, thus explaining the infertility phenotype.
MTRNR2L5
| dbSNP name | rs4394744(T,C); rs11004927(C,T) |
| cytoBand name | 10q21.1 |
| EntrezGene GeneID | 100463289 |
| snpEff Gene Name | PCDH15 |
| EntrezGene Description | MT-RNR2-like 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3163 |
ADO
| dbSNP name | rs224082(C,T); rs10995312(T,C); rs1509964(C,T); rs188386742(C,T); rs9990(C,T) |
| cytoBand name | 10q21.3 |
| EntrezGene GeneID | 84890 |
| EntrezGene Description | 2-aminoethanethiol (cysteamine) dioxygenase |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2856 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Mild hearing impairment (13%);
[Eyes];
Nystagmus, horizontal, mild (44%)
GENITOURINARY:
[Bladder];
Urinary urgency (57%)
SKELETAL:
[Spine];
Scoliosis (35%)
NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia;
Ataxic gait;
Spasticity;
Hyperreflexia;
Dysarthria (74%);
Dystonia (57%);
Dysmetria;
Cognitive impairment, mild (44%);
Cerebellar atrophy;
Cortical atrophy (43%);
Nonspecific leukoencephalopathy (52%)
MISCELLANEOUS:
Variable age at onset (range 2 to 59 years, mean 24 years);
High intrafamilial and interfamilial variability;
High frequency among French-Canadians;
About 50% of patients become wheelchair-bound at an average age of
37 years
MOLECULAR BASIS:
Caused by mutation in the methionyl-tRNA synthetase 2 gene (MARS2,
609728.0001)
OMIM Title
*611392 2-@AMINOETHANETHIOL DIOXYGENASE; ADO
;;CHROMOSOME 10 OPEN READING FRAME 22; C10ORF22;;
CYSTEAMINE DIOXYGENASE
OMIM Description
DESCRIPTION
Human thiol dioxygenases include cysteine dioxygenase (CDO; 603943) and
cysteamine (2-aminoethanethiol) dioxygenase (ADO; EC 1.13.11.19). CDO
adds 2 oxygen atoms to free cysteine, whereas ADO adds 2 oxygen atoms to
free cysteamine to form hypotaurine (Dominy et al., 2007).
CLONING
To identify the ADO protein, Dominy et al. (2007) searched in silico for
sequences similar to those in CDO, including the cupin motif, which is
found in proteins that bind metal cofactors. In CDO, which binds iron,
the cupin motif is unusual in the lack of a conserved glutamate. Dominy
et al. (2007) identified a predicted 771-amino acid Ado protein (Gm237)
in mouse that had about 14% overall sequence identity with CDO and, like
CDO, was missing the highly conserved glutamate found in other cupins.
Dominy et al. (2007) also identified a human ortholog, which shares 85%
sequence similarity with the mouse protein. An antibody raised against
mouse Ado showed that the protein is ubiquitously expressed, with
highest levels in brain, heart, and skeletal muscle. This pattern
differs from that of CDO, which is primarily expressed in liver.
GENE FUNCTION
Dominy et al. (2007) demonstrated that mouse Ado has strong and specific
dioxygenase activity in vitro towards cysteamine but not cysteine.
Recombinant Ado was shown to bind iron. Overexpression of Ado in
HepG2/C3A cells increased the production of hypotaurine from cysteamine.
Similar results were found with human ADO. When endogenous expression of
ADO was reduced by RNA-mediated interference, hypotaurine production
decreased. Dominy et al. (2007) noted that the demonstration of high
levels of ADO in brain challenges the previous assumption that most of
the taurine in the brain is a consequence of CDO activity.
MAPPING
Hartz (2012) mapped the ADO gene to chromosome 10q21.3 based on an
alignment of the ADO sequence (GenBank GENBANK AK027453) with the
genomic sequence (GRCh37).
JMJD1C-AS1
| dbSNP name | rs1061259(G,C); rs10761770(A,G) |
| ccdsGene name | CCDS41532.1 |
| cytoBand name | 10q21.3 |
| EntrezGene GeneID | 221037 |
| EntrezGene Symbol | JMJD1C |
| snpEff Gene Name | JMJD1C |
| EntrezGene Description | jumonji domain containing 1C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4298 |
| ESP Afr MAF | 0.181586 |
| ESP All MAF | 0.439934 |
| ESP Eur/Amr MAF | 0.437028 |
| ExAC AF | 0.719 |
ANXA2P3
| dbSNP name | rs7898508(A,G); rs113973928(C,T); rs1227236(A,G); rs16920432(G,A) |
| cytoBand name | 10q21.3 |
| EntrezGene GeneID | 305 |
| EntrezGene Description | annexin A2 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3085 |
HKDC1
| dbSNP name | rs57245644(C,T); rs10998652(C,T); rs953724(C,T); rs12268341(A,G); rs77852351(G,A); rs140497144(T,G); rs7089277(G,T); rs7089312(G,A); rs5030941(C,T); rs374522976(A,G); rs4746822(C,T); rs4746823(A,G); rs4746824(C,A); rs2394529(G,C); rs4746825(C,T); rs4746826(G,A); rs5030944(G,A); rs10762265(T,C); rs2394530(T,A); rs9645499(G,A); rs9645500(T,G); rs9645501(G,A); rs10762266(G,T); rs12221182(C,T); rs7923953(T,C); rs12780191(C,T); rs12253459(A,G); rs10998654(A,C); rs12253517(A,G); rs4072136(C,T); rs4075240(G,A); rs72812190(C,T); rs10823321(G,A); rs1983128(G,A); rs1983127(G,T); rs79937321(C,T); rs10762267(G,A); rs72812195(T,C); rs7068302(A,G); rs12358818(C,T); rs10082355(T,C); rs10082520(G,T); rs79728940(A,C); rs16926179(T,A); rs7091301(T,C); rs7073527(G,A); rs4746827(G,A); rs5030945(C,T); rs5030946(C,A); rs17566219(G,A); rs4746828(C,T); rs35746503(C,T); rs874556(C,T); rs10998656(G,A); rs5030970(A,T); rs5030971(T,A); rs5030972(G,A); rs10128247(A,G); rs10998657(A,G); rs10823322(G,C); rs7083041(G,C); rs10762268(T,C); rs2394531(G,C); rs2894079(C,T); rs7075720(T,C); rs72814208(G,A); rs72814209(C,T); rs7904936(T,C); rs10998659(T,A); rs150155033(C,A); rs12246517(G,A); rs2394532(G,A); rs74910409(A,G); rs5030973(C,T); rs72814218(G,A); rs72814220(C,A); rs72814224(A,G); rs7899445(T,C); rs7914955(G,C); rs7918356(G,C); rs116033721(G,A); rs7918272(C,G); rs112258245(G,A); rs72814226(C,G); rs113229581(C,G); rs58261904(T,C); rs1967236(T,G); rs73280660(A,G); rs1472815(C,A); rs1021964(C,T); rs75352473(G,C); rs60981987(C,T); rs57236635(C,T); rs7903151(T,C); rs7918950(G,A); rs7092167(T,C); rs7092458(T,C); rs113443343(G,A); rs3740600(G,A); rs4745978(T,C); rs78582637(C,G); rs10732416(T,C); rs61868712(C,T); rs10823324(G,A); rs186560786(G,T); rs74138345(T,C); rs12257901(G,A); rs151020388(A,C); rs1911225(A,T); rs79169762(G,A); rs72814245(C,T); rs12261533(G,A); rs925024(G,A); rs2102339(C,T); rs4746830(C,T); rs10998675(A,G); rs2279930(C,G); rs61455565(C,G); rs1111335(T,C); rs41314996(C,G); rs1106676(T,G); rs10823326(A,G); rs74138346(C,T); rs10998677(G,A); rs77607834(T,C); rs16926201(C,T); rs4746831(A,G); rs6480393(T,C); rs10998679(C,T); rs906219(C,A); rs4746832(A,G); rs2611(G,C) |
| ccdsGene name | CCDS7288.1 |
| cytoBand name | 10q22.1 |
| EntrezGene GeneID | 80201 |
| EntrezGene Description | hexokinase domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HKDC1:NM_025130:exon3:c.C341T:p.T114M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6654 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2TB90 |
| dbNSFP Uniprot ID | HKDC1_HUMAN |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0122377622378 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.002497 |
| ESP All MAF | 0.007535 |
| ESP Eur/Amr MAF | 0.010116 |
| ExAC AF | 0.014,8.132e-06 |
NEUROG3
| dbSNP name | rs4536103(A,G) |
| ccdsGene name | CCDS31212.1 |
| cytoBand name | 10q22.1 |
| EntrezGene GeneID | 50674 |
| EntrezGene Description | neurogenin 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NEUROG3:NM_020999:exon2:c.T596C:p.F199S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y4Z2 |
| dbNSFP Uniprot ID | NGN3_HUMAN |
| dbNSFP KGp1 AF | 0.453296703297 |
| dbNSFP KGp1 Afr AF | 0.24593495935 |
| dbNSFP KGp1 Amr AF | 0.585635359116 |
| dbNSFP KGp1 Asn AF | 0.276223776224 |
| dbNSFP KGp1 Eur AF | 0.658311345646 |
| dbSNP GMAF | 0.4527 |
| ESP Afr MAF | 0.394622 |
| ESP All MAF | 0.412246 |
| ESP Eur/Amr MAF | 0.321264 |
| ExAC AF | 0.534 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Decreased height compared to unaffected siblings
SKELETAL:
Osteoarthritis (hips, knees, shoulders, wrists, hands);
Joint stiffness;
[Spine];
Irregular endplates;
Mild platyspondyly;
Schmorl's nodes;
Anterior wedging;
[Hands];
Enlarged MCP joints;
Enlarged PIP and DIP joints;
Heberden's nodes
MISCELLANEOUS:
Onset of osteoarthritis in teens to early adulthood
MOLECULAR BASIS:
Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1,
120140.0003)
OMIM Title
*604882 NEUROGENIN 3; NEUROG3
;;NGN3;;
ATOH5
OMIM Description
DESCRIPTION
Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is
required for endocrine cell development in the pancreas and intestine
(Wang et al., 2006). It belongs to a family of basic helix-loop-helix
transcription factors involved in the determination of neural precursor
cells in the neuroectoderm (Gradwohl et al., 2000).
CLONING
By in situ hybridization, Sommer et al. (1996) found that mouse Ngn3 was
most strongly expressed in a restricted region of the developing spinal
cord, just dorsal to the floor plate. Expression was detectable as early
as embryonic day 9 and persisted until day 14. Ngn3 was also expressed
in the developing hypothalamic region and in pancreatic islet cell
progenitors.
GENE STRUCTURE
Sommer et al. (1996) determined that the mouse Ngn3 gene contains a
single coding exon.
GENE FUNCTION
Spence et al. (2011) established a robust and efficient process to
direct the differentiation of human pluripotent stem cells into
intestinal tissue in vitro using a temporal series of growth factor
manipulations to mimic embryonic intestinal development. Using this
culture system as a model to study human intestinal development, Spence
et al. (2011) identified that the combined activity of WNT3A (606359)
and FGF4 (164980) is required for hindgut specification, whereas FGF4
alone is sufficient to promote hindgut morphogenesis. Spence et al.
(2011) also determined that NEUROG3 is both necessary and sufficient for
human enteroendocrine cell development in vitro. Spence et al. (2011)
concluded that human intestinal stem cells form de novo during
development.
Talchai et al. (2012) showed that, unexpectedly, somatic ablation of
Foxo1 (136533) in Neurog3+ enteroendocrine progenitor cells gives rise
to gut insulin-positive cells that express markers of mature beta cells
and secrete bioactive insulin as well as C peptide in response to
glucose and sulfonylureas. Lineage tracing experiments showed that gut
insulin-positive cells arise cell autonomously from Foxo1-deficient
cells. Inducible Fox1 ablation in adult mice also resulted in the
generation of gut insulin-positive cells. Following ablation by the
beta-cell toxin streptozotocin, gut insulin-positive cells regenerated
and produced insulin, reversing hyperglycemia in mice. Talchai et al.
(2012) concluded that their data indicated that Neurog3+ enteroendocrine
progenitors require active Foxo1 to prevent differentiation into
insulin-positive cells, and suggested that Foxo1 ablation in gut
epithelium may provide an approach to restore insulin production in type
1 diabetes.
MOLECULAR GENETICS
Kim et al. (2001) concluded that genetic variability in neurogenin-3
gene does not contribute to the etiology of maturity-onset diabetes of
the young (see 125853) or other forms of autosomal dominant diabetes.
In 3 unrelated boys with congenital malabsorptive diarrhea (DIAR4;
610370), Wang et al. (2006) identified 2 different homozygous mutations
in the NEUROG3 gene (604882.0001; 604882.0002). Both mutations rendered
the NEUROG3 protein unable to activate NEUROD1 (601724), a downstream
target of NEUROG3, and compromised the ability of NEUROG3 to bind to an
E-box element in the NEUROD1 promoter. The injection of wildtype but not
mutant NEUROG3 mRNA into Xenopus embryos induced NEUROD1 expression. The
authors referred to the disorder in these boys as 'enteric
anendocrinosis.'
ANIMAL MODEL
Mouse Ngn3 is expressed in discrete regions of the nervous system and in
scattered cells in the embryonic pancreas (Sommer et al., 1996).
Gradwohl et al. (2000) showed that Ngn3-positive cells did not express
insulin or glucagon, suggesting that Ngn3 marks early precursors of
pancreatic endocrine cells. Mice lacking Ngn3 function failed to
generate any pancreatic endocrine cells and died postnatally from
diabetes. Expression of the pancreatic transcription factors Isl1
(600366), Pax4 (167413), Pax6 (607108), and NeuroD (601724) was lost,
and endocrine precursors were lacking in the mutant pancreatic
epithelium. Thus, Ngn3 was required for the specification of a common
precursor of the 4 pancreatic endocrine cell types.
Lee et al. (2002) found that glucagon-secreting A cells,
somatostatin-secreting D cells, and gastrin-secreting G cells were
absent from the epithelium of the glandular stomach of Ngn3 -/- mice,
and the number of serotonin-expressing enterochromaffin cells was
dramatically decreased. In addition, Ngn3 -/- mice displayed intestinal
metaplasia of the gastric epithelium. Lee et al. (2002) concluded that
NGN3 is required for differentiation of enteroendocrine cells in the
stomach and maintenance of gastric epithelial cell identity.
Zhou et al. (2008) used a strategy of reexpressing key developmental
regulators in vivo to identify a specific combination of 3 transcription
factors, Neurog3, Pdx1 (600733), and Mafa (610303), that reprogrammed
differentiated pancreatic exocrine cells in adult mice into cells that
closely resembled beta cells. Induced beta cells were indistinguishable
from endogenous islet beta cells in size, shape, and ultrastructure.
They expressed genes essential for beta cell function and could
ameliorate hyperglycemia by remodeling local vasculature and secreting
insulin. Zhou et al. (2008) concluded that their study provided an
example of cellular reprogramming using defined factors in an adult
organ and suggested a general paradigm for directing cell reprogramming
without reversion to a pluripotent stem cell state.
TYSND1
| dbSNP name | rs76147716(G,C); rs1053105(C,T); rs78540960(T,C); rs41277980(A,G); rs2394647(C,T); rs113019713(C,T); rs79175235(G,A); rs151252509(G,A); rs78543871(G,A); rs4746969(G,T); rs6480442(C,T); rs10823487(G,T); rs10823488(A,G); rs79841478(C,A); rs76975890(C,G); rs10999156(C,T); rs4746021(G,A); rs4746022(T,G); rs3763735(T,C); rs2394648(G,A); rs3750774(C,A) |
| ccdsGene name | CCDS31213.1 |
| cytoBand name | 10q22.1 |
| EntrezGene GeneID | 219743 |
| EntrezGene Description | trypsin domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TYSND1:NM_173555:exon4:c.C1559T:p.T520M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7312 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2T9J0 |
| dbNSFP Uniprot ID | TYSD1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 5.692e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, acquired
ABDOMEN:
[Gastrointestinal];
Poor feeding
NEUROLOGIC:
[Central nervous system];
Jerking movements;
Posturing;
Seizures, intractable;
Hypertonia;
Psychomotor retardation;
Brain imaging shows generalized atrophy;
Hypoplastic cerebellar vermis
LABORATORY ABNORMALITIES:
Decreased plasma serine;
Decreased plasma glycine;
Decreased CSF serine;
Decreased CSF glycine
MISCELLANEOUS:
Onset in infancy;
Treatment with serine and glycine replacement may alleviate features
if started at birth;
Lack of treatment results in early death
MOLECULAR BASIS:
Caused by mutation in the phosphoserine aminotransferase-1 gene (PSAT1,
610936.0001)
OMIM Title
*611017 TRYPSIN DOMAIN-CONTAINING PROTEIN 1; TYSND1
OMIM Description
DESCRIPTION
All peroxisomal proteins are synthesized in the cytosol, and 2 distinct
peroxisomal targeting signals (PTSs), the C-terminal PTS1 and N-terminal
PTS2, are used for transport of these proteins into peroxisomes.
Proteolytic cleavage of the N-terminal targeting sequence of PTS2
proteins accompanies import into peroxisomes, and many PTS1 proteins
undergo C-terminal processing once in the peroxisomal matrix. TYSND1
processes both PTS1 and PTS2 proteins involved in beta-oxidation of
fatty acids (Kurochkin et al., 2007).
CLONING
By database analysis, Kurochkin et al. (2005) identified mouse Tysnd1
and its rat and human homologs. The mouse Tysnd1 protein has a PTS1
motif and 2 protease-related domains.
Kurochkin et al. (2007) stated that mouse Tysnd1 contains 568 amino
acids and has 2 trypsin-like serine and cysteine peptidase domains.
Western blot analysis of transfected COS-7 cells revealed a 59-kD
protein corresponding to full-length recombinant Tysnd1 and a 49-kD
protein representing the processed form. Fractionation of rat liver
homogenate and Western blot analysis showed that endogenous Tysnd1 was
synthesized as a 59-kD protein and converted to 49- and 27-kD forms
following import into peroxisomes. Confocal microscopy localized Tysnd1
to peroxisomes of transfected Chinese hamster ovary cells.
GENE FUNCTION
Kurochkin et al. (2007) showed that mouse Tysnd1 processed the
PTS2-containing peroxisomal precursor 3-oxoacyl-CoA thiolase
(prethiolase, or ACAA1; 604054) and several PTS1-containing peroxisomal
enzymes, including peroxisomal acyl-CoA oxidase (ACOX1; 609751), to
their mature forms in transfected COS-7 cells. Small interfering
RNA-mediated downregulation of TYSND1 in human embryonic kidney cells
blocked processing of these peroxisomal enzymes. Additional studies
showed that Tysnd1 directly processed peroxisomal enzymes in vitro,
including prethiolase, which it cleaved between cys26 and ser27 to
produce the mature form observed in vivo. Tysnd1 processing activity was
abolished by N-ethylmaleimide, an inhibitor of cysteine proteinases.
Kurochkin et al. (2007) determined that Tysnd1 itself is cleaved between
cys110 and ala111, presumably removing an inhibitory N-terminal
fragment.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the TYSND1
gene to chromosome 10 (TMAP D10S1466).
GLUD1P3
| dbSNP name | rs11000758(A,T); rs11000759(G,A); rs11000760(G,A); rs193170695(C,T); rs12264025(A,G) |
| cytoBand name | 10q22.2 |
| EntrezGene GeneID | 2749 |
| snpEff Gene Name | RP11-574K11.20 |
| EntrezGene Description | glutamate dehydrogenase 1 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3838 |
LOC101929234
| dbSNP name | rs111434632(C,T) |
| cytoBand name | 10q22.2 |
| EntrezGene GeneID | 101929234 |
| snpEff Gene Name | NCRNA00245 |
| EntrezGene Description | uncharacterized LOC101929234 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
DLG5-AS1
| dbSNP name | rs148307304(T,C); rs78485346(T,G); rs7894701(A,G); rs1650146(A,G); rs72806018(T,C); rs148619396(C,T) |
| cytoBand name | 10q22.3 |
| EntrezGene GeneID | 100128292 |
| snpEff Gene Name | DLG5 |
| EntrezGene Description | DLG5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01148 |
EIF5AL1
| dbSNP name | rs1250784(C,T); rs1250785(A,C); rs116942435(G,T); rs1250789(A,C) |
| cytoBand name | 10q22.3 |
| EntrezGene GeneID | 143244 |
| EntrezGene Description | eukaryotic translation initiation factor 5A-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1566 |
BEND3P3
| dbSNP name | rs3824719(G,A); rs139472300(C,T); rs144197203(G,T); rs61863474(A,G); rs61863475(C,T); rs3740277(G,A); rs3012938(C,T); rs3824720(G,A); rs61863476(T,G); rs2913142(A,G); rs150631002(C,T); rs2983793(A,G); rs61863478(T,C); rs2913143(G,A); rs17491496(C,T); rs7072350(G,A); rs144005307(T,G) |
| cytoBand name | 10q22.3 |
| EntrezGene GeneID | 650623 |
| snpEff Gene Name | RP11-119F19.4 |
| EntrezGene Description | BEN domain containing 3 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1777 |
KLLN
| dbSNP name | rs141469860(G,A); rs188956302(T,C); rs113730541(G,A); rs369197917(A,G); rs1903860(T,C) |
| cytoBand name | 10q23.31 |
| EntrezGene GeneID | 100144748 |
| EntrezGene Description | killin, p53-regulated DNA replication inhibitor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01194 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Septal bulge of left ventricular outflow tract;
Wolff-Parkinson-White arrhythmia (rare)
MISCELLANEOUS:
Early onset in some patients;
Highly penetrant, but low morbidity
MOLECULAR BASIS:
Caused by mutation in the cardiac muscle alpha actin gene (ACTC1,
102540.0003)
OMIM Title
*612105 KILLIN; KLLN
OMIM Description
DESCRIPTION
KLLN is a high-affinity DNA-binding protein that functions as a
transcription factor (Wang et al., 2013).
CLONING
Using differential display to identify p53 (TP53; 191170)-induced
transcripts in human cancer cell lines, followed by screening a kidney
cDNA library, Cho and Liang (2008) cloned KLLN. The deduced 178-amino
acid protein has 2 nuclear localization signals and a calculated
molecular mass of 30 kD. Northern blot analysis detected a 4.0-kb
transcript expressed at low levels only in kidney and lung. Western blot
analysis of fractionated cells showed killin in the nuclear compartment.
Fluorescence-tagged killin localized to nuclei and had a 'beads on a
string' appearance characteristic of DNA-binding proteins.
GENE FUNCTION
Cho and Liang (2008) found that expression of killin was induced by
ectopic expression of p53 and by activation of endogenous p53 in
response to genotoxic stress in human cell lines, and killin expression
triggered S phase growth arrest followed by apoptosis. Chromatin
immunoprecipitation analysis and reporter gene assays showed that p53
bound and activated the killin promoter. Knockdown of killin blocked
p53-mediated apoptosis but had no effect on p53-induced p21 (CDKN1A;
116899) expression or growth arrest at G1 phase. In vitro-translated
killin bound both single- and double-stranded DNA. Mutation analysis
localized the DNA-binding and cytotoxic domain to 42 amino acids near
the N terminus. This domain contains multiple WxxR or KxxW motifs and is
rich in basic amino acids. A peptide covering this region bound double-
and single-stranded DNA and an artificial replication fork, and it
inhibited DNA synthesis in vitro and in vivo. Cho and Liang (2008)
concluded that killin mediates p53-induced S phase checkpoint control
and eliminates precancerous cells should they escape p21-mediated G1
blockade.
By analyzing 188 normal breast tissues and 1,247 malignant breast
cancers of various subtypes, Wang et al. (2013) found that loss of KLLN
was associated with tumor progression and increasing histologic grade in
invasive carcinomas. In androgen receptor (AR; 313700)-positive breast
cancer cell lines, but not AR-negative cell lines, dihydrotestosterone
activated expression of both KLLN and PTEN from their shared
bidirectional promoter. In turn, KLLN directly promoted expression of
TP53 (191170) and TP73 (601990) with consequent elevated apoptosis and
cell cycle arrest.
MAPPING
By genomic sequence analysis, Cho and Liang (2008) mapped the KLLN gene
to chromosome 10q23 in close proximity to the PTEN gene (601728).
GENE STRUCTURE
Cho and Liang (2008) determined that the KLLN gene contains 1 exon. The
194-bp region that separates the KLLN and PTEN genes contains a
p53-binding promoter that appears responsive for both PTEN and KLLN.
Bennett et al. (2010) showed that there are 2 distinct p53 binding
sites, one for KLLN and the other for PTEN. The PTEN p53 binding site
was outside of the germline methylated region, whereas the putative KLLN
p53 binding site was within the methylated region.
MOLECULAR GENETICS
Bennett et al. (2010) found that germline KLLN promoter epigenetic
modification (hypermethylation; 612105.0001) accounted for one-third of
germline PTEN mutation-negative Cowden syndrome and of those whose
phenotypic features resemble Cowden syndrome (see CWS4, 615107),
prominently those with breast and thyroid disease. In their series, more
than 40% of PTEN mutation-negative classic Cowden syndrome and 33% of
mutation-negative Cowden-like syndrome patients had germline epigenetic
inactivation of the KLLN promoter.
RNLS
| dbSNP name | rs372095171(T,C); rs10749568(A,G); rs72818070(A,T); rs72818071(C,T); rs45585838(C,T); rs12415812(C,T); rs142735579(G,A); rs114627683(C,T); rs116015352(A,G); rs187054622(C,T); rs12416116(C,A); rs999951(C,G); rs999952(G,A); rs7923201(C,A); rs10749570(T,G); rs7089186(A,G); rs199571771(A,C); rs73360729(G,A); rs73360731(C,G); rs115430566(T,A); rs2872068(G,A); rs185882241(A,G); rs4934390(C,A); rs3781196(G,T); rs372796201(C,T); rs1946391(G,A); rs7069968(C,T); rs10749571(A,G); rs372154987(T,C); rs1048956(C,T); rs115186306(G,A); rs75497967(G,A); rs1426615(A,T); rs147676698(T,C); rs73360737(A,G); rs114489728(A,C); rs723947(G,C); rs2162361(C,T); rs4934391(G,A); rs4934392(A,G); rs1426616(C,A); rs7097903(G,C); rs60888743(A,G); rs117659278(A,G); rs1035796(T,C); rs1035797(C,A); rs1834637(T,C); rs11202700(T,G); rs78485719(C,T); rs1537142(A,G); rs11202702(G,A); rs11202704(T,C); rs1426617(T,C); rs7086211(A,G); rs185137214(T,C); rs11202705(T,G); rs183891524(A,C); rs7906629(C,A); rs10887799(T,C); rs187284387(C,T); rs79523478(C,G); rs116512733(T,C); rs375726965(C,T); rs149917199(T,C); rs72818084(G,A); rs142202317(G,C); rs2195013(A,G); rs11516994(C,A); rs11202706(A,G); rs286483(G,A); rs10788590(T,C); rs181957120(T,C); rs2872069(G,A); rs2312538(G,A); rs145015714(T,C); rs148560853(G,C); rs141661954(A,T); rs111363331(A,C); rs73360762(A,G); rs7905573(C,T); rs7905600(C,T); rs4933476(C,T); rs115300440(G,A); rs141008690(G,A); rs186533683(A,C); rs7919335(T,G); rs7899861(G,A); rs11202709(A,G); rs11202710(G,A); rs11202711(A,G); rs10887800(A,G); rs76914642(T,C); rs812631(C,T); rs6586125(C,G); rs1426618(T,C); rs188329731(T,C); rs7091066(T,G); rs369666268(C,T); rs185876204(A,C); rs10887801(G,T); rs141772460(C,T); rs7100373(T,C); rs111229051(T,C); rs114355375(C,T); rs1582783(C,T); rs1582784(C,A); rs11202712(G,A); rs149843511(C,T); rs11202713(C,T); rs147731441(A,G); rs181153975(C,T); rs12219687(G,A); rs11202715(T,G); rs10887802(A,G); rs73360775(A,T); rs112340551(A,G); rs72818100(C,G); rs10887803(A,G); rs61853517(A,G); rs11202716(G,C); rs115194473(A,G); rs10887804(T,C); rs72820003(A,C); rs11202719(C,G); rs1426619(C,T); rs369232189(C,T); rs61855363(C,T); rs115398175(A,G); rs7895582(A,T); rs11594050(C,T); rs114082074(A,T); rs7914501(C,T); rs7089911(G,C); rs34953613(T,C); rs1346226(T,G); rs10887806(C,T); rs7096330(C,T); rs11202723(A,T); rs3781201(A,G); rs1426621(G,T); rs17424286(G,T); rs145625044(T,C); rs181238142(T,G); rs72820004(G,A); rs7895674(G,A); rs7912780(A,T); rs7342099(T,A); rs143813743(T,C); rs7091137(T,A); rs7069120(G,A); rs55894538(G,T); rs148310680(C,T); rs75015615(C,T); rs139841921(G,T); rs6586126(A,G); rs77662052(T,C); rs7917640(C,T); rs118113849(C,T); rs806695(A,G); rs792222(C,G); rs701892(C,T); rs752709(G,A); rs72820008(G,A); rs792224(G,C); rs792225(G,A); rs151266028(C,T); rs1086833(C,G); rs11492684(C,T); rs7914096(T,G); rs139787090(G,A); rs4575174(A,C); rs2081616(T,C); rs2081617(G,C); rs145011528(T,A); rs56155841(C,A); rs792228(G,A); rs111624315(G,C); rs61855396(G,A); rs792229(C,T); rs10788592(T,C); rs2488273(T,C); rs76997589(A,G); rs75923476(T,C); rs4934396(A,G); rs57412532(C,T); rs146930922(T,G); rs1648512(G,A); rs11202731(C,T); rs10749577(G,A); rs114615091(C,A); rs74378451(A,G); rs116515376(T,C); rs180737744(A,C); rs3740279(C,T); rs12220632(G,A); rs72820014(T,G); rs12572530(T,C); rs17111348(G,T); rs79418681(T,C); rs10887809(C,G); rs12264161(C,T); rs1616888(A,T); rs3891323(G,C); rs72820015(C,G); rs1613409(T,A); rs7920126(T,A); rs792221(C,T); rs6586128(T,C); rs12217988(G,A); rs792220(T,C); rs4934397(C,A); rs11202734(C,A); rs72474857(G,A); rs6586129(C,T); rs11202735(G,A); rs59184458(G,A); rs61260851(G,A); rs792219(A,G); rs57949777(G,C); rs371944527(C,T); rs61855400(C,T); rs792218(G,A); rs792217(C,T); rs78765429(C,A); rs7916050(C,T); rs1648523(C,T); rs1774970(G,A); rs11202736(A,T); rs1582223(G,A); rs1582224(A,G); rs1774971(C,A); rs7097606(C,T); rs1648520(T,C); rs701893(G,A); rs72820018(T,C); rs7073491(C,A); rs7090991(A,G); rs7073755(C,T); rs12244164(C,T); rs74149714(C,A); rs74149715(C,A); rs792232(G,A); rs78762515(G,T); rs61855401(G,A); rs12573401(G,A); rs181831622(G,A); rs796945(C,T); rs792234(A,G); rs1774973(T,A); rs1648511(A,T); rs146363440(A,T); rs1067839(A,G); rs1067840(A,T); rs114987088(G,A); rs792235(A,G); rs78461573(A,G); rs10887813(T,G); rs6586130(A,G); rs3891849(T,C); rs811558(T,C); rs1935584(A,C); rs7897033(C,A); rs4934401(G,A); rs4933478(G,A); rs2488270(C,T); rs77479488(G,A); rs79890293(G,A); rs1617881(C,T); rs7922053(A,C); rs148742521(T,A); rs2433340(A,G); rs792230(C,T); rs1426620(C,T); rs12771145(T,C); rs78995264(C,T); rs1342451(C,A); rs1813675(A,G); rs792205(C,T); rs792207(A,C); rs792208(C,G); rs17096268(T,G); rs10509544(T,G); rs813782(T,G); rs792209(C,T); rs76172074(G,T); rs77628250(C,A); rs792210(G,A); rs12266064(T,C); rs792211(G,T); rs814242(A,G); rs792212(C,T); rs792213(A,C); rs792214(G,C); rs76836971(C,T); rs17111999(T,C); rs140875108(T,A); rs12411841(T,C); rs792215(A,C); rs806694(T,C); rs4933480(T,A); rs116599345(G,A); rs193091335(T,A); rs72820026(C,T); rs10736351(T,C); rs10887816(G,A); rs115307620(T,C); rs4934403(C,T); rs6586132(T,G); rs148567422(T,C); rs7907732(T,C); rs10887817(G,A); rs7918921(G,A); rs10887818(C,T); rs10788597(T,C); rs1418482(T,C); rs78930597(G,A); rs78992735(A,G); rs7913372(A,G); rs75938471(A,C); rs4934404(G,T); rs111972721(A,T); rs7921352(T,C); rs10788598(A,G); rs77178069(T,A); rs113417233(C,T); rs10788599(G,A); rs72820030(G,A); rs7909697(G,A); rs7910594(C,G); rs113792064(G,A); rs138336836(A,C); rs115631766(C,A); rs10788600(T,C); rs7911996(T,C); rs72820031(T,A); rs1578696(C,T); rs17112152(C,T); rs1935582(T,A); rs72820032(C,T); rs1857157(A,G); rs73360914(T,C); rs1935581(C,T); rs78788450(A,G); rs10509545(A,C); rs1935580(T,C); rs142032357(C,T); rs182332414(G,A); rs141612249(G,A); rs12782228(T,C); rs10887820(T,C); rs10887821(T,C); rs12241686(T,A); rs77487319(T,C); rs10749585(T,C); rs2096194(G,A); rs12357948(C,T); rs10749586(T,G); rs6586134(G,A); rs4606392(A,T); rs4934406(C,T); rs10749588(G,A); rs7922551(T,C); rs4509673(T,C); rs4520503(G,C); rs2872092(T,C); rs7907866(C,T); rs149724253(A,C); rs10736352(T,C); rs10736353(C,G); rs12359950(C,A); rs10736355(A,T); rs11202746(A,C); rs7919420(G,A); rs10887822(C,T); rs10749589(A,G); rs10788602(T,A); rs11202748(C,T); rs10887823(A,G); rs1935579(G,A); rs150090290(G,C); rs10749590(C,T); rs10887824(A,G); rs10509546(G,A); rs7899828(A,T); rs4934407(C,T); rs1361749(T,C); rs1935578(T,C); rs2185785(A,G); rs2153855(G,T); rs7096710(C,A); rs1891431(C,T); rs11202750(T,A); rs1342455(C,A); rs1342456(A,G); rs10749591(T,A); rs73355409(G,A); rs4934408(T,C); rs7916937(T,C); rs11202752(C,T); rs6586139(T,C); rs4934409(A,T); rs7077182(C,G); rs2312610(T,C); rs4934410(T,C); rs4933482(C,G); rs4933483(C,A); rs112552187(A,G); rs4934411(G,C); rs73355416(T,C); rs12413825(C,A); rs138817863(G,A); rs1418481(A,G); rs7904229(C,A); rs141101339(T,G); rs1342450(C,G); rs12778446(T,C); rs4934412(G,A); rs115363373(T,C); rs1750274(C,A); rs74147206(C,T); rs4934413(C,T); rs11202754(A,T); rs72820049(C,T); rs2488271(G,A); rs2437878(C,T); rs2477957(T,G); rs113690462(T,G); rs7076491(T,C); rs1169043(A,G); rs1183901(T,C); rs2153856(A,G); rs2185786(T,C); rs2576181(T,G); rs1342458(A,T); rs1177587(A,T); rs1342457(A,G); rs2576180(G,C); rs17343157(C,G); rs2477956(T,C); rs4145084(C,T); rs17112571(G,A); rs17112575(C,G); rs147835016(G,A); rs1325907(G,A); rs1325906(G,A); rs2986118(G,T); rs2765457(A,C); rs2437877(C,T); rs2437876(T,C); rs2765450(G,A); rs2576179(T,C); rs12359844(C,A); rs12356177(T,C); rs149070509(T,C); rs2576177(G,A); rs4934414(G,T); rs7917100(T,A); rs2576176(A,T); rs17096280(A,G); rs12256470(T,C); rs2148127(T,C); rs7081712(C,T); rs138740869(T,C); rs67679562(G,A); rs72820062(C,T); rs9664569(T,G); rs1974053(A,G); rs2437875(A,C); rs17343533(G,T); rs2437874(A,G); rs2576175(G,C); rs10887827(G,C); rs2576174(C,T); rs369710873(G,T); rs2765448(T,G); rs2477955(G,A); rs2576173(A,G); rs11202757(T,C); rs7902230(T,C); rs10509551(G,T); rs1536252(G,A); rs12572235(C,T); rs2576172(T,C); rs10788605(T,C); rs2576171(T,C); rs183768796(G,T); rs2576170(T,C); rs725683(C,T); rs2077890(T,C); rs725684(T,C); rs10887829(A,C); rs2765444(G,A); rs1325900(G,T); rs2477954(T,C); rs1409134(C,T); rs7906679(A,G); rs7920866(G,A); rs2765442(G,A); rs10887830(A,G); rs2477953(C,T); rs10887831(C,T); rs2765441(G,A); rs12413139(C,T); rs2576166(C,G); rs7075544(T,C); rs111635907(T,C); rs370311244(C,A); rs58424396(T,C); rs11202761(C,T); rs112004939(G,A); rs1980812(A,G); rs111838299(T,C); rs1359580(T,C); rs374690342(G,A); rs111379682(G,A); rs12571939(A,G); rs113549465(C,G); rs2437871(A,C); rs2477952(G,A); rs1952122(C,T); rs1925937(A,G); rs1325903(G,A); rs1325904(T,C); rs112577039(T,C); rs2765456(T,C); rs745354(C,T); rs2209553(C,T); rs113000330(A,G); rs61640455(C,T); rs12357364(G,A); rs12360281(A,C); rs12360297(A,G); rs2765454(G,A); rs72820074(C,T); rs149498598(T,A); rs10736357(T,C); rs10736358(C,T); rs10736359(G,A); rs113603556(G,A); rs11202766(C,T); rs73355485(G,A); rs73355487(C,G); rs2576159(A,T); rs2576158(C,A); rs79436975(G,A); rs11202767(C,A); rs112107857(A,C); rs10788606(G,A); rs74147213(T,C); rs191131595(T,C); rs2765453(T,G); rs2576156(A,G); rs12219242(T,C); rs34393743(A,G); rs59252570(A,G); rs72820082(C,A); rs11202769(C,T); rs9664314(T,C); rs12249510(C,T); rs11202772(G,A); rs10430716(G,A); rs142316091(C,T); rs74147218(A,C); rs10430643(T,C); rs372438010(T,C); rs138257191(T,C); rs6586140(T,G); rs7901991(C,T); rs113817828(C,T); rs7077844(T,C); rs74147222(G,A); rs74147223(T,A); rs1325899(G,T); rs1409133(T,C); rs113178232(C,T); rs2576162(G,A); rs149227506(A,T); rs113269502(G,C); rs74147229(T,G); rs72820087(G,A); rs2477959(T,C); rs74147230(C,T); rs2576164(T,C); rs2576163(A,T); rs59337681(C,A); rs112434041(A,G); rs12247690(C,T); rs2861367(A,G); rs1359582(T,G); rs58081364(T,C); rs11202776(C,T); rs1325905(T,A); rs2209555(G,C); rs2209556(A,C); rs2576161(T,C); rs2576160(G,A); rs2225016(C,T); rs10887832(A,T); rs78121194(T,C); rs55834089(T,C); rs7904690(G,A); rs111846521(T,C); rs74147235(A,G); rs112944464(T,A); rs77335205(G,T); rs141945823(C,T); rs113923976(A,G); rs74535095(G,C); rs2576155(C,T); rs112061592(T,C); rs79981780(T,C); rs72820095(T,C); rs78412955(A,G); rs112535033(G,T); rs2296545(C,G) |
| ccdsGene name | CCDS31239.1 |
| cytoBand name | 10q23.31 |
| EntrezGene GeneID | 55328 |
| EntrezGene Description | renalase, FAD-dependent amine oxidase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RNLS:NM_001031709:exon3:c.A277G:p.I93V,RNLS:NM_018363:exon3:c.A277G:p.I93V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6733 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5VYX0 |
| dbNSFP Uniprot ID | RNLS_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.004539 |
| ESP All MAF | 0.001538 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 5.286e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Saccadic pursuit (rare)
SKELETAL:
[Spine];
Scoliosis;
[Feet];
Pes cavus
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Difficulty walking;
Loss of independent ambulation approximately 30 years after onset;
Pyramidal signs;
Hyperreflexia;
Mild upper limb involvement;
Extensor plantar responses;
[Peripheral nervous system];
Distal sensory impairment in lower limbs;
Axonal neuropathy (in some patients)
MISCELLANEOUS:
Onset in childhood or adolescence (range 6 to 15 years);
Slow progression
MOLECULAR BASIS:
Caused by mutation in the DDHD domain-containing protein 1 gene (DDHD1,
614603.0001)
OMIM Title
*609360 RENALASE; RNLS
;;CHROMOSOME 10 OPEN READING FRAME 59; C10ORF59
OMIM Description
DESCRIPTION
Renalase is a flavin adenine dinucleotide-dependent amine oxidase that
is secreted into the blood from the kidney (Xu et al., 2005).
CLONING
By searching databases for transcripts likely to encode proteins
secreted from the kidney, Xu et al. (2005) identified a cDNA clone
encoding renalase. The deduced 342-amino acid protein has a calculated
molecular mass of 37.8 kD. Renalase contains an N-terminal signal
sequence and an amino oxidase domain. Northern blot analysis of several
tissues detected robust expression of a 1.5-kb transcript in kidney, and
lower expression in heart, skeletal muscle, and liver. A minor
transcript of about 2.4 kb was detected in skeletal muscle, and a minor
transcript of 1.2 kb was detected in kidney and liver. In situ
hybridization detected renalase in renal glomeruli and proximal tubules,
and in cardiomyocytes. Western blot analysis detected renalase at an
apparent molecular mass of about 35 kD in human urine. There was also a
signal at 67 to 75 kD, suggesting that the protein may form a doublet.
Renalase was also detected in the plasma of healthy individuals, but not
in the plasma of patients with end-stage renal disease on hemodialysis.
GENE FUNCTION
Xu et al. (2005) demonstrated that epitope-tagged renalase was secreted
from transfected human embryonic kidney cells. Purified and recombinant
renalase metabolized catecholamines, with dopamine as the preferred
substrate, followed by epinephrine and norepinephrine. Within 30 seconds
of a single bolus injection of recombinant renalase into rats, systolic,
diastolic, and mean arterial pressure were decreased in a dose-dependent
manner. Renalase also decreased cardiac contractility and heart rate,
but peripheral vascular resistance was unchanged.
GENE STRUCTURE
Xu et al. (2005) determined that the renalase gene contains 9 exons and
spans about 311 kb.
MAPPING
By genomic sequence analysis, Xu et al. (2005) mapped the RNLS gene to
chromosome 10q23.33.
CH25H
| dbSNP name | rs75732804(T,A); rs201617007(G,A) |
| cytoBand name | 10q23.31 |
| EntrezGene GeneID | 9023 |
| EntrezGene Description | cholesterol 25-hydroxylase |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01102 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Limbs];
Normal radii
NEUROLOGIC:
[Central nervous system];
Hypoplastic cerebellar vermis
HEMATOLOGY:
Severe thrombocytopenia (birth);
Pancytopenia (childhood);
Megakaryocytopenia;
Elevated serum thrombopoietin (TPO)
MOLECULAR BASIS:
Caused by mutations in myeloproliferative leukemia virus oncogene
(MPL, 159530.0001)
OMIM Title
*604551 CHOLESTEROL 25-HYDROXYLASE; CH25H
OMIM Description
DESCRIPTION
CH25H is an interferon (IFN)-stimulated gene than encodes an endoplasmic
reticulum (ER)-associated enzyme that converts cholesterol to
25-hydroxycholesterol (25HC). The soluble factor 25HC controls sterol
biosynthesis through regulation of sterol-responsive element-binding
proteins (see 184756) and nuclear receptors. In addition, 25HC has broad
antiviral activity (summary by Liu et al., 2013).
CLONING
Oxysterols regulate the expression of genes involved in cholesterol and
lipid metabolism. By screening pools of murine hepatic cDNAs for the
ability to convert cholesterol to oxysterols, Lund et al. (1998) cloned
mouse cholesterol 25-hydroxylase. They isolated the human CH25H cDNA by
hybridization screening of a lung cDNA library using an EST sequence
with homology to the mouse enzyme sequence. The deduced 272-amino acid
peptide has characteristics of a polytopic membrane protein and contains
clusters of histidine residues essential for catalytic activity.
Northern blot analysis showed very low levels of cholesterol
25-hydroxylase mRNA in 16 different tissues. Immunohistochemistry
detected cholesterol 25-hydroxylase in the ER and a perinuclear
compartment of transfected cells.
GENE STRUCTURE
Lund et al. (1998) isolated a genomic cholesterol 25-hydroxylase clone
and showed that the CH25H gene lacks introns.
MAPPING
By fluorescence in situ hybridization and by somatic and radiation
hybrid DNA panel mapping, Lund et al. (1998) mapped the CH25H gene to
chromosome 10q23.
GENE FUNCTION
Using mouse and human cells, Liu et al. (2013) showed that CH25H had
broad antiviral activity against acutely pathogenic viruses, such as
Ebola virus, Rift Valley fever virus, Nipah virus, and Russian
spring-summer encephalitis virus, and against chronic persistent
viruses, such as human immunodeficiency virus (HIV)-1, herpes simplex
virus, vesicular stomatitis virus, and murine gammaherpes virus (MHV68).
Virus growth was suppressed by blocking membrane fusion between virus
and cell. Liu et al. (2013) concluded that 25HC plays a beneficial role
in promoting host immunity against viral infections.
Using quantitative metabolome profiling of naturally occurring
oxysterols in mice upon infection or IFN stimulation, Blanc et al.
(2013) identified 25HC as the only macrophage-synthesized and -secreted
oxysterol. Ifnb (147640) was the primary mediator of macrophage
production of 25HC, and Stat1 (600555) was also required. Chromatin
immunoprecipitation analysis showed that Stat1 bound the Ch25h promoter.
Blanc et al. (2013) concluded that CH25H activation is coupled to the
IFN response through a direct molecular link with STAT1.
ANIMAL MODEL
Liu et al. (2013) found that mice lacking Ch25h were more susceptible
than wildtype mice to lytic infection with MHV68. Administration of 25HC
to humanized mice suppressed HIV replication and reversed T-cell
depletion.
Reboldi et al. (2014) found that activated mouse macrophages lacking
Ch25h were unable to produce Il1 family cytokines, such as Il1b
(147720), but were able to produce Il6 (147620) or Il23 (605580). Mice
lacking Ch25h had increased numbers of Il17a (603149)-positive cells in
spleen and lymph nodes and increased circulating neutrophils, whereas
mice lacking Gpr183 (605741), a receptor for a downstream product of
Ch25h, did not show these effects. RNA sequence analysis of Ch25h-null
macrophages revealed a striking elevation in transcripts of Srebp target
genes. Reboldi et al. (2014) noted that 25HC antagonizes processing of
SREBP1 (SREBF1; 184756) and SREBP2 (SREBF2; 600481) by promoting their
INSIG (602055)-mediated retention in the ER, and they showed that
repression of SREBP processing contributed to 25HC-mediated
downregulation of Il1b and inflammasome activity. Mice lacking Ch25h
underwent exacerbated experimental autoimmune encephalitis, but they
showed more resistance to Listeria growth, accompanied by elevated serum
Il1b, Il1a (147760), and Il18 (600953). Reboldi et al. (2014) concluded
that CH25H and 25HC play essential roles in the negative-feedback
mechanism regulating IL1 family cytokine production during type I IFN
inflammatory conditions by repressing IL1B expression and inflammasome
activity.
LIPA
| dbSNP name | rs13500(G,A); rs1131706(A,T); rs4509676(C,G); rs11594137(A,C); rs4554789(T,C); rs3802656(G,A); rs12246667(C,T); rs115859966(G,A); rs10749600(G,A); rs10749601(C,G); rs11203038(A,C); rs7908760(C,A); rs6586174(T,C); rs7077817(A,G); rs17117526(T,C); rs12359411(T,A); rs7910150(T,A); rs56916314(A,T); rs10509568(A,G); rs10509569(T,A); rs12780342(C,T); rs7922269(T,G); rs6586175(A,G); rs12358054(T,C); rs1556478(C,T); rs12415827(G,A); rs2297475(A,G); rs2297473(T,G); rs2297472(G,A); rs2254747(C,T); rs2254670(T,C); rs2254636(T,C); rs75001468(G,A); rs74149931(G,A); rs2071511(C,T); rs2071510(T,G); rs140686447(G,A); rs2071509(C,G); rs61853096(A,T); rs7094730(A,C); rs11203041(A,G); rs11203042(T,C); rs11203043(G,A); rs2266006(A,G); rs11813977(G,A); rs6586176(A,C); rs1041390(G,A); rs7896502(A,G); rs143953314(G,T); rs1041389(C,T); rs1041388(G,A); rs188392672(C,T); rs885561(T,C); rs951647(G,C); rs150002999(A,G); rs12257915(C,T); rs6586177(T,A); rs61853098(G,A); rs6586178(T,C); rs150110345(G,A); rs111709511(C,T); rs35472070(G,A); rs7073192(T,C); rs7069914(A,G); rs1576817(T,C); rs369974930(A,T); rs1029074(A,G); rs17117789(C,G); rs115778471(G,T); rs2902563(T,C); rs11203046(C,T); rs7074555(G,A); rs11203047(T,C); rs3892343(C,G); rs374318496(G,A); rs869820(A,G); rs12267584(C,G); rs1412445(C,T); rs1320496(C,T); rs1412444(C,T); rs140677191(C,T); rs1332329(A,C); rs12240489(C,T); rs11203048(A,T); rs77414759(A,T); rs2246949(C,T); rs2246942(A,G); rs2246941(C,A); rs10887934(C,T); rs374662554(A,C); rs3740044(G,C); rs2246833(C,T); rs2246828(G,A); rs928415(G,A); rs2250781(C,A); rs2250645(C,T); rs2250644(C,T); rs116428196(G,A); rs2902561(A,T); rs2863757(T,A); rs2250398(A,G); rs2243548(C,T); rs7081622(A,T); rs2243547(A,C); rs143585388(T,C); rs12262734(A,C); rs1332328(C,T); rs1332326(T,G); rs11203051(C,G) |
| ccdsGene name | CCDS7401.1 |
| cytoBand name | 10q23.31 |
| EntrezGene GeneID | 3988 |
| EntrezGene Description | lipase A, lysosomal acid, cholesterol esterase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LIPA:NM_000235:exon4:c.C379T:p.R127W,LIPA:NM_001127605:exon4:c.C379T:p.R127W,LIPA:NM_001288979:exon2:c.C31T:p.R11W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5559 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EUT7 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 4.879e-05,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
RESPIRATORY:
Respiratory infections, recurrent
GENITOURINARY:
[Kidneys];
Glomerulonephritis, autoimmune
SKIN, NAILS, HAIR:
[Skin];
Purpura
HEMATOLOGY:
Thrombocytopenia, autoimmune
IMMUNOLOGY:
Recurrent bacterial infections;
Hypogammaglobulinemia;
Normal numbers of B cells;
Reduced numbers of memory B cells;
B cells lack surface CD19 and CD81 expression;
Defective antibody production;
Normal numbers of T cells
LABORATORY ABNORMALITIES:
Low serum IgG and IgA;
Low or normal serum IgM
MISCELLANEOUS:
Onset in early childhood;
One patient has been reported (as of July 2010)
MOLECULAR BASIS:
Caused by mutation in the CD81 antigen gene (CD81, 186845.0001)
OMIM Title
*613497 LIPASE A, LYSOSOMAL ACID; LIPA
;;LYSOSOMAL ACID LIPASE; LAL;;
CHOLESTEROL ESTER HYDROLASE
OMIM Description
CLONING
Anderson and Sando (1991) reported that the amino acid sequence of LAL
as deduced from the 2.6-kb cDNA nucleotide sequence is 58% identical to
that of human gastric lipase (LIPF; 601980), which is involved in the
preduodenal breakdown of ingested triglycerides.
Anderson et al. (1994) isolated and sequenced the gene for LIPA.
GENE FUNCTION
The distinct kinetic and physical properties of lipases A and B (LIPB;
247980) were defined by Warner et al. (1980). They stated that the
natural substrate for LIPB was not known, and that it was not clear that
LIPB is a lysosomal hydrolase. LIPA may serve an important role in
cellular metabolism by releasing cholesterol. The liberated cholesterol
suppresses further cholesterol synthesis and stimulates esterification
of cholesterol within the cell.
GENE STRUCTURE
Aslanidis et al. (1994) summarized the exon structure of the LIPA gene,
which consists of 10 exons, together with the sizes of genomic EcoRI and
SacI fragments hybridizing to each exon. The DNA sequence of the
putative promoter region was presented.
Anderson et al. (1994) found that the LIPA gene is spread over 36 kb of
genomic DNA. The 5-prime flanking region is GC-rich and has
characteristics of a 'housekeeping' gene promoter.
MAPPING
Koch et al. (1979, 1981) assigned lysosomal acid lipase A to chromosome
10 by human-Chinese hamster somatic cell hybrids. Judging from the close
concordance with soluble glutamate oxaloacetate transaminase (GOT1;
138180), these loci were thought to be close together on the long arm of
10. Lipase A is encoded by chromosome 19 in mouse (Koch et al., 1981).
GOT1 is also on chromosome 10q in man and 19 in mouse.
By fluorescence in situ hybridization, Anderson et al. (1993) mapped the
LIPA locus to 10q23.2-q.23.3. It was clearly distinct from the locus for
pancreatic lipase (246600) at 10q26.1.
MOLECULAR GENETICS
Cholesteryl ester storage disease (CESD) and Wolman disease are
autosomal recessive allelic disorders (278000) associated with reduced
activity and genetic defects of lysosomal acid lipase. Aslanidis et al.
(1996) provided evidence that the strikingly more severe course of
Wolman disease is caused by genetic defects of LAL that leave no
residual enzyme activity. In a CESD patient, a G-to-A transition at
position -1 of the exon 8 splice donor site (613497.0002) resulted in
skipping of exon 8 in 97% of the mRNA originating from this allele,
while 3% was spliced correctly, resulting in full-length LAL enzyme. Two
sibs with Wolman disease were homozygous for a splice site mutation
involving the same donor site but permitting no correct splicing or
subsequent synthesis of functional enzyme (613497.0004).
Pagani et al. (1996) described the molecular basis of CESD in 3
patients. They identified mutations by sequence analysis of LAL cDNA and
genomic DNA. The role of the mutations as the direct cause of the
disease was confirmed by measuring the LAL enzymatic activity of
extracts from cells transfected with LAL mutants. The 3 CESD patients
were found to be compound heterozygotes. Pagani et al. (1996) identified
3 different missense mutations, 2 splicing defects, and a null allele.
NUDT9P1
| dbSNP name | rs78985163(T,C); rs12266933(G,A); rs11186457(A,G) |
| cytoBand name | 10q23.32 |
| EntrezGene GeneID | 119369 |
| snpEff Gene Name | RP11-56M3.1 |
| EntrezGene Description | nudix (nucleoside diphosphate linked moiety X)-type motif 9 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05096 |
PPP1R3C
| dbSNP name | rs12261209(C,T); rs62620038(A,G) |
| cytoBand name | 10q23.32 |
| EntrezGene GeneID | 5507 |
| EntrezGene Description | protein phosphatase 1, regulatory subunit 3C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.073 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602999 PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 3C; PPP1R3C
;;PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 5; PPP1R5
OMIM Description
DESCRIPTION
Protein phosphatase-1 (PP1; see 176875) participates in the regulation
of a wide variety of cellular functions by reversible protein
phosphorylation. The ability of PP1 to regulate diverse functions
resides in its capacity to interact with a variety of regulatory
subunits that may target PP1 to specific subcellular locations, modulate
its substrate specificity, and allow its activity to be responsive to
extracellular signals. Several targeting subunits of PP1 have been
identified, including PPP1R5, the glycogen-binding subunits PPP1R3
(600917) and PPP1R4, and the nuclear inhibitor of PP1 (PPP1R8; 602636).
CLONING
Doherty et al. (1996) identified the novel PP1 binding subunit PPP1R5
from a human gallbladder cDNA library, by searching an EST database for
sequences related to the rat liver glycogen-binding subunit PPP1R4.
Overlapping assemblies of ESTs resulted in an estimated mRNA of at least
2.5 kb. Because there was more than one potential initiation codon, the
complete open reading frame predicted a protein of 36.4 kD and 317 amino
acids, or 35.6 kD and 312 amino acids. The protein contained a motif
involved in the binding of PPP1R3 and PPP1R4 to PP1 and a region
homologous to a postulated glycogen-binding site in PPP1R3. The amino
acid sequence of the PPP1R5 protein showed 42% identity and 51%
similarity to rat liver PPP1R4. Whereas rat PPP1R4 appears to be a
liver-specific protein, the PPP1R5 protein was identified in cDNA
libraries from several adult tissues and cells. Doherty et al. (1996)
detected a 36-kD PPP1R5 protein on immunoblot of rat liver and skeletal
muscle extracts using an antibody to a PPP1R5 fusion protein. Doherty et
al. (1996) demonstrated that PPP1R5 binds to PP1, inhibits the
phosphorylase phosphatase activity of PP1, and, unlike PPP1R4, is not
regulated by phosphorylase a.
GENE FUNCTION
Fernandez-Sanchez et al. (2003) showed that full-length laforin (EPM2A;
607566) interacted with PPP1R5. However, a minimal central region of
PPP1R5 (amino acids 116 to 238), including the binding sites for
glycogen and for glycogen synthase (GYS1; 138570), was sufficient to
interact with laforin. Point mutagenesis of the PPP1R5 glycogen
synthase-binding site completely blocked interaction with laforin.
Fernandez-Sanchez et al. (2003) identified an EPM2A missense mutation
found in Lafora disease (254780) patients that had no effect on the
phosphatase or glycogen-binding activities of laforin but disrupted
laforin interaction with PPP1R5, suggesting that binding to PPP1R5 may
be critical for laforin function.
MAPPING
Doherty et al. (1996) found that the extreme 3-prime region of the
assembled PPP1R5 cDNA overlapped 2 sequence tagged sites (TMAP WI-11129;
TMAP TIGR-A004S47) that had been localized to human chromosome
10q23-q24, placing PPP1R5 in this region.
FGFBP3
| dbSNP name | rs11186737(C,T); rs117997708(T,A); rs1890897(C,T) |
| cytoBand name | 10q23.32 |
| EntrezGene GeneID | 143282 |
| EntrezGene Description | fibroblast growth factor binding protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3251 |
MARK2P9
| dbSNP name | rs74151633(C,T); rs2209972(C,T); rs967878(G,T) |
| cytoBand name | 10q23.33 |
| EntrezGene GeneID | 100507674 |
| snpEff Gene Name | AL161652.2 |
| EntrezGene Description | MAP/microtubule affinity-regulating kinase 2 pseudogene 9 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02847 |
PIPSL
| dbSNP name | rs12768993(G,A); rs78953916(T,A); rs829225(A,G); rs149493826(T,A); rs11813252(C,T); rs1977861(C,G) |
| cytoBand name | 10q23.33 |
| EntrezGene GeneID | 266971 |
| snpEff Gene Name | SLC35G1 |
| EntrezGene Description | PIP5K1A and PSMD4-like, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1814 |
C10orf12
| dbSNP name | rs3814163(C,T); rs3829856(A,C); rs7894200(A,C); rs375398676(A,G); rs61735270(G,A) |
| ccdsGene name | CCDS7452.1 |
| CosmicCodingMuts gene | C10orf12 |
| cytoBand name | 10q24.1 |
| EntrezGene GeneID | 26148 |
| EntrezGene Description | chromosome 10 open reading frame 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C10orf12:NM_015652:exon1:c.C1458T:p.L486L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.168 |
| ESP Afr MAF | 0.2399 |
| ESP All MAF | 0.097186 |
| ESP Eur/Amr MAF | 0.02407 |
| ExAC AF | 0.110,1.626e-05 |
FRAT1
| dbSNP name | rs3781373(C,T); rs1334892(G,T) |
| cytoBand name | 10q24.1 |
| EntrezGene GeneID | 10023 |
| EntrezGene Description | frequently rearranged in advanced T-cell lymphomas |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3724 |
FRAT2
| dbSNP name | rs915196(A,G); rs189336756(T,C) |
| cytoBand name | 10q24.1 |
| EntrezGene GeneID | 23401 |
| EntrezGene Description | frequently rearranged in advanced T-cell lymphomas 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08402 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Obesity;
Central fat distribution
GENITOURINARY:
[External genitalia, male];
Precocious puberty, gonadotropin-independent;
[Internal genitalia, female];
Oligomenorrhea;
Infertility
SKIN, NAILS, HAIR:
[Skin];
Acne;
[Hair];
Hirsutism;
Androgenic alopecia (in some patients)
ENDOCRINE FEATURES:
Hyperandrogenism;
Delayed conversion of oral cortisone acetate to plasma cortisol;
Low tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone
(THE) ratio;
Low urinary cortols-to-cortolone ratio;
Low to normal level of cortisol metabolites;
High level of cortisone metabolites;
High to high-normal cortisol secretion rate
MOLECULAR BASIS:
Caused by mutation in the hexose-6-phosphate dehydrogenase gene (H6PD,
138090.0001)
OMIM Title
*605006 FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS 2; FRAT2
OMIM Description
CLONING
Dorsal accumulation of beta-catenin (CTNNB1; 116806) in early Xenopus
embryos is required for body axis formation. Beta-catenin is dorsally
stabilized by the localized inhibition of the kinase GSK3 (see GSK3B;
605004). Using a yeast 2-hybrid system to identify a cytoplasmic
regulator of Xenopus GSK3, Yost et al. (1998) isolated an oocyte cDNA
encoding a 169-amino acid protein that they termed GSK3-binding protein,
or GBP. By searching sequence databases, Yost et al. (1998) identified 2
homologous human sequences, FRAT1 (602503) and FRAT2, a partial sequence
that shares 59% amino acid identity with FRAT1. Sequence analysis
predicted that GBP and the FRAT proteins contain 3 well-conserved
regions.
By screening a fetal lung cDNA library with an FT2S probe obtained from
a gastric cancer cell line that corresponds to an FRAT2 EST, Saitoh et
al. (2001) isolated a full-length cDNA encoding FRAT2. The deduced
233-amino acid protein, which is 77% identical to FRAT1, contains an
N-terminal acidic domain followed by a proline-rich domain and a
GSK3B-binding domain near the C terminus, which is highly divergent from
that of FRAT1. Northern blot analysis detected a 2.4-kb transcript, with
highest expression in pancreas, heart, spleen, placenta, skeletal
muscle, liver, peripheral blood leukocytes, and fetal kidney. Expression
was higher in gastric cancer, cervical cancer, and chronic myelogenous
leukemia cell lines than in other cancer cell lines.
GENE FUNCTION
Binding and functional analyses by Yost et al. (1998) revealed that the
GSK3-binding and -inhibitory activities of GBP and FRAT2 reside in the
C-terminal conserved domain III sequence. The authors proposed that GBP,
FRAT1, and FRAT2 form a family of GSK3-binding proteins that inhibit the
phosphorylation of beta-catenin, preventing its degradation by the
ubiquitin-proteasome pathway.
By functional analysis in the Xenopus axis duplication assay, Saitoh et
al. (2001) showed that FRAT2 is a positive regulator of the WNT (see
164975) signaling pathway. Saitoh et al. (2001) suggested that
upregulation of FRAT2 in human cancer may be implicated in
carcinogenesis through activation of the WNT signaling pathway.
MAPPING
By in silico analysis, Saitoh et al. (2001) mapped the FRAT2 gene to
10q24.1.
ANIMAL MODEL
Inhibition of GSK3 by FRAT was thought to be important for Wnt signal
transduction through beta-catenin. To test this hypothesis, van
Amerongen et al. (2005) developed triple-knockout mice lacking Frat1,
Frat2, and Frat3. They found that Frat-null mice were viable, healthy,
and fertile. In addition, in vitro assays of primary Frat-deficient
cells showed that Wnt signaling through beta-catenin was unaffected. Van
Amerongen et al. (2005) concluded that Wnt signaling in higher
vertebrates is not dependent on Frat.
C10orf62
| dbSNP name | rs7093840(G,C); rs7093643(A,G); rs61863261(C,A) |
| ccdsGene name | CCDS31261.1 |
| cytoBand name | 10q24.2 |
| EntrezGene GeneID | 414157 |
| EntrezGene Description | chromosome 10 open reading frame 62 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C10orf62:NM_001009997:exon1:c.G363C:p.E121D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5T681 |
| dbNSFP Uniprot ID | CJ062_HUMAN |
| dbNSFP KGp1 AF | 0.254120879121 |
| dbNSFP KGp1 Afr AF | 0.341463414634 |
| dbNSFP KGp1 Amr AF | 0.25138121547 |
| dbNSFP KGp1 Asn AF | 0.124125874126 |
| dbNSFP KGp1 Eur AF | 0.296833773087 |
| dbSNP GMAF | 0.2534 |
| ESP Afr MAF | 0.33409 |
| ESP All MAF | 0.320698 |
| ESP Eur/Amr MAF | 0.313837 |
| ExAC AF | 0.289,1.626e-04 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
RESPIRATORY:
[Lung];
Respiratory paralysis
ABDOMEN:
[Gastrointestinal];
Vomiting;
Abdominal colic
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness
NEUROLOGIC:
[Peripheral nervous system];
Neuropathy (motor and sensory);
Paresthesia;
Paralysis
HEMATOLOGY:
Hemolytic anemia;
Porphyria
LABORATORY ABNORMALITIES:
Erythrocyte delta-aminolevulinate dehydratase (ALAD) deficiency;
Elevated urinary delta-aminolevulinic acid and porphyrins
MISCELLANEOUS:
Very rare;
Asymptomatic heterozygotes susceptible to lead toxicity;
Exacerbation following stress, decreased food intake, or alcohol use
MOLECULAR BASIS:
Caused by mutation in the delta-aminolevulinate dehydratase gene (ALAD,
125270.0001)
OMIM Title
*612766 CHROMOSOME 19 OPEN READING FRAME 62; C19ORF62
;;MEDIATOR OF RAP80 INTERACTIONS AND TARGETING, 40-KD; MERIT40;;
NEW COMPONENT OF BRCA1 A COMPLEX 1; NBA1
OMIM Description
CLONING
Using mass spectrometry to identify components of a BRCA1
(113705)-associated DNA repair complex, Feng et al. (2009) and Shao et
al. (2009) independently identified MERIT40. The deduced protein
contains 329 amino acids and has a calculated molecular mass of about
36.5 kD.
Using a genetic screen, Wang et al. (2009) identified NBA1 as a gene
required for resistance to ionizing radiation (IR). NBA1 contains a von
Willebrand factor (VWF; 613160) type A (VWA) domain homologous to the
VWA domain of the proteasome subunit PSMD4 (601648).
GENE FUNCTION
Using coimmunoprecipitation assays, Feng et al. (2009) confirmed that
MERIT40 was part of a BRCA1-associated protein complex containing BRE
(610497), BRCC36 (BRCC3; 300617), CCDC98 (611143), and RAP80 (UIMC1;
609433). The C-terminal regions of MERIT40 and BRE interacted directly,
and the interaction stabilized BRE against degradation. The MERIT40-BRE
interaction also stabilized the entire protein complex, which was
required for efficient BRCA1 foci formation and function at sites of DNA
damage.
Wang et al. (2009) found that NBA1 was part of a BRCA1-associated
complex in human cell lines and was required for BRCA1 focus formation.
Knockdown of NBA1 via short hairpin RNA led to increased sensitivity of
cells to DNA damage caused by IR, ultraviolet radiation, and chemical
DNA-damaging agents. NBA1-depleted human osteosarcoma cells were unable
to arrest efficiently in G2 in response to IR. Similar to BRE, NBA1 was
incorporated into the BRCA1-associated complex via the N-terminal region
of ABRA1 (CCDC98), which then mediated the interaction of NBA1 and BRE
with RAP80 and BRCC36.
RAP80 targets BRCA1-associated complex components, including the
deubiquitinating enzyme BRCC36, to polyubiquitin structures at DNA
double-strand breaks (DSBs). Shao et al. (2009) identified MERIT40 as a
RAP80-associated protein essential for BRCA1-RAP80 complex protein
interactions, stability, and DSB targeting. Moreover, MERIT40 was
required for RAP80-associated deubiquitinating activity of BRCC36, a
critical component of viability responses to IR. Shao et al. (2009)
concluded that MERIT40 links BRCA1-RAP80 complex integrity, DSB
recognition, and ubiquitin chain hydrolysis to the DNA damage response.
MAPPING
Hartz (2009) mapped the C19ORF62 gene to chromosome 19p13.11 based on an
alignment of the C19ORF62 sequence (GenBank GENBANK AF161491) with the
genomic sequence (build 36.1).
ABCC2
| dbSNP name | rs717620(C,T); rs4919395(A,G); rs2756103(A,C); rs2756104(C,T); rs927344(A,T); rs4148384(G,C); rs146371543(G,A); rs7901377(C,T); rs7393085(C,G); rs7393105(C,A); rs2756105(C,T); rs10786571(T,G); rs79389568(G,T); rs10786572(G,A); rs35683214(G,A); rs10748791(C,T); rs10748792(C,T); rs2756106(C,T); rs7906080(G,A); rs7922376(T,A); rs7922379(T,G); rs10786573(C,T); rs4148385(A,C); rs4148386(G,A); rs2145852(C,T); rs2756107(C,T); rs2145853(A,G); rs2180990(G,C); rs6584326(G,C); rs7899883(T,G); rs4148388(G,A); rs4148389(G,A); rs4148390(T,G); rs4919396(A,G); rs2804401(C,A); rs2756108(C,T); rs148713114(T,G); rs2073336(A,T); rs2804400(C,T); rs7899330(T,C); rs7914602(G,A); rs78495498(C,G); rs6584327(A,C); rs143863790(T,A); rs2804398(A,T); rs2756109(G,T); rs2804397(A,G); rs10883413(T,C); rs72838105(A,T); rs2224506(G,C); rs2273697(G,A); rs373960214(C,T); rs2756111(C,T); rs11190291(C,T); rs2756112(A,G); rs2073337(A,G); rs2281637(C,A); rs2756113(T,C); rs2756114(T,C); rs74152770(G,C); rs7076773(C,A); rs3740074(C,T); rs4148394(A,C); rs10883414(G,C); rs2902299(C,A); rs138638773(C,T); rs3740073(T,C); rs202226998(C,A); rs2002042(C,T); rs56139910(T,C); rs4077146(G,A); rs4148395(G,A); rs41318031(C,T); rs4148396(T,C); rs4148397(A,G); rs4148398(A,G); rs4148399(T,G); rs56050010(A,G); rs78812905(C,T); rs7476245(G,A); rs55672373(C,T); rs55804858(C,T); rs17222723(T,A); rs139641475(G,A); rs12771624(C,T); rs3758395(T,C); rs3780882(A,G); rs17216177(T,C); rs3740067(C,G); rs34456559(A,G); rs17216317(C,T); rs3740066(C,T); rs17216310(C,T); rs72838129(T,C); rs17216282(G,C); rs3740065(A,G); rs7920448(T,C); rs3740064(G,A); rs1137968(G,T); rs72838134(T,G); rs183388509(A,G); rs72838136(G,A); rs72838138(G,A); rs72838141(G,A); rs3780880(C,G); rs111866537(C,T); rs113513789(G,A); rs72838143(G,A); rs72838146(C,T); rs72838149(T,C); rs72838150(G,A); rs56333232(G,A); rs8187707(C,T); rs17216212(G,A); rs77106298(C,T); rs3740063(A,G); rs8187710(G,A) |
| ccdsGene name | CCDS7484.1 |
| cytoBand name | 10q24.2 |
| EntrezGene GeneID | 1244 |
| EntrezGene Description | ATP-binding cassette, sub-family C (CFTR/MRP), member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCC2:NM_000392:exon28:c.C3872T:p.P1291L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5498 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q92887 |
| dbNSFP Uniprot ID | MRP2_HUMAN |
| dbNSFP KGp1 AF | 0.00686813186813 |
| dbNSFP KGp1 Afr AF | 0.0264227642276 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.03291 |
| ESP All MAF | 0.011379 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.003529 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Blurred vision;
Diplopia;
Photophobia;
Eyelid apraxia;
Supranuclear gaze palsy
ABDOMEN:
[Gastrointestinal];
Dysphagia
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Bradykinesia;
Akinesia;
Rigidity;
Axial dystonia;
Poor mobility;
Gait imbalance;
Falls;
Supranuclear gaze palsy;
Dysarthria;
Retrocollis;
Tremor (30%);
Limb dystonia (18%);
Mutism;
Frontolimbic dementia;
Neuropathology shows neuronal loss in basal ganglia, brainstem, and
cerebellum;
Tau-immunoreactive inclusions in neurons and astrocytes;
Tau inclusions are 'flame-shaped' or 'tuft-like';
Granulovacuolar degeneration;
Gliosis;
Neurofibrillary tangles;
[Behavioral/psychiatric manifestations];
Forgetfulness;
Irritability;
Apathy;
Frontal release signs (45%)
MISCELLANEOUS:
Autosomal dominant with incomplete penetrance;
Average age at onset 66 years although earlier onset may occur;
Median survival 5.7 years;
May show good response to levodopa;
Genetic heterogeneity (see PSNP2 609454);
Phenotypic overlap with frontotemporal dementia (600274);
Associated with the tau (157140) H1 haplotype
MOLECULAR BASIS:
Caused by mutation in the microtubule-associated protein tau gene
(MAPT, 157140.0019)
OMIM Title
*601107 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 2; ABCC2
;;MULTISPECIFIC ORGANIC ANION TRANSPORTER, CANALICULAR; CMOAT;;
MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2; MRP2
OMIM Description
CLONING
Paulusma et al. (1996) used the animal model of Dubin-Johnson syndrome
(DJS; 237500), the TR- rat, to elucidate the canalicular multispecific
organic anion transporter (cMOAT), which mediates hepatobiliary
excretion of numerous organic anions. From studies of the cDNA for rat
cmoat, which is similar to human multidrug resistance protein (MRP;
158343), they presented evidence suggesting that MRP and cMOAT are
expressed in the basolateral and canalicular (apical) parts of the
hepatocyte, respectively, and that cMOAT but not MRP is involved in
biliary organic anion transport. They also showed that the 2 proteins
are encoded by 2 different genes. In the TR- rat, a single nucleotide
deletion in the cmoat gene resulted in reduced mRNA and absent protein.
GENE FUNCTION
Evers et al. (1998), who referred to cMOAT as multidrug
resistance-associated protein-2 (MRP2), studied its drug export activity
in polarized kidney in MDCK cells. In contrast to MRP1 (158343), cMOAT
was found predominantly intracellularly in nonpolarized cells,
suggesting the cMOAT requires a polarized cell for plasma membrane
routing. They found that when kidney epithelial MDCK cells were grown in
a monolayer, cMOAT localized to the apical plasma membrane. Their
studies demonstrated that cMOAT causes transport of organic anions,
including a substrate not shown to be transported by organic anion
transporters previously. Transport was inhibited only inefficiently by
compounds known to block MRP1. They also showed that cMOAT caused
transport of the anticancer drug vinblastine to the apical side of a
cell monolayer. They concluded that cMOAT is a 5-prime-adenosine
triphosphate binding cassette transporter that may be involved in drug
resistance in mammalian cells.
Using microarray analysis and quantitative RT-PCR, Xu et al. (2012)
found that expression of microRNA-297 (MIR297; 615520) was downregulated
in chemotherapy-resistant human colorectal carcinoma cell lines compared
with their parental cell lines. Downregulation of MIR297 was inversely
proportional to expression of a putative target, MRP2. Quantitative
RT-PCR and Western blot analyses revealed that expression of MIR297 and
MRP2 progressively decreased and increased, respectively, with clinical
stage in human colorectal carcinomas. Reporter gene assays confirmed
that MRP2 was a direct target of MIR297. Expression of an MIR297 mimic
increased cell sensitivity to anticancer drugs and induced apoptosis in
colorectal cancer cells in vitro and in vivo following injection into
nude mice.
GENE STRUCTURE
Toh et al. (1999) determined the exon/intron structure of the human
MRP2/CMOAT gene. They found that the human gene contains 32 exons and
spans 200 kb or more genomic DNA.
MAPPING
By fluorescence in situ hybridization (FISH), Taniguchi et al. (1996)
mapped the human CMOAT gene to 10q24. Also by FISH, van Kuijck et al.
(1997) mapped the CMOAT gene to human 10q24 and mouse 19D2. Gopalan et
al. (1998) likewise mapped the cmoat gene to mouse chromosome 19.
MOLECULAR GENETICS
Zimniak (1993) suggested that the defect in Dubin-Johnson syndrome may
reside in the CMOAT gene. Dubin-Johnson syndrome is an autosomal
recessive disorder characterized by conjugated hyperbilirubinemia, an
increase in the urinary excretion of coproporphyrin isomer I, deposition
of melanin-like pigment in hepatocytes, and prolonged retention of
sulfobromophthalein, but otherwise normal liver function. Consistent
with findings of defects in the homologous cmoat gene in 2 rat models of
hyperbilirubinemia (Paulusma et al., 1996, Ito et al., 1997), Wada et
al. (1998) reported 2 deletions and a missense mutation in the active
transport family signature region in the CMOAT gene in patients with
DJS.
In a 63-year-old Japanese man with DJS, born of first-cousin parents,
Kajihara et al. (1998) identified homozygosity for a splice site
mutation in the ABCC2 gene (601107.0006).
Toh et al. (1999) identified 3 mutations, 2 of which were novel, in the
MRP2/CMOAT gene in DJS patients (601107.0001 and
601107.0003-601107.0004, respectively).
All mutations identified to that time were in the cytoplasmic domain,
which includes 2 ATP-binding cassettes and the linker region, or in the
adjacent putative transmembrane domain.
Mor-Cohen et al. (2001) analyzed the ABCC2 gene in 35 Israeli DJS
patients from 24 unrelated families, most of whom were ascertained
previously by Shani et al. (1970) and had been followed for more than 3
decades, including 22 DJS patients from 13 Iranian Jewish families, 5
from 4 Moroccan Jewish families, 2 from mixed Moroccan and Iranian
families, 3 of Ashkenazi Jewish origin, and 3 of Turkish, Kurdish, and
Afghan Jewish origin, respectively. All 22 Iranian Jewish patients were
homozygous for an I1173F mutation (601107.0007) in ABCC2, and all 5
Moroccan Jewish patients were homozygous for an R1150H mutation
(601107.0008). Both mutations were unique to those specific populations.
In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified
compound heterozygosity for an R768W mutation (601107.0001) and a
nonsense mutation (R1066X; 601107.0009) in ABCC2. Both mutations had
previously been found in adult patients, although compound
heterozygosity for the 2 mutations was novel.
PAX2
| dbSNP name | rs4278455(A,T); rs6421335(C,T); rs4919488(G,A); rs4244341(T,G); rs57264262(A,C); rs11190681(T,C); rs12259313(C,T); rs11817070(G,A); rs7921610(A,G); rs7921931(G,A); rs10883538(T,C); rs72843852(C,T); rs77474743(T,C); rs11190684(G,C); rs34556107(C,T); rs73347607(T,G); rs142381751(T,C); rs55960653(T,C); rs4638248(A,C); rs59227439(G,A); rs4601695(C,T); rs4338467(T,G); rs4638249(A,G); rs9988739(G,A); rs4623826(A,G); rs7079266(G,A); rs12260647(G,A); rs11190685(G,A); rs7894069(T,C); rs7909092(G,A); rs113526429(C,T); rs34187063(C,T); rs11599767(C,T); rs11599825(G,A); rs59792575(A,G); rs56830181(G,C); rs11591622(G,T); rs60145745(G,A); rs58783205(A,C); rs55889623(A,G); rs60163501(C,T); rs10786607(A,G); rs57464361(G,A); rs61871654(C,G); rs11190688(G,A); rs73347635(A,G); rs57346201(A,G); rs7068349(A,G); rs60956400(C,G); rs61527719(G,A); rs11190692(A,G); rs11190693(A,T); rs3922761(C,T); rs4381304(A,C); rs4539243(G,A); rs75661212(C,T); rs58955156(G,A); rs3862027(C,T); rs57097683(A,C); rs12774757(G,C); rs4450110(A,G); rs77136923(C,T); rs10883539(T,G); rs4600144(T,C); rs58061250(T,C); rs60336873(A,G); rs11190695(G,T); rs11190696(G,A); rs2863046(G,A); rs10883540(C,T); rs10883541(G,A); rs7895504(T,G); rs11190697(C,T); rs56376707(C,T); rs7918029(C,A); rs17113441(T,G); rs11190698(A,C); rs188635568(C,T); rs11190699(A,G); rs12357097(G,A); rs11190700(G,A); rs199876625(G,A); rs7901210(C,G); rs7904804(C,G); rs188780905(T,G); rs17113450(C,G); rs4559621(G,A); rs998799(T,G); rs11190701(T,C); rs12357009(G,C); rs182518539(C,T); rs35987146(A,G); rs56131066(A,C); rs10786608(C,T); rs71488071(C,T); rs11190705(G,A); rs56064122(G,T); rs72843858(C,T); rs10883542(T,C); rs11190706(G,A); rs11190707(G,T); rs11190708(C,T); rs187932778(C,T); rs61608651(C,G); rs11190709(G,A); rs10883543(G,T); rs11190710(C,A); rs1006545(G,T); rs1006544(C,T); rs77175835(C,T); rs2902399(G,A); rs10748798(C,T); rs61873480(G,A); rs4919492(G,A); rs71488072(G,A); rs7072737(A,G); rs4548562(G,T); rs4551692(G,A); rs4919493(T,C); rs12769015(T,C); rs10748799(T,C); rs12570050(T,G); rs12266644(G,T); rs4917911(G,A); rs117284422(C,T); rs11812391(C,T); rs4919494(C,T); rs74152682(C,T); rs60349629(G,T); rs79520577(G,A); rs12773509(C,T); rs12780810(G,C); rs2077642(C,T); rs79552202(G,A); rs78118302(T,C); rs56283258(T,A); rs12769518(T,C); rs79269299(T,C); rs56327778(A,T); rs11594822(T,C); rs1800897(C,T); rs199724772(C,G); rs1800898(A,C); rs59107884(A,G); rs4919498(A,G); rs927638(C,T); rs876671(G,C); rs876670(G,A); rs75945547(C,T); rs11190716(T,C); rs1969816(C,T); rs1812930(G,C); rs10883544(A,C); rs3862028(A,G); rs7917026(C,T); rs17113490(G,A); rs4919499(G,A); rs12766403(A,G); rs75964204(G,T); rs17113495(T,G); rs12773936(C,T); rs11815022(C,T); rs12268707(A,G); rs11595703(G,C); rs11190717(G,A); rs78423757(A,G) |
| ccdsGene name | CCDS7499.1 |
| cytoBand name | 10q24.31 |
| EntrezGene GeneID | 5076 |
| EntrezGene Description | paired box 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PAX2:NM_003988:exon7:c.C867G:p.N289K,PAX2:NM_003990:exon8:c.C936G:p.N312K,PAX2:NM_003987:exon8:c.C936G:p.N312K,PAX2:NM_000278:exon7:c.C867G:p.N289K,PAX2:NM_003989:exon7:c.C867G:p.N289K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.838 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3V5U4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 2.846e-04,1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Mandibular and submandibular pain, episodic, triggered by eating and
yawning;
[Eyes];
Lacrimation, episodic;
Ocular pain, episodic;
[Nose];
Rhinorrhea, episodic
CARDIOVASCULAR:
[Heart];
Autonomic reflex asystolic syncopal events;
Tachycardia;
Bradycardia
ABDOMEN:
[Gastrointestinal];
Rectal pain, episodic, triggered by defecation
GENITOURINARY:
[Bladder];
Painful micturition (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Reddish discoloration, episodic, associated with pain;
Skin flushing, episodic, associated with pain
NEUROLOGIC:
[Peripheral nervous system];
Burning pain, episodic;
Autonomic reflex asystolic syncopal events;
Nonepileptic tonic attacks (most common in infants and young children)
MISCELLANEOUS:
Onset in neonatal period or infancy;
Presents with 4 types of painful episodes - (1) Birth crisis, babies
are born red and stiff (2) Rectal crisis, triggered by defecation
or emotional factors (3) Ocular crisis (4) Mandibular crisis, triggered
by eating or yawning;
Attacks tend to decrease with age;
Allelic disorder to primary erythermalgia (133020)
MOLECULAR BASIS:
Caused by mutation in the type IX, voltage-gated sodium channel, alpha
subunit gene (SCN9A, 603415.0008)
OMIM Title
*167409 PAIRED BOX GENE 2; PAX2
OMIM Description
CLONING
Stapleton et al. (1993) isolated a PAX2 cosmid clone by screening with a
PCR probe of the PAX2 paired box. They subcloned and sequenced DNA
fragments containing the first 3 exons. That the amino acid sequence
encoded by the first 3 exons is identical between human and mouse
indicated high evolutionary conservation.
GENE STRUCTURE
Sanyanusin et al. (1996) obtained the complete genomic structure of the
human PAX2 gene. They described 5 genomic lambda clones containing human
PAX2 gene sequences, 4 of which had previously been reported by them
(Sanyanusin et al., 1995). The fifth clone, which included exons 7 and
8, was obtained by Sanyanusin et al. (1996) from a subgenomic lambda
cDNA library of size-fractionated EcoRI fragments ranging in size from 6
to 8 kb. Sequencing and restriction mapping of these clones showed that
the human PAX2 gene is composed of 12 exons spanning approximately 70
kb. They also found 2 alternatively spliced exons corresponding to exon
10 (Ward et al., 1994) and a 69-bp inserted sequence that they
designated as exon 6. The 69-bp insert is homologous to a 69-bp insert
reported in the murine Pax2 gene by Dressler et al. (1990). Sanyanusin
et al. (1996) identified a (CA)n dinucleotide repeat polymorphism in
PAX2 which they mapped immediately upstream of exon 9.
MAPPING
Pilz et al. (1993) used mouse cDNA probes for Pax2 to map the human
homolog of the gene in somatic cell hybrids. PAX2 showed complete
concordance with human chromosome 10. Further analysis with hybrids made
from a human cell line with a reciprocal translocation showed that PAX2
maps to 10q11.2-qter. The homologous gene maps to mouse chromosome 19.
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization (FISH), Stapleton et al. (1993) assigned PAX2 to 10q25.
Narahara et al. (1997) described a 5-year-old boy with a de novo
t(10;13) translocation and optic nerve coloboma-renal syndrome (120330).
By FISH using a YAC clone containing the PAX2 gene and YAC clones
adjoining FRA10B, a fragile site at 10q25.2, Narahara et al. (1997)
demonstrated that the 10q break had occurred just within the PAX2 gene
and was proximal to FRA10B. They refined the regional mapping of the
PAX2 gene to the junction of bands 10q24.3 and 10q25.1.
Using FISH, BAC end sequencing, and genomic database analysis, Gough et
al. (2003) determined that the order of selected genes on chromosome
10q24, from centromere to telomere, is CYP2C9 (601130), PAX2, HOX11
(TLX1; 186770), and NFKB2 (164012).
GENE FUNCTION
In the developing kidney, induction of nephrogenesis by the ureter is
accompanied by an increase in expression levels of the PAX2 gene. This
is followed by an increase in expression of WT1 (607102), the Wilms
tumor suppressor gene, as mesenchymal cells condense and differentiate.
In studies in cultured cells, Dehbi et al. (1996) demonstrated that PAX2
isoforms are capable of transactivating the WT1 promoter. Deletion
mutagenesis of the WT1 promoter identified an element responsible for
mediating PAX2 responsiveness, locating it between nucleotides -33 and
-71 relative to the first WT1 transcription start site. They
demonstrated that PAX2 can stimulate expression of the endogenous WT1
gene. These results suggested to Dehbi et al. (1996) that a role for
PAX2 during mesenchyme-to-epithelium transition in renal development is
to induce WT1 expression.
Using in situ hybridization on paraffin-embedded human embryo sections
at 5 different stages (days 32 to 60), Tellier et al. (2000) showed that
PAX2 is expressed (1) in the optic vesicle and later in the retina, (2)
in the otic vesicle and later in the semicircular canals of the inner
ear, and (3) in mesonephros, metanephros, adrenals, spinal cord, and
hindbrain.
Using cDNA microarray analysis, Cai et al. (2005) found that high NaCl
concentrations increased Pax2 mRNA expression in mouse inner medullary
epithelial cells. Pax2 expression was osmoregulated in renal medullary
epithelial cells in vivo and in cell culture, and increased Pax2
expression protected cells against high NaCl concentration-induced
apoptosis.
Wu et al. (2005) showed that tamoxifen and estrogen have distinct but
overlapping target gene profiles. Among the overlapping target genes, Wu
et al. (2005) identified a paired box gene, PAX2, that is crucially
involved in cell proliferation and carcinogenesis in the endometrium. Wu
et al. (2005) showed that PAX2 is activated by estrogen and tamoxifen in
endometrial carcinomas but not in normal endometrium, and that this
activation is associated with cancer-linked hypomethylation of the PAX2
promoter.
Hurtado et al. (2008) implicated PAX2 in a previously unrecognized role,
as a crucial mediator of estrogen receptor (ER; see 133430) repression
of ERBB2 (164870) by the anticancer drug tamoxifen. They showed that
PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and
regulation of ERBB2 transcription, the outcome of which determines
tamoxifen response in breast cancer cells. The repression of ERBB2 by
ER-PAX2 links these 2 breast cancer subtypes and suggests that
aggressive ERBB2-positive tumors can originate from ER-positive luminal
tumors by circumventing this repressive mechanism. Hurtado et al. (2008)
concluded that their data provided mechanistic insight into the
molecular basis of endocrine resistance in breast cancer.
PATHOGENESIS
Patek et al. (2003) used immunochemistry to reexamine the hypothesis
that glomerulosclerosis such as that seen in Denys-Drash syndrome
(194080) can be caused by loss of WT1 and persistent expression of PAX2
by podocytes (Yang et al., 1999). They stated that their results, based
on rat and mouse models of glomerulosclerosis, did not support the view
that WT1 represses PAX2 expression by podocytes, which was based on the
inverse correlation between WT1 and PAX2 in podocyte precursors and
evidence that WT1 can repress PAX2 promoter activity in transient
transfection assays (Eccles et al., 2002; Ryan et al., 1995). Patek et
al. (2003) suggested that podocyte PAX2 expression may reflect
reexpression rather than persistent expression, and may be the
consequence of glomerulosclerosis.
MOLECULAR GENETICS
- Papillorenal Syndrome
The PAX2 gene is expressed in primitive cells of the kidney, ureter,
eye, ear, and central nervous system. Based on the known expression
pattern of PAX2, Sanyanusin et al. (1995) predicted that the phenotype
caused by mutations of PAX2 would probably consist of autosomal dominant
eye malformations, sensorineural hearing loss, and renal hypoplasia.
Pursuing this suspicion, they found deletion of a single nucleotide in
exon 5 of the PAX2 gene (167409.0001) in a father and 3 of his 5 sons
who had optic nerve colobomas, renal hypoplasia, mild proteinuria, and
vesicoureteral reflux. The nucleotide deletion caused a frameshift in
the conserved octapeptide sequence. The phenotype was similar to that of
Krd mutant mice which lack a portion of chromosome 19 that is homologous
to human 10q24 and includes the Pax2 gene. These mice have reduced
thickness of the renal cortex, a reduced number of glomeruli at birth,
and reduced amplitudes on electroretinogram. In the Krd mouse, the
deletion of chromosome 19 was transgene-induced (Keller et al., 1994).
Coloboma of the optic nerve with renal disease (120330) is a recognized
syndrome. Renal dysplasia and retinal aplasia are combined in the
Loken-Senior syndrome (266900). Ocular abnormalities occur also with
familial juvenile nephronophthisis (256100), but that disorder maps to
chromosome 2.
Tellier et al. (1998) observed heterozygous PAX2 gene mutations in a
patient with sporadic RCS (167409.0009), 3 patients with renal
hypoplasia either isolated or associated with microphthalmia and retinal
degeneration (619insG; 167409.0002), and 1 patient with isolated renal
hypoplasia (167409.0005). The recurrent 619insG mutation had previously
been reported in 1 sporadic and 2 familial cases of RCS; the same
mutation in Pax2 is responsible for the 1Neu mutant, a mouse model for
human RCS. No PAX2 mutation was found in 2 patients with CHARGE or
CHARGE/DiGeorge syndrome (188400). The study confirmed the critical role
of PAX2 in human renal and ocular development and probably otic
development. It also demonstrated that PAX2 mutations can be responsible
for renal hypoplasia, either isolated or associated with various
ophthalmologic manifestations ranging from retinal coloboma to
microphthalmia.
Schimmenti et al. (1999) described a mildly affected Caucasian mother
and daughter and a severely affected African American girl, all of whom
had PAX2 homoguanine tract (7G) missense mutations. The mother and
daughter had optic nerve colobomas and the daughter had vesicoureteral
reflux. The severely affected girl developed renal failure and had
bilateral colobomatous eye defects. Additionally, this girl developed
hydrocephalus associated with platybasia and a Chiari-1 malformation.
The severely affected girl showed a previously described mutation
(Sanyanusin et al., 1995; Schimmenti et al., 1995), the insertion of a
guanine into the homoguanine tract of 7 residues between positions 613
and 619 (167409.0002). The mother and daughter demonstrated
heterozygosity for a previously undescribed mutation: a contraction of
the homonucleotide tract from 7 guanines to 6 guanines in exon 2 of PAX2
(167409.0008), leading to a premature stop codon 2 amino acids
downstream. This mutation was not present in unaffected relatives. Thus,
the known phenotype associated with mutations in PAX2 was expanded to
include brain malformations. The homoguanine tract in PAX2 is a hotspot
for spontaneous expansion or contraction mutations and demonstrates the
importance of homonucleotide tract mutations in human malformation
syndromes.
In a study of 9 patients with renal-coloboma syndrome, Amiel et al.
(2000) screened the entire coding sequence of the PAX2 gene and found 5
heterozygous mutations. The 619insG mutation was detected in 3 unrelated
cases and the dinucleotide insertion GG at the same position was found
in an isolated case, further confirming the stretch of 7 guanines as a
mutation hotspot. The 619insG mutation was detected in 2 isolated cases
and in a family with 3 affected sibs whose unaffected parents did not
carry the mutation, suggesting germline mosaicism (false paternity
excluded).
To gain insight into the cause of renal abnormalities in patients with
PAX2 mutations, Porteous et al. (2000) analyzed kidney anomalies in
patients with RCS, including a large Brazilian kindred in which they had
identified a novel mutation. In a total of 29 patients, renal hypoplasia
was the most common congenital renal abnormality. To determine the
direct effects of PAX2 mutations on kidney development, fetal kidneys of
mice carrying a Pax2(1Neu) mutation were examined. At embryonic day 15
(E15), heterozygous mutant kidneys were approximately 60% the size of
those of wildtype littermates, and the number of nephrons was strikingly
reduced. Heterozygous mutant mice showed increased apoptotic cell death
during fetal kidney development, but the increased apoptosis was not
associated with random stochastic inactivation of Pax2 expression in
mutant kidneys; Pax2 was shown to be biallelically expressed during
kidney development. The findings supported the conclusion that
heterozygous mutations of the PAX2 gene are associated with increased
apoptosis and reduced branching of the ureteric bud, due to reduced PAX2
dosage during a critical window in kidney development.
In a child with atypical bilateral optic nerve coloboma and congenital
renal hypoplasia, Chung et al. (2001) reported a novel heterozygous PAX2
mutation leading to a prematurely truncated protein. The mutation was
not found in the parents. The authors concluded that the causal
relationship between PAX2 gene mutations and the renal-coloboma syndrome
was further supported by this novel mutation.
To investigate whether PAX2 mutations occur in patients with isolated
renal hypoplasia, Nishimoto et al. (2001) analyzed DNA from 20 patients
with bilateral renal hypoplasia associated with decreased renal
function. Heterozygous PAX2 mutations were detected in 2 patients:
1566C-A (167409.0010) and 1318C-T (167409.0011), respectively. The 2
changes directly introduced stop codons, presumably resulting in a
message for a truncated PAX2 protein that lacked a partial
transactivation domain. Ophthalmologic examination revealed very mild,
asymptomatic coloboma in the second patient, whereas the fundus was
normal in the first. The mutation cosegregated with renal hypoplasia in
the family of the first patient, appearing de novo in the patient's
mother. Nishimoto et al. (2001) concluded that isolated renal hypoplasia
can be part of the spectrum of the renal-coloboma syndrome.
Martinovic-Bouriel et al. (2010) analyzed the PAX2 gene in 2 fetuses
with renal anomalies and optic nerve colobomas and in 18 fetuses with
isolated renal disease, of which 10 had uni- or bilateral renoureteral
agenesis, 6 had enlarged dysplastic kidneys, and 2 had small dysplastic
kidneys. In the 2 fetuses with papillorenal syndrome, the authors
identified a frameshift and a splice site mutation in the PAX2 gene,
respectively, but no mutations were detected in the 18 fetuses with
isolated renal disease.
In 2 of 20 unrelated children and young adults with congenital anomalies
of the kidney and urinary tract (CAKUT) resulting in renal failure and
renal transplantation but with no apparent ocular abnormalities,
Negrisolo et al. (2011) identified 2 different de novo heterozygous
mutations in the PAX2 gene: a nonsense mutation and a splice site
mutation, respectively. One patient was later found to have myopia and
isotropy of the right eye. The other patient showed bilateral excavation
of the optic disc on optic fundus reexamination. Negrisolo et al. (2011)
concluded that patients with CAKUT without apparent ocular abnormalities
should be screened for mutations in the PAX2 gene, and that ocular
abnormalities may be underdiagnosed in patients with PAX2 mutations.
Bower et al. (2012) reviewed published cases of PAX2 mutations as well
as data from a consortium of 3 laboratories, and identified a total of
53 unique PAX2 mutations and 12 other PAX2 variants in 173 individuals
from 86 families. The most frequently reported recurring mutation was
76dup (167409.0002). Renal disease was the most highly penetrant feature
in this series, being identified in 159 (92%) of 173 mutation-positive
individuals, whereas ophthalmologic abnormalities were found in 134
(77%). Bower et al. (2012) stated that no clear genotype/phenotype
correlations emerged from this study, and noted that the tremendous
intrafamilial variability described in renal coloboma syndrome suggests
that factors other than PAX2 genotype play a significant role. Bower et
al. (2012) reviewed 4 case series involving isolated renal disease
(Nishimoto et al., 2001; Salomon et al., 2001; Weber et al., 2006;
Martinovic-Bouriel et al., 2010) in which 13 (9%) of 148 individuals had
mutations in the PAX2 gene. Further ophthalmologic evaluation revealed
optic nerve abnormalities in 10 of the 13 mutation-positive individuals,
with the remaining 3 having reportedly normal eye examinations.
Barua et al. (2014) identified 8 different missense mutations in the
PAX2 gene in 7 (8%) of 85 individuals with CAKUT. Seven patients had a
heterozygous mutation, whereas 1 patient with a more severe phenotype
and extrarenal abnormalities was compound heterozygous. Parental DNA
available from 3 of the patients showed that the mutations occurred de
novo. Functional studies of the variants were not performed, but 6
occurred in the transactivation domain.
- Focal Segmental Glomerulosclerosis 7
In affected members of 7 unrelated families with focal segmental
glomerulosclerosis-7 (FSGS7; 616002), Barua et al. (2014) identified 7
different heterozygous mutations in the PAX2 gene (see, e.g.,
167409.0013 and 167409.0014). Six families carried a missense mutation,
and 1 with a more severe phenotype carried a nonsense mutation. The
mutation in the first family was found by whole-exome sequencing, and
the subsequent mutations were found by sequencing this gene in a cohort
of 175 patients with familial disease. PAX2 mutations were found in 4%
of the total FSGS cohort. In vitro functional expression studies of some
of the mutations showed that some perturbed protein function by
affecting proper binding to DNA and transactivation activity or by
enhancing the repressor activity of PAX2. The findings indicated that
PAX2 mutations can cause disease through haploinsufficiency or a
dominant-negative effect, and expanded the phenotypic spectrum
associated with PAX2 mutations.
- Exclusion Studies
Based on the expression pattern of PAX2, Tellier et al. (2000) screened
the entire coding region of the PAX2 gene for mutations in 34 patients
fulfilling the diagnostic criteria for CHARGE association (214800) using
2 polymorphisms to look for deletions and SSCP of the 12 exons to look
for nucleotide variations. No disease-causing mutations were identified,
suggesting that mutation of the PAX2 gene is not a common cause of
CHARGE association. The authors suggested that the expression pattern of
PAX2 is consistent with the possibility that unidentified PAX2
downstream targets and effectors could be candidate genes for CHARGE.
HPS6
| dbSNP name | rs372494008(C,T); rs3816(T,G) |
| ccdsGene name | CCDS7527.1 |
| cytoBand name | 10q24.32 |
| EntrezGene GeneID | 79803 |
| EntrezGene Description | Hermansky-Pudlak syndrome 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HPS6:NM_024747:exon1:c.C2099T:p.A700V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.3795 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86YV9 |
| dbNSFP Uniprot ID | HPS6_HUMAN |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Nausea;
Vomiting
NEUROLOGIC:
[Central nervous system];
Migraine with aura;
Migraine without aura;
Photophobia;
Phonophobia;
Hemiparesis;
Hemiplegia;
Hemisensory attacks
MISCELLANEOUS:
May be triggered by minor head trauma;
Genetic heterogeneity, see FHM1, (141500) and MGR1, (157300)
OMIM Title
*607522 HPS6 GENE; HPS6
;;RUBY-EYE, MOUSE, HOMOLOG OF; RU
OMIM Description
DESCRIPTION
The HPS6 gene encodes a protein involved in the biogenesis of
lysosome-related organelles complex-2 (BLOC2) (Zhang et al., 2003).
CLONING
In mice there are at least 16 naturally occurring hypopigmentation
models of Hermansky-Pudlak syndrome (HPS; 203300), and 9 of these have
been characterized at the molecular level. Zhang et al. (2003) used
positional candidate and transgenic rescue approaches to identify the
genes mutated in ruby-eye-2 (ru2; 607521) and ruby-eye (ru), 2 'mimic'
mouse models of HPS. They determined that these genes are orthologs of
the human genes mutated in individuals with HPS5 and HPS6, respectively.
Both genes are found only in higher eukaryotes. The human ru ortholog
contains 775 amino acids and is 80% identical to the mouse protein.
Northern blot analysis of mouse tissues detected a 2.6-kb ru transcript
in all tissues tested, with lowest expression in skeletal muscle. Zhang
et al. (2003) concluded that ru and ru2 represent a novel class of genes
that have evolved in higher organisms to govern the synthesis of highly
specialized lysosome-related organelles.
GENE FUNCTION
By coimmunoprecipitation and yeast 2-hybrid analyses, Zhang et al.
(2003) showed that the ru and ru2 proteins directly interact in a
complex that they referred to as 'biogenesis of lysosome-related
organelles complex-2,' or BLOC2.
GENE STRUCTURE
By genomic sequence analysis, Zhang et al. (2003) determined that a
single large exon contains the entire open reading frame in both the
mouse ru gene and the human HPS6 gene.
MAPPING
By genomic sequence analysis, Zhang et al. (2003) mapped the mouse ru
gene to chromosome 19 and the human HPS6 gene to chromosome 10q24.32.
MOLECULAR GENETICS
In a 39-year-old Belgian woman with Hermansky-Pudlak syndrome (HPS6;
614075), Zhang et al. (2003) identified a homozygous 4-bp deletion
(607522.0001) in the HPS6 gene.
Huizing et al. (2009) identified homozygous or compound heterozygous
mutations (607522.0003-607522.0007) in the HPS6 gene in 4 unrelated
patients with Hermansky-Pudlak syndrome. All mutations except 1 resulted
in a truncated protein. The phenotype was characterized by early-onset
nystagmus, oculocutaneous albinism, and a mild bleeding diathesis, but
no pulmonary fibrosis, granulomatous colitis, or renal involvement.
However, 2 patients had gastrointestinal symptoms. In vitro cellular
studies performed on patient melanocytes indicated aberrant cytoplasmic
distribution patterns of melanogenic proteins and increased trafficking
of TYRP1 (115501) through the plasma membrane, indicating a defect in
lysosomal-related organelles.
ANIMAL MODEL
Zhang et al. (2003) stated that ru and ru2 mice are completely
indistinguishable in appearance. Although lysosomal morphology is normal
in both mice, kidney proximal tubule cells secrete lysosomal enzymes
into urine at greatly reduced rates in both. Platelet dense granules are
very deficient in critical components such as serotonin and adenine
nucleotides in both, leading to functionally abnormal platelets and
prolonged bleeding times. Another subcellular organelle, the mast cell
granule, undergoes unregulated 'kiss-and-run' fusion at the plasma
membrane of mast cells of ru mice.
RPEL1
| dbSNP name | rs116500144(T,C); rs4917386(C,T); rs182419281(A,G) |
| cytoBand name | 10q24.33 |
| EntrezGene GeneID | 729020 |
| EntrezGene Symbol | LOC729020 |
| snpEff Gene Name | RP11-332O19.5 |
| EntrezGene Description | rcRPE |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
MIR936
| dbSNP name | rs140657237(C,T) |
| ccdsGene name | CCDS7554.1 |
| cytoBand name | 10q25.1 |
| EntrezGene GeneID | 100126326 |
| snpEff Gene Name | COL17A1 |
| EntrezGene Description | microRNA 936 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.002497 |
| ESP All MAF | 0.006766 |
| ESP Eur/Amr MAF | 0.008953 |
| ExAC AF | 0.008311 |
MIR4482
| dbSNP name | rs45596840(G,A); rs641071(G,T) |
| cytoBand name | 10q25.1 |
| EntrezGene GeneID | 100616323 |
| EntrezGene Symbol | MIR4482-1 |
| snpEff Gene Name | GSTO1 |
| EntrezGene Description | microRNA 4482-1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2112 |
| ExAC AF | 0.103 |
CCDC147-AS1
| dbSNP name | rs11192019(C,T); rs12250794(C,T); rs11192020(C,A) |
| cytoBand name | 10q25.1 |
| EntrezGene GeneID | 100505869 |
| snpEff Gene Name | CCDC147 |
| EntrezGene Description | CCDC147 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2557 |
PDCD4-AS1
| dbSNP name | rs76937993(C,T); rs1322995(G,A); rs1322996(C,T); rs11597928(G,C); rs3763692(G,A) |
| cytoBand name | 10q25.2 |
| EntrezGene GeneID | 282997 |
| snpEff Gene Name | PDCD4 |
| EntrezGene Description | PDCD4 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01102 |
ADRA2A
| dbSNP name | rs11195419(C,A); rs553668(A,G); rs3750625(C,A) |
| cytoBand name | 10q25.2 |
| EntrezGene GeneID | 150 |
| EntrezGene Description | adrenoceptor alpha 2A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1703 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, sensorineural, especially affecting high frequencies
CARDIOVASCULAR:
[Vascular];
Hypertension
GENITOURINARY:
[Kidneys];
Glomerulonephropathy;
Hematuria, gross and microscopic;
Proteinuria;
End-stage renal failure;
Thinning of the glomerular basement membrane (early in the disease);
Thickening of the glomerular basement membrane (later in the disease);
Splitting of the glomerular basement membrane;
Diffuse lamellation of the glomerular basement membrane
LABORATORY ABNORMALITIES:
Hematuria, gross and microscopic;
Proteinuria
MISCELLANEOUS:
Progressive disorder;
Hearing loss is variable
MOLECULAR BASIS:
Caused by mutation in the collagen, type IV, alpha-3 gene (COL4A3,
120070.0009)
OMIM Title
*104210 ALPHA-2A-ADRENERGIC RECEPTOR; ADRA2A
;;ADRAR;;
ALPHA-2-ADRENERGIC RECEPTOR, PLATELET TYPE;;
ADRENOCEPTOR, ALPHA-2A; ADRA2
OMIM Description
DESCRIPTION
A variety of neurotransmitter and hormone receptors elicit their
responses through biochemical pathways that involve transduction
elements known as guanine nucleotide regulatory (G) proteins. Among
these are several types of receptors for epinephrine (adrenaline), which
are termed adrenergic receptors. The alpha-2-adrenergic receptors
inhibit adenylate cyclase (summary by Kobilka et al., 1987).
CLONING
Kobilka et al. (1987) cloned the gene for the human platelet
alpha-2-adrenergic receptor by using oligonucleotides corresponding to
the partial amino acid sequence of the purified receptor. The deduced
protein contains 450 amino acids. The protein sequence is most similar
to those of human beta-2- and beta-1-adrenergic receptors. The greatest
homology is found in the 7 putative transmembrane-spanning domains.
Similarities to the muscarinic cholinergic receptors are also evident.
GENE STRUCTURE
Kobilka et al. (1987) showed that the coding block of the ADRAR gene is
contained within a single exon.
MAPPING
Yang-Feng et al. (1987) mapped the ADRAR locus to 10q23-q25 by somatic
cell hybridization and in situ hybridization. Hoehe et al. (1988)
identified a DraI RFLP of the ADRAR gene.
By study of interspecific backcrosses, Oakey et al. (1991) assigned the
Adra2r gene to the distal region of mouse chromosome 19.
GENE FUNCTION
An aspartic acid residue at position 79 is highly conserved among G
protein-coupled receptors. Surprenant et al. (1992) found that when
asp79 was mutated to asparagine, cells transfected with the mutant
adrenoceptor showed inhibition of adenylyl cyclase and calcium currents
by agonists but did not increase potassium currents. Because distinct G
proteins appear to couple adrenoceptors to potassium and calcium
currents, the findings suggested that the mutant adrenoceptor could not
achieve the conformation necessary to activate G proteins that mediate
potassium channel activation.
Xu et al. (2003) presented evidence that ADRA2A and ADRB1 (109630) form
heterodimers when coexpressed in cultured cells, and that ADRA2A
expression affects the internalization and ligand-binding
characteristics of ADRB1.
Using congenic strains from the diabetic Goto-Kakizaki rat, Rosengren et
al. (2010) identified a 1.4-Mb genomic locus that was linked to impaired
insulin granule docking at the plasma membrane and reduced beta-cell
exocytosis. In this locus, Adra2a was significantly overexpressed. The
alpha-2A-adrenergic receptor mediates adrenergic suppression of insulin
secretion. Pharmacologic receptor antagonism, silencing of receptor
expression, or blockade of downstream effectors rescued insulin
secretion in congenic islets.
MOLECULAR GENETICS
Halperin et al. (1997) reported a significant increase in plasma
norepinephrine in attention-deficit hyperactivity disorder (ADHD;
143465) children with reading and other cognitive disabilities compared
to ADHD children without learning disabilities (LD). Comings et al.
(1999) examined the hypothesis that ADHD with or without LD is
associated with dysfunction at a molecular genetic level by testing for
associations and additive effects between polymorphisms at 3
noradrenergic genes: the adrenergic alpha-2A receptor (ADRA2A),
adrenergic alpha-2C receptor (ADRA2C; 104250), and dopamine
beta-hydroxylase (DBH; 223360) genes. A total of 336 subjects (274
individuals with Tourette syndrome (137580) and 62 normal controls) were
genotyped. Regression analysis showed a significant correlation between
scores for ADHD, a history of LD, and poor grade-school academic
performance that was greatest for the additive effect of all 3 genes.
Combined, these 3 genes accounted for 3.5% of the variance of the ADHD
score (p = 0.0005). There was a significant increase in the number of
variant norepinephrine genes progressing from subjects without ADHD (A-)
or learning disabilities (LD-) to A+/LD- to A-/LD+ to A+/LD+ (p =
0.0017), but no comparable effect for dopamine genes. These data
supported an association between norepinephrine genes and ADHD,
especially in ADHD subjects with LD.
In a Brazilian sample of 92 ADHD patients and their biologic parents,
Roman et al. (2003) studied the -1291C-G SNP (dbSNP rs1800544) that was
previously reported by Comings et al. (1999) to be associated with ADHD
scores, particularly inattention scores. No association was observed
through the Haplotype Relative Risk method, although an influence of the
GG genotype on inattention and combined ADHD scores was detected. To
further investigate the -1291C-G SNP, Roman et al. (2006) studied a new
sample of 128 Brazilian ADHD probands. Patients were genotyped and
symptoms for each ADHD cluster (inattention, hyperactivity/impulsivity,
and combined) were obtained. An association with inattention symptoms
was again detected in individuals with the GG genotype (p = 0.017).
Rosengren et al. (2010) identified a single-nucleotide polymorphism in
the human ADRA2A gene, dbSNP rs553668, for which risk allele carriers
exhibited overexpression of alpha-2A-adrenergic receptor, reduced
insulin secretion, and increased type 2 diabetes risk. Human pancreatic
islets from risk allele carriers exhibited reduced granule docking and
secreted less insulin in response to glucose; both effects were
counteracted by pharmacologic alpha-2A-adrenergic receptor antagonists.
ANIMAL MODEL
Alpha-2-adrenergic receptors have a critical role in regulating
neurotransmitter release from sympathetic nerves and from adrenergic
neurons in the central nervous system. To help elucidate the individual
roles of the 3 highly homologous alpha-2-adrenergic receptors (ADRA2A;
ADRA2B, 104260; and ADRA2C) in this process, Hein et al. (1999) studied
neurotransmitter release in mice in which the genes encoding the 3
alpha-2-adrenergic receptor subtypes were disrupted. Hein et al. (1999)
demonstrated that both the ADRA2A and ADRA2C subtypes are required for
normal presynaptic control of transmitter release from sympathetic
nerves in the heart and from central noradrenergic neurons. ADRA2A
receptors inhibited transmitter release at high stimulation frequencies,
whereas the ADRA2C subtype modulated neurotransmission at lower levels
of nerve activity. Both low and high frequency regulation seemed to be
physiologically important, as mice lacking both ADRA2A and ADRA2C
receptor subtypes had elevated plasma noradrenaline concentrations and
developed cardiac hypertrophy with decreased left ventricular
contractility by 4 months of age.
A substantial percentage of human pregnancies are lost as spontaneous
abortions after implantation. This is often caused by an inadequately
developed placenta. Proper development of the placental vascular system
is essential to nutrient and gas exchange between mother and developing
embryo. Philipp et al. (2002) showed that alpha-2-adrenoceptors, which
are activated by adrenaline and noradrenaline, are important regulators
of placental structure and function. Mice with deletions in the genes
Adra2a, Adra2b, and Adra2c died between embryonic days 9.5 and 11.5 from
a severe defect in yolk-sac and placenta development. In wildtype
placentae, alpha-2-adrenoceptors are abundantly expressed in giant
cells, which secrete angiogenic factors to initiate development of the
placental vascular labyrinth. In placentae deficient in the 3
adrenoceptors encoded by the 3 genes deleted in these mice, the density
of fetal blood vessels in the labyrinth was markedly lower than normal,
leading to death of the embryos as a result of reduced oxygen and
nutrient supply. Basal phosphorylation of the extracellular
signal-regulated kinases ERK1 (601795) and ERK2 (176948) was also lower
than normal, suggesting that activation of the mitogen-activated protein
kinase (MAP kinase) pathway by alpha-2-adrenoceptors is required for
placenta and yolk-sac vascular development. Thus, alpha-2-adrenoceptors
are essential at the placental interface between mother and embryo to
establish the circulatory system of the placenta and thus maintain
pregnancy.
DCLRE1A
| dbSNP name | rs17228897(C,T); rs114046014(C,T); rs17235304(T,A); rs77331538(A,G); rs4463806(T,C); rs10787507(G,C); rs190783038(C,T); rs143627130(T,A); rs148054632(T,C); rs10885514(G,A); rs114428108(T,C); rs17235192(T,G); rs17235185(G,A); rs17235171(A,G); rs115851556(G,A); rs149562559(T,C); rs17235164(T,C); rs139656011(C,A); rs17228772(T,G); rs17228765(T,C); rs17228758(G,A); rs17235136(G,T); rs17228730(G,C); rs17228723(G,A); rs17235129(T,C); rs17235122(T,G); rs3750898(C,G); rs17235087(A,C); rs17228686(C,A); rs17228679(T,C); rs200247419(A,G); rs61755344(T,G); rs17228672(C,T); rs17235066(T,C); rs17235045(A,G); rs17228658(C,T); rs3829213(A,G) |
| ccdsGene name | CCDS7584.1 |
| cytoBand name | 10q25.3 |
| EntrezGene GeneID | 9937 |
| EntrezGene Description | DNA cross-link repair 1A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DCLRE1A:NM_001271816:exon2:c.A247C:p.S83R,DCLRE1A:NM_014881:exon1:c.A247C:p.S83R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5596 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6PJP8 |
| dbNSFP Uniprot ID | DCR1A_HUMAN |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.017249 |
| ESP All MAF | 0.006074 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.001862 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Normal kidneys
SKELETAL:
[Limbs];
Osteolysis of patellae (bone loss of posterior patella);
[Hands];
Osteolysis of scaphoids (bone loss and fragmentation of scaphoid);
Short fourth metacarpals;
[Feet];
Osteolysis of tali (bone loss and fragmentation of posterior talus)
MISCELLANEOUS:
Onset 13-15 years
OMIM Title
*609682 DNA CROSS-LINK REPAIR PROTEIN 1A; DCLRE1A
;;SNM1, S. CEREVISIAE, HOMOLOG OF; SNM1;;
SNM1, S. CEREVISIAE, HOMOLOG OF, A; SNM1A;;
KIAA0086
OMIM Description
DESCRIPTION
DNA interstrand cross-links prevent strand separation, thereby
physically blocking transcription, replication, and segregation of DNA.
DCLRE1A is one of several evolutionarily conserved genes involved in
repair of interstrand cross-links (Dronkert et al., 2000).
CLONING
By sequencing clones obtained from a size-fractionated human immature
myeloid cell line cDNA library, Nagase et al. (1995) cloned DCLRE1A,
which they called KIAA0086. The deduced 1,040-amino acid protein shares
33.3% identity over 192 amino acids with the S. cerevisiae DNA repair
protein Snm1. Northern blot analysis detected expression in all tissues
and cell lines examined except peripheral blood leukocytes.
Dronkert et al. (2000) determined that human DCLRE1A, which they called
SNM1, contains a nuclear localization signal and a zinc finger motif in
its N-terminal half and 8 motifs shared with SNM1-like proteins of
various species in its C-terminal half. Fluorescence-tagged SNM1
localized to nuclei of transfected human fibroblasts and Chinese hamster
ovary cells, but it was excluded from nucleoli.
Using Northern blot analysis, Richie et al. (2002) detected a 4.5-kb
SNM1 transcript in all tissues examined, with highest expression in
pancreas and brain. Fluorescence-tagged SNM1 localized to the nucleus of
individual transfected HeLa and human breast carcinoma cells in 3
distinct patterns: diffuse nuclear staining, multiple nuclear foci, or 1
or 2 larger nuclear bodies.
GENE FUNCTION
Dronkert et al. (2000) found that cells overexpressing human SNM1
underwent morphologic changes consistent with apoptosis a few days after
SNM1 introduction.
Richie et al. (2002) found that exposure of cells to ionizing radiation
or to an interstrand cross-linking agent altered the pattern of SNM1
nuclear localization. Under these conditions, the number of cells
exhibiting SNM1 bodies decreased and the population of cells with SNM1
foci increased. Immunofluorescence studies indicated that SNM1
colocalized with 53BP1 (TP53BP1; 605230) before and after exposure to
ionizing radiation, and coimmunoprecipitation assays confirmed the
interaction. SNM1 foci formed after ionizing radiation were largely
coincident with foci formed by MRE11 (MRE11A; 600814) and to a lesser
extent with those formed by BRCA1 (113705), but not with those formed by
RAD51 (179617). Focus formation by SNM1 did not require ATM (607585).
GENE STRUCTURE
Demuth and Digweed (1998) determined that the DCLRE1A gene contains 9
exons and spans about 20 kb. The upstream region contains a GC box, but
no TATA box, and has 1 SP1 (189906) site, 3 AP1 (see JUN; 165160) sites,
4 AP4 (TFAP4; 600743) sites, and 1 NFKB (see 164011) site.
MAPPING
By examining a panel of human-rodent hybrid cell lines, Nagase et al.
(1995) mapped the DCLRE1A gene to chromosome 10.
ANIMAL MODEL
Dronkert et al. (2000) found that Snm1 -/- mice were viable and fertile
and showed no major abnormalities, but they were hypersensitive to
mitomycin C compared with wildtype mice. Snm1 -/- mouse embryonic stem
cells grew at a rate comparable to wildtype stem cells, but they were
2-fold more sensitive to mitomycin C. Mutant and wildtype stem cells
showed the same sensitivity to other DNA interstrand cross-linking
agents, ultraviolet irradiation, and gamma irradiation.
NHLRC2
| dbSNP name | rs118152996(C,T); rs73345579(C,G); rs2419857(G,A); rs2301180(T,C); rs369800370(A,G); rs17702348(G,C); rs73345583(A,G); rs7073100(T,C); rs73345585(A,G); rs11196534(A,G); rs149960344(A,G); rs117477265(C,T); rs4373875(C,A); rs17091073(C,G); rs6585248(C,T); rs11196535(C,T); rs146269630(A,C); rs7080052(T,G); rs79562456(G,A); rs57502477(C,T); rs4589246(G,C); rs4381326(T,C); rs61247084(T,A); rs144060858(C,T); rs7914144(A,G); rs11815031(A,T); rs73345590(A,G); rs11196537(T,C); rs10885515(T,C); rs73345595(T,C); rs4323816(A,G); rs143917979(G,A); rs4385846(G,T); rs6585250(A,G); rs6585251(C,A); rs7924081(A,G); rs10219135(T,C); rs73347506(A,G); rs75860943(G,C); rs10787508(G,C); rs140827983(A,G); rs73347509(T,G); rs146365037(C,T); rs73347512(C,T); rs10787509(C,T); rs145010912(A,G); rs4345919(G,A); rs7919159(T,A); rs4244310(G,T); rs141310732(T,C); rs73347518(A,G); rs143353388(G,A); rs73347521(G,T); rs73358693(A,T); rs7075874(G,C) |
| ccdsGene name | CCDS7585.1 |
| cytoBand name | 10q25.3 |
| EntrezGene GeneID | 374354 |
| EntrezGene Description | NHL repeat containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NHLRC2:NM_198514:exon6:c.A1115G:p.D372G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.581 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NBF2 |
| dbNSFP Uniprot ID | NHLC2_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.001999 |
| ESP Eur/Amr MAF | 0.002907 |
| ExAC AF | 0.002716 |
PNLIPRP3
| dbSNP name | rs10885929(C,T); rs4751963(G,C); rs10885930(C,A); rs1549827(T,A); rs11197677(C,T); rs2033399(A,G); rs17094727(T,C); rs36117446(G,A); rs140407354(G,C); rs10787671(T,A); rs12265880(T,C); rs12250863(G,A); rs1431488(G,C); rs1431487(T,C); rs7094204(A,G); rs10510019(T,C); rs1431486(T,G); rs1431485(T,C); rs12262608(T,C); rs10787672(A,G); rs79691373(C,T); rs17094739(C,T); rs17094741(T,C); rs17094744(A,G); rs75629279(T,C); rs11197680(T,G); rs17094748(T,A); rs78848017(G,A); rs111547243(C,A); rs77410701(A,T); rs76187368(T,C); rs78092246(A,G); rs11197681(T,G); rs10885932(G,A); rs12415255(G,A); rs74851039(A,G); rs1367763(G,A); rs4751964(C,T); rs2116287(A,G); rs201551337(G,A); rs2033398(A,T); rs200054779(G,C); rs4237500(A,G); rs76343439(T,C); rs1529614(T,C); rs7893631(A,G); rs10885936(G,T); rs7073523(G,A); rs12243884(G,A); rs71500858(C,A); rs7099741(T,C); rs7082136(G,A); rs4492731(G,A); rs76551231(T,C); rs1118786(A,G); rs1594483(T,C); rs4485017(T,C); rs7071213(T,C); rs4751966(T,C); rs10885937(G,A); rs4751967(C,T); rs35151131(T,C); rs6585398(T,C); rs2099312(G,C); rs2082379(A,G); rs11528290(A,T); rs11197682(A,C); rs10885938(C,G); rs7098561(T,C); rs192897019(C,T); rs1119265(T,C); rs4751969(A,G); rs7090468(G,A); rs7090296(A,G); rs11197685(T,A); rs4751970(A,G); rs7923775(G,A); rs67570003(T,C); rs891665(C,T); rs4592354(T,C); rs2099244(C,A); rs7093179(T,A); rs12257773(C,T); rs7080915(G,C); rs1897515(G,T); rs1897516(C,T); rs60072620(C,T); rs988524(C,A); rs10749215(G,A); rs1431483(G,A); rs7069129(A,G); rs7069270(A,G); rs12255203(C,A); rs12255207(C,G); rs7070032(C,T); rs11596038(G,A); rs7074178(C,T); rs7074313(C,T); rs10736249(A,G); rs989022(C,A); rs721181(C,T); rs67933372(G,C); rs139899035(C,A); rs7908185(A,T); rs764695(A,T); rs11197687(C,T); rs7077408(T,C); rs4751586(T,C); rs55674364(G,A); rs10749216(T,G); rs10736250(C,T); rs2217632(G,A); rs1897520(A,G); rs6585399(C,G); rs7087485(T,G); rs41300225(G,A); rs10736251(G,A); rs1897519(A,G); rs10749217(A,C); rs10885939(C,T); rs7906587(C,T); rs12247930(A,G); rs2163486(A,G); rs113201543(A,T); rs186276944(C,T); rs12241434(T,C); rs7088387(G,A); rs7091461(A,G); rs112980458(G,A); rs10885940(A,G); rs7916123(G,A); rs6585400(A,G); rs149057898(T,C); rs116302267(T,A); rs77214259(G,C); rs1431482(A,T); rs4529824(C,G); rs2420285(A,G); rs61729315(C,T); rs76805457(A,G); rs7898331(C,T) |
| ccdsGene name | CCDS31292.1 |
| cytoBand name | 10q25.3 |
| EntrezGene GeneID | 119548 |
| EntrezGene Description | pancreatic lipase-related protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PNLIPRP3:NM_001011709:exon4:c.G400C:p.V134L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6311 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q17RR3 |
| dbNSFP Uniprot ID | LIPR3_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 1.626e-04,8.132e-06 |
ENO4
| dbSNP name | rs1637568(G,A); rs1681752(A,G); rs1681749(C,T); rs9421247(C,T); rs1616412(C,T); rs7083543(C,T); rs7087685(G,A); rs12248084(A,T); rs138127890(T,G); rs9421248(T,C); rs147225796(T,C); rs150721071(C,T); rs373435336(G,A); rs1637570(G,A); rs4752015(A,G); rs11197834(G,A); rs1681754(C,A); rs9420215(T,C); rs2170862(G,A); rs138090001(G,A); rs2627197(A,T); rs9421249(C,T); rs369980125(C,T); rs2627196(A,T); rs9421250(A,T); rs79002897(A,G); rs1681727(T,C); rs7896612(A,G); rs375376469(C,A); rs115088144(G,A); rs1637571(G,A); rs1637572(C,A); rs1681726(G,T); rs1637573(C,T); rs12768743(C,G); rs149624578(C,T); rs1617023(G,T); rs1637574(A,G); rs76563982(C,T); rs2531687(G,A); rs2531688(G,C); rs12240686(A,G); rs143300555(T,A); rs11197841(A,T); rs2531691(C,T); rs182724669(T,A); rs192354475(A,G); rs11197843(G,T); rs2429365(C,T); rs2449807(T,G) |
| cytoBand name | 10q25.3 |
| EntrezGene GeneID | 387712 |
| EntrezGene Description | enolase family member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ENO4:NM_001242699:exon4:c.C595T:p.P199S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.603 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
NANOS1
| dbSNP name | rs614465(A,C); rs546753(A,G); rs546808(C,A) |
| cytoBand name | 10q26.11 |
| EntrezGene GeneID | 340719 |
| snpEff Gene Name | EIF3A |
| EntrezGene Description | nanos homolog 1 (Drosophila) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, progressive sensorineural (most severe at high frequencies,
but ultimately affecting all frequencies);
Tinnitus
MISCELLANEOUS:
Onset in second decade, but sometimes earlier;
Hearing loss is usually severe by age 20 years;
Noise exposure causes more severe hearing loss at high frequencies
(2,000 to 8,000 Hz)
MOLECULAR BASIS:
Caused by mutation in the purinergic receptor P2X, ligand-gated ion
channel, 2 gene (P2RX2, 600844.0001)
OMIM Title
*608226 NANOS, DROSOPHILA, HOMOLOG OF, 1; NANOS1
;;NOS1
OMIM Description
CLONING
In Drosophila, the Pumilio (see PUM2; 607205) and Nanos genes encode
proteins that interact and are required for development of germ stem
cells in 1 or both sexes. By searching an EST database for sequences
similar to the C terminus of a Xenopus Nanos homolog, Xcat2, followed by
screening a human testis cDNA library, Jaruzelska et al. (2003) cloned
NANOS1, or NOS1. The deduced 292-amino acid protein has a calculated
molecular mass of 32 kD. The C terminus contains a conserved RNA-binding
domain that consist of 2 zinc fingers of about 52 amino acids. The NOS1
transcript has a long 3-prime untranslated region. Database analysis
detected homologous proteins in several vertebrate and invertebrate
species, and the zinc finger region of NANOS1 shares 62% identity with
the zinc finger region of Drosophila Nanos. Northern blot analysis
detected a 2.0-kb transcript expressed exclusively in testis. RT-PCR
also detected expression in embryonic stem cells and in fetal testis and
fetal ovary. Immunohistochemical localization of NOS1 in adult testis
detected abundant expression in spermatogonia, with strongest staining
in the perinuclear cytoplasm. Like PUM2, NOS1 was expressed during
meiosis in spermatocytes. Neither protein was present in late
postmeiotic-stage germ cells.
Using quantitative PCR, Angeles Julaton and Reijo Pera (2011) detected
variable NANOS1 expression in all 10 fetal tissues and 8 adult tissues
examined. Highest expression was detected in fetal brain, spleen,
kidney, and liver and in adult spleen. Lowest expression was detected in
adult leukocytes. Western blot analysis detected NANOS1 at an apparent
molecular mass of 60 kD in adult and fetal testis and ovary.
GENE STRUCTURE
Jaruzelska et al. (2003) determined that the NANOS1 gene contains a
single exon.
MAPPING
Hartz (2013) mapped the NANOS1 gene to chromosome 10q26.11 based on an
alignment of the NANOS1 sequence (GenBank GENBANK AF275269) with the
genomic sequence (GRCh37).
GENE FUNCTION
By coimmunoprecipitation experiments with cotransfected COS-7 cells,
Jaruzelska et al. (2003) demonstrated that NOS1 interacts with PUM2.
Yeast 2-hybrid analysis of truncation mutants revealed that a region of
PUM2 that included the RNA-binding domain and 155 upstream amino acids
interacted with the zinc finger domain of NOS1.
Wang and Lin (2004) showed that removing the translational repressor
Nanos from either Drosophila germline stem cells or their precursors,
the primordial germ cells, causes both cell types to differentiate into
germline cysts. Thus, Nanos is essential for both establishing and
maintaining germline stem cells by preventing their precocious entry
into oogenesis.
MOLECULAR GENETICS
Kusz-Zamelczyk et al. (2013) screened 195 infertile Polish men with
nonobstructive azoospermia or severe oligozoospermia, who were known to
be negative for azoospermia factor (AZF) microdeletions (see 415000),
and identified heterozygous mutations in 4 unrelated azoospermic
patients (608226.0001 and 608226.0002) and in 1 patient with severe
oligoasthenoteratozoospermia (608226.0003). The mutations were not found
in 400 fertile Polish men or in the 1000 Genomes Project database. All
female carriers of NANOS1 mutations were fertile.
CTBP2
| dbSNP name | rs3740535(T,C); rs7099361(T,C); rs78563051(C,A); rs184468357(C,T); rs6597871(G,A); rs368889942(C,T); rs113490229(C,G); rs112584426(C,G); rs4962715(G,A); rs56052207(C,T); rs3213907(G,C); rs7097802(T,C); rs74831105(T,C); rs111768849(C,T); rs115449381(C,T); rs112736962(C,T); rs10901849(A,G); rs11245454(G,A); rs11245455(C,T); rs11245456(C,G); rs3781446(T,C); rs7899208(T,C); rs77356756(A,T); rs66682442(C,T); rs77505998(A,G); rs7912679(G,C); rs4962716(T,C); rs12414708(G,A); rs112073554(C,T); rs7904165(A,G); rs7898262(C,T); rs73373188(G,A); rs111326344(A,G); rs1982225(T,A); rs373126313(G,A); rs2289432(T,G); rs4962717(A,G); rs56014807(C,G); rs4962718(C,T); rs74160999(C,T); rs112503155(G,C); rs3781444(A,G); rs11598549(G,A); rs4962413(T,C); rs4962414(T,C); rs11817643(C,T); rs74161000(C,T); rs7923776(C,T); rs58796909(C,T); rs3781442(G,A); rs12771627(G,A); rs12414632(G,A); rs4348846(G,A); rs750599(C,T); rs3781441(C,A); rs1078044(G,A); rs79533275(G,A); rs111796539(G,A); rs1107957(C,G); rs750689(G,A); rs893850(A,G); rs4962415(T,C); rs3781436(C,T); rs1561589(G,A); rs76616677(T,C); rs3781433(G,A); rs1561588(T,C); rs1970811(T,C); rs2028398(A,G); rs2028397(A,G); rs4962719(A,G); rs7901528(T,C); rs4962720(G,T); rs4962416(T,C); rs4962417(T,C); rs141045318(C,T); rs4962418(G,A); rs4962419(G,A); rs7077275(T,C); rs12769019(A,G); rs12769682(G,C); rs2018366(T,C); rs10732902(C,T); rs11245462(A,G); rs78235974(G,C); rs4962721(T,C); rs74838560(G,C); rs58102619(G,C); rs12781214(C,T); rs114428750(G,C); rs4962722(A,T); rs3781428(C,T); rs112211310(G,T); rs373886872(G,A); rs3781427(A,G); rs80013110(C,T); rs3781426(C,T); rs7090603(G,A); rs78693819(C,T); rs60306160(C,T); rs12776353(G,A); rs2363895(A,G); rs3781424(T,C); rs3781423(G,C); rs4962723(C,T); rs139529238(C,T); rs112483963(C,T); rs79781293(C,T); rs11245465(A,T); rs11245467(A,C); rs74854772(A,G); rs10901850(C,T); rs11594890(G,A); rs3824797(T,C); rs3781422(T,A); rs111259522(C,T); rs149478368(C,T); rs141130090(A,G); rs75684761(G,A); rs144420649(G,A); rs3781421(C,T); rs3781420(T,C); rs3853767(A,G); rs74163310(C,T); rs73375125(T,C); rs4962420(C,T); rs4109292(G,A); rs9664044(C,T); rs58102404(T,C); rs3781419(T,G); rs3781418(A,C); rs34260682(G,A); rs12357688(C,T); rs7073257(G,A); rs7086797(C,T); rs74163313(G,T); rs3781416(G,A); rs79358071(G,A); rs3781415(C,T); rs35728204(C,T); rs4411245(G,A); rs115827849(C,T); rs114402039(A,G); rs115114718(G,A); rs74163314(C,T); rs11245469(C,T); rs10444192(C,T); rs2363893(C,T); rs2949367(G,A); rs2946994(G,C); rs3012075(A,G); rs3781409(C,T); rs145765785(A,T); rs2938006(C,T); rs2938005(C,T); rs3012068(A,G); rs3781403(C,T); rs2363892(T,C); rs146439517(A,C); rs2949370(C,A); rs374606606(G,A); rs2938004(A,G); rs58762526(G,A); rs2938003(C,T); rs11245472(G,C); rs2938002(C,G); rs2919286(C,T); rs2949369(C,T); rs2913113(G,A); rs138473454(G,A); rs73375152(C,T); rs2938001(C,T); rs7920614(G,A); rs76798703(C,G); rs2913112(G,A); rs893857(G,A); rs7081189(C,T); rs12761407(G,A); rs35060373(T,C); rs2839737(C,A); rs144665239(C,T); rs112983737(C,T); rs1561586(A,G); rs3781399(C,T); rs190346577(C,T); rs2043953(G,A); rs74163317(G,C); rs372423050(C,T); rs2913111(G,A); rs3012074(A,G); rs73375155(C,A); rs10901851(A,C); rs876147(G,A); rs139317426(C,A); rs60389023(T,C); rs1077497(T,C); rs893856(G,A); rs11818446(T,C); rs181325513(T,C); rs75383642(C,T); rs12255887(G,A); rs11245478(G,C); rs4962421(G,A); rs3781396(C,G); rs2949368(T,C); rs2937999(C,G); rs2028395(G,C); rs3781395(C,T); rs3781394(G,A); rs2289431(C,A); rs35631492(C,G); rs11245479(C,T); rs11245480(C,G); rs2946993(T,C); rs56250138(C,T); rs10901852(G,C); rs77348043(G,A); rs4962422(C,T); rs116454906(T,C); rs4962424(T,A); rs2935654(G,C); rs73375166(T,C); rs2936546(G,A); rs75535257(T,C); rs11245481(G,A); rs3012063(C,T); rs4962724(A,G); rs4962725(T,C); rs7923530(G,A); rs11245482(T,C); rs3012064(C,T); rs10901854(T,C); rs12242908(A,G); rs7083961(C,T); rs2949371(A,G); rs2949372(A,G); rs12243317(A,G); rs67279759(C,G); rs7075394(G,T); rs75196297(A,C); rs7095721(A,G); rs147151723(G,A); rs61192649(A,G); rs12246440(C,T); rs12251156(T,C); rs369577892(A,T); rs12246653(C,G); rs3012065(T,C); rs3012066(A,C); rs2946996(C,T); rs377403833(C,A); rs2919290(T,A); rs718949(A,G); rs718947(A,G); rs718948(T,C); rs61870324(G,A); rs1965803(T,C); rs1985011(T,G); rs7903340(G,C); rs2938010(T,G); rs115805226(A,T); rs117795922(C,T); rs61870342(T,C); rs1465884(C,T); rs117128427(G,A); rs998836(T,C); rs998835(C,G); rs998834(C,T); rs2938009(A,C); rs7899537(A,G); rs7893862(C,T); rs1036678(A,G); rs6597873(C,T); rs7902895(C,T); rs7916377(T,C); rs6597875(T,A); rs75024603(C,T); rs7093976(T,C); rs7083273(C,T); rs6597876(T,C); rs6597877(C,T); rs6597878(T,C); rs2919287(G,A); rs117490084(G,C); rs78453308(G,A); rs2936540(C,A); rs6597879(C,T); rs3012069(G,T); rs2946998(C,T); rs190657855(C,A); rs61870344(G,A); rs2946999(G,T); rs2949373(G,A); rs12253369(C,T); rs12414266(A,T); rs11245486(C,T); rs10901859(T,C); rs12414127(C,T); rs117657338(C,T); rs56262689(T,C); rs115979624(G,A); rs73377227(C,A); rs55766533(T,C); rs114033670(G,A); rs2919288(A,G); rs2938008(A,T); rs893852(T,C); rs2919289(C,T); rs117008712(C,T); rs2936542(G,A); rs185434303(A,G); rs12573411(A,T); rs2936543(C,T); rs2935652(A,G); rs2935651(C,T); rs4021187(C,T); rs2935650(A,G); rs34329149(T,C); rs35517340(G,T); rs35435680(C,T); rs80114072(G,A); rs7087286(T,C); rs7080718(C,T); rs7091659(T,G); rs10901860(A,C); rs11245488(A,G); rs7085356(C,T); rs10901862(G,C); rs141776361(C,T); rs11245489(G,A); rs11818271(A,G); rs114521087(G,A); rs116026927(T,C); rs3889706(C,T); rs4021186(C,A); rs11596863(G,A); rs77030534(C,T); rs75804465(G,A); rs147098428(C,T); rs180931887(G,C); rs77863419(T,C); rs2935649(T,C); rs79693773(C,T); rs78509941(G,A); rs76121638(T,C); rs34798300(G,T); rs78495100(C,G); rs3012070(C,T); rs35397478(C,T); rs74906699(A,G); rs116787550(G,T); rs151140349(C,T); rs77308213(A,T); rs145665070(C,T); rs147734203(G,A); rs76764192(G,T); rs35244319(C,T); rs145775109(G,A); rs61310902(C,T); rs71488644(T,C); rs35354883(A,G); rs74680209(C,T); rs76381664(G,A); rs112612788(T,C); rs371904609(C,A); rs376762793(G,A); rs202067972(T,A); rs200394522(T,A); rs75574618(C,T); rs61148818(G,A); rs58189629(C,A); rs116863798(G,A); rs2935648(A,C); rs57727064(A,G); rs71488645(G,A); rs77289652(G,C); rs112183818(C,T); rs71488646(T,C); rs71488647(G,A); rs55910185(G,A); rs56148630(G,A); rs76159337(T,C); rs12770388(G,T); rs76546814(T,C); rs57299337(A,G); rs56171930(T,C); rs55858631(G,C); rs60686205(C,A); rs112788731(T,C); rs56288010(C,T); rs35480484(G,A); rs35060479(C,T); rs113560612(G,A); rs58688187(C,T); rs71488648(G,A); rs59530965(T,C); rs181602266(C,T); rs12776607(T,C); rs12761801(C,T); rs7068152(C,A); rs12762037(C,T); rs75224029(C,T); rs17643549(C,T); rs147135459(C,T); rs117076139(C,G); rs140039810(G,A); rs10794197(G,A); rs73377252(G,A); rs148564677(T,C); rs1152657(A,G); rs376217987(C,T); rs1152658(C,T); rs17152614(T,C); rs1152659(A,G); rs73377256(C,T); rs17152617(G,T); rs1152660(A,T); rs1152661(C,T); rs11245497(C,T); rs141134162(G,A); rs1152663(A,G); rs76886370(C,T); rs115425543(T,C); rs3853769(G,T); rs118022420(A,T); rs1254705(T,A); rs76195450(G,A); rs7087635(A,T); rs1152669(A,G); rs7081340(C,A); rs17152631(T,C); rs1152671(C,G); rs79510457(C,A); rs35145201(C,T); rs1152676(T,C); rs1152677(A,G); rs112979045(T,A); rs1152678(T,A); rs12356887(G,A); rs2280618(G,A); rs77817275(C,T); rs117449309(A,G); rs1152679(A,G); rs1996667(G,A); rs75763750(G,T); rs74493873(T,C); rs12782655(T,C); rs12777451(G,A); rs75666288(A,G); rs371323775(C,T); rs1152684(G,C); rs1152685(C,T); rs1152686(A,G); rs77132634(C,A); rs2293295(T,C); rs1152687(C,T); rs140822691(C,T); rs374138746(G,A); rs80240756(T,C); rs78887032(T,C); rs75490304(G,A); rs114275600(C,G); rs71488649(G,C); rs190396534(C,G); rs744451(C,T); rs75968465(A,T); rs17643974(C,T); rs138273079(T,C); rs57948717(T,A); rs1152689(T,A); rs4962726(A,T); rs149923485(A,T); rs71488650(C,T); rs71488651(A,G); rs71488652(G,A); rs71488653(T,C); rs71488655(C,A); rs57447348(G,C); rs189848574(G,A); rs11245505(C,A); rs1152690(T,C); rs1152691(A,G); rs78602836(G,A); rs1152692(A,G); rs35620663(T,G); rs78302054(C,A); rs75248860(C,T); rs1152693(G,C); rs139183786(G,C); rs769277(T,C); rs60097619(G,A); rs74163336(C,T); rs57151285(C,A); rs11815895(T,C); rs11814706(C,T); rs59536048(G,C); rs57608434(A,T); rs143270964(C,T); rs74163338(G,A); rs75068074(A,T); rs1254703(T,C); rs79794398(C,T); rs35741436(G,A); rs189635781(G,A); rs1152694(A,T); rs139249483(C,T); rs12763981(T,C); rs117364178(T,C); rs56820580(C,T); rs34580354(G,A); rs12784380(G,A); rs7920600(C,T); rs7899408(T,C); rs7908461(G,A); rs76924178(G,A); rs7908482(G,A); rs1152695(A,G); rs7899253(A,G); rs7899422(A,G); rs1152696(A,G); rs7912889(G,A); rs58748869(T,C); rs80306589(T,C); rs57137921(T,C); rs58308339(A,G); rs77609338(C,T); rs12779410(G,T); rs74163339(T,C); rs112943520(C,T); rs113105054(C,A); rs111678364(A,G); rs112284497(G,A); rs113538453(A,G); rs112749452(G,C); rs74163340(G,A); rs74163341(C,G); rs74163342(A,G); rs7906290(C,T); rs74163343(G,A); rs1152697(T,C); rs117484172(T,C); rs74163344(G,A); rs74163345(A,G); rs74163346(T,C); rs78669834(C,T); rs11245506(A,G); rs190524515(A,G); rs1152699(T,C); rs183028512(T,C); rs116498738(T,C); rs1254702(A,C); rs151089006(G,C); rs10794199(T,C); rs76822519(C,A); rs150221381(C,T); rs1254701(A,G); rs1254700(A,C); rs114157798(G,C); rs59096759(C,T); rs1254699(T,C); rs72833011(C,T); rs1254698(T,C); rs75132258(C,T); rs17152657(C,G); rs12356434(G,A); rs10901863(C,T); rs7901224(G,A); rs10466248(C,T); rs11245509(C,G); rs17711828(T,C); rs12264453(T,C); rs76899271(G,A); rs10510139(C,T); rs75088436(T,C); rs2225079(G,A); rs2209683(T,C); rs2209684(C,T); rs17644226(T,C); rs10510140(A,C); rs150152295(G,A); rs10901864(T,A); rs10794200(A,G); rs7080312(C,T); rs10510141(T,C); rs2460567(G,C); rs4962425(T,C); rs75979600(G,T); rs11245513(G,A); rs12250942(C,T); rs17644332(C,T); rs75031371(G,C); rs10901865(A,G); rs17152670(C,T); rs10510142(A,G); rs74573605(T,A); rs7918241(T,C); rs79921628(G,C); rs10901867(G,A); rs17644414(C,T); rs1693623(A,G); rs76928654(G,A); rs7080079(G,C); rs2454054(T,C); rs1693624(T,C); rs76294329(A,G); rs1475384(C,T); rs10901868(T,C); rs11245515(T,C); rs374872373(C,G); rs1715873(A,G); rs151162712(C,T); rs138499637(A,G); rs79156297(G,A); rs80195828(T,C); rs56963364(G,C); rs7090538(T,C); rs73379146(C,T); rs111447798(A,G); rs73379147(C,T); rs74751161(T,C); rs186486840(G,A); rs114474222(C,T); rs1715874(A,G); rs11245517(G,A); rs2008596(A,G); rs35991519(A,G); rs73379151(C,G); rs56016170(T,C); rs11245518(G,A); rs1693626(A,G); rs1715875(G,A); rs1693627(G,A); rs75456377(G,A); rs77230580(C,T); rs74163351(C,G); rs72833017(T,C); rs74163352(G,A); rs74584610(A,G); rs6597883(T,C); rs1693628(G,A); rs7074878(A,G); rs74163353(G,C); rs1041191(C,T); rs74163354(G,A); rs34480374(A,T); rs7082937(G,A); rs1715860(A,C); rs1693657(G,T); rs12354622(G,A); rs12355882(C,G); rs35106605(T,G); rs1693656(G,A); rs1693655(C,T); rs7071092(C,G); rs12254098(T,G); rs11245522(T,C); rs7086481(T,A); rs192830472(G,A); rs10901870(C,T); rs74163356(T,C); rs1715859(T,C); rs141243000(A,G); rs143462876(T,C); rs1915146(A,G); rs115116488(G,A); rs10794201(C,T); rs80094042(G,A) |
| ccdsGene name | CCDS7643.1 |
| cytoBand name | 10q26.13 |
| EntrezGene GeneID | 1488 |
| EntrezGene Description | C-terminal binding protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CTBP2:NM_022802:exon1:c.T359A:p.V120E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6192 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P56545-2 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.001153 |
| ESP Eur/Amr MAF | 0.001744 |
| ExAC AF | 2.684e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
Micrognathia;
[Ears];
Stenotic external auditory canal;
[Eyes];
Prominent eyes;
[Nose];
Depressed nasal bridge;
Short, upturned nose;
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Ventricular hypertrophy;
Patent foramen ovale
RESPIRATORY:
Apnea
CHEST:
[External features];
Small chest;
[Ribs, sternum, clavicles, and scapulae];
Elongated clavicles
ABDOMEN:
[Gastrointestinal];
Meckel diverticulum
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
[Spine];
Wafer-thin platyspondyly;
[Pelvis];
Wide sacrosciatic notch;
Hypoplastic pelvis;
Trident configuration of acetabular roof;
[Limbs];
Radial hypoplasia;
Ulnar hypoplasia;
Rhizomelic limb shortening;
Irregular proximal humeral metaphyses;
Gracile long bones;
[Hands];
Transverse palmar creases;
Prominent palmar flexion creases;
Brachydactyly;
Ulnar deviation of the hands
SKIN, NAILS, HAIR:
[Skin];
Transverse palmar creases;
Prominent palmar flexion creases;
Cutis marmorata;
[Hair];
Fragile scalp hair;
Sparse hair
NEUROLOGIC:
[Central nervous system];
Progressive CNS degeneration;
Seizure;
Progressive ventriculomegaly;
Small cerebellum;
Brain atrophy;
Encephalomyelopathy;
Thin corpus callosum;
Diffuse, severe neuronal loss;
Gliosis;
Generalized myelin loss
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios
MISCELLANEOUS:
Death in early infancy
OMIM Title
*602619 C-TERMINAL-BINDING PROTEIN 2; CTBP2
OMIM Description
CLONING
The E1a region of group C adenoviruses encodes 2 nearly identical
proteins that are largely responsible for the oncogenic properties of
adenoviruses. The CTBP1 (602618) protein binds to the C-terminal half of
these E1A proteins. Katsanis and Fisher (1998) identified CTBP2 by
searching for expressed sequence tags (ESTs) with homology to CTBP1. The
predicted 445-amino acid CTBP2 protein is 72% identical to CTBP1.
Northern blot analysis showed that the CTBP2 gene was expressed as a
3.8-kb mRNA in all tissues tested, with the most abundant expression in
heart, skeletal muscle, and pancreas.
Furusawa et al. (1999) identified the mouse homologs of CTBP1 and CTBP2
in a yeast 2-hybrid screen for proteins that interact with delta-EF1
(TCF8; 189909), a transcriptional repressor that binds the E2-box
(CACCTG) and related sequences. Using Northern blot analysis and in situ
hybridization with mouse embryos, Furusawa et al. (1999) detected
expression of 2 Ctbp2 transcripts confined to the embryonic stages.
Ctbp1 and Ctbp2 expression correlated with delta-EF1 expression.
Schmitz et al. (2000) identified an alternate product of the CTBP2
locus, which they named RIBEYE. They cloned full-length cDNAs
corresponding to RIBEYE in bovine, rat, and human. Human RIBEYE encodes
a deduced protein of 985 amino acids. Based on sequence analysis, the
authors defined a unique N-terminal A domain of RIBEYE and a C-terminal
B domain identical to the previously identified CTBP2. They found that
RIBEYE and CTBP2 are transcribed from distinct promoters of the CTBP2
gene. The unique N-terminal sequences of RIBEYE and CTBP2 are encoded by
separate 5-prime exons, and the shared C-terminal sequences are encoded
by 8 common 3-prime exons. By Northern blot analysis and immunoblotting,
Schmitz et al. (2000) detected a 120-kD RIBEYE product expressed only in
the retina, whereas the 50-kD CTBP2 product was observed ubiquitously in
most tissues. Using immunocytochemistry, they demonstrated that RIBEYE
is a specific component of synaptic ribbons in the retina and
hypothesized that RIBEYE may be a general component of all synaptic
ribbons. Using transfection experiments, Schmitz et al. (2000)
demonstrated that the N-terminal A domain of RIBEYE can form protein
aggregates. They hypothesized that the A domain may function in the
formation of stable ribbon structures, whereas the B domain may be
exposed on the surface of the ribbons. The B domain shares homology with
2-hydroxyacid dehydrogenases and binds to NAD+ with high affinity. They
hypothesized that the B domain may serve as an enzyme in synaptic
vesicle priming on synaptic ribbons and in transcriptional repression.
GENE FUNCTION
Using a yeast 2-hybrid assay and mutation analysis, Turner and Crossley
(1998) found that mouse Ctbp2 interacted with the pro-val-asp-leu-thr
motif in the repression domain of Bklf (KLF3; 609392). When tethered to
a promoter by a heterologous DNA-binding domain, Ctbp2 functioned as a
potent repressor. Ctbp2 also interacted with the mammalian transcription
factors Evi1 (165215), Tcf8, and Fog (ZFPM1; 601950). Turner and
Crossley (1998) concluded that CTBP2 is a mammalian corepressor that
targets diverse transcriptional regulators.
Using 2-hybrid and direct binding assays, Furusawa et al. (1999) showed
that Ctbp2 bound the short medial portion of delta-EF1 containing the
PLDLSL motif. In cotransfection experiments, they observed that Ctbp2
enhanced transrepression activity of delta-EF1. The authors hypothesized
that Ctbp1 and Ctbp2 function as corepressors of delta-EF1 action.
In Drosophila and in vertebrates, the Polycomb (Pc) group (PcG) genes
have been identified as being part of a cellular memory system that is
responsible for the stable and heritable repression of gene expression.
PC2 (603079), a human Pc homolog, CBX2 (602770), HPH1 (602978), HPH2
(602979), BMI1 (164831), and RING1 (602045) form a complex that
localizes in large nuclear domains termed PcG domains. Using a yeast
2-hybrid assay, Sewalt et al. (1999) found that CTBP2 interacts with PC2
and that Xenopus Ctbp1 interacts with Xenopus Pc. The CTBP2 and PC2
interaction also exists in vivo, since the proteins coimmunoprecipitate
with each other and partially colocalize in large PcG domains in
interphase nuclei. CTBP1 showed the same localization pattern. As with
PC2, chimeric LexA-CTBP2 and LexA-CTBP1 proteins repressed gene activity
when targeted to a reporter gene. Sewalt et al. (1999) suggested that
the CTBP proteins target PC2, and thereby the PcG complex, to particular
loci in chromatin that contain binding sites for specific repressors of
gene activity, thereby forming a complex between the repressors and the
PcG complex, with CTBP as a bridging protein. They speculated that the
interference of the adenoviral E1A protein with the transcription
machinery of the infected cell may involve interference with
PcG-mediated repression through disruption of the CTBP-PcG interaction.
Zhang et al. (2002) demonstrated that CTBP binding to cellular and viral
transcriptional repressors is regulated by NAD+ and NADH, with NADH
being 2 to 3 orders of magnitude more effective. Levels of free nuclear
nicotinamide adenine dinucleotides, determined using 2-photon
microscopy, corresponded to the levels required for half-maximal CTBP
binding and were considerably lower than those previously reported.
Agents capable of increasing NADH levels stimulated CTBP binding to its
partners in vivo and potentiated CTBP-mediated repression. Zhang et al.
(2002) proposed that this ability to detect changes in nuclear NAD+/NADH
ratio allows CTBP to serve as a redox sensor for transcription.
CTBP is recruited to DNA by transcription factors that contain a PXDLS
motif. Shi et al. (2003) reported the identification of a CTBP complex
that contains the essential components for both gene targeting and
coordinated histone modifications, allowing for the effective repression
of genes targeted by CTBP. This complex has a molecular mass of about
1.3 to 1.5 million and contains CTBP1 and CTBP2 as well as G9A (604599),
EUHMT (607001), COREST (607675), HDAC1 (601241) and HDAC2 (605164),
NPAO, REBB1, ZNF217 (602967), and KIAA0222. Immunoprecipitation with G9A
antibodies brought down the same components as well as HPC2 (ELAC2;
605367). Shi et al. (2003) found that inhibiting the expression of CTBP
and its associated histone-modifying activities by RNA-interference
resulted in alterations of histone modifications at the promoter of the
tumor invasion suppressor gene E-cadherin (192090) and increased
promoter activity in a reporter assay.
Using a promoter pull-down assay followed by mass spectrometry analysis,
Flajollet et al. (2009) identified RREB1 (602209) as a protein that
bound the HLA-G (142871) promoter. RREB1 exerted repressive activity on
the promoter in HLA-G-negative cells that was mediated by recruitment of
HDAC1 and CTBP1 and/or CTBP2. The HLA-G promoter contains 3 RREB1 target
sites. Flajollet et al. (2009) proposed that the repressive activity of
RREB1 on the HLA-G promoter may be regulated by posttranslational
modifications governing its association with CTBP.
MAPPING
Thomas et al. (2008) identified the CTBP2 gene on chromosome 10q26.13,
within a region associated with susceptibility to prostate cancer
(176807).
CTAGE7P
| dbSNP name | rs1177699(C,T); rs149953039(C,T); rs55975328(C,T); rs112214906(A,G) |
| cytoBand name | 10q26.3 |
| EntrezGene GeneID | 387723 |
| EntrezGene Symbol | LINC00959 |
| EntrezGene Description | long intergenic non-protein coding RNA 959 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retrotransposed |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2392 |
| ExAC AF | 0.270,8.152e-06 |
UTF1
| dbSNP name | rs2998111(C,T); rs3008362(T,C) |
| cytoBand name | 10q26.3 |
| EntrezGene GeneID | 8433 |
| EntrezGene Description | undifferentiated embryonic cell transcription factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3287 |
| ESP Afr MAF | 0.421717 |
| ESP All MAF | 0.201453 |
| ESP Eur/Amr MAF | 0.112508 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Epidermolysis bullosa, dystrophic;
Blistering, recurrent;
Skin fragility;
Erosions;
Pruritis, intense;
Prurigo;
Nodular lesions;
Lichenified lesions;
Hypertrophic scarring;
Milia;
Albopapuloid lesions may occur;
ELECTRON MICROSCOPY:;
Sublamina densa level of tissue separation beneath basal membrane;
Decreased number of anchoring fibrils at dermal-epidermal junction;
Hypotrophic anchoring fibrils;
Decreased staining for collagen VII;
[Nails];
Dystrophic nails;
Nail atrophy
MISCELLANEOUS:
Variable age at onset from childhood to adulthood;
Blisters are precipitated by minor skin trauma;
Blistering and erosions tend to occur on extensor surfaces or over
bony prominences;
Blistering frequency may decrease with age;
Intrafamilial variability;
See also dominant DEB (131750), an allelic disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by mutation in the collagen type VII, alpha-1 gene (COL7A1,
120120.0009).
OMIM Title
*604130 UNDIFFERENTIATED EMBRYONIC CELL TRANSCRIPTION FACTOR 1; UTF1
OMIM Description
CLONING
Several transcription factors are expressed in undifferentiated
embryonic carcinoma (EC) cells and are downregulated during
differentiation of these cells. Such factors may be involved in
maintenance of the undifferentiated state. Fukushima et al. (1998)
cloned human UTF1 from a human teratocarcinoma cell line cDNA library.
The cDNA encodes a 341-amino acid polypeptide that is 64% identical to
mouse UTF1. The sequence contains 2 domains, one at the N terminus and
the other at the C terminus, that are highly conserved between mouse and
human sequences. The C-terminal conserved domain contains a leucine
zipper motif. Southern blot and genomic analyses revealed that the gene
exists in single copy and that no UTF1-related gene exists in the human
genome. RNase protection assay showed that UTF1 is expressed only in
human EC cell lines; Western blot analysis demonstrated that UTF1
protein is present only in the undifferentiated state in EC cells.
Phosphatase treatment followed by Western blot analysis indicated that
UTF1 is partially phosphorylated. In vitro assays showed that UTF1
boosts transcription through binding to the transcription factor ATF2
(123811) and also binds to the TATA-binding protein-containing complex
(TFIID; see 313650).
MAPPING
Fukushima et al. (1998) used fluorescence in situ hybridization to map
the UTF1 gene to human chromosome 10q26, a region sharing homology of
synteny with mouse chromosome 7F5, where mouse UTF1 is located.
SPRN
| dbSNP name | rs116634431(C,T); rs1329151(G,T); rs2297032(C,T); rs2297033(C,T); rs10857714(C,A); rs10776681(C,A); rs182942849(C,T) |
| cytoBand name | 10q26.3 |
| EntrezGene GeneID | 503542 |
| snpEff Gene Name | AL360181.1 |
| EntrezGene Description | shadow of prion protein homolog (zebrafish) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02204 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Intrauterine growth retardation;
Low birth weight (27%);
Failure to thrive
HEAD AND NECK:
[Face];
Long face (74%);
High, broad forehead (68%);
Broad chin (42%);
[Ears];
Large, prominent ears (59%);
Anteverted ears;
Overfolded helices;
[Eyes];
Hypermetropia (36%);
Pale irides (45%);
Strabismus (45%);
Upward-slanted palpebral fissures (68%);
Blepharophimosis (36%);
Ptosis (50%);
Epicanthal folds (68%);
[Nose];
Tubular nose (82%);
Pear-shaped nose (82%);
Bulbous nasal tip (95%);
High nasal bridge;
[Mouth];
High, narrow palate (50%);
Cleft lip;
Cleft palate;
Everted lower lip;
Open mouth;
[Teeth];
Small widely spaced teeth
CARDIOVASCULAR:
[Heart];
Heart defects (27%);
Atrial septal defect;
Ventricular septal defect;
Pulmonary valve stenosis;
Bicuspid aortic valve;
Aortic dilatation (reported in 1 patient)
CHEST:
[External features];
Pectus excavatum (23%);
Widely spaced nipples
GENITOURINARY:
Kidney/urologic anomalies (32%);
[External male genitalia];
Cryptorchidism;
[Kidneys];
Hydronephrosis;
Duplex renal system;
[Bladder];
Vesicoureteric reflux
SKELETAL:
Hypermobile joints;
[Spine];
Scoliosis/kyphosis (36%);
[Pelvis];
Hip dislocation (27%);
[Limbs];
Slender lower limbs (41%);
[Hands];
Narrow hands (28%);
Long, slender fingers (61%);
Hypoplasia of the hand muscles (29%);
[Feet];
Positional foot deformity (27%)
SKIN, NAILS, HAIR:
[Skin];
Dry skin;
Eczema;
Pigmentary abnormalities;
Sacral dimple;
[Hair];
Abnormal hair pigmentation (55%);
Abnormal hair texture (55%)
MUSCLE, SOFT TISSUE:
Hypoplasia of the hand muscles (29%)
NEUROLOGIC:
[Central nervous system];
Developmental delay (100%);
Mental retardation, mild to severe;
Poor speech development;
Hypotonia (96%);
Seizures (50%);
Ventriculomegaly (38%);
[Behavioral/psychiatric manifestations];
Friendly behavior (89%)
VOICE:
Nasal speech (50%)
MISCELLANEOUS:
All cases are de novo;
Estimated prevalence of 1 in 16,000;
Contiguous gene deletion of 17q21.3 involves a region which harbors
a 900kb inversion polymorphism
MOLECULAR BASIS:
Caused by mutation in the KAT8 regulatory NSL complex subunit 1 gene
(KANSL1, 612452.0001);
Contiguous gene syndrome caused by microdeletion (600-800kb) of chromosome
17q21.31 encompassing genes CRHR1 (122561), MAPT (157140), STH
(607067), IMP5 (608284), and KANSL1 (612452)
OMIM Title
*610447 SHADOW OF PRION PROTEIN; SPRN
;;SHADOO;;
SHO
OMIM Description
CLONING
By EST database searching for zebrafish prion protein (PrP; 176640)
homologs, Premzl et al. (2003) identified, and subsequently cloned, a
novel zebrafish cDNA, SPRN (shadow of PrP), encoding a protein
designated shadoo (Sho). Further database searches revealed
well-conserved orthologs in other fish (Fugu and tetraodon) and in
mammals (human, mouse, and rat) (Premzl et al., 2003, 2004). The deduced
human protein contains 151 amino acids (Premzl et al., 2003). The
mammalian proteins share 81 to 95% sequence identity. Alignment of all
fish and mammalian Sho proteins showed that all have an N-terminal
peptide sequence with an endoplasmic reticulum targeting signal for
extracellular transport, a basic RG-rich region, a hydrophobic stretch
in the middle of the protein that contains the same unusual composition
of small aliphatic residues (GAV) as PrP and PrP-like proteins, and a
C-terminal region with a putative N-glycosylation site and a possible
GPI anchor site (Premzl et al., 2003, 2004). Database searches revealed
that SPRN is expressed in mouse and rat embryo, brain, and retina, in
human hippocampus, and in zebrafish embryo and retina. Using RT-PCR,
Premzl et al. (2003) confirmed SPRN expression in human, rat, and mouse
brain. RT-PCR of rat cDNA from multiple tissues indicated that SPRN is
almost exclusively expressed in brain, with faint expression in lung and
stomach. Phylogenetic footprinting on aligned human, mouse, and Fugu
SPRN genes detected 16 conserved motifs, 3 of which are known
transcription factor-binding sites for a receptor and transcription
factors specific to or associated with expression in the brain (Premzl
et al., 2004), suggesting an important function in this tissue.
EVOLUTION
Premzl et al. (2003, 2004) found that conservation of the SPRN-coding
exon between mammals and fish satisfied the criteria for gene orthology.
They noted that the gene order and orientation of SPRN and 2 proximal
genes, an amine oxidase and a GTP-binding protein (MTG1), indicated that
no rearrangement occurred in this genomic fragment after the
evolutionary divergence of mammals and fish 450 million years ago.
Premzl et al. (2004) found that the gene density and GC content are much
higher in the SPRN genomic environment than in the PRNP (PrP)
environment. In addition, in contrast to genes encoding members of the
PrP family, SPRN contains no transposable elements. Premzl et al. (2004)
suggested that this may be the result of functional selection.
GENE STRUCTURE
Premzl et al. (2003) determined that the zebrafish, mouse, and human
SPRN genes all contain 2 exons, with the ORF contained entirely within
exon 2.
MAPPING
By sequence analysis, Premzl et al. (2003) mapped the human SPRN gene to
chromosome 10q26.3 and the mouse gene to chromosome 7. Premzl et al.
(2004) found an apparent duplication of the human SPRN gene about 140 kb
downstream of SPRN.
MOLECULAR GENETICS
Beck et al. (2008) presented evidence that variation in the SPRN gene
may be associated with Creutzfeldt-Jakob disease (CJD; 123400). Two of
107 patients with variant CJD were found to have a 1-bp insertion in the
SPRN gene, which was not identified in 861 controls (p = 0.01). The 1-bp
insertion in codon 46 was predicted to result in frameshift and a
putative 294-amino acid protein if translation occurred; however, the
authors were unable to show whether the transcript exists. In addition,
2 linked SNPs, -11A-G and 20T-C, in the SPRN gene were associated with
risk of sporadic CJD (p = 0.009). The findings supported the hypothesis
that SPRN variants may be involved in prion disease.
SPRNP1
| dbSNP name | rs2987799(T,G); rs114993466(G,A); rs9630003(G,A); rs115561117(G,A); rs3020499(A,G); rs111317133(C,T); rs114521045(C,T) |
| cytoBand name | 10q26.3 |
| EntrezGene GeneID | 399833 |
| snpEff Gene Name | SPRN |
| EntrezGene Description | shadow of prion protein homolog (zebrafish) pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4311 |
IFITM1
| dbSNP name | rs9667990(C,G) |
| ccdsGene name | CCDS41584.1 |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 8519 |
| EntrezGene Description | interferon induced transmembrane protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IFITM1:NM_003641:exon1:c.C37G:p.P13A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P13164 |
| dbNSFP Uniprot ID | IFM1_HUMAN |
| dbNSFP KGp1 AF | 0.923076923077 |
| dbNSFP KGp1 Afr AF | 0.900406504065 |
| dbNSFP KGp1 Amr AF | 0.947513812155 |
| dbNSFP KGp1 Asn AF | 0.935314685315 |
| dbNSFP KGp1 Eur AF | 0.916886543536 |
| dbSNP GMAF | 0.07713 |
| ExAC AF | 1.0 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
MUSCLE, SOFT TISSUE:
Muscle atrophy, distal;
Muscle weakness, distal;
Weakness of the extensor muscles of the hands (initially);
Weakness of all intrinsic hand muscles (later);
Weakness of the anterior tibial muscle and toe extensors;
Steppage gait;
Walking difficulties;
Myopathic changes seen muscle biopsy;
Rimmed vacuoles
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Adult onset (range 40 to 60 years);
Slowly progressive;
High incidence in Sweden and Finland;
Incidence of 1 in 100 in some local Nordic areas;
Homozygotes have earlier onset and a more severe disorder
MOLECULAR BASIS:
Caused by mutation in the TIA1 cytotoxic granule-associated RNA-binding
protein gene (TIA1, 603518.0001)
OMIM Title
*604456 INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 1; IFITM1
;;INTERFERON-INDUCED PROTEIN 17; IFI17;;
LEU13;;
CD225
OMIM Description
CLONING
In addition to their role in the defense against microbial infections,
interferons (IFNs; see, for example, 147570) exhibit antiproliferative
and differentiating activities that may confer on them potential as
antitumor agents. Exposure to IFNs leads to a modulation in the levels
of many cellular proteins that mediate the pleiotropic effects of
interferons. These effects may be mediated by soluble factors or by
cell-cell interactions involving specific membrane proteins. Deblandre
et al. (1995) identified a 17-kD membrane protein, IFI17, that was
inducible on tumor cell lines by interferon-alpha (147660) and, usually
to a lesser extent, by interferon-gamma (IFNG; 147570). Expression as
detected by FACS analysis or immunoprecipitation was correlated with
sensitivity of the cell lines to growth suppression by interferon. Using
mRNA extracted from HeLa cells incubated with interferon-alpha, the
authors screened a cDNA expression library by panning with a monoclonal
anti-IFI17. They obtained a cDNA sequence encoding a protein that is
identical except for 1 residue to the 125-amino acid protein 9-27 that
Reid et al. (1989) had isolated from a lymphoid cell cosmid library.
By whole-mount in situ hybridization, Lange et al. (2003) found that
expression of mouse fragilis, fragilis-2, and fragilis-3 was restricted
to the epiblast at embryonic days 5.5 and 6.5. By embryonic day 7.5, all
3 transcripts showed variable expression in a cluster of founder
primordial germ cells, and at embryonic days 11.5 and 12.5, all 3
transcripts were detected in gonadal germ cells. The 3 transcripts
showed unique patterns of expression in other tissues during mouse
development.
GENE FUNCTION
Reid et al. (1989) showed that transcription of the IFITM1 gene is
controlled by a 13-bp IFN-stimulated response element in the 5-prime
flanking region of the gene.
To determine precisely how germ cells are specified, Saitou et al.
(2002) performed a genetic screen between single nascent germ cells and
their somatic neighbors that share common ancestry. They demonstrated
that fragilis, a member of the IFN-inducible transmembrane protein
family, marks the onset of germ cell competence, and they proposed that
through homotypic association, it demarcates germ cells from somatic
neighbors. Using single cell gene expression profiles, Saitou et al.
(2002) showed that only those cells with the highest expression of
fragilis subsequently express 'stella' (see 608408), a murine gene that
was detected exclusively in lineage-restricted germ cells. The
stella-positive nascent germ cells exhibited repression of HOXB1
(142968), which may explain their escape from a somatic cell fate and
the retention of pluripotency.
Tanaka et al. (2005) determined that mouse Ifitm1 and Ifitm3 are
expressed on the cell surface of primordial germ cells in a
developmentally-regulated manner and that they appear to modulate cell
adhesion and influence cell differentiation. Ifitm1 activity was
required for primordial germ cell transit, and Ifitm1 acted as a
repulsive molecule, repelling non-Ifitm1-expressing primordial germ
cells from the mesoderm into the endoderm. In contrast, Ifitm3 was
expressed in migratory primordial germ cells and behaved as a homing
signal, enabling the cells to respond to environmental cues that guided
their localization. The guidance activities of Ifitm1 and Ifitm3 were
mediated by their unique N-terminal domains.
GENE STRUCTURE
Reid et al. (1989) found that the IFITM1 gene contains 2 exons.
Perry et al. (1999) found that the promoter of the bovine ISG17 gene was
similar to that of the ISG15 gene (147571) in placement of a tandem
IFN-stimulatory response element (ISRE) at position -90, but unique in
the presence of 3 additional ISREs at positions -123, -332, and -525.
MAPPING
By genomic sequence analysis, Lange et al. (2003) mapped the IFITM1 gene
to an IFITM gene cluster on chromosome 11p15.5. The order of the genes,
from telomere to centromere, is IFITM5 (614757), IFITM2 (605578),
IFITM1, and IFITM3 (605579), and the cluster spans about 26.5 kb. Lange
et al. (2003) stated that IFITM2 maps to the plus strand and that all
other IFITM genes map to the minus strand. However, Gross (2012)
determined that, in addition to IFITM2, the IFITM1 gene maps to the plus
strand based on an alignment of the IFITM1 sequence (GenBank GENBANK
BC000897) with the genomic sequence (GRCh37).
Lange et al. (2003) mapped the mouse Ifitm gene cluster to a region of
chromosome 7F5 that shares homology of synteny with human chromosome
11p15.5. The mouse Ifitm gene cluster contains 5 genes, whereas the
human cluster contains only 4 genes.
EVOLUTION
By phylogenetic analysis, Lange et al. (2003) found that only 2 mouse
fragilis genes, fragilis-4 (Ifitm5) and either fragilis (Ifitm3),
fragilis-2 (Ifitm1), or fragilis-3 (Ifitm2), have been conserved from
mouse to human. They suggested that subsequent gene duplications may
have occurred independently in both species.
HRAS
| dbSNP name | rs12628(A,G) |
| ccdsGene name | CCDS7699.1 |
| CosmicCodingMuts gene | HRAS |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 3265 |
| EntrezGene Description | Harvey rat sarcoma viral oncogene homolog |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HRAS:NM_176795:exon2:c.T81C:p.H27H,HRAS:NM_005343:exon2:c.T81C:p.H27H,HRAS:NM_001130442:exon2:c.T81C:p.H27H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.2971 |
| ESP Afr MAF | 0.374943 |
| ESP All MAF | 0.354529 |
| ESP Eur/Amr MAF | 0.34407 |
| ExAC AF | 0.313 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Muscles cramps;
'Steppage' gait;
Foot drop;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
Low to normal range of motor nerve conduction velocity (NCV) (25-45
m/s);
Axonal degeneration/regeneration on nerve biopsy;
Segmental demyelination/remyelination;
Rare 'onion bulb' formations
MISCELLANEOUS:
Onset in second decade;
Begins in feet and legs (peroneal distribution);
Upper limb involvement occurs later;
Rapid disease progression from ages 40 to 50 years;
Features intermediate between demyelinating CMT and axonal CMT;
Genetic heterogeneity (see, e.g., CMTDIB 606482, CMTDID 607791)
OMIM Title
*606487 HRAS-LIKE SUPPRESSOR; HRASLS
OMIM Description
CLONING
By differential display between 2 mouse cell lines, Akiyama et al.
(1999) cloned a cDNA encoding a novel mouse protein, called A-C1, and
showed that it modulates an HRAS (190020)-mediated signaling pathway in
vitro. Ito et al. (2001) isolated a partial cDNA encoding the human
homolog, designated HRASLS, by RT-PCR with mRNA extracted from renal
cell carcinoma cells. They used 5-prime and 3-prime RACE to obtain a
full-length HRASLS cDNA encoding a 168-amino acid protein that shares
83% sequence identity with the mouse protein. HRASLS contains 2
consensus sequence motifs, DXXG and NKXD, suggesting involvement in a
ras-signaling pathway. DXXG is involved in binding to Mg(2+) and
gamma-phosphate when GTP is bound, and NKXD is important for binding to
the guanine ring. Northern blot analysis detected expression of a 1.1-kb
transcript in skeletal muscles, testis, heart, brain, and thyroid.
Expression was also detected at low levels in normal bone, but at high
levels in osteosarcoma cells.
MAPPING
By fluorescence in situ hybridization, Ito et al. (2001) mapped the
HRASLS gene to chromosome 3q28-q29.
MIR210HG
| dbSNP name | rs1056812(C,T); rs3088205(G,A); rs35714706(A,G); rs35110387(A,C); rs3740651(A,G); rs3740650(C,G); rs12792868(T,A); rs28458276(G,A); rs7936401(G,A); rs7927267(A,G); rs7935908(G,A) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 100506211 |
| snpEff Gene Name | RASSF7 |
| EntrezGene Description | MIR210 host gene (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09734 |
LOC143666
| dbSNP name | rs78117166(C,T); rs12285942(C,A); rs78082951(T,A) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 143666 |
| snpEff Gene Name | PHRF1 |
| EntrezGene Description | uncharacterized LOC143666 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1024 |
TALDO1
| dbSNP name | rs28455833(A,G); rs181382219(T,C); rs3901233(T,A); rs57887347(C,T); rs141966152(G,A); rs7945912(A,T); rs3932434(C,T); rs7478765(A,C); rs11246302(A,G); rs142190989(T,C); rs141574406(G,A); rs3895063(G,A); rs138591878(G,C); rs149640294(C,G); rs10902219(G,A); rs147912588(A,G); rs182853065(C,G); rs11246306(C,T); rs58412459(G,A); rs4963163(A,C); rs145267165(A,C); rs4963124(G,C); rs142263629(C,T); rs3891028(G,C) |
| ccdsGene name | CCDS7712.1 |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 6888 |
| EntrezGene Description | transaldolase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TALDO1:NM_006755:exon2:c.C181G:p.L61V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6019 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F2Z393 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.00227 |
| ESP All MAF | 0.000846 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 3.253e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Absent eyebrows;
Absent eyelashes;
[Teeth];
Normal teeth
SKIN, NAILS, HAIR:
[Skin];
Normal sweating;
[Nails];
Onychodystrophy;
Micronychia;
Onycholysis;
[Hair];
Alopecia;
Brittle hair (in some patients);
Pili torti (in some patients);
Sparse body hair (in some patients);
Absent body hair
NEUROLOGIC:
[Central nervous system];
No mental retardation
METABOLIC FEATURES:
Normal sweating
MISCELLANEOUS:
Three families described (last curated January 2014)
MOLECULAR BASIS:
Caused by mutation in the keratin 85 gene (KRT85, 602767.0001)
OMIM Title
*602063 TRANSALDOLASE 1; TALDO1
OMIM Description
DESCRIPTION
Transaldolase (EC 2.2.1.2) is the key enzyme of the pentose phosphate
pathway, which is responsible for generation of reducing equivalents to
protect cellular integrity from reactive oxygen intermediates (Banki et
al., 1997).
CLONING
Banki et al. (1994) cloned the TALDO1 gene. The deduced 336-amino acid
protein has a predicted molecular mass of 38 kD and shows 58% overall
sequence homology with the 37-kD yeast transaldolase.
Kusuda et al. (1998) isolated the cDNA for the mouse homolog of TALDO1
and determined the nucleotide sequence covering the complete coding
region.
GENE STRUCTURE
Banki et al. (1994) determined that, unlike the intronless yeast
transaldolase gene, the human TALDO1 gene contains 5 exons, the second
and third of which are developed by insertion of a retrotransposable
element. Detection of a retrotransposon in the coding sequence of the
human transaldolase gene demonstrated the importance of these repetitive
elements in the evolution of the eukaryotic genome.
MAPPING
By Southern blot analysis of human/mouse somatic cell hybrid DNA, Banki
et al. (1997) mapped TALDO1 to the region 11pter-p13. By fluorescence in
situ hybridization (FISH), they narrowed the assignment to
11p15.5-p15.4. A truncated and mutated segment of exon 5 terminating
with a poly(A) tail was identified in a pseudogene locus (TALDOP1) on
chromosome 1. RT-PCR studies of mouse/human somatic cell hybrids
revealed the presence of the functional gene on chromosome 11 and its
absence on chromosome 1. Mapping of radiation hybrids placed TALDO1
between the markers WI-1421 and D11S922 on 11p15.
By FISH, Kusuda et al. (1997) concluded that the functional TALDO1 gene
is located on 1p34.1-p33. Kusuda et al. (1998) mapped a paralogous gene
to 11p15, where Banki et al. (1997) had mapped the TALDO1 gene. Kusuda
et al. (1998) symbolized the gene on chromosome 11 as TALDOR (TALDO
related). The exon sequence of TALDOR was almost identical to that of
TALDO but its exons corresponding to exons 4 and 5 of TALDO were found
to be split by 4 introns.
By FISH using cDNA as a probe, Kusuda et al. (1998) showed that the
mouse transaldolase gene is localized to bands F3-F4 of chromosome 7 as
a single-copy gene. This chromosomal region is known to be syntenic to
human chromosome 11p15 rather than to 1p34.1-p33, suggesting that TALDOR
is the ancestral form. The existence of TALDOR implied a duplication of
the mammalian transaldolase gene after divergence of rodent and primate.
Hashimoto (1998) concluded that the functional TALDO gene is on human
chromosome 11 and a pseudogene on human chromosome 1.
MOLECULAR GENETICS
Verhoeven et al. (2001) described a patient with transaldolase
deficiency (606003) caused by a homozygous 3-bp deletion (602063.0001)
in the TALDO1 gene, resulting in the absence of serine at position 171
of the transaldolase protein. This amino acid is invariable between
species and is located in a conserved region, indicating its importance
for enzyme activity.
ANIMAL MODEL
Perl et al. (2006) found that Taldo1-null mice developed normally, but
males were sterile due to functional and structural defects of
mitochondria. Reduced motility in Taldo1-null spermatozoa was associated
with diminished mitochondrial reactive oxygen intermediate production,
reduced calcium levels, intracellular acidosis, and compensatory
downregulation of carbonic anhydrase IV (CA4; 114760) and overexpression
of Cd38 (107270) and gamma-glutamyltransferase (GGT1; 612346).
NS3BP
| dbSNP name | rs7111003(C,T); rs147299513(C,T); rs56364586(C,T); rs6597984(T,G); rs117060799(G,A) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 100506518 |
| EntrezGene Symbol | LOC100506518 |
| snpEff Gene Name | AP006621.5 |
| EntrezGene Description | uncharacterized LOC100506518 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2824 |
TOLLIP-AS1
| dbSNP name | rs5743851(A,G) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 255512 |
| snpEff Gene Name | TOLLIP |
| EntrezGene Description | TOLLIP antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03627 |
KRTAP5-3
| dbSNP name | rs1989592(A,G); rs57186801(G,A); rs60210378(G,A); rs7108521(G,T); rs7129160(C,T) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 387266 |
| EntrezGene Description | keratin associated protein 5-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2548 |
KRTAP5-4
| dbSNP name | rs10768781(T,A); rs6578597(A,C) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 387267 |
| EntrezGene Description | keratin associated protein 5-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4816 |
KRTAP5-5
| dbSNP name | rs4752770(G,T); rs4752769(C,T); rs10838011(C,A); rs10838014(G,C) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 439915 |
| EntrezGene Description | keratin associated protein 5-5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4601 |
| ESP Afr MAF | 0.317356 |
| ESP All MAF | 0.389752 |
| ESP Eur/Amr MAF | 0.426826 |
| ExAC AF | 0.551 |
FAM99A
| dbSNP name | rs74047730(C,T); rs72850916(A,G) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 387742 |
| snpEff Gene Name | AP006285.1 |
| EntrezGene Description | family with sequence similarity 99, member A (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03168 |
ASCL2
| dbSNP name | rs968528(T,A) |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 430 |
| EntrezGene Description | achaete-scute family bHLH transcription factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4013 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataract, zonular pulverulent;
Cataract, posterior polar;
Cataract, nuclear coralliform;
Cataract, embryonal nuclear;
Cataract, Coppock-like
MISCELLANEOUS:
Congenital cataracts, sometimes requiring extraction in childhood
due to impairment of vision
MOLECULAR BASIS:
Caused by mutation in the gap junction, alpha-3, 46kD protein gene
(GJA3, 121015.0001)
OMIM Title
*601886 ACHAETE-SCUTE COMPLEX, DROSOPHILA, HOMOLOG OF, 2; ASCL2
;;ACHAETE-SCUTE HOMOLOG 2; ASH2; HASH2
OMIM Description
CLONING
The mammalian Achaete-Scute homologs are conserved mammalian cognates of
the Drosophila Achaete-Scute complex. In rodents, 2 such genes have been
identified: Mash1 (ASCL1; 100790), which is expressed in neuronal
progenita, and Mash2 (ASCL2), which is expressed in spongiotrophoblast
cells and their precursors. Both are members of the basic
helix-loop-helix (bHLH) gene family, which includes MYC (190080) and
MYOD1 (159970). Mash1 and Mash2 function as lineage-specific
transcription factors essential for development of the neurectoderm and
trophectoderm, respectively. Alders et al. (1997) noted that in mouse,
the Mash2 gene is subject to genomic imprinting, with only the maternal
allele being active. Alders et al. (1997) isolated the human homolog of
the MASH2 gene, which they designated HASH2. Expression studies showed
that HASH2 was expressed in extravillous trophoblast cells only. The
lack of expression in nonmalignant hydatidiform (androgenetic) moles
indicated that HASH2 is imprinted in man.
GENE FUNCTION
Luscher-Firzlaff et al. (2008) observed that human ASH2 cooperated with
HRAS (190020) to transform primary rat embryo fibroblasts (REFs).
Furthermore, transformation of REFs by MYC and HRAS required the
presence of rat Ash2. In an animal model, human ASH2/HRAS-transformed
REFs formed rapidly growing tumors characteristic of fibrosarcomas that,
compared with tumors derived from MYC/HRAS-transformed cells, were
poorly differentiated. ASH2 protein expression was increased in most
human tumors and tumor cell lines examined, and knockdown of ASH2
inhibited proliferation in 2 human tumor cell lines. Luscher-Firzlaff et
al. (2008) concluded that ASH2 can act as an oncoprotein.
Liu et al. (2014) showed that expression of ASCL2 is selectively
upregulated in follicular T-helper (T-FH) cells. Ectopic expression of
ASCL2 upregulated CXCR5 (601613) but not BCL6 (109565), and
downregulated CCR7 (600242) expression in T cells in vitro, as well as
accelerating T-cell migration to the follicles and T-FH cell development
in vivo in mice. Genomewide analysis indicated that ASCL2 directly
regulates T-FH-related genes, whereas it inhibits expression of
T-helper-1 (TH1; see 606652) and TH17 (see 603149) signature genes.
Acute deletion of ASCL2, as well as blockade of its function with the
ID3 protein (600277) in CD4-positive T cells (see 186940), resulted in
impaired T-FH-cell development. Conversely, mutation of ID3, known to
cause antibody-mediated autoimmunity, greatly enhanced T-FH-cell
generation and germinal center response. Liu et al. (2014) concluded
that ASCL2 directly initiates T-FH-cell development.
MAPPING
Alders et al. (1997) noted that the mouse Mash2 gene maps to distal
chromosome 7 and is closely linked to 3 other imprinted genes, Ins2
(176730), Igf2 (147470), and H19 (103280). They mapped the human HASH2
gene to the conserved syntenic human chromosome region 11p15.5. Alders
et al. (1997) showed that the human gene maps proximal to and in close
proximity of IGF2, and that the gene order in this region is
HASH2-INS-IGF2-H19-tel.
ANIMAL MODEL
Alders et al. (1997) noted that mice deficient for Mash2 die at 10 days
postcoitum due to placental failure (Guillemot et al., 1994). In
contrast, chimeric mice with heterozygous extraembryonic tissues and
homozygous embryonic tissues are viable and normal, indicating that this
gene, although essential for development of the placenta, is not
important for development of the embryo proper. Mice carrying the
homozygously mutated Mash2 gene die at 10 days postcoitum, as do
heterozygous mice who inherited the mutant allele from their mother,
consistent with genomic imprinting in which only the maternal allele is
active. Heterozygous mice who inherited the mutant allele from their
father are viable. This phenomenon of paternal imprinting of a gene
being critical for development of a placenta is an exception to the
common imprinting rule: nuclear transplantation studies in mice have
shown that imprinting is biased toward embryonic versus extraembryonic
tissues with preferential expression of the maternal and paternal
alleles in the embryo and placenta, respectively.
TSSC4
| dbSNP name | rs2234278(A,C); rs2234279(C,G); rs2234283(A,C) |
| ccdsGene name | CCDS7735.1 |
| cytoBand name | 11p15.5 |
| EntrezGene GeneID | 10078 |
| EntrezGene Description | tumor suppressing subtransferable candidate 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TSSC4:NM_005706:exon2:c.A50C:p.H17P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0196 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5U2 |
| dbNSFP Uniprot ID | TSSC4_HUMAN |
| dbNSFP KGp1 AF | 0.010989010989 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0211081794195 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.00641 |
| ESP All MAF | 0.019234 |
| ESP Eur/Amr MAF | 0.025764 |
| ExAC AF | 0.018 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolonged QT interval on EKG;
Syncope;
Torsade de pointes;
Ventricular fibrillation;
Sudden cardiac death
MISCELLANEOUS:
Association of cardiac events with exercise;
Genetic heterogeneity (see LQT1 192500);
Patients with more severe phenotype have been reported with mutations
in more than 1 LQTS-related gene;
GEI (gene-environment interaction) - association of cardiac events
with drug administration
MOLECULAR BASIS:
Caused by mutation in the sodium channel, voltage-gated, type V, alpha
polypeptide gene (SCN5A, 600163.0001)
OMIM Title
*603852 TUMOR-SUPPRESSING SUBCHROMOSOMAL TRANSFERABLE FRAGMENT CANDIDATE GENE
4; TSSC4
;;TUMOR-SUPPRESSING STF cDNA 4
OMIM Description
DESCRIPTION
The TSSC4 gene is a nonimprinted tumor suppressor gene that resides in
the imprinted gene domain on chromosome 11p15.5 (Lee et al., 1999).
CLONING
Because of the large number of imprinted genes on 11p15, spanning
approximately 1 Mb, this region appears to represent 1 of 2 known large
imprinted domains in the human genome, the other being the
Prader-Willi/Angelman syndrome domain of 15q11-q13 (see 105830). Koi et
al. (1993) isolated a subchromosomal transferable fragment (STF) that
suppresses in vitro growth of the rhabdomyosarcoma cell line RD,
confirming the existence of 1 or more tumor suppressor genes within this
region. Hu et al. (1997) found that the STF spans approximately 2.5 Mb,
with D11S12 at its proximal end and D11S1318 at its distal end. Within a
cluster of imprinted genes in this STF, Lee et al. (1999) identified 2
novel genes, designated TSSC4 and TSSC6 (603853), that were not
imprinted in any of the fetal or extraembryonic tissues examined. The
TSSC4 cDNA encodes a predicted protein of 349 amino acids that shows no
close similarity to previously reported proteins. Northern blot analysis
revealed that the TSSC4 gene was expressed as an approximately 1.6-kb
transcript in fetal brain, lung, liver, and kidney. The TSSC4 and TSSC6
genes are both located in the center of the 1-Mb imprinted domain on
11p15 that contains the 7 imprinted genes. Thus, the imprinted gene
domain of 11p15 appears to contain at least 2 imprinted subdomains,
between which the TSSC4 and TSSC6 genes substantially escape imprinting,
due either to a lack of initial silencing or to an early developmental
relaxation of imprinting.
OTHER FEATURES
Lee et al. (1999) noted that 7 imprinted genes had been identified on
11p15: IGF2 (147470), which encodes an important autocrine growth factor
in cancer; H19 (103280), an untranslated RNA whose imprinting regulates
IGF2; ASCL2 (601886), a homolog of Drosophila achaete-scute that is
expressed in the trophoblast; KCNQ1 (607542), which encodes a
voltage-gated potassium channel; p57(KIP2) (CDKN1C; 600856), which
encodes a cyclin-dependent kinase inhibitor; TSSC5 (IMPT1; 602631),
which encodes a predicted transmembrane transporter; and TSSC3 (602131),
also known as IPL, a homolog of a mouse apoptosis-inducing gene. With
the exception of IGF2, all of these genes are expressed from the
maternal allele.
OR52B4
| dbSNP name | rs188379419(A,G); rs11031960(C,T); rs7929171(G,C) |
| ccdsGene name | CCDS41609.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 143496 |
| EntrezGene Description | olfactory receptor, family 52, subfamily B, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52B4:NM_001005161:exon1:c.T706C:p.C236R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK2 |
| dbNSFP Uniprot ID | O52B4_HUMAN |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.002887 |
| ESP All MAF | 0.005719 |
| ESP Eur/Amr MAF | 0.007114 |
| ExAC AF | 0.007081 |
OR52K2
| dbSNP name | rs11032296(C,T); rs331537(G,A); rs7934336(C,T) |
| ccdsGene name | CCDS31351.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119774 |
| EntrezGene Description | olfactory receptor, family 52, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52K2:NM_001005172:exon1:c.C370T:p.R124C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0089 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK3 |
| dbNSFP Uniprot ID | O52K2_HUMAN |
| dbNSFP KGp1 AF | 0.0315934065934 |
| dbNSFP KGp1 Afr AF | 0.132113821138 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.03168 |
| ESP Afr MAF | 0.105861 |
| ESP All MAF | 0.037313 |
| ESP Eur/Amr MAF | 0.00221 |
| ExAC AF | 0.011 |
OR52K1
| dbSNP name | rs96489(A,G) |
| ccdsGene name | CCDS31352.1 |
| CosmicCodingMuts gene | OR52K1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390036 |
| EntrezGene Description | olfactory receptor, family 52, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52K1:NM_001005171:exon1:c.A155G:p.Q52R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK4 |
| dbNSFP Uniprot ID | O52K1_HUMAN |
| dbNSFP KGp1 AF | 0.353937728938 |
| dbNSFP KGp1 Afr AF | 0.548780487805 |
| dbNSFP KGp1 Amr AF | 0.265193370166 |
| dbNSFP KGp1 Asn AF | 0.34965034965 |
| dbNSFP KGp1 Eur AF | 0.27308707124 |
| dbSNP GMAF | 0.3545 |
| ESP Afr MAF | 0.495684 |
| ESP All MAF | 0.366518 |
| ESP Eur/Amr MAF | 0.295952 |
| ExAC AF | 0.316 |
OR52M1
| dbSNP name | rs2709182(C,T); rs61747520(T,C); rs2657167(C,G) |
| ccdsGene name | CCDS31353.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119772 |
| EntrezGene Description | olfactory receptor, family 52, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52M1:NM_001004137:exon1:c.C291T:p.D97D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4265 |
| ESP Afr MAF | 0.495002 |
| ESP All MAF | 0.486306 |
| ESP Eur/Amr MAF | 0.481852 |
| ExAC AF | 0.460,8.132e-06,1.626e-05 |
OR52I2
| dbSNP name | rs7128702(T,C); rs56002758(A,G); rs1847632(C,T); rs55804480(C,T) |
| ccdsGene name | CCDS31355.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 143502 |
| EntrezGene Description | olfactory receptor, family 52, subfamily I, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52I2:NM_001005170:exon1:c.T74C:p.L25P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH67 |
| dbNSFP Uniprot ID | O52I2_HUMAN |
| dbNSFP KGp1 AF | 0.117673992674 |
| dbNSFP KGp1 Afr AF | 0.371951219512 |
| dbNSFP KGp1 Amr AF | 0.0966850828729 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0514511873351 |
| dbSNP GMAF | 0.1175 |
| ESP Afr MAF | 0.257156 |
| ESP All MAF | 0.130097 |
| ESP Eur/Amr MAF | 0.06503 |
| ExAC AF | 0.065 |
OR52I1
| dbSNP name | rs78745657(C,G); rs61997192(T,C) |
| ccdsGene name | CCDS59223.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390037 |
| EntrezGene Description | olfactory receptor, family 52, subfamily I, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52I1:NM_001005169:exon1:c.C601G:p.L201V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0501 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK6 |
| dbNSFP Uniprot ID | O52I1_HUMAN |
| dbNSFP KGp1 AF | 0.0173992673993 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0367132867133 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.01745 |
| ESP Afr MAF | 0.017038 |
| ESP All MAF | 0.005927 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.006644 |
OR51D1
| dbSNP name | rs138224979(C,G); rs61740347(T,C); rs905871(A,G); rs61746547(A,G); rs79020081(T,C) |
| ccdsGene name | CCDS31357.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390038 |
| EntrezGene Description | olfactory receptor, family 51, subfamily D, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51D1:NM_001004751:exon1:c.C170G:p.T57S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGF3 |
| dbNSFP Uniprot ID | O51D1_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.007497 |
| ESP All MAF | 0.002616 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.000862 |
OR51F1
| dbSNP name | rs1030726(C,A); rs1030725(A,G); rs17324609(G,A); rs1030724(A,G); rs1030723(G,A); rs11033793(T,C); rs12792898(T,C); rs12788102(A,G); rs11033795(C,T); rs11033796(G,A); rs11033797(A,G); rs117939637(G,A); rs11033800(C,A); rs11033801(A,G); rs16938394(A,G); rs17324812(T,C) |
| ccdsGene name | CCDS31359.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 256892 |
| EntrezGene Description | olfactory receptor, family 51, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51F1:NM_001004752:exon1:c.G880T:p.D294Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NGY5 |
| dbNSFP Uniprot ID | O51F1_HUMAN |
| dbNSFP KGp1 AF | 0.22619047619 |
| dbNSFP KGp1 Afr AF | 0.457317073171 |
| dbNSFP KGp1 Amr AF | 0.226519337017 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.246701846966 |
| dbSNP GMAF | 0.2259 |
| ESP Afr MAF | 0.446842 |
| ESP All MAF | 0.318895 |
| ESP Eur/Amr MAF | 0.253374 |
| ExAC AF | 0.206,2.480e-05 |
OR52R1
| dbSNP name | rs2053116(A,C); rs6578533(T,A); rs73403015(T,C); rs7941731(A,G); rs75407816(G,A); rs17327254(A,G); rs61740077(G,A); rs76140227(C,T) |
| ccdsGene name | CCDS31360.2 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119695 |
| EntrezGene Description | olfactory receptor, family 52, subfamily R, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52R1:NM_001005177:exon1:c.T733G:p.S245A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGF1 |
| dbNSFP Uniprot ID | O52R1_HUMAN |
| dbNSFP KGp1 AF | 0.312728937729 |
| dbNSFP KGp1 Afr AF | 0.55081300813 |
| dbNSFP KGp1 Amr AF | 0.32320441989 |
| dbNSFP KGp1 Asn AF | 0.0174825174825 |
| dbNSFP KGp1 Eur AF | 0.37598944591 |
| dbSNP GMAF | 0.3127 |
| ESP Afr MAF | 0.48478 |
| ESP All MAF | 0.406601 |
| ESP Eur/Amr MAF | 0.350977 |
| ExAC AF | 0.305 |
OR51F2
| dbSNP name | rs111849521(C,T); rs35003053(A,G); rs7114668(C,A); rs7103540(T,A) |
| ccdsGene name | CCDS31361.1 |
| CosmicCodingMuts gene | OR51F2 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119694 |
| EntrezGene Description | olfactory receptor, family 51, subfamily F, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51F2:NM_001004753:exon1:c.C178T:p.L60L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.017946 |
| ESP All MAF | 0.006232 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.001757 |
OR51S1
| dbSNP name | rs112869374(G,C); rs12361955(G,A); rs57238061(A,G); rs7117260(A,C); rs7117389(A,G); rs143546045(G,A); rs11602455(G,A); rs11602499(G,C); rs12417164(A,T); rs35918613(G,C); rs11601065(T,G); rs375695111(G,A) |
| ccdsGene name | CCDS31362.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119692 |
| EntrezGene Description | olfactory receptor, family 51, subfamily S, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51S1:NM_001004758:exon1:c.C931G:p.L311V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0406 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ8 |
| dbNSFP Uniprot ID | O51S1_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.005452 |
| ESP All MAF | 0.001846 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0003578 |
OR51T1
| dbSNP name | rs374794229(A,T) |
| ccdsGene name | CCDS31363.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 401665 |
| EntrezGene Description | olfactory receptor, family 51, subfamily T, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51T1:NM_001004759:exon1:c.A82T:p.M28L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.1646 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ9 |
| dbNSFP Uniprot ID | O51T1_HUMAN |
OR51A7
| dbSNP name | rs11034596(G,A); rs78548289(C,A); rs7108225(T,C); rs7941509(C,T); rs10500627(C,G) |
| ccdsGene name | CCDS31364.1 |
| CosmicCodingMuts gene | OR51A7 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119687 |
| EntrezGene Description | olfactory receptor, family 51, subfamily A, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51A7:NM_001004749:exon1:c.G22A:p.E8K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH64 |
| dbNSFP Uniprot ID | O51A7_HUMAN |
| dbNSFP KGp1 AF | 0.216117216117 |
| dbNSFP KGp1 Afr AF | 0.0934959349593 |
| dbNSFP KGp1 Amr AF | 0.132596685083 |
| dbNSFP KGp1 Asn AF | 0.543706293706 |
| dbNSFP KGp1 Eur AF | 0.0883905013193 |
| dbSNP GMAF | 0.2158 |
| ESP Afr MAF | 0.079055 |
| ESP All MAF | 0.078166 |
| ESP Eur/Amr MAF | 0.077711 |
| ExAC AF | 0.130,8.134e-06 |
OR51G2
| dbSNP name | rs61747513(G,A); rs12419598(C,G); rs16907312(G,T) |
| ccdsGene name | CCDS31365.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 81282 |
| EntrezGene Description | olfactory receptor, family 51, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51G2:NM_001005238:exon1:c.C493T:p.P165S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0013 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK0 |
| dbNSFP Uniprot ID | O51G2_HUMAN |
| dbNSFP KGp1 AF | 0.0357142857143 |
| dbNSFP KGp1 Afr AF | 0.150406504065 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03581 |
| ESP Afr MAF | 0.131985 |
| ESP All MAF | 0.045315 |
| ESP Eur/Amr MAF | 0.000931 |
| ExAC AF | 0.012 |
OR51G1
| dbSNP name | rs79536656(A,G); rs34583466(G,C); rs12796015(A,G); rs111446872(C,T); rs35264256(C,T); rs35666095(T,C); rs61732340(T,C) |
| ccdsGene name | CCDS31366.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 79324 |
| EntrezGene Description | olfactory receptor, family 51, subfamily G, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51G1:NM_001005237:exon1:c.T842C:p.V281A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGK1 |
| dbNSFP Uniprot ID | O51G1_HUMAN |
| dbNSFP KGp1 AF | 0.021978021978 |
| dbNSFP KGp1 Afr AF | 0.0955284552846 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02204 |
| ESP Afr MAF | 0.056565 |
| ESP All MAF | 0.019772 |
| ESP Eur/Amr MAF | 0.000931 |
| ExAC AF | 0.005619 |
OR51A4
| dbSNP name | rs28698374(G,A); rs2595988(G,C) |
| ccdsGene name | CCDS31367.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 401666 |
| EntrezGene Description | olfactory receptor, family 51, subfamily A, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51A4:NM_001005329:exon1:c.C863T:p.T288M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ6 |
| dbNSFP Uniprot ID | O51A4_HUMAN |
| dbNSFP KGp1 AF | 0.849358974359 |
| dbNSFP KGp1 Afr AF | 0.780487804878 |
| dbNSFP KGp1 Amr AF | 0.895027624309 |
| dbNSFP KGp1 Asn AF | 0.917832167832 |
| dbNSFP KGp1 Eur AF | 0.820580474934 |
| dbSNP GMAF | 0.1497 |
| ESP Afr MAF | 0.2 |
| ESP All MAF | 0.16659 |
| ESP Eur/Amr MAF | 0.149488 |
| ExAC AF | 0.849 |
OR51L1
| dbSNP name | rs2445290(A,G); rs11035066(C,T); rs10768448(C,T); rs10768450(C,T); rs61734126(C,G) |
| ccdsGene name | CCDS31369.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119682 |
| EntrezGene Description | olfactory receptor, family 51, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51L1:NM_001004755:exon1:c.A204G:p.L68L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1983 |
| ESP Afr MAF | 0.146524 |
| ESP All MAF | 0.14733 |
| ESP Eur/Amr MAF | 0.147743 |
| ExAC AF | 0.835 |
OR52J3
| dbSNP name | rs142724471(C,T); rs2500016(A,G); rs2500017(G,A); rs17350764(G,A); rs2500019(A,G) |
| ccdsGene name | CCDS31370.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119679 |
| EntrezGene Description | olfactory receptor, family 52, subfamily J, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52J3:NM_001001916:exon1:c.C145T:p.L49L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0003172 |
OR52E2
| dbSNP name | rs2445332(C,T); rs2500052(G,A); rs74458775(T,C); rs72873928(A,G); rs2445333(T,C); rs61746343(T,C); rs11035396(G,A); rs114382179(C,T); rs116709433(G,A); rs16909440(T,C) |
| ccdsGene name | CCDS31371.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 119678 |
| EntrezGene Description | olfactory receptor, family 52, subfamily E, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52E2:NM_001005164:exon1:c.G912A:p.V304V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1038 |
| ESP Afr MAF | 0.106542 |
| ESP All MAF | 0.061394 |
| ESP Eur/Amr MAF | 0.038274 |
| ExAC AF | 0.936 |
OR52A5
| dbSNP name | rs2472530(A,G) |
| ccdsGene name | CCDS31373.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390054 |
| EntrezGene Description | olfactory receptor, family 52, subfamily A, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52A5:NM_001005160:exon1:c.T612C:p.F204F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2218 |
| ESP Afr MAF | 0.049977 |
| ESP All MAF | 0.157178 |
| ESP Eur/Amr MAF | 0.212075 |
| ExAC AF | 0.22 |
OR52A1
| dbSNP name | rs10768611(A,G); rs77308879(C,A) |
| ccdsGene name | CCDS31374.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 23538 |
| EntrezGene Description | olfactory receptor, family 52, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52A1:NM_012375:exon1:c.T814C:p.S272P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UKL2 |
| dbNSFP Uniprot ID | O52A1_HUMAN |
| dbNSFP KGp1 AF | 0.971611721612 |
| dbNSFP KGp1 Afr AF | 0.888211382114 |
| dbNSFP KGp1 Amr AF | 0.983425414365 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.998680738786 |
| dbSNP GMAF | 0.02847 |
| ESP Afr MAF | 0.094048 |
| ESP All MAF | 0.032159 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.991 |
OR51V1
| dbSNP name | rs11512276(C,A); rs61738413(C,G); rs11036212(G,A) |
| ccdsGene name | CCDS31375.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 283111 |
| EntrezGene Description | olfactory receptor, family 51, subfamily V, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51V1:NM_001004760:exon1:c.G286T:p.G96W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H2C8 |
| dbNSFP Uniprot ID | O51V1_HUMAN |
| dbNSFP KGp1 AF | 0.46978021978 |
| dbNSFP KGp1 Afr AF | 0.34756097561 |
| dbNSFP KGp1 Amr AF | 0.541436464088 |
| dbNSFP KGp1 Asn AF | 0.258741258741 |
| dbNSFP KGp1 Eur AF | 0.674142480211 |
| dbSNP GMAF | 0.4706 |
| ESP Afr MAF | 0.389596 |
| ESP All MAF | 0.4016 |
| ESP Eur/Amr MAF | 0.294672 |
| ExAC AF | 0.405,0.319 |
HBD
| dbSNP name | rs16911951(A,G); rs181334077(T,C); rs77044643(A,C); rs61746501(G,A); rs35406175(G,A); rs189737412(A,G) |
| ccdsGene name | CCDS31376.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 3045 |
| EntrezGene Description | hemoglobin, delta |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3045&%3Brs=35406175 |
| Annovar Function | HBD:NM_000519:exon1:c.C14T:p.T5I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6767 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P02042 |
| dbNSFP Uniprot ID | HBD_HUMAN |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3045&%3Brs=35406175 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.001616 |
| ESP Eur/Amr MAF | 0.002327 |
| ExAC AF | 1.431e-03,3.253e-05 |
OMIM Clinical Significance
Heme:
Beta polypeptide hemoglobin chain;
Anemia;
Microcytosis;
Hypochromia;
Congenital dyserythropoietic anemia (Irish type);
Mild hemolytic anemia (e.g. Hb Extremadura 141900.0074);
Hemolytic microcytic anemia in compound heterozygosity with Hb C (e.g.
Hb Korle-bu 141900.0153);
Macrocytic hemolytic disease (e.g. Hb Redondo 141900.0404);
Erythrocytosis (e.g. Hb Brigham 141900.0028);
Congenital Heinz body anemia (e.g. Hb Bruxelles 141900.0033);
Sickle cell anemia (homozygous Hb SS 141900.0243);
Painful crises;
Aplastic crises;
Acute splenic sequestration;
Splenomegaly;
Dactylitis;
Ischemia;
Avascular necrosis;
Leg ulcers;
Cholelithiasis;
Priapism;
Osteonecrosis;
Osteomyelitis;
Drug-induced hemolysis (e.g. Hb Zurich 141900.0310) Methemoglobinemia
(e.g., HbM Saskatoon 141900.0165) Erythremia (e.g., Hb Osler 141900.0211)
Skin:
Jaundice;
Cyanosis (e.g. Hb M Saskatoon 141900.0165)
GI:
Cholelithiasis;
Splenomegaly (e.g. Hb Jacksonville 141900.0401);
Splenic syndrome (e.g. Hb S 141900.0243)
GU:
Hematuria (e.g. Hb Sarrebourg 141900.0435);
Urine concentrating defect (e.g. Hb S 141900.0243)
Misc:
Resistance to falciparum malaria (e.g. Hb S. 141900.0243);
Beta-delta fusion variant (e.g. Hb Lincoln Park 141900.0157);
Lab:
Abnormal red cell morphology;
Bone marrow erythroid hyperplasia;
Increased numbers of multinucleate red cell precursors;
Inclusion bodies in normoblasts;
Altered hemoglobin A(2) levels;
Altered hemoglobin F levels;
Unstable hemoglobin (e.g. Hb Koln 141900.0151);
Diminished oxygen affinity (e.g. Hb Chico 141900.0048);
Increased oxygen affinity (e.g. Hb Heathrow 141900.0102);
Increased N-terminal glycation (e.g. Hb Himeji 141900.0107);
Discrepant Hb A1c measurement (e.g. Hb Marseille 141900.0171);
Unusually low Hb A(1c) level (e.g. Hb Kodaira 141900.0409);
Red cell inclusion bodies (e.g. Hb Matera 141900.0173);
Red cell sickling (e.g. Hb S 141900.0243);
Non-Hb S red cell sickling (e.g. Hb C (Georgetown) 141900.0039);
Electrophoretic migration as Hb S (e.g. Hb Muskegon 141900.0432);
Increased red cell sickling tendency (e.g. Hb S (OMAN) 141900.0245)
Inheritance:
Autosomal dominant for some such as methemoglobinemia, polycythemia,
and Heinz body hemolytic anemia;
Autosomal recessive for others such as sickle cell disease and thalassemia
major
OMIM Title
+141900 HEMOGLOBIN--BETA LOCUS; HBB
METHEMOGLOBINEMIA, BETA-GLOBIN TYPE, INCLUDED;;
ERYTHREMIA, BETA-GLOBIN TYPE, INCLUDED
OMIM Description
DESCRIPTION
The alpha (HBA1, 141800; HBA2, 141850) and beta (HBB) loci determine the
structure of the 2 types of polypeptide chains in adult hemoglobin, HbA.
Mutant beta globin that sickles causes sickle cell anemia (603903).
Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of
detectable beta globin causes beta-plus-thalassemia. For clinical
purposes, beta-thalassemia (613985) is divided into thalassemia major
(transfusion dependent), thalassemia intermedia (of intermediate
severity), and thalassemia minor (asymptomatic).
GENE STRUCTURE
Fine detail of both the mouse (Miller et al., 1978) and the human
beta-globin gene was determined in the 1970s (Flavell et al., 1978). The
mouse beta-globin gene is interrupted by 2 intervening sequences of DNA
that divide it into 3 discontinuous segments. The entire gene, including
the coding, intervening and untranslated regions, is transcribed into a
colinear 15S mRNA precursor. Because mature globin mRNA is smaller (10S)
and does not contain the intervening sequences, the 15S precursor must
be processed.
Using restriction endonucleases and recombinant DNA techniques, Flavell
et al. (1978) prepared a map of the human beta- and delta- (142000)
globin genes. The beta-globin gene contains a nonglobin DNA insert about
800-1000 basepairs in length, present within the sequence coding for
amino acids 101-120. A similar untranscribed sequence may be present in
the delta gene.
MAPPING
Use of a combination of somatic cell hybridization and hybridization of
DNA probes permitted assignment of the beta hemoglobin locus to
chromosome 11 (Deisseroth et al., 1978). Parallel experiments showed
that the gamma globin genes (HBG1, 142200; HBG2, 142250) are also on
chromosome 11, a result to be expected from other data indicating
linkage of beta and gamma.
Flavell et al. (1978) found that the distance between the beta and delta
genes is about 7,000 nucleotide pairs and that the delta gene is to the
5-prime side of the beta gene, as predicted by other evidence.
Polymorphism was found at the third nucleotide of the codon for amino
acid number 50 (Wilson et al., 1977).
The order of the genes in the beta-globin cluster was proved by
restriction enzyme studies (Fritsch et al., 1979); starting with the
5-prime end, the order is gamma-G--gamma-A--delta--beta--Hpa I. By
'liquid' molecular hybridization, Haigh et al. (1979) studied mouse-man
hybrid rearrangements involving chromosome 11 and assigned the
nonalpha-globin cluster to the region 11p11-p15.
Housman et al. (1979) concluded from study of Chinese-hamster ovary cell
lines containing chromosome 11 or selected parts thereof that the beta
hemoglobin complex (NAG, nonalpha-globin genes) is in interband
p1205-p1208.
Lebo et al. (1981) studied the linkage between 2 restriction
polymorphisms, the HpaI polymorphism on the 3-prime side of the
beta-globin gene and the SacI polymorphism on the 5-prime side of the
insulin gene. They found 4 recombinants in 34 meioses (12%), giving 90%
confidence limits for the interval as 6-22 cM.
From in situ hybridization studies, Morton et al. (1984) concluded that
the beta-globin gene is situated at 11p15. Their studies included a
t(7;11)(q22;p15) in which the beta-globin locus appeared to be at the
junction point. Interest relates to the translocation cell line coming
from a patient with erythroleukemia and the fact that the ERBB oncogene
(131550) is located on chromosome 7 (7pter-q22).
By high-resolution chromosome sorting of human chromosomes carrying
segments of chromosome 11 and by spot blotting with various
gene-specific probes, Lebo et al. (1985) concluded that the loci for
parathyroid hormone, beta-globin, and insulin are all located on 11p15.
By in situ hybridization studies of chromosome 11 rearrangements,
Magenis et al. (1985) likewise assigned HBB to 11p15. In an addendum,
they referred to studies of a t(7;11) rearrangement that further
narrowed the HBB assignment to 11p15.4-11pter.
By high-resolution cytogenetics and in situ hybridization, Lin et al.
(1985) placed the beta-globin gene in the 11p15.4-p15.5 segment. Through
reanalysis of a Chinese hamster/human cell hybrid that had lost all
human chromosomes except 11, Gerhard et al. (1987) reached the
conclusion that the beta-globin gene complex is located on 11p15 and
that the insulin and HRAS1 genes are located in a segment of DNA
approximately 10 Mb long.
- Pseudogenes
The eta locus is 1 of 5 ancient beta-related globin genes linked in a
cluster, 5-prime--epsilon (142100)--gamma--eta--delta--beta--3-prime,
that arose from tandem duplications (Koop et al., 1986). The eta locus
was embryonically expressed in early eutherians and persisted as a
functional gene in artiodactyls (e.g., goat), but became a pseudogene in
proto-primates and was lost from rodents and lagomorphs. Sequence
studies show that the goat eta gene is orthologous to the pseudogene
located between the gamma and delta loci of primates and called
psi-beta-1. (The Hb beta-1 pseudogene (psi-beta-1) can be symbolized
HBBP or HBBP1.)
GENE FUNCTION
Dye and Proudfoot (2001) performed in vivo analysis of transcriptional
termination for the human beta-globin gene and demonstrated
cotranscriptional cleavage (CoTC). This primary cleavage event within
beta-globin pre-mRNA, downstream of the poly(A) site, is critical for
efficient transcriptional termination by RNA polymerase II (see 180660).
Teixeira et al. (2004) showed that the CoTC process in the human
beta-globin gene involves an RNA self-cleaving activity. They
characterized the autocatalytic core of the CoTC ribozyme and showed its
functional role in efficient termination in vivo. The identified core
CoTC is highly conserved in the 3-prime flanking regions of other
primate beta-globin genes. Functionally, it resembles the 3-prime
processive, self-cleaving ribozymes described for the protein-encoding
genes from the myxomycetes Didymium iridis and Physarum polycephalum,
indicating evolutionary conservation of this molecular process. Teixeira
et al. (2004) predicted that regulated autocatalytic cleavage elements
within pre-mRNAs may be a general phenomenon and that functionally it
may provide an entry point for exonucleases involved in mRNA maturation,
turnover, and, in particular, transcriptional termination.
It is increasingly appreciated that the spatial organization of DNA in
the cell nucleus is a key contributor to genomic function. Simonis et
al. (2006) developed 4C technology (chromosome conformation capture
(3C)-on-chip), which allowed for an unbiased genomewide search for DNA
loci that contact a given locus in the nuclear space. They demonstrated
that active and inactive genes are engaged in many long-range
interchromosomal interactions and can also form interchromosomal
contacts. The active beta-globin locus in the mouse fetal liver
preferentially contacts transcribed, but not necessarily
tissue-specific, loci elsewhere on chromosome 7, whereas the inactive
locus in fetal brain contacts different transcriptionally silent loci. A
housekeeping gene in a gene-dense region on chromosome 8 of the mouse,
Rad23a (600061), formed long-range contacts predominantly with other
active gene clusters, both in cis and in trans, and many of these intra-
and interchromosomal interactions were conserved between the tissues
analyzed. The data demonstrated that chromosomes fold into areas of
active chromatin and areas of inactive chromatin and established 4C
technology as a powerful tool to study nuclear architecture.
Schoenfelder et al. (2010) found that mouse Hbb and Hba associated with
hundreds of active genes from nearly all chromosomes in nuclear foci
that they called 'transcription factories.' The 2 globin genes
preferentially associated with a specific and partially overlapping
subset of active genes. Schoenfelder et al. (2010) also noted that
expression of the Hbb locus is dependent upon Klf1 (600599), while
expression of the Hba locus is only partially dependent on Klf1.
Immunofluorescence analysis of mouse erythroid cells showed that most
Klf1 localized to the cytoplasm and nuclear Klf1 was present in discrete
sites that overlapped with RNAII foci. Klf1 knockout in mouse erythroid
cells specifically disrupted the association of Klf1-regulated genes
within the Hbb-associated network. Klf1 knockout more weakly disrupted
interactions within the specific Hba network. Schoenfelder et al. (2010)
concluded that transcriptional regulation involves a complex
3-dimensional network rather than factors acting on single genes in
isolation.
BIOCHEMICAL FEATURES
- Crystal Structure
Andersen et al. (2012) presented the crystal structure of the dimeric
porcine haptoglobin (140100)-hemoglobin complex determined at
2.9-angstrom resolution. This structure revealed that haptoglobin
molecules dimerize through an unexpected beta-strand swap between 2
complement control protein (CCP) domains, defining a new fusion CCP
domain structure. The haptoglobin serine protease domain forms extensive
interactions with both the alpha- and beta-subunits of hemoglobin,
explaining the tight binding between haptoglobin and hemoglobin. The
hemoglobin-interacting region in the alpha-beta dimer is highly
overlapping with the interface between the 2 alpha-beta dimers that
constitute the native hemoglobin tetramer. Several hemoglobin residues
prone to oxidative modification after exposure to heme-induced reactive
oxygen species are buried in the haptoglobin-hemoglobin interface, thus
showing a direct protective role of haptoglobin. The haptoglobin loop
previously shown to be essential for binding of haptoglobin-hemoglobin
to the macrophage scavenger receptor CD163 (605545) protrudes from the
surface of the distal end of the complex, adjacent to the associated
hemoglobin alpha-subunit. Small-angle x-ray scattering measurements of
human haptoglobin-hemoglobin bound to the ligand-binding fragment of
CD163 confirmed receptor binding in this area, and showed that the rigid
dimeric complex can bind 2 receptors.
MOLECULAR GENETICS
- Beta-Thalassemias
The beta-thalassemias were among the first human genetic diseases to be
examined by means of new techniques of recombinant DNA analysis. In
general, the molecular pathology of disorders resulting from mutations
in the nonalpha-globin gene region is the best known, this elucidation
having started with sickle cell anemia in the late 1940s. Steinberg and
Adams (1982) reviewed the molecular defects identified in thalassemias:
(1) gene deletion, e.g., of the terminal portion of the beta gene (Orkin
et al., 1979); (2) chain termination (nonsense) mutations (Chang and
Kan, 1979; Trecartin et al., 1981); (3) point mutation in an intervening
sequence (Spritz et al., 1981; Westaway and Williamson, 1981); (4) point
mutation at an intervening sequence splice junction (Baird et al.,
1981); (5) frameshift deletion (Orkin and Goff, 1981); (6) fusion genes,
e.g., the hemoglobins Lepore; and (7) single amino acid mutation leading
to very unstable globin, e.g., Hb Vicksburg (beta leu75-to-ter).
Since it had been shown by cDNA-DNA hybridization that some cases of
severe alpha-thalassemia result from deletion of all or most of the
alpha globin genes, Ottolenghi et al. (1975) applied similar techniques
to a study of whether beta genes were present in the forms of
beta-thalassemia with no synthesis of beta chains. They studied material
from persons heterozygous for beta-zero-thalassemia and
delta-beta-thalassemia and concluded that at least one of the haploid
genomes in this patient had a substantially intact beta globin gene. The
beta globin structural gene is intact in beta-zero-thalassemia (Kan et
al., 1975) but deleted in both hereditary persistence of fetal
hemoglobin (Kan et al., 1975) and delta-beta-thalassemia (Ottolenghi et
al., 1975); see 141749.
The possibility that the genetic lesions in beta-plus-thalassemia lie at
splicing sites within intervening sequences of the beta globin gene was
discussed by Maquat et al. (1980). Beta-zero-thalassemia is
heterogeneous. Some cases have absent beta-globin mRNA. Some have a
structurally abnormal beta-globin mRNA, usually in reduced amounts.
Baird et al. (1981) found a nucleotide change at the splice junction at
the 5-prime end of the large intervening sequence (IVS2) as the defect
in 3 cases (1 Italian; 2 Iranian).
In a family of Scottish-Irish descent, Pirastu et al. (1983) studied a
new type of gamma-delta-beta thalassemia. The proposita presented with
hemolytic disease of the newborn which was characterized by microcytic
anemia. Initial restriction enzyme analysis showed no grossly abnormal
pattern, but studies of polymorphic restriction sites and gene dosage
showed extensive deletion of the entire beta-globin cluster. In situ
hybridization with radioactive beta-globin gene probes showed that only
one 11p homolog contained the beta-globin gene cluster. Kazazian et al.
(1982) observed a similar extensive deletion in a Mexican family.
Cai and Kan (1990) demonstrated the usefulness of denaturing gradient
gel electrophoresis for detecting beta-thalassemia mutations and
suggested that it might be a useful nonradioactive means of detecting
mutations in other genetic disorders. Other methods are hybridization
with allele-specific oligonucleotide probes, ribonuclease or chemical
cleavage, and restriction endonuclease analysis. PCR greatly facilitated
implementation of all these detection methods.
Matsuno et al. (1992) invoked possible gene conversion at the chi
sequence near the 5-prime end of exon 2 (codons 31-34) as the
explanation for the finding of a beta-thalassemia mutation common in
southeast Asia (frameshift mutation in codons 41 and 42; see
141900.0326), as well as in Japan, on 2 different restriction frameworks
(haplotypes). They presumed that the 6 families found in Japan with this
particular mutation had inherited it from ancestors who had migrated to
Japan from southeast Asia.
By analysis of family data on 15 restriction site polymorphisms (RSPs),
Chakravarti et al. (1984) identified a 'hotspot' for meiotic
recombination at the 5-prime end of the beta gene. Recombination
leftward (in the 5-prime direction) from a point called chi near the end
of the beta-globin gene is 3 to 30 times the expected rate; in the use
of RSPs in prenatal diagnosis, it had been assumed that a marker 10 kb
from a mutant gene would recombine at a rate of 10(-5) per kb, leading
to a diagnostic error of 1 in 10,000. However, their data suggested the
error rate using 'loci' on opposite sides of chi may be as high as 1 in
312. By a computer search of the DNA sequences of the beta cluster, they
located a chi sequence (5-prime-GCTGGTGG-3-prime) at the 5-prime end of
the second intervening sequence of the beta gene. This chi sequence, a
promoter of generalized recombination in lambda phage, has been found in
high frequency in the mouse genome, especially in immunoglobulin DNA. A
recombinational hotspot has been found in the mouse major
histocompatibility complex.
In a large Amish pedigree, Gerhard et al. (1984) observed an apparent
crossover within the beta-globin gene cluster in the region of the
recombinational 'hotspot' postulated by Chakravarti et al. (1984) on the
basis of linkage disequilibrium in population data. It was also possible
to identify the orientation of the beta-globin cluster vis-a-vis the
centromere: cen--5-prime--epsilon--beta--3-prime--pter.
Camaschella et al. (1988) identified recombination between 2 paternal
chromosomes in a region 5-prime to the beta gene, previously indicated
to contain a 'hotspot' for recombination. The recombination was
identified because in the course of prenatal diagnosis by linkage to
RFLPs, a homozygous beta-thalassemia fetus was misdiagnosed as
beta-thalassemia trait.
In the course of studying an Irish family with beta-thalassemia due to
the Q39X mutation in the HBB gene (141900.0312), Hall et al. (1993)
found a fourth case of recombination in the beta-globin gene cluster.
The event had occurred 5-prime of the polymorphic RsaI site at position
-550 bp upstream of the beta-globin gene mRNA cap site, within the
9.1-kb region shown to be a hotspot for recombination.
Huang et al. (1986) reported the same 'TATA' box mutation leading to the
same nondeletion form of beta-thalassemia in Chinese as had been
reported in American blacks by Antonarakis et al. (1984); see
141900.0379. There are other illustrations indicating that mutations in
the beta-globin gene can recur.
Orkin et al. (1982) developed and applied a new strategy for the
comprehensive analysis of existing mutations in a class of human
disease. They combined analysis of various restriction enzyme
polymorphisms in the beta-globin gene cluster with direct examination of
beta-globin structural genes in Mediterranean persons with
beta-thalassemia. The approach was prompted by the finding that specific
mutant genes are strongly linked to patterns of restriction site
polymorphism (haplotypes) in this region of the genome. They isolated 8
different mutant genes among the 9 different haplotypes represented in
Mediterraneans. Seven of the 8 genes were present in Italians from
various locales in Italy, and 6 in Greeks. Several were previously
unknown mutations, and 1 of these possibly affects transcription. The
strategy is probably applicable to the analysis of heterogeneity in
other diseases of single-copy genes. When linkage analysis can be
performed in the family, the haplotype analysis will be highly useful in
prenatal diagnosis of beta-thalassemia. Indeed, the method of
haplotyping proved highly useful both in tracing the origin of mutations
and in family studies (see Antonarakis et al., 1982). Losekoot et al.
(1992) described a method for rapid detection of beta-globin haplotypes
(referred to by them as framework) by denaturing gradient gel
electrophoresis.
Rosatelli et al. (1987) analyzed the molecular defect in 494 Sardinian
beta-thalassemia heterozygotes. The most prevalent mutation, accounting
for 95.4% of cases, was the nonsense mutation at codon 39 (141900.0312).
The remainder, in decreasing order of frequency, were a frameshift at
codon 6 (2.2%), beta-plus IVS1, nucleotide 110 (0.4%), and beta-plus
IVS2, nucleotide 745 (0.4%). The DNA sequences along the human
beta-globin cluster are highly polymorphic; over 20 polymorphic
restriction endonuclease sites have been described in this 60-kb region.
RFLP haplotypes have been useful in defining various thalassemia
lesions, such as deletions, for prenatal diagnosis of beta-thalassemia,
and for tracing the origin and migration of mutant genes.
Pirastu et al. (1987) found that the predominant beta-thalassemia in
Sardinia, the beta-zero type due to nonsense mutation (CAG-to-TAG) at
beta-39 (141900.0312), resides on 9 different chromosome haplotypes. One
of the haplotypes included a cytosine-to-thymine point mutation 196
nucleotides upstream from the A-gamma-globin gene (142200.0027). The
gamma-A mutation at position -196 is associated with high levels of
production of fetal hemoglobin. The beta-39 nonsense mutation may have
gotten onto the -196 chromosome through crossing-over. A chromosome
carrying such a double mutation could be expected to impart selective
advantage because the beta-thalassemia would protect against malaria
while the increased gamma-globin production would ameliorate the
severity of the beta-thalassemia. A similar mechanism may have been
operative in the case of another haplotype which combined the beta-39
nonsense mutation with triple gamma loci produced by the addition of a
second G-gamma-globin gene. Pirastu et al. (1987) proposed a schema by
which the findings were explained by a single initial mutation with
subsequent crossovers between the 5-prime and 3-prime blocks of genes
producing 6 other chromosomes and then the creation of 2 others by
crossing-over and gene conversion. Additional diversity could have
arisen through other beta-39 mutations. The mutation identified in a
family of northern European origin by Chehab et al. (1986) was of this
type.
Direct sequencing of specific regions of genomic DNA became feasible
with the invention of PCR, which permits amplification of specific
regions of DNA (Church and Gilbert, 1984; Saiki et al., 1986). For
example, Wong et al. (1986) amplified human mitochondrial DNA and
sequenced it directly. Wong et al. (1987) applied a combination of PCR
and direct sequence analysis of the amplified product to the study of
beta-thalassemia in 5 patients whose mutant alleles had not been
characterized. They found 2 previously undescribed mutations along with
3 previously known ones. One new allele was a frameshift at codons
106-107 and the other was an A-to-C transversion at the cap site (+1) of
the beta-globin gene. The latter was the first natural mutation observed
at the cap site (141900.0387).
In a study of beta-thalassemia in Spain, Amselem et al. (1988)
demonstrated the usefulness of the dot-blot hybridization of
PCR-amplified genomic DNA in both rapid population surveys and prenatal
diagnosis. They found 7 different beta-thalassemia mutations. The
nonsense codon 39 accounted for 64%, whereas the IVS1 position 110
mutation (141900.0364), the most common cause of beta-thalassemia in the
eastern part of the Mediterranean basin, was underrepresented (8.5%).
The IVS1 mutation at position 6 (141900.0360) accounted for 15% of the
defects and led to a more severe form of beta(+)-thalassemia than
originally described in most patients with this mutation.
Diaz-Chico et al. (1988) described 2 families, 1 Yugoslavian and 1
Canadian, with heterozygous thalassemia characterized by mild anemia
with severe microcytosis and hypochromia, normal levels of hemoglobin
A(2), and slightly raised hemoglobin F levels. In both families the
condition resulted from large deletions which included all functional
and pseudogenes of the beta-globin gene cluster. The deletion was at
least 148 kb in the Yugoslavian family and 185 kb in the Canadian
family.
Aulehla-Scholz et al. (1989) described a deletion comprising about 300
basepairs in a female heterozygote, resulting in loss of exon 1, part of
IVS1, and the 5-prime beta-globin gene promoter region.
Laig et al. (1989) identified new beta-thalassemia mutations in northern
and northeastern Thailand.
Rund et al. (1991) studied beta-thalassemia among Kurdistan Jews. They
identified 13 distinct mutations among 42 sibships, of which 3 were
previously undescribed. Four of the mutations (see 141900.0331,
141900.0341, 141900.0373, 141900.0383) were unique to Kurdish Jews and
two-thirds of the mutant chromosomes carried the mutations unique to
Kurdish Jews. Haplotype and geographic analyses suggested that
thalassemia in central Kurdistan has evolved from multiple mutational
events. Genetic admixture with the local population appears to be the
primary mechanism of the evolution of thalassemia in Turkish Kurdistan,
whereas there is evidence for a founder effect in Iranian Kurdistan.
Huang et al. (1990) used DNA from dried blood specimens amplified by PCR
to study the distribution of beta-thalassemia mutations in southern,
western, and eastern China.
As indicated by the work of Villegas et al. (1992), Oron et al. (1994),
and Traeger-Synodinos et al. (1996), thalassemia intermedia is caused by
interaction between a triplicated alpha-globin locus (leading to
alpha-globin overproduction) and beta-thalassemia heterozygosity.
Traeger-Synodinos et al. (1996) reported 3 cases of beta-thalassemia
heterozygosity with homozygous alpha-globin gene triplication and 17
beta-thalassemia heterozygotes with a single additional alpha-globin
gene. Garewal et al. (1994) likewise reported 2 patients with a clinical
presentation of thalassemia intermedia due to homozygosity for
alpha-gene triplication and heterozygosity for an HBB gene mutation.
Landin et al. (1996) noted that 34 of 316 beta-globin variants due to
single amino acid substitutions could be caused by more than 1 type of
point mutation at the DNA level. They also noted that 3 beta-globin
variants (Hb Edmonton, Hb Bristol, and Hb Beckman) and 1 alpha-globin
variant (Hb J-Kurosh) could not be produced by a single nucleotide
substitution; 2 substitutions were required.
Several hemoglobin variants were first detected in the course of study
of glycated hemoglobin (HbA1c) in diabetics, e.g., 141900.0429 and
141900.0477. The alternative situation, diagnosis of diabetes during the
performance of hemoglobin electrophoresis for study of anemia, was
observed by Millar et al. (2002).
Sierakowska et al. (1996) found that treatment of mammalian cells stably
expressing the IVS2-654 beta HBB gene (141900.0348) with antisense
oligonucleotides targeted at the aberrant splice sites restored correct
splicing in a dose-dependent fashion, generating correct human
beta-globin mRNA and polypeptide. Both products persisted for up to 72
hours after treatment. The oligonucleotides modified splicing by a true
antisense mechanism without overt unspecific effects on cells growth and
splicing of other pre-mRNAs. This novel approach in which antisense
oligonucleotides are used to restore rather than to downregulate the
activity of the target gene is applicable to other splicing mutants and
is of potential clinical interest.
- Erythrocytosis
Huisman et al. (1996) listed (in their Table 6B) 38 HBB variants causing
erythrocytosis, plus 20 others causing mild erythrocytosis and 1 causing
erythrocytosis in combination with hemolysis. (Some authors, Boyer et
al. (1972), Charache et al. (1975), and Brennan et al. (1982), use
polycythemia rather than erythrocytosis as the designation for the
compensatory increase in red blood cell mass that accompanies
hemoglobins with increased oxygen affinity. The 2 terms must be
considered synonymous. Some, e.g., Hamilton et al. (1969), use
erythremia. Although also a synonym of polycythemia and erythrocytosis,
erythemia has become essentially obsolete.)
- Hereditary Persistence of Fetal Hemoglobin
Part of the mutational repertoire of the beta-globin locus is hereditary
persistence of fetal hemoglobin (HPFH; 141749) due to deletion. Two
types (types I and II) occur in blacks and have as their basis deletion
of the delta and beta loci. An Italian type and an Indian type are
likewise deletion forms of HPFH; see review by Saglio et al. (1986). In
2 Italian brothers with a G-gamma/A-gamma form of hereditary persistence
of fetal hemoglobin, Camaschella et al. (1990) demonstrated a deletion
starting 3.2 kb upstream from the delta gene and ending within the
enhancer region 3-prime to the beta-globin gene. The deletion removed 1
of the 4 binding sites for an erythroid specific transcriptional factor
(NF-E1). It appeared that the residual enhancer element, relocated near
gamma genes, may increase fetal hemoglobin expression.
- Delta-Beta Thalassemia
In the so-called Corfu form of delta-beta-thalassemia, Kulozik et al.
(1988) found that a deletion removed 7,201 basepairs containing part of
the delta-globin gene and sequences upstream. The beta-globin gene
contained a G-to-A mutation at position 5 in IVS1. The gamma-globin gene
promoters were normal. In transfected HeLa cells, a normal message was
produced from the mutated beta-globin gene at a level of approximately
20% of the normal, the remaining 80% being spliced at cryptic sites in
exon 1 and intron 1. This indicated that the mutation in the beta-globin
gene is not the sole cause of the complete absence of hemoglobin A in
this form of thalassemia. Kulozik et al. (1988) concluded that the
7.2-kb deletion contains sequences necessary for the normal activation
of the beta-globin gene. In the homozygous state there is complete
absence of hemoglobin A and hemoglobin A(2) and a high level of
hemoglobin F. Traeger-Synodinos et al. (1991) gave further data on the
Corfu mutation.
- Protection Against Malaria
Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
subjects and transmission experiments involving 60 children and over
6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
variants HbC (141900.0038) and HbS (141900.0243), which are protective
against malaria, are associated with transmission of the parasite from
the human host to the Anopheles mosquito vector. They found that HbC and
HbS were associated with significant 2-fold in vivo (p = 1.0 x 10(-6))
and 4-fold ex vivo (p = 7.0 x 10(-5)) increases of parasite transmission
from host to vector. Gouagna et al. (2010) concluded that human genetic
variation at the HBB locus can influence the efficiency of malaria
transmission, possibly by promoting sexual differentiation of P.
falciparum as a downstream phenotypic event. Alternatively, Gouagna et
al. (2010) suggested that the higher infectivity of individuals with HBB
variants in their study could be due to less frequent use of
antimalarial drugs. In a commentary, Pasvol (2010) noted that little is
known regarding the mechanisms involved in switching from the parasite
asexual stages to the induction of gametogenesis, but that the
hemoglobinopathies may provide a scenario beneficial to both host and
parasite.
- Reviews
Kazazian and Boehm (1988) gave an update on the variety of
beta-thalassemias. Large deletions are a rare cause of beta-thalassemia;
as of early 1989, 63 single nucleotide substitutions or small deletions
and 7 large deletions had been described as the basis of
beta-thalassemia (Kazazian, 1989).
Huisman (1990) provided a list of over 110 different beta-thalassemia
alleles, most of them of the nondeletional type.
Huisman (1992) edited an up-to-date listing of the deletions, mutations,
and frameshifts leading to beta-thalassemia, which had been published 3
times previously, and added a new table on the delta-thalassemias,
prepared by Erol Baysal. Kazazian et al. (1992) tabulated a total of 9
beta-globin mutations producing dominant thalassemia-like phenotypes.
Widespread ethnic derivation was demonstrated.
Krawczak et al. (1992) reviewed the mutational spectrum of single
basepair substitutions in mRNA splice junctions on the basis of 101
different examples of point mutations occurring in the vicinity of
splice junctions and held to be responsible for human genetic disease.
The data comprised 62 mutations at 5-prime splice sites, 26 at 3-prime
splice sites, and 13 that resulted in the creation of novel splice sites
such as HbE. They estimated that up to 15% of all point mutations
causing human genetic disease result in an mRNA splicing defect.
Carver and Kutlar (1995) listed 323 beta-chain variants as of January
1995. This number did not include beta-chain variants with deletions
and/or insertions or those with extended polypeptide chains. Baysal and
Carver (1995) provided an update (eighth edition) of their catalog, or
repository, of beta-thalassemia and delta-thalassemia.
Huisman et al. (1996) provided a syllabus of human hemoglobin variants
listing the characteristics as well as precise molecular change of known
beta-globin mutants; these numbered 335 single-base mutations and 17
variants with 2 amino acid replacements as of January 1996. They also
included hemoglobin variants resulting from fusion of parts of the
beta-chain and delta-chain, variants with elongated beta-chains at both
the C-terminal and N-terminal ends, and variants with small deletions
and/or insertions in the beta-chain. Not included were deletions and
mutations that result in beta-thalassemia, even if such a change, point
mutation, or frameshift occurred in one of the coding regions of the HBB
gene. Information regarding these abnormalities were provided elsewhere,
e.g., Baysal and Carver (1995).
Huisman et al. (1996) stated that 138 of the 146 codons of the HBB gene
have been mutated; 5 mutations are known for 6 codons (22, 67, 97, 121,
143, and 146), 6 mutations for codon 92, and 7 mutations for codon 99.
Most of the mutations have been deduced from the sequence of the amino
acid sequence of the variant protein and the known sequence of the HBB
gene; slightly more than 10% of the mutations have been determined
through DNA sequencing. Occasionally discrepancy was observed, such as
at position 50 and 67 of the beta-globin chain.
- Database of Hemoglobin Variants
Hardison et al. (2002) constructed a web-accessible relational database
of hemoglobin variants and thalassemia mutations called HbVar, in which
old and new data are incorporated. Queries can be formulated based on
fields in the database. For example, tables of common categories of
variants, such as all variants involving the HBA1 gene (141800) or all
those that result in high oxygen affinity, can be assembled. More
precise queries are possible, such as 'all beta-globin variants
associated with instability and found in Scottish populations.'
- Locus Control Region Beta
Cases of gamma-delta-beta thalassemia are known in which the beta gene
is intact but deletion 'in cis' occurs upstream, even at a distance, in
a region designated LCRB. In a remarkable case reported by Curtin et al.
(1985), a deletion extended from the third exon of the G-gamma gene
upstream for about 100 kb. The A-gamma, pseudo-beta, delta, and beta
genes in cis were intact. This malfunction of the beta-globin gene on a
chromosome in which the deletion is located 25 kb away suggests that
chromatin structure and conformation are important for globin gene
expression. In experiments in which the human beta-globin locus was
introduced into the mouse genome, Talbot et al. (1989) found a 6.5-kb
control region which allowed achievement of endogenous levels of
beta-globin expression. The control region included an erythroid
cell-specific DNase I hypersensitive site (HS). Using pulsed field gel
electrophoresis and PCR, Driscoll et al. (1989) found, in a case of
gamma-delta-beta-thalassemia, a de novo deletion on a maternally
inherited chromosome 11 involving about 30 kb of sequences 5-prime to
the epsilon gene. The deletion extended from -9.5 kb to -39 kb 5-prime
of epsilon and included 3 of the 4 DNase I hypersensitive sites (at
-10.9 kb, -14.7 kb, and -18 kb 5-prime of epsilon). The remaining
sequences of the beta-globin complex, including the DNase I
hypersensitive sites at -6.1 kb and all structural genes in cis to the
deletion, were physically intact. Again, a significance of the
hypersensitive sites in regulating globin-gene expression was
demonstrated.
Epsilon-gamma-delta-beta-thalassemias are all caused by deletions of the
beta-globin gene cluster on 11p. At the molecular level, the deletions
fall into 2 categories: group I removes all or a greater part of the
beta-globin cluster, including the beta-globin gene; group II removes
extensive upstream regions leaving the beta-globin gene itself intact
despite which its expression is silenced because of inactivation of the
upstream beta-locus control region. A group I deletion was reported by
Curtin et al. (1985). A group I deletion was reported in a Chilean
family by Game et al. (2003), and an upstream deletion (group II) was
reported in a Dutch family by Harteveld et al. (2003). Rooks et al.
(2005) described 3 novel epsilon-gamma-delta-beta-thalassemia deletions
in 3 English families, referred to as English II, III, and IV to
distinguish them from the family of Curtin et al. (1985), which was also
English (I). Two of the deletions removed the entire beta-globin gene
complex, including a variable number of flanking olfactory receptor
genes.
The significance of the hypersensitive sites to globin gene expression
had also been demonstrated by Grosveld et al. (1987) who achieved high
levels of position-independent beta-gene expression in transgenic mice
with a specially constructed beta-globin minilocus in which 5-prime and
3-prime hypersensitive sequences flanked a beta-globin gene. The
hypersensitive sequences, termed locus-activating regions (LARs), are
erythroid-tissue-specific and developmentally stable. Curtin et al.
(1989) performed experiments similar to those of Grosveld et al. (1987)
with like results. (A similar positive control region for the cluster of
alpha-globin genes was deduced by Hatton et al. (1990) on the basis of
deletion in a case of alpha-thalassemia; see 141800.) See 187550 for
evidence of an unlinked remote regulator of HBB gene expression. Townes
and Behringer (1990) reviewed the topic of the locus activating region.
They presented a model for developmental control of human globin gene
expression (see their Figure 2). With respect to the cap site of the
human epsilon-globin gene, LAR site I is located at position -6.1 kb;
site II, at -10.9 kb; site III, at -14.7 kb; and site IV, at -18 kb.
Moon and Ley (1990) cloned murine DNA sequences homologous to the human
LAR site II. These sequences are linked to the mouse beta-globin gene
cluster in the same basic arrangement as the human beta-globin gene
cluster. Furthermore, the 2 LARs share 70% identical sequence and
several enhancer-type functions. LAR sequences are almost certainly not
confined to the human beta-globin locus. The investigators stated that
these sequences may be critical components of any gene family that
comprises multiple members that are regulated differently during
development.
Perichon et al. (1993) demonstrated interethnic polymorphism of 1
segment of the LCRB region in sickle cell anemia patients. Distinct
polymorphic patterns of a simple sequence repeat were observed in strong
linkage disequilibrium with each of the 5 major beta-S haplotypes.
Studies by Grosveld et al. (1987) and by Blom van Assendelft et al.
(1989) established that 6 DNase I hypersensitive sites flank the globin
genes. One HS site is located 20 kb downstream of the beta-globin
cluster and 5 HS sites are located 6-22 kb upstream within the locus
control region (LCR). Peterson et al. (1996) examined the effects of
deletion of the LCR 5-prime HS3 element and the 5-prime HS2 element on
globin gene expression by recombining a 2.3-kb deletion of 5-prime HS3
or a 1.9-kb deletion of 5-prime HS2 into a beta-globin locus YAC, which
was then used to produce transgenic mice. When the LCR 5-prime HS3
element is deleted there is decreased expression of epsilon-globin in
the yolk sac. Deletion of 5-prime HS2 resulted in a minor but
statistically significant decrease in epsilon-, gamma-, and beta-globin
expression. From these results Peterson et al. (1996) concluded that
there is functional redundancy among the HS sites. The effects of the
5-prime HS3 deletion on epsilon-globin gene expression led them to
conclude that specific interactions between the HSs and the globin genes
underlie activation of globin genes during specific stages of
development.
Epner et al. (1998) deleted the murine beta-globin LCR from its native
chromosomal location. The approximately 25-kb deletion eliminated all
sequences and structures homologous to those defined as the human LCR.
In differentiated embryonic stem cells and erythroleukemia cells
containing the LCR-deleted chromosome, DNase I sensitivity of the
beta-globin domain was established and maintained, developmental
regulation of the locus was intact, and beta-like globin RNA levels were
reduced 5 to 25% of normal. Thus, in the native murine beta-globin
locus, the LCR was necessary for normal levels of transcription, but
other elements were sufficient to establish the open chromatin
structure, transcription, and developmental specificity of the locus.
These findings suggest a contributory rather than dominant function for
the LCR in its native location.
Bauchwitz and Costantini (2000) quantified the effects of beta-globin
sequence modifications on epsilon-, gamma-, and delta-globin levels in
transgenic mice. Embryonic day 11.5 primitive erythroid cells showed a
large increase in epsilon-globin in the absence of the beta-globin gene,
which is weakly expressed at that stage of development. Embryonic day
17.5 fetal liver and adult erythroid cells, in which beta-globin
expression approaches its maximum, showed only a small stimulation of
gamma- and delta-globin levels in the absence of beta-globin sequence.
Analysis of erythroid colonies produced by in vitro differentiation of
embryonic stem cells indicated that the absence of the human beta-globin
gene had no effect on gamma-globin expression. The authors concluded
that competitive influences need not be linked directly to
transcriptional level or distance from the LCR, and that the large
increases in gamma-globin levels seen in some human deletional
beta-thalassemias and hereditary persistence of fetal hemoglobin
conditions are most likely due to effects other than loss of beta-globin
competition. In transgenic mice with beta-globin sequences inserted
between epsilon and the LCR in a beta-locus, the expression of epsilon-,
gamma-, and delta-globins suggested that stage-specific sensitivity to
loss of LCR activity may be a more important parameter than position
relative to the LCR.
Alami et al. (2000) created a yeast artificial chromosome containing an
unmodified human beta-globin locus, and introduced it into transgenic
mice at various locations in the genome. The locus was not subject to
detectable stable position effects but did undergo mild-to-severe
variegating position effects at 3 of the 4 noncentromeric integration
sites tested. The distance and the orientation of the LCR relative to
the regulated gene contributed to the likelihood of variegating position
effects, and affected the magnitude of its transcriptional enhancement.
DNaseI hypersensitive site (HSS) formation varied with the proportion of
expressing cells (variegation), rather than the level of gene
expression, suggesting that silencing of the transgene may be associated
with a lack of HSS formation in the LCR region. The authors concluded
that transcriptional enhancement and variegating position effects are
caused by fundamentally different but interdependent mechanisms.
Navas et al. (2002) generated transgenic mouse lines carrying a
beta-globin locus YAC lacking the LCR to determine if the LCR is
required for globin gene activation. Beta-globin gene expression was
analyzed by RNase protection, but no detectable levels of epsilon-,
gamma-, and beta-globin gene transcripts were produced at any stage of
development. Lack of gamma-globin gene expression was also seen in a
beta-YAC transgenic mouse carrying a gamma-globin promoter mutant that
causes hereditary persistence of fetal hemoglobin (see 142200.0026) and
an HS3 core deletion that specifically abolishes gamma-globin gene
expression during definitive erythropoiesis. The authors concluded that
the presence of the LCR is a minimum requirement for globin gene
expression.
Navas et al. (2003) assessed the contribution of the GT6 motif within
HS3 of the LCR on downstream globin gene expression by mutating GT6 in a
beta-globin locus YAC and measuring the activity of beta-globin genes in
GT6-mutated beta-YAC transgenic mice. They found reduced expression of
epsilon- and gamma-globin genes during embryonic erythropoiesis. During
definitive erythropoiesis, gamma-globin gene expression was
significantly reduced while beta-globin gene expression was virtually
indistinguishable from that of wildtype controls. Navas et al. (2003)
concluded that the GT6 motif is required for normal epsilon- and
gamma-globin gene expression during embryonic erythropoiesis and for
gamma-globin gene expression during definitive erythropoiesis in the
fetal liver.
Bottardi et al. (2005) noted that abnormal epigenetic regulation of gene
expression contributes significantly to a variety of human pathologies
including cancer. Deletion of HS2 at the human beta-globin locus control
region can lead to abnormal epigenetic regulation of globin genes in
transgenic mice. The authors used 2 HS2-deleted transgenic mouse lines
as a model to demonstrate that heritable alteration of chromatin
organization at the human beta-globin locus in multipotent hematopoietic
progenitors can contribute to the abnormal expression of the beta-globin
gene in mature erythroid cells. This alteration was characterized by
specific patterns of histone covalent modifications that were inherited
during erythropoiesis and, moreover, was plastic because it could be
reverted by transient treatment with a histone deacetylase inhibitor.
Bottardi et al. (2005) concluded that aberrant epigenetic regulation can
be detected and modified before tissue-specific gene transcription.
- Note Regarding the Allelic Variants Section
In the allelic variants listed below, as well as in the allelic variants
listed under the other globin genes, the codon count begins with the
first amino acid of the mature protein because a large portion of the
variants were characterized on the basis of a protein rather than the
gene itself. It is more customary for the count to begin with the
methionine initiator codon as number one. Thus, the HbS mutation
(141900.0243) is designated glu6-to-val; in the gene based system of
counting now used, it would be designated glu7-to-val. Some
inconsistency is represented by the fact that some initiator mutations
in the globin genes are indicated by a system counting from the
initiator methionine; e.g., beta-thalassemia due to met1-to-ile
(141900.0430).
ANIMAL MODEL
Ciavatta et al. (1995) created a mouse model of beta-zero-thalassemia by
targeted deletion of both adult beta-like globin genes, beta(maj) and
beta(min), in mouse embryonic stem cells. Heterozygous animals derived
from the targeted cells were severely anemic with dramatically reduced
hemoglobin levels, abnormal red cell morphology, splenomegaly, and
markedly increased reticulocyte counts. Homozygous animals died in
utero; however, heterozygous mice were fertile and transmitted the
deleted allele to progeny. The anemic phenotype was completely rescued
in progeny derived from mating beta-zero-thalassemic animals with
transgenic mice expressing high levels of human hemoglobin A. The
authors suggested that beta-zero-thalassemic mice could be used to test
genetic therapy for beta-zero-thalassemia and could be bred with
transgenic mice expressing high levels of hemoglobin S to produce an
improved mouse model of sickle cell disease.
Hemoglobin disorders were among the first to be considered for gene
therapy. Transcriptional silencing of genes transferred into
hematopoietic stem cells, however, posed one of the most significant
challenges to its success. If the transferred gene is not completely
silenced, a progressive decline in gene expression as mice age often is
encountered. These phenomena were observed to various degrees in mouse
transplant experiments using retroviral vectors containing a human
beta-globin gene, even when cis-linked to locus control region
derivatives. Kalberer et al. (2000) investigated whether ex vivo
preselection of retrovirally transduced stem cells on the basis of
expression of the green fluorescent protein driven by the CpG island
phosphoglycerate kinase (311800) promoter could ensure subsequent
long-term expression of a cis-linked beta-globin gene in the erythroid
lineage of transplanted mice. They observed that 100% of 7 mice
engrafted with preselected cells concurrently expressed human
beta-globin and green fluorescent protein in 20 to 95% of their red
blood cells for up to 9.5 months posttransplantation, the longest time
point assessed. This expression pattern was successfully transferred to
secondary transplant recipients. In the presence of the beta-locus
control region hypersensitivity site 2 alone, human beta-globin mRNA
expression levels ranged from 0.15 to 20% with human beta-globin chains
detected by HPLC. Neither the proportion of positive blood cells nor the
average expression levels declined with time in translated recipients.
Persons and Nienhuis (2000) discussed the background of the work by
Kalberer et al. (2000), including position effect variegation (PEV).
Both PEV and silencing mechanisms may act on a transferred globin gene
residing in chromatin outside of the normal globin locus during the
important terminal phases of erythroblast development when globin
transcripts normally accumulate rapidly despite heterochromatization and
shutdown of the rest of the genome.
HISTORY
By autoradiography using heavy-labeled hemoglobin-specific messenger
RNA, Price et al. (1972) found labeling of a chromosome 2 and a group B
chromosome. They concluded, incorrectly as it turned out, that the
beta-gamma-delta linkage group was on a group B chromosome since the
zone of labeling was longer on that chromosome than on chromosome 2
(which by this reasoning was presumed to carry the alpha locus or loci).
Study of a case of the Wolf-Hirschhorn syndrome (4p-) suggested that the
B group chromosome involved is chromosome 4. Barbosa et al. (1975)
excluded a recombination fraction of less than 0.30 for MN and Hb-beta.
McCurdy et al. (1975) thought the beta locus in some persons might be
duplicated; they observed a black woman who had hemoglobin A and 2
different variant hemoglobins, each with a beta-globin change. One of
these, however, proved to be a posttranslational change (Charache et
al., 1977). El-Hazmi et al. (1986) suggested that the presence of 2
beta-globin genes might account for the finding of triple HpaI fragments
in a case of sickle cell anemia. They explained its origin by unequal
crossing-over.
Housman et al. (1979) used a panel of hybrid hamster-human cells deleted
by x-ray and selected by a double antibody technique (the method of Kao,
Jones, and Puck) to assign the NAG cluster to 11p12, between LDHA
distally and ACP2 proximally. The orientation of the cluster in relation
to the centromere was not known.
Although some workers have put the insulin (176730), beta-globin, and
HRAS (190020) genes on 11p15, Chaganti et al. (1985) located these
differently by in situ hybridization to meiotic chromosomes: INS,
11p14.1; HRAS, 11p14.1; HBB, 11p11.22; and PTH (not previously
assigned), 11p11.21.
OR51B4
| dbSNP name | rs62000994(C,T); rs10837771(A,G); rs7118113(C,T); rs61739194(T,C) |
| ccdsGene name | CCDS7757.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 79339 |
| EntrezGene Description | olfactory receptor, family 51, subfamily B, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51B4:NM_033179:exon1:c.G553A:p.A185T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y5P0 |
| dbNSFP Uniprot ID | O51B4_HUMAN |
| dbNSFP KGp1 AF | 0.0352564102564 |
| dbNSFP KGp1 Afr AF | 0.146341463415 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03535 |
| ESP Afr MAF | 0.138346 |
| ESP All MAF | 0.048553 |
| ESP Eur/Amr MAF | 0.00256 |
| ExAC AF | 0.014 |
OR51B2
| dbSNP name | rs7934105(C,T); rs7933257(G,A); rs11036814(A,C); rs11036815(G,A); rs10742622(T,C); rs10768793(A,G); rs7937237(C,G); rs10837814(G,A); rs7952293(A,G); rs4910750(G,A) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 79345 |
| snpEff Gene Name | HBE1 |
| EntrezGene Description | olfactory receptor, family 51, subfamily B, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2452 |
| ESP Afr MAF | 0.196141 |
| ESP All MAF | 0.124033 |
| ESP Eur/Amr MAF | 0.087433 |
| ExAC AF | 0.834 |
OR51B6
| dbSNP name | rs4910755(A,C); rs4910756(A,G); rs10837882(T,A); rs77135024(G,A); rs7483122(T,C); rs77989044(T,C); rs5006887(C,T); rs5006885(T,G); rs5006884(C,T); rs115333544(C,A); rs5006883(T,C); rs5006882(A,G); rs7106330(G,C); rs5024042(C,A); rs5024041(T,C) |
| ccdsGene name | CCDS31379.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390058 |
| EntrezGene Description | olfactory receptor, family 51, subfamily B, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51B6:NM_001004750:exon1:c.A14C:p.K5T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H340 |
| dbNSFP Uniprot ID | O51B6_HUMAN |
| dbNSFP KGp1 AF | 0.216117216117 |
| dbNSFP KGp1 Afr AF | 0.325203252033 |
| dbNSFP KGp1 Amr AF | 0.24861878453 |
| dbNSFP KGp1 Asn AF | 0.0524475524476 |
| dbNSFP KGp1 Eur AF | 0.253298153034 |
| dbSNP GMAF | 0.2144 |
| ESP Afr MAF | 0.294866 |
| ESP All MAF | 0.274392 |
| ESP Eur/Amr MAF | 0.263905 |
| ExAC AF | 0.239,3.579e-04,8.134e-06 |
OR51M1
| dbSNP name | rs116535306(G,T); rs1498467(T,G); rs74683499(C,T); rs1498468(C,T); rs114517600(C,T); rs1498469(T,C); rs9783355(C,A); rs2736531(T,G); rs10768906(G,A); rs10768907(T,C); rs116479174(A,G) |
| ccdsGene name | CCDS53596.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390059 |
| EntrezGene Description | olfactory receptor, family 51, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51M1:NM_001004756:exon1:c.G18T:p.S6S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01056 |
| ESP Afr MAF | 0.040155 |
| ESP All MAF | 0.013288 |
| ESP Eur/Amr MAF | 0.000727 |
| ExAC AF | 3.562e-03,7.353e-05,7.353e-05 |
OR51Q1
| dbSNP name | rs2736590(G,C); rs2736588(C,T); rs2736587(T,C); rs10838092(C,T); rs10838093(T,C); rs10838094(G,A); rs10838095(G,A); rs2736586(G,A); rs2647574(C,T); rs2647573(T,C) |
| ccdsGene name | CCDS31381.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390061 |
| EntrezGene Description | olfactory receptor, family 51, subfamily Q, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51Q1:NM_001004757:exon1:c.G12C:p.V4V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4619 |
| ESP Afr MAF | 0.360064 |
| ESP All MAF | 0.381964 |
| ESP Eur/Amr MAF | 0.393181 |
| ExAC AF | 0.431 |
OR51I1
| dbSNP name | rs77336780(C,G); rs1498486(C,A); rs11037444(G,A); rs138147374(C,T); rs11037445(C,G); rs114245652(A,G); rs16930982(C,T); rs151279140(T,C); rs16930998(G,A) |
| ccdsGene name | CCDS31382.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390063 |
| EntrezGene Description | olfactory receptor, family 51, subfamily I, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51I1:NM_001005288:exon1:c.G911C:p.G304A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H343 |
| dbNSFP Uniprot ID | O51I1_HUMAN |
| dbNSFP KGp1 AF | 0.0805860805861 |
| dbNSFP KGp1 Afr AF | 0.0630081300813 |
| dbNSFP KGp1 Amr AF | 0.0662983425414 |
| dbNSFP KGp1 Asn AF | 0.148601398601 |
| dbNSFP KGp1 Eur AF | 0.0474934036939 |
| dbSNP GMAF | 0.08081 |
| ESP Afr MAF | 0.092458 |
| ESP All MAF | 0.059172 |
| ESP Eur/Amr MAF | 0.042122 |
| ExAC AF | 0.066 |
OR51I2
| dbSNP name | rs2030094(G,T); rs12577167(A,G); rs11037502(G,A) |
| ccdsGene name | CCDS31383.1 |
| CosmicCodingMuts gene | OR51I2 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390064 |
| EntrezGene Description | olfactory receptor, family 51, subfamily I, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR51I2:NM_001004754:exon1:c.G120T:p.G40G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4063 |
| ESP Afr MAF | 0.466379 |
| ESP All MAF | 0.49269 |
| ESP Eur/Amr MAF | 0.493833 |
| ExAC AF | 0.448,5.692e-05,8.132e-06 |
OR52D1
| dbSNP name | rs417425(A,G); rs404280(C,T); rs2467219(T,C); rs7950082(A,T); rs444878(T,C); rs392296(G,A) |
| ccdsGene name | CCDS31384.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390066 |
| EntrezGene Description | olfactory receptor, family 52, subfamily D, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52D1:NM_001005163:exon1:c.A348G:p.S116S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.06152 |
| ESP Afr MAF | 0.05702 |
| ESP All MAF | 0.038858 |
| ESP Eur/Amr MAF | 0.029556 |
| ExAC AF | 0.969 |
UBQLNL
| dbSNP name | rs1044392(A,G); rs151315992(G,A); rs10769023(C,T); rs393044(A,C); rs2017433(G,A); rs2017434(A,G); rs872751(T,G); rs2047456(A,G); rs7933557(T,A) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 143630 |
| EntrezGene Description | ubiquilin-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4353 |
OR52H1
| dbSNP name | rs7934354(A,G); rs1995158(A,G); rs1995157(C,A); rs1995156(C,T); rs1566275(T,C); rs10769054(C,T) |
| ccdsGene name | CCDS31386.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390067 |
| EntrezGene Description | olfactory receptor, family 52, subfamily H, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52H1:NM_001005289:exon1:c.T848C:p.M283T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ2 |
| dbNSFP Uniprot ID | O52H1_HUMAN |
| dbNSFP KGp1 AF | 0.155677655678 |
| dbNSFP KGp1 Afr AF | 0.172764227642 |
| dbNSFP KGp1 Amr AF | 0.0773480662983 |
| dbNSFP KGp1 Asn AF | 0.363636363636 |
| dbNSFP KGp1 Eur AF | 0.0250659630607 |
| dbSNP GMAF | 0.1561 |
| ESP Afr MAF | 0.138801 |
| ESP All MAF | 0.060172 |
| ESP Eur/Amr MAF | 0.019898 |
| ExAC AF | 0.082,8.134e-06 |
OR52B6
| dbSNP name | rs1077126(A,G); rs2341434(A,G); rs892336(T,C); rs2163946(A,G); rs10838375(G,C); rs74053516(C,A); rs10769086(G,A) |
| ccdsGene name | CCDS41611.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 340980 |
| EntrezGene Description | olfactory receptor, family 52, subfamily B, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52B6:NM_001005162:exon1:c.A169G:p.T57A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGF0 |
| dbNSFP Uniprot ID | O52B6_HUMAN |
| dbNSFP KGp1 AF | 0.546703296703 |
| dbNSFP KGp1 Afr AF | 0.628048780488 |
| dbNSFP KGp1 Amr AF | 0.527624309392 |
| dbNSFP KGp1 Asn AF | 0.763986013986 |
| dbNSFP KGp1 Eur AF | 0.339050131926 |
| dbSNP GMAF | 0.4541 |
| ESP Afr MAF | 0.439535 |
| ESP All MAF | 0.395126 |
| ESP Eur/Amr MAF | 0.311915 |
| ExAC AF | 0.428 |
TRIM6
| dbSNP name | rs12272467(G,A); rs7927012(T,C); rs12800884(G,A); rs7936854(G,A); rs4255566(C,T); rs870727(C,G); rs2001778(G,A); rs2011014(A,C); rs756035(G,T); rs7482225(T,C); rs56253733(G,T); rs7952456(G,A); rs7121553(A,G); rs7121942(A,G); rs7125514(A,C); rs77528720(C,T); rs6578665(C,T); rs4910823(A,G); rs58676908(T,C); rs72880092(T,C); rs10769112(A,G); rs10769114(G,A); rs11038294(C,T); rs73400343(A,G); rs11038295(G,C); rs185629881(C,T); rs11602842(A,G); rs10769115(C,T); rs10742736(G,A); rs7108470(A,G); rs10769118(C,A); rs3751006(A,G); rs17304278(T,C); rs1074353(G,A); rs1074354(C,T); rs75742187(C,T); rs3763881(G,A); rs6578666(T,A); rs10500653(T,C); rs1368693(G,A); rs7104061(G,A); rs10742742(A,C); rs11038323(A,C); rs12278274(T,G); rs10838424(G,A); rs11824446(G,C); rs10734530(T,C); rs10734531(G,A); rs11822879(A,C); rs80031403(C,A); rs10769121(G,A); rs12271988(C,T); rs61890858(T,C); rs56108003(C,T); rs4910828(T,C); rs11038336(A,G); rs7945868(G,A); rs76635660(G,T); rs3740999(A,C); rs7125403(G,T); rs3824950(G,A); rs10769124(G,A); rs140306650(G,T); rs1813324(G,A); rs34210833(G,T); rs7120093(A,G); rs7120209(A,G); rs7104648(C,T); rs11038346(T,A) |
| ccdsGene name | CCDS55738.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 101927800 |
| EntrezGene Symbol | LOC101927800 |
| EntrezGene Description | uncharacterized LOC101927800 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | TRIM6:NM_001003818:exon8:c.G1290T:p.W430C,TRIM6:NM_001198644:exon7:c.G681T:p.W227C,TRIM6:NM_058166:exon8:c.G1206T:p.W402C,TRIM6:NM_001198645:exon6:c.G681T:p.W227C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7111 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PFM0 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 6.506e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Atrial fibrillation, isolated;
Rapid heart beat;
Irregular heart beat;
Thromboembolic stroke may occur
MISCELLANEOUS:
Genetic heterogeneity (see, e.g., ATFB1, 608583);
Allelic disorder to long QT syndrome-1 (LQT1, 192500)
MOLECULAR BASIS:
Caused by mutation in the potassium voltage-gated channel, KQT-like
subfamily, member 1 gene (KCNQ1, 607542.0032)
OMIM Title
*607564 TRIPARTITE MOTIF-CONTAINING PROTEIN 6; TRIM6
OMIM Description
CLONING
Using a B-box domain consensus sequence to screen EST databases for
novel TRIM family members, Reymond et al. (2001) identified and cloned
mouse and human TRIM6. The deduced protein contains an N-terminal RING
domain, a type-2 B-box domain, a coiled-coil region, and 3 C-terminal
RFP (602165)-like domains. Northern blot analysis of adult human tissues
and in situ hybridization of mouse embryos indicated ubiquitous
expression. Fluorescence-tagged TRIM6 showed punctate cytoplasmic
expression in transfected osteocarcinoma and HeLa cells. Disruption of
the RING domain, the B-box domain, or the coiled-coil region caused
redistribution and more diffuse staining of cytoplasmic and nuclear
structures.
GENE FUNCTION
Using several in vitro and in vivo protein-protein interaction
techniques, Reymond et al. (2001) found that TRIM6 forms
high-molecular-mass homomultimer complexes. Mutation analysis of other
TRIM proteins suggested that the coiled-coil domain mediates complex
formation.
MAPPING
By radiation hybrid analysis, Reymond et al. (2001) mapped the TRIM6
gene to chromosome 11p15, where it resides within a TRIM gene cluster
that includes TRIM5, TRIM21 (SSA1; 109092), TRIM22 (606559), TRIM34
(605684), and a TRIM pseudogene.
OR56B1
| dbSNP name | rs12792180(C,T); rs7397032(T,C); rs7396766(A,C); rs62617826(G,A) |
| ccdsGene name | CCDS31395.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390072 |
| EntrezGene Symbol | OR52N4 |
| EntrezGene Description | olfactory receptor, family 52, subfamily N, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56B1:NM_001005180:exon1:c.C39T:p.S13S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1221 |
| ESP Afr MAF | 0.092004 |
| ESP All MAF | 0.097953 |
| ESP Eur/Amr MAF | 0.101001 |
| ExAC AF | 0.096,8.132e-06 |
OR52N4
| dbSNP name | rs7936512(C,T); rs7394584(T,G); rs4910844(A,T); rs12363178(T,G); rs7396938(A,T); rs73406197(T,C) |
| ccdsGene name | CCDS44528.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390072 |
| EntrezGene Description | olfactory receptor, family 52, subfamily N, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52N4:NM_001005175:exon1:c.C317T:p.T106I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI2 |
| dbNSFP Uniprot ID | O52N4_HUMAN |
| dbNSFP KGp1 AF | 0.928113553114 |
| dbNSFP KGp1 Afr AF | 0.886178861789 |
| dbNSFP KGp1 Amr AF | 0.906077348066 |
| dbNSFP KGp1 Asn AF | 0.917832167832 |
| dbNSFP KGp1 Eur AF | 0.973614775726 |
| dbSNP GMAF | 0.07208 |
| ESP Afr MAF | 0.102908 |
| ESP All MAF | 0.053709 |
| ESP Eur/Amr MAF | 0.028508 |
| ExAC AF | 0.944,1.383e-04 |
OR52N1
| dbSNP name | rs7934670(A,T); rs115404910(C,G); rs7948009(G,A); rs10769224(C,T); rs10742787(C,T) |
| ccdsGene name | CCDS31398.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 79473 |
| EntrezGene Description | olfactory receptor, family 52, subfamily N, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52N1:NM_001001913:exon1:c.T739A:p.F247I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH53 |
| dbNSFP Uniprot ID | O52N1_HUMAN |
| dbNSFP KGp1 AF | 0.92673992674 |
| dbNSFP KGp1 Afr AF | 0.882113821138 |
| dbNSFP KGp1 Amr AF | 0.908839779006 |
| dbNSFP KGp1 Asn AF | 0.914335664336 |
| dbNSFP KGp1 Eur AF | 0.973614775726 |
| dbSNP GMAF | 0.07346 |
| ESP Afr MAF | 0.114039 |
| ESP All MAF | 0.060643 |
| ESP Eur/Amr MAF | 0.033287 |
| ExAC AF | 0.944 |
OR52N2
| dbSNP name | rs73394373(C,T); rs4758435(C,T); rs8181529(T,G); rs8181512(A,G) |
| ccdsGene name | CCDS31399.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390077 |
| EntrezGene Description | olfactory receptor, family 52, subfamily N, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52N2:NM_001005174:exon1:c.C178T:p.P60S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0009 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI0 |
| dbNSFP Uniprot ID | O52N2_HUMAN |
| dbNSFP KGp1 AF | 0.0384615384615 |
| dbNSFP KGp1 Afr AF | 0.158536585366 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03811 |
| ESP Afr MAF | 0.11881 |
| ESP All MAF | 0.041404 |
| ESP Eur/Amr MAF | 0.001746 |
| ExAC AF | 0.012 |
OR52E6
| dbSNP name | rs10742809(A,C); rs4357719(T,C); rs61737712(G,A); rs4362172(T,C); rs4592451(A,G); rs4495918(C,A); rs61739208(G,C); rs10769272(G,C); rs4362173(T,C); rs200523283(G,A); rs10742810(G,A) |
| ccdsGene name | CCDS53597.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390078 |
| EntrezGene Description | olfactory receptor, family 52, subfamily E, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52E6:NM_001005167:exon1:c.T596G:p.M199R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RD3 |
| dbNSFP Uniprot ID | O52E6_HUMAN |
| dbNSFP KGp1 AF | 0.343864468864 |
| dbNSFP KGp1 Afr AF | 0.207317073171 |
| dbNSFP KGp1 Amr AF | 0.317679558011 |
| dbNSFP KGp1 Asn AF | 0.461538461538 |
| dbNSFP KGp1 Eur AF | 0.356200527704 |
| dbSNP GMAF | 0.343 |
| ESP Afr MAF | 0.234212 |
| ESP All MAF | 0.294828 |
| ESP Eur/Amr MAF | 0.325885 |
| ExAC AF | 0.337 |
OR52E8
| dbSNP name | rs12419602(T,A); rs146982724(C,T); rs112180979(C,T); rs78277670(C,T) |
| ccdsGene name | CCDS31400.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390079 |
| EntrezGene Description | olfactory receptor, family 52, subfamily E, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52E8:NM_001005168:exon1:c.A954T:p.X318Y, |
| Annovar Mutation type | stoploss |
| Annovar Region type | exonic |
| snpEff Effect | stop_lost |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.385531135531 |
| dbNSFP KGp1 Afr AF | 0.319105691057 |
| dbNSFP KGp1 Amr AF | 0.430939226519 |
| dbNSFP KGp1 Asn AF | 0.372377622378 |
| dbNSFP KGp1 Eur AF | 0.416886543536 |
| dbSNP GMAF | 0.3866 |
| ESP Afr MAF | 0.385173 |
| ESP All MAF | 0.410631 |
| ESP Eur/Amr MAF | 0.423301 |
| ExAC AF | 0.392 |
OR52E4
| dbSNP name | rs16914094(T,G); rs4758168(G,A); rs4757986(G,T); rs11823809(T,C); rs1453435(A,C); rs11823828(T,G); rs4757987(G,A); rs11823842(T,C); rs113763081(G,A) |
| ccdsGene name | CCDS31401.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390081 |
| EntrezGene Description | olfactory receptor, family 52, subfamily E, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52E4:NM_001005165:exon1:c.T147G:p.F49L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGH9 |
| dbNSFP Uniprot ID | O52E4_HUMAN |
| dbNSFP KGp1 AF | 0.0160256410256 |
| dbNSFP KGp1 Afr AF | 0.0691056910569 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01607 |
| ESP Afr MAF | 0.039755 |
| ESP All MAF | 0.013622 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.003993 |
OR56A3
| dbSNP name | rs1840178(T,C); rs10769378(A,G) |
| ccdsGene name | CCDS41614.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390083 |
| EntrezGene Description | olfactory receptor, family 56, subfamily A, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56A3:NM_001003443:exon1:c.T152C:p.M51T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH54 |
| dbNSFP Uniprot ID | O56A3_HUMAN |
| dbNSFP KGp1 AF | 0.569139194139 |
| dbNSFP KGp1 Afr AF | 0.473577235772 |
| dbNSFP KGp1 Amr AF | 0.646408839779 |
| dbNSFP KGp1 Asn AF | 0.645104895105 |
| dbNSFP KGp1 Eur AF | 0.536939313984 |
| dbSNP GMAF | 0.4302 |
| ESP Afr MAF | 0.490005 |
| ESP All MAF | 0.456518 |
| ESP Eur/Amr MAF | 0.439362 |
| ExAC AF | 0.566 |
OR56A5
| dbSNP name | rs7113548(G,A); rs7114672(C,T) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390084 |
| snpEff Gene Name | RP11-451K18.7 |
| EntrezGene Description | olfactory receptor, family 56, subfamily A, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56A5:NM_001146033:exon1:c.C432T:p.V144V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.247 |
| ESP Afr MAF | 0.214595 |
| ESP All MAF | 0.259308 |
| ESP Eur/Amr MAF | 0.278755 |
| ExAC AF | 0.253 |
OR52L1
| dbSNP name | rs4237768(A,G); rs61732631(C,T); rs116235360(G,A); rs4354673(T,G); rs4436524(A,G); rs61750896(G,A); rs4501959(C,T); rs61738944(A,G) |
| ccdsGene name | CCDS44529.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 338751 |
| EntrezGene Description | olfactory receptor, family 52, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52L1:NM_001005173:exon1:c.T889C:p.W297R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGH7 |
| dbNSFP Uniprot ID | O52L1_HUMAN |
| dbNSFP KGp1 AF | 0.84478021978 |
| dbNSFP KGp1 Afr AF | 0.774390243902 |
| dbNSFP KGp1 Amr AF | 0.861878453039 |
| dbNSFP KGp1 Asn AF | 0.895104895105 |
| dbNSFP KGp1 Eur AF | 0.844327176781 |
| dbSNP GMAF | 0.1556 |
| ESP Afr MAF | 0.212099 |
| ESP All MAF | 0.187668 |
| ESP Eur/Amr MAF | 0.175625 |
| ExAC AF | 0.835 |
OR56A4
| dbSNP name | rs11040248(A,G); rs11040249(T,C); rs10839221(G,A) |
| ccdsGene name | CCDS31404.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120793 |
| EntrezGene Description | olfactory receptor, family 56, subfamily A, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56A4:NM_001005179:exon1:c.T798C:p.L266L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.163 |
| ESP Afr MAF | 0.107905 |
| ESP All MAF | 0.2338 |
| ESP Eur/Amr MAF | 0.298301 |
| ExAC AF | 0.244 |
OR56A1
| dbSNP name | rs11040335(T,C) |
| ccdsGene name | CCDS31405.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120796 |
| EntrezGene Description | olfactory receptor, family 56, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56A1:NM_001001917:exon1:c.A879G:p.A293A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.27 |
| ESP Afr MAF | 0.268741 |
| ESP All MAF | 0.336309 |
| ESP Eur/Amr MAF | 0.370926 |
| ExAC AF | 0.329 |
OR56B4
| dbSNP name | rs4758387(T,C); rs1462983(C,T); rs138861608(C,T) |
| ccdsGene name | CCDS31406.1 |
| CosmicCodingMuts gene | OR56B4 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 196335 |
| EntrezGene Description | olfactory receptor, family 56, subfamily B, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR56B4:NM_001005181:exon1:c.T144C:p.N48N, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1331 |
| ESP Afr MAF | 0.355747 |
| ESP All MAF | 0.158073 |
| ESP Eur/Amr MAF | 0.056797 |
| ExAC AF | 0.094 |
OR52B2
| dbSNP name | rs77344022(C,T) |
| ccdsGene name | CCDS53598.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 255725 |
| EntrezGene Description | olfactory receptor, family 52, subfamily B, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52B2:NM_001004052:exon1:c.G707A:p.R236Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RD2 |
| dbNSFP Uniprot ID | O52B2_HUMAN |
| dbNSFP KGp1 AF | 0.0247252747253 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0157342657343 |
| dbNSFP KGp1 Eur AF | 0.0395778364116 |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.030458 |
| ESP All MAF | 0.028533 |
| ESP Eur/Amr MAF | 0.027593 |
| ExAC AF | 0.029 |
OR52W1
| dbSNP name | rs10839531(A,G); rs11040799(T,A); rs325609(A,G) |
| ccdsGene name | CCDS31407.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120787 |
| EntrezGene Description | olfactory receptor, family 52, subfamily W, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR52W1:NM_001005178:exon1:c.A716G:p.H239R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IF63 |
| dbNSFP Uniprot ID | O52W1_HUMAN |
| dbNSFP KGp1 AF | 0.712912087912 |
| dbNSFP KGp1 Afr AF | 0.247967479675 |
| dbNSFP KGp1 Amr AF | 0.792817679558 |
| dbNSFP KGp1 Asn AF | 0.961538461538 |
| dbNSFP KGp1 Eur AF | 0.788918205805 |
| dbSNP GMAF | 0.2865 |
| ESP Afr MAF | 0.329169 |
| ESP All MAF | 0.377251 |
| ESP Eur/Amr MAF | 0.226839 |
| ExAC AF | 0.756,4.489e-03 |
PRKCDBP
| dbSNP name | rs12294600(G,A); rs1051992(A,G); rs11544764(C,T); rs2682123(C,G) |
| ccdsGene name | CCDS7762.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 112464 |
| EntrezGene Description | protein kinase C, delta binding protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRKCDBP:NM_145040:exon2:c.C763T:p.L255F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q969G5 |
| dbNSFP Uniprot ID | PRDBP_HUMAN |
| dbNSFP KGp1 AF | 0.0521978021978 |
| dbNSFP KGp1 Afr AF | 0.189024390244 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0145118733509 |
| dbSNP GMAF | 0.05188 |
| ESP Afr MAF | 0.175829 |
| ESP All MAF | 0.067724 |
| ESP Eur/Amr MAF | 0.012337 |
| ExAC AF | 0.025 |
TIMM10B
| dbSNP name | rs11555935(C,A); rs1048121(G,A); rs59421287(C,A); rs1140221(G,A) |
| ccdsGene name | CCDS7766.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 26515 |
| snpEff Gene Name | FXC1 |
| EntrezGene Description | translocase of inner mitochondrial membrane 10 homolog B (yeast) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TIMM10B:NM_012192:exon1:c.C34A:p.R12R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1561 |
| ESP Afr MAF | 0.206724 |
| ESP All MAF | 0.198322 |
| ESP Eur/Amr MAF | 0.194018 |
| ExAC AF | 0.168 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases;
Multifactorial
NEUROLOGIC:
[Central nervous system];
Mental retardation in 75%;
Seizures in 15-30%;
EEG abnormalities in 20-50%;
[Behavioral/psychiatric manifestations];
Impaired social interactions;
Impaired use of nonverbal behaviors, such as eye-to-eye gaze, facial
expression, body posture, and gestures;
Impaired ability to form peer relationships;
Impaired language development;
Lack of spontaneous play;
Restrictive behavior, interests, and activities;
Stereotyped, repetitive behavior;
Inflexible adherence to routines or rituals
LABORATORY ABNORMALITIES:
Increased serum serotonin in 25%
MISCELLANEOUS:
Onset by 3 years of age;
Male to female ratio 4:1;
Occurs in 2-5 per 10,000 individuals;
Genetic heterogeneity (see 209850);
Associated with tuberous sclerosis (191100);
Associated with untreated phenylketonuria (261600);
Associated with Fragile X syndrome (300624)
OMIM Title
*607388 FRACTURE CALLUS 1, RAT, HOMOLOG OF; FXC1
;;TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 10, YEAST, HOMOLOG OF,
B; TIMM10B; TIM10B
OMIM Description
DESCRIPTION
FXC1, or TIMM10B, belongs to a family of evolutionarily conserved
proteins that are organized in heterooligomeric complexes in the
mitochondrial intermembrane space. These proteins mediate the import and
insertion of hydrophobic membrane proteins into the mitochondrial inner
membrane.
CLONING
By database searching with the human and S. pombe TIMM8A (300356)
sequences as queries, Jin et al. (1999) identified several novel members
of the TIM family, including FXC1. The FXC1 protein contains 103 amino
acids and resembles the rat sequence described by Hadjiargyrou et al.
(1998) as being encoded by an early gene induced during fracture callus
formation. The protein has a series of glutamine residues (7 in human, 5
in mouse, 4 in rat, and none in fly) at its N terminus. Northern blot
analysis detected ubiquitous, barely detectable expression of a 3.2-kb
FXC1 transcript in adult human tissues. Hadjiargyrou et al. (1998)
detected a single Fxc1 transcript in all rat tissues examined, as well
as in mouse osteoblast-like (MC3T3) cells and rat osteosarcoma cells.
GENE FUNCTION
In the mouse MC3T3 cell model of osteoblast differentiation,
Hadjiargyrou et al. (1998) found that Fxc1 expression decreased
dramatically during the proliferative stages, but increased 3- to 4-fold
during the phase when these cells exhibit osteoblastic functions, such
as production and deposition of matrix molecules. The results suggested
that FXC1 may play a role during the production and deposition of matrix
molecules in osteoblasts.
MAPPING
By FISH and radiation hybrid analysis, Jin et al. (1999) mapped the FXC1
gene to chromosome 11p15.5-p15.2.
GVINP1
| dbSNP name | rs10839600(C,T); rs2063083(G,A); rs10769715(T,A); rs7951709(C,T); rs7937911(A,G); rs7130858(G,A); rs61735337(C,T); rs3741274(T,C); rs3741273(C,T); rs11040980(C,T); rs11040981(G,A); rs185348624(C,T); rs11040983(C,T); rs17262495(T,C); rs7112561(G,A); rs79294030(G,A); rs12284429(A,G); rs11040984(T,C); rs11040985(C,T); rs7114441(C,T); rs7102825(T,C); rs79708590(G,A); rs58825115(G,A); rs10839601(G,A); rs10839602(C,T); rs10839603(G,A); rs12223353(C,T); rs10839604(G,C); rs16917397(T,G); rs7112649(G,C); rs77964599(C,T); rs7105443(T,C) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 387751 |
| EntrezGene Description | GTPase, very large interferon inducible pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
OR2AG2
| dbSNP name | rs116457946(T,C); rs7924459(G,C); rs11828782(C,A); rs10839616(C,G); rs7102536(T,C) |
| ccdsGene name | CCDS31413.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 338755 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AG, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AG2:NM_001004490:exon1:c.A918G:p.G306G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01377 |
| ESP Afr MAF | 0.0393 |
| ESP All MAF | 0.013391 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.004229 |
OR2AG1
| dbSNP name | rs11826041(A,G); rs11041022(T,C); rs74328035(T,C); rs2659880(G,T); rs2659879(C,G); rs497681(G,A) |
| ccdsGene name | CCDS31414.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 144125 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AG, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AG1:NM_001004489:exon1:c.A125G:p.N42S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0083 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H205 |
| dbNSFP Uniprot ID | O2AG1_HUMAN |
| dbNSFP KGp1 AF | 0.0380036630037 |
| dbNSFP KGp1 Afr AF | 0.154471544715 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03811 |
| ESP Afr MAF | 0.12517 |
| ESP All MAF | 0.042866 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.012 |
OR6A2
| dbSNP name | rs866347(A,G); rs7122644(G,A) |
| ccdsGene name | CCDS7772.1 |
| CosmicCodingMuts gene | OR6A2 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 8590 |
| EntrezGene Description | olfactory receptor, family 6, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6A2:NM_003696:exon1:c.T162C:p.S54S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2948 |
| ESP Afr MAF | 0.478192 |
| ESP All MAF | 0.314992 |
| ESP Eur/Amr MAF | 0.231378 |
| ExAC AF | 0.731,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608495 OLFACTORY RECEPTOR, FAMILY 6, SUBFAMILY A, MEMBER 2; OR6A2
;;OR6A1;;
OR11-55
OMIM Description
DESCRIPTION
Olfactory receptor genes, such as OR6A2, are members of a large
multigene family encoding transmembrane signaling proteins required for
odorant discrimination. Many of these genes are arranged in large
olfactory gene clusters on human chromosomes 6, 11, and 17, as well as
distributed on other chromosomes (Buettner et al., 1998).
CLONING
By screening and PCR amplification of artificial chromosomes and genomic
libraries, Buettner et al. (1998) cloned OR6A2, which they designated
OR11-55. The deduced protein contains several transmembrane domains.
MAPPING
By genomic sequence analysis and FISH, Buettner et al. (1998) mapped the
OR6A2 gene to chromosome 11p15, where it resides in a gene cluster with
several other olfactory receptor genes.
OR10A5
| dbSNP name | rs114783985(C,T) |
| ccdsGene name | CCDS7773.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 144124 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A5:NM_178168:exon1:c.C689T:p.P230L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0796 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H207 |
| dbNSFP Uniprot ID | O10A5_HUMAN |
| dbNSFP KGp1 AF | 0.010989010989 |
| dbNSFP KGp1 Afr AF | 0.0447154471545 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.038846 |
| ESP All MAF | 0.01316 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.003887 |
OR10A2
| dbSNP name | rs3930075(A,G); rs2741764(G,A); rs7117739(C,G); rs10839631(A,G); rs10839632(T,C); rs7926083(A,C) |
| ccdsGene name | CCDS31415.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 341276 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A2:NM_001004460:exon1:c.A128G:p.H43R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H208 |
| dbNSFP Uniprot ID | O10A2_HUMAN |
| dbNSFP KGp1 AF | 0.307234432234 |
| dbNSFP KGp1 Afr AF | 0.197154471545 |
| dbNSFP KGp1 Amr AF | 0.353591160221 |
| dbNSFP KGp1 Asn AF | 0.307692307692 |
| dbNSFP KGp1 Eur AF | 0.356200527704 |
| dbSNP GMAF | 0.3067 |
| ESP Afr MAF | 0.201045 |
| ESP All MAF | 0.315068 |
| ESP Eur/Amr MAF | 0.373487 |
| ExAC AF | 0.353 |
OR10A4
| dbSNP name | rs2595453(T,C); rs16919049(C,T); rs10839635(G,A) |
| ccdsGene name | CCDS7774.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 283297 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A4:NM_207186:exon1:c.T617C:p.L206P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.035 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H209 |
| dbNSFP Uniprot ID | O10A4_HUMAN |
| dbNSFP KGp1 AF | 0.0288461538462 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0441988950276 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0580474934037 |
| dbSNP GMAF | 0.02893 |
| ESP Afr MAF | 0.012949 |
| ESP All MAF | 0.042789 |
| ESP Eur/Amr MAF | 0.058077 |
| ExAC AF | 0.04 |
OR2D2
| dbSNP name | rs139334477(T,C); rs2741804(A,G); rs1965207(T,C); rs1965208(A,G) |
| ccdsGene name | CCDS31416.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120776 |
| EntrezGene Description | olfactory receptor, family 2, subfamily D, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2D2:NM_003700:exon1:c.A831G:p.A277A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.001136 |
| ESP All MAF | 0.000385 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.88e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608494 OLFACTORY RECEPTOR, FAMILY 2, SUBFAMILY D, MEMBER 2; OR2D2
;;OR11-610
OMIM Description
Olfactory receptor genes are members of a large multigene family
encoding transmembrane signaling proteins required for odorant
discrimination. Many of these genes are arranged in large olfactory gene
clusters on human chromosomes 6, 11, and 17, as well as distributed on
other chromosomes (Buettner et al., 1998). See also 164342.
CLONING
By screening and PCR amplification of artificial chromosomes and genomic
libraries, Buettner et al. (1998) cloned OR2D2, which they designated
OR11-610. The deduced protein contains several transmembrane domains.
MAPPING
By genomic sequence analysis and FISH, Buettner et al. (1998) mapped the
OR2D2 gene to chromosome 11p15, where it resides in a gene cluster with
several other olfactory receptor genes.
OR2D3
| dbSNP name | rs10839658(C,A); rs11605995(A,C); rs77720614(C,T); rs10839659(G,C); rs2035844(T,C); rs115093724(C,T) |
| ccdsGene name | CCDS31417.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120775 |
| EntrezGene Description | olfactory receptor, family 2, subfamily D, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2D3:NM_001004684:exon1:c.C244A:p.L82I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGH3 |
| dbNSFP Uniprot ID | OR2D3_HUMAN |
| dbNSFP KGp1 AF | 0.460164835165 |
| dbNSFP KGp1 Afr AF | 0.30081300813 |
| dbNSFP KGp1 Amr AF | 0.511049723757 |
| dbNSFP KGp1 Asn AF | 0.328671328671 |
| dbNSFP KGp1 Eur AF | 0.638522427441 |
| dbSNP GMAF | 0.4601 |
| ESP Afr MAF | 0.313494 |
| ESP All MAF | 0.48153 |
| ESP Eur/Amr MAF | 0.376513 |
| ExAC AF | 0.524 |
NLRP14
| dbSNP name | rs2291536(G,A); rs77022116(C,T); rs7924566(T,A); rs1388529(C,T); rs12098870(G,A); rs1388530(T,C); rs1388531(G,A); rs10769754(G,A); rs10769755(T,C); rs7106879(A,G); rs149255947(A,G); rs12293857(A,C); rs4758152(T,G); rs7936892(T,A); rs12795873(A,T); rs12287453(T,C); rs112074841(T,A); rs10742999(A,G); rs12288888(T,C); rs12146685(G,T); rs7104375(C,A); rs182073372(G,A); rs59822758(C,T); rs10839692(G,A); rs902732(A,G); rs902733(G,A); rs12365934(T,A); rs11041144(T,C); rs964502(C,T); rs11041145(A,G); rs10769758(C,A); rs12295155(A,C); rs116086302(A,G); rs902734(G,A); rs902735(T,C); rs376202051(T,C); rs902736(G,T); rs10839693(C,A); rs10839694(T,A); rs10839695(C,T); rs12275610(T,C); rs10839696(C,T); rs11041146(G,C); rs12274426(A,G); rs10839697(A,G); rs10839698(A,T); rs180946242(C,A); rs10743000(T,G); rs34951118(T,C); rs10734613(C,G); rs10743002(C,A); rs11041147(G,C); rs721322(A,T); rs7119717(G,A); rs7119719(G,A); rs7120622(C,T); rs10500674(A,G); rs10839699(G,A); rs11041148(T,C); rs142073781(T,G); rs16921681(A,G); rs11041149(G,A); rs17279697(T,A); rs12801277(A,C); rs146049510(C,T); rs61063081(G,A); rs7103238(T,G); rs7114066(G,C); rs147766537(A,G); rs969232(C,G); rs969233(A,G); rs61879044(C,T); rs113165851(A,G); rs13377349(A,C); rs10160478(T,C); rs10160603(G,A); rs10160479(T,A); rs61879045(G,A); rs61879046(A,T); rs10160529(T,G); rs10160485(A,G); rs10160530(T,C); rs7123944(C,T); rs76670455(C,T); rs16921740(C,A); rs6578821(C,A); rs12285069(A,T); rs1491821(G,A); rs115129530(G,A); rs11041152(T,C); rs16921787(C,T); rs7125766(A,G); rs77018717(C,T); rs7109723(G,T); rs75044836(C,T); rs10734614(C,T); rs78820892(A,G); rs76145501(A,G); rs7929282(T,C); rs7940208(C,G); rs1844907(C,T); rs35911793(G,C); rs12807652(C,T); rs7118931(T,C); rs11041154(G,A); rs4439493(A,T); rs10839700(G,T); rs1552727(G,A); rs1552726(G,A); rs151305338(T,C); rs1491828(G,A); rs10839701(G,A); rs10839702(G,C); rs10839703(G,A); rs1552725(A,T); rs1552724(G,A); rs1552723(G,A); rs1552722(T,C); rs35533608(G,A); rs115665389(G,A); rs2220671(G,A); rs1826328(C,T); rs111327517(A,G); rs4758153(T,C); rs143914746(C,T); rs10769759(G,T); rs74050293(C,G); rs10769760(T,G); rs1602570(T,C); rs1907614(G,A); rs115586847(A,G); rs137900317(A,G); rs142244782(G,T); rs16921928(G,A); rs116813923(C,T); rs4758154(A,C); rs16921930(G,A); rs139416949(G,A); rs149603210(A,G); rs1491831(T,A); rs57999181(A,T); rs79188844(C,G); rs142681085(A,T); rs373837075(C,T); rs10839708(G,A); rs10500676(A,G); rs145397155(C,T); rs1491830(A,G); rs10839709(T,G); rs10743004(C,G); rs10743005(G,A); rs12270388(A,T); rs35898585(C,T); rs1388539(G,A); rs7102463(C,A); rs16921990(G,A); rs1979669(A,G); rs1907613(A,G); rs1388538(A,G); rs114451077(T,C); rs998365(T,C); rs4758155(A,G); rs149743312(C,T); rs10839710(T,G); rs184221366(T,G); rs151142805(T,C); rs7109582(A,T); rs7124365(C,T); rs80183870(G,A); rs147079382(G,A); rs4758156(C,T); rs61879051(C,A); rs2220670(A,G); rs4758157(T,A); rs116432287(C,G); rs10769762(A,C); rs17280682(C,T); rs10769763(C,A); rs147121259(T,C) |
| ccdsGene name | CCDS7776.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 338323 |
| EntrezGene Description | NLR family, pyrin domain containing 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NLRP14:NM_176822:exon4:c.C1190T:p.T397I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6606 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86W24 |
| dbNSFP Uniprot ID | NAL14_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.019764 |
| ESP All MAF | 0.007927 |
| ESP Eur/Amr MAF | 0.001862 |
| ExAC AF | 0.003123 |
RBMXL2
| dbSNP name | rs11041169(C,G); rs7119420(G,C) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 27288 |
| EntrezGene Description | RNA binding motif protein, X-linked-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1781 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural
SKELETAL:
[Pelvis];
Shallow acetabulae;
Hip dislocation;
[Limbs];
Proximal radio-ulnar synostosis;
Limited pronation/supination of forearm;
Radial bowing;
Ulnar bowing;
[Hands];
Fifth finger clinodactyly;
Syndactyly
SKIN, NAILS, HAIR:
[Skin];
Petechiae;
Purpura
HEMATOLOGY:
Thrombocytopenia, congenital;
Megakaryocytopenia;
Aplastic anemia;
Pancytopenia
LABORATORY ABNORMALITIES:
No chromosomal breakage;
Normal karyotype
MOLECULAR BASIS:
Caused by mutation in the homeo box-A11 gene (HOXA11, 142958.0001)
OMIM Title
*605444 RNA-BINDING MOTIF PROTEIN, X CHROMOSOME, LIKE 2; RBMXL2
;;HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN G-T;;
HNRNPGT;;
HNRPGT
OMIM Description
CLONING
The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of
nuclear RNA-binding proteins that have a role in pre-RNA splicing (see
600124 and 164020). All mammals have a Y chromosome-encoded homolog of
the X-linked HNPRG gene (RBMX; 300199), called RBMY (400006), which is
thought to have a role in male fertility and is a candidate for the
azoospermia factor gene. In a 2-hybrid screen for proteins that interact
with the human RBMY protein, Elliott et al. (2000) a cDNA from a human
testis library encoding a new member of the hnRNP family, HNRPGT. The
deduced 392-amino acid protein shares 77% and 53% sequence identity with
the HNRPG and RBMY proteins, respectively. The HNRPGT gene contains an
uninterrupted open reading frame without introns, consistent with
derivation from a retroposon. However, unlike many retroposon-derived
genes, HNRPGT is not a pseudogene. Antiserum raised to the conceptual
reading frame of HNRPGT identified a highly expressed protein in germ
cells which primarily localizes to the nuclei of meiotic spermatocytes.
The antiserum also detected a similar protein in the testis of several
mammals, suggesting that the protein is highly conserved and that the
retrotransposition event generating the HNRPGT gene predated the common
ancestor of mouse and man.
By Northern blot analysis of mouse tissues, Ehrmann et al. (2008)
detected a 1.5-kb Hnrnpgt transcript exclusively in testis. Western blot
analysis of mouse testis detected Hnrnpgt beginning at day 13, when germ
cells initiate meiosis I, and expression was strong thereafter.
Immunohistochemical analysis revealed that Hnrnpgt localized to nuclei
of primary spermatocytes, with less expression in round spermatids.
MAPPING
By fluorescence in situ hybridization and radiation hybrid analysis,
Elliott et al. (2000) mapped the RBMXL2 gene to chromosome 11p15.
Ehrmann et al. (2008) stated that the mouse Rbmxl2 gene maps to a region
of chromosome 7 that shares homology of synteny with human chromosome
11p15.
EVOLUTION
Using phylogenetic analysis, Ehrmann et al. (2008) found that the
HNRNPGT gene is ancient, originating prior to the divergence of the 4
main groups of placental mammals between 101 and 108 million years ago.
Pairwise analysis of the mouse and human HNRNPGT genes showed that they
are being maintained by positive selection.
ANIMAL MODEL
Ehrmann et al. (2008) inactivated the Hnrnpgt gene in embryonic stem
(ES) cells and studied its function during spermatogenesis in chimeric
mice. They found that germ cells containing a heterozygous disruption of
the Hnrnpgt gene were unable to contribute to the germline. Chimeric
mice with a high level of mutant germ cells were infertile, with low
sperm counts, degenerate seminiferous tubules, and abnormal sperm
morphology. Chimeras made from a 1:1 mix of mutant and wildtype ES cell
clones transmitted wildtype germ cells only. The data suggested that all
the major stages of spermatogenesis can proceed within seminiferous
tubules populated by germ cells heterozygous for the Hnrnpgt deletion,
but functional sperm containing the deletion are not produced, and there
is failure of seminiferous tubule survival in adults.
CYB5R2
| dbSNP name | rs72851374(T,A); rs72851375(G,A); rs11758(G,C); rs76915129(G,A); rs1128627(A,T); rs13172(G,A); rs112522871(C,G); rs55826178(C,G); rs112623324(G,A); rs74051970(C,T); rs61683338(C,G); rs11041521(T,A); rs11041522(A,G); rs55635523(T,C); rs113446266(G,T); rs67173996(G,A); rs59114959(A,T); rs12794507(C,T); rs11041523(T,C); rs12796110(A,C); rs12801394(T,C); rs62620008(C,A); rs72851388(C,T); rs61733057(A,C); rs6578893(G,A); rs80051774(A,G); rs10743030(A,C); rs79389241(T,A); rs72851391(C,T); rs116522458(G,A); rs4631871(T,C); rs61733056(C,T); rs7942361(A,G); rs35045958(G,A); rs7928127(C,T); rs113868354(T,G); rs12577557(G,C); rs7931064(G,T); rs77186229(C,G); rs1122643(C,T); rs78306657(A,G); rs7950642(A,G); rs76900209(A,G); rs10839839(C,G); rs4300385(G,C); rs3897382(A,G) |
| ccdsGene name | CCDS7780.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 51700 |
| EntrezGene Description | cytochrome b5 reductase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CYB5R2:NM_016229:exon6:c.A454T:p.M152L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5089 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6BCY4 |
| dbNSFP Uniprot ID | NB5R2_HUMAN |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.011358 |
| ESP All MAF | 0.003925 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001269 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Spine];
Scoliosis;
[Hands];
Claw hand deformity;
[Feet];
Pes cavus;
Talipes equinovarus
NEUROLOGIC:
Normal early motor milestones;
[Peripheral nervous system];
Lower and upper limb muscle weakness due to peripheral neuropathy;
Lower and upper limb muscle atrophy due to peripheral neuropathy;
Clumsy gait;
'Steppage' gait;
Foot drop;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
Neuropathic changes seen on EMG;
Normal to decreased nerve conduction velocities (NCV);
Loss of large myelinated fibers seen on nerve biopsy;
Regenerating axons;
Demyelination;
Thin myelination;
Occasional early 'onion' bulb formations
MISCELLANEOUS:
Onset in early childhood (2-4 years);
Severe course;
Clinical and pathologic features of both demyelinating and axonal
CMT;
Allelic to several forms of autosomal recessive CMT (see 214400)
MOLECULAR BASIS:
Caused by mutation in the ganglioside-induced differentiation-associated
protein-1 gene (GDAP1, 606598.0006)
OMIM Title
*608342 CYTOCHROME b5 REDUCTASE 2; CYB5R2
;;B5R.2
OMIM Description
CLONING
By searching EST databases for consensus NADPH- and flavin-binding
sites, followed by RT-PCR of a hepatoma cell line cDNA library, Zhu et
al. (1999) cloned CYB5R2, which they designated B5R.2. The deduced
protein contains 2 FAD-binding motifs and 3 NADPH-binding motifs. Unlike
CYB5R3 (250800) and CYB5R1 (608341), CYB5R2 has no N-terminal membrane
anchor. Northern blot analysis showed a restricted tissue distribution
for CYB5R2, whereas expression of CYB5R1 was widespread.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the CYB5R2
gene to chromosome 11 (TMAP STS-N90805).
OR5P2
| dbSNP name | rs7949771(T,C); rs72484720(T,C); rs73406603(G,A); rs73406604(T,C); rs115188826(C,T); rs73406606(G,A); rs73406607(C,T); rs73406609(C,T); rs1482804(C,T) |
| ccdsGene name | CCDS7782.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120065 |
| EntrezGene Description | olfactory receptor, family 5, subfamily P, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5P2:NM_153444:exon1:c.A952G:p.N318D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WZ92 |
| dbNSFP Uniprot ID | OR5P2_HUMAN |
| dbNSFP KGp1 AF | 0.268772893773 |
| dbNSFP KGp1 Afr AF | 0.365853658537 |
| dbNSFP KGp1 Amr AF | 0.276243093923 |
| dbNSFP KGp1 Asn AF | 0.148601398601 |
| dbNSFP KGp1 Eur AF | 0.292875989446 |
| dbSNP GMAF | 0.2677 |
| ESP Afr MAF | 0.323055 |
| ESP All MAF | 0.295469 |
| ESP Eur/Amr MAF | 0.28192 |
| ExAC AF | 0.257 |
OR5P3
| dbSNP name | rs61525942(A,G); rs1482791(T,C); rs1482792(A,G); rs1482793(C,T) |
| ccdsGene name | CCDS7783.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 120066 |
| EntrezGene Description | olfactory receptor, family 5, subfamily P, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5P3:NM_153445:exon1:c.T553C:p.L185L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0124 |
| ESP Afr MAF | 0.058124 |
| ESP All MAF | 0.019981 |
| ESP Eur/Amr MAF | 0.000582 |
| ExAC AF | 0.00511 |
OR5E1P
| dbSNP name | rs61759825(A,G); rs17221305(G,A); rs4758022(A,G) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 26343 |
| snpEff Gene Name | RP11-494M8.4 |
| EntrezGene Description | olfactory receptor, family 5, subfamily E, member 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2071 |
| ExAC AF | 0.159 |
OR10A6
| dbSNP name | rs4758258(A,G); rs7933807(A,C); rs7928451(G,A); rs12272735(A,G) |
| ccdsGene name | CCDS31420.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 390093 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A6:NM_001004461:exon1:c.T860C:p.L287P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH74 |
| dbNSFP Uniprot ID | O10A6_HUMAN |
| dbNSFP KGp1 AF | 0.779304029304 |
| dbNSFP KGp1 Afr AF | 0.719512195122 |
| dbNSFP KGp1 Amr AF | 0.817679558011 |
| dbNSFP KGp1 Asn AF | 0.791958041958 |
| dbNSFP KGp1 Eur AF | 0.790237467018 |
| dbSNP GMAF | 0.2204 |
| ESP Afr MAF | 0.262608 |
| ESP All MAF | 0.234493 |
| ESP Eur/Amr MAF | 0.220088 |
| ExAC AF | 0.792 |
OR10A3
| dbSNP name | rs148188824(A,G) |
| ccdsGene name | CCDS31421.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 26496 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A3:NM_001003745:exon1:c.T461C:p.M154T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0414 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P58181 |
| dbNSFP Uniprot ID | O10A3_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000847 |
| ESP Eur/Amr MAF | 0.001164 |
| ExAC AF | 9.027e-04,1.626e-05 |
SNORA45B
| dbSNP name | rs2073686(G,A) |
| ccdsGene name | CCDS7790.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 677826 |
| EntrezGene Symbol | SNORA45 |
| snpEff Gene Name | RPL27A |
| EntrezGene Description | small nucleolar RNA, H/ACA box 45 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1855 |
| ESP Afr MAF | 0.108124 |
| ESP All MAF | 0.156589 |
| ESP Eur/Amr MAF | 0.177906 |
| ExAC AF | 0.177 |
KRT8P41
| dbSNP name | rs12578071(G,C); rs2133214(G,T); rs16914802(G,A); rs7949022(G,A); rs79988840(C,T) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 283102 |
| snpEff Gene Name | SCUBE2 |
| EntrezGene Description | keratin 8 pseudogene 41 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2456 |
SNORA23
| dbSNP name | rs2290423(T,G) |
| ccdsGene name | CCDS31425.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 677808 |
| snpEff Gene Name | IPO7 |
| EntrezGene Description | small nucleolar RNA, H/ACA box 23 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4591 |
| ESP Afr MAF | 0.493135 |
| ESP All MAF | 0.490385 |
| ESP Eur/Amr MAF | 0.489174 |
| ExAC AF | 0.473 |
LOC644656
| dbSNP name | rs116541990(T,C) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 644656 |
| snpEff Gene Name | ZNF143 |
| EntrezGene Description | uncharacterized LOC644656 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02525 |
ADM
| dbSNP name | rs2228573(C,G) |
| ccdsGene name | CCDS7801.1 |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 133 |
| EntrezGene Description | adrenomedullin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ADM:NM_001124:exon4:c.C254G:p.P85R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0114 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P35318 |
| dbNSFP Uniprot ID | ADML_HUMAN |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0264227642276 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.015007 |
| ESP All MAF | 0.005085 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001635 |
OMIM Clinical Significance
Endocrine:
Chronic adrenal insufficiency
Skin:
Hyperpigmentation
Lab:
Hypernatriuria;
Hypokaliuria;
Decreased plasma total cortisol;
Decreased urine free cortisol;
No response of PTC, UFC and 17-OHCS to ACTH stimulation
Inheritance:
Autosomal dominant
OMIM Title
*103275 ADRENOMEDULLIN; ADM
OMIM Description
DESCRIPTION
The ADM gene encodes for a preprohormone, which is posttranslationally
modified to generate 2 biologically active peptides: adrenomedullin and
proadrenomedullin N-terminal 20 peptide (PAMP). Expression of these
peptides is widespread, and they have several functions, including
vasodilatation, bronchodilatation, hormone secretion regulation, growth
modulation, angiogenesis promotion, and antimicrobial activity, among
others (Fernandez et al., 2008).
CLONING
Adrenomedullin, a hypotensive peptide found in human pheochromocytoma,
consists of 52 amino acids, has 1 intramolecular disulfide bond, and
shows slight homology with the calcitonin gene-related peptide (CGRP;
114130). It may function as a hormone in circulation control because it
is found in blood in a considerable concentration. Kitamura et al.
(1993) constructed a cDNA library of pheochromocytoma and isolated
therefrom a cDNA clone encoding an adrenomedullin precursor. The
precursor, called preproadrenomedullin, is 185 amino acids long. By
RNA-blot analysis, human adrenomedullin mRNA was found to be highly
expressed in several tissues, including adrenal medulla, cardiac
ventricle, lung, and kidney, as well as pheochromocytoma.
GENE FUNCTION
Richards et al. (1996) reviewed information accumulated on
adrenomedullin since its original description by Kitamura et al. (1993).
Udono et al. (2001) explored the effects of hypoxia on the production
and secretion of adrenomedullin and endothelin-1 (EDN1; 131240) in human
retinal pigment epithelial (RPE) cells. They found that ADM mRNA levels
and immunoreactive ADM levels in the medium were increased by hypoxia in
all 3 RPE cell lines studied. Immunoreactive EDN1 was detected in 2
cultured media. Hypoxia treatment for 28 hours increased immunoreactive
EDN1 levels approximately 1.3-fold in 1 cultured cell medium but
decreased it in 2 cell lines. Treatment with ADM ameliorated the
hypoxia-induced decrease in the cell number. Exogenous EDN1 had no
significant effect on the number of cells under normoxia or hypoxia.
Udono et al. (2001) concluded that the ADM induced by hypoxia may have
protective roles against hypoxic cell damage in RPE cells.
McLatchie et al. (1998) demonstrated that a complex consisting of
receptor activity-modifying protein-2 (RAMP2; 605154) and calcitonin
receptor-like receptor (CRLR; 114190) can function as an adrenomedullin
receptor. To investigate whether ADM has implications as a
pathophysiologic substance in pregnancy-induced hypertension, Makino et
al. (2001) measured the changes of expression of RAMP2 and CRLR in
fetomaternal tissues in normotensive pregnant women and
pregnancy-induced hypertensive women by Northern blot analysis. RAMP2
and CRLR mRNA was significantly decreased in the umbilical artery and
uterus of the patients with pregnancy-induced hypertension. On the other
hand, RAMP2 mRNA was significantly increased in the fetal membrane of
the patients with pregnancy-induced hypertension. In addition, there was
a significant negative correlation between the RAMP2 mRNA levels in the
umbilical artery and uterine muscle and blood pressure. However, there
was no correlation between the mRNA level and blood pressure in fetal
membrane and placenta, suggesting that there is no close relationship to
the pathogenesis in pregnancy-induced hypertension. These findings
suggested that the reduced expression of RAMP2 and CRLR functioning as
components of an adrenomedullin receptor in umbilical artery and uterus
may have some role in pregnancy-induced hypertension.
By immunohistochemical analysis, Ma et al. (2006) found that
adrenomedullin was widely distributed in nociceptors of dorsal root
ganglion and in axon terminals in the superficial dorsal horn of rat
spinal cord. Ma et al. (2006) showed that injection of adrenomedullin
caused a pain response in rats and that the response involved the PI3
kinase (see PIK3CG; 601232) signaling pathway.
GENE STRUCTURE
Ishimitsu et al. (1994) found that the genomic ADM DNA consists of 4
exons and 3 introns, with the 5-prime flanking region containing TATA,
CAAT, and GC boxes. There are also multiple binding sites for activator
protein-2 (AP2TF; 107580) and a cAMP-regulated enhancer element.
MAPPING
By Southern blot analyses of human/hamster somatic hybrid cell lines,
Ishimitsu et al. (1994) demonstrated that the ADM gene is represented by
a single locus on chromosome 11. Okazaki et al. (1996) mapped the Adm
gene to the distal region of mouse chromosome 7, a region that shows
syntenic homology to human 11p15-q13; the human ADM gene is probably
located at 11p15.4 (van Heyningen and Jones, 1993).
ANIMAL MODEL
To elucidate the functions of adrenomedullin, Caron and Smithies (2001)
replaced the coding region of the Adm gene in mice with a sequence
encoding enhanced green fluorescent protein while leaving the Adm
promoter intact. They found that Adm -/- embryos die at midgestation
with extreme hydrops fetalis and cardiovascular abnormalities, including
overdeveloped ventricular trabeculae and underdeveloped arterial walls.
These data suggested that genetically determined absence of Adm may be
one cause of nonimmune hydrops fetalis (236750) in humans.
Li et al. (2006) found that female Adm +/- mice had reduced fertility
characterized by smaller litters, fetal growth restriction, and
placental insufficiency. Fetal Adm was expressed in the trophectoderm as
early as embryonic day 3.5 in preimplantation blastocysts, and Adm
expression was significantly increased in both maternal uterine and
fetal cells during the implantation period. Adm +/- females had abnormal
implantation spacing and overcrowded conceptuses in the uterine horns.
Placentas from growth-restricted embryos showed defects in trophoblast
cell invasion and other morphologic defects. Li et al. (2006) concluded
that levels of maternal Adm and, to a lesser extent, embryonic Adm play
a critical role in implantation, placentation, and fetal growth.
Caron et al. (2007) generated mice with genetically controlled levels of
Adm mRNA ranging from 50% to 140% of wildtype levels. These changes in
Adm gene expression had no effect on basal blood pressure. Although
pregnancy and sepsis increase plasma Adm levels, genetically reducing
Adm production did not affect the transient hypotension that occurs
during normal pregnancy or hypotension induced by lipopolysaccharide.
Reduction of Adm also had no effect on hypertension induced by renin
(REN; 179820) overexpression. However, 50% normal expression of Adm
enhanced cardiac hypertrophy and renal damage in male, but not female,
mice with renin-induced hypertension.
Fernandez et al. (2008) observed that mice with conditional homozygous
knockout of the Adm gene in the brain were viable without gross
abnormalities. However, they showed impaired motor coordination and were
hyperactive and overanxious compared to wildtype littermates. There were
no differences in circulating levels of ACTH or corticosterone between
knockout and wildtype mice, and both groups of mice responded similarly
to stimulant or antianxiolytic medications. Animals with no brain Adm
were less resistant to hypobaric hypoxia than wildtype mice, suggesting
that Adm has a neuroprotective function. Certain brains regions of
knockout mice, including the hippocampus, cerebral cortex, and
cerebellum, showed hyperpolymerized tubulin as a consequence of Adm
downregulation. Fernandez et al. (2008) concluded that Adm performs a
beneficial action in the brain by maintaining homeostasis both under
normal and stress conditions.
MIR4485
| dbSNP name | rs7350542(A,G) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 100616263 |
| snpEff Gene Name | AMPD3 |
| EntrezGene Description | microRNA 4485 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2668 |
| ExAC AF | 0.221 |
MTRNR2L8
| dbSNP name | rs190299947(G,T); rs4910148(G,A); rs371530372(A,G) |
| cytoBand name | 11p15.4 |
| EntrezGene GeneID | 100463486 |
| snpEff Gene Name | AMPD3 |
| EntrezGene Description | MT-RNR2-like 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
RASSF10
| dbSNP name | rs1141090(C,A) |
| cytoBand name | 11p15.2 |
| EntrezGene GeneID | 644943 |
| EntrezGene Description | Ras association (RalGDS/AF-6) domain family (N-terminal) member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3448 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial muscle weakness;
[Ears];
Hearing loss, sensorineural;
Absent brainstem auditory-evoked responses;
[Eyes];
Absent pupillary reflex;
Optic atrophy;
Nystagmus;
Visual loss;
[Mouth];
Tongue fasciculations;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory insufficiency;
Sleep hypoventilation (rare)
ABDOMEN:
[Gastrointestinal];
Dysphagia (in some patients)
SKELETAL:
[Spine];
Scoliosis (in some patients);
Kyphoscoliosis (in some patients);
[Hands];
Claw hands
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal, distal, and axial, severe;
Upper limb muscle weakness may be more severe than lower limb weakness;
Hypotonia;
Muscle atrophy, diffuse, severe;
Neurogenic changes seen on EMG;
Fibrillations
NEUROLOGIC:
[Central nervous system];
Cranial nerve palsies;
Bulbar palsy;
Ataxia;
Loss of independent ambulation;
Decreased spontaneous movements;
Inability to hold head up;
Clumsiness;
Cognition is preserved;
[Peripheral nervous system];
Areflexia;
Axonal sensorimotor neuropathy;
Sural nerve biopsy shows loss of large myelinated fibers;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients)
LABORATORY ABNORMALITIES:
Abnormal acylcarnitine profiles;
Organic aciduria
MISCELLANEOUS:
Onset in first few years of life;
Progressive disorder;
Variable severity;
Early death from respiratory failure may occur;
Some patients show significant clinical improvement with riboflavin
supplementation
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 52 (riboflavin transporter),
member 2 gene (SLC52A2, 607882.0001)
OMIM Title
*614713 RAS ASSOCIATION DOMAIN FAMILY, MEMBER 10; RASSF10
OMIM Description
CLONING
By searching a database for sequences similar to RASSF7 (143023) and
RASSF8 (608231), Sherwood et al. (2008) identified human RASSF10. The
deduced protein contains an N-terminal RAS (HRAS; 190020)-association
domain and a central coiled-coil domain.
By RT-PCR and 5-prime RACE of human bone marrow RNA, Hesson et al.
(2009) cloned RASSF10. The deduced protein contains 507 amino acids.
Hill et al. (2011) reported that the deduced 507-amino acid RASSF10
protein contains an N-terminal RAS-association domain and a central
coiled-coil domain, as well as a nuclear localization signal and 2
nuclear export signals. RASSF10 localized to the cytoplasm during
interphase and to centrosomes and microtubules during mitosis.
GENE FUNCTION
Hesson et al. (2009) found that RASSF10 was inactivated by methylation
in a majority of childhood leukemias examined.
Hill et al. (2011) found that the RASSF10 gene was inactivated by CpG
methylation in a majority of WHO grade II to III astrocytomas and WHO
grade IV primary glioblastomas, but not in grade I astrocytomas or
control brain tissue. Overexpression of RASSF10 reduced proliferation
and colony-forming ability of 2 glioma cell lines in which endogenous
RASSF10 expression was downregulated. Conversely, knockdown of RASSF10
via RNA interference in RASSF10-expressing U87 glioma cells stimulated
anchorage-independent growth and increased cell viability and
proliferative capacity. RASSF10 did not appear to have a role in cell
migration.
GENE STRUCTURE
Hesson et al. (2009) determined that RASSF10 is a single-exon gene. It
contains a large CpG island that covers most of the gene.
MAPPING
By genomic sequence analysis, Sherwood et al. (2008) mapped the RASSF9
gene to chromosome 11p15.2.
KCNJ11
| dbSNP name | rs2285676(A,G); rs5210(G,A); rs77674298(G,C); rs5213(C,T); rs5215(C,T); rs5219(T,C) |
| cytoBand name | 11p15.1 |
| EntrezGene GeneID | 3767 |
| EntrezGene Description | potassium inwardly-rectifying channel, subfamily J, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4674 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Malar hypoplasia;
Asymmetric face;
[Ears];
Prominent ears;
[Eyes];
Blepharophimosis;
Downslanting eyebrows;
[Nose];
Narrow nose;
Hypoplastic alae nasi;
Flat nasal bridge;
Post-choanal stenosis;
Pseudocleft of the columella;
[Mouth];
Everted lower lip;
High arched palate;
Cleft palate;
[Teeth];
Dental crowding
RESPIRATORY:
[Nasopharynx];
Tightly coiled epiglottis;
Shortened aryepiglottic folds;
[Larynx];
Laryngomalacia;
Stridor;
Globular cuneiform cartilage
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Slender ribs;
Hooked clavicles;
Hypoplastic glenoid fossa;
Pectus excavatum
SKELETAL:
Joint contractures (improves with time);
[Skull];
Small anterior cranial fossa;
Maxillary hypoplasia;
Craniosynostosis;
[Limbs];
Elbow contractures;
Knee contractures;
Dislocated radial head;
Ulnar bowing;
Slender long bones;
Femoral bowing;
Distal shortening of ulna;
[Hands];
Slender hands;
Arachnodactyly;
Camptodactyly;
Hypoplastic distal digital creases;
Long thumbs;
Long, slender metacarpals;
Long, slender phalanges;
[Feet];
Slender feet;
Long halluces;
Clubfeet;
Hallux valgus;
Camptodactyly
SKIN, NAILS, HAIR:
[Hair];
Downslanting eyebrows
NEUROLOGIC:
[Central nervous system];
Cerebellar enlargement;
Normal intelligence
PRENATAL MANIFESTATIONS:
[Placenta and umbilical cord];
Single umbilical artery
MOLECULAR BASIS:
Caused by mutation in the scavenger receptor class F, member 2 gene
(SCARF2, 613619.0001)
OMIM Title
*600937 POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
;;POTASSIUM CHANNEL, INWARDLY RECTIFYING, BIR SUBUNIT;;
BETA-CELL INWARD RECTIFIER SUBUNIT; BIR;;
INWARDLY RECTIFYING POTASSIUM CHANNEL Kir6.2
OMIM Description
DESCRIPTION
ATP-sensitive K+ (KATP) channels couple cell metabolism to membrane
excitability in various cell types, including pancreatic beta cells,
neurons, endocrine cells, and muscle cells. The archetypal KATP channel
is an octameric complex of KCNJ11 subunits and either SUR1 (ABCC8;
600509) subunits in pancreatic beta cells and many neurons or SUR2
(ABCC9; 601439) subunits in muscle. Four KCNJ11 subunits form the
channel pore, and each is associated with a SUR subunit that contributes
to regulation of channel gating (summary by Girard et al., 2009).
CLONING
Inagaki et al. (1995) cloned a member of the inwardly rectifying
potassium channel family, which they called BIR, for 'beta-cell inward
rectifier,' or Kir6.2, in the nomenclature of Chandy and Gutman (1993).
The channel was expressed in large amounts in rat pancreatic islets and
glucose-responsive insulin-secreting cell lines. The sequence showed a
single open reading frame encoding a 390-amino acid protein with 2
putative transmembrane segments. The mouse homolog also had a single
open reading frame encoding a 390-amino acid protein with 96% amino acid
identity with human BIR.
GENE STRUCTURE
Inagaki et al. (1995) determined that KCNJ11, the gene encoding human
BIR, is intronless in the protein-coding region. Several other genes
encoding inward rectifiers lack introns.
MAPPING
By fluorescence in situ hybridization, Inagaki et al. (1995) mapped the
BIR gene to 11p15.1. The sequence obtained from 1 lambda clone at the
3-prime end of the SUR gene (ABCC8; 600509) matched a part of the gene
encoding BIR; with a sense primer near the 3-prime end of the SUR gene
and an antisense primer near the 5-prime end of the BIR gene they
PCR-amplified an approximately 4.5-kb fragment. Thus, the authors
determined that the 2 genes are clustered at 11p15.1, with the BIR gene
immediately 3-prime of the SUR gene. The SUR gene had previously been
mapped to 11p15.1 by fluorescence in situ hybridization (Thomas et al.,
1995).
GENE FUNCTION
In pancreatic beta cells, ATP-potassium channels are crucial for the
regulation of glucose-induced insulin secretion and are the target for
the sulfonylureas, oral hypoglycemic agents widely used in the treatment
of noninsulin-dependent diabetes mellitus (NIDDM; 125853), and for
diazoxide, a potassium channel opener. The sulfonylurea receptor (SUR)
is a member of the ATP-binding cassette superfamily with multiple
transmembrane-spanning domains and 2 potential nucleotide-binding folds.
Inagaki et al. (1995) demonstrated that coexpression of BIR with SUR
reconstituted an inwardly rectifying potassium conductance of 76
picosiemens that was sensitive to ATP and was inhibited by sulfonylureas
and activated by diazoxide. The data indicated to the authors that these
pancreatic beta-cell potassium channels are a complex composed of at
least 2 subunits: BIR and SUR.
Inagaki et al. (1996) cloned rat SUR2 (601439) and found that
coexpression of SUR2 and BIR in COS-1 cells reconstituted the properties
of K(ATP) channels described in cardiac and skeletal muscle. However,
they found that the SUR2/BIR channel is less sensitive than the SUR/BIR
channel both to ATP and to the sulfonylurea glibenclamide, and is
activated by the cardiac K(ATP) channel openers cromakalim and pinacidil
but not by diazoxide. The affinity of SUR2 for sulfonylureas is 500
times lower than that of SUR.
MOLECULAR GENETICS
- Hyperinsulinemic Hypoglycemia
Thomas et al. (1996) screened genomic DNA from members of 15 families
with hyperinsulinemic hypoglycemia (HHF2; 601820) for mutations in the
KCNJ11 gene. In a male infant with profound hypoglycemia, born of
consanguineous Iranian parents, Thomas et al. (1996) identified
homozygosity for a 649T-C mutation (600937.0001). His parents were
heterozygous for the mutation.
Using SSCP and nucleotide sequence analysis, Nestorowicz et al. (1997)
screened 78 patients with hyperinsulinism for mutations in the KCNJ11
gene and identified homozygosity for a nonsense mutation (600937.0009)
in 1 patient.
De Lonlay et al. (1997) showed that in cases of the focal form, but not
those of the diffuse form, of hyperinsulinemic hypoglycemia there was
specific loss of maternal alleles of the imprinted chromosome region
11p15 in cells of the hyperplastic area of the pancreas but not in
normal pancreatic cells. This somatic event was consistent with a
proliferative monoclonal lesion. It involves disruption of the balance
between monoallelic expression of several maternally and paternally
expressed genes. Thus, they provided the first molecular explanation for
the heterogeneity of sporadic forms of PHHI such that it is possible to
perform only partial pancreatectomy, limited to the focal somatic
lesion, so as to avoid iatrogenic diabetes in patients with focal
adenomatous hyperplasia. It is possible that in these cases of somatic
loss of maternal 11p15.1, there is reduction to homozygosity for a
recessive ABCC8 or KCNJ11 mutation on the paternal allele, since both
ABCC8 and KCNJ11 are located in the 11p15.1 region.
Tornovsky et al. (2004) screened 15 patients with neonatal
hyperinsulinemic hypoglycemia for mutations in the ABCC8 and KCNJ11
genes and identified 12 mutations in 11 patients. Homozygosity for a
mutation in the promoter (600937.0010) and in exon 1 (600937.0011) of
the KCNJ11 gene were identified in an Israeli Bedouin and an Arab
patient, respectively.
Henwood et al. (2005) measured acute insulin responses (AIRs) to
calcium, leucine, glucose, and tolbutamide in 22 infants with recessive
ABCC8 or KCNJ11 mutations (see, e.g., 600937.0019), 8 of whom had
diffuse hyperinsulinism and 14 of whom had focal hyperinsulinism. Of the
24 total mutations, 7 showed evidence of residual K(ATP) channel
function: 2 of the patients with partial defects were homozygous and 4
heterozygous for amino acid substitutions or insertions, and 1 was a
compound heterozygote for 2 premature stop codons.
Lin et al. (2008) investigated the mechanisms by which
hyperinsulinism-associated mutations of arg301 (R301) in KCNJ11 (e.g.,
R301H; 600937.0019) lead to channel dysfunction. They found that R301
mutations in rat Kcnj11 resulted in reduced channel expression at the
cell surface in transfected cells and caused rapid, spontaneous current
decay, or inactivation. Mutagenesis studies indicated that R301 is near
the Kcnj11 subunit-subunit interface and likely stabilizes channel
activity. To evaluate the effects of channel inactivation on beta cell
function, Lin et al. (2008) expressed an alternative R301 mutation,
R301A, which induces channel inactivation without affecting channel
surface expression, in a rat insulinoma cell line. Expression of Kcnj11
with R301A resulted in more depolarized membrane potential and elevated
insulin secretion at basal glucose concentration compared with cells
expressing wildtype channels. Lin et al. (2008) concluded that mutations
at R301 may cause channel inactivation by disrupting subunit-subunit
interactions, and that this gating defect is sufficient to cause loss of
channel function and hyperinsulinism.
Pinney et al. (2008) identified 14 different dominantly inherited K(ATP)
channel mutations in 16 unrelated families, 13 with mutations in the
ABCC8 gene (see, e.g., 600509.0011) and 3 with mutations in the KCNJ11
gene (see, e.g., 600937.0020). Unlike recessive mutations, dominantly
inherited K(ATP) mutant subunits trafficked normally to the plasma
membrane when expressed in simian kidney cells; dominant mutations also
resulted in different channel-gating defects, with dominant ABCC8
mutations diminishing channel responses to magnesium adenosine
diphosphate or diazoxide and dominant KCNJ11 mutations impairing channel
opening even in the absence of nucleotides. Pinney et al. (2008)
concluded that there are distinctive features of dominant K(ATP)
hyperinsulinism compared to the more common and more severe recessive
form, including retention of normal subunit trafficking, impaired
channel activity, and a milder hypoglycemia phenotype that may escape
detection in infancy and is often responsive to diazoxide medical
therapy.
Taneja et al. (2009) reported that the Kir6.2 channel contains a
diacidic ER exit signal DXE at codons 280 to 282, which promotes
concentration of the channel into COPII-enriched ER exit sites prior to
ER export via a process that requires Sar1-GTPase (607690). They
identified an E282K mutation (600937.0022) in a Swedish patient with
HHF2 with focal adenomatous hyperplasia. The E282K mutation abrogated
the ER exit signal and prevented ER export and surface expression of the
channel. When coexpressed, the E282K-mutant subunit was able to
associate with the wildtype Kir6.2 and form functional channels, and
unlike most mutations did not cause protein misfolding. Since in focal
congenital hyperinsulinism, the maternal chromosome containing the
K(ATP) channel genes is lost, beta-cells of the patient lacked wildtype
Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal
chromosome. The resultant absence of functional KATP channels leads to
insulin hypersecretion. Taneja et al. (2009) concluded that surface
expression of K(ATP) channels is critically dependent on the
Sar1-GTPase-dependent ER exit mechanism, and abrogation of the diacidic
ER exit signal leads to congenital hyperinsulinism.
- Diabetes Mellitus Type II
Hani et al. (1998) identified an association between an E23K variant in
the KCNJ11 gene (600937.0014) and type II diabetes mellitus (125853) in
French families.
Hansen et al. (2005) studied the effects of the E23K polymorphism and a
PPARG P12A polymorphism (601487.0002) on the risk of type II diabetes
and found that the polymorphisms may act in an additive manner to
increase the risk of type II diabetes.
- Permanent Neonatal Diabetes
Because ATP-sensitive potassium channels mediate glucose-stimulated
insulin secretion from the pancreatic beta cells, Gloyn et al. (2004)
hypothesized that activating mutations in the KCNJ11 gene might cause
neonatal diabetes. They studied 29 patients with permanent neonatal
diabetes (PNDM; 606176) characterized by ketoacidosis or marked
hyperglycemia who were treated with insulin. The patients did not
secrete insulin in response to glucose or glucagon but did secrete
insulin in response to tolbutamide. Four of the patients also had severe
developmental delay and muscle weakness; 3 of them also had epilepsy and
mild dysmorphic features (DEND; see 606176). Gloyn et al. (2004)
sequenced the KCNJ11 gene in all 29 patients and identified 6 novel,
heterozygous missense mutations in 10. In 4 of the 10 families, the
mutation was an arg201-to-his (R201H) substitution (600937.0002). In 2
patients, the diabetes was familial. In 8 patients, the diabetes arose
from a spontaneous mutation (see, e.g., V59M; 600937.0003). When the
most common mutation, R201H, was coexpressed with SUR in Xenopus
oocytes, the ability of ATP to block mutant ATP-sensitive potassium
channels was greatly reduced. Thus, whereas inactivating mutations of
KCNJ11 lead to uncontrolled insulin secretion and congenital
hyperinsulinism, activating mutations cause neonatal diabetes. Gloyn et
al. (2004) concluded that heterozygous activating mutations of the
KCNJ11 gene are a common cause (approximately 34%) of permanent neonatal
diabetes. In a high proportion (80%) of subjects studied in their
series, the mutation occurred de novo.
Gloyn et al. (2005) identified 3 novel heterozygous mutations (see,
e.g., 600937.0017-600937.0018) in 3 of 11 probands with clinically
defined TNDM who did not have chromosome 6q24 abnormalities. The
mutations cosegregated with diabetes in 2 families and were not found in
100 controls. All 3 probands had insulin-treated diabetes diagnosed in
the first 4 months of life and went into remission by 7 to 17 months of
age. In transformed Xenopus oocytes, all 3 heterozygous mutations
resulted in a reduction in sensitivity to ATP when compared with
wildtype; however, the effect was less than that of PNDM-associated
mutations. Gloyn et al. (2005) concluded that mutations in KCNJ11 can
cause both remitting and permanent diabetes, suggesting that a fixed ion
channel abnormality may result in a fluctuating glycemic phenotype.
Yorifuji et al. (2005) found a missense mutation in the KCNJ11 gene
(600937.0012) in a 4-generation family with dominantly inherited
diabetes mellitus observed in 3 generations (see 610582). The onset and
severity of the diabetes were variable: transient neonatal diabetes,
childhood-onset diabetes, gestational diabetes, or adult-onset diabetes.
In a 20-year-old woman who had transient neonatal diabetes mellitus that
recurred at age 7 years, Colombo et al. (2005) identified heterozygosity
for a de novo R201H mutation in the KCNJ11 gene.
Proks et al. (2005) studied the MgATP sensitivity of KCNJ11-mutant
K(ATP) channels expressed in Xenopus oocytes. In contrast to wildtype
channels, Mg(2+) dramatically reduced the ATP sensitivity of
heterozygous R201C (600937.0004), R201H, V59M, and V59G (600937.0005)
channels. This effect was predominantly mediated via the
nucleotide-binding domains of SUR1 (ABCC8; 600509) and resulted from an
enhanced stimulatory action of MgATP. Proks et al. (2005) concluded that
KCNJ11 mutations increase the current magnitude of heterozygous K(ATP)
channels by increasing MgATP activation and by decreasing ATP
inhibition. The fraction of unblocked K(ATP) current at physiologic
MgATP concentrations correlated with the severity of the clinical
phenotype.
- Association with Impaired Exercise Stress Response
Reyes et al. (2009) found that the E23K polymorphism was overrepresented
in individuals with dilated cardiomyopathy (see 115200) and congestive
heart failure (CHF) compared to controls, and that the KK genotype was
associated with abnormal cardiopulmonary exercise stress testing. Reyes
et al. (2009) suggested that E23K might represent a biomarker for
impaired stress performance.
GENOTYPE/PHENOTYPE CORRELATIONS
To determine why some mutations in the KCNJ11 gene cause PNDM in
isolation whereas others cause PNDM associated with marked developmental
delay, muscle weakness, and epilepsy, Proks et al. (2004) expressed
wildtype or mutant Kir6.2/sulfonylurea receptor-1 channels in Xenopus
oocytes. All of the mutations investigated (R201C, Q52R, and V59G)
increased resting whole-cell K(ATP) currents by reducing channel
inhibition by ATP, but in the simulated heterozygous state, the mutation
causing PNDM alone (R201C) produced smaller K(ATP) currents and less
change in ATP sensitivity than mutations associated with severe disease
(Q52R and V59G). These findings suggested that increased K(ATP) currents
hyperpolarize pancreatic beta cells and impair insulin secretion,
whereas larger K(ATP) currents are required to influence extra
pancreatic cell function. Proks et al. (2004) also found that mutations
causing PNDM alone impaired ATP sensitivity directly (at the binding
site), whereas those associated with severe disease acted indirectly by
biasing the channel conformation toward the open state. The effect of
the mutation on ATP sensitivity in the heterozygous state reflected the
different contributions of a single subunit in the Kir6.2 tetramer to
ATP inhibition and to the energy of the open state. The results showed
that mutations in the slide helix of Kir6.2 (V59G) influence the channel
kinetics, providing evidence that this domain is involved in Kir channel
gating and suggesting that the efficacy of sulfonylurea therapy in PNDM
may vary with genotype.
Massa et al. (2005) screened the KCNJ11 gene in 18 Italian patients with
what they termed 'permanent diabetes mellitus of infancy' (PDMI),
including 12 patients with onset within 3 months after birth and 6 with
onset between 3 months to 1 year of age. Five different heterozygous
mutations were identified in 8 patients with diabetes diagnosed between
day 3 and day 182. Two of these mutations were novel. Four of the 8
patients also had motor and/or developmental delay. Massa et al. (2005)
concluded that KCNJ11 mutations are a common cause of PNDM either in
isolation or associated with developmental delay.
The beta-cell ATP-sensitive potassium channel is a key component of
stimulus-secretion coupling in the pancreatic beta cell. The channel
couples metabolism to membrane electrical events, bringing about insulin
secretion. Given the critical role of this channel in glucose
homeostasis, it is not surprising that mutations in the genes encoding
the 2 essential subunits of the channel, KCNJ11 and ABCC8, can result in
either hypoglycemia or hyperglycemia. Gloyn et al. (2006) reviewed the
loss-of-function mutations in KCNJ11 and ABCC8, which can cause
oversecretion of insulin and result in hyperinsulinemia of infancy. They
reviewed the management of patients in whom mutations in these genes are
found.
From a study of 49 patients with activating Kir6.2 mutations,
Slingerland and Hattersley (2006) concluded that these mutations cause a
severe reduction in fetal insulin secretion and hence fetal growth but
that this is independent of mutation severity. Postnatal catch-up
required insulin treatment but was complete, except in those with
epilepsy.
ANIMAL MODEL
Miki et al. (1997) generated transgenic mice expressing a
dominant-negative mutation within the conserved gly-tyr-gly motif of the
putative K(+)-permeable domain of Kcnj11. The gene was inserted
downstream of the human insulin promoter region for selective expression
in pancreatic beta cells. Transgenic mice developed hypoglycemia with
hyperinsulinemia as neonates and hyperglycemia with hypoinsulinemia and
decreased beta cell numbers as adults. Kcnj11 function was impaired in
the beta cells of transgenic mice with hyperglycemia, and both resting
membrane potential and basal calcium concentrations were significantly
elevated in transgenic mice. Miki et al. (1997) also observed a high
frequency of apoptotic beta cells prior to the development of
hyperglycemia, suggesting a role for Kcnj11 in cell survival as well as
in regulating insulin secretion.
Koster et al. (2000) generated transgenic mice expressing pancreatic
beta-cell K(ATP) channels with reduced ATP sensitivity. They used
transgenes with truncation of the N-terminal 30 amino acids of the
Kir6.2 subunit, and a double mutant with the 30-amino acid truncation
and a lys185-to-gln mutation. These transgenes were fused at the C
terminus with the green fluorescent protein to allow for detection under
ultraviolet illumination. Transgenic animals developed severe
hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days, and
typically died within 5 days. Nevertheless, islet morphology, insulin
localization, and alpha- and beta-cell distributions were normal (before
day 3), pointing to reduced insulin secretion as causal. The data
indicated that normal K(ATP) channel activity is critical for
maintenance of euglycemia and that overactivity can cause diabetes by
inhibiting insulin secretion.
In mice with a conditional deletion of Hnf4a (600281) in pancreatic beta
cells, Gupta et al. (2005) observed hyperinsulinemia in fasted and fed
animals but also impaired glucose tolerance. Islet perfusion and
calcium-imaging studies showed abnormal beta cell responses to
stimulation by glucose and sulfonylureas, explainable in part by a 60%
reduction in expression of the potassium channel subunit Kir6.2.
Cotransfection assays revealed that the Kir6.2 gene is a transcriptional
target of HNF4A. Gupta et al. (2005) concluded that HNF4A is required in
the pancreatic beta cell for regulation of the pathway of insulin
secretion dependent on the ATP-dependent potassium channel.
ATP-sensitive potassium channels are activated by various metabolic
stresses, including hypoxia. The substantia nigra pars reticulata, the
area with the highest expression of ATP-sensitive potassium channels in
the brain, plays a pivotal role in the control of seizures. Yamada et
al. (2001) studied mutant mice lacking the Kir6.2 subunit of
ATP-sensitive potassium channels and found that they were susceptible to
generalized seizures after brief hypoxia. In normal mice, the substantia
nigra pars reticulata neuron activity was inactivated during hypoxia by
the opening of the postsynaptic ATP-sensitive potassium channels,
whereas in knockout mice, the activity of these neurons was enhanced.
ATP-sensitive potassium channels exert a depressant effect on substantia
nigra pars reticulata neuronal activity during hypoxia and may be
involved in the nigral protection mechanism against generalized
seizures.
Girard et al. (2009) created a mouse strain conditionally expressing the
human Kir6.2 V59M mutation (600937.0003) specifically in pancreatic beta
cells. Kir6.2(V59M) mRNA was expressed at a level comparable to that of
endogenous wildtype Kir6.2 mRNA. Mutant mice (beta-V59M mice) developed
severe diabetes soon after birth, and by 5 weeks of age, blood glucose
levels were markedly increased and insulin was undetectable. Isolated
beta-V59M islets displayed a reduced percentage of beta cells, abnormal
morphology, abnormal calcium oscillations, lower insulin content, and
decreased expression of Kir6.2, Sur1, and insulin mRNA. Beta-V59M islets
secreted substantially less insulin and showed a smaller increase in
intracellular calcium in response to glucose than wildtype islets, which
was due to reduced sensitivity of Kir6.2(V69M) channels to ATP or
glucose. Current and secretion events downstream of channel closure
remained intact.
By using mice carrying the human V59M mutation in Kir6.2 (600937.0003)
targeted to either muscle or nerve, Clark et al. (2010) showed that
analogous motor impairments originate in the central nervous system
rather than in muscle or peripheral nerves. Clark et al. (2010) also
identified locomotor hyperactivity as a feature of K(ATP) channel
overactivity. Clark et al. (2010) concluded that their finding suggested
that drugs targeted against neuronal, rather than muscle, K(ATP)
channels are needed to treat the motor deficits and that such drugs
require high blood-brain barrier permeability.
MRGPRX4
| dbSNP name | rs2468774(C,G); rs2445180(T,G); rs1869788(A,G); rs2445179(T,C); rs11024532(C,T); rs4630269(C,T) |
| ccdsGene name | CCDS7831.1 |
| cytoBand name | 11p15.1 |
| EntrezGene GeneID | 117196 |
| EntrezGene Description | MAS-related GPR, member X4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MRGPRX4:NM_054032:exon1:c.C24G:p.F8L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96LA9 |
| dbNSFP Uniprot ID | MRGX4_HUMAN |
| dbNSFP KGp1 AF | 0.343406593407 |
| dbNSFP KGp1 Afr AF | 0.231707317073 |
| dbNSFP KGp1 Amr AF | 0.331491712707 |
| dbNSFP KGp1 Asn AF | 0.480769230769 |
| dbNSFP KGp1 Eur AF | 0.317941952507 |
| dbSNP GMAF | 0.3439 |
| ESP Afr MAF | 0.245566 |
| ESP All MAF | 0.271796 |
| ESP Eur/Amr MAF | 0.285232 |
| ExAC AF | 0.301 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Weakness of the facial muscles;
[Eyes];
Slow eye movements (onset in second decade);
Ocular gaze palsies (onset in second decade)
GENITOURINARY:
[Bladder];
Incontinence
ABDOMEN:
[Gastrointestinal];
Dysphagia (onset in second decade);
Chewing difficulties;
Incontinence
SKELETAL:
[Spine];
Scoliosis (less common);
[Feet];
Shortening of the Achilles tendon;
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness;
Normal muscle biopsy;
EMG shows reduction of voluntary recruitment
NEUROLOGIC:
[Central nervous system];
Upper and lower motor neuron degeneration;
Spastic paraplegia, lower limb;
Stiffness of the lower limbs;
Delayed motor development;
Loss of motor milestones;
Upper limb involvement (onset in the first decade);
Spastic tetraplegia (onset in the second decade);
Bulbar involvement;
Dysarthria;
Anarthria;
Hyperreflexia;
Extensor plantar responses;
Early involvement of the corticospinal pathways;
Weakness of the facial muscles;
Normal cognition and intellectual function;
Atrophy of the motor cortex in older patients seen on MRI;
T2-weighted hyperintensities in the corticospinal tracts and posterior
arms of the internal capsule in older patients seen on MRI;
Decreased or absent motor evoked potentials (MEP), indicating dysfunction
of the corticospinal tracts
MISCELLANEOUS:
Onset within first 2 years of life;
Progressive disorder;
Some patients never achieve walking or running;
Most patients become wheelchair-bound;
Allelic disorder to juvenile-onset amyotrophic lateral sclerosis (ALS2,
205100);
Allelic disorder to juvenile primary lateral sclerosis (PLSJ, 606353)
MOLECULAR BASIS:
Caused by mutation in the alsin gene (ALS2, 606352.0005)
OMIM Title
*607230 MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER X4; MRGPRX4
;;MRGX4
OMIM Description
CLONING
Dong et al. (2001) identified, in the mouse and human genomes, a family
of G protein-coupled receptors (GPCRs) related to the MAS1 oncogene
(165180), including MRGX4. Several pseudogenes were also identified. The
predicted MRG proteins contain transmembrane, extracellular, and
cytoplasmic domains. A subset of MRGs was expressed in specific
subpopulations of sensory neurons that detect painful stimuli. The
expression patterns of these genes thus revealed an unexpected degree of
molecular diversity among nociceptive neurons. Some MRGs could be
specifically activated in heterologous cells by RFamide neuropeptides
such as NPFF and NPAF (see 604643), which are analgesic in vivo. The
authors concluded that MRGs may regulate nociceptor function and/or
development, including the sensation or modulation of pain.
MAPPING
By genomic sequence analysis, Dong et al. (2001) mapped the MRGX4 gene
to chromosome 11.
LOC494141
| dbSNP name | rs2468790(T,A); rs4757627(C,A); rs2468789(T,G); rs2251440(T,C); rs3100768(T,G); rs11024553(G,A) |
| cytoBand name | 11p15.1 |
| EntrezGene GeneID | 494141 |
| snpEff Gene Name | RP11-113D6.10 |
| EntrezGene Description | solute carrier family 25, member 51 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4917 |
MRGPRX1
| dbSNP name | rs11599929(C,T); rs72890000(C,T); rs2014931(T,C); rs78179510(C,T) |
| ccdsGene name | CCDS7846.1 |
| CosmicCodingMuts gene | MRGPRX1 |
| cytoBand name | 11p15.1 |
| EntrezGene GeneID | 259249 |
| EntrezGene Description | MAS-related GPR, member X1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MRGPRX1:NM_147199:exon1:c.G588A:p.L196L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2833 |
| ESP Afr MAF | 0.275524 |
| ESP All MAF | 0.23696 |
| ESP Eur/Amr MAF | 0.217219 |
| ExAC AF | 0.257 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Weakness of the facial muscles;
[Eyes];
Slow eye movements (onset in second decade);
Ocular gaze palsies (onset in second decade)
GENITOURINARY:
[Bladder];
Incontinence
ABDOMEN:
[Gastrointestinal];
Dysphagia (onset in second decade);
Chewing difficulties;
Incontinence
SKELETAL:
[Spine];
Scoliosis (less common);
[Feet];
Shortening of the Achilles tendon;
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness;
Normal muscle biopsy;
EMG shows reduction of voluntary recruitment
NEUROLOGIC:
[Central nervous system];
Upper and lower motor neuron degeneration;
Spastic paraplegia, lower limb;
Stiffness of the lower limbs;
Delayed motor development;
Loss of motor milestones;
Upper limb involvement (onset in the first decade);
Spastic tetraplegia (onset in the second decade);
Bulbar involvement;
Dysarthria;
Anarthria;
Hyperreflexia;
Extensor plantar responses;
Early involvement of the corticospinal pathways;
Weakness of the facial muscles;
Normal cognition and intellectual function;
Atrophy of the motor cortex in older patients seen on MRI;
T2-weighted hyperintensities in the corticospinal tracts and posterior
arms of the internal capsule in older patients seen on MRI;
Decreased or absent motor evoked potentials (MEP), indicating dysfunction
of the corticospinal tracts
MISCELLANEOUS:
Onset within first 2 years of life;
Progressive disorder;
Some patients never achieve walking or running;
Most patients become wheelchair-bound;
Allelic disorder to juvenile-onset amyotrophic lateral sclerosis (ALS2,
205100);
Allelic disorder to juvenile primary lateral sclerosis (PLSJ, 606353)
MOLECULAR BASIS:
Caused by mutation in the alsin gene (ALS2, 606352.0005)
OMIM Title
*607227 MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER X1; MRGPRX1
;;MRGX1
OMIM Description
CLONING
Dong et al. (2001) identified, in the mouse and human genomes, a family
of G protein-coupled receptors (GPCRs) related to the MAS1 oncogene
(165180), including MRGX1. Several pseudogenes were also identified. The
predicted MRG proteins contain transmembrane, extracellular, and
cytoplasmic domains. A subset of MRGs was expressed in specific
subpopulations of sensory neurons that detect painful stimuli. The
expression patterns of these genes thus revealed an unexpected degree of
molecular diversity among nociceptive neurons. Some MRGs could be
specifically activated in heterologous cells by RFamide neuropeptides
such as NPFF and NPAF (see 604643), which are analgesic in vivo. The
authors concluded that MRGs may regulate nociceptor function and/or
development, including the sensation or modulation of pain.
MAPPING
By genomic sequence analysis, Dong et al. (2001) mapped the MRGX1 gene
to chromosome 11.
ANIMAL MODEL
Liu et al. (2009) found that mice lacking a cluster of 12 Mrgpr genes on
mouse chromosome 7 showed significant deficits in itch and scratching
behavior induced by chloroquine, but not histamine. Pain was not
affected. In vitro studies showed that chloroquine directly excited
dorsal root ganglia sensory neurons in an Mrgpr-dependent manner, and
that chloroquine specifically activated mouse MrgprA3 and human MRGPRX1.
MrgprA3-expressing neurons also responded to histamine and coexpressed
gastrin-releasing peptide, a peptide involved in itch sensation, and
MrgprC11. Activation of these neurons with the MrgprC11-specific agonist
BAM8-22 induced itch in wildtype but not mutant mice.
FANCF
| dbSNP name | rs450946(G,A); rs444923(C,T); rs12294705(T,C); rs4447177(G,A) |
| cytoBand name | 11p14.3 |
| EntrezGene GeneID | 2188 |
| snpEff Gene Name | AC103801.2 |
| EntrezGene Description | Fanconi anemia, complementation group F |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1203 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Isolated cases
HEAD AND NECK:
[Head];
Dolichocephaly;
[Face];
High, broad forehead;
Frontal bossing;
Deep, prominent philtrum;
[Ears];
Thick earlobes;
Anteverted ears;
[Eyes];
Retinoblastoma;
Hypotelorism;
Epicanthal folds;
[Nose];
Short, bulbous nose;
[Mouth];
Thin upper lip;
Thick, everted lower lip
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Delayed language development;
Axial hypotonia;
Diplegia;
Hypoplasia of the corpus callosum (2 patients)
NEOPLASIA:
Retinoblastoma
MISCELLANEOUS:
Contiguous gene deletion syndrome;
Most cases are de novo occurrences, but rare autosomal dominant inheritance
has been reported
MOLECULAR BASIS:
Contiguous gene deletion of at least 16Mb encompassing 39 genes on
13q14
OMIM Title
*613897 FANCF GENE; FANCF
OMIM Description
CLONING
By complementation cloning, de Winter et al. (2000) identified the gene
mutated in Fanconi anemia group F (603467). They found that the FANCF
gene encodes a polypeptide with homology to the prokaryotic RNA-binding
protein ROM. The region of homology with ROM comprises the N terminus of
the prokaryotic protein, which is the region involved in RNA binding.
The homologous region in FANCF is predicted to form an alpha-helical
structure. De Winter et al. (2000) suggested that this homology may
provide a foothold for functional analysis of the pathway that is
defective in FA patients.
GENE STRUCTURE
De Winter et al. (2000) determined that the FANCF gene has no introns.
MAPPING
De Winter et al. (2000) found that the FANCF cDNA was identical to
several ESTs mapped to chromosome 11p15, between microsatellite markers
D11S1359 and D11S929.
GENE FUNCTION
De Winter et al. (2000) studied the subcellular localizations and mutual
interactions of the FA proteins in human lymphoblasts. FANCF was found
predominantly in the nucleus, where it complexes with FANCA (607139),
FANCC (227645), and FANCG (602956). These interactions were detected in
wildtype and FANCD (FANCD2; 227646) lymphoblasts, but not in
lymphoblasts of other FA complementation groups. The authors
hypothesized that each of the FA proteins, except FANCD, is required for
complex formation, and that the multiprotein FA complex serves a nuclear
function to maintain genomic integrity.
By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al.
(2003) identified 3 distinct multiprotein complexes associated with BLM
(RECQL3; 604610). One of the complexes, designated BRAFT, contained the
Fanconi anemia core complementation group proteins FANCA (607139),
FANCG, FANCC, FANCE (600901), and FANCF, as well as topoisomerase
III-alpha (TOP3A; 601243) and replication protein A (RPA; see 179835).
BLM complexes isolated from an FA cell line had a lower molecular mass,
likely due to loss of FANCA and other FA components. BLM- and
FANCA-associated complexes had DNA unwinding activity, and BLM was
required for this activity.
Using yeast 2-hybrid and coimmunoprecipitation assays, Tremblay et al.
(2008) found that HES1 (139605), a NOTCH1 (190198) pathway component
involved in hematopoietic stem cell (HSC) self-renewal, interacted
directly with FANCA, FANCF, FANCG, and FANCL (PHF9; 608111), but not
with other FA core complex components. Mutation analysis showed that
interactions with individual FA core components required different
domains within HES1. HES1 did not interact with FA core components if
any of them contained an FA-related mutation, suggesting that a
functional FA pathway is required for HES1 interaction. Depletion of
HES1 from HeLa cells resulted in failure of normal interactions between
individual FA core components, as well as altered protein levels and
mislocalization of some FA core components. Depletion of HES1 also
increased cell sensitivity to the DNA crosslinking agent mitomycin C
(MMC) and reduced MMC-induced monoubiquitination of FANCD2 and
localization of FANCD2 to MMC-induced foci. Tremblay et al. (2008)
concluded that interaction with HES1 is required for normal FA core
complex function in the DNA damage response. They proposed that the HSC
defect in FA may result from the inability of HES1 to interact with the
defective FA core complex.
FIBIN
| dbSNP name | rs7111860(T,G); rs7892(C,G); rs2350934(G,A); rs139159677(C,T); rs11029769(G,A) |
| cytoBand name | 11p14.2 |
| EntrezGene GeneID | 387758 |
| EntrezGene Description | fin bud initiation factor homolog (zebrafish) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09642 |
MIR8068
| dbSNP name | rs78258445(G,A) |
| cytoBand name | 11p14.1 |
| snpEff Gene Name | RP11-22P4.1 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0101 |
| ExAC AF | 0.001686 |
KCNA4
| dbSNP name | rs80263336(T,C); rs140083893(G,A); rs3802914(G,A); rs201817148(T,C); rs1323860(A,G); rs10835608(C,T); rs534311(C,T); rs140143455(G,C) |
| ccdsGene name | CCDS41629.1 |
| cytoBand name | 11p14.1 |
| EntrezGene GeneID | 3739 |
| EntrezGene Description | potassium voltage-gated channel, shaker-related subfamily, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNA4:NM_002233:exon2:c.A287G:p.H96R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6549 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P22459 |
| dbNSFP Uniprot ID | KCNA4_HUMAN |
| ESP Afr MAF | 0.000239 |
| ESP All MAF | 0.000317 |
| ESP Eur/Amr MAF | 0.000355 |
| ExAC AF | 0.0003018 |
OMIM Clinical Significance
Neuro:
Ataxia due to posterior column degeneration;
Progressive vibratory and postural sensibility loss;
Muscle stretch reflex losses;
Flexor plantar responses;
Pain and temperature sensations preserved;
No cerebellar or pyramidal tract involvement
Skel:
Scoliosis
Misc:
Age of onset between 19 and 30 years
Inheritance:
Autosomal dominant
OMIM Title
*176266 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER
4; KCNA4
;;POTASSIUM CHANNEL, FETAL SKELETAL MUSCLE;;
POTASSIUM CHANNEL, TYPE A;;
POTASSIUM CHANNEL, RAPIDLY INACTIVATING;;
POTASSIUM CHANNEL, CARDIAC;;
POTASSIUM CHANNEL 2; PCN2;;
HK1
OMIM Description
CLONING
Potassium voltage-gated ion channels are highly diverse membrane
proteins that seem to be present in nearly every eukaryotic cell (see
176260). The rat genome encodes a potassium-channel (K-channel) family
(RCK) homologous to the Shaker channels of Drosophila (Stuehmer et al.,
1989). Only 1 member of this rat K-channel family, RCK4, was found to
express A-type, i.e., rapidly inactivating, K-channels. Philipson et al.
(1990) provided the sequence of the cDNA corresponding to a fetal
skeletal muscle potassium channel related to RCK4. The predicted
653-amino acid PCN2 protein shares 55% sequence identity with PCN1
(176267) (Philipson et al., 1991). Tamkun et al. (1991) cloned a
full-length human cDNA showing 97% identity to RCK4 and referred to it
as HK1. HK1 mRNA was expressed in heart, in particular in the atrium and
ventricle. Therefore, they concluded that the K-channel formed by this
protein might be important in the regulation of the fast repolarizing
phase of action potentials in heart and thus might influence the
duration of cardiac action potential.
GENE FUNCTION
Gu et al. (2003) found that Kv1 axonal targeting required its T1
tetramerization domain. When fused to unpolarized CD4 (186940) or
dendritic transferrin receptor (TFR; 190010), T1 domains from Kv1.1
(176260), Kv1.2 (176262), and Kv1.4 promoted their axonal surface
expression. Moreover, mutations in the T1 domain of Kv1.2 that
eliminated association with Kv-beta-2 (601142) compromised axonal
targeting, but not surface expression, of CD4-T1 fusion proteins. The
authors concluded that proper association of Kv-beta with the Kv1 T1
domain is essential for axonal targeting.
The combinatorial association between distinct alpha and beta subunits
is thought to determine whether Kv channels function as noninactivating
delayed rectifiers or as rapidly inactivating A-type channels. Oliver et
al. (2004) showed that membrane lipids can convert A-type channels into
delayed rectifiers and vice versa. Phosphoinositides, particularly
phosphatidylinositol-4,5-bisphosphate (PIP2), remove N-type inactivation
from A-type channels by immobilizing the inactivation domains.
Conversely, arachidonic acid and its amide anandamide endow delayed
rectifiers with rapid voltage-dependent inactivation. Oliver et al.
(2004) concluded that the bidirectional control of Kv channel gating by
lipids may provide a mechanism for the dynamic regulation of electrical
signaling in the nervous system.
MAPPING
Grandy et al. (1992) mapped the KCNA4 gene to 11p14-p13. Using PCR,
Gessler et al. (1992) produced a genomic HK1 DNA probe to map the gene
on human chromosome 11p14 by study of somatic cell hybrids and by pulsed
field gel electrophoresis (PFGE). The somatic cell hybrid analysis
demonstrated that the gene is in the WAGR region (see 194072). PFGE
analysis and comparison with the well-established PFGE map of the region
localized the gene to 11p14, 200 to 600 kb telomeric to FSHB (136530).
Thus, as the FSHB gene is located at 11p14, close to the 11p13/p14
boundary, the HK1 gene could be assigned to the proximal part of that
band, namely, 11p14.1. From observations in cases of WAGR leading to
deletion in this region, Gessler et al. (1992) concluded that a
hemizygous deletion of HK1 may have little phenotypic effect, perhaps
because of less stringent requirements for the control of expression
levels for this gene. The HK1 gene is located in the wrong position to
be a plausible candidate gene for the long QT syndrome (LQT1; 192500).
Philipson et al. (1993) mapped a potassium channel gene, which they
symbolized KCNA4, to 11q13.4-q14.1 by a combination of segregation in a
panel of reduced human-mouse somatic cell hybrids and isotopic in situ
hybridization. Klocke et al. (1993) listed the KCNA8 gene, mapped by
others to 11p, as the same as KCNA4.
LINC00294
| dbSNP name | rs2273552(G,A); rs2273554(T,A); rs4756561(T,C); rs4756563(A,G); rs4756564(A,G) |
| cytoBand name | 11p13 |
| EntrezGene GeneID | 283267 |
| snpEff Gene Name | TCP11L1 |
| EntrezGene Description | long intergenic non-protein coding RNA 294 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3861 |
MIR1343
| dbSNP name | rs2986407(T,C); rs11032942(T,C) |
| ccdsGene name | CCDS7896.1 |
| cytoBand name | 11p13 |
| EntrezGene GeneID | 100616437 |
| snpEff Gene Name | PDHX |
| EntrezGene Description | microRNA 1343 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2163 |
| ExAC AF | 0.606 |
PAMR1
| dbSNP name | rs140125122(G,T); rs114924477(A,G); rs1048193(C,G); rs115802375(A,C); rs75435433(T,C); rs16927472(T,C); rs80106476(C,T); rs185752023(T,C); rs61736408(T,C); rs199577710(C,T); rs35216474(C,T); rs675227(G,C); rs79815479(T,C); rs677897(A,G); rs598072(T,G); rs78137813(G,A); rs599338(A,G); rs599773(T,C); rs67910620(T,C); rs614084(T,C); rs12788533(C,G); rs79182220(G,A); rs644755(A,G); rs1148935(A,G); rs1400489(A,G); rs113777401(G,C); rs12793233(T,C); rs11033122(C,T); rs11033123(G,A); rs116189476(T,C); rs2421896(A,G); rs144143217(A,C); rs2421895(G,A); rs150018566(G,A); rs2210627(G,T); rs190713615(T,C); rs11525350(G,C); rs137939047(G,A); rs7111380(C,T); rs2222137(C,A); rs2203656(A,C); rs113022516(T,G); rs7944997(C,T); rs1850368(A,C); rs113888189(C,A); rs79242196(C,T); rs114980302(G,T); rs12365646(T,C); rs116018194(G,A); rs75882309(C,T); rs7939075(T,C); rs11033125(C,T); rs56168073(T,A); rs1400495(A,G); rs34162672(A,G); rs115308231(T,G); rs113528545(A,G); rs34147223(C,T); rs74849412(C,T); rs17787246(T,C); rs7927488(T,C); rs7943580(C,A); rs1516986(G,C); rs1516987(T,C); rs10836398(A,G); rs78974138(T,C); rs1356333(G,A); rs140102183(G,A); rs35880213(G,A); rs76141437(A,G); rs189168549(A,G); rs7934974(C,A); rs1516988(T,C); rs144732811(C,G); rs7943168(C,T); rs147489895(G,T); rs79545974(A,G); rs7947578(C,T); rs11033132(A,T); rs11033133(A,T); rs7129500(A,C); rs7129975(A,C); rs7130305(G,T); rs1400490(G,T); rs1400491(C,G); rs113491445(C,T); rs614527(A,G); rs11033135(T,C); rs111560586(T,A); rs187128881(G,C); rs11033136(A,G); rs7112485(G,A); rs7128765(T,A); rs7128897(T,C); rs7112810(A,T); rs10501139(T,C); rs16927492(T,C); rs113165133(C,T); rs10501140(T,C); rs10836401(T,C); rs11602786(T,C); rs10836402(G,A); rs112455464(G,A); rs1400492(G,C); rs116100766(C,A); rs6484787(G,A); rs113683538(A,G); rs7929043(C,T); rs111776637(T,C); rs78160672(C,A); rs10836404(A,G); rs12795640(G,A); rs113129532(T,C); rs7933803(C,T); rs7933964(A,G); rs16927500(G,A); rs34190626(A,C); rs61620632(C,T); rs61880922(T,C); rs78105856(T,C); rs36048818(C,T); rs11033140(C,T); rs149389367(G,C); rs116103153(C,T); rs7949277(C,G); rs1996369(C,G); rs138442633(A,C); rs12799002(A,G); rs16927508(C,T); rs16927509(T,A); rs7478896(C,T); rs1464157(A,G); rs1878379(A,C); rs938654(C,A); rs7106288(G,A); rs185735468(G,A); rs144928277(A,G); rs11033141(A,G); rs67367407(C,A); rs11033142(C,T); rs147852757(T,G); rs114520545(C,T); rs182728853(A,T); rs188658448(A,T); rs114010348(C,T); rs938655(C,T); rs7102175(C,G); rs4638283(G,A); rs4277086(G,A); rs4463824(A,T); rs4456236(A,C); rs12420172(G,A); rs78827023(G,A); rs592268(A,G); rs658383(T,C); rs145053786(C,T); rs138978810(G,A); rs150487973(T,C); rs149459915(C,T); rs10742348(A,G); rs10836405(T,C); rs1173909(A,G); rs148459880(A,T); rs620750(G,T); rs12421661(G,A); rs619914(T,C); rs684748(C,G); rs4756234(G,A); rs686971(C,A); rs16927514(T,C); rs12295628(C,T); rs117711020(G,C); rs621363(G,A); rs116828394(T,C); rs114281362(C,T); rs115346031(C,G); rs623562(G,A); rs652845(A,G); rs116334620(C,T); rs115704458(T,A); rs117145777(T,C); rs114596389(C,A); rs649640(A,G); rs114135026(C,G); rs638035(C,T); rs116736599(G,T); rs638517(T,G); rs115873113(T,G); rs117524439(C,A); rs635313(T,C); rs938656(A,G); rs634809(A,G); rs115838855(G,T); rs138610739(C,T); rs682512(G,A); rs10836406(T,C); rs10768140(T,G); rs609060(A,G); rs7115890(T,A); rs589406(C,T); rs1173912(C,T); rs4142611(A,G); rs116200455(G,C); rs590102(G,A); rs17726212(A,G); rs181489623(G,A); rs642327(C,G); rs16927542(A,G); rs11033146(C,T); rs115483325(A,G); rs663074(A,G); rs694961(G,A); rs112661148(A,G); rs581513(T,G); rs636328(A,G); rs927404(C,A); rs2676460(T,G); rs2676461(C,G); rs2676462(T,C); rs2676463(C,T); rs2256406(C,T); rs12285962(T,C); rs2256404(A,G); rs658907(C,A); rs582555(C,T); rs140225440(C,A); rs7942287(A,G); rs1996368(G,A); rs60476670(A,G); rs61880927(G,A); rs7946272(C,T); rs672057(A,G); rs628925(C,T); rs660411(G,A); rs659981(G,A); rs658652(C,T); rs658649(A,G); rs657755(C,G); rs112590511(G,A); rs629328(A,T); rs629236(A,G); rs628393(G,C); rs612861(G,A); rs627426(T,C); rs601295(T,A); rs183756177(C,T); rs599933(C,A); rs599836(T,C); rs599506(A,C); rs599060(T,C); rs613556(A,T); rs112651358(C,T); rs613107(T,A); rs11522594(C,T); rs597762(G,C); rs11499812(T,C); rs586291(G,T); rs1850367(A,G); rs1850366(C,T); rs1850365(A,C); rs1607122(T,C); rs11033151(A,G); rs2781018(T,C); rs2781017(G,C); rs2676477(T,A); rs1711692(A,G); rs583220(G,C); rs112849231(C,G); rs678948(G,T); rs677550(C,G); rs581660(C,T); rs647574(T,C); rs646660(C,T); rs1760317(T,G); rs631981(C,T); rs12291121(T,A); rs663084(A,C); rs631093(T,G); rs9633872(C,T); rs4756240(A,G); rs2781009(A,G); rs200970367(A,T); rs617261(G,A); rs11033155(G,C); rs7106280(G,C); rs10768146(T,C); rs769149(C,T); rs61879560(A,G); rs1400497(G,A); rs12799337(A,T); rs55992420(G,A); rs11033157(C,T); rs10836409(C,G); rs75454958(C,A); rs2421956(T,A); rs635896(C,T); rs635366(G,T); rs10742350(C,T); rs10742351(C,A); rs10742352(A,G); rs10734438(C,T); rs10734439(C,T); rs749218(G,A); rs17482(G,A); rs140487451(A,G); rs6484791(A,G); rs619997(G,C); rs591707(G,C); rs7932452(G,C); rs589475(C,T); rs653649(G,C); rs35295103(C,T); rs650950(T,C); rs656009(G,A); rs650479(C,G); rs16927595(T,G); rs144465470(G,A); rs2184206(C,T); rs12285506(G,A); rs1760315(G,A); rs1659635(A,G); rs16926171(T,C); rs1659634(T,C); rs1760314(C,T); rs1760313(G,C); rs1760312(C,T); rs1760311(A,G); rs695121(T,C); rs626301(G,C); rs729878(G,C); rs627119(A,G); rs628867(A,C); rs638888(T,C); rs1010394(C,G); rs638009(T,C); rs637585(C,T); rs113265849(T,C); rs113257062(C,T); rs623929(G,T); rs610966(A,G); rs12800242(T,C); rs12803861(A,C); rs16927622(C,G); rs114190226(T,C); rs1996370(T,C); rs479011(G,C); rs61879580(C,T); rs61879581(G,C); rs61879582(T,C); rs61879583(A,G); rs17795210(C,T); rs115075709(C,G); rs17795246(C,T); rs114178304(G,A); rs61642976(G,A); rs61179815(G,T); rs61089142(G,T); rs141831312(T,G); rs116088476(G,T); rs55990649(A,G); rs55782193(C,G); rs609664(A,G); rs625659(A,G); rs609602(C,G); rs625568(A,C); rs567402(G,T); rs116130406(A,G); rs7952594(T,C); rs7937700(C,A); rs56694684(G,A) |
| ccdsGene name | CCDS7898.1 |
| CosmicCodingMuts gene | PAMR1 |
| cytoBand name | 11p13 |
| EntrezGene GeneID | 25891 |
| EntrezGene Description | peptidase domain containing associated with muscle regeneration 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PAMR1:NM_015430:exon11:c.G1649A:p.R550Q,PAMR1:NM_001282676:exon8:c.G1265A:p.R422Q,PAMR1:NM_001001991:exon10:c.G1598A:p.R533Q,PAMR1:NM_001282675:exon12:c.G1478A:p.R493Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7933 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6UXH9 |
| dbNSFP Uniprot ID | PAMR1_HUMAN |
| ExAC AF | 7.319e-05 |
MIR3973
| dbSNP name | rs144294597(C,T); rs146564407(C,T) |
| ccdsGene name | CCDS31462.1 |
| cytoBand name | 11p13 |
| EntrezGene GeneID | 100616311 |
| snpEff Gene Name | LDLRAD3 |
| EntrezGene Description | microRNA 3973 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
RAG1
| dbSNP name | rs872053(A,G); rs3740955(A,G); rs1980131(A,G); rs4151040(C,T); rs4151045(T,C); rs1056403(G,A) |
| cytoBand name | 11p12 |
| EntrezGene GeneID | 5896 |
| EntrezGene Description | recombination activating gene 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06749 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Postnatal growth retardation
HEAD AND NECK:
[Head];
Brachycephaly;
Microcephaly, postnatal;
[Face];
Wide face;
Micrognathia;
Midface hypoplasia;
[Ears];
Low-set ears;
Misshapen ears;
Posteriorly angulated ears;
Hearing loss;
[Eyes];
Hypertelorism;
Strabismus;
Infraorbital creases;
[Nose];
Anteverted nares;
Depressed nasal bridge;
[Mouth];
Thin upper lip;
Downturned mouth;
Thick lower lip;
Gingival hyperplasia;
[Teeth];
Abnormal spacing of the teeth
CARDIOVASCULAR:
[Heart];
Congenital heart defects;
Conotruncal defects;
Tetralogy of Fallot;
Double-outlet right ventricle;
Ventricular septal defect;
Atrial septal defect;
Pulmonary valve stenosis;
[Vascular];
Patent ductus arteriosus
CHEST:
[External features];
Pectus excavatum, progressive;
[Ribs, sternum, clavicles, and scapulae];
Radiographic studies show a single ossification center in the sternum
GENITOURINARY:
Genitourinary anomalies (48%);
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis;
Dilated collecting tubules
SKELETAL:
Joint contractures;
[Spine];
Scoliosis, progressive;
[Hands];
Camptodactyly;
Fifth finger clinodactyly;
[Feet];
Deep plantar furrows
SKIN, NAILS, HAIR:
[Hair];
Low posterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation, moderate to severe;
Seizures;
Delayed myelination;
Hypertonia;
Hypotonia;
Cerebral atrophy;
Ventriculomegaly
LABORATORY ABNORMALITIES:
Cytogenetics - recombinant chromosome 8 characterized by duplication
of 8q22.1-qter and deletion of 8pter-p23.1
MISCELLANEOUS:
Asymptomatic carriers of a pericentric chromosome 8 inversion, inv(8),
have a 6.2% risk of having an affected child with an unbalanced recombinant
chromosome 8, Rec(8).
MOLECULAR BASIS:
Caused by duplication of 8q22.1-qter and deletion of 8pter-p23.1
OMIM Title
*179615 RECOMBINATION-ACTIVATING GENE 1; RAG1
OMIM Description
CLONING
Schatz et al. (1989) isolated the RAG1 gene, which activates the V(D)J
recombination when introduced into NIH 3T3 fibroblasts. Nucleotide
sequencing of human and mouse RAG1 cDNA clones encode predicted 119-kD
proteins of 1,043 and 1,040 amino acids, respectively, with 90% sequence
identity. The RAG1 gene has been conserved between species that carry
out the V(D)J recombination, and its pattern of expression correlates
exactly with the pattern of expression of V(D)J recombinase activity.
Oettinger et al. (1990) gave a corrected length of 6.6 kb for the RAG1
cDNA.
GENE FUNCTION
Schatz et al. (1989) raised the question of whether RAG1 activates the
V(D)J recombination indirectly or whether it may encode the V(D)J
recombinase itself. The scid mouse, caused by a recessive mutation on
chromosome 16 of that species, has disruption of normal V(D)J
recombination. Schatz et al. (1989) reported that Southern blots of DNA
from a variety of somatic cell hybrids demonstrated that the murine
equivalent of RAG1 does not map to chromosome 16, thus indicating that
it is not the site of the mutation in the scid mouse. There is some
reason to think that the scid gene does not encode the V(D)J recombinase
because myeloid and fibroblastoid cells show an increased sensitivity to
radiation-induced damage in that mutant mouse, suggesting that the
defect is in a ubiquitously expressed factor involving both V(D)J
recombination and the repair of chromosomal damage (Fulop and Phillips,
1990).
Formation of double-strand breaks at recombination signal sequences is
an early step in V(D)J recombination. McBlane et al. (1995) showed that
purified RAG1 and RAG2 (179616) proteins are sufficient to carry out
this reaction. The cleavage reaction can be divided into 2 distinct
steps, nicking and hairpin formation, each of which requires the
presence of a signal sequence and both RAG proteins.
By site-directed mutagenesis of acidic amino acid residues in RAG1 and
RAG2, Landree et al. (1999) and Kim et al. (1999) identified 3 RAG1
mutants that retained normal binding of recombination signal sequences
but were catalytically inactive for both nicking and hairpin formation.
The data suggested that 1 active site in RAG1 performs both of these
steps and that at least 1 of these amino acid residues contacts and
coordinates a metal ion, which is required for cleavage. The results
also suggested that RAG1 contains most, if not all, of the active site
of the RAG1/RAG2 V(D)J recombinase.
Schultz et al. (2001) identified 2 RAG1 mutants, glu547 to gln (E547Q)
and glu423 to gln (E423Q), that were proficient for DNA cleavage but
severely defective for coding and signal joint formation, providing
direct evidence that RAG1 is critical for joining in vivo and strongly
suggesting that the postcleavage complex is important in end joining.
The E423Q mutant was severely defective for both hairpin opening in
vitro and coding joint formation in vivo. These data suggested that the
hairpin opening activity of the RAG proteins plays an important
physiologic role in V(D)J recombination.
Hikida et al. (1996) reported that RAG1 and RAG2 are expressed in mature
mouse B cells after culture with interleukin-4 (147780) in association
with costimuli (lipopolysaccharide and other cytokines). Reexpression
was also detected in draining lymph nodes from immunized mice. Hikida et
al. (1996) noted that previously reported studies had indicated that
RAG1 and RAG2 were expressed only in immature B cells.
Immunoglobulin and T-cell receptor genes are assembled from component
gene segments in developing lymphocytes by a site-specific recombination
reaction which mediates V(D)J joining. Agrawal et al. (1998) showed that
RAG1 and RAG2 are essential to this reaction. Together they form a
transposase capable of excising a piece of DNA-containing recombination
signals from a donor site and inserting it into a target DNA molecule.
The products formed contain a short duplication of target DNA
immediately flanking the transposed reactions. The results supported the
theory that RAG1 and RAG2 were once components of a transposable
element, and that the split nature of immunoglobulin and T-cell receptor
genes derived from germline insertion of this element into an ancestral
receptor gene soon after the evolutionary divergence of jawed and
jawless vertebrates. Thus the repertoire of the human immune system may
owe to 1 transposon insertion, which occurred 450 million years ago in
an ancestor of the jawed vertebrates. Vertebrates seemed to have tamed
this ancient transposon for generation of the immune repertoire. It was
surprising when RAG1 and RAG2 were discovered (by Schatz and Oettinger
working as graduate students in the laboratory of David Baltimore
(Schatz et al., 1989)) to be located within such a small segment of the
genome. This was a lucky circumstance since the selection system they
used required that both be present in the fragment. The work of Agrawal
et al. (1998) explained the reason for this close situation: they once
had to fit in a small transposable element.
Like Agrawal et al. (1998), Hiom et al. (1998) concluded that the
RAG-mediated V(D)J recombination system evolved from an ancient mobile
DNA element. They suggested that repeated transposition may have
promoted the expansion of the antigen receptor loci. They stated further
that the inappropriate diversion of V(D)J rearrangement to a
transpositional pathway may help explain certain types of DNA
translocation associated with lymphatic tumors.
Roman and Baltimore (1996) presented genetic evidence that RAG1 is
directly involved in the recognition of the DNA substrate. The RAG1
genomic locus was originally isolated by its ability to activate
recombination in the fibroblast line 3TGR. 3TGR harbors an integrated
retroviral recombination substrate that contains a neomycin (neo)
resistance gene, which is dependent on inversion via V(D)J recombination
for its transcriptional activation. Two murine RAG1 cDNAs, called M2 and
M6 by them, were originally isolated by their group (Schatz et al.,
1989), but only 1 of the clones (M2) encoded a protein that complemented
recombination in 3TGR cells; M6 was inactive. Roman and Baltimore (1996)
showed that the M6 cDNA contained a single amino acid substitution
(H109L) in the RAG1 gene that rendered its activity sensitive to the
sequence of the V(D)J coding region abutting the heptamer site in the
recombination signal sequence. These results indicated to Roman and
Baltimore (1996) that RAG1 interacts directly with DNA.
Yu et al. (1999) investigated the regulation of RAG1 and RAG2 in vivo
with bacterial artificial chromosome (BAC) transgenes containing a
fluorescent indicator. Coordinate expression of RAG1 and RAG2 in B and T
cells was regulated by distinct genetic elements found on the 5-prime
side of the RAG2 gene. This observation suggested a mechanism by which
asymmetrically disposed cis DNA elements could influence the expression
of the primordial transposon and thereby capture RAGs for vertebrate
evolution.
During development of B and T cells, the RAG1/RAG2 protein complex
cleaves DNA at conserved recombination signal sequences (RSS) to
initiate V(D)J recombination. RAG1/RAG2 also catalyzes transpositional
strand transfer of RSS-containing substrates into target DNA to form
branched DNA intermediates. Melek and Gellert (2000) showed that
RAG1/RAG2 can resolve these intermediates by 2 pathways. RAG1/RAG2
catalyzes hairpin formation on target DNA adjacent to transposed RSS
ends in a manner consistent with a model leading to chromosome
translocations. Alternatively, disintegration removes transposed donor
DNA from the intermediate. At high magnesium concentrations, such as
those present in mammalian cells, disintegration is the favored pathway
of resolution. The authors suggested that this may explain in part why
RAG1/RAG2-mediated transposition does not occur at high frequency in
cells.
Janeway (2001) reviewed the workings of the immune system in providing
protection against infection. He discussed both innate immunity and
adaptive immunity, and reviewed the source of adaptive immunity:
invasion of a retroposon. Adaptive immunity only became possible after
the acquisition of a retroposon that invaded the genome of an unknown
organism many millions of years ago. It is thought that this organism
had to have been a vertebrate, as only vertebrates have both of the
elements of the retroposon: (1) the 2 genes that encode a site-specific
recombinase, known as RAG1 and RAG2, and (2) the 2 sites that apparently
were used by the retroposon to invade a member of the primordial
immunoglobulin gene family, namely, the recognition signal sequences.
These are short DNA sequences that are found adjacent to all Ig and
T-cell receptor gene segments. One of these is made up of a
heptamer-12-bp nonamer, and the other is made up of a heptamer-23-bp
nonamer. These recognition signal sequences and the DNA that lies
between them must be removed by the RAG1/RAG2 heterodimer to form 2
joints, one of which is religated to form a coding joint that encodes
the variable exon of all immunoglobulins and T-cell receptors. Janeway
(2001) stated that 'The invasion of a primordial Ig gene by a retroposon
has only 'recently' been described, but the evidence for it is so strong
that it almost has to be correct.` The site-directed recombinase,
RAG1/RAG2, acts on germline gene segments to produce all antibody
molecules and T-cell receptors of the adaptive immune system, as proven
by the total inability of RAG1 and/or RAG2 knockout mice to rearrange
their receptor gene segments.
Huye et al. (2002) mutated the 86 conserved basic amino acids of RAG1 to
alanine and tested the mutant proteins for DNA binding, nicking, hairpin
formation, and joining. They identified several of these amino acids
outside the canonical RAG1 N-terminal DNA nonamer-binding domain that
are located in the C terminus and are critical for DNA binding. Mutants
of these residues retained the ability to interact with RAG2. Several
step arrest mutants had defects in nicking or hairpin formation; the
latter were centrally located. The authors also identified 4 C-terminal
mutants defective specifically for joining. Analysis of the coding
joints formed by some of these mutants revealed deletions and insertions
resulting from aberrant hairpin opening, similar to the junctions found
in scid mice. These scid junctions are deficient for the catalytic
subunit of DNA-dependent protein kinase (PRKDC; 600899), suggesting that
the RAG proteins and PRKDC perform overlapping functions in coding joint
formation. Huye et al. (2002) observed 12 mutants with alterations that
affected amino acids mutated in human inherited immunodeficiency
syndromes, indicating that these residues are critical for recombination
of the endogenous antigen receptor loci in developing lymphocytes.
Corneo et al. (2007) found that removing certain portions of murine Rag
proteins revealed robust alternative nonhomologous end-joining (NHEJ)
activity in NHEJ-deficient cells and some alternative joining activity
even in wildtype cells. Corneo et al. (2007) proposed a 2-tier model in
which the Rag proteins collaborate with NHEJ factors to preserve genomic
integrity during V(D)J recombination.
Using chromatin immunoprecipitation analysis, Ji et al. (2010)
demonstrated that mouse Rag protein binding was tightly regulated during
lymphocyte development, focusing on a small region encompassing J and,
where present, J-proximal D gene segments in IgH (see 147100), Igk (see
147200), Tcrb (see 186930), and Tcra (see 186880) loci. These regions,
which the authors termed recombination centers, were rich in activating
histone modifications and RNA polymerase II (see 180660). Rag2 bound
broadly in the genome at sites with substantial trimethylation at lys4
of H3 (see 602810). In contrast, Rag1 binding was more specific,
occurring primarily with recombination signal sequences (RSS) flanking
V, D, and J gene segments. Ji et al. (2010) proposed that recombination
centers are specialized sites of high local RAG concentration that
facilitate RSS binding and synapsis and help regulate recombination
order.
The ETV6/RUNX1 fusion gene (see 600618), found in 25% of childhood acute
lymphoblastic leukemia cases (ALL; 613065), is acquired in utero but
requires additional somatic mutations for overt leukemia. Papaemmanuil
et al. (2014) used exome and low-coverage whole-genome sequencing to
characterize secondary events associated with leukemic transformation in
ETV6/RUNX1 ALL. RAG-mediated deletions emerged as the dominant
mutational process, characterized by recombination signal sequence
motifs near breakpoints, incorporation of nontemplated sequence at
junctions, approximately 30-fold enrichment at promoters and enhancers
of genes actively transcribed in B-cell development, and an unexpectedly
high ratio of recurrent to nonrecurrent structural variants. Single-cell
tracking showed that this mechanism is active throughout leukemic
evolution, with evidence of localized clustering and reiterated
deletions.
MAPPING
Oettinger et al. (1992) mapped the RAG1 and RAG2 loci to 11p by Southern
analysis of hybrid cell lines derived from patients with the WAGR
syndrome (194070) and from mutagenized cell hybrids selected for
deletions in chromosome 11. The RAG locus defined a new interval of
human 11p which was not known to contain any genetically mapped human
disease. Guided by the localization of the human genes, they mapped the
homologous loci to mouse chromosome 2. Sherrington et al. (1992)
confirmed the assignment of the RAG1 and RAG2 genes to human 11p13. The
results of study of a somatic cell hybrid panel placed the RAG1 gene
near CD44 and proximal to CAT. They pointed out that these
recombinase-activating genes are thus not linked to
ataxia-telangiectasia complementation groups A, C, or D, which have been
mapped to the region 11q22-q23, and are presumably not directly
responsible for the phenotype of that disorder (see 208900). Ichihara et
al. (1992) mapped both RAG1 and RAG2 to 11p13-p12 by fluorescence in
situ hybridization. Blanquet et al. (1992) had determined by in situ
hybridization that the RAG1 gene is located in the 14q21.3-q22.2 region.
This assignment must have been in error; possibly the probe used was not
in fact from that gene (Oettinger, 1993).
MOLECULAR GENETICS
Schwarz et al. (1996) reported that patients with severe combined
immunodeficiency can be divided into those with B lymphocytes
(T-negative, B-positive SCID) and those without (T-negative, B-negative
SCID; 601457). They searched for RAG1 and RAG2 mutations in B-negative
SCID patients through the use of SSCP analysis with primer cassettes
overlapping the entire RAG1 and RAG2 coding regions. Six of 14
B-negative SCID patients were found to carry mutations of the
recombinase activating genes. Mutations resulted in a functional
inability to form antigen receptors through genetic recombination. In 4
families, 4 B-negative SCID patients exhibited an altered migration
pattern for RAG1 amplimers. They identified 2 missense mutations
(179615.0001 and 179615.0004) and 2 nonsense mutations (179615.0002 and
179615.0003) in RAG1. In 1 case there was a paternal deletion which
encompassed the RAG1 and RAG2 loci on chromosome 11p13. Transient
transfection assays revealed that the SCID-associated RAG1 and RAG2
mutations exhibited either a complete loss or a marked reduction of
V(D)J recombination activity. The mutations were not detected in B+ SCID
patients or in 35 healthy subjects.
Villa et al. (1998) reported that patients with Omenn syndrome (603554),
a severe immunodeficiency characterized by the presence of activated,
anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels,
have missense mutations in either the RAG1 or RAG2 (179616) genes that
result is partial activity of the 2 proteins. Two of the amino acid
substitutions map within the RAG1 homeodomain and decrease DNA binding
activity, while 3 others lower the efficiency of RAG1/RAG2 interaction.
These findings provided evidence indicating that the immunodeficiency
manifested in patients with Omenn syndrome arises from mutations that
decrease the efficiency of V(D)J recombination.
Santagata et al. (2000) reported 7 patients with Omenn syndrome and a
novel class of genetic lesions: frameshift mutations within the 5-prime
coding region of RAG1. They demonstrated in transient expression
experiments that these frameshift deletion alleles remain partially
functional for both deletional and inversional recombination. This
explained the partial rearrangement phenotype observed in these
patients. The rearrangement activity is mediated by truncated RAG1
proteins that are generated by alternative ATG initiator codon usage
3-prime to the frameshift deletion and that demonstrate improper
cellular localization. These results suggested a novel mechanism for the
development of immunodeficiency in a subset of Omenn syndrome patients.
Corneo et al. (2001) identified the same RAG1 mutations (179615.0010;
179615.0015) in patients with Omenn syndrome and T-, B- SCID. The
findings suggested that an additional factor was required for the Omenn
syndrome phenotype.
Tabori et al. (2004) performed mutation analyses of PCR products of the
RAG1 and RAG2 genes in 6 cases of T-, B- SCID and 8 cases of Omenn
syndrome. Consanguinity was reported in 7 of the 14 families. None of
the patients had a mutation in the RAG1 gene, but Tabori et al. (2004)
found 4 missense mutations in the RAG2 gene in 6 of 8 Omenn syndrome
patients and in 4 of 6 SCID patients (see 179616.0007).
De Villartay et al. (2005) reported 4 unrelated infants born to first
cousins who presented with a novel immunodeficiency consisting of
alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe
cytomegalovirus (CMV) infection, and autoimmunity (609889). They
identified homozygous mutations in the RAG1 gene (e.g., 179615.0017) in
all 4 patients. De Villartay et al. (2005) concluded that hypomorphic
RAG1 mutations result in residual RAG1 activity and are compatible with
the presence of both B and T lymphocytes. They suggested that the
immunologic phenotypes associated with RAG1 mutations are dependent on
both genetic background and the microbial environment.
In 3 children with T-, B-, NK+ SCID from 2 related families of
Athabascan-speaking Dine Indians from the Canadian Northwest
Territories, Xiao et al. (2009) identified homozygosity for a missense
mutation in the RAG1 gene (179615.0023).
Yu et al. (2014) performed deep sequencing on
complementarity-determining region-3 (CDR3) of T-cell receptor
(TCR)-beta (see 186930) in CD4 (186940)-positive and CD8 (see
186910)-positive T cells from 2 patients with autoimmunity and/or
granulomatous disease, but not severe immunodeficiency, caused by RAG1
or IL2RG (308380) mutations; 5 patients with Omenn syndrome caused by
RAG1 or RAG2 mutations; 2 patients with Omenn syndrome-like phenotypes
caused by a ZAP70 (176947) mutation (see 269840) or by atypical DiGeorge
syndrome (188400); and 4 healthy controls. They found that patients with
Omenn syndrome due to RAG1 or RAG2 mutations had poor TCR-beta diversity
compared with controls and patients with Omenn syndrome not due to RAG1
or RAG2 mutations. The 2 patients with RAG1 or IL2RG mutations
associated with autoimmunity and granulomatous disease did not have
diminished diversity, but instead had skewed V-J pairing and CDR3 amino
acid use. Yu et al. (2014) concluded that RAG enzymatic function may be
necessary for normal CDR3 junctional diversity and that aberrant TCR
generation, but not numeric diversity, may contribute to immune
dysregulation in patients with hypomorphic forms of SCID.
ANIMAL MODEL
Mombaerts et al. (1992) introduced a mutation in the V(D)J recombination
activating gene RAG1 into the germline of mice via gene targeting in
embryonic stem cells. They found that such mice had small lymphoid
organs that did not contain mature B and T lymphocytes. The phenotype
was that of 'nonleaky' scid mice. Although RAG1 expression had been
reported in the central nervous system of the mouse, no obvious
neuroanatomical or behavioral abnormalities were found in the
RAG1-deficient mice.
Wienholds et al. (2002) generated viable and fertile Rag1-deficient
zebrafish using chemical mutagenesis and reverse genetics. They noted
that their cryopreserved sperm bank could also be a resource for mutants
of most zebrafish genes.
Khiong et al. (2007) identified an apparently healthy female C57BL/10
mouse with an abnormally high percentage of memory-phenotype Cd8 (see
186910)-positive T lymphocytes. Nearly 25% of F2 offspring of F1
intercrossed mice had the same phenotype, which the authors termed MM
for 'memory mutant,' indicating autosomal recessive inheritance. Khiong
et al. (2007) identified a spontaneous point mutation in the Rag1 gene
in MM mice that caused an arg972-to-glu (R972E) substitution in the core
domain of the protein. The R972E substitution reduced Rag1 rearranging
activity, but did not cause loss of the Rag1 protein. T- and B-cell
development was blocked in MM mice at the Cd4 (186940)/Cd8
double-negative-3 and Cd43 (SPN; 182160)-positive/B220(med) (PTPRC;
151460) stages, respectively. MM mice had elevated serum IgE, IgG, and
IgM, but not IgA, as well as eosinophilia and reduced lymphocyte
numbers. They also displayed erythroderma, hepatosplenomegaly, and
excess Cd4-positive T cells. Khiong et al. (2007) concluded that the MM
mouse is a model of Omenn syndrome.
Giblin et al. (2009) generated a knockin mouse model with a hypomorphic
ser723-to-cys (S723C) mutation in Rag1. The S723C mutant mice had
impaired lymphocyte development and decreased V(D)J rearrangements. In
contrast with Rag1 -/- mice, the S723C hypomorph resulted in aberrant
double-strand breaks within loci undergoing rearrangement. The S723C
mutation predisposed mice to thymic lymphomas associated with
chromosomal translocations in a p53 (191170) mutant background.
Heterozygosity for the mutant allele accelerated age-associated immune
system dysfunction. Giblin et al. (2009) concluded that aberrant
RAG1/RAG2 activity is implicated in lymphoid tumor development and
premature immunosenescence.
RAG2
| dbSNP name | rs10836573(T,C) |
| cytoBand name | 11p12 |
| EntrezGene GeneID | 5897 |
| EntrezGene Description | recombination activating gene 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4068 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Postnatal growth retardation
HEAD AND NECK:
[Head];
Brachycephaly;
Microcephaly, postnatal;
[Face];
Wide face;
Micrognathia;
Midface hypoplasia;
[Ears];
Low-set ears;
Misshapen ears;
Posteriorly angulated ears;
Hearing loss;
[Eyes];
Hypertelorism;
Strabismus;
Infraorbital creases;
[Nose];
Anteverted nares;
Depressed nasal bridge;
[Mouth];
Thin upper lip;
Downturned mouth;
Thick lower lip;
Gingival hyperplasia;
[Teeth];
Abnormal spacing of the teeth
CARDIOVASCULAR:
[Heart];
Congenital heart defects;
Conotruncal defects;
Tetralogy of Fallot;
Double-outlet right ventricle;
Ventricular septal defect;
Atrial septal defect;
Pulmonary valve stenosis;
[Vascular];
Patent ductus arteriosus
CHEST:
[External features];
Pectus excavatum, progressive;
[Ribs, sternum, clavicles, and scapulae];
Radiographic studies show a single ossification center in the sternum
GENITOURINARY:
Genitourinary anomalies (48%);
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis;
Dilated collecting tubules
SKELETAL:
Joint contractures;
[Spine];
Scoliosis, progressive;
[Hands];
Camptodactyly;
Fifth finger clinodactyly;
[Feet];
Deep plantar furrows
SKIN, NAILS, HAIR:
[Hair];
Low posterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation, moderate to severe;
Seizures;
Delayed myelination;
Hypertonia;
Hypotonia;
Cerebral atrophy;
Ventriculomegaly
LABORATORY ABNORMALITIES:
Cytogenetics - recombinant chromosome 8 characterized by duplication
of 8q22.1-qter and deletion of 8pter-p23.1
MISCELLANEOUS:
Asymptomatic carriers of a pericentric chromosome 8 inversion, inv(8),
have a 6.2% risk of having an affected child with an unbalanced recombinant
chromosome 8, Rec(8).
MOLECULAR BASIS:
Caused by duplication of 8q22.1-qter and deletion of 8pter-p23.1
OMIM Title
*179616 RECOMBINATION-ACTIVATING GENE 2; RAG2
OMIM Description
CLONING
Oettinger et al. (1990) demonstrated that cotransfection of the RAG1
gene (179615) with an adjacent gene, RAG2, results in at least a
1,000-fold increase in the frequency of V(D)J recombination, whereas
RAG1 alone inefficiently induces recombinase activity. Oettinger et al.
(1990) reported that the 2.1-kb RAG2 cDNA encodes a putative protein of
527 amino acids whose sequence is unrelated to that of RAG1. Like RAG1,
RAG2 is conserved between species that carry out V(D)J recombination,
and its pattern of expression correlates precisely with that of V(D)J
recombinase activity. It is likely that the RAG1 and RAG2 gene products
participate directly in the recombination reaction.
GENE FUNCTION
Lin and Desiderio (1994) found that in an immature B-cell line and in
normal thymocytes, RAG2 protein accumulated preferentially in the G0/G1
phases of the cell cycle and declined by at least 20-fold before cells
entered S phase. The amount of RAG2 protein remained low throughout the
S, G2, and M phases. The amount of RAG1 protein showed considerably less
fluctuation. The variation in RAG2 protein is likely to be established,
at least in part, by a posttranscriptional mechanism. These observations
suggested to Lin and Desiderio (1994) that V(D)J rearrangement occurs
entirely or preferentially within G0/G1.
Formation of double-strand breaks at recombination signal sequences is
an early step in V(D)J recombination. McBlane et al. (1995) showed that
purified RAG1 and RAG2 proteins are sufficient to carry out this
reaction. The cleavage reaction can be divided into 2 distinct steps,
nicking and hairpin formation, each of which requires the presence of a
signal sequence and both RAG proteins.
By site-directed mutagenesis of acidic amino acid residues in RAG1 and
RAG2, Landree et al. (1999) and Kim et al. (1999) identified 3 RAG1
mutants that retained normal binding of recombination signal sequences
but were catalytically inactive for both nicking and hairpin formation.
The data suggested that 1 active site in RAG1 performs both of these
steps and that at least one of these amino acids contacts and
coordinates a metal ion, which is required for cleavage. The results
also suggested that RAG1 contains most, if not all, of the active site
of the RAG1/RAG2 V(D)J recombinase.
Hikida et al. (1996) reported that RAG1 and RAG2 are expressed in mature
mouse B cells after culture with interleukin-4 (147780) in association
with costimuli (lipopolysaccharide and other cytokines). Reexpression
was also detected in draining lymph nodes from immunized mice. Hikida et
al. (1996) noted that previously reported studies had indicated that
RAG1 and RAG2 were expressed only in immature B cells.
Yu et al. (1999) investigated the regulation of RAG1 and RAG2 in vivo
with bacterial artificial chromosome (BAC) transgenes containing a
fluorescent indicator. Coordinate expression of RAG1 and RAG2 in B and T
cells was regulated by distinct genetic elements found on the 5-prime
side of the RAG2 gene. This observation suggested a mechanism by which
asymmetrically disposed cis DNA elements could influence the expression
of the primordial transposon and thereby capture RAGs for vertebrate
evolution.
During development of B and T cells, the RAG1/RAG2 protein complex
cleaves DNA at conserved recombination signal sequences (RSS) to
initiate V(D)J recombination. RAG1/RAG2 also catalyzes transpositional
strand transfer of RSS-containing substrates into target DNA to form
branched DNA intermediates. Melek and Gellert (2000) showed that
RAG1/RAG2 can resolve these intermediates by 2 pathways. RAG1/RAG2
catalyzes hairpin formation on target DNA adjacent to transposed RSS
ends in a manner consistent with a model leading to chromosome
translocations. Alternatively, disintegration removes transposed donor
DNA from the intermediate. At high magnesium concentrations, such as
those present in mammalian cells, disintegration is the favored pathway
of resolution. The authors suggested that this may explain in part why
RAG1/RAG2-mediated transposition does not occur at high frequency in
cells.
The 'kelch' motif, named after a sequence first identified in
Drosophila, is a 44- to 56-amino acid segment with low primary sequence
identity. It is characterized by the presence of 4 hydrophobic residues
followed by a double-glycine element and, after variable spacing,
tyrosine and tryptophan residues separated by 6 amino acids. Typically,
4 to 7 of these motifs form a kelch repeat domain and a beta propeller,
with each motif forming a 4-stranded beta sheet corresponding to 1 blade
of the propeller (Adams et al., 2000). By hydrophobic cluster and
gapped-BLAST analysis, Callebaut and Mornon (1998) determined that the
N-terminal 355 residues of RAG2 are composed of a 6-fold kelch repeat
forming a 6-bladed propeller in the active core. They proposed that the
propeller structure of RAG2 could serve as a binding scaffold for RAG1
(179615) on one side and for DNA on the other.
Qiu et al. (2001) used site-directed mutagenesis targeting each
conserved basic amino acid in RAG2, which revealed several
separation-of-function mutants. Analysis of these mutants showed that
RAG2 helps recognize or cleave distorted DNA intermediates and plays an
essential role in the joining step of V(D)J recombination. Moreover, the
discovery that some mutants blocked RAG-mediated hairpin opening in
vitro provided a critical link between this biochemical activity and
coding joint formation in vivo.
Corneo et al. (2007) found that removing certain portions of murine Rag
proteins revealed robust alternative nonhomologous end-joining (NHEJ)
activity in NHEJ-deficient cells and some alternative joining activity
even in wildtype cells. Corneo et al. (2007) proposed a 2-tier model in
which the Rag proteins collaborate with NHEJ factors to preserve genomic
integrity during V(D)J recombination.
Matthews et al. (2007) showed that RAG2 contains a plant homeodomain
(PHD) finger that specifically recognizes histone H3 (see 602810)
trimethylated at lysine-4. The high-resolution crystal structure of the
mouse RAG2 PHD finger bound to H3K4me3 reveals the molecular basis of
H3K4me3 recognition by RAG2. Mutations that abrogate RAG2's recognition
of H3K4me3 severely impaired V(D)J recombination in vivo. Reducing the
level of H3K4me3 similarly led to a decrease in V(D)J recombination in
vivo. Notably, a conserved tryptophan residue (W453) that constitutes a
key structural component of the K4me3-binding surface and is essential
for RAG2's recognition of H3K4me3 is mutated in patients with
immunodeficiency syndromes (Omenn syndrome; 603554). Taken together,
Matthews et al. (2007) concluded that their results identified a novel
function for histone methylation in mammalian DNA recombination.
Furthermore, their results provided the first evidence indicating that
disrupting the read-out of histone modifications can cause an inherited
human disease.
Deriano et al. (2011) showed that the RAG2 C terminus, although
dispensable for recombination, is critical for maintaining genomic
stability. Thymocytes from 'core' Rag2 homozygous (Rag2c/c) mice show
dramatic disruption of Tcr-alpha (TCRA; see 186880)/delta (see 186810)
locus integrity. Furthermore, all Rag2c/c p53 (191170)-null mice, unlike
Rag1c/c p53-null and p53-null animals, rapidly develop thymic lymphomas
bearing complex chromosomal translocations, amplifications, and
deletions involving the Tcr-alpha/delta and Igh (147100) loci. Deriano
et al. (2011) also found these features in lymphomas from Atm-null mice.
Deriano et al. (2011) showed that, like ATM (607585) deficiency, core
RAG2 severely destabilizes the RAG postcleavage complex. Deriano et al.
(2011) concluded that their results revealed a novel genome guardian
role for RAG2 and suggested that similar 'end release/end persistence'
mechanisms underlie genomic instability and lymphomagenesis in Rag2c/c
p53-null and Atm-null mice.
Using chromatin immunoprecipitation analysis, Ji et al. (2010)
demonstrated that mouse Rag protein binding was tightly regulated during
lymphocyte development, focusing on a small region encompassing J and,
where present, J-proximal D gene segments in IgH, Igk (see 147200), Tcrb
(see 186930), and Tcra loci. These regions, which the authors termed
recombination centers, were rich in activating histone modifications and
RNA polymerase II (see 180660). Rag2 bound broadly in the genome at
sites with substantial trimethylation at lys4 of H3 (see 601128). In
contrast, Rag1 binding was more specific, occurring primarily with
recombination signal sequences (RSS) flanking V, D, and J gene segments.
Ji et al. (2010) proposed that recombination centers are specialized
sites of high local RAG concentration that facilitate RSS binding and
synapsis and help regulate recombination order.
GENE STRUCTURE
Oettinger et al. (1990) reported that the genomic size of RAG2 is
approximately 18 kb. The convergently transcribed RAG1 and RAG2 genes
are unusual in that most, if not all, of their coding and 3-prime
untranslated sequences are contained in a single exon.
MAPPING
Oettinger et al. (1990) found that RAG1 and RAG2 are only 8 kb apart.
BIOCHEMICAL FEATURES
- Crystal Structure
Matthews et al. (2007) determined the crystal structure of the RAG2
PHD-H3K4me3 complex at 1.15-angstrom resolution. The structure revealed
that, instead of being closed on both sides, the back, and the top (as
observed with other PHD fingers), the RAG2 PHD K4me3-binding surface is
open on the top, and resembles an 'aromatic channel' rather than an
'aromatic cage.' The authors suggested that this 'channel' conformation
may provide a mechanism to modulate histone binding.
MOLECULAR GENETICS
Schwarz et al. (1996) reported that patients with severe combined
immunodeficiency can be divided into those with B lymphocytes
(B-positive SCID) and those without (B-negative SCID; 601457). They
searched for RAG1 and RAG2 mutations in B-negative SCID patients through
the use of SSCP analysis with primer cassettes overlapping the entire
RAG1 and RAG2 coding regions. Six of 14 B-negative SCID patients were
found to carry mutations of the recombinase activating genes. Mutations
resulted in a functional inability to form antigen receptors through
genetic recombination. In 2 families, 3 patients exhibited an altered
migration pattern for RAG2 amplimers. The PCR products were then
sequenced. Two related patients were found to be homozygous for a
missense mutation leading to cys476-to-tyr mutation in RAG2
(179616.0001). One patient was found to have inherited a RAG2 missense
mutation (R229Q; 179616.0002) from the mother and a deletion involving
RAG1 and RAG2 from the father. Transient transfection assays revealed
that the SCID-associated RAG2 mutations exhibited either a complete loss
or a marked reduction of V(D)J recombination activity.
Villa et al. (1998) reported that patients with Omenn syndrome (603554),
a severe immunodeficiency characterized by the presence of activated,
anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels,
have missense mutations in either the RAG1 (179615) or RAG2 genes that
result in partial activity of the 2 proteins. Two of the amino acid
substitutions map within the RAG1 homeodomain and decrease DNA binding
activity, while 3 others lower the efficiency of RAG1/RAG2 interaction.
These findings provided evidence indicating that the immunodeficiency
manifested in patients with Omenn syndrome arises from mutations that
decrease the efficiency of V(D)J recombination.
Gomez et al. (2000) identified a gly95-to-arg mutation (179616.0005) and
a deletion of ile273 (179616.0006) within the predicted second beta
strand of repeats 2 and 5 of the RAG2 kelch domain that led to Omenn
syndrome and SCID, respectively, in 2 patients. By confocal microscopy
analysis, they determined that the mutations did not impair nuclear
localization but did reduce the capacity of RAG2 to interact with RAG1
and to mediate recombination signal cleavage. Furthermore, by analysis
of a panel of mutants, they showed that the hydrophobic and gly-rich
regions within the second strand of the beta sheet are critical for
RAG1-RAG2 interaction.
Tabori et al. (2004) performed mutation analyses of PCR products of the
RAG1 and RAG2 genes in 6 cases of T-negative/B-negative SCID and 8 cases
of Omenn syndrome. Consanguinity was reported in 7 of the 14 families.
None of the patients had a mutation in the RAG1 gene, but Tabori et al.
(2004) found 4 missense mutations in the RAG2 gene in 6 of 8 Omenn
syndrome patients and in 4 of 6 SCID patients (see 179616.0007).
Yu et al. (2014) performed deep sequencing on
complementarity-determining region-3 (CDR3) of TCR-beta in CD4
(186940)-positive and CD8 (see 186910)-positive T cells from 2 patients
with autoimmunity and/or granulomatous disease, but not severe
immunodeficiency, caused by RAG1 or IL2RG (308380) mutations; 5 patients
with Omenn syndrome caused by RAG1 or RAG2 mutations; 2 patients with
Omenn syndrome-like phenotypes caused by a ZAP70 (176947) mutation (see
269840) or by atypical DiGeorge syndrome (188400); and 4 healthy
controls. They found that patients with Omenn syndrome due to RAG1 or
RAG2 mutations had poor TCR-beta diversity compared with controls and
patients with Omenn syndrome not due to RAG1 or RAG2 mutations. The 2
patients with RAG1 or IL2RG mutations associated with autoimmunity and
granulomatous disease did not have diminished diversity, but instead had
skewed V-J pairing and CDR3 amino acid use. Yu et al. (2014) concluded
that RAG enzymatic function may be necessary for normal CDR3 junctional
diversity and that aberrant TCR generation, but not numeric diversity,
may contribute to immune dysregulation in patients with hypomorphic
forms of SCID.
ANIMAL MODEL
In transgenic mice carrying a germline mutation in which a large portion
in the RAG2 coding region was deleted, Shinkai et al. (1992) found that
although homozygotes were viable, they failed to produce mature B or T
lymphocytes. Immature lymphoid cells were present in primary lymphoid
organs; however, these cells did not rearrange their immunoglobulin or
T-cell receptor loci. Thus, loss of RAG2 function results in total
inability to initiate V(D)J rearrangement, leading to a severe combined
immunodeficiency (SCID) phenotype. Since the SCID phenotype was the only
obvious abnormality detected in these mice, RAG2 function and V(D)J
recombinase activity, per se, must not be required for development of
cells other than lymphocytes.
Shankaran et al. (2001) found that mice lacking the lymphocyte-specific
Rag2 gene, the Ifn receptor signal transcription factor Stat1 (600555),
Ifngr1 (107470), or both Rag2 and Stat1, are significantly more
susceptible to chemically induced tumor formation than wildtype mice,
suggesting that T, NKT, and/or B cells are essential to suppress
development of chemically induced tumors. Spontaneous malignant tumors
did not occur in wildtype mice, occurred late in half of mice lacking
either Rag2 or Stat1, but occurred early in 82% of mice lacking both
genes. Transplanted chemically induced tumors from lymphocyte-deficient
mice (Shankaran et al., 2001) or from Ifng-unresponsive mice (Kaplan et
al., 1998), but not tumors from immunocompetent hosts, were rejected by
wildtype mice, indicating that the tumors from immunodeficient mice are
more immunogenic and that lymphocytes and the IFNG/STAT1 signaling
pathway collaborate to shape the immunogenic phenotype of tumors that
eventually form in immunocompetent hosts. Shankaran et al. (2001)
proposed that tumors are imprinted by the immunologic environment in
which they form and that 'cancer immunoediting' rather than
'immunosurveillance' best describes the protective and sculpting actions
of the immune response on developing tumors.
Rideout et al. (2002) used immune-deficient Rag2 -/- mice as nuclear
donors for transfer into enucleated oocytes and cultured the resulting
blastocysts to isolate an isogenic embryonic stem (ES) cell line. One of
the mutated alleles in the Rag2 -/- ES cells was repaired by homologous
recombination, thereby restoring normal Rag2 gene structure. Mutant mice
were treated with the repaired ES cells in 2 ways: (1) immune-competent
mice were generated from the repaired ES cells by tetraploid embryo
complementation and were used as bone marrow donors for transplantation,
and (2) hematopoietic precursors were derived by in vitro
differentiation from the repaired ES cells and engrafted into mutant
mice. Mature myeloid and lymphoid cells as well as immunoglobulins
became detectable 3 to 4 weeks after transplantation. These results
established a paradigm for the treatment of a genetic disorder by
combining therapeutic cloning with gene therapy.
Marrella et al. (2007) generated a knockin mouse model in which
endogenous Rag2 was replaced with Rag2 carrying the R229Q mutation
identified in patients with Omenn syndrome and SCID. These mice showed
T-cell oligoclonality, a lack of circulating B cells, and peripheral
eosinophilia. In addition, T-cell infiltration of gut and skin caused
diarrhea, alopecia, and, in some mice, severe erythrodermia. The
findings were associated with reduced thymic expression of Aire (607358)
and markedly reduced regulatory T cells and NKT lymphocytes. Marrella et
al. (2007) concluded that Rag2 R229Q homozygous mice mimic most symptoms
of human Omenn syndrome and that the pathophysiology of Omenn syndrome
involves impaired immune tolerance and defective immune regulation.
DKFZp779M0652
| dbSNP name | rs184834132(C,T); rs3740704(A,C); rs2666891(G,C) |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 374387 |
| snpEff Gene Name | CTD-2210P24.4 |
| EntrezGene Description | uncharacterized DKFZp779M0652 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001377 |
NDUFS3
| dbSNP name | rs4303193(G,T); rs2233354(C,T); rs2030166(C,T); rs4256934(A,G); rs368446373(C,T); rs12798028(C,T); rs4147730(G,A) |
| ccdsGene name | CCDS7941.1 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 4722 |
| EntrezGene Description | NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NDUFS3:NM_004551:exon5:c.C406T:p.R136C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8079 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75489 |
| dbNSFP Uniprot ID | NDUS3_HUMAN |
| ESP Afr MAF | 0.000682 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001057 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolonged QT interval on EKG;
Syncope;
Torsade de pointes;
Ventricular fibrillation;
Sudden cardiac death
MISCELLANEOUS:
Association of cardiac events with exercise;
Genetic heterogeneity (see LQT1 192500);
Patients with more severe phenotype have been reported with mutations
in more than 1 LQTS-related gene;
GEI (gene-environment interaction) - association of cardiac events
with drug administration
MOLECULAR BASIS:
Caused by mutation in the sodium channel, voltage-gated, type V, alpha
polypeptide gene (SCN5A, 600163.0001)
OMIM Title
*603846 NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 3; NDUFS3
;;COMPLEX I, MITOCHONDRIAL RESPIRATORY CHAIN, 30-KD SUBUNIT
OMIM Description
DESCRIPTION
The multisubunit NADH:ubiquinone oxidoreductase (complex I) is the first
enzyme complex in the electron transport chain of mitochondria. The
iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits.
See NDUFS1 (157655).
CLONING
By a combination of EST database searching and RT-PCR, Loeffen et al.
(1998) isolated cDNAs encoding NDUFS2 (602985), NDUFS3, and NDUFS6
(603848), the human homologs of the bovine 49-kD, 30-kD, and 13-kD
subunits of the IP fraction. The predicted 264-amino acid human NDUFS3
protein shares 90% identity with the bovine protein. The first 36 amino
acids of human NDUFS3 comprise a possible mitochondrial targeting
sequence.
Smeitink and van den Heuvel (1999) reviewed the available molecular data
regarding the human nuclear-encoded complex I subunits. They stated that
a small form of complex I, consisting of 14 subunits, is found in
Escherichia coli (Weidner et al., 1993). In this bacterium, all complex
I genes are organized as an operon, called 'Nuo' after the
NADH:ubiquinone oxidase. In most eukaryotes, homologs of NuoB-NuoG and
NuoI are nuclear genes; NDUFS3 is the homolog of NuoC. Comparative
studies showed that the number of nuclear-encoded complex I subunits
increases with the evolutionary complexity of the organism. The 7 human
nuclear-encoded counterparts of the Escherichia coli Nuo proteins,
namely, NDUFV1 (161015), NDUFV2 (600532), NDUFS1, NDUFS2, NDUFS3, NDUFS7
(601825), and NDUFS8 (602141), would be predicted to carry out essential
aspects of complex I function.
GENE FUNCTION
Using human and mouse cells and tissues, Martinvalet et al. (2008) found
that GZMA (140050) activated mitochondrial outer membrane
permeabilization- and caspase-independent cell death pathways by
cleaving NDUFS3 after lys56. NDUFS3 cleavage generated reactive oxygen
species, disrupted the mitochondrial membrane potential, and interfered
with NADH oxidation and ATP synthesis. The generation of reactive oxygen
species induced translocation of the SET complex (see 600960) from the
cytosol to the nucleus, followed by GZMA-mediated activation of the SET
complex DNases NM23H1 (NME1; 156490) and TREX1 (606609), leading to DNA
damage and cell death. SET complex translocation, DNase activation, and
cell death were blocked by superoxide scavengers or by overexpression of
a cleavage-resistant NDUFS3 mutant. Martinvalet et al. (2008) concluded
that cleavage of NDUFS3 is the first step in GZMA-induced cell death.
MAPPING
By analysis of somatic cell hybrids, Loeffen et al. (1998) mapped the
NDUFS3 gene to chromosome 11. By radiation hybrid analysis, Emahazion et
al. (1998) mapped the NDUFS3 to 11p11.11.
MOLECULAR GENETICS
In a patient with complex I deficiency (252010) and features of Leigh
syndrome (256000), Benit et al. (2004) identified compound
heterozygosity for mutations in the NDUFS3 gene (T145I, 603846.0001 and
R199W, 603846.0002).
In a patient with complex I deficiency, Haack et al. (2012) identified
homozygosity for the R199W mutation.
OR4B1
| dbSNP name | rs10769329(T,G); rs61731419(G,A); rs11606506(G,A); rs10838833(C,T); rs61731414(A,G); rs12292056(C,A); rs7130086(C,A) |
| ccdsGene name | CCDS31485.1 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 119765 |
| EntrezGene Description | olfactory receptor, family 4, subfamily B, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4B1:NM_001005470:exon1:c.T60G:p.A20A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01561 |
| ESP Afr MAF | 0.068151 |
| ESP All MAF | 0.023388 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.994,8.132e-06 |
OR4X2
| dbSNP name | rs7120775(C,G) |
| ccdsGene name | CCDS31486.1 |
| CosmicCodingMuts gene | OR4X2 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 119764 |
| EntrezGene Description | olfactory receptor, family 4, subfamily X, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4X2:NM_001004727:exon1:c.C81G:p.Y27X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.166666666667 |
| dbNSFP KGp1 Afr AF | 0.258130081301 |
| dbNSFP KGp1 Amr AF | 0.127071823204 |
| dbNSFP KGp1 Asn AF | 0.162587412587 |
| dbNSFP KGp1 Eur AF | 0.129287598945 |
| dbSNP GMAF | 0.1671 |
| ESP Afr MAF | 0.268741 |
| ESP All MAF | 0.178489 |
| ESP Eur/Amr MAF | 0.132271 |
| ExAC AF | 0.148,7.514e-03 |
OR4X1
| dbSNP name | rs141012609(G,A); rs1503193(A,G); rs10838850(C,T); rs16905753(C,T); rs61746892(G,A); rs10838851(T,A); rs10838852(C,T) |
| ccdsGene name | CCDS31487.1 |
| CosmicCodingMuts gene | OR4X1 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 390113 |
| EntrezGene Description | olfactory receptor, family 4, subfamily X, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4X1:NM_001004726:exon1:c.G427A:p.V143M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.1112 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH49 |
| dbNSFP Uniprot ID | OR4X1_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.002953 |
| ESP All MAF | 0.004616 |
| ESP Eur/Amr MAF | 0.005468 |
| ExAC AF | 0.00514 |
OR4S1
| dbSNP name | rs753095(C,T) |
| ccdsGene name | CCDS31488.1 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 256148 |
| EntrezGene Description | olfactory receptor, family 4, subfamily S, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4S1:NM_001004725:exon1:c.C870T:p.N290N, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3696 |
| ESP Afr MAF | 0.48796 |
| ESP All MAF | 0.362748 |
| ESP Eur/Amr MAF | 0.298627 |
| ExAC AF | 0.338 |
OR4A47
| dbSNP name | rs7103557(A,C); rs7103992(G,A) |
| ccdsGene name | CCDS31490.1 |
| cytoBand name | 11p11.2 |
| EntrezGene GeneID | 403253 |
| EntrezGene Description | olfactory receptor, family 4, subfamily A, member 47 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4A47:NM_001005512:exon1:c.A310C:p.I104L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IF82 |
| dbNSFP Uniprot ID | O4A47_HUMAN |
| dbNSFP KGp1 AF | 0.538919413919 |
| dbNSFP KGp1 Afr AF | 0.369918699187 |
| dbNSFP KGp1 Amr AF | 0.621546961326 |
| dbNSFP KGp1 Asn AF | 0.493006993007 |
| dbNSFP KGp1 Eur AF | 0.643799472296 |
| dbSNP GMAF | 0.4614 |
| ESP Afr MAF | 0.440027 |
| ESP All MAF | 0.43976 |
| ESP Eur/Amr MAF | 0.378199 |
| ExAC AF | 0.576 |
OR4C13
| dbSNP name | rs28378220(C,T); rs28662375(G,A); rs16914589(C,T) |
| ccdsGene name | CCDS31495.1 |
| cytoBand name | 11p11.12 |
| EntrezGene GeneID | 283092 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4C13:NM_001001955:exon1:c.C5T:p.A2V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGP0 |
| dbNSFP Uniprot ID | OR4CD_HUMAN |
| dbNSFP KGp1 AF | 0.0837912087912 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0497237569061 |
| dbNSFP KGp1 Asn AF | 0.188811188811 |
| dbNSFP KGp1 Eur AF | 0.0725593667546 |
| dbSNP GMAF | 0.08402 |
| ESP Afr MAF | 0.011358 |
| ESP All MAF | 0.03694 |
| ESP Eur/Amr MAF | 0.050047 |
| ExAC AF | 0.061 |
OR4C12
| dbSNP name | rs11040695(C,T); rs4598671(C,A) |
| cytoBand name | 11p11.12 |
| EntrezGene GeneID | 283093 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1423 |
OR4A5
| dbSNP name | rs113879457(G,A); rs34285763(G,A); rs10902343(T,C); rs113366921(C,T) |
| cytoBand name | 11p11.12 |
| EntrezGene GeneID | 81318 |
| EntrezGene Description | olfactory receptor, family 4, subfamily A, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 9.113e-05 |
OR4C46
| dbSNP name | rs11246606(C,T); rs77689730(C,T); rs113759681(T,A); rs11246607(C,T); rs11246608(G,A) |
| ccdsGene name | CCDS31498.1 |
| cytoBand name | 11p11.12 |
| EntrezGene GeneID | 119749 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 46 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4C46:NM_001004703:exon1:c.C179T:p.S60F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NHA9 |
| dbNSFP Uniprot ID | O4C46_HUMAN |
| dbNSFP KGp1 AF | 0.162087912088 |
| dbNSFP KGp1 Afr AF | 0.158536585366 |
| dbNSFP KGp1 Amr AF | 0.146408839779 |
| dbNSFP KGp1 Asn AF | 0.216783216783 |
| dbNSFP KGp1 Eur AF | 0.130606860158 |
| dbSNP GMAF | 0.1612 |
| ESP Afr MAF | 0.214221 |
| ESP All MAF | 0.18193 |
| ESP Eur/Amr MAF | 0.165386 |
| ExAC AF | 0.194 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Full cheeks;
[Eyes];
Upward gaze palsy
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Pulmonic stenosis
RESPIRATORY:
[Airways];
Bronchial asthma
ABDOMEN:
[Gastrointestinal];
Pyloric stenosis
SKELETAL:
Arthrogryposis;
Joint contractures of the hips, knees, hands, and elbows;
[Pelvis];
Avascular necrosis of the femoral head;
[Hands];
Camptodactyly;
Trigger deformity of the fingers;
[Feet];
Overriding toes
SKIN, NAILS, HAIR:
[Skin];
Atopic dermatitis
MISCELLANEOUS:
One family with 3 affected girls has been reported (as of October
2011)
OMIM Title
*614273 OLFACTORY RECEPTOR, FAMILY 4, SUBFAMILY C, MEMBER 46; OR4C46
OMIM Description
MAPPING
Hartz (2011) mapped the OR4C46 gene to chromosome 11p11.12 based on an
alignment of the OR4C46 sequence (GenBank GENBANK AC126345) with the
genomic sequence (GRCh37).
OR4A16
| dbSNP name | rs7121804(G,A); rs11229158(C,A); rs117538213(T,C); rs10896659(A,T) |
| ccdsGene name | CCDS31499.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 81327 |
| EntrezGene Description | olfactory receptor, family 4, subfamily A, member 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4A16:NM_001005274:exon1:c.G546A:p.L182L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03811 |
| ESP Afr MAF | 0.056565 |
| ESP All MAF | 0.059874 |
| ESP Eur/Amr MAF | 0.061569 |
| ExAC AF | 0.050,8.132e-06 |
OR4A15
| dbSNP name | rs147718236(G,A) |
| ccdsGene name | CCDS31500.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 81328 |
| EntrezGene Description | olfactory receptor, family 4, subfamily A, member 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4A15:NM_001005275:exon1:c.G814A:p.V272I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0139 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGL6 |
| dbNSFP Uniprot ID | O4A15_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0001057 |
OR4C15
| dbSNP name | rs11828099(T,C); rs9804659(A,G); rs8181485(C,T); rs113104876(G,A); rs12790125(G,A) |
| ccdsGene name | CCDS31501.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 81309 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4C15:NM_001001920:exon1:c.T238C:p.F80L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0043 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGM1 |
| dbNSFP Uniprot ID | OR4CF_HUMAN |
| dbNSFP KGp1 AF | 0.0137362637363 |
| dbNSFP KGp1 Afr AF | 0.0548780487805 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01377 |
| ESP Afr MAF | 0.045888 |
| ESP All MAF | 0.01593 |
| ESP Eur/Amr MAF | 0.000582 |
| ExAC AF | 0.004481 |
OR4C16
| dbSNP name | rs1459101(C,T); rs12800642(G,T); rs34100491(C,T); rs557667(C,T); rs557590(A,G); rs79740520(C,T); rs559449(T,C) |
| ccdsGene name | CCDS31502.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219428 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4C16:NM_001004701:exon1:c.C49T:p.Q17X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.277014652015 |
| dbNSFP KGp1 Afr AF | 0.0955284552846 |
| dbNSFP KGp1 Amr AF | 0.348066298343 |
| dbNSFP KGp1 Asn AF | 0.374125874126 |
| dbNSFP KGp1 Eur AF | 0.287598944591 |
| dbSNP GMAF | 0.2764 |
| ESP Afr MAF | 0.127442 |
| ESP All MAF | 0.219409 |
| ESP Eur/Amr MAF | 0.266527 |
| ExAC AF | 0.278 |
OR4C11
| dbSNP name | rs113017126(C,A); rs11230346(A,T); rs491160(G,T) |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219429 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
| ESP Afr MAF | 0.048573 |
| ESP All MAF | 0.017547 |
| ESP Eur/Amr MAF | 0.000628 |
| ExAC AF | 0.00536 |
OR4P4
| dbSNP name | rs76160133(C,G); rs57403436(T,G); rs73469483(T,G) |
| ccdsGene name | CCDS31504.1 |
| CosmicCodingMuts gene | OR4P4 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 81300 |
| EntrezGene Description | olfactory receptor, family 4, subfamily P, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4P4:NM_001004124:exon1:c.C189G:p.Y63X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.188186813187 |
| dbNSFP KGp1 Afr AF | 0.0731707317073 |
| dbNSFP KGp1 Amr AF | 0.209944751381 |
| dbNSFP KGp1 Asn AF | 0.368881118881 |
| dbNSFP KGp1 Eur AF | 0.116094986807 |
| dbSNP GMAF | 0.1869 |
| ESP Afr MAF | 0.108895 |
| ESP All MAF | 0.134213 |
| ESP Eur/Amr MAF | 0.147905 |
| ExAC AF | 0.197 |
OR4S2
| dbSNP name | rs17146960(T,A); rs76435051(G,A); rs11230541(T,C); rs114634058(C,T) |
| ccdsGene name | CCDS31505.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219431 |
| EntrezGene Description | olfactory receptor, family 4, subfamily S, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4S2:NM_001004059:exon1:c.T214A:p.S72T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH73 |
| dbNSFP Uniprot ID | OR4S2_HUMAN |
| dbNSFP KGp1 AF | 0.0265567765568 |
| dbNSFP KGp1 Afr AF | 0.115853658537 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.065995 |
| ESP All MAF | 0.023355 |
| ESP Eur/Amr MAF | 0.000371 |
| ExAC AF | 0.006176 |
OR4C6
| dbSNP name | rs144757960(A,G); rs11230600(T,C) |
| ccdsGene name | CCDS31506.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219432 |
| EntrezGene Description | olfactory receptor, family 4, subfamily C, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4C6:NM_001004704:exon1:c.A165G:p.S55S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.017955 |
| ESP All MAF | 0.006081 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001781 |
OR5D13
| dbSNP name | rs297118(G,A) |
| ccdsGene name | CCDS31507.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 390142 |
| EntrezGene Description | olfactory receptor, family 5, subfamily D, member 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5D13:NM_001001967:exon1:c.G185A:p.C62Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGL4 |
| dbNSFP Uniprot ID | OR5DD_HUMAN |
| dbNSFP KGp1 AF | 0.973901098901 |
| dbNSFP KGp1 Afr AF | 0.894308943089 |
| dbNSFP KGp1 Amr AF | 0.988950276243 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.998680738786 |
| dbSNP GMAF | 0.02617 |
| ESP Afr MAF | 0.083409 |
| ESP All MAF | 0.02871 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.992 |
OR5D14
| dbSNP name | rs76383258(A,T); rs297054(T,G); rs297055(T,C) |
| ccdsGene name | CCDS31508.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219436 |
| EntrezGene Description | olfactory receptor, family 5, subfamily D, member 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5D14:NM_001004735:exon1:c.A305T:p.Q102L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGL3 |
| dbNSFP Uniprot ID | OR5DE_HUMAN |
| dbNSFP KGp1 AF | 0.14652014652 |
| dbNSFP KGp1 Afr AF | 0.10162601626 |
| dbNSFP KGp1 Amr AF | 0.154696132597 |
| dbNSFP KGp1 Asn AF | 0.251748251748 |
| dbNSFP KGp1 Eur AF | 0.0923482849604 |
| dbSNP GMAF | 0.1455 |
| ESP Afr MAF | 0.128182 |
| ESP All MAF | 0.115148 |
| ESP Eur/Amr MAF | 0.108473 |
| ExAC AF | 0.147 |
OR5L1
| dbSNP name | rs59122940(G,A) |
| ccdsGene name | CCDS31509.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219437 |
| EntrezGene Description | olfactory receptor, family 5, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5L1:NM_001004738:exon1:c.G349A:p.V117M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGL2 |
| dbNSFP Uniprot ID | OR5L1_HUMAN |
| dbNSFP KGp1 AF | 0.0311355311355 |
| dbNSFP KGp1 Afr AF | 0.134146341463 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03122 |
| ESP Afr MAF | 0.080455 |
| ESP All MAF | 0.027478 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 7.026e-03,1.626e-05 |
OR5D18
| dbSNP name | rs297082(T,A); rs297081(A,G); rs55832853(A,G) |
| ccdsGene name | CCDS31510.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 219438 |
| EntrezGene Description | olfactory receptor, family 5, subfamily D, member 18 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5D18:NM_001001952:exon1:c.T12A:p.T4T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.010227 |
| ESP All MAF | 0.003464 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.999 |
OR5L2
| dbSNP name | rs17148058(T,G); rs7102394(C,T); rs7102663(C,T) |
| ccdsGene name | CCDS31511.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 26338 |
| EntrezGene Description | olfactory receptor, family 5, subfamily L, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5L2:NM_001004739:exon1:c.T242G:p.M81R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0008 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGL0 |
| dbNSFP Uniprot ID | OR5L2_HUMAN |
| dbNSFP KGp1 AF | 0.0306776556777 |
| dbNSFP KGp1 Afr AF | 0.134146341463 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03076 |
| ESP Afr MAF | 0.080682 |
| ESP All MAF | 0.027555 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.007002 |
OR5D16
| dbSNP name | rs6591699(G,T); rs6591700(G,A); rs11231253(C,T) |
| ccdsGene name | CCDS31512.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 390144 |
| EntrezGene Description | olfactory receptor, family 5, subfamily D, member 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5D16:NM_001005496:exon1:c.G75T:p.L25L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3228 |
| ESP Afr MAF | 0.366652 |
| ESP All MAF | 0.37071 |
| ESP Eur/Amr MAF | 0.372789 |
| ExAC AF | 0.656 |
OR5W2
| dbSNP name | rs11231529(G,A); rs2457239(G,A); rs115502637(T,G); rs139033114(T,C) |
| ccdsGene name | CCDS31513.1 |
| cytoBand name | 11q11 |
| EntrezGene GeneID | 390148 |
| EntrezGene Description | olfactory receptor, family 5, subfamily W, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5W2:NM_001001960:exon1:c.A125G:p.N42S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5402 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH69 |
| dbNSFP Uniprot ID | OR5W2_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.003408 |
| ESP All MAF | 0.001231 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0003578 |
OR5F1
| dbSNP name | rs2449134(C,T); rs145426776(A,G); rs2128152(T,G) |
| ccdsGene name | CCDS31515.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 338674 |
| EntrezGene Description | olfactory receptor, family 5, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5F1:NM_003697:exon1:c.G881A:p.S294N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95221 |
| dbNSFP Uniprot ID | OR5F1_HUMAN |
| dbNSFP KGp1 AF | 0.975274725275 |
| dbNSFP KGp1 Afr AF | 0.90243902439 |
| dbNSFP KGp1 Amr AF | 0.988950276243 |
| dbNSFP KGp1 Asn AF | 0.998251748252 |
| dbNSFP KGp1 Eur AF | 0.998680738786 |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.078828 |
| ESP All MAF | 0.027166 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.992 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608492 OLFACTORY RECEPTOR, FAMILY 5, SUBFAMILY F, MEMBER 1; OR5F1
;;OR11-10
OMIM Description
Olfactory receptor genes are members of a large multigene family
encoding transmembrane signaling proteins required for odorant
discrimination. Many of these genes are arranged in large olfactory gene
clusters on human chromosomes 6, 11, and 17, as well as distributed on
other chromosomes (Buettner et al., 1998). See also 164342.
CLONING
By screening and PCR amplification of artificial chromosomes and genomic
libraries, Buettner et al. (1998) cloned OR5F1, which they designated
OR11-10. The deduced protein contains several transmembrane domains.
MAPPING
By genomic sequence analysis and FISH, Buettner et al. (1998) mapped the
OR5F1 gene to chromosome 11q12, where it resides in a gene cluster with
several other olfactory receptor genes.
OR5AS1
| dbSNP name | rs1482011(G,A) |
| ccdsGene name | CCDS31516.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219447 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AS, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AS1:NM_001001921:exon1:c.G258A:p.L86L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.02571 |
| ESP Afr MAF | 0.082917 |
| ESP All MAF | 0.028552 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.992 |
OR8I2
| dbSNP name | rs17150021(A,T) |
| ccdsGene name | CCDS31517.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 120586 |
| EntrezGene Description | olfactory receptor, family 8, subfamily I, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8I2:NM_001003750:exon1:c.A417T:p.K139N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N0Y5 |
| dbNSFP Uniprot ID | OR8I2_HUMAN |
| dbNSFP KGp1 AF | 0.0384615384615 |
| dbNSFP KGp1 Afr AF | 0.164634146341 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.03857 |
| ESP Afr MAF | 0.106997 |
| ESP All MAF | 0.036478 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.009555 |
OR8H2
| dbSNP name | rs140386955(A,G); rs2512961(C,T); rs2449148(A,G); rs1842696(G,A) |
| ccdsGene name | CCDS31518.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390151 |
| EntrezGene Description | olfactory receptor, family 8, subfamily H, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8H2:NM_001005200:exon1:c.A269G:p.N90S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0227 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N162 |
| dbNSFP Uniprot ID | OR8H2_HUMAN |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.018401 |
| ESP All MAF | 0.006311 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 1.748e-03,8.132e-06 |
OR8H3
| dbSNP name | rs7107077(C,A); rs144691899(C,T); rs61745899(A,G); rs11606538(G,A); rs11604579(A,G) |
| ccdsGene name | CCDS31519.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390152 |
| EntrezGene Description | olfactory receptor, family 8, subfamily H, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8H3:NM_001005201:exon1:c.C139A:p.L47I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N146 |
| dbNSFP Uniprot ID | OR8H3_HUMAN |
| dbNSFP KGp1 AF | 0.0489926739927 |
| dbNSFP KGp1 Afr AF | 0.142276422764 |
| dbNSFP KGp1 Amr AF | 0.0497237569061 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.023746701847 |
| dbSNP GMAF | 0.04913 |
| ESP Afr MAF | 0.142435 |
| ESP All MAF | 0.074188 |
| ESP Eur/Amr MAF | 0.039223 |
| ExAC AF | 0.043 |
OR8J3
| dbSNP name | rs1384094(C,A); rs1947923(T,C) |
| ccdsGene name | CCDS31520.1 |
| CosmicCodingMuts gene | OR8J3 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 81168 |
| EntrezGene Description | olfactory receptor, family 8, subfamily J, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8J3:NM_001004064:exon1:c.G622T:p.V208F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0133 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGG0 |
| dbNSFP Uniprot ID | OR8J3_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.011813 |
| ESP All MAF | 0.004079 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001204 |
OR5T2
| dbSNP name | rs10791893(C,G); rs3919907(G,T) |
| ccdsGene name | CCDS31523.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219464 |
| EntrezGene Description | olfactory receptor, family 5, subfamily T, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5T2:NM_001004746:exon1:c.G259C:p.V87L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGG2 |
| dbNSFP Uniprot ID | OR5T2_HUMAN |
| dbNSFP KGp1 AF | 0.900183150183 |
| dbNSFP KGp1 Afr AF | 0.794715447154 |
| dbNSFP KGp1 Amr AF | 0.933701657459 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.877308707124 |
| dbSNP GMAF | 0.1001 |
| ESP Afr MAF | 0.209223 |
| ESP All MAF | 0.15284 |
| ESP Eur/Amr MAF | 0.123953 |
| ExAC AF | 0.900,8.134e-06 |
OR5T1
| dbSNP name | rs150918659(T,G); rs12360890(A,G); rs7125697(G,C) |
| ccdsGene name | CCDS31525.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390155 |
| EntrezGene Description | olfactory receptor, family 5, subfamily T, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5T1:NM_001004745:exon1:c.T280G:p.L94V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NG75 |
| dbNSFP Uniprot ID | OR5T1_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.018174 |
| ESP All MAF | 0.006157 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001805 |
OR8H1
| dbSNP name | rs114873440(G,A); rs1842674(G,A); rs11600896(C,T) |
| ccdsGene name | CCDS31526.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219469 |
| EntrezGene Description | olfactory receptor, family 8, subfamily H, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8H1:NM_001005199:exon1:c.C388T:p.R130C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0061 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGG4 |
| dbNSFP Uniprot ID | OR8H1_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.018401 |
| ESP All MAF | 0.006234 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001822 |
OR8K3
| dbSNP name | rs960193(T,G); rs117366703(C,T) |
| ccdsGene name | CCDS31527.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219473 |
| EntrezGene Description | olfactory receptor, family 8, subfamily K, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8K3:NM_001005202:exon1:c.T365G:p.L122R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH51 |
| dbNSFP Uniprot ID | OR8K3_HUMAN |
| dbNSFP KGp1 AF | 0.761904761905 |
| dbNSFP KGp1 Afr AF | 0.772357723577 |
| dbNSFP KGp1 Amr AF | 0.817679558011 |
| dbNSFP KGp1 Asn AF | 0.846153846154 |
| dbNSFP KGp1 Eur AF | 0.664907651715 |
| dbSNP GMAF | 0.2388 |
| ESP Afr MAF | 0.271695 |
| ESP All MAF | 0.318378 |
| ESP Eur/Amr MAF | 0.342295 |
| ExAC AF | 0.721,4.880e-05 |
OR8K1
| dbSNP name | rs1905055(T,C); rs10896271(A,G); rs10896272(C,A) |
| ccdsGene name | CCDS31528.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390157 |
| EntrezGene Description | olfactory receptor, family 8, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8K1:NM_001002907:exon1:c.T2C:p.M1T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | start_lost |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP Uniprot Acc | Q8NGG5 |
| dbNSFP Uniprot ID | OR8K1_HUMAN |
| dbNSFP KGp1 AF | 0.760531135531 |
| dbNSFP KGp1 Afr AF | 0.772357723577 |
| dbNSFP KGp1 Amr AF | 0.812154696133 |
| dbNSFP KGp1 Asn AF | 0.846153846154 |
| dbNSFP KGp1 Eur AF | 0.663588390501 |
| dbSNP GMAF | 0.2401 |
| ESP Afr MAF | 0.280554 |
| ESP All MAF | 0.320994 |
| ESP Eur/Amr MAF | 0.341713 |
| ExAC AF | 0.72 |
OR8J1
| dbSNP name | rs7942390(A,G); rs10896290(A,G); rs7928704(C,T) |
| ccdsGene name | CCDS31529.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219477 |
| EntrezGene Description | olfactory receptor, family 8, subfamily J, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8J1:NM_001005205:exon1:c.A24G:p.R8R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1804 |
| ESP Afr MAF | 0.063182 |
| ESP All MAF | 0.09923 |
| ESP Eur/Amr MAF | 0.117695 |
| ExAC AF | 0.884 |
OR8U1
| dbSNP name | rs11228165(C,T); rs11228166(A,G); rs12788990(A,G); rs10791961(C,G) |
| ccdsGene name | CCDS41647.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219417 |
| EntrezGene Description | olfactory receptor, family 8, subfamily U, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8U1:NM_001005204:exon1:c.C57T:p.D19D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4141 |
| ExAC AF | 0.512 |
OR5R1
| dbSNP name | rs998544(G,A); rs7930678(A,G); rs12785840(A,G); rs7933772(T,C); rs6591324(A,G); rs7931261(A,G) |
| ccdsGene name | CCDS31530.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219479 |
| EntrezGene Description | olfactory receptor, family 5, subfamily R, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5R1:NM_001004744:exon1:c.C821T:p.A274V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH85 |
| dbNSFP Uniprot ID | OR5R1_HUMAN |
| dbNSFP KGp1 AF | 0.427197802198 |
| dbNSFP KGp1 Afr AF | 0.172764227642 |
| dbNSFP KGp1 Amr AF | 0.582872928177 |
| dbNSFP KGp1 Asn AF | 0.643356643357 |
| dbNSFP KGp1 Eur AF | 0.354881266491 |
| dbSNP GMAF | 0.4256 |
| ESP Afr MAF | 0.215811 |
| ESP All MAF | 0.318532 |
| ESP Eur/Amr MAF | 0.371159 |
| ExAC AF | 0.432 |
OR5M9
| dbSNP name | rs61902868(G,A); rs61902869(G,T); rs61902870(A,G); rs61902871(G,A) |
| ccdsGene name | CCDS31531.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390162 |
| EntrezGene Description | olfactory receptor, family 5, subfamily M, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5M9:NM_001004743:exon1:c.C758T:p.P253L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGP3 |
| dbNSFP Uniprot ID | OR5M9_HUMAN |
| dbNSFP KGp1 AF | 0.0709706959707 |
| dbNSFP KGp1 Afr AF | 0.146341463415 |
| dbNSFP KGp1 Amr AF | 0.0359116022099 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0923482849604 |
| dbSNP GMAF | 0.07117 |
| ESP Afr MAF | 0.096774 |
| ESP All MAF | 0.086194 |
| ESP Eur/Amr MAF | 0.080773 |
| ExAC AF | 0.073,8.133e-06 |
OR5M11
| dbSNP name | rs628524(C,T) |
| ccdsGene name | CCDS53629.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219487 |
| EntrezGene Description | olfactory receptor, family 5, subfamily M, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5M11:NM_001005245:exon1:c.G512A:p.S171N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RB7 |
| dbNSFP Uniprot ID | OR5MB_HUMAN |
| dbNSFP KGp1 AF | 0.676282051282 |
| dbNSFP KGp1 Afr AF | 0.288617886179 |
| dbNSFP KGp1 Amr AF | 0.779005524862 |
| dbNSFP KGp1 Asn AF | 0.870629370629 |
| dbNSFP KGp1 Eur AF | 0.732189973615 |
| dbSNP GMAF | 0.3246 |
| ESP Afr MAF | 0.439532 |
| ESP All MAF | 0.354374 |
| ESP Eur/Amr MAF | 0.252424 |
| ExAC AF | 0.743 |
OR5M10
| dbSNP name | rs10792043(C,A) |
| ccdsGene name | CCDS53630.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390167 |
| EntrezGene Description | olfactory receptor, family 5, subfamily M, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5M10:NM_001004741:exon1:c.G205T:p.V69L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IEU7 |
| dbNSFP Uniprot ID | OR5MA_HUMAN |
| dbNSFP KGp1 AF | 0.635073260073 |
| dbNSFP KGp1 Afr AF | 0.278455284553 |
| dbNSFP KGp1 Amr AF | 0.737569060773 |
| dbNSFP KGp1 Asn AF | 0.870629370629 |
| dbNSFP KGp1 Eur AF | 0.639841688654 |
| dbSNP GMAF | 0.3659 |
| ESP Afr MAF | 0.412731 |
| ESP All MAF | 0.415421 |
| ESP Eur/Amr MAF | 0.334581 |
| ExAC AF | 0.677 |
OR5M1
| dbSNP name | rs4939078(C,G) |
| ccdsGene name | CCDS53631.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390168 |
| EntrezGene Description | olfactory receptor, family 5, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5M1:NM_001004740:exon1:c.G845C:p.S282T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGP8 |
| dbNSFP Uniprot ID | OR5M1_HUMAN |
| dbNSFP KGp1 AF | 0.396978021978 |
| dbNSFP KGp1 Afr AF | 0.156504065041 |
| dbNSFP KGp1 Amr AF | 0.546961325967 |
| dbNSFP KGp1 Asn AF | 0.618881118881 |
| dbNSFP KGp1 Eur AF | 0.313984168865 |
| dbSNP GMAF | 0.3953 |
| ESP Afr MAF | 0.198144 |
| ESP All MAF | 0.26796 |
| ESP Eur/Amr MAF | 0.29917 |
| ExAC AF | 0.378 |
OR5AP2
| dbSNP name | rs140197428(G,A); rs11606499(C,T) |
| ccdsGene name | CCDS31534.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 338675 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AP, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AP2:NM_001002925:exon1:c.C707T:p.S236L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0023 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGF4 |
| dbNSFP Uniprot ID | O5AP2_HUMAN |
| dbNSFP KGp1 AF | 0.00228937728938 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.002296 |
| ESP Afr MAF | 0.001136 |
| ESP All MAF | 0.003078 |
| ESP Eur/Amr MAF | 0.004074 |
| ExAC AF | 0.002692 |
OR5AR1
| dbSNP name | rs11228710(C,T) |
| ccdsGene name | CCDS31535.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219493 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AR, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AR1:NM_001004730:exon1:c.C55T:p.Q19X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.624084249084 |
| dbNSFP KGp1 Afr AF | 0.241869918699 |
| dbNSFP KGp1 Amr AF | 0.75138121547 |
| dbNSFP KGp1 Asn AF | 0.798951048951 |
| dbNSFP KGp1 Eur AF | 0.679419525066 |
| dbSNP GMAF | 0.377 |
| ESP Afr MAF | 0.337801 |
| ESP All MAF | 0.42966 |
| ESP Eur/Amr MAF | 0.310521 |
| ExAC AF | 0.688 |
OR9G1
| dbSNP name | rs75293840(C,T) |
| ccdsGene name | CCDS31536.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390174 |
| EntrezGene Description | olfactory receptor, family 9, subfamily G, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR9G9:NM_001013358:exon1:c.C634T:p.L212F,OR9G1:NM_001005213:exon1:c.C634T:p.L212F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0219 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH87 |
| dbNSFP Uniprot ID | OR9G1_HUMAN |
| dbNSFP KGp1 AF | 0.00732600732601 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.036801 |
| ESP All MAF | 0.012544 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.003741 |
OR9G4
| dbSNP name | rs513873(A,G); rs577576(T,C); rs1397053(T,C) |
| ccdsGene name | CCDS31537.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 283189 |
| EntrezGene Description | olfactory receptor, family 9, subfamily G, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR9G4:NM_001005284:exon1:c.T665C:p.V222A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGQ1 |
| dbNSFP Uniprot ID | OR9G4_HUMAN |
| dbNSFP KGp1 AF | 0.203754578755 |
| dbNSFP KGp1 Afr AF | 0.227642276423 |
| dbNSFP KGp1 Amr AF | 0.149171270718 |
| dbNSFP KGp1 Asn AF | 0.0804195804196 |
| dbNSFP KGp1 Eur AF | 0.307387862797 |
| dbSNP GMAF | 0.2043 |
| ESP Afr MAF | 0.238982 |
| ESP All MAF | 0.292212 |
| ESP Eur/Amr MAF | 0.319483 |
| ExAC AF | 0.254 |
MIR6128
| dbSNP name | rs67042258(G,A) |
| cytoBand name | 11q12.1 |
| snpEff Gene Name | OR9G4 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2126 |
| ExAC AF | 0.217 |
OR5AK2
| dbSNP name | rs2853083(G,A); rs62001000(A,G); rs61886711(G,A); rs142758369(G,A) |
| ccdsGene name | CCDS31538.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390181 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AK, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AK2:NM_001005323:exon1:c.G276A:p.M92I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH90 |
| dbNSFP Uniprot ID | O5AK2_HUMAN |
| dbNSFP KGp1 AF | 0.71978021978 |
| dbNSFP KGp1 Afr AF | 0.943089430894 |
| dbNSFP KGp1 Amr AF | 0.593922651934 |
| dbNSFP KGp1 Asn AF | 0.741258741259 |
| dbNSFP KGp1 Eur AF | 0.618733509235 |
| dbSNP GMAF | 0.2805 |
| ESP Afr MAF | 0.110859 |
| ESP All MAF | 0.301801 |
| ESP Eur/Amr MAF | 0.399651 |
| ExAC AF | 0.636 |
OR5AK4P
| dbSNP name | rs11228882(C,T) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219525 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AK, member 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1575 |
APLNR
| dbSNP name | rs1044235(T,G); rs2282623(C,T); rs2282624(C,T); rs2282625(G,A); rs746886(G,A); rs948846(G,A); rs746887(A,G); rs948847(G,T) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 187 |
| EntrezGene Description | apelin receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06474 |
OMIM Clinical Significance
Skel:
Skeletal dysplasia;
Severely retarded ossification of epiphyses, pelvis, hands, and feet
Limbs:
Abnormal modeling of bones of hands and feet
Neuro:
No mental retardation
Inheritance:
Autosomal recessive
OMIM Title
*600052 APELIN RECEPTOR; APLNR
;;APJ PUTATIVE RECEPTOR PROTEIN RELATED TO ANGIOTENSIN RECEPTOR; APJ;;
ANGIOTENSIN RECEPTOR-LIKE 1; AGTRL1
OMIM Description
CLONING
In the course of a search for genes closely related to the vasopressin
receptor gene (AVPR2; 300538), O'Dowd et al. (1993) found a putative
receptor protein related to the angiotensin receptor (AGTR1A; 106165).
The AGTRL1 gene, which they designated APJ, was cloned using PCR with a
set of degenerate primers based on a conserved 7-transmembrane domain
found in members of the G protein-coupled receptor (GPCR) gene family.
The identity to the AGTR1A gene ranged from 40 to 50% in the hydrophobic
transmembrane region of APJ. Transcripts of the gene were detected in
many regions of the brain.
GENE FUNCTION
Tatemoto et al. (1998) stated that apelin (300297) is an endogenous
ligand for the APJ receptor.
Cayabyab et al. (2000) reported that in addition to the chemokine
receptors CCR5 (601373) and CXCR4 (162643), primary HIV-1 isolates can
also use APJ as a coreceptor. CAT reporter assays showed that synthetic
apelin peptides inhibited HIV-1 entry into CD4 (186940)-APJ-expressing
cells.
Using cDNA microarray analysis on paired samples of left ventricle
obtained before and after placement of a left ventricular assist device
in 11 patients, Chen et al. (2003) found that APJ was the most
significantly upregulated gene. Using immunoassay and
immunohistochemical techniques, they demonstrated that apelin is
localized primarily in the endothelium of the coronary arteries and is
found at a higher concentration in cardiac tissue after mechanical
offloading. The authors also demonstrated increases in the plasma level
of apelin in patients with left ventricular dysfunction. Chen et al.
(2003) concluded that their findings imply an important apelin-APJ
paracrine signaling pathway in the heart.
Scimia et al. (2012) reported that genetic loss of APJ, a G
protein-coupled receptor, confers resistance to chronic pressure
overload by markedly reducing myocardial hypertrophy and heart failure.
In contrast, mice lacking apelin, the endogenous APJ ligand, remain
sensitive, suggesting an apelin-independent function of APJ. Freshly
isolated APJ-null cardiomyocytes exhibit an attenuated response to
stretch, indicating that APJ is a mechanosensor. Activation of APJ by
stretch increases cardiomyocyte cell size and induces molecular markers
of hypertrophy. Whereas apelin stimulates APJ to activate G-alpha-i (see
139310) and elicits a protective response, stretch signals in an
APJ-dependent, G protein-independent fashion to induce hypertrophy.
Stretch-mediated hypertrophy is prevented by knockdown of beta-arrestins
(e.g., 107940) or by pharmacologic doses of apelin acting through
G-alpha-i. Scimia et al. (2012) concluded that, taken together, their
data indicated that APJ is a bifunctional receptor for both mechanical
stretch and the endogenous peptide apelin. By sensing the balance
between these stimuli, APJ occupies a pivotal point linking sustained
overload to cardiomyocyte hypertrophy.
Pauli et al. (2014) studied the relationship between Toddler (also known
as Apela/Elabela/Ende, 615594) and APJ/apelin receptors through genetic
interaction and receptor internalization experiments. Loss or
overproduction of Toddler reduced cell movements during zebrafish
gastrulation; mesodermal and endodermal cells were slow to internalize
and migrate. Both the local and ubiquitous expression of Toddler were
able to rescue gastrulation movements in Toddler mutants, suggesting
that Toddler acts as a motogen, a signal that promotes cell migration.
Toddler activates G protein-coupled APJ/apelin receptor signaling, as
evidenced by Toddler-induced internalization of APJ/apelin receptors and
rescue of Toddler mutants through expression of the known receptor
agonist apelin. Pauli et al. (2014) concluded that their findings
indicated that Toddler promotes cell movement during zebrafish
gastrulation by activation of APJ/apelin receptor signaling and that
Toddler does not seem to act as a chemoattractant or -repellent, but
rather as a global, signal that promotes the movement of mesendodermal
cells. Since both loss and overproduction of Toddler reduce cell
movement, Toddler levels need to be tightly regulated during
gastrulation.
MAPPING
By PCR analysis of somatic cell lines, O'Dowd et al. (1993) mapped the
APJ gene to chromosome 11. High-resolution mapping by fluorescence in
situ hybridization sublocalized the gene to 11q12.
OR6Q1
| dbSNP name | rs921135(A,G); rs2513726(A,G); rs7123727(C,T); rs1374570(G,C) |
| ccdsGene name | CCDS31541.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219956 |
| EntrezGene Symbol | OR9Q1 |
| EntrezGene Description | olfactory receptor, family 9, subfamily Q, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6Q1:NM_001005186:exon1:c.A299G:p.D100G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGQ2 |
| dbNSFP Uniprot ID | OR6Q1_HUMAN |
| dbNSFP KGp1 AF | 0.384615384615 |
| dbNSFP KGp1 Afr AF | 0.313008130081 |
| dbNSFP KGp1 Amr AF | 0.265193370166 |
| dbNSFP KGp1 Asn AF | 0.657342657343 |
| dbNSFP KGp1 Eur AF | 0.282321899736 |
| dbSNP GMAF | 0.3857 |
| ESP Afr MAF | 0.336665 |
| ESP All MAF | 0.311451 |
| ESP Eur/Amr MAF | 0.298534 |
| ExAC AF | 0.351 |
OR9I1
| dbSNP name | rs189405120(C,G) |
| ccdsGene name | CCDS31542.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219956 |
| EntrezGene Symbol | OR9Q1 |
| EntrezGene Description | olfactory receptor, family 9, subfamily Q, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR9I1:NM_001005211:exon1:c.G440C:p.G147A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0972 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGQ6 |
| dbNSFP Uniprot ID | OR9I1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 1.627e-05,4.067e-05 |
OR9Q2
| dbSNP name | rs61902821(T,C); rs34337292(T,C); rs7120468(C,T); rs73470064(C,T); rs1451317(C,A) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219957 |
| EntrezGene Description | olfactory receptor, family 9, subfamily Q, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1648 |
| ESP Afr MAF | 0.110404 |
| ESP All MAF | 0.209097 |
| ESP Eur/Amr MAF | 0.25966 |
| ExAC AF | 0.222 |
OR1S2
| dbSNP name | rs11229279(G,A); rs11229280(G,A) |
| ccdsGene name | CCDS31545.1 |
| CosmicCodingMuts gene | OR1S2 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219958 |
| EntrezGene Description | olfactory receptor, family 1, subfamily S, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1S2:NM_001004459:exon1:c.C459T:p.F153F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4091 |
| ESP Afr MAF | 0.248978 |
| ESP All MAF | 0.300139 |
| ESP Eur/Amr MAF | 0.32635 |
| ExAC AF | 0.372,8.132e-06 |
OR1S1
| dbSNP name | rs1966836(A,G); rs1966835(T,C); rs1966834(A,G); rs143246332(G,A); rs61746527(A,G); rs2903566(G,T); rs7103026(A,G); rs7103033(A,G) |
| ccdsGene name | CCDS31546.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219959 |
| EntrezGene Description | olfactory receptor, family 1, subfamily S, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1S1:NM_001004458:exon1:c.A13G:p.S5G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH92 |
| dbNSFP Uniprot ID | OR1S1_HUMAN |
| dbNSFP KGp1 AF | 0.650641025641 |
| dbNSFP KGp1 Afr AF | 0.369918699187 |
| dbNSFP KGp1 Amr AF | 0.723756906077 |
| dbNSFP KGp1 Asn AF | 0.839160839161 |
| dbNSFP KGp1 Eur AF | 0.655672823219 |
| dbSNP GMAF | 0.3485 |
| ESP Afr MAF | 0.417992 |
| ESP All MAF | 0.406572 |
| ESP Eur/Amr MAF | 0.31669 |
| ExAC AF | 0.699,8.133e-06 |
OR10Q1
| dbSNP name | rs116816829(C,T); rs11229301(G,A); rs61902844(G,A); rs4245219(C,G) |
| ccdsGene name | CCDS31547.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219960 |
| EntrezGene Description | olfactory receptor, family 10, subfamily Q, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10Q1:NM_001004471:exon1:c.G952A:p.A318T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGQ4 |
| dbNSFP Uniprot ID | O10Q1_HUMAN |
| dbNSFP KGp1 AF | 0.0247252747253 |
| dbNSFP KGp1 Afr AF | 0.105691056911 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.079509 |
| ESP All MAF | 0.027325 |
| ESP Eur/Amr MAF | 0.000582 |
| ExAC AF | 0.008133 |
OR10W1
| dbSNP name | rs56102847(T,C); rs10792156(C,T); rs56302613(C,G); rs7111538(C,T); rs12284213(G,A); rs7936538(G,A) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 81341 |
| EntrezGene Description | olfactory receptor, family 10, subfamily W, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.045 |
OR5B17
| dbSNP name | rs4127353(T,C); rs55810057(A,G); rs4939208(A,T) |
| ccdsGene name | CCDS31548.1 |
| CosmicCodingMuts gene | OR5B17 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219965 |
| EntrezGene Description | olfactory receptor, family 5, subfamily B, member 17 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5B17:NM_001005489:exon1:c.A923G:p.Y308C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGF7 |
| dbNSFP Uniprot ID | OR5BH_HUMAN |
| dbNSFP KGp1 AF | 0.714285714286 |
| dbNSFP KGp1 Afr AF | 0.674796747967 |
| dbNSFP KGp1 Amr AF | 0.754143646409 |
| dbNSFP KGp1 Asn AF | 0.833916083916 |
| dbNSFP KGp1 Eur AF | 0.630606860158 |
| dbSNP GMAF | 0.286 |
| ESP Afr MAF | 0.263971 |
| ESP All MAF | 0.331204 |
| ESP Eur/Amr MAF | 0.365658 |
| ExAC AF | 0.683 |
OR5B3
| dbSNP name | rs12279895(T,C); rs12271646(C,G); rs11229409(C,G); rs11229410(T,C); rs11229411(C,T); rs12280114(T,C); rs11229412(C,A); rs11229413(A,G) |
| ccdsGene name | CCDS31549.1 |
| CosmicCodingMuts gene | OR5B3 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 441608 |
| EntrezGene Description | olfactory receptor, family 5, subfamily B, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5B3:NM_001005469:exon1:c.A887G:p.K296R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH48 |
| dbNSFP Uniprot ID | OR5B3_HUMAN |
| dbNSFP KGp1 AF | 0.299908424908 |
| dbNSFP KGp1 Afr AF | 0.396341463415 |
| dbNSFP KGp1 Amr AF | 0.245856353591 |
| dbNSFP KGp1 Asn AF | 0.166083916084 |
| dbNSFP KGp1 Eur AF | 0.364116094987 |
| dbSNP GMAF | 0.3003 |
| ESP Afr MAF | 0.327578 |
| ESP All MAF | 0.349061 |
| ESP Eur/Amr MAF | 0.36007 |
| ExAC AF | 0.319 |
OR5B2
| dbSNP name | rs10466659(A,G); rs4298923(A,G); rs1893902(A,G) |
| ccdsGene name | CCDS31550.1 |
| CosmicCodingMuts gene | OR5B2 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390190 |
| EntrezGene Description | olfactory receptor, family 5, subfamily B, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5B2:NM_001005566:exon1:c.T623C:p.V208A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96R09 |
| dbNSFP Uniprot ID | OR5B2_HUMAN |
| dbNSFP KGp1 AF | 0.217948717949 |
| dbNSFP KGp1 Afr AF | 0.323170731707 |
| dbNSFP KGp1 Amr AF | 0.165745856354 |
| dbNSFP KGp1 Asn AF | 0.166083916084 |
| dbNSFP KGp1 Eur AF | 0.213720316623 |
| dbSNP GMAF | 0.2181 |
| ESP Afr MAF | 0.234666 |
| ESP All MAF | 0.222214 |
| ESP Eur/Amr MAF | 0.215832 |
| ExAC AF | 0.218 |
OR5B12
| dbSNP name | rs11229457(C,T); rs4938895(A,G) |
| ccdsGene name | CCDS31551.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390191 |
| EntrezGene Description | olfactory receptor, family 5, subfamily B, member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5B12:NM_001004733:exon1:c.G422A:p.C141Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96R08 |
| dbNSFP Uniprot ID | OR5BC_HUMAN |
| dbNSFP KGp1 AF | 0.186355311355 |
| dbNSFP KGp1 Afr AF | 0.258130081301 |
| dbNSFP KGp1 Amr AF | 0.157458563536 |
| dbNSFP KGp1 Asn AF | 0.141608391608 |
| dbNSFP KGp1 Eur AF | 0.187335092348 |
| dbSNP GMAF | 0.1864 |
| ESP Afr MAF | 0.234666 |
| ESP All MAF | 0.221598 |
| ESP Eur/Amr MAF | 0.214901 |
| ExAC AF | 0.218 |
MPEG1
| dbSNP name | rs3847(A,G); rs5029315(G,T); rs180853837(C,T); rs544864(C,T) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219972 |
| snpEff Gene Name | DTX4 |
| EntrezGene Description | macrophage expressed 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4307 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Behavioral/psychiatric manifestations];
Inability to recognize someone familiar by the face alone
OMIM Title
*610390 MACROPHAGE EXPRESSED GENE 1
;;MPEG1;;
MPG1
OMIM Description
CLONING
Using differential display analysis, Spilsbury et al. (1995) identified
mouse Mpeg1 from a peritoneal-derived macrophage cDNA library. Using
primers from the Mpeg1 ORF for PCR, Spilsbury et al. (1995) isolated a
partial human MPEG1 gene from placental DNA. The deduced 669-amino acid
mouse protein contains a predicted N-terminal signal peptide, a
potential cleavage site, and several predicted phosphorylation,
N-glycosylation, and N-myristylation sites. Mpeg1 is threonine rich and
shares 27.3% sequence identity with mouse perforin (PRF1; 170280) over
an 88-amino acid region predicted to form 2 antiparallel amphipathic
helices involved in insertion into the lipid bilayer. Northern blot
analysis detected a 4.2-kb MPG1 transcript in human myelomonocytic
cells, both in monocytes and peritoneal macrophages. Northern blot
analysis of normal mouse tissues showed high Mpeg1 expression in
macrophages and weak expression in bone marrow. Mpeg1 expression in
mouse cells and cell lines was also restricted to mature macrophage and
macrophage-like cells, with increased Mpeg1 expression detected as
progenitor cells differentiated into macrophages.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the MPEG1
gene to chromosome 11 (TMAP STS-T98251).
OR5AN1
| dbSNP name | rs7941190(G,C) |
| ccdsGene name | CCDS31559.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390195 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AN, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AN1:NM_001004729:exon1:c.G867C:p.L289F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI8 |
| dbNSFP Uniprot ID | O5AN1_HUMAN |
| dbNSFP KGp1 AF | 0.664835164835 |
| dbNSFP KGp1 Afr AF | 0.522357723577 |
| dbNSFP KGp1 Amr AF | 0.707182320442 |
| dbNSFP KGp1 Asn AF | 0.704545454545 |
| dbNSFP KGp1 Eur AF | 0.707124010554 |
| dbSNP GMAF | 0.3347 |
| ESP Afr MAF | 0.468423 |
| ESP All MAF | 0.360299 |
| ESP Eur/Amr MAF | 0.304889 |
| ExAC AF | 0.687 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Brownish macular and lentiginous lesions, disseminated, present on
extremities, trunk, and neck;
HISTOLOGY:;
Digitiform acanthosis of the rete ridges;
Pronounced hyperpigmentation at tips of rete ridges;
Small horn cysts;
Acanthosis, mild;
Hypergranulosis, focal
MISCELLANEOUS:
Age of onset varies between 18 years and 53 years
MOLECULAR BASIS:
Caused by mutation in the protein O-glucosyltransferase-1 gene (POGLUT1,
615618.0001)
OMIM Title
*615702 OLFACTORY RECEPTOR, FAMILY 5, SUBFAMILY AN, MEMBER 1; OR5AN1
;;OR11-244
OMIM Description
DESCRIPTION
Humans have used musk for at least 2 millennia due to its distinctive
fragrance, which has significant physiologic effects. OR5AN1 is an
olfactory receptor that responds to muscone, the active ingredient in
musk odor secretions from the stink glands of male musk deer, civet cat,
musk shrew, and muskrat (Shirasu et al., 2014).
CLONING
By calcium imaging of mouse olfactory neurons, followed by single-cell
RT-PCR analysis, Shirasu et al. (2014) cloned several candidate muscone
olfactory receptor genes, including Mor215-1. Database analysis
identified human OR5AN1 as having 68% amino acid identity to Mor215-1.
ANIMAL MODEL
Using in vivo optical imaging studies in mice, Shirasu et al. (2014)
localized muscone-responsive glomeruli to the anterodorsomedial
olfactory bulb. Surgical alteration of mice revealed that mice with
bilateral lesions in each dorsomedial bulbar area could find eugenol,
but usually not muscone. Imaging studies showed that Mor215-1 glomeruli
were located in the dorsomedial and ventral region of the olfactory
bulb, a pattern similar to that of muscone-responsive glomeruli. By
expression in human embryonic kidney cells and Xenopus oocytes, Shirasu
et al. (2014) confirmed that mouse Mor215-1 and human OR5AN1 responded
to muscone.
MAPPING
Gross (2014) mapped the OR5AN1 gene to chromosome 11q12.1 based on an
alignment of the OR5AN1 sequence (GenBank GENBANK AB065806) with the
genomic sequence (GRCh37).
OR5A2
| dbSNP name | rs1453547(G,A) |
| ccdsGene name | CCDS31560.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219981 |
| EntrezGene Description | olfactory receptor, family 5, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5A2:NM_001001954:exon1:c.C515T:p.P172L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI9 |
| dbNSFP Uniprot ID | OR5A2_HUMAN |
| dbNSFP KGp1 AF | 0.159798534799 |
| dbNSFP KGp1 Afr AF | 0.0386178861789 |
| dbNSFP KGp1 Amr AF | 0.162983425414 |
| dbNSFP KGp1 Asn AF | 0.124125874126 |
| dbNSFP KGp1 Eur AF | 0.263852242744 |
| dbSNP GMAF | 0.1593 |
| ESP Afr MAF | 0.058155 |
| ESP All MAF | 0.193504 |
| ESP Eur/Amr MAF | 0.262864 |
| ExAC AF | 0.209 |
OR5A1
| dbSNP name | rs138097107(C,T); rs11605572(C,G); rs183397950(C,T); rs6591536(G,A); rs7941591(T,C); rs17591107(C,T) |
| ccdsGene name | CCDS31561.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219982 |
| EntrezGene Description | olfactory receptor, family 5, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5A1:NM_001004728:exon1:c.C5T:p.S2F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0007 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ0 |
| dbNSFP Uniprot ID | OR5A1_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000385 |
| ESP Eur/Amr MAF | 0.000582 |
| ExAC AF | 0.0005611 |
OR4D6
| dbSNP name | rs1453544(A,G); rs1453543(A,G); rs17153770(T,C); rs17500380(A,C); rs1453542(G,C); rs1453541(T,C) |
| ccdsGene name | CCDS31562.1 |
| CosmicCodingMuts gene | OR4D6 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219983 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D6:NM_001004708:exon1:c.A175G:p.M59V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGJ1 |
| dbNSFP Uniprot ID | OR4D6_HUMAN |
| dbNSFP KGp1 AF | 0.159798534799 |
| dbNSFP KGp1 Afr AF | 0.0365853658537 |
| dbNSFP KGp1 Amr AF | 0.162983425414 |
| dbNSFP KGp1 Asn AF | 0.124125874126 |
| dbNSFP KGp1 Eur AF | 0.265171503958 |
| dbSNP GMAF | 0.1593 |
| ESP Afr MAF | 0.055429 |
| ESP All MAF | 0.193042 |
| ESP Eur/Amr MAF | 0.263562 |
| ExAC AF | 0.209 |
OR4D11
| dbSNP name | rs7120079(T,C) |
| ccdsGene name | CCDS31563.1 |
| CosmicCodingMuts gene | OR4D11 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 219986 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D11:NM_001004706:exon1:c.T589C:p.F197L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI4 |
| dbNSFP Uniprot ID | OR4DB_HUMAN |
| dbNSFP KGp1 AF | 0.295787545788 |
| dbNSFP KGp1 Afr AF | 0.361788617886 |
| dbNSFP KGp1 Amr AF | 0.245856353591 |
| dbNSFP KGp1 Asn AF | 0.263986013986 |
| dbNSFP KGp1 Eur AF | 0.300791556728 |
| dbSNP GMAF | 0.2957 |
| ESP Afr MAF | 0.278283 |
| ESP All MAF | 0.294027 |
| ESP Eur/Amr MAF | 0.302095 |
| ExAC AF | 0.296 |
OR4D9
| dbSNP name | rs76175424(A,G); rs75125922(G,A); rs17501584(A,G) |
| ccdsGene name | CCDS31564.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390199 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D9:NM_001004711:exon1:c.A300G:p.Q100Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03627 |
| ESP Afr MAF | 0.102453 |
| ESP All MAF | 0.034868 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.01 |
OR10V1
| dbSNP name | rs499033(T,C); rs472177(A,G); rs537595(C,T) |
| ccdsGene name | CCDS31565.1 |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 390201 |
| EntrezGene Description | olfactory receptor, family 10, subfamily V, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10V1:NM_001005324:exon1:c.A368G:p.Q123R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGI7 |
| dbNSFP Uniprot ID | O10V1_HUMAN |
| dbNSFP KGp1 AF | 0.962912087912 |
| dbNSFP KGp1 Afr AF | 0.993902439024 |
| dbNSFP KGp1 Amr AF | 0.958563535912 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.916886543536 |
| dbSNP GMAF | 0.03719 |
| ESP Afr MAF | 0.017492 |
| ESP All MAF | 0.063655 |
| ESP Eur/Amr MAF | 0.087311 |
| ExAC AF | 0.937,8.134e-06 |
OR10V2P
| dbSNP name | rs11230067(G,T); rs507235(T,C); rs497596(G,A); rs504320(C,G) |
| cytoBand name | 11q12.1 |
| EntrezGene GeneID | 81343 |
| snpEff Gene Name | STX3 |
| EntrezGene Description | olfactory receptor, family 10, subfamily V, member 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03811 |
| ExAC AF | 0.057 |
LRRC10B
| dbSNP name | rs751984(T,C) |
| cytoBand name | 11q12.2 |
| EntrezGene GeneID | 390205 |
| snpEff Gene Name | SYT7 |
| EntrezGene Description | leucine rich repeat containing 10B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.247 |
FEN1
| dbSNP name | rs695869(C,T); rs4246215(G,T) |
| cytoBand name | 11q12.2 |
| EntrezGene GeneID | 2237 |
| snpEff Gene Name | FADS1 |
| EntrezGene Description | flap structure-specific endonuclease 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008724 |
OMIM Clinical Significance
INHERITANCE:
?Autosomal dominant;
?Autosomal recessive
GROWTH:
[Height];
Short stature (reported in 2 families)
HEAD AND NECK:
[Head];
Microcephaly
SKELETAL:
[Spine];
Kyphoscoliosis (1 patient);
[Hands];
Partial distal aphalangia;
[Feet];
Duplication of metacarpal IV;
Absent/hypoplastic toes;
Cutaneous syndactyly;
Normal great toes
SKIN, NAILS, HAIR:
[Nails];
Hypoplastic nails of affected digits
NEUROLOGIC:
[Central nervous system];
Cognitive deficits
MISCELLANEOUS:
Three families have been reported (last curated November 2010);
The mode of inheritance is unclear
OMIM Title
*600393 FLAP STRUCTURE-SPECIFIC ENDONUCLEASE 1; FEN1
;;MATURATION FACTOR 1; MF1
OMIM Description
CLONING
Harrington and Lieber (1994) purified and cloned the gene for a DNA
structure-specific endonuclease, FEN1, from mouse cells. In a second
publication, Harrington and Lieber (1994) showed that functional domains
within FEN1 and RAD2 (133530) define a family of structure-specific
endonucleases. The murine protein recognizes 5-prime DNA flap structures
that have been proposed in DNA replication, repair, and recombination.
Hiraoka et al. (1995) reported the sequence of the human FEN1 gene. They
showed that the translated sequence is identical to the peptide sequence
obtained from maturation factor-1 (MF1), which is 1 of the 10 essential
proteins for cell-free DNA replication. The human protein has the same
structure-specific DNA endonuclease activity as the murine protein.
GENE FUNCTION
Gordenin et al. (1997) examined the mechanism of expansion of triplet
repeat sequences. They pointed to the work of Kolodner and colleagues
(Tishkoff et al., 1997) concerning RAD27 endonuclease, which, as well as
its mammalian homolog FEN1, is responsible for removing a 5-prime flap
that is generated by displacement synthesis when DNA polymerase
encounters the 5-prime end of a downstream Okazaki fragment. Gordenin et
al. (1997) stated that 'an emerging view holds that the integrity of DNA
is determined by a critical interplay between DNA metabolic enzymes and
specific DNA sequences, which we term At-Risk Motifs (ARMs).' According
to their hypothesis, FEN1-resistant flap sequences provide a class of
ARMs in that they are poor substrates for a specific enzymatic process
that normally protects the genome against mutations.
FEN1 removes 5-prime overhanging flaps in DNA repair and processes the
5-prime ends of Okazaki fragments in lagging strand DNA synthesis.
Hosfield et al. (1998) noted that the crystal structure of Pyrococcus
furiosus FEN1, active-site metal ions, and mutational information
indicated interactions for the single- and double-stranded portions of
the flap DNA substrate and identified an unusual DNA-binding motif. The
active-site structure of the enzyme suggested that DNA binding induces
FEN1 to clamp onto the cleavage junction to form the productive complex.
The conserved FEN1 carboxyl terminus binds proliferating cell nuclear
antigen (PCNA) and positions FEN1 to act primarily as an exonuclease in
DNA replication, in contrast to its endonuclease activity in DNA repair.
Hosfield et al. (1998) predicted that FEN1 mutations altering PCNA
binding should reduce activity during replication, likely causing DNA
repeat expansions as seen in some cancers and genetic diseases.
The mechanism by which trinucleotide expansion occurs in human genes is
not understood. It has been hypothesized that DNA secondary structure
may actively participate by preventing FEN1 cleavage of displaced
Okazaki fragments. Spiro et al. (1999) showed that secondary structure
can, indeed, play a role in expansion through a FEN1-dependent
mechanism. They found that secondary structure inhibits flap processing
at CAG, CGG, or CTG repeats in a length-dependent manner by concealing
the 5-prime end of the flap that is necessary for both binding and
cleavage by FEN1. Thus, secondary structure can defeat the protective
function of FEN1, leading to site-specific expansions. However, Spiro et
al. (1999) found that when FEN1 is absent from the cell, alternative
pathways to simple inhibition of flap processing contribute to
expansion.
The flap endonuclease, FEN1, is an evolutionarily conserved component of
DNA replication from archaebacteria to humans. Based on in vitro
results, it processes Okazaki fragments during replication and is
involved in base excision repair. FEN1 removes the last primer
ribonucleotide on the lagging strand and it cleaves a 5-prime flap that
may result from strand displacement during replication or during base
excision repair. Its biologic importance has been revealed largely
through studies in the yeast Saccharomyces cerevisiae, wherein deletion
of the homologous gene Rad27 results in genome instability and mutagen
sensitivity. While the in vivo function of Rad27 has been well
characterized through genetic and biochemical approaches, little is
understood about the in vivo functions of human FEN1. Greene et al.
(1999) explored the function of human FEN1 in yeast. They found that the
human FEN1 protein complements a yeast Rad27 null mutant for a variety
of defects including mutagen sensitivity, genetic instability, and the
synthetic lethal interactions such as a Rad27/Rad51 mutant. Furthermore,
a mutant form of FEN1 lacking nuclease function exhibited
dominant-negative effects on cell growth and genome instability similar
to those seen with the homologous yeast Rad27 mutation. This genetic
impact was stronger when the human and yeast PCNA-binding domains were
exchanged. These findings indicated that the human FEN1 and yeast Rad27
proteins act on the same substrate in vivo. They defined a sensitive
yeast system for the identification and characterization of mutations in
FEN1.
Hasan et al. (2001) found that p300 (602700) formed a complex with FEN1
and acetylated FEN1 in vitro. Furthermore, FEN1 acetylation was observed
in vivo and was enhanced upon ultraviolet treatment of human cells.
Acetylation of the FEN1 C terminus by p300 significantly reduced DNA
binding and nuclease activity of FEN1. PCNA was able to stimulate both
acetylated and unacetylated FEN1 activity to the same extent. These
results identified acetylation as a novel regulatory modification of
FEN1 and suggested that p300 is not only a component of the chromatin
remodeling machinery but might also play a critical role in regulating
DNA metabolic events.
Huggins et al. (2002) prepared model nucleosome substrates containing
FEN1-cleavable DNA flaps. They found that human FEN1 bound and cleaved
such substrates with efficiencies similar to that displayed with naked
DNA. Moreover, both FEN1 and human DNA ligase I (126391) could operate
successively on DNA within the same nucleosome. These results suggested
that some base excision repair steps may not require nucleosome
remodeling in vivo and that FEN1 activity during Okazaki fragment
processing can occur on nucleosomal substrates.
Werner syndrome (WRN; 277700) is a genetic disorder characterized by
genomic instability, elevated recombination, and replication defects.
The WRN gene encodes a RecQ helicase (RECQL2; 604611). Sharma et al.
(2004) examined the ability of WRN to rescue cellular phenotypes of a
yeast dna2 mutant defective in a helicase-endonuclease that participates
with FEN1 in Okazaki fragment processing. Complementation studies
indicated that a conserved noncatalytic C-terminal domain of human WRN
rescued dna2-1 mutant phenotypes of growth, cell cycle arrest, and
sensitivity to the replication inhibitor hydroxyurea or DNA-damaging
agent methylmethane sulfonate. Physical interactions between WRN and
yeast FEN1 were demonstrated by coimmunoprecipitation, affinity
pull-down experiments, and by ELISA assays with purified recombinant
proteins. Biochemical analyses demonstrated that the C-terminal domain
of WRN or BLM (604610) stimulated FEN1 cleavage of its proposed
physiologic substrates during replication. Sharma et al. (2004)
suggested that the WRN-FEN1 interaction is biologically important in DNA
metabolism and supported a role of the conserved noncatalytic domain of
a human RecQ helicase in DNA replication intermediate processing.
MAPPING
Using human genomic clones homologous to the mouse Fen1 gene, Hiraoka et
al. (1995) found that fluorescence in situ hybridization yielded 2
hybridization signals on 11q12 and 1p22.2. The localization on human
11q12 was confirmed using radiation-reduced hybrids. The mouse Fen1 gene
was assigned to chromosome 19 based on somatic cell hybrids.
MOLECULAR GENETICS
Data from Saccharomyces cerevisiae suggested that FEN1 plays a role in
expansion of repetitive DNA tracts. Otto et al. (2001) hypothesized that
insufficiency of FEN1 or a mutant FEN1 might contribute to the
occurrence of expansion events of long repetitive DNA tracts after
polymerase slippage events during lagging strand synthesis in a
condition such as Huntington disease (HD; 143100). They studied 15 HD
parent/child pairs that demonstrated intergenerational increases in CAG
length of greater than 10 repeats for possible mutations or
polymorphisms within the FEN1 gene that could underlie the saltatory
repeat expansions seen in these individuals. No alterations were
observed compared to 50 controls, excluding FEN1 as a trans-acting
factor underlying trinucleotide repeat expansion.
Zheng et al. (2007) screened 253 human specimens of 12 common cancers
for FEN1 mutations by directly sequencing the coding region of the gene.
The authors detected 5 mutations in 71 nonsmall cell lung carcinoma
specimens. They also identified a missense mutation in melanoma and a
silent mutation in esophageal cancer. The same mutations were not found
in corresponding paired normal tissues, suggesting they were somatic
mutations. Two additional mutations were identified from breast
adenocarcinomas and another in a kidney hypernephroma. Nuclease activity
profiling analysis revealed that several mutations were defective in
5-prime exonuclease (EXO) and gep-dependent endonuclease (GEN)
activities, but retained flap-dependent endonuclease activity.
ANIMAL MODEL
Because mutations in some genes involved in DNA replication and repair
cause cancer predisposition, Kucherlapati et al. (2002) investigated the
possibility that FEN1 may function in tumorigenesis of the
gastrointestinal tract. Using gene knockout approaches, they introduced
a null mutation into mouse Fen1. Mice homozygous for the Fen1 mutation
were not obtained, suggesting that absence of Fen1 expression leads to
embryonic lethality. Most Fen1 heterozygous animals appeared normal.
However, when combined with a mutation in the adenomatous polyposis coli
(APC; 611731) gene, double heterozygous animals had increased numbers of
adenocarcinomas and decreased survival. The tumors from these mice
showed microsatellite instability. Because one copy of the Fen1 gene
remained intact in tumors, Fen1 haploinsufficiency appears to lead to
rapid progression of cancer.
Using a gene targeting approach, Zheng et al. (2007) generated mice
heterozygous and homozygous for a Fen1 point mutation, E160D, which
abolished more than 90% of the 5-prime exonuclease (EXO) and
gap-dependent endonuclease (GEN) activities of Fen1 but retained the
flap-specific endonuclease activity. Selective elimination of nuclease
activities led to frequent spontaneous mutations and accumulation of
incompletely digested DNA fragments in apoptotic cells. Heterozygous and
homozygous mice developed autoimmunity, chronic inflammation, and
cancer, primarily benign lung adenoma, but malignant testis, ovary, and
liver tumors were also seen. Zheng et al. (2007) concluded that the
mutator phenotype resulted in the initiation of cancer, whereas the
chronic inflammation promoted cancer progression.
C11orf83
| dbSNP name | rs7129040(T,A) |
| cytoBand name | 11q12.3 |
| EntrezGene GeneID | 790955 |
| snpEff Gene Name | METTL12 |
| EntrezGene Description | chromosome 11 open reading frame 83 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | ambiguous_orf |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06566 |
ZBTB3
| dbSNP name | rs141099182(G,A); rs7945873(C,T); rs544641(G,C); rs150580761(G,A); rs80108110(A,G) |
| cytoBand name | 11q12.3 |
| EntrezGene GeneID | 79842 |
| EntrezGene Description | zinc finger and BTB domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01286 |
SLC3A2
| dbSNP name | rs479958(A,G); rs577071(C,G); rs11231252(G,A); rs10897300(A,G); rs560603(G,A); rs12221878(C,G); rs146834691(T,G); rs143064031(G,A); rs561385(A,G); rs507101(C,G); rs74572195(G,A); rs10897301(A,G); rs138244590(G,A); rs481235(C,G); rs147861683(A,G); rs10792362(T,C); rs113905617(G,A); rs373690343(G,A); rs519473(C,T); rs7101685(C,T); rs7944051(C,T); rs201220940(C,T) |
| ccdsGene name | CCDS31590.1 |
| cytoBand name | 11q12.3 |
| EntrezGene GeneID | 6520 |
| EntrezGene Description | solute carrier family 3 (amino acid transporter heavy chain), member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC3A2:NM_002394:exon12:c.C1546T:p.P516S,SLC3A2:NM_001012664:exon10:c.C1360T:p.P454S,SLC3A2:NM_001013251:exon9:c.C1243T:p.P415S,SLC3A2:NM_001012662:exon12:c.C1549T:p.P517S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8129 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P08195-3 |
| dbNSFP KGp1 AF | 0.00778388278388 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.007805 |
| ESP Afr MAF | 0.010223 |
| ESP All MAF | 0.003539 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001195 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Keratosis pilaris;
Follicular keratosis;
[Nails];
Onychodystrophy;
[Hair];
Hypotrichosis;
Short hair;
Brittle hair;
Beaded hair on microscopy
MISCELLANEOUS:
Genetic heterogeneity;
Onset in infancy;
Variable severity;
Hair regrowth may occur later in life
MOLECULAR BASIS:
Caused by mutation in the keratin 81 gene (KRT81, 602153.0001);
Caused by mutation in the keratin 83 gene (KRT83, 602765.0001);
Caused by mutation in the keratin 86 gene (KRT86, 601928.0001).
OMIM Title
*158070 SOLUTE CARRIER FAMILY 3 (ACTIVATOR OF DIBASIC AND NEUTRAL AMINO ACID
TRANSPORT), MEMBER 2; SLC3A2
;;MDU1;;
ANTIGEN DEFINED BY MONOCLONAL ANTIBODY 4F2, HEAVY CHAIN;;
4F2 HEAVY CHAIN; 4F2HC;;
CD98 HEAVY CHAIN; CD98; CD98HC
MONOCLONAL ANTIBODY 44D7, INCLUDED
OMIM Description
CLONING
Haynes et al. (1981) defined a monoclonal antibody variously called 4F2
and MDU1. (MDU1 is derived from 'monoclonal, Duke University.')
Lumadue et al. (1987) presented the cDNA-derived amino acid sequence of
lymphocyte activation antigen 4F2. Their data indicate that the molecule
is 529 amino acids long with an internal signal sequence and a single
transmembrane domain. Because of the expression of the molecule on
actively proliferating cells of various origins, including embryonic
skin and lung, basal-layer keratinocytes, fibrosarcomas, osteosarcomas,
and rhabdomyosarcomas, the 4F2 molecule may play a role in cell
division.
Hemler and Strominger (1982) showed that 4F2 recognizes a determinant on
the 65-kD polypeptide backbone of the heavy chain of an approximately
120-kD cell surface glycoprotein that also has a 40-kD unglycosylated
light chain (SLC7A5; 600182).
Quackenbush et al. (1987) isolated a cDNA for the heavy chain. The
sequence suggests that the heavy chain cDNA encodes a type II membrane
glycoprotein. The cDNAs are derived from a single-copy gene that has
been highly conserved during mammalian evolution.
Regulation of expression of the heavy chain gene was studied by Lindsten
et al. (1988).
GENE FUNCTION
Posillico et al. (1985) demonstrated that the cell surface protein
identified by 4F2 modulates intracellular calcium. It is a heteromeric
glycoprotein with unique tissue distribution including activated T
cells, neuroendocrine cells, and all malignant cell lines.
Michalak et al. (1986) showed that both the 44D7 and the 4F2 monoclonal
antibodies inhibit specifically the sodium-dependent calcium fluxes
characteristic of Na+/Ca(2+) exchanges of cardiac and skeletal muscle.
Quackenbush et al. (1987) reviewed the evidence pointing to a role of
the 4F2 molecule in the regulation of intracellular calcium
concentration and the concomitant control of growth, excitability, and
endocrine secretion.
Amino acid transport across cellular plasma membranes depends on several
parallel-functioning transporters and exchangers. The widespread
transport system L accounts for a sodium-independent exchange of large
neutral amino acids, whereas the system y(+)L exchanges positively
charged amino acids and/or neutral amino acids together with sodium. The
4F2 heavy chain alone facilitates amino acid transport through both the
L-type and the y(+)L-type systems, depending on the cellular system.
Mastroberardino et al. (1998) identified the permease-related protein
E16 (600182) as the first light chain of the 4F2 heavy chain and showed
that the resulting heterodimeric complex mediates L-type amino acid
transport. They hypothesized that at least one other related light chain
may associate with the 4F2 heavy chain to produce a heterodimeric
transporter with y(+)L transport characteristics.
The MDU1 gene is associated with endocrine cell function including that
of pancreatic islet cells, thyroid C cells, and parathyroid cells
(Posillico et al., 1987). Antibodies to the MDU1 cell surface
glycoprotein modulate intracellular calcium and can stimulate
parathyroid hormone secretion.
Sato et al. (1999) determined that uptake of cystine in Xenopus oocytes
increased substantially when mouse xCT (607933) cRNA was coinjected with
4f2hc cRNA. Injection of either cRNA alone did not enhance uptake of
cystine and glutamate.
GENE STRUCTURE
Gottesdiener et al. (1988) showed that the gene for the heavy chain of
4F2 spans 8 kb and is composed of 9 exons. The 5-prime upstream region
of the gene displays properties characteristic of housekeeping genes: it
is GC rich and hypomethylated in peripheral blood lymphocyte DNA and
contains multiple binding sites for the Sp1 transcription factor, while
lacking TATA and CCAAT sequences. This region of the gene also displays
sequence homologies with several other inducible T-cell genes, including
interleukin-2, interleukin-2 receptor alpha chain, dihydrofolate
reductase, thymidine kinase, and transferrin receptor genes.
MAPPING
Messer Peters et al. (1982) mapped the gene which codes the
species-specific determinant defined by monoclonal antibody 4F2 to human
chromosome 11. Hybrid human-mouse cell lines heterogeneous for 4F2
antigen expression were sorted using the fluorescence-activated cell
sorter (FACS) to yield populations homogeneous with respect to the
presence or absence of this determinant. FACS permits the rapid
chromosome mapping of genes for cell surface antigens. Isozyme analysis
showed that chromosome 11 markers were similarly present or absent.
Assignment to chromosome 11 was confirmed by use of a hybrid line
containing only this human chromosome. Immunoprecipitation of the 4F2
determinant from the '11 only' hybrid resulted in a heavy subunit of
approximate molecular weight 100,000 and a light subunit of molecular
weight 41,000. Antibody 4F2 is directed against the heavy chain only;
hence, the origin of the light chain in the '11 only' cell line was
unclear.
Francke et al. (1983) assigned the gene for 4F2 antigen to the long arm
of chromosome 11. Two other antigens, called by them A3D8 and A1G3,
mapped to the short arm of chromosome 11. Rochelle et al. (1992)
indicated that the corresponding locus in the mouse is located on
chromosome 19 near the centromere. Comparative mapping suggests that
MDU1 is located in the proximal portion of 11q, perhaps 11q13. Courseaux
et al. (1996) used a combination of methods to refine maps of an
approximately 5-Mb region of 11q13. They proposed the following gene
order:
cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM,
ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
ANIMAL MODEL
Feral et al. (2005) found that Cd98hc null mouse cells were defective in
integrin-dependent cell spreading and cell migration, and they showed
increased sensitivity to anchorage deprivation-induced apoptosis.
Furthermore, Cd98hc was required for efficient adhesion-induced
activation of Akt (see 164730) and Rac (see 602048) GTPase. Cd98
promotes amino acid transport through its light chains; however, a
Cd98hc mutant that could interact with beta-1 integrin (135630) but not
with light chains restored integrin-dependent signaling and protection
from apoptosis. In addition, Cd98hc null embryonic stem cells lost their
tumorigenic potential in vivo.
Using cell culture and mice with deletion of Cd98hc in smooth muscle
cells, Fogelstrand et al. (2009) showed that Cd98hc is markedly
upregulated in neointimal and cultured vascular smooth muscle cells, and
that activated, but not quiescent, vascular smooth muscle cells require
Cd98hc for survival. In vivo, lack of Cd98hc does not affect normal
vessel morphology but does reduce intimal hyperplasia after arterial
injury. In vitro, loss of Cd98hc suppresses proliferation and induces
apoptosis of vascular smooth muscle cells. Fogelstrand et al. (2009)
concluded that CD98hc is important for vascular smooth muscle cell
proliferation and survival and that activated vascular smooth muscle
cells are physiologically dependent on CD98hc, indicating that CD98hc
may be a therapeutic target for vasoocclusive disorders.
By specifically deleting Cd98 in mouse T cells, Cantor et al. (2011)
prevented experimental autoimmune diabetes and reduced T-cell clonal
expansion without impairing T-cell homing to pancreatic islets. Unlike
Cd98 deletion in B lymphocytes, Cd98-null T cells showed only modestly
impaired antigen-driven and homeostatic proliferation. Cd98-null T cells
were activated by antigen, produced cytokines, and mediated efficient
cell-mediated target cell lysis. Mutation analysis and generation of
recombinant Cd98 showed that T-cell clonal expansion required the Cd98
integrin-binding domain. T cells bearing a Cd98 integrin-binding domain
and expanded in vitro could adoptively transfer diabetes. Cantor et al.
(2011) concluded that clonal expansion and the integrin-binding domain
of CD98 are required for the pathogenesis of autoimmune disease.
MIR3680-2
| dbSNP name | rs7942667(G,A); rs1211246(T,C); rs78682302(G,A); rs55763207(A,T); rs1193852(A,C); rs7938140(A,T); rs75254733(T,G); rs118020373(C,A); rs184003342(A,C); rs112870974(C,T); rs1193772(T,C); rs111446429(T,C); rs1193773(T,A); rs1193774(A,G); rs7931671(T,C); rs184125781(G,A); rs1193775(T,A); rs146139888(A,G); rs190622622(A,G); rs141268736(C,T); rs7925477(G,A); rs181969863(G,A); rs116467621(T,C); rs112315550(C,T); rs1193734(T,C); rs113303994(T,C); rs141946986(C,T); rs146219459(C,G); rs148032956(T,C); rs1193788(C,T); rs150049930(G,A); rs10897401(A,C); rs117481816(C,G); rs145170558(A,G); rs145775529(T,G); rs112875818(T,C); rs140417044(C,T); rs113007099(C,T); rs112197355(C,T); rs112428201(C,T); rs75208640(A,G); rs115658183(G,C); rs150686627(C,T); rs139914185(C,G); rs147497987(C,G); rs113592019(T,C); rs145485166(C,T); rs142729370(G,A); rs111635538(C,T); rs184272556(A,G); rs111280691(C,T); rs17158015(A,C); rs61930191(G,T); rs78006956(C,A); rs7925699(C,A); rs147521443(T,C); rs140081215(C,T); rs722508(A,G); rs17158018(G,A); rs1944086(C,T); rs114640693(C,T); rs151066697(C,A); rs1723212(G,T); rs114745131(G,T); rs17158022(A,C); rs139810394(A,G); rs1789323(C,A); rs1723199(C,A); rs146751045(C,T); rs17158027(C,T); rs79240629(C,A); rs3948871(C,T); rs115476586(C,T); rs76614219(T,C); rs1193789(G,A); rs76679981(T,C); rs191058001(C,G); rs112465295(A,G); rs1152246(C,T); rs75473082(C,G); rs60147282(T,A); rs1193727(C,T); rs1152245(G,T); rs11828966(T,C); rs1152244(C,T); rs1193726(A,C); rs113236928(T,C); rs1205166(A,G); rs1205186(G,A); rs113554055(A,G); rs111653918(C,T); rs79596479(G,A); rs80173408(T,C); rs75074324(C,G); rs1789327(T,C); rs113941435(A,C); rs1608760(T,C); rs1193905(C,G); rs61930192(T,G); rs185747576(T,C); rs190062511(G,A); rs143391661(T,G); rs1193904(T,G); rs115873027(T,C); rs4570581(G,C); rs540141(C,G); rs527027(C,A); rs139989498(C,T); rs565747(A,G); rs554430(T,C); rs1193729(C,T); rs113062762(A,C); rs111272836(C,A); rs112981837(C,T); rs112315286(C,G); rs149860666(G,C); rs145326159(A,G); rs181802555(G,A); rs142851004(C,T); rs114729707(A,G); rs139661433(C,A); rs145477679(C,A); rs148734125(T,G); rs488633(C,A); rs112530937(C,T); rs113689016(C,T); rs113986434(A,C); rs111873113(G,A); rs549144(G,T); rs72542451(G,A); rs72542452(T,C); rs72542454(T,C); rs143032319(G,C); rs1790218(G,A); rs486460(A,G); rs184244508(C,A); rs74528792(C,G); rs3937020(A,G); rs116604200(G,T); rs191326629(G,C); rs191550883(A,G); rs509997(A,G); rs74955140(G,A); rs474815(C,A); rs59922153(G,A); rs75823238(T,A); rs79286283(C,T); rs111954939(T,C); rs474874(A,G); rs112501844(A,C); rs75586965(A,G); rs112753913(C,G); rs557879(G,A); rs576641(T,C); rs117447942(G,T); rs77350650(C,A); rs74390468(T,C); rs575009(T,G); rs7102023(C,T); rs572017(A,C); rs524724(T,C); rs144811801(C,T); rs116466741(T,C); rs1723213(T,C); rs1783634(A,G); rs515213(T,C); rs376984844(G,C); rs513338(T,G); rs138325180(G,A); rs187444168(C,T); rs483012(G,A); rs192676274(T,G); rs7114405(G,A); rs543429(C,T); rs76214310(A,G); rs557658(A,G); rs74487747(A,G); rs77360396(G,A); rs180965881(T,A); rs534799(A,G); rs7104164(G,A); rs532085(C,T); rs148167601(C,T); rs111482186(A,G); rs505653(T,C); rs474096(C,A); rs11826575(A,T); rs1201559(C,T); rs474191(G,A); rs473345(T,C); rs140992047(C,T); rs548885(T,C); rs12421764(T,C); rs113036348(C,T); rs144143711(A,T); rs1193718(C,T); rs4445638(T,C); rs78236542(T,G); rs565787(T,A); rs3915142(A,G); rs371731448(G,A); rs144168435(G,A); rs7130728(C,T); rs114618503(A,G); rs505409(C,T); rs141817912(C,T); rs1789334(C,T); rs1404608(T,C); rs111268896(T,C); rs144630477(G,A); rs538716(C,A); rs61927968(C,T); rs527869(G,A); rs6591785(T,C); rs523928(C,T); rs7121603(C,T); rs6591787(T,G); rs147182613(C,T); rs181213876(G,A); rs111581772(A,G); rs117355747(A,C); rs1783635(C,T); rs149534824(G,C); rs146855122(G,A); rs117071614(G,A); rs146119230(G,A); rs138893701(A,T); rs118157800(A,G); rs76211894(T,C); rs61927971(C,T); rs111616127(T,C); rs112782474(G,C); rs113412852(G,A); rs111795249(C,G); rs117369218(C,T); rs114063840(G,T); rs116432392(A,C); rs76016537(G,C); rs145739011(C,T); rs148033246(C,G); rs564917(T,C); rs1790226(C,T); rs144353939(T,C); rs142385432(C,T); rs114423739(G,A); rs11231434(C,T); rs142015710(C,G); rs1783637(C,T); rs192190168(G,A); rs507312(G,C); rs78008666(T,C); rs147768689(G,A); rs117287838(A,G); rs111373362(C,T); rs113243283(G,C); rs75738772(G,A); rs76560761(T,A); rs191628230(T,A); rs1193787(C,T); rs182107013(G,A); rs1790219(T,C); rs142210177(T,C); rs145425615(C,T); rs543715(A,G); rs147286449(T,C); rs113840505(G,A); rs493922(G,A); rs471135(C,T); rs112250024(A,T); rs114283148(T,G); rs549715(G,A); rs550809(A,G); rs142596336(T,A); rs146847488(A,G); rs1152249(C,T); rs111379272(C,T); rs79853512(A,G); rs517391(A,G); rs141538307(G,A); rs112545613(C,T); rs114852417(G,A); rs115884404(G,C); rs77191891(G,A); rs61409388(C,T); rs1193722(T,G); rs113395081(G,T); rs56121458(G,C); rs1525066(G,A); rs184280831(A,G); rs1525065(C,T); rs113247971(G,A); rs138650190(C,G); rs187251404(G,A); rs146454003(G,T); rs61927990(C,T); rs146159506(G,T); rs140155775(G,C); rs11231441(C,T); rs76085625(C,A); rs117486493(T,C); rs17158152(T,C); rs113650574(A,G); rs146057331(T,G); rs547428(G,A); rs17158154(G,T); rs4963260(C,A); rs114805758(A,G); rs75454209(G,C); rs113832568(A,C); rs74331913(C,T); rs61927991(C,T); rs558903(C,T); rs4963401(T,C); rs145071402(T,C); rs4121883(A,G); rs505807(A,C); rs111849748(C,T); rs141886403(C,T); rs112793786(C,T); rs112419955(C,T); rs61927992(C,T); rs186892371(G,T); rs3898161(G,A); rs192149264(T,C); rs185099990(A,G); rs490724(A,G); rs116797937(G,T); rs12293171(C,T); rs73483759(G,A); rs113595086(C,T); rs79056633(G,A); rs78420293(G,C); rs112194523(A,G); rs517655(A,G); rs516763(T,G); rs7128461(T,C); rs12283500(G,A); rs76250168(C,G); rs2850630(G,A); rs189490349(G,A); rs75054278(G,A); rs144502971(C,T); rs114163931(A,G); rs72542470(T,G); rs10897407(A,G); rs113253118(C,T); rs113747568(T,C); rs113849261(C,T); rs566456(G,A); rs145622195(T,C); rs4121881(A,G); rs510547(C,T); rs55652716(A,G); rs188848827(A,G); rs117747972(T,A); rs112745008(G,C); rs556730(A,G); rs494608(T,C); rs17158192(A,G); rs186811423(C,T); rs7119705(G,A); rs193182758(A,T); rs61927994(A,G); rs115002947(C,T); rs511480(A,G); rs114117246(G,A); rs10750998(C,T); rs112436996(A,G); rs563948(A,G); rs187369500(A,G); rs113446545(C,T); rs4963405(T,C); rs11605137(C,T); rs558472(A,C); rs61927995(G,A); rs113712774(G,C); rs111739037(C,T); rs112033274(C,T); rs148659900(T,C); rs114211605(G,A); rs502642(T,C); rs61927997(G,C); rs499003(A,C); rs61927998(C,T); rs471044(A,G); rs113230491(C,T); rs192175613(C,T); rs144353523(C,T); rs146698573(T,A); rs115563062(T,G); rs7952297(G,A); rs61927999(C,T); rs111858293(C,T); rs688999(A,G); rs113699949(C,G); rs113779758(C,T); rs538309(T,C); rs61928008(T,C); rs191685612(C,T); rs146996028(T,C); rs526686(A,G); rs190459207(G,A); rs115153487(T,C); rs492995(A,G); rs117312995(G,A); rs57727018(A,G); rs10897411(T,C); rs607277(T,C); rs488374(T,C); rs610369(T,A); rs4085831(G,A); rs623990(T,C); rs377563593(C,T); rs637143(A,C); rs511686(T,C); rs546750(G,A); rs11602076(C,T); rs142102968(T,C); rs55998369(T,C); rs77112960(C,T); rs58957962(C,A); rs57882576(A,G); rs554212(G,C); rs61928012(C,A); rs79205534(C,T); rs10897412(T,A); rs61928013(T,C); rs72928246(C,T); rs7104584(C,G); rs11231448(C,T); rs11231449(C,T); rs11231450(A,G); rs12290345(T,C); rs12282281(A,G); rs11231451(A,T); rs12288592(G,C); rs60168208(T,C); rs79702925(T,C); rs604285(C,T); rs7939699(T,C); rs79455650(T,A); rs11231453(T,C); rs11231454(C,T); rs7925182(G,A); rs7940738(A,G); rs72928251(C,G); rs77413249(A,C); rs12281225(C,A); rs58159522(T,C); rs12288190(A,G); rs190834510(T,A); rs537473(T,G); rs28437742(A,C); rs61928014(T,C); rs79487798(C,T); rs7101446(T,G); rs7116119(C,T); rs7104489(T,A); rs61997169(C,T); rs7109920(A,G); rs4088469(G,A); rs11231455(G,C); rs629907(T,C); rs630759(A,G); rs631157(A,C); rs4357693(G,T); rs7129183(C,T); rs61928015(G,A); rs78640827(G,A); rs4963410(G,A); rs4246213(A,G); rs4246214(G,A); rs10466691(C,T); rs4088474(T,C); rs4369412(G,A); rs668284(T,C); rs4313592(T,C); rs4369413(G,A); rs6591796(A,G); rs61928016(A,T); rs61928017(G,T); rs866906(G,T); rs866905(C,T); rs4088473(A,G); rs12272694(G,A); rs637122(T,A); rs7104097(T,C); rs4088472(G,A); rs4088470(A,C); rs7131511(A,G); rs537178(T,A); rs10466692(T,C); rs7118732(G,A); rs4963411(C,G); rs4963412(A,G); rs4963413(T,C); rs4963415(C,T); rs9666270(G,A); rs7109027(A,T); rs9665791(A,G); rs11231459(A,G); rs11231460(G,T); rs7126715(G,A); rs7112909(A,T); rs61928018(T,C); rs118187559(C,T); rs593748(G,C); rs11231461(C,T); rs519252(C,T); rs17158280(C,T); rs11231463(A,G); rs4370940(A,G); rs11231464(A,G); rs148037703(G,A); rs4963416(T,C); rs7111246(C,G); rs9665872(C,A); rs7935983(G,A); rs501657(A,G); rs58687967(C,T); rs11231465(G,A); rs523493(A,G); rs7937224(C,T); rs7937356(C,A); rs60320069(G,A); rs629479(T,C); rs7939687(G,A); rs7924658(T,C); rs12287151(G,A); rs7121823(C,T); rs117595613(T,C); rs11231474(G,A); rs12224397(T,C); rs665080(A,C); rs11231476(G,A); rs4963266(C,T); rs113922743(G,A); rs61928043(A,C); rs61928044(T,C); rs681291(C,G); rs11501493(G,T); rs60590185(G,T); rs142706455(A,G); rs537227(G,C); rs189544113(G,A); rs560011(C,T); rs11821194(C,T); rs7934347(G,A); rs631174(T,C); rs10897414(A,G); rs11821807(C,T); rs518291(G,A); rs11533236(G,C); rs10897415(A,G); rs139329882(G,C); rs6591802(T,C); rs4963417(A,C); rs146743441(G,T); rs114479269(G,A); rs7116851(G,A); rs12792143(A,T); rs524339(A,G); rs613729(C,A); rs627647(A,G); rs7952627(G,T); rs642637(G,A); rs642659(C,G); rs4102216(A,G); rs61928056(G,A); rs4102215(A,C); rs76696079(C,G); rs4102214(A,G); rs7127167(A,G); rs4506657(C,T); rs55823811(G,A); rs541583(A,G); rs61928058(G,A); rs11231494(A,G); rs61928059(C,G); rs515867(T,C); rs66811727(G,A); rs56867396(G,A); rs510713(T,G); rs17158337(T,C); rs10501393(T,A); rs4454724(T,C); rs4466837(G,A); rs6591805(G,T); rs7127532(G,C); rs56207718(G,T); rs67952179(G,C); rs143613526(T,C); rs2212017(A,G); rs4475926(G,C); rs2226452(C,T); rs60092232(A,G); rs11534566(T,C); rs28828158(A,G); rs4439514(T,C); rs12286792(G,C); rs77221087(G,A); rs12281180(A,G); rs61929663(G,A); rs138283171(T,C); rs144501625(G,A); rs145078626(T,G); rs11822642(C,T); rs143509232(C,T); rs61929666(A,C); rs117563546(C,T); rs117734384(C,T); rs142672736(A,G); rs61929667(G,C); rs139898760(C,T); rs61403139(C,T); rs77741961(G,A); rs11231495(G,A); rs947808(C,T); rs61929669(C,A); rs1305(T,C); rs2298410(C,T); rs117950205(T,C); rs2282479(G,C); rs2282480(A,G); rs80332616(C,T); rs9633996(T,C); rs2154751(G,A); rs11231497(G,C); rs61929693(G,A); rs11231498(A,G); rs4360702(T,C); rs2275999(A,G); rs11231499(G,A); rs57210597(G,C); rs11231501(T,A); rs115216338(A,C); rs7123815(G,A); rs75033782(G,T); rs74430559(G,A); rs148333457(C,A); rs12287410(A,G); rs12280687(C,G); rs79304790(G,C); rs7944411(A,G); rs148551283(G,A); rs7932642(G,A); rs75823534(T,C); rs75043826(C,T); rs2507928(T,C); rs6591806(C,G); rs2732326(A,G); rs192056349(T,C); rs6591807(T,C); rs60484516(T,A); rs7935716(C,G); rs2849654(C,A); rs57819251(G,A); rs80023662(C,T); rs143291718(C,A); rs2849652(C,T); rs78133074(C,G); rs2264666(A,G); rs2732323(T,A); rs940611(C,G); rs75204695(A,G); rs59008891(G,A); rs10897423(G,A); rs10897424(T,C); rs11231507(T,C); rs115912814(C,T); rs9971506(T,C); rs11823214(C,A); rs61929699(C,T); rs10897427(C,T); rs2212798(C,T); rs2226772(A,T); rs190636279(G,A); rs950009(C,A); rs7125704(T,C); rs76848303(G,A); rs12272556(G,C); rs12803628(T,A); rs1404504(T,G); rs1404503(G,A); rs10897430(C,T); rs2269400(C,T); rs2239679(C,G); rs670784(G,C); rs7935128(G,T); rs7106153(T,C); rs6591808(A,G); rs6591809(T,A); rs933187(A,T); rs933186(C,T); rs7123161(C,T); rs57247740(C,T); rs599280(A,G); rs11231510(A,G); rs114692322(T,A); rs77495840(G,A); rs77178266(C,G); rs3740633(C,G); rs61399443(C,T); rs116171286(T,C); rs60912926(A,G); rs7103797(G,T); rs3781604(A,G); rs3781603(G,C); rs1404501(T,G); rs73490130(G,T); rs10897431(G,A); rs58005677(C,T); rs60321320(C,T); rs73490135(T,C); rs1788279(G,T); rs138148172(G,A); rs73490137(G,A); rs12281802(T,C); rs12418950(A,G); rs10792417(T,G); rs141645994(G,C); rs7929104(G,A); rs4963423(C,T); rs75233837(C,T); rs59884256(G,A); rs9633988(A,C); rs73490141(C,T); rs61681238(A,G); rs10897432(C,T); rs4963271(A,G); rs73490145(A,G); rs73490147(G,A); rs180833881(A,G); rs72930190(G,T); rs584905(T,C); rs870073(G,T); rs870074(G,A); rs73490150(A,T); rs57706792(T,C); rs73490151(T,C); rs11231516(G,T); rs4432030(C,T); rs4471424(T,C); rs1973811(T,C); rs1554656(A,G) |
| ccdsGene name | CCDS41661.1 |
| CosmicCodingMuts gene | SLC22A10 |
| cytoBand name | 11q12.3 |
| EntrezGene GeneID | 387775 |
| EntrezGene Symbol | SLC22A10 |
| snpEff Gene Name | SLC22A10 |
| EntrezGene Description | solute carrier family 22, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC22A10:NM_001039752:exon3:c.G619T:p.G207C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7555 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q63ZE4 |
| dbNSFP Uniprot ID | S22AA_HUMAN |
| dbNSFP KGp1 AF | 0.014652014652 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0263852242744 |
| dbSNP GMAF | 0.01469 |
| ESP Afr MAF | 0.004484 |
| ESP All MAF | 0.023402 |
| ESP Eur/Amr MAF | 0.032466 |
| ExAC AF | 0.026,8.163e-06 |
TRMT112
| dbSNP name | rs10128595(C,A); rs4930698(G,C); rs28364831(A,C); rs9787810(C,T) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 51504 |
| snpEff Gene Name | ESRRA |
| EntrezGene Description | tRNA methyltransferase 11-2 homolog (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08861 |
| ESP Afr MAF | 0.21604 |
| ESP All MAF | 0.067017 |
| ESP Eur/Amr MAF | 0.0022 |
LOC100996455
| dbSNP name | rs6591849(A,G); rs10792434(G,A); rs114330554(G,T) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 100996455 |
| snpEff Gene Name | AP003774.4 |
| EntrezGene Description | uncharacterized LOC100996455 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2511 |
PYGM
| dbSNP name | rs566653(G,A); rs555974(T,G); rs137986928(C,A); rs7126110(C,G); rs565688(T,A); rs625172(A,G); rs368381557(G,A); rs185011712(G,A); rs630966(C,G); rs589691(C,T); rs490980(C,T); rs489192(G,T); rs483962(A,G) |
| ccdsGene name | CCDS8079.1 |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 5837 |
| EntrezGene Description | phosphorylase, glycogen, muscle |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PYGM:NM_005609:exon16:c.G1885T:p.D629Y,PYGM:NM_001164716:exon14:c.G1621T:p.D541Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8565 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NDY6 |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.001136 |
| ESP All MAF | 0.000462 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0002196 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Pigmentary retinopathy;
Abnormal electroretinograms in heterozygotes;
Inferior and inferonasal retinal pigmentation (e.g. 180380.0004
and 180380.0025);
Superior hemisphere field impairment (e.g. 180380.0004 and 180380.0025);
Early onset night blindness and abnormal fundus (e.g. 180380.0013);
Cataracts (e.g. 180380.0016)
MISCELLANEOUS:
Mild asymmetric regional disease (e.g. 180380.0029);
Onset in first decade (e.g. 180380.0028)
MOLECULAR BASIS:
Caused by mutation in the rhodopsin gene (RHO, 180380.0001)
OMIM Title
*613733 MEN1 GENE; MEN1
;;MENIN
OMIM Description
DESCRIPTION
The MEN1 gene encodes menin, a nuclear scaffold protein that regulates
gene transcription by coordinating chromatin remodeling. Menin interacts
with several transcription factors, including JUND (165162), NFKB
(164011), and SMAD3 (603109). MEN1 is considered to act as a tumor
suppressor gene (summary by Canaff et al., 2012).
CLONING
Chandrasekharappa et al. (1997) identified several candidate genes
within the multiple endocrine neoplasia type I (MEN1; 131100) minimal
interval on chromosome 11q13. One of the genes (MEN1) was found to
encode a deduced 610-amino acid protein, which the authors designated
menin. Northern blot analysis revealed ubiquitous expression of a 2.8-kb
MEN1 transcript.
To identify additional candidate genes in the segment of less than 300
kb where the MEN1 locus is situated, the European Consortium on MEN1
(1997) used a BAC to isolate cDNAs from a bovine parathyroid cDNA
library by direct selection. One of the novel genes they identified,
which they called SCG2 (suppressor candidate gene-2), proved to be
identical to the MEN1 gene reported by Chandrasekharappa et al. (1997).
The SCG2 transcript was 2.9 kb in all tissues studied, with an
additional 4.2-kb transcript also being present in the pancreas and
thymus. A human SCG2 cDNA clone, covering 2.3 kb at the 3-prime end of
the gene, was isolated by hybridization screening. Northern blot
analysis with this human sequence gave results identical to those from
the bovine sequence.
GENE STRUCTURE
Chandrasekharappa et al. (1997) determined that the MEN1 gene contains
10 exons.
MAPPING
Chandrasekharappa et al. (1997) identified the MEN1 gene on chromosome
11q13.
GENE FUNCTION
Based on immunofluorescence, Western blotting of subcellular fractions,
and epitope tagging with enhanced green fluorescent protein, Guru et al.
(1998) demonstrated that menin is located primarily in the nucleus. They
identified at least 2 independent nuclear localizations signals (NLSs),
both located in the C-terminal fourth of the protein. They pointed out
that among the 68 then-known independent disease-associated mutations,
none of the 22 missense and 3 in-frame deletions affected either of the
putative NLS sequences. However, if expressed, none of the truncated
menin proteins resulting from the 43 known frameshift/nonsense mutations
would retain both the NLSs.
Using a yeast 2-hybrid screen with menin as the bait, Agarwal et al.
(1999) identified the transcription factor JunD (165162) as a direct
menin-interacting partner. Menin did not interact directly with other
Jun and Fos family members. The menin-JunD interaction was confirmed in
vitro and in vivo. Menin repressed transcriptional activation mediated
by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive
reporter, or by JunD from an AP1-responsive reporter. Several naturally
occurring and clustered MEN1 missense mutations disrupted menin
interaction with JunD. These observations suggest that the tumor
suppressor function of menin involves direct binding to JunD and
inhibition of JunD-activated transcription.
Kaji et al. (2001) showed that menin inactivation by antisense RNA
antagonizes transforming growth factor-beta (TGFB; 190180)-mediated cell
growth inhibition. Menin interacts with SMAD3 (603109), and antisense
menin suppresses TGFB-induced and SMAD3-induced transcriptional activity
by inhibiting SMAD3/4-DNA binding at specific transcriptional regulatory
sites. These results implicated a mechanism of tumorigenesis by menin
inactivation.
To investigate how menin expression is regulated in both man and mouse,
Zablewska et al. (2003) assayed a greater than 1 kb region upstream of
the second exon of the MEN1 gene for promoter activity in luciferase
reporter vectors. The basic promoter was located closely upstream of the
most commonly expressed first exon. The region further upstream modified
the activity. Repetitive elements of the short interspersed/Alu type
covered the entire human upstream regulatory region and were the only
apparent motif in common with its murine ortholog. They found that
overexpression of menin in an inducible cell culture system
downregulated the proximal promoter. In response to downregulation of
MEN1 expression by RNA interference, the regulatory region activated the
promoter in a compensatory manner. They concluded that their data
confirmed that the expression of the MEN1 gene is regulated by feedback
from its product menin.
To explore telomerase regulation, Lin and Elledge (2003) employed a
general genetic screen in HeLa cells to identify negative regulators of
TERT (187270). They discovered 3 tumor suppressor/oncogene pathways
involved in TERT repression, including menin, which is a direct
repressor of TERT. Depleting menin immortalized primary human
fibroblasts and caused a transformation phenotype when coupled with
expression of simian virus 40 large and small T antigen and oncogenic
RAS (190020).
Human ML-2 leukemia cells lack a normal MLL (159555) gene and
exclusively express an MLL/AF6 (MLLT4; 159559) fusion protein. Yokoyama
et al. (2005) showed that MLL/AF6 associated with menin (MEN1) in ML-2
cells. Chromatin immunoprecipitation analysis showed both proteins
present on upstream sites of the HOXA7 (142950), HOXA9 (142956), and
HOXA10 (142957) promoters. Deletions and point mutations performed in
the MLL portion of the MLL/ENL (MLLT1; 159556) fusion protein revealed a
high affinity menin-binding motif (RXRFP) near the N-terminus.
Interaction between oncogenic MLL and menin was required for initiation
of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin
was essential to maintain MLL-associated myeloid transformation. Acute
genetic ablation of menin in mice reversed aberrant Hox gene expression
mediated by MLL-menin promoter-associated complexes and specifically
abrogated differentiation arrest and oncogenic properties of
MLL-transformed leukemic blasts.
BIOCHEMICAL FEATURES
- Crystal Structure
Huang et al. (2012) reported the crystal structures of human menin in
its free form and in complexes with MLL1 (159555) or with JUND (165162),
or with an MLL1-LEDGF (603620) heterodimer. These structures showed that
menin contains a deep pocket that binds short peptides of MLL1 or JUND
in the same manner, but that it can have opposite effects on
transcription. The menin-JUND interaction blocks JUN N-terminal
kinase-mediated JUND phosphorylation and suppresses JUND-induced
transcription. In contrast, menin promotes gene transcription by binding
the transcription activator MLL1 through the peptide pocket while still
interacting with the chromatin-anchoring protein LEDGF at a distinct
surface formed by both menin and MLL1.
MOLECULAR GENETICS
- Multiple Endocrine Neoplasia Type I
Chandrasekharappa et al. (1997) identified mutations in the MEN1 gene
(613733.0001-613733.0012) in 14 probands from 15 families with multiple
endocrine neoplasia type I. Twelve different heterozygous mutations were
identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame
deletions). Most of the mutations predicted loss of function of the
protein, consistent with a tumor suppressor mechanism.
By mutation analysis of the SCG2 in 10 unrelated families with multiple
endocrine neoplasia type I, the European Consortium on MEN1 (1997)
identified 1 polymorphism and 9 different heterozygous mutations (1
missense, 4 nonsense, 1 insertional, and 3 deletional frameshifts) that
segregated with the disease, thus providing confirmation for the
identification of the MEN1 gene.
Giraud et al. (1998) studied a total of 84 families and/or isolated
patients with either MEN1 or MEN1-related inherited endocrine tumors.
They screened for MEN1 germline mutations by heteroduplex and sequence
analysis of the gene-coding region of the MEN1 gene and its untranslated
exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1
families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19
(31.5%) atypical MEN1-related inherited cases. They characterized 52
distinct mutations in a total of 62 MEN1 germline alterations.
Truncating mutations, frameshifts and nonsense mutations, accounted for
35 of the 52 alterations. No genotype/phenotype correlation could be
made. Age-related penetrance was estimated to be more than 95% over age
30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1
families.
Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families
from 7 countries, 13 isolated MEN1 cases without family history of the
disease, 8 acromegaly families, and 4 familial isolated
hyperparathyroidism (FIHP) families. Mutations were identified in
samples from 27 MEN1 families and 9 isolated cases. The 22 different
mutations were distributed across most of the 9 translated exons and
included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense
mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands,
a 1466del12 (613733.0032) mutation was identified in 6 families with
identical 11q13 haplotypes and in 2 isolated cases, indicating a common
founder. One frameshift mutation caused by 359del4 (GTCT) was identified
in 1 isolated case and 4 kindreds of different origin and haplotypes;
this mutation therefore represents a common 'warm' spot in the MEN1
gene. By analyzing the DNA of the parents of an isolated case, 1
mutation was confirmed to be de novo. No mutation was found in any of
the acromegaly and small FIHP families, suggesting that genetic defects
other than the MEN1 gene might be involved, and that additional families
of these types need to be analyzed.
In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a
complete sequencing analysis of the entire MEN1 gene. Mutations were
identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations,
and a complex alteration consisting of a deletion and an insertion that
can be explained by a hairpin loop model. Two of the mutations had been
described; the other 7 were novel, and they were scattered throughout
the coding sequence of the gene. As in previous series, no correlation
was found between phenotype and genotype.
The observation of loss of heterozygosity involving 11q13 in MEN1 tumors
and the inactivating germline mutations found in patients suggest that
the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit'
model of hereditary cancer. The second hit in MEN1 tumors typically
involves large chromosomal deletions that include 11q13. However, this
only represents one mechanism by which the second hit may occur. Pannett
and Thakker (2001) searched for other mechanisms, such as intragenic
deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1
tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not
have LOH at 11q13 as assessed using the flanking markers D11S480,
D11S1883, and PYGM centromerically and D11S449 and D11S913
telomerically. They found 4 somatic mutations, which consisted of 2
missense mutations and 2 frameshift mutations, in 2 parathyroid tumors,
1 insulinoma, and 1 lipoma. The authors concluded that the role of the
MEN1 gene is consistent with that of a tumor suppressor gene, as
postulated by the Knudson '2-hit' hypothesis.
By exhaustive sequence analysis of probands belonging to 170 unrelated
MEN1 families collected through a French clinical network, Wautot et al.
(2002) identified 165 mutations located in coding parts of the MEN1
gene, which represented 114 distinct MEN1 germline alterations. The
mutations, which were spread over the entire coding sequence, included
56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion
in-frame mutations. These mutations were included in a MEN1
locus-specific database available on the Internet together with
approximately 240 germline and somatic MEN1 mutations listed from
international published data. Taken together, most missense and in-frame
MEN1 genomic alterations affected 1 or all domains of menin interacting
with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3
major effectors in transcription and cell growth regulation. No
correlation was observed between genotype and MEN1 phenotype.
Turner et al. (2002) ascertained 34 unrelated MEN1 probands and
performed DNA sequence analysis. They identified 17 different mutations
in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5
frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift
insertions, 1 donor splice site mutation, and a G-to-A transition that
resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4
mutation was found in 7 unrelated families, and the tumors in these
families varied considerably, indicating a lack of genotype-phenotype
correlation. However, this IVS4 mutation is the most frequently
occurring germline MEN1 mutation, accounting for approximately 10% of
all mutations, and together with 5 others at codons 83-84, 118-119
(613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516
(613733.0028) accounts for 36.6% of all mutations.
In 3 members of a Japanese family with MEN1 and a predisposition to
insulinoma, Okamoto et al. (2002) identified a heterozygous germline
mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis
of 72 MEN1 patients with or without germline mutations in exon 4 and
with or without insulinomas showed a significant difference (p =
0.0022), suggesting a possible correlation between insulinoma
development and mutations in exon 4 where JunD binding occurs.
Park et al. (2003) investigated 5 Korean families with MEN1, 1 family
with familial isolated hyperparathyroidism and 1 family with familial
pituitary adenoma. Four germline mutations were identified in 5 typical
MEN1 families. All of these mutations led to truncated proteins or a
change in the amino acids of the functional domains. No MEN1 germline
mutations were detected in the 2 families with FIHP or familial
pituitary adenoma.
- Familial Isolated Primary Hyperparathyroidism
In a Caucasian English family in which 7 family members from 2
generations had primary isolated hyperparathyroidism (FIHP; 145000), Teh
et al. (1998) found that affected members had a germline missense
mutation in the MEN1 gene (613733.0020). This appeared to be the first
study to demonstrate that familial isolated primary hyperparathyroidism
can occur as a variant of MEN1. The pattern of transmission was
autosomal dominant with high penetrance, as in MEN1. Clinically, the
hyperparathyroidism ran a rather mild course, as evidenced by 2 affected
subjects who declined surgery and yet developed no obvious
complications. Pathologically, the multiglandular parathyroid disease
was consistent with that of MEN1. In 2 individuals, Teh et al. (1998)
demonstrated loss of heterozygosity (LOH) in the parathyroid tumors,
consistent with the Knudson 2-hit model.
In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years,
all with hyperparathyroidism due to parathyroid adenomas (145000),
Fujimori et al. (1998) identified a missense mutation in the MEN1 gene
(613733.0021).
- Somatic Mutations in the MEN1 Gene
Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of
parathyroid tumors not associated with MEN1, representing 54% of
parathyroid tumors with 11q13 LOH. The authors suggested that
parathyroid tumor formation in kindreds with somatic mutation of MEN1
may be initiated by germline mutation of an unidentified tumor
suppressor gene or oncogene. The finding of somatic mutation
(613733.0013) in a single tumor from a member of such a kindred
indicated that somatic MEN1 gene mutation may also contribute to
tumorigenesis in such individuals. Previous studies had found frequent
11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma
(19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors
(78%), thyroid follicular tumors (15%), and aldosteronomas (36%).
Heppner et al. (1997) suggested that many of these tumors likewise may
have MEN1 somatic mutations.
Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and
DNA sequencing of the coding exons to study the MEN1 gene in 49
parathyroid lesions of patients with nonfamilial primary
hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6
of which had previously unrecognized somatic missense and frameshift
deletion mutations of the MEN1 gene. Many of these mutations were
predicted to encode a nonfunctional menin protein, consistent with a
tumor suppressor mechanism. While the clinical and biochemical
characteristics of hyperparathyroidism were apparently unrelated to LOH
at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1
gene mutations in small parathyroid adenomas of patients who had slight
hypercalcemia and normal serum parathyroid hormone (168450) levels
suggested that altered MEN1 gene function may also be important for the
development of mild sporadic primary hyperparathyroidism.
Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for
alterations involving the MEN1 gene. Thirteen tumors showed LOH at
11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was
detected. In tumors without LOH, no mutations were detected. The
mutations consisted of 3 small deletions, 1 insertion, and 2 missense
mutations that had not been reported in MEN1 patients or parathyroid
tumors previously. Using mRNA in situ hybridization, the expression of
the MEN1 gene was studied. The authors concluded that there was no
difference in MEN1 expression between normal and tumor tissue, and that
their findings of inactivating mutations in tumors with LOH at 11q13
confirmed the role of the MEN1 tumor suppressor gene in a subset of
sporadic parathyroid tumors.
Prezant et al. (1998) screened the complete coding sequence of the MEN1
gene for mutations in 45 sporadic anterior pituitary tumors, including
14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy
fingerprinting and sequence analysis. No pathogenic sequence changes
were found in the MEN1 coding region. The MEN1 gene was expressed in 43
of these tumors with sufficient RNA, including 1 tumor with LOH for
several polymorphic markers on chromosomal region 11q13. Also, both
alleles were expressed in 19 tumors in which the constitutional DNA was
heterozygous for intragenic polymorphisms. The authors concluded that
inactivation of the MEN1 tumor suppressor gene, by mutation or by
imprinting, does not appear to play a prominent role in sporadic
pituitary adenoma pathogenesis.
Heppner et al. (1999) studied whether somatic inactivation of the MEN1
gene contributes to the pathogenesis of sporadic adrenocortical
neoplasms. Thirty-three tumors and cell lines were screened for
mutations throughout the MEN1 open reading frame and adjacent splice
junctions. No mutations were detected within the MEN1 coding region. The
authors concluded that somatic mutations within the MEN1 coding region
do not occur commonly in sporadic adrenocortical tumors, although the
majority of adrenocortical carcinomas exhibited 11q13 LOH.
To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer
et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and
subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017).
This deletion was present only in the tumor tissue, and not in the
normal tissue from the same patient.
To identify chromosomal regions that may contain loci for tumor
suppressor genes involved in adrenocortical tumor development, Kjellman
et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21
adenomas) for loss of heterozygosity (LOH). The vast majority of LOH
detected was in the carcinomas involving chromosomes 2, 4, 11, and 18;
little was found in the adenomas. The Carney complex (160980) and the
MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27
(13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of
the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM
region that is separate from the Carney complex locus. LOH for PYGM was
detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the
cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed
LOH on chromosome 11, and these were selected for MEN1 mutation
analysis. In 6 cases a common polymorphism was found, but no mutation
was detected. The authors concluded that LOH in 2p16 was strongly
associated with the malignant phenotype, and LOH in 11q13 occurred
frequently in carcinomas, but was not associated with a MEN1 mutation,
suggesting the involvement of a different tumor suppressor gene on this
chromosome.
Hibernomas are benign tumors of brown fat, frequently characterized by
aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed
chromosome 11 changes in 5 hibernomas in detail by metaphase
fluorescence in situ hybridization. In all cases, complex rearrangements
leading to loss of chromosome 11 material were found. Deletions were
present not only in those chromosomes that were shown to be rearranged
by G-banding, but in 4 cases also in the ostensibly normal homologs,
resulting in homozygous loss of several loci. Among these, the MEN1 gene
was most frequently deleted. In addition to the MEN1 deletions,
heterozygous loss of a second region, approximately 3 Mb distal to MEN1,
was found in all 5 cases, adding to previous evidence for a second tumor
suppressor locus in 11q13.
Tahara et al. (2000) analyzed 81 parathyroid glands from 22 Japanese
uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3
flanking markers (PYGM, 608455; D11S4946; and D11S449), and for
mutations of the MEN1-coding exons by PCR-based SSCP analysis and
sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1
of 6 demonstrated a previously unrecognized somatic frameshift deletion
in MEN1. They inferred that this mutation would result in a
nonfunctional menin protein, consistent with a tumor suppressor
mechanism. Clinical and pathologic characteristics of
hyperparathyroidism were unrelated to the presence or absence of loss of
heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded
that somatic inactivation of the MEN1 gene contributes to the
pathogenesis of uremia-associated parathyroid tumors, but its role in
this disease appears to be very limited.
Sato et al. (2001) reported a male patient with adult-onset,
hypophosphatemic osteomalacia who had been treated with
1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary
hyperparathyroidism developed. Sequence analysis of the coding exons of
the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic
parathyroid glands, accompanied by loss of heterozygosity at the 11q13
locus in 1 gland. These findings suggested that the repeated increase in
serum phosphate concentrations for a prolonged period may be related to
tumorigenesis of the parathyroid gland.
Jiao et al. (2011) explored the genetic basis of pancreatic
neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10
nonfamilial PanNETs and then screened the most commonly mutated genes in
58 additional PanNETs. The most frequently mutated genes specify
proteins implicated in chromatin remodeling: 44% of the tumors had
somatic inactivating mutations in MEN1, and 43% had mutations in genes
encoding either of the 2 subunits of a transcription/chromatin
remodeling complex consisting of DAXX (death domain-associated protein,
603186) and ATRX (300032). Clinically, mutations in the MEN1 and
DAXX/ATRX genes were associated with better prognosis. Jiao et al.
(2011) also found mutations in genes in the mTOR (601231) pathway in 14%
of the tumors, a finding that could potentially be used to stratify
patients for treatments with mTOR inhibitors.
ANIMAL MODEL
To examine the role of MEN1 in tumor formation, Crabtree et al. (2001)
generated a mouse model through homologous recombination of the mouse
homolog Men1. Homozygous null mice died in utero at embryonic days 11.5
to 12.5, whereas heterozygous mice developed features remarkably similar
to those of the human disorder. As early as 9 months, pancreatic islets
showed a range of lesions from hyperplasia to insulin-producing islet
cell tumors, and parathyroid adenomas were frequently observed. Larger,
more numerous tumors involving pancreatic islets, parathyroids, thyroid,
adrenal cortex, and pituitary were seen by 16 months. All of the tumors
tested showed loss of the wildtype Men1 allele, further supporting the
role of MEN1 as a tumor suppressor gene.
Busygina et al. (2004) generated a null allele of Mnn1, the Drosophila
homolog of the MEN1 gene, and showed that homozygous inactivation
resulted in morphologically normal flies that are hypersensitive to
ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and
cisplatinum). The spectrum of agents to which mutant flies were
sensitive and analysis of the molecular mechanisms of this sensitivity
suggested a defect in nucleotide excision repair. Drosophila Mnn1
mutants had an elevated rate of both sporadic and DNA damage-induced
mutations. In a genetic background heterozygous for lats (LATS1;
603473), which is a Drosophila and vertebrate tumor suppressor gene,
homozygous inactivation of Mnn1 enhanced somatic mutation of the second
allele of lats and formation of multiple primary tumors. Busygina et al.
(2004) concluded that Mnn1 is a novel member of the class of autosomal
dominant cancer genes that function in maintenance of genomic integrity,
similar to the BRCA1 (113705) and MSH2 (609309) genes.
To examine the potential role of Men1 in hematopoiesis, Chen et al.
(2006) targeted Men1 excision in a temporally-controlled manner.
Disruption of Men1 in mice after birth gradually led to decreased total
white blood cell count but did not significantly reduce red blood cell
numbers. There was also reduced Hoxa9 (142956) expression and reduced
colony formation by hematopoietic progenitors. Chen et al. (2006)
determined that Men1 directly activated Hoxa9 expression, at least in
part, by binding to the Hoxa9 locus, facilitated the methylation of
histone H3 on lysine-4 (H3K4), and recruited the methylated H3K4-binding
protein Chd1 (602118) to the locus.
TMEM262
| dbSNP name | rs525781(A,G); rs7105865(A,G) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 100130348 |
| EntrezGene Symbol | LOC100130348 |
| snpEff Gene Name | AP003068.6 |
| EntrezGene Description | putative uncharacterized protein FLJ42147 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM262:NM_001242631:exon1:c.T4C:p.W2R,TMEM262:NM_001282448:exon1:c.T4C:p.W2R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.997252747253 |
| dbNSFP KGp1 Afr AF | 0.989837398374 |
| dbNSFP KGp1 Amr AF | 0.997237569061 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.002755 |
| ExAC AF | 0.999 |
ZNHIT2
| dbSNP name | rs1546532(G,A) |
| ccdsGene name | CCDS8094.1 |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 741 |
| EntrezGene Description | zinc finger, HIT-type containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNHIT2:NM_014205:exon1:c.C1074T:p.A358A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.07484 |
| ESP Afr MAF | 0.086552 |
| ESP All MAF | 0.067175 |
| ESP Eur/Amr MAF | 0.057249 |
| ExAC AF | 0.915 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604575 ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 2; ZNHIT2
;;HIT-TYPE ZINC FINGER DOMAIN-CONTAINING PROTEIN 2;;
CHROMOSOME 11 OPEN READING FRAME 5; C11ORF5;;
FON
OMIM Description
CLONING
By genome sequence sampling, subcloning, and sequence homology searches,
Lemmens et al. (2000) obtained a cDNA for C11ORF5, also termed FON. The
C11ORF5 cDNA encodes a deduced 403-amino acid acidic (pI 5.8) protein
predicted to have 11 phosphorylation and 6 N-myristoylation sites. The
human and mouse C11ORF5 proteins have 81% sequence identity. Northern
blot analysis revealed low expression of a 1.4-kb transcript in all
tissues tested except for testis in which high expression was seen.
Additional 4- and 7-kb transcripts were seen in skeletal muscle and
heart. In mice, in situ hybridization revealed high expression of
C11orf5 in adult testis, particularly in seminiferous tubules, and lower
expression in all other tissues tested.
GENE STRUCTURE
The C11ORF5 gene contains only 1 exon (Lemmens et al., 2000).
MAPPING
The European Consortium on MEN1 (1997) described 3 gene clusters in the
11q13 region. One 40-kb cluster, termed FAUNA (FAU neighboring area),
contains 7 genes, including FAU (134690), TM7SF2 (603414), and C11ORF5
(Lemmens et al., 1998).
The C11ORF5 gene is positioned in the same transcriptional orientation
as FAU, which is 4 kb upstream. It is located 171 nucleotides upstream
of TM7SF2 in a tail-to-tail configuration (Lemmens et al., 2000).
NEAT1
| dbSNP name | rs680413(G,T); rs73484377(G,A); rs512715(C,G) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 283131 |
| EntrezGene Description | nuclear paraspeckle assembly transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1212 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
RESPIRATORY:
[Lung];
Respiratory paralysis
ABDOMEN:
[Gastrointestinal];
Vomiting;
Abdominal colic
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness
NEUROLOGIC:
[Peripheral nervous system];
Neuropathy (motor and sensory);
Paresthesia;
Paralysis
HEMATOLOGY:
Hemolytic anemia;
Porphyria
LABORATORY ABNORMALITIES:
Erythrocyte delta-aminolevulinate dehydratase (ALAD) deficiency;
Elevated urinary delta-aminolevulinic acid and porphyrins
MISCELLANEOUS:
Very rare;
Asymptomatic heterozygotes susceptible to lead toxicity;
Exacerbation following stress, decreased food intake, or alcohol use
MOLECULAR BASIS:
Caused by mutation in the delta-aminolevulinate dehydratase gene (ALAD,
125270.0001)
OMIM Title
*612769 NONCODING RNA 84; NCRNA00084
;;NONCODING NUCLEAR-ENRICHED ABUNDANT TRANSCRIPT 1; NEAT1
TROPHOBLAST-DERIVED NONCODING RNA, INCLUDED; TNCRNA, INCLUDED
OMIM Description
CLONING
Using expression arrays to identify polyadenylated RNA transcripts
displaying nuclear enrichment in human cell lines, Hutchinson et al.
(2007) identified XIST (314670), NCRNA00084, which they called NEAT1,
and NEAT2 (MALAT1; 607924). The primary NEAT1 transcript is a 3.7-kb,
predominantly unspliced, polyadenylated noncoding RNA. It shares no
sequence identity with NEAT2. Hutchinson et al. (2007) also identified
mouse Neat1, which encodes a transcript of about 3.2 kb, but they found
no Neat1 orthologs in nonmammalian species. Northern blot analysis
detected broad expression of an approximately 4-kb NEAT1 transcript in
human tissues, with highest expression in ovary, prostate, colon, and
pancreas. A transcript of over 17 kb was also suggested by Northern blot
analysis, and quantitative RT-PCR indicated that this was a minor
transcript. Hutchinson et al. (2007) noted that a short noncoding RNA,
designated TNCRNA, originates from the 3-prime end of NEAT1 and is
expressed exclusively in trophoblasts. RNA FISH analysis confirmed
nuclear enrichment of NEAT1 and NEAT2 in human and mouse cell lines.
Both proteins localized with SC35 (SFRS2; 600813) nuclear speckles,
although NEAT2 was more centrally located and NEAT1 more peripherally
located.
GENE FUNCTION
Trophoblasts lack expression of all classical major histocompatibility
complex (MHC) antigens, and suppression of class II MHC antigens in
trophoblasts results from inhibition of MHC2TA (600005). By transfecting
a murine B-cell line with TNCRNA, Geirsson et al. (2003) showed that
TNCRNA suppressed class II expression by inhibiting Mhc2ta promoter III
activity. Inhibition did not involve methylation of the promoter.
Clemson et al. (2009) showed that depletion of NEAT1 RNA via RNA
interference in human and mouse cell lines eradicated paraspeckles and
relocalized the paraspeckle proteins PSP1 (PSPC1; 612408) and p54 (NONO;
300084) to the nucleoplasmic space. Conversely, overexpression of mouse
Neat1 led to a corresponding increase in the number of paraspeckles.
Coimmunoprecipitation analysis showed that PSP1 and p54 interacted with
NEAT1 in a paraspeckle complex. PSP1 deleted of its RNA-recognition
motifs no longer associated with NEAT1 or paraspeckles. During the
progression from mitosis to newly formed daughter nuclei, the earliest
paraspeckles were detected when there were at least 2 foci of NEAT1 RNA,
and these paraspeckles were usually located next to the genomic NEAT1
locus and overlapping NEAT1 foci. Clemson et al. (2009) concluded that
NEAT1 is an essential structural determinant of paraspeckles.
MAPPING
By genomic sequence analysis, Geirsson et al. (2003) mapped the
NCRNA00084 gene to chromosome 11q13. Hutchinson et al. (2007) determined
that the NCRNA00084 and MALAT1 genes are less than 70 kb apart on
chromosome 11q13.1. They mapped the mouse Ncrna00084 gene to a region of
chromosome 19A that shares homology of synteny with human chromosome
11q13.1.
MIR612
| dbSNP name | rs550894(C,A); rs12803915(G,A) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 693197 |
| snpEff Gene Name | AP000769.4 |
| EntrezGene Description | microRNA 612 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | non_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1754 |
| ESP Afr MAF | 0.111331 |
| ESP All MAF | 0.099025 |
| ESP Eur/Amr MAF | 0.093697 |
| ExAC AF | 0.104 |
MALAT1
| dbSNP name | rs77535011(A,C); rs60236485(G,A); rs7927113(G,A); rs664589(C,G); rs73497102(G,A); rs3200401(C,T) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 378938 |
| EntrezGene Description | metastasis associated lung adenocarcinoma transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | non_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01423 |
| ESP Afr MAF | 0.04119 |
| ESP All MAF | 0.013103 |
| ESP Eur/Amr MAF | 0.000755 |
| ExAC AF | 3.373e-03,8.671e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Follicular hyperkeratosis of occipital scalp, nape of neck, and extensor
surfaces of upper limbs;
Erythema in affected areas;
Pruritus in affected areas;
HISTOLOGY:;
Abnormal hair follicles with thin, atrophic shafts;
Hair shafts often coiled within skin;
Marked swelling of precortical region;
ELECTRON MICROSCOPY:;
Elliptical nodes (in some patients);
Trichoschisis (in some patients);
Pili torti (in some patients);
Tapered hair;
[Hair];
Fragile hair that breaks easily;
Short, sparse hair on scalp;
Eyebrows and eyelashes may be sparse;
Beard, axillary, and pubic hair usually normal
MOLECULAR BASIS:
Caused by mutation in the desmoglein 4 gene (DSG4, 607892.0001)
OMIM Title
*607924 METASTASIS-ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT 1; MALAT1
;;ALPHA GENE;;
PRO1073;;
NONCODING NUCLEAR-ENRICHED ABUNDANT TRANSCRIPT 2; NEAT2;;
NONCODING RNA 47; NCRNA00047
ALPHA/TFEB FUSION GENE, INCLUDED;;
MALAT1-ASSOCIATED SMALL CYTOPLASMIC RNA, INCLUDED; MASCRNA, INCLUDED
OMIM Description
CLONING
The Alpha gene was identified by James et al. (1994) and by Guru et al.
(1997). It is unusual in that it is very AT-rich, transcribed in an
intronless fashion, and contains no ORF of significant length.
By subtractive hybridization to identify genes upregulated in aggressive
nonsmall cell lung cancer, followed by 5-prime and 3-prime RACE, Ji et
al. (2003) cloned 2 splice variants of MALAT1. The transcripts have
putative open reading frames for peptides of about 50 amino acids, but
no translation start sites have Kozak sequences. No MALAT1 protein was
synthesized in an in vitro translation system. Northern blot analysis
detected a MALAT1 transcript in human lung carcinoma cell lines.
Real-time RT-PCR detected variable MALAT1 expression in normal tissues,
with highest expression in pancreas and lung. MALAT1 homologs in several
mammalian EST databases showed a high degree of sequence conservation.
Using expression arrays to identify polyadenylated RNAs displaying
nuclear enrichment in human cell lines, Hutchinson et al. (2007)
identified XIST (314670), NEAT1 (NCRNA00084; 612769), and MALAT1, which
they called NEAT2. Like NEAT1, NEAT2 is a large, infrequently spliced
noncoding RNA, but it shares no sequence identity with NEAT1. Northern
blot analysis detected broad expression of a NEAT2 transcript of over 6
kb, with highest expression in ovary, prostate, and colon. Hutchinson et
al. (2007) also cloned mouse Neat2, and Northern blot analysis detected
a broadly expressed transcript of about 7 kb in mouse tissues. Neat2
orthologs were conserved within multiple mammalian species, but not in
nonmammalian species. RNA FISH analysis confirmed nuclear enrichment of
NEAT1 and NEAT2 in human and mouse cell lines. Both proteins localized
with SC35 (SFRS2; 600813) at nuclear speckles, although NEAT2 was more
centrally located and NEAT1 more peripherally located.
Wilusz et al. (2008) identified mascRNA, a highly conserved
61-nucleotide RNA that originates from the 3-prime end of the human
MALAT1 transcript. The mascRNA transcript was predicted to fold into a
tRNA-like cloverleaf. It terminates in a CCA motif, which is not encoded
in the genome and is a hallmark of the 3-prime ends of tRNAs and similar
structures. However, the predicted anticodon loop of mascRNA is poorly
conserved, and mascRNA was not aminoacylated in HeLa cells. Like the
mature 7-kb MALAT1 transcript, Northern blot analysis detected mascRNA
expression in all human tissues and cell lines examined. Northern blot
analysis of fractionated mouse cells showed that Malat1 localized to the
nucleus, whereas mascRNA localized to the cytoplasm in mouse cells and
HeLa cells.
GENE FUNCTION
Ji et al. (2003) found that MALAT1 was one of several genes whose
expression was increased in nonsmall cell lung cancers prior to
metastasizing. MALAT1 expression was associated with cancers in a stage-
and histology-specific manner. Ji et al. (2003) suggested that MALAT1
expression may be a prognostic parameter for patient survival in stage I
nonsmall cell lung cancer.
Wilusz et al. (2008) found that RNase P (see 606116) cleaved the nascent
MALAT1 transcript downstream of a genomically encoded poly(A)-rich tract
to simultaneously generate the poly(A) 3-prime end of the mature MALAT1
transcript and the 5-prime end of mascRNA. RNase Z (see ELAC2; 605367)
processed the 3-prime end of mascRNA, followed by the addition of the
CCA motif. Wilusz et al. (2008) also found that the nuclear MALAT1
transcript was stabilized by U-rich motifs, whereas cytoplasmic mascRNA
had a relatively short half-life.
MAPPING
The Alpha gene maps near the multiple endocrine neoplasia type-1 locus
(MEN1; 131100) on chromosome 11q13, a region implicated in chromosomal
abnormalities of various tumors (James et al., 1994; Guru et al., 1997;
van Asseldonk et al., 2000).
Hutchinson et al. (2007) determined that the MALAT1 and NCRNA00084 genes
are less than 70 kb apart on chromosome 11q13.1. They mapped the mouse
Malat1 gene to a region of chromosome 19A that shares homology of
synteny with human chromosome 11q13.1.
CYTOGENETICS
Davis et al. (2003) cloned an Alpha/TFEB (600744) fusion gene in renal
tumors harboring a t(6;11)(p21.1;q13) translocation. They found that the
Alpha gene was rearranged with the first intron of TFEB, just upstream
of TFEB's initiation ATG, preserving the entire TFEB coding sequence.
Kuiper et al. (2003) collected 3 cases of renal cell carcinoma (RCC;
605074) from patients 14 to 42 years of age, wherein a t(6;11)(p21;q13)
translocation was the sole cytogenetic abnormality. Molecular analysis
revealed fusion of the TFEB gene on chromosome 6 to the Alpha gene on
chromosome 11. The Alpha/TFEB fusion gene linked all coding exons of the
TFEB gene to 5-prime upstream regulatory sequences of the Alpha gene.
Alpha/TFEB mRNA levels were significantly upregulated in primary tumor
cells as compared with wildtype TFEB mRNA levels in normal kidney
samples, resulting in a dramatic upregulation of TFEB protein levels.
The TFEB protein encoded by the Alpha/TFEB fusion gene was efficiently
targeted to the nucleus. Kuiper et al. (2003) speculated that this
resulted in severely unbalanced nuclear ratios of MITF (156845)/TFE
subfamily members and that this imbalance may lead to changes in the
expression of downstream target genes, ultimately resulting in the
development of RCC.
SSSCA1-AS1
| dbSNP name | rs1346(A,T); rs1784220(G,T); rs59286748(A,T) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 254100 |
| snpEff Gene Name | FAM89B |
| EntrezGene Description | SSSCA1 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1612 |
FAM89B
| dbSNP name | rs80283068(C,T) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 23625 |
| snpEff Gene Name | SSSCA1 |
| EntrezGene Description | family with sequence similarity 89, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01791 |
AP5B1
| dbSNP name | rs2508302(T,C); rs2508301(G,T); rs494003(G,A); rs522800(G,C); rs2508299(G,T); rs10896043(T,C); rs376246099(A,G); rs7107453(C,A); rs370617040(G,A); rs56798161(G,A); rs610037(A,C); rs12146493(G,A) |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 91056 |
| snpEff Gene Name | AP001266.1 |
| EntrezGene Description | adaptor-related protein complex 5, beta 1 subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008264 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor growth
HEAD AND NECK:
[Head];
Microcephaly (in some patients);
[Face];
Midface hypoplasia;
[Nose];
Depressed nasal bridge
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Head nodding;
Poor speech;
[Peripheral nervous system];
Hyperreflexia;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients)
MOLECULAR BASIS:
Caused by mutation in the homolog of the Drosophila lines 1 gene (LINS1,
610350.0001)
OMIM Title
*614367 ADAPTOR-RELATED PROTEIN COMPLEX 5, BETA-1 SUBUNIT; AP5B1
;;ADAPTOR-RELATED PROTEIN COMPLEX 5, BETA SUBUNIT;;
BETA-5;;
DKFZp761E198
OMIM Description
DESCRIPTION
AP5B1, or beta-5, appears to be a large subunit of an adaptor protein
complex, AP5, that has a role in endocytosis (Hirst et al., 2011).
CLONING
Using C14ORF108 (MUDENG; 614368) as bait in a yeast 2-hybrid screen of a
placenta cDNA library, Hirst et al. (2011) cloned DKFZp761E198, or
beta-5. The deduced 878-amino acid protein has a calculated molecular
mass of 94 kD. DKFZp761E198 contains a long N-terminal alpha-helical
solenoid, followed by an unstructured flexible linker and a putative
C-terminal appendage domain. DKFZp761E198 shares significant similarity
with beta-adaptin (see AP1B1; 600157) and beta-COP (COPB; 600959).
Database analysis detected DKFZp761E198 orthologs in at least 2
representatives from each of the 5 major eukaryotic supergroups, but not
in S. cerevisiae.
GENE FUNCTION
By Western blot analysis of HeLa cell lysates, Hirst et al. (2011) found
that knockdown of DKFZp761E198 via small interfering RNA reduced
expression of C14ORF108. Knockdown of either DKFZp761E198 or C14ORF108
caused relocalization of the lysosomal membrane protein CIMPR (IGF2R;
147280) and the retromere protein VPS26 (605506) from fine puncta to
large perinuclear puncta. Hirst et al. (2011) hypothesized that
DKFZp761E198 functions as a large beta subunit in a novel adaptor
protein complex, AP5, with a role in endocytosis. AP complexes normally
contain a second large subunit, a medium-sized mu subunit, and a small
sigma subunit. Hirst et al. (2011) found that C14ORF108 had
characteristics of an AP5 mu subunit. Therefore, they proposed that
DKFZp761E198 and C14ORF108 be renamed beta-5 and mu-5, respectively.
Hirst et al. (2011) noted that Slabicki et al. (2010) immunoprecipitated
DKFZp761E198 and C14ORF108 with KIAA0415 (613653) and C20ORF29 (AP5S1;
614824) and proposed that KIAA0415 and C20ORF29 may function as the
second large subunit (zeta) and the sigma-5 subunit of AP5,
respectively.
MAPPING
Hartz (2011) mapped the DKFZp761E198 gene to chromosome 11q13.1 based on
an alignment of the DKFZp761E198 sequence (GenBank GENBANK AF193040)
with the genomic sequence (GRCh37).
CATSPER1
| dbSNP name | rs72932605(C,T); rs7946140(G,A); rs12416952(T,C); rs12416953(T,G); rs12421022(C,T); rs142066072(C,G); rs12790034(T,C); rs145780664(C,T); rs1783569(T,C); rs61895579(A,G); rs3829937(G,A); rs3814748(C,T); rs3814747(C,T); rs34114713(C,G); rs10791838(T,G); rs1783563(T,C); rs2845570(G,T); rs151326038(C,T); rs111913197(C,A); rs10896075(A,G); rs10750773(T,C); rs116238678(G,A); rs56947039(G,A); rs114764419(C,G); rs1203998(C,T); rs139889481(C,T); rs1893316(G,A); rs947847(A,G) |
| ccdsGene name | CCDS8127.1 |
| cytoBand name | 11q13.1 |
| EntrezGene GeneID | 101927968 |
| EntrezGene Symbol | LOC101927968 |
| EntrezGene Description | uncharacterized LOC101927968 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CATSPER1:NM_053054:exon1:c.G148A:p.V50M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5825 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NEC5 |
| dbNSFP Uniprot ID | CTSR1_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.007724 |
| ESP All MAF | 0.002617 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0007157 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
High forehead;
[Ears];
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Downslanting palpebral fissures;
Ptosis;
[Nose];
Small concave nose;
Low nasal bridge;
[Mouth];
Tented mouth;
Gingival hyperplasia;
[Teeth];
Poor dental development
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux disease;
Poor swallowing
NEUROLOGIC:
[Central nervous system];
Psychomotor retardation;
Mental retardation, severe;
Regression of motor development;
Decreased active movements;
Seizures, complex, myoclonic;
Cerebral atrophy, frontotemporal, progressive;
Enlarged ventricles;
Enlarged cisterna magna;
Thin corpus callosum;
Caudate nuclei atrophy;
Periventricular white matter changes
IMMUNOLOGY:
Multiple respiratory infections
MISCELLANEOUS:
One family has been reported;
Progressive disorder;
Phenotype may be influenced by maternal alcohol consumption during
pregnancy
OMIM Title
*606389 CATION CHANNEL, SPERM-ASSOCIATED, 1; CATSPER1
;;CATSPER
OMIM Description
DESCRIPTION
CATSPER is a sperm-specific ion channel that mediates calcium entry into
sperm and is essential for sperm hyperactivated motility and male
fertility. The CASTPER complex contains 4 pore-forming subunits,
CATSPER1, CATSPER2 (607249), CATSPER3 (609120), and CATSPER4 (609121),
and at least 2 auxiliary proteins, CATSPERB (611169) and CATSPERG
(613452). Each pore-forming subunit has 6 transmembrane-spanning domains
and an intracellular C-terminal coiled-coil domain. In addition,
CATSPER1 has an intracellular N-terminal histidine-rich region. Both the
pore-forming subunits and the auxiliary subunits of CATSPER localize to
the sperm principal piece (review by Ren and Xia, 2010).
CLONING
While searching for calcium channels, Ren et al. (2001) identified an
EST cDNA expressed only in testis. They cloned the corresponding
full-length cDNA from human and mouse testis by PCR and library
screening. The CATSPER gene encodes a protein of 686 amino acids that is
expressed exclusively in testis. The amino acid sequence of CATSPER most
closely resembles a single 6-transmembrane-spanning repeat of the
voltage-dependent calcium channel 4-repeat structure. Human CATSPER
exhibits a high degree of homology (55% identity) with its mouse
counterpart, especially in the transmembrane domains and histidine-rich
region. The transmembrane domains share 81% identity and the pore
regions 89% identity. Using immunofluorescence, Ren et al. (2001)
detected the expression of CATSPER within the principal piece of the
sperm tail.
GENE FUNCTION
Kirichok et al. (2006) used a simple approach to patch-clamp spermatozoa
and to characterize whole-spermatozoan currents and identified a
constitutively active flagellar calcium channel that is strongly
potentiated by intracellular alkalinization. This current is not present
in spermatozoa lacking the sperm-specific putative ion channel protein
Catsper1. This plasma membrane protein of the 6 transmembrane-spanning
ion channel superfamily is specifically localized to the principal piece
of the sperm tail and is required for sperm cell hyperactivation and
male fertility (Ren et al., 2001; Carlson et al., 2003). Kirichok et al.
(2006) concluded that their results identified Catsper1 as a component
of the key flagellar calcium channel, and suggested that intracellular
alkalinization potentiates Catsper current to increase intraflagellar
calcium and induce sperm hyperactivation.
Strunker et al. (2011) demonstrated that progesterone activates the
sperm-specific, pH-sensitive CatSper calcium ion channel. They found
that both progesterone and alkaline pH stimulate a rapid calcium ion
influx with almost no latency, incompatible with a signaling pathway
involving metabotrophic receptors and second messengers. The calcium ion
signals evoked by alkaline pH and progesterone were inhibited by 2 Ca(V)
channel blockers. Patch-clamp recordings from sperm revealed an
alkaline-activated current carried by mono- and divalent ions that
exhibited all the hallmarks of sperm-specific CatSper calcium ion
channels. Progesterone substantially enhanced the CatSper current. The
alkaline- and progesterone-activated CatSper current was inhibited by
both Ca(V) channel blockers. Strunker et al. (2011) concluded that their
results resolved a long-standing controversy over the nongenomic
progesterone signaling. In human sperm, either the CatSper channel
itself or an associated protein serves as the nongenomic progesterone
receptor.
Lishko et al. (2011) elucidated the mechanism of the nongenomic action
of progesterone on human spermatozoa by identifying the calcium ion
channel activated by progesterone. By applying the patch-clamp technique
to mature human spermatozoa, Lishko et al. (2011) found that nanomolar
concentrations of progesterone dramatically potentiate CatSper, a
pH-dependent calcium ion channel of the sperm flagellum. Lishko et al.
(2011) demonstrated that human CatSper is synergistically activated by
elevation of intracellular pH and extracellular progesterone.
Interestingly, human CatSper can be further potentiated by
prostaglandins, but apparently through a binding site other than that of
progesterone. Because their experimental conditions did not support
second messenger signaling, CatSper or a directly associated protein may
serve as the elusive nongenomic progesterone receptor of sperm. Given
that the CatSper-associated progesterone receptor is sperm-specific and
structurally different from the genomic progesterone receptor (607311),
it represents a promising target for the development of a new class of
nonhormonal contraceptives.
GENE STRUCTURE
Avenarius et al. (2009) noted that the CATSPER1 gene comprises 12 coding
exons.
MAPPING
Avenarius et al. (2009) identified the CATSPER1 gene on chromosome
11q13.1 by genomic sequence analysis.
MOLECULAR GENETICS
In 3 infertile males with spermatogenic failure-7 (612997) from 2
consanguineous Iranian families, Avenarius et al. (2009) identified
homozygosity for 1 of 2 separate insertion mutations in the CATSPER1
gene. CATSPER1 is one of 4 members of the sperm-specific CATSPER
voltage-gated calcium channel family shown to be essential for normal
male fertility in mice. The results suggested that CATSPER1 is also
essential for normal male fertility in humans.
ANIMAL MODEL
To study its function in vivo, Ren et al. (2001) disrupted mouse Catsper
in embryonic stem cells by homologous recombination. Catsper
homozygous-deficient mice were born at expected mendelian ratios and
were indistinguishable from wildtype littermates in survival rates,
appearance, and gross behavior. Homozygous-deficient females mated with
heterozygous-deficient or wildtype males were fertile. Homozygous male
mutants mated with wildtype females displayed mounting behavior
indistinguishable from that of wildtype males but were completely
infertile. Body and testis weights of the mutant mice were not different
from those of wildtype counterparts; sperm counts were not significantly
different, and sperm appeared morphologically similar. However, Catsper
-/- sperm were sluggish and displayed less directed movements. Further
investigation indicated that Catsper is required to penetrate the egg.
Catsper -/- sperm incubated with zona pellucida-free eggs were able to
fertilize the eggs, indicating that Catsper is not required for egg
activation. Ren et al. (2001) demonstrated that Catsper is required for
cAMP-induced calcium influx.
CD248
| dbSNP name | rs3741367(T,C) |
| ccdsGene name | CCDS8134.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 57124 |
| EntrezGene Description | CD248 molecule, endosialin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CD248:NM_020404:exon1:c.A1370G:p.H457R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HCU0 |
| dbNSFP Uniprot ID | CD248_HUMAN |
| dbNSFP KGp1 AF | 0.347527472527 |
| dbNSFP KGp1 Afr AF | 0.211382113821 |
| dbNSFP KGp1 Amr AF | 0.522099447514 |
| dbNSFP KGp1 Asn AF | 0.230769230769 |
| dbNSFP KGp1 Eur AF | 0.440633245383 |
| dbSNP GMAF | 0.348 |
| ESP Afr MAF | 0.227045 |
| ESP All MAF | 0.375982 |
| ESP Eur/Amr MAF | 0.45227 |
| ExAC AF | 0.399 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Prominent occiput;
[Face];
Retrognathia;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Short palpebral fissures;
Long eyelashes;
Optic nerve atrophy;
[Nose];
Broad nose;
[Mouth];
High-arched palate
RESPIRATORY:
Hypoventilation
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Feeding problems
SKELETAL:
Recurrent fractures;
[Spine];
Thoracic scoliosis;
[Hands];
Clenched hands;
Overlapping fingers
SKIN, NAILS, HAIR:
[Hair];
Long eyelashes
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Hypotonia;
Seizures;
Cerebral atrophy;
Small corpus callosum
LABORATORY ABNORMALITIES:
Glucosidase I deficiency in liver and fibroblasts;
Abnormal urinary oligosaccharides;
Hypogammaglobulinemia
MISCELLANEOUS:
Onset at birth;
Two families have been reported (last curated April 2014)
MOLECULAR BASIS:
Caused by mutation in the mannosyl-oligosaccharide glucosidase gene
(MOGS, 601336.0001)
OMIM Title
*606064 CD248 ANTIGEN; CD248
;;TUMOR ENDOTHELIAL MARKER 1; TEM1;;
ENDOSIALIN
OMIM Description
CLONING
By serial analysis of gene expression (SAGE), St Croix et al. (2000)
identified transcripts of pan endothelial markers (PEMs) and tumor
endothelial markers (TEMs), including TEM1. RT-PCR and in situ
hybridization analyses demonstrated that TEM1 expression was restricted
to neoplastic endothelial tissue and to metastatic lesions. The authors
identified TEM1 in other angiogenic tissues, namely corpus luteum and
the granulation tissue of healing wounds, supporting the concept that in
many cases tumors represent unhealed wounds.
Endosialin, an antigen recognized by monoclonal antibody FB5, is
expressed as a 165-kD cell surface glycoprotein on tumor blood vessel
endothelium in several cancers, but is not detectable in normal tissue.
By immunoaffinity and biochemical purification of endosialin from a
neuroblastoma cell line, followed by microsequence analysis and EST
database searching, Christian et al. (2001) isolated a full-length cDNA
encoding endosialin, which is identical to TEM1. Sequence analysis
predicted that the 757-amino acid type I membrane protein contains a
signal peptide; 5 globular extracellular domains, including a C-type
lectin (see 605306) domain, a Sushi/SCR/CCP (see 300187) domain, and 3
EGF (131530) repeats; a mucin (see 158340)-like region; a transmembrane
segment; and a short cytoplasmic tail. Carbohydrate analysis indicated
that the endosialin protein carries abundantly sialylated, O-linked
oligosaccharides and is reduced to 120 kD by sialidase treatment or to
95 kD with additional O-glycanase treatment. The N-terminal 360 residues
of endosialin are homologous to thrombomodulin (THBD; 188040) and
complement component 1q receptor (120577). Northern blot analysis
revealed expression of a single 2.6-kb transcript in
endosialin-expressing cell lines. Christian et al. (2001) noted that
mice and rats have close homologs of the TEM1 gene. Carson-Walter et al.
(2001) determined that TEM1 shares 77% amino acid identity with the
mouse protein.
Using in situ hybridization analysis of human colorectal cancer,
Carson-Walter et al. (2001) demonstrated that TEM1 was expressed clearly
in the endothelial cells of the tumor stroma but not in the endothelial
cells of normal colonic tissue. Mouse Tem1 was abundantly expressed in
vessels infiltrating both mouse melanoma and human colon carcinoma cells
implanted into mice. Using in situ hybridization to assay expression in
various normal adult mouse tissues, Carson-Walter et al. (2001) detected
only weak staining of endothelial cells in adrenal gland, brain, heart,
intestine, lung, skeletal muscle, and pancreas. In embryos, they
detected Tem1 in the vasculature of developing embryonic liver and
brain.
MAPPING
By somatic cell hybrid and genomic sequence analyses, Christian et al.
(2001) mapped the CD248 gene to 11q13.
ANIMAL MODEL
Nanda et al. (2006) found that Tem1-null mice were healthy and fertile,
with no tissue abnormalities and normal wound healing. There were no
differences in the growth rates of the Lewis lung carcinoma tumor cell
line and a sarcoma cell line after subcutaneous injection into Tem1-null
or wildtype nude mice. However, when tumor fragments from a colorectal
carcinoma were implanted on the serosal surface of the large intestine,
tumor volume and the degree of metastases were reduced in the absence of
Tem1. Abdominal tumors in Tem1-null mice also showed a higher number of
smaller vessels and a decreased number of larger vessels compared with
those in wildtype mice.
CCDC87
| dbSNP name | rs486584(C,T) |
| ccdsGene name | CCDS8145.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 55231 |
| EntrezGene Description | coiled-coil domain containing 87 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC87:NM_018219:exon1:c.G2361A:p.L787L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4151 |
| ESP Afr MAF | 0.191591 |
| ESP All MAF | 0.414473 |
| ESP Eur/Amr MAF | 0.471362 |
| ExAC AF | 0.512 |
CARNS1
| dbSNP name | rs1790734(G,A); rs887318(C,T); rs12288107(T,G); rs1790733(A,G); rs868167(C,A); rs1790747(T,C); rs200939791(C,T); rs1790748(T,A); rs1626067(G,A); rs11227791(G,A) |
| ccdsGene name | CCDS44658.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 57571 |
| EntrezGene Description | carnosine synthase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CARNS1:NM_001166222:exon10:c.C2353T:p.R785C,CARNS1:NM_020811:exon9:c.C1984T:p.R662C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.938 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A5YM72-3 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.00095 |
| ESP Eur/Amr MAF | 0.001423 |
| ExAC AF | 0.001419 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary urgency
MUSCLE, SOFT TISSUE:
Mild weakness of the small hand muscles
NEUROLOGIC:
[Central nervous system];
Spastic paraplegia;
Spastic gait;
Lower limb muscle weakness, proximal;
Hyperreflexia
MISCELLANEOUS:
Average age at onset 16.6 years;
One 4-generation Chinese family has been reported (as of 04/2010)
OMIM Title
*613368 CARNOSINE SYNTHASE 1; CARNS1
;;ATP-GRASP DOMAIN-CONTAINING PROTEIN 1; ATPGD1;;
KIAA1394
OMIM Description
DESCRIPTION
CARNS1 (EC 6.3.2.11), a member of the ATP-grasp family of ATPases,
catalyzes the formation of carnosine (beta-alanyl-L-histidine) and
homocarnosine (gamma-aminobutyryl-L-histidine), which are found mainly
in skeletal muscle and the central nervous system, respectively (Drozak
et al., 2010).
CLONING
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (2000) cloned CARNS1, which they designated
KIAA1394. RT-PCR ELISA detected very high CARNS1 expression in whole
adult and fetal brain and in all specific adult brain regions examined.
High expression was also detected in heart and skeletal muscle, with
much lower expression in other tissues examined.
By searching databases for orthologs of chicken Atpgd1, followed by PCR
of mouse muscle/brain and human brain cDNA libraries, Drozak et al.
(2010) cloned mouse and human CARNS1, which they called ATPGD1. The
deduced proteins contain 957 and 950 amino acids, respectively, and both
contain 2 ATP-grasp domains, with highest conservation in the C-terminal
catalytic domain. Gel filtration analysis showed that mouse Atpgd1, like
the chicken enzyme, was expressed as a homotetramer of about 430 kD in
transfected HEK293 cells.
GENE FUNCTION
Drozak et al. (2010) showed that, in the presence of L-histidine and
ATP, purified chicken Atpgd1 converted beta-alanine to carnosine plus
ADP and inorganic phosphate. Mouse and human ATPGD1 catalyzed the same
reaction following expression in HEK293 cells. All 3 enzymes were not
specific with respect to the amino acid serving as the acceptor,
although L-histidine was preferred, and all 3 were also more efficient
in synthesizing carnosine than homocarnosine and other dipeptides.
Drozak et al. (2010) suggested that the lower catalytic efficiency of
homocarnosine synthesis is compensated for by the high concentration of
gamma-aminobutyric acid substrate in brain.
GENE STRUCTURE
Drozak et al. (2010) determined that CARNS1 contains 9 coding exons.
Exon 1 encodes the initiator ATG only.
MAPPING
By genomic sequence analysis, Drozak et al. (2010) mapped the CARNS1
gene to chromosome 11q13. They mapped the mouse Carns1 gene to
chromosome 19.
GPR152
| dbSNP name | rs949252(A,G); rs1638558(C,T); rs1638559(G,C) |
| ccdsGene name | CCDS8165.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 390212 |
| EntrezGene Description | G protein-coupled receptor 152 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR152:NM_206997:exon1:c.T1287C:p.A429A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1097 |
| ESP Afr MAF | 0.450909 |
| ESP All MAF | 0.154888 |
| ESP Eur/Amr MAF | 0.00326 |
| ExAC AF | 0.043 |
NUDT8
| dbSNP name | rs56102510(T,C); rs7124513(C,T) |
| ccdsGene name | CCDS58151.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 254552 |
| EntrezGene Description | nudix (nucleoside diphosphate linked moiety X)-type motif 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NUDT8:NM_001243750:exon4:c.A504G:p.L168L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.095647 |
| ESP All MAF | 0.031141 |
| ESP Eur/Amr MAF | 0.002771 |
| ExAC AF | 0.008902 |
ALDH3B2
| dbSNP name | rs116443716(C,T); rs1551885(A,G); rs2447570(T,C); rs866907(T,C); rs78402723(A,G); rs1551886(T,C); rs1979375(G,A); rs1979376(G,A); rs116105566(C,T); rs57134963(G,C); rs56131633(G,A); rs61423854(C,G); rs112907181(G,A); rs113012592(C,T); rs2447571(T,C); rs142189245(G,A); rs148026822(C,T); rs1551887(G,A); rs1551888(C,T); rs1871032(C,T); rs74946629(C,T); rs112071378(C,T); rs74508424(T,G); rs76408306(C,T); rs76550666(A,G); rs4646823(C,A); rs2126716(G,C); rs3825021(C,T); rs112604855(G,C); rs3928535(T,C); rs12288316(G,T); rs116654357(C,A); rs34589365(A,G); rs112472355(A,G); rs76053964(C,A); rs4313593(T,C); rs4569014(T,C); rs5019163(G,A); rs115626499(G,A); rs5019164(C,G); rs76415628(C,T); rs4587733(G,T); rs4581451(T,C); rs10791909(T,A); rs11227878(T,C); rs9787887(G,A); rs4930472(T,C); rs76785262(C,T); rs7943880(C,T); rs4646820(C,A); rs2279126(C,T); rs2279125(A,T); rs2279124(C,G); rs2279123(T,C); rs7947754(A,C); rs7947978(A,C); rs148071621(C,T); rs3808972(C,T); rs17510687(C,T); rs144035114(T,C); rs2514062(T,C); rs2447598(G,A); rs150828156(A,G); rs58272674(A,C); rs116091371(T,A); rs149940934(G,C); rs1903829(G,C); rs2514060(T,G); rs7114210(G,A); rs140094164(A,C); rs115759998(A,T); rs150988104(C,T); rs4930475(A,G); rs149746604(T,G); rs57178591(G,A); rs12285813(A,C); rs6591274(G,A); rs2514058(A,G); rs2447593(A,C); rs143040762(C,G); rs148533754(T,A); rs190448227(C,A) |
| ccdsGene name | CCDS31622.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 222 |
| EntrezGene Description | aldehyde dehydrogenase 3 family, member B2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ALDH3B2:NM_000695:exon7:c.G664A:p.V222M,ALDH3B2:NM_001031615:exon7:c.G664A:p.V222M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5205 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DSX1 |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.013182 |
| ESP All MAF | 0.004543 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001293 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Hypertension due to renal disease
GENITOURINARY:
[Kidneys];
Proteinuria;
Microscopic hematuria;
Nephrotic syndrome;
Renal failure;
End-stage renal disease;
Enlarged glomeruli;
Mesangial and subendothelial granular or fibrillar deposits which
show immunoreactivity to fibronectin
MISCELLANEOUS:
Onset of proteinuria in the second to fourth decades;
Onset of end-stage renal disease 15 to 20 years after onset;
Slow progression
MOLECULAR BASIS:
Caused by mutation in the fibronectin 1 gene (FN1, 135600.0001)
OMIM Title
*601917 ALDEHYDE DEHYDROGENASE 3 FAMILY, MEMBER B2; ALDH3B2
;;ALDEHYDE DEHYDROGENASE 8; ALDH8;;
ACETALDEHYDE DEHYDROGENASE 8
OMIM Description
CLONING
Hsu et al. (1995) and Hsu and Chang (1996) reported the cloning,
sequencing and expression of the human ALDH8 gene. Hsu and Chang (1996)
reported that ALDH8 encodes a deduced 385-amino acid protein with 2 ALDH
conserved regions. Northern blot analysis detected expression of ALDH8
in the salivary gland and in no other tissues examined.
GENE STRUCTURE
Hsu et al. (1997) determined the structure of the ALDH7 (600466) and
ALDH8 genes. The ALDH7 gene spans about 20 kb of genomic DNA and
contains 9 coding exons. The ALDH8 gene spans over 10 kb and contains at
least 10 exons. The ALDH8 gene contains an in-frame stop codon at the
seventeenth codon position from the first initiator methionine. The
coding region of the ALDH7 gene shows about 86% nucleotide identity with
the corresponding region of the ALDH8 gene. The numbers and positions of
the introns of the 2 genes are conserved, suggesting that gene
duplication is involved in the expansion of the ALDH gene family. The
human ALDH7 and ALDH8 genes have a close evolutionary relationship with
human ALDH3 (100660).
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ALDH8
gene to chromosome 11 (TMAP U37519).
TCIRG1
| dbSNP name | rs79557925(G,A); rs112230656(G,A); rs72926459(G,T); rs191388932(G,A); rs12273861(G,T); rs906713(A,G); rs12418239(G,A); rs2075609(A,G); rs11228127(C,T) |
| ccdsGene name | CCDS53670.1 |
| cytoBand name | 11q13.2 |
| EntrezGene GeneID | 10312 |
| EntrezGene Description | T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCIRG1:NM_006019:exon10:c.G1138A:p.V380M,TCIRG1:NM_006053:exon5:c.G490A:p.V164M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7242 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q13488 |
| dbNSFP Uniprot ID | VPP3_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 2.441e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604592 T CELL IMMUNE REGULATOR 1; TCIRG1
;;ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A3; ATP6V0A3;;
VACUOLAR PROTON PUMP, ALPHA SUBUNIT 3
TIRC7, INCLUDED;;
OC116, INCLUDED
OMIM Description
DESCRIPTION
The TCIRG1 gene encodes several protein isoforms, with 2 main isoforms.
The full-length isoform a (OC116) encodes the A3 subunit of vacuolar
H(+)-ATPase, which is involved in regulation of the pH of intracellular
compartments and organelles of eukaryotic cells, including the pH of
osteoclasts. The shorter isoform b (TIRC7) encodes a T-cell-specific
membrane protein that plays an essential role in T-lymphocyte activation
and immune response (summary by Smirnova et al., 2005 and Makaryan et
al., 2014).
CLONING
Osteoclasts, multinucleated giant cells responsible for bone resorption,
degrade inorganic and organic components of bone in a local area
subjacent to the matrix attachment site. This degradation is dependent
in part on acidification of the subosteoclastic resorption lacuna via
the activation of carbonic anhydrase II (CA2; 611492) and a
vacuolar-type proton pump. Using differential hybridization to screen an
osteoclastoma library, Li et al. (1996) obtained a cDNA, which they
called OC116, for a vacuolar proton pump polypeptide. OC116 encodes an
822-amino acid protein that has an abundance of hydrophilic residues in
the N-terminal 390 amino acids. Analysis of hydrophobicity plots
suggested that the C-terminal 432 amino acids comprise 6 transmembrane
regions. Northern blot analysis detected high levels of the 2.7-kb OC116
transcript in the osteoclastoma tumor, with lower levels in a pancreatic
adenocarcinoma cell line and none in skeletal muscle, liver, kidney,
brain, osteoclastoma stromal cells, or a panel of human cell lines.
Using differential display RT-PCR, Utku et al. (1998) identified a novel
cDNA, which they called TIRC7, that encodes a protein essential in
T-cell activation. The deduced 614-amino acid TIRC7 protein is predicted
to have an N-terminal cytoplasmic domain, a 7-transmembrane domain
structure, and an extracellular C domain. There are multiple putative
phosphorylation sites for protein kinases C (176960) and A (176911) as
well as N-linked glycosylation sites. Northern blot analysis revealed
that alloantigen stimulation resulted in a 20-fold upregulation of the
expected 2.5- as well as a 4.0-kb transcript of TCIRG1. TCIRG1
expression could be blocked by cyclosporine A, suggesting that its
expression occurs via the calcineurin signaling pathway. Northern blot
analysis also revealed that TIRC7 is almost exclusively expressed in
immune system tissues but not in various B-cell lines. Western blot
analysis detected TIRC7 predominantly in membrane extracts of human
lymphocytes as a single protein of 75 kD.
By screening a human genomic PAC library, Heinemann et al. (1999)
determined that TIRC7 and OC116 are alternatively spliced products of
the same gene, called TCIRG1. Only TIRC7 mRNA is expressed by
alloactivated T lymphocytes. TCIRG1 gives rise to 2 separate proteins
via alternative splicing: the full-length isoform a (OC116) and the
shorter isoform b (TIRC7), which lacks the first 5 exons of the longer
variant (summary by Makaryan et al., 2014).
Using RT-PCR, Smirnova et al. (2005) identified and validated 6
alternative splice events in TCIRG1 in addition to the previously
characterized isoforms a and b. All isoforms were expressed in most of
the 28 human tissues studied. The complex nature of splicing in TCIRG1
suggested that this gene may be involved in other processes besides
immune response and bone resorption.
GENE STRUCTURE
Heinemann et al. (1999) determined that TIRC7 contains 15 exons spanning
7.9 kb, whereas OC116 contains 20 exons with the last 14 introns and
exons being identical to TIRC7.
MAPPING
By FISH, Heinemann et al. (1999) mapped the TCIRG1 gene to chromosome
11q13.4-q13.5.
MOLECULAR GENETICS
- Autosomal Recessive Osteopetrosis 1
Infantile malignant autosomal recessive osteopetrosis (see OPTB1,
259700) is a severe bone disease with a fatal outcome, generally within
the first decade of life. Osteoclasts are present in normal or elevated
numbers in individuals affected by autosomal recessive osteopetrosis,
suggesting that the defect is not in osteoclast differentiation but in a
gene involved in the functional capacity of mature osteoclasts. The
disorder was mapped to 11q13, a region containing many potential
candidate genes for osteopetrosis, including TCIRG1. TCIRG1 is
specifically expressed in osteoclasts in the ruffled borders, which are
areas of intense membrane infolding actively involved in bone
resorption. In 5 of 9 patients with infantile malignant osteopetrosis,
Frattini et al. (2000) found that the TCIRG1 gene was mutated. Kornak et
al. (2000) identified TCIRG1 mutations in at least 1 allele among 5 of
10 patients with infantile malignant osteopetrosis.
By sequencing the TCIRG1 gene (called ATP6i by them) in autosomal
recessive osteopetrosis patients from 44 unrelated families with a
worldwide distribution, Sobacchi et al. (2001) established that TCIRG1
mutations are responsible for 50% of patients affected by this disorder.
The vast majority of mutations (40 of 42 alleles, including 7 deletions,
2 insertions, 10 nonsense substitutions, and 21 splice site mutations)
are predicted to cause severe abnormalities in the protein product and
likely represent null alleles. Nine unrelated osteopetrosis patients
from Costa Rica, where osteopetrosis is apparently much more frequent
than elsewhere, were analyzed. All 9 Costa Rican patients bore either or
both of 2 missense mutations (gly405 to arg, 604592.0005; arg444 to leu,
604592.0006) in amino acid residues which are evolutionarily conserved
from yeast to humans.
In a series of 6 patients with autosomal recessive osteopetrosis,
Scimeca et al. (2003) identified 4 novel mutations in the TCIRG1 gene,
in addition to the previously described G405R mutation.
Susani et al. (2004) performed genetic analysis of TCIRG1 in 55 patients
with autosomal recessive osteopetrosis, 25 of whom were previously
unreported, and identified 9 novel mutations. Because substitutions in
splicing regulatory sequences represented a large portion (40%) of the
TCIRG1 variations, Susani et al. (2004) developed a functional splicing
assay to distinguish between polymorphic variants and disease-causing
mutations. Three intronic nucleotide substitutions flanking the splice
sites were studied using hybrid minigenes, and an abnormal processing of
the transcripts was demonstrated in all cases. Cotransfection
experiments with complementary U1 small nuclear RNAs (U1 snRNAs; 180680)
showed that in 1 case the defect at the 5-prime splice site was
corrected. These findings indicated the feasibility of the hybrid
minigene approach to detect splicing defects, particularly in patients
in whom RNA is not available. In addition, the results suggested that
modified U1 snRNAs may represent a therapeutic strategy for autosomal
recessive osteopetrosis patients with a U1 small nuclear
ribonucleoprotein (snRNP)-dependent splicing defect.
In a child from a consanguineous Turkish kindred who manifested
osteopetrosis and distal RTA (see CA2 deficiency, 259730), Borthwick et
al. (2003) excluded defects in CA2 and found instead penetrance of 2
separate recessive disorders, each affecting a different,
tissue-specific subunit of the vacuolar proton pump H(+)-ATPase. The
osteopetrosis was the result of a homozygous deletion in the TCIRG1 gene
(604592.0007), whereas the distal RTA was associated with a homozygous
mutation in the ATP6V1B1 gene (192132.0005), which encodes the
kidney-specific B1 subunit of H(+)-ATPase. Borthwick et al. (2003)
concluded that coinheritance of 2 rare recessive disorders created a
phenocopy of CA2 deficiency in this patient.
The genes for 3 bone mineral density (BMD)-related phenotypes (autosomal
dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma,
and autosomal recessive osteopetrosis) are all in the chromosome
11q12-13 region. Carn et al. (2002) reported linkage of peak BMD in a
large sample of healthy premenopausal sister pairs to this same
chromosomal region, suggesting that the genes underlying these 3
disorders may also play a role in determining peak BMD within the normal
population. To test this hypothesis, they examined the TCIRG1 gene,
which encodes an osteoclast-specific subunit (OC116) of the vacuolar
proton pump. They identified 3 variants in the sequence of TCIRG1, but
only 1 had sufficient heterozygosity for use in genetic analyses. Their
findings were consistent with linkage to femoral neck BMD, but not to
spine BMD, in a sample of 995 healthy premenopausal sister pairs.
However, further analysis, using both population and family-based
disequilibrium approaches, did not demonstrate any evidence of
association between TCIRG1 and the spine or femoral neck BMD. The
authors concluded that the chromosomal region that contains OC116
possibly harbors a gene that affects peak BMD, but their results
indicate that polymorphisms in the OC116 gene do not affect peak BMD.
- Associations Pending Confirmation
See 604592.0008 for discussion of a possible association between
variation in the TCIRG1 gene and autosomal dominant severe congenital
neutropenia (see 202700).
ANIMAL MODEL
In a rat model, Utku et al. (1998) showed that anti-TIRC7 prolonged
renal allograft survival. In mice, Li et al. (1999) found that
inactivation of the Tcirg1 gene caused osteoclast-rich osteopetrosis.
Scimeca et al. (2000) found deletion involving the 5-prime portion of
the Tcirg1 gene underlying the spontaneous oc/oc mutation in mice.
Schinke et al. (2009) analyzed 2 osteopetrotic mouse models, Src
(190090)-deficient mice and Tcirg1-deficient (oc/oc) mice, and observed
that contact radiographs at 2 weeks of age revealed an osteopetrorickets
phenotype specifically in oc/oc mice, whose high bone mass was
accompanied by rachitic widening of the growth plates and by severe
growth retardation, 2 characteristics not seen in Src -/- mice.
Nondecalcified histology confirmed that only oc/oc mice had a
demineralization defect of hypertrophic cartilage and bone matrix,
whereas in Src -/- mice the increased bone matrix was normally
mineralized. Quantification of these observations by histomorphometry
confirmed that Src -/- mice displayed osteopetrosis, whereas oc/oc mice
displayed osteopetrorickets, demonstrating that osteoclast dysfunction
does not necessarily cause a defect in skeletal mineralization. Because
urinary calcium levels were significantly lower in oc/oc mice than their
wildtype littermates, Schinke et al. (2009) analyzed Tcirg1 expression
in the stomach and detected specific expression of Tcirg1 in the fundus,
a region of the stomach involved in gastric acid production; measurement
of gastric pH confirmed hypochlorhydria in oc/oc mice. Schinke et al.
(2009) generated mice with a combined deficiency in both Src and Cckbr
(118445), which encodes a gastrin receptor that affects acid secretion
by parietal cells, and observed the development of osteopetrorickets, a
phenotype not seen in Cckbr -/- mice or in Src -/- mice. Schinke et al.
(2009) concluded that osteopetrosis and osteopetrorickets are distinct
phenotypes, depending on the site or sites of defective acidification.
MRGPRD
| dbSNP name | rs34847539(T,C) |
| ccdsGene name | CCDS31625.1 |
| cytoBand name | 11q13.3 |
| EntrezGene GeneID | 116512 |
| EntrezGene Description | MAS-related GPR, member D |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MRGPRD:NM_198923:exon1:c.A453G:p.T151T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.348 |
| ESP Afr MAF | 0.190909 |
| ESP All MAF | 0.313212 |
| ESP Eur/Amr MAF | 0.375873 |
| ExAC AF | 0.607 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Weakness of the facial muscles;
[Eyes];
Slow eye movements (onset in second decade);
Ocular gaze palsies (onset in second decade)
GENITOURINARY:
[Bladder];
Incontinence
ABDOMEN:
[Gastrointestinal];
Dysphagia (onset in second decade);
Chewing difficulties;
Incontinence
SKELETAL:
[Spine];
Scoliosis (less common);
[Feet];
Shortening of the Achilles tendon;
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness;
Normal muscle biopsy;
EMG shows reduction of voluntary recruitment
NEUROLOGIC:
[Central nervous system];
Upper and lower motor neuron degeneration;
Spastic paraplegia, lower limb;
Stiffness of the lower limbs;
Delayed motor development;
Loss of motor milestones;
Upper limb involvement (onset in the first decade);
Spastic tetraplegia (onset in the second decade);
Bulbar involvement;
Dysarthria;
Anarthria;
Hyperreflexia;
Extensor plantar responses;
Early involvement of the corticospinal pathways;
Weakness of the facial muscles;
Normal cognition and intellectual function;
Atrophy of the motor cortex in older patients seen on MRI;
T2-weighted hyperintensities in the corticospinal tracts and posterior
arms of the internal capsule in older patients seen on MRI;
Decreased or absent motor evoked potentials (MEP), indicating dysfunction
of the corticospinal tracts
MISCELLANEOUS:
Onset within first 2 years of life;
Progressive disorder;
Some patients never achieve walking or running;
Most patients become wheelchair-bound;
Allelic disorder to juvenile-onset amyotrophic lateral sclerosis (ALS2,
205100);
Allelic disorder to juvenile primary lateral sclerosis (PLSJ, 606353)
MOLECULAR BASIS:
Caused by mutation in the alsin gene (ALS2, 606352.0005)
OMIM Title
*607231 MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER D; MRGPRD
;;MRGD
OMIM Description
CLONING
Dong et al. (2001) identified, in the mouse and human genomes, a family
of G protein-coupled receptors (GPCRs) related to the MAS1 oncogene
(165180), including MRGD. Several pseudogenes were also identified. The
predicted MRG proteins contain transmembrane, extracellular, and
cytoplasmic domains. A subset of MRGs was expressed in specific
subpopulations of sensory neurons that detect painful stimuli. The
expression patterns of these genes thus revealed an unexpected degree of
molecular diversity among nociceptive neurons. Some MRGs could be
specifically activated in heterologous cells by RFamide neuropeptides
such as NPFF and NPAF (see 604643), which are analgesic in vivo. The
authors concluded that MRGs may regulate nociceptor function and/or
development, including the sensation or modulation of pain.
MAPPING
By genomic sequence analysis, Dong et al. (2001) mapped the MRGD gene to
chromosome 11.
MYEOV
| dbSNP name | rs11228608(A,G); rs148961066(C,A); rs7117236(C,T); rs7103126(T,C); rs17856376(A,G); rs73512137(C,T) |
| cytoBand name | 11q13.3 |
| EntrezGene GeneID | 26579 |
| EntrezGene Description | myeloma overexpressed |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3655 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Progressive high-frequency hearing loss (onset 20-30 years);
Tinnitus;
[Teeth];
Dentinogenesis imperfecta
MISCELLANEOUS:
Allelic with dentinogenesis imperfecta 1 (125490) and dentin dysplasia,
type II (125420)
MOLECULAR BASIS:
Caused by mutation in the dentin sialophosphoprotein gene (DSPP, 125485.0003)
OMIM Title
*605625 MYELOMA OVEREXPRESSED GENE; MYEOV
OMIM Description
Translocations involving the immunoglobulin heavy chain locus (IgH; see
147100) at 14q32.3 are mediated by errors during VDJ recombination
either early in development or during class-switch recombination at
later stages in B-cell development. Such translocations occur in as many
as 70% of multiple myelomas and plasma cell leukemias. See 254500.
By cloning gastric carcinoma tumor DNA into phage vectors, probing with
human Alu repetitive sequences, and exon-trap analysis, Janssen et al.
(2000) isolated a cDNA encoding MYEOV (myeloma overexpressed gene).
Sequence analysis predicted that the 313-amino acid protein contains no
known functional motifs except for an RNP1 motif typical of RNA-binding
proteins and a leucine-isoleucine tail similar to cytoplasmically
exposed membrane proteins with a C-terminal membrane anchor. Northern
blot analysis detected a major 2.8-kb and a minor 3.5-kb transcript in
various tumor cell lines. In 3 of 7 multiple myeloma cell lines with a
t(11;14)(q13;q32) and cyclin D1 (CCND1; 168461) overexpression, Northern
blot analysis determined that MYEOV was overexpressed. In all 7 cell
lines, the breakpoint was mapped to the 360-kb region between the 2
genes. MYEOV overexpression was associated with the juxtaposition of an
enhancer to the MYEOV gene.
Using FISH, Janssen et al. (2000) mapped the MYEOV gene to 11q13.1, 360
kb centromeric to CCND1.
DNA amplifications at 11q13 are frequently observed in esophageal
squamous cell carcinoma (133239) and correlate with a malignant
phenotype. Although this amplicon spans a region of several megabases
and harbors numerous genes, CCND1 and EMS1 (164765) are thought to be
the relevant candidates in esophageal carcinoma. Janssen et al. (2002)
investigated whether the putative transforming gene MYEOV, mapping 360
kb centromeric to CCND1 and activated concomitantly with CCND1 in a
subset of t(11;14)(q13;q32) positive multiple myeloma cell lines,
represents a target of 11q13 amplification in esophageal carcinoma. They
tested 31 esophageal squamous cell carcinoma cell lines and 48 primary
tumors for copy number levels of MYEOV and demonstrated that MYEOV was
always coamplified with CCND1. However, its activation was sometimes
inhibited by an epigenetic mechanism.
FGF4
| dbSNP name | rs3740639(C,T) |
| cytoBand name | 11q13.3 |
| EntrezGene GeneID | 2249 |
| EntrezGene Description | fibroblast growth factor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.208 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Blindness;
Corneal opacities;
Megalocornea
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Shallow glenoid fossa
SKELETAL:
[Skull];
Temporomandibular joint fusion;
Obtuse mandibular angle;
Absent coronoid process;
[Pelvis];
Coxa valga;
[Limbs];
Mesomelia (upper limbs);
Lateral humeral condyle aplasia;
Radiohumeral dislocation;
Proximal radioulnar dislocation;
Bowed radii;
Absent radial heads;
Short fibula;
[Hands];
Ulnar deviated club hands;
Decreased mobility 3rd-5th fingers
OMIM Title
*164980 FIBROBLAST GROWTH FACTOR 4; FGF4
;;HEPARIN SECRETORY TRANSFORMING PROTEIN 1; HSTF1;;
ONCOGENE HST;;
HUMAN STOMACH CANCER, TRANSFORMING FACTOR FROM;;
FGF-RELATED ONCOGENE;;
KAPOSI SARCOMA ONCOGENE; KFGF
OMIM Description
CLONING
Sakamoto et al. (1986) tested the capacity for malignant transformation
of DNA from 21 stomach cancers, 16 stomach cancers metastatic to lymph
nodes, and 21 specimens of apparently noncancerous stomach mucosa from a
total of 26 patients with stomach cancer. The DNA was transferred to NIH
3T3 cells by the calcium precipitation technique. Transforming ability
was shown by 3 samples: a primary cancer, a metastatic cancer, and a
presumably normal gastric mucosa. The transforming gene from the primary
cancer was cloned. It bore no homology with previously reported
transforming sequences. Taira et al. (1987) isolated an HST cDNA clone
that had an efficient transforming activity in a focus-forming assay
when it was inserted into an expression vector. Characterization of this
clone allowed Taira et al. (1987) to predict that a 206-amino acid
protein product was responsible for this transforming activity. In an
addendum, Taira et al. (1987) indicated that 42.3% homology existed
between the amino acid residues of 1 ORF (open reading frame) of HST and
part of bovine basic fibroblast growth factor. They suggested that
further studies would elucidate the role of the HST gene in the
development of stomach cancer which, they stated, has the highest
incidence of all known cancers.
Both HST and INT2 (164950) are in the fibroblast growth factor family of
oncogenes. Yoshida et al. (1988) reported expression of HST1 in a human
teratoma cell line and in 5 of 9 surgically resected human testicular
germ cell tumors including seminomas and embryonal carcinomas. HST1, for
which the designation HSTF1 was proposed for human gene nomenclature, is
a heparin-binding growth factor with significant homology to human
fibroblast growth factors and the mouse Int-2 protein. Huebner et al.
(1988) isolated the same oncogene by transfection of Kaposi sarcoma DNA
and demonstrated its significant homology to both basic and acidic FGFs
( see 134920 and 131220). Because of its origin from Kaposi sarcoma and
because of its similarity to FGFs, they designated the oncogene 'K-FGF.'
GENE STRUCTURE
Huebner et al. (1988) found that sequences adjacent to the 3-prime end
of the K-FGF coding sequence in transfectants probably derived from the
part of the genome lying between 12p12 and 12q13. Whether the
juxtaposition of the chromosome 11-linked K-FGF gene to the chromosome
12-linked sequences within the original transfectants was pure accident
remained to be determined. (It had earlier been demonstrated that
sequences from the FMS oncogene on chromosome 5 were included in the
transfectant.)
MAPPING
By in situ hybridization, Adelaide et al. (1988) mapped the HST gene to
chromosome 11q13. This is also the location of the INT2 gene.
Furthermore, Adelaide et al. (1988) found the 2 genes to be coamplified
in a human melanoma.
Huebner et al. (1988) mapped the K-FGF oncogene to 11q11-q23 by
hybridization studies using DNA from rodent-human somatic cell hybrids
and then localized it more precisely to 11q13 by in situ hybridization.
The 11q13 region is also the site of the BCL1 gene (168461), which is
involved in the 11;14 translocation characteristic of some B-cell
tumors; see 151400. The oncogene SEA (165110) has also been mapped to
11q13. By pulsed-field gel electrophoresis and by analysis of
overlapping cosmid clones, Wada et al. (1988) concluded that HST1 is
located about 35 kb downstream of INT2 in the same transcriptional
orientation.
GENE FUNCTION
For a review of the role of this gene in limb development, see Johnson
and Tabin (1997).
Zuniga et al. (1999) reported that the secreted bone morphogenetic
protein (BMP) antagonist gremlin (GREM1; 603054) relays the Sonic
hedgehog (SHH; 600725) signal from the polarizing region to the apical
ectodermal ridge. Mesenchymal gremlin expression is lost in limb buds of
mouse embryos homozygous for the 'limb deformity' (ld) mutation, which
disrupts establishment of the Snhh/Fgf4 feedback loop. Grafting
gremlin-expressing cells into ld mutant limb buds rescued Fgf4
expression and restored the Shh/Fgf4 feedback loop. Analysis of Shh-null
mutant embryos revealed that Shh signaling is required for maintenance
of gremlin and formin (FMN1; 136535), the gene disrupted by the ld
mutations. In contrast, formin, gremlin, and Fgf4 activation were
independent of Shh signaling. Zuniga et al. (1999) concluded that the
study uncovered the cascade by which the SHH signal is relayed from the
posterior mesenchyme to the apical ectodermal ridge and established that
formin-dependent activation of the BMP antagonist gremlin is sufficient
to induce FGF4 and establish the SHH/FGF4 feedback loop.
Kratochwil et al. (2002) concluded that FGF4 is a direct target of LEF1
(153245) and Wnt signaling during tooth development in mice. Kratochwil
et al. (2002) showed that beads soaked with recombinant FGF4 protein
could fully overcome the developmental arrest of tooth germs seen in
Lef1-deficient mice. The FGF4 beads also induced delayed expression of
Shh (600725) in the epithelium. Using a chemical inhibitor of FGF
signaling, Kratochwil et al. (2002) was able to mimic the arrest of
tooth development seen in Lef1-deficient mice. The authors hypothesized
that the sole function of LEF1 in odontogenesis may be to activate Fgf4
and to connect the Wnt and FGF signaling pathways at a specific
developmental step.
Vertebrate limb outgrowth is driven by a positive feedback loop
involving SHH, gremlin, and FGF4. By overexpressing individual
components of the loop at a time after these genes are normally
downregulated in chicken embryos, Scherz et al. (2004) found that Shh no
longer maintains gremlin in the posterior limb. Shh-expressing cells and
their descendants cannot express gremlin. The proliferation of these
descendants forms a barrier separating the Shh signal from
gremlin-expressing cells, which breaks down the Shh-Fgf4 loop and
thereby affects limb size and provides a mechanism explaining regulative
properties of the limb bud.
Mariani et al. (2008) demonstrated that mouse limbs lacking Fgf4, Fgf9
(600921), and Fgf17 (603725) have normal skeletal pattern, indicating
that Fgf8 (600483) is sufficient among apical ectodermal ridge
fibroblast growth factors (AER-FGF) to sustain normal limb formation.
Inactivation of Fgf8 alone causes a mild skeletal phenotype; however,
when Mariani et al. (2008) also removed different combinations of the
other AER-FGF genes, they obtained unexpected skeletal phenotypes of
increasing severity, reflecting the contribution that each FGF can make
to the total AER-FGF signal. Analysis of the compound mutant limb buds
revealed that, in addition to sustaining cell survival, AER-FGFs
regulate proximal-distal patterning gene expression during early limb
bud development, providing genetic evidence that AER-FGFs function to
specify a distal domain and challenging the longstanding hypothesis that
AER-FGF signaling is permissive rather than instructive for limb
patterning. Mariani et al. (2008) also developed a 2-signal model for
proximal-distal patterning to explain early specification.
Spence et al. (2011) established a robust and efficient process to
direct the differentiation of human pluripotent stem cells into
intestinal tissue in vitro using a temporal series of growth factor
manipulations to mimic embryonic intestinal development. Using this
culture system as a model to study human intestinal development, Spence
et al. (2011) identified that the combined activity of WNT3A (606359)
and FGF4 is required for hindgut specification, whereas FGF4 alone is
sufficient to promote hindgut morphogenesis. Spence et al. (2011)
concluded that human intestinal stem cells form de novo during
development. Spence et al. (2011) also determined that NEUROG3 (604882)
is both necessary and sufficient for human enteroendocrine cell
development in vitro.
ANIMAL MODEL
Feldman et al. (1995) demonstrated that Fgf4 -/- embryos die on
embryonic day 5.0. To circumvent this early lethality and assess Fgf4
function in limb development, Sun et al. (2000) used the Cre/loxP system
and found that Shh expression is maintained and limb formation is normal
when Fgf4 is inactivated in mouse limbs, contradicting another model
which suggested that Fgf4 expression is not maintained in Shh -/- mouse
limbs. Sun et al. (2000) also found that maintenance of Fgf9 (600921)
and Fgf17 (603725) expression is dependent on Shh, whereas Fgf8 (600483)
expression is not. Sun et al. (2000) developed a model in which no
individual Fgf expressed in the apical ectodermal ridge is solely
necessary to maintain Shh expression, but instead the combined activity
of 2 or more apical ectodermal ridge Fgfs function in a positive
feedback loop with Shh to control limb development.
To determine the role of fibroblast growth factor signaling from the
apical ectodermal ridge, Sun et al. (2002) inactivated Fgf4 and Fgf8
(600483) in apical ectodermal ridge cells or their precursors at
different stages of mouse limb development. Sun et al. (2002) showed
that Fgf4 and Fgf8 regulate cell number in the nascent limb bud and are
required for survival of cells located far from the apical ectodermal
ridge. On the basis of the skeletal phenotypes observed, Sun et al.
(2002) concluded that these functions are essential to ensure that
sufficient progenitor cells are available to form the normal complement
of skeletal elements, and perhaps other limb tissues. In the absence of
both Fgf4 and Fgf8 activities, limb development fails. None of 23
newborn double knockout mice examined had hindlimbs. In contrast,
forelimbs contained elements of all 3 limb segments but were shorter and
thinner than normal. Sun et al. (2002) found that in double homozygotes,
forelimb proximal elements were invariably missing or severely
hypoplastic when distal elements were present. They suggested that these
observations argue against the progress zone model, which had been the
prevailing model of limb proximal-distal patterning. Sun et al. (2002)
hypothesized that limb skeletal patterning is achieved as a function of
basic cellular processes including cell division, cell survival, and
stereotypic behaviors of chondrocyte progenitors such as aggregate
formation.
In a series of experiments involving removal of the apical ectodermal
ridge from chick limb buds, Dudley et al. (2002) demonstrated that the
various limb bud segments are specified early in limb development as
distinct domains, with subsequent development involving expansion of
progenitor populations before differentiation. Dudley et al. (2002) also
found that the distal limb mesenchyme becomes progressively determined,
that is, irreversibly fixed, to a progressively limited range of
potential proximodistal fates. Their observations, coupled with those of
Sun et al. (2002), refuted the progress zone model of vertebrate limb
development.
Limb bud outgrowth is driven by signals in a positive feedback loop
involving fibroblast growth factor genes, Sonic hedgehog (SHH; 600725),
and gremlin-1 (GREM1; 603054). Precise termination of these signals is
essential to restrict limb bud size. That the sequence in mouse limb
buds is different from that in chick limb buds drove Verheyden and Sun
(2008) to explore alternative mechanisms. By analyzing compound mouse
mutants defective in genes comprising the positive loop, Verheyden and
Sun (2008) provided genetic evidence that Fgf signaling can repress
Grem1 expression, revealing a novel Fgf/Grem1 inhibitory loop. The
repression occurs in both mouse and chick limb buds and is dependent on
high Fgf activity. These data supported a mechanism where the positive
Fgf/Shh loop drives outgrowth and an increase in Fgf signaling, which
triggers the Fgf/Grem1 inhibitory loop. The inhibitory loop then
operates to terminate outgrowth signals in the order observed in either
mouse or chick limb buds. Verheyden and Sun (2008) concluded that their
study unveils the concept of a self-promoting and self-terminating
circuit that may be used to attain proper tissue size in a broad
spectrum of developmental and regenerative settings. Verheyden and Sun
(2008) demonstrated that Fgf8 repression of Fgf4 expression is dependent
on Grem1 but not Sonic hedgehog.
Parker et al. (2009) used a multibreed association analysis in the
domestic dog to demonstrate that expression of a recently acquired
retrogene encoding Fgf4 is strongly associated with chondrodysplasia, a
short-legged phenotype that defines at least 19 dog breeds including
dachshund, corgi, and basset hound. Parker et al. (2009) identified an
approximately 5-kb insert in affected dogs that contained a conserved
Fgfr retrogene. Neither the introns nor the upstream promoters of the
gene were present in the insert; however, all exons were present, with
no alterations in the coding sequence, as well as the 3-prime
untranslated region (UTR) and polyadenylate tail characteristic of
retrotransposition of processed mRNA. Parker et al. (2009) then showed
that the Fgfr retrogene is expressed. The retrogene is inserted in the
middle of a long interspersed nuclear element (LINE) with both LINEs and
SINEs upstream.
KRTAP5-7
| dbSNP name | rs12271894(C,T); rs11234042(C,A) |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 440050 |
| snpEff Gene Name | NADSYN1 |
| EntrezGene Description | keratin associated protein 5-7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intragenic |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.103636 |
| ESP All MAF | 0.035725 |
| ESP Eur/Amr MAF | 0.000932 |
| ExAC AF | 0.01 |
KRTAP5-9
| dbSNP name | rs760420(C,T); rs10792769(A,G); rs61733899(C,T); rs2664(T,C); rs2663(G,A); rs2665(T,A) |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 3846 |
| EntrezGene Description | keratin associated protein 5-9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1313 |
OMIM Clinical Significance
Oncology:
Kaposi sarcoma
Skin:
Red-purple nodules, plaques, and macules;
Limb edema
Misc:
Rarely familial
Inheritance:
Autosomal dominant
OMIM Title
*148021 KERATIN ASSOCIATED PROTEIN 5-9; KRTAP5-9
;;KERATIN, CUTICLE, ULTRAHIGH-SULFUR, 1; KRN1
OMIM Description
BIOCHEMICAL FEATURES
Three proteins are encountered in hair keratin: high-sulfur, low-sulfur
and high-tyrosine (Fraser et al., 1973). Human hair contains virtually
none of the third type, but about 40% of the first (Gillespie and
Frenkel, 1974).
By electrophoresis, Baden and Lee (1974) found polymorphism of one of
the polypeptide chains of the alpha-fibrous proteins of human hair. A
variant polypeptide was present in about 5% of Caucasians. Family
studies showed codominant inheritance. No correlation with color,
thickness or texture could be determined. Physical properties other than
the electrophoretic ones were normal. A rather wide variability in hair
from different individuals is indicated by quantitative amino acid
composition, particularly of cysteine and tyrosine (Fraser et al.,
1973). Certain portions of the molecule may require high specificity and
therefore be restrictive in their composition, whereas others may be
more permissive.
Hrdy et al. (1977) found the electrophoretic polymorphism to be limited
to Caucasians. (It occurred in one black and one American Indian with
presumed Caucasian admixture.) Six of 150 Caucasian samples showed the
variant.
Marshall (1980, 1983) observed genetic variation in both the high-sulfur
and the low-sulfur protein fractions of fingernails. Baden (1986)
suggested that the low-sulfur variant of hair (Baden et al., 1975) may
be the same as Marshall's low-sulfur variant of fingernails. For
economic reasons, the protein and gene sequences for sheep wool keratins
have been determined by Australian scientists. During development, as
many as 50 to 100 keratin genes are active in the hair follicle. Hair
keratin proteins are classified into 2 large groups, the intermediate
filament (IF) proteins and the intermediate filament-associated, or
matrix, proteins (IFAPs); within each group the proteins can be further
classified into 2 or more families. The hair IF keratin genes comprise 2
families, designated type I and type II, with 4 major components in
each.
MAPPING
MacKinnon et al. (1991) reported studies of the map location of hair IF
keratin genes. The IFAP group of keratin proteins comprises several
families, with most proteins containing a large number of cysteine
residues. Genes encoding one of these families, known as the
ultrahigh-sulfur keratin (UHSK) proteins because they contain more than
30% cysteine residues, were isolated and their site of expression mapped
to human hair and wool cuticle by tissue in situ hybridization. By means
of a somatic cell hybrid panel, MacKinnon et al. (1991) mapped a human
hair cuticle ultrahigh-sulfur keratin gene (KRN1) to 11pter-q21. With
the probe used, in situ hybridization pointed to localization in 2
regions of chromosome 11: the distal part of 11p15, most likely 11p15.5,
and the distal part of 11q13, most likely 11q13.5. A probe from the
3-prime noncoding region of KRN1 mapped to 11q13.5. The sequence that
mapped to 11p15.5 was termed KRN1-like (148022). Richard et al. (1991)
described a high resolution radiation hybrid map of 11q12-q13, which
placed KRN1 between SEA (165110) and a group of genes that were not
separated out and included HSTF1 (164980).
KRTAP5-10
| dbSNP name | rs7120471(A,C) |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 387273 |
| EntrezGene Description | keratin associated protein 5-10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4582 |
INPPL1
| dbSNP name | rs73528804(C,G); rs12288631(T,C); rs2276048(A,G); rs2276047(A,G); rs12361913(C,T); rs17162091(C,T); rs17847219(C,A); rs61749194(C,A); rs61749195(C,A); rs714548(C,T); rs61736312(A,G); rs2276046(T,C); rs10751199(A,G); rs11548491(C,G); rs11235472(C,G); rs9886(G,C) |
| ccdsGene name | CCDS8213.1 |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 3636 |
| EntrezGene Description | inositol polyphosphate phosphatase-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | INPPL1:NM_001567:exon16:c.C1894A:p.L632I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7253 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O15357 |
| dbNSFP Uniprot ID | SHIP2_HUMAN |
| dbNSFP KGp1 AF | 0.0178571428571 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0367132867133 |
| dbNSFP KGp1 Eur AF | 0.0131926121372 |
| dbSNP GMAF | 0.01791 |
| ESP Afr MAF | 0.014545 |
| ESP All MAF | 0.014785 |
| ESP Eur/Amr MAF | 0.014908 |
| ExAC AF | 0.024 |
OMIM Clinical Significance
GU:
Nocturnal enuresis
Inheritance:
Autosomal dominant (12q13-q21);
heterogeneity
OMIM Title
*600829 INOSITOL POLYPHOSPHATE PHOSPHATASE-LIKE 1; INPPL1
;;SH2-CONTAINING INOSITOL PHOSPHATASE 2; SHIP2
OMIM Description
CLONING
Hejna et al. (1995) cloned a novel human cDNA that appeared to belong to
a family of inositol triphosphate phosphatases. They designated the gene
inositol polyphosphate phosphatase like-1 (INPPL1).
Pesesse et al. (1997) cloned the INPPL1 gene, which they called SHIP2,
but their clone differed at the N- and C-terminal ends from the sequence
of Hejna et al. (1995). SHIP2 encodes a 1,258-amino acid protein with a
predicted molecular mass of 142 kD. Northern blot analysis detected
particularly high levels of SHIP2 in human heart, skeletal muscle, and
placenta. SHIP2 was also expressed in dog thyroid cells in primary
culture, where the expression was enhanced in thyroid-stimulating
hormone (TSH; see 188540)- and epidermal growth factor (EGF;
131530)-stimulated cells.
Schurmans et al. (1999) reported the cDNA sequence, genomic structure,
promoter analysis, and gene expression in the embryo and adult mouse of
murine Ship2.
MAPPING
By PCR using primers from the INPPL1 cDNA sequence, Hejna et al. (1995)
screened an NIGMS human/rodent somatic cell hybrid mapping panel and
assigned the INPPL1 gene to chromosome 11. They narrowed the
localization to 11q23 using a chromosome 11-specific deletion panel.
GENE FUNCTION
Habib et al. (1998) raised antibodies against SHIP2 to examine the
effects of growth factors and insulin (176730) on the metabolism of this
protein. Immunoblot analysis revealed that SHIP2 was widely expressed in
fibroblast and nonhematopoietic tumor cell lines, unlike the SHIP
protein (601582), which was found only in cell lines of hematopoietic
origin. The SHIP2 antiserum precipitated a protein of approximately 145
kD, along with an activity which hydrolyzed phosphatidylinositol
3,4,5-triphosphate to phosphatidylinositol 3,4-bisphosphate. Tyrosine
phosphorylation of SHIP2 occurred in response to treatment of cells with
EGF, platelet-derived growth factor (PDGF; see 190040), nerve growth
factor (NGF; 162030), insulin-like growth factor-1 (IGF1; 147440), or
insulin. EGF and PDGF induced transient tyrosine phosphorylation of
SHIP2, while treatment of cells with NGF, IGF1, or insulin resulted in
prolonged tyrosine phosphorylation of SHIP2. Habib et al. (1998)
concluded that their data suggests that SHIP2 may play a significant
role in regulation of phosphatidylinositol 3-prime-kinase signaling by
growth factors and insulin.
Using human epithelial cell lines and primary human corneal and
epidermal keratinocytes, Yu et al. (2008) showed that microRNA-184
(MIR184; 613146) interfered with the ability of MIR205 (613147) to
downregulate expression of SHIP2. A synthetic antagomir targeting MIR205
or ectopic expression of MIR184 induced SHIP2 expression in
keratinocytes, with coordinated damping of AKT (see 164730) signaling
and increased apoptosis. Examination of the 3-prime UTR of SHIP2
revealed overlapping binding sites for MIR184 and MIR205. Coexpression
of MIR184 with MIR205 reversed MIR205-induced inhibition of a reporter
gene containing the SHIP2 3-prime UTR. MIR184 had no direct effect on
SHIP2 expression, but instead interfered with MIR205 binding to the
3-prime UTR of SHIP2.
MOLECULAR GENETICS
- Opsismodysplasia
In affected individuals from 7 families with opsismodysplasia (258480),
Below et al. (2013) identified homozygosity or compound heterozygosity
for mutations in the INPPL1 gene (see, e.g., 600829.0001-600829.0004)
that were present in heterozygosity in the unaffected parents for whom
DNA was available.
In affected individuals from 10 families with opsismodysplasia, Huber et
al. (2013) identified homozygosity or compound heterozygosity for 12
distinct mutations in INPPL1 (see, e.g., 600829.0005-600829.0009),
including 2 nonsense, 4 frameshift, 2 splice site, and 4 missense
mutations.
- Diabetes Mellitus Type 2
Kagawa et al. (2005) studied the relationship between single-nucleotide
polymorphisms (SNPs) in the SHIP2 gene and the pathogenesis of type 2
diabetes (125853) in a Japanese population. They identified 10
polymorphisms including 4 missense mutations. Among them, SNP3 (L632I)
was located in the 5-prime-phosphatase catalytic region, and SNP5
(N982S) was adjacent to the phosphotyrosine-binding domain binding
consensus motif in the C terminus. SNP3 was found more frequently in
control subjects than in type 2 diabetic patients, suggesting that this
mutation might protect from insulin resistance. Transfection study
showed that expression of SNP3-SHIP2 inhibited insulin-induced
PI(3,4,5)-triphosphate production and AKT2 (164731) phosphorylation less
potently than expression of wildtype SHIP2 in Chinese hamster ovary
cells overexpressing human insulin receptors (CHO-IR). Kagawa et al.
(2005) concluded that polymorphisms of SHIP2 are implicated, at least in
part, in type 2 diabetes, possibly by affecting the metabolic and/or
mitogenic insulin signaling in the Japanese population.
ANIMAL MODEL
Clement et al. (2001) generated mice lacking the Ship2 gene. Loss of
Ship2 led to increased sensitivity to insulin, which was characterized
by severe neonatal hypoglycemia, deregulated expression of the genes
involved in gluconeogenesis, and perinatal death. Adult mice that were
heterozygous for the Ship2 mutation had increased glucose tolerance and
insulin sensitivity associated with an increased recruitment of the
GLUT4 glucose transporter (138190) and increased glycogen synthesis in
skeletal muscles. Clement et al. (2001) suggested that the results show
that SHIP2 is a potent negative regulator of insulin signaling and
insulin sensitivity in vivo. In an erratum, the authors noted that the
7.3-kb genomic DNA fragment deleted in these mice included, in addition
to exons 19 to 29 of the Ship2 gene, the last exon of the Phox2a gene
(602753); deletion of this exon would give rise to a completely
nonfunctional Phox2a protein if expressed. They stated that it was
unknown whether the insulin sensitivity observed in their mice resulted
from inactivation of either the Ship2 or Phox2a genes alone, or of both
genes.
By targeting the translation-initiating ATG codon and deleting the first
18 exons encoding Inppl1, Sleeman et al. (2005) generated Inppl1 -/-
mice that were null for Inppl1 mRNA and protein. The mice were viable,
had normal glucose and insulin levels, and normal insulin and glucose
tolerances. However, they were highly resistant to weight gain when
placed on a high-fat diet. Sleeman et al. (2005) suggested that INPPL1
mediates obesity resistance but not changes in glucose and insulin
homeostasis.
OR2AT4
| dbSNP name | rs111801887(T,C) |
| ccdsGene name | CCDS31639.1 |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 341152 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AT, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AT4:NM_001005285:exon1:c.A687G:p.S229S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01882 |
| ESP Afr MAF | 0.108864 |
| ESP All MAF | 0.036963 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.009287 |
TPBGL
| dbSNP name | rs72998594(C,G); rs59390914(G,C); rs111408324(G,A) |
| cytoBand name | 11q13.4 |
| EntrezGene GeneID | 100507050 |
| snpEff Gene Name | CTD-2562J17.4 |
| EntrezGene Description | trophoblast glycoprotein-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06979 |
OMP
| dbSNP name | rs2233549(G,A) |
| ccdsGene name | CCDS53682.1 |
| cytoBand name | 11q13.5 |
| EntrezGene GeneID | 4975 |
| EntrezGene Description | olfactory marker protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OMP:NM_006189:exon1:c.G225A:p.P75P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2181 |
| ESP Afr MAF | 0.181943 |
| ESP All MAF | 0.191181 |
| ESP Eur/Amr MAF | 0.195902 |
| ExAC AF | 0.219 |
OMIM Clinical Significance
Mouth:
Odontoma
GI:
Dysphagia
Lab:
Esophageal smooth muscle hypertrophy
Inheritance:
Autosomal dominant
OMIM Title
*164340 OLFACTORY MARKER PROTEIN; OMP
OMIM Description
DESCRIPTION
Olfactory marker protein, a 19-kD cytosolic protein, is uniquely
associated with the mature olfactory receptor neurons of many vertebrate
species (summary by Rogers et al., 1987).
CLONING
Rogers et al. (1987) isolated cDNA clones corresponding to mRNA for rat
OMP. Evans et al. (1993) isolated the human OMP gene.
MAPPING
By molecular genetic mapping of the mouse Omp gene to a series of
radiation-induced albino deletion chromosomes, Rinchik et al. (1992)
established that the gene maps distal to tyrosinase (TYR; 606933) and
proximal to the globin locus, in an interval of approximately 2 cM on
chromosome 7. This analysis placed Omp in the same minimal deletion
interval as the mouse mutant 'shaker-1' (sh-1), an autosomal recessive
deafness mutant with associated circling and head-tossing behavior and
hyperactivity. Homozygotes have abnormalities in eighth-nerve and
cochlear potentials, in the absence of detectable structural changes in
the cochlea. As a prelude to positional cloning of the defect in sh-1,
Brown et al. (1992) undertook to refine its genetic location by RFLV
analysis of an extensive intraspecific backcross segregating for the
sh-1 mutation. Typing for Omp, they observed a single recombinant in
1,000 progeny. This suggested that Omp maps within 200 kb of sh-1 and
may in fact constitute the locus.
Evans et al. (1993) mapped the human OMP gene to chromosome 11q,
immediately centromeric to tyrosinase, by analysis of somatic cell
hybrids carrying derived human chromosomes 11 and by dual hybridization
of interface chromosomes with the TYR and OMP genes.
GENE FUNCTION
To address the function of OMP, which is a cytoplasmic protein expressed
almost exclusively in mature olfactory sensory neurons, Buiakova et al.
(1996) generated OMP-deficient mice by gene targeting in embryonic stem
cells. They found that these OMP-null mice are compromised in their
ability to respond to odor stimuli. The maximal response to several
odorants was 20% to 40% smaller in the mutant than in controls. In
addition, the onset and recovery kinetics following isoamyl acetate
stimulation were prolonged in the null mice. Furthermore, the ability of
the mutants to respond to the second odor pulse of a pair was impaired,
over a range of concentrations. These results implied that neural
activity directed toward the olfactory bulb is also reduced. Bulbar
activity of tyrosine hydroxylase (191290), the rate-limiting enzyme of
catecholamine biosynthesis, and the content of the neuropeptide
cholecystokinin were reduced by 65% and 50%, respectively. Both the
olfactory neuroepithelium and the olfactory nerve projection to the
olfactory bulb could be shown to be reduced in the OMP-null mouse.
Buiakova et al. (1996) concluded that OMP is a novel modulatory
component of the odor detection/signal transduction cascade.
MIR5579
| dbSNP name | rs11237828(T,C) |
| cytoBand name | 11q14.1 |
| EntrezGene GeneID | 100847000 |
| snpEff Gene Name | ODZ4 |
| EntrezGene Description | microRNA 5579 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2585 |
| ExAC AF | 0.068 |
FAM181B
| dbSNP name | rs191303825(T,C); rs3780(C,T) |
| cytoBand name | 11q14.1 |
| EntrezGene GeneID | 220382 |
| EntrezGene Description | family with sequence similarity 181, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
CCDC89
| dbSNP name | rs1237203(C,T); rs290186(G,A); rs290185(T,C) |
| cytoBand name | 11q14.1 |
| EntrezGene GeneID | 220388 |
| snpEff Gene Name | CREBZF |
| EntrezGene Description | coiled-coil domain containing 89 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4242 |
OR7E2P
| dbSNP name | rs117249944(T,A) |
| cytoBand name | 11q14.2 |
| EntrezGene GeneID | 8587 |
| snpEff Gene Name | PRSS23 |
| EntrezGene Description | olfactory receptor, family 7, subfamily E, member 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06703 |
FZD4
| dbSNP name | rs143372848(G,C); rs713065(A,G); rs10898563(A,G); rs4944641(C,G); rs3802892(G,A); rs3740661(T,C) |
| cytoBand name | 11q14.2 |
| EntrezGene GeneID | 8322 |
| snpEff Gene Name | PRSS23 |
| EntrezGene Description | frizzled family receptor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0124 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604579 FRIZZLED, DROSOPHILA, HOMOLOG OF, 4; FZD4
OMIM Description
DESCRIPTION
Members of the 'frizzled' (FZ) gene family (see 606143) encode
7-transmembrane domain proteins that are receptors for Wnt (see Wnt5A;
164975) signaling proteins.
CLONING
By screening a human fetal lung cDNA library with an FZD4 cDNA fragment
isolated from a human gastric cancer cDNA pool, Kirikoshi et al. (1999)
obtained a full-length cDNA of FZD4. FZD4 encodes a deduced 537-amino
acid protein that has a cysteine-rich domain (CRD) in the N-terminal
extracellular region, 2 cysteine residues in the second and third
extracellular loops, 2 extracellular N-linked glycosylation sites, and
the S/T-X-V motif in the C terminus. Amino acid sequence identity with
other FZD proteins ranged from 39 to 52% in the N terminus to 42 to 69%
in the transmembrane domains. Northern blot analysis revealed expression
of a 7.7-kb transcript in large amounts in adult heart, skeletal muscle,
ovary, and fetal kidney, in moderate amounts in adult liver, kidney,
pancreas, spleen, and fetal lung, and in small amounts in placenta,
adult lung, prostate, testis, colon, fetal brain, and liver. Expression
was also strong in HeLa cells but not in several cancer cell lines.
By screening a fetal lung cDNA library using the C terminus of FZD4 as
probe, followed by PCR of a fetal kidney cDNA library, Sagara et al.
(2001) cloned an FZD4 variant, which they called FZD4S. FZD4S is
unspliced and includes exon 1, intron 1, and exon 2. The deduced protein
contains only 125 amino acids due to the introduction of a stop codon
within the retained intron. The N-terminal 98 amino acids of FZD4S are
identical to those of the full-length FZD4 protein, but the last 27
residues are unique. Compared with FZD4, FZD4S retains the N-terminal
signal peptide and the N-terminal part of the CRD, but not the latter
half of the CRD or the 7 transmembrane domains, indicating that FZD4S is
likely to be a soluble protein. Northern blot analysis detected modest
expression of a 10.0-kb mRNA in fetal kidney and faint expression in
adult heart and fetal lung. RNA dot blot analysis detected expression in
adult heart and lung and in fetal kidney and lung.
GENE FUNCTION
Sagara et al. (2001) injected synthetic FZD4S mRNA into the ventral
marginal zone of Xenopus embryos at the 4-cell stage. The injected FZD4S
did not induce axis duplication by itself, but augmented the axis
duplication potential of coinjected Xenopus Wnt8 (see 601396) mRNA.
Sagara et al. (2001) concluded that the FZD4S variant of FZD4 is a
soluble protein that can activate the WNT signaling pathway.
The findings of Robitaille et al. (2002) supported a function for FZD4
in retinal angiogenesis. Robitaille et al. (2002) injected Xenopus
laevis embryos with wildtype and familial exudative vitreoretinopathy
(FEVR; 133780)-associated FZD4 mutants. They found that wildtype FZD4,
but not mutant FZD4, activated CAMK2 (see 114078) and PKC (see 176960),
components of the Wnt/Ca(2+) signaling pathway.
Chen et al. (2003) found that endocytosis of FZD4 in human embryonic
kidney cells was dependent on added WNT5A protein and was accomplished
by the multifunctional adaptor protein beta-arrestin-2 (107941), which
was recruited to FZD4 by binding to phosphorylated dishevelled-2 (DVL2;
602151). The authors concluded that their findings provided a previously
unrecognized mechanism for receptor recruitment of beta-arrestin and
demonstrated that dishevelled plays an important role in the endocytosis
of frizzled, as well as in promoting signaling.
Using a complementation assay, Kaykas et al. (2004) found that FZD4
could form homodimers. It could also form heterodimers with other FZD
proteins, including rat Fzd1 (603408), rat Fzd2 (600667), Xenopus Fzd7
(603410), and human FZD9 (601766). Strongest affinity was displayed by
proteins with similar amino acid sequence. Kaykas et al. (2004) found
that an FEVR-associated FZD4 mutant with a frameshift at leu501
(604579.0002), which does not accumulate at the plasma membrane, was
trapped in the endoplasmic reticulum. Through heterodimerization, this
mutant FZD4 could trap wildtype FZD4 and inhibit its signaling.
Incomplete retinal vascularization occurs in both Norrie disease
(310600) and FEVR. Norrin, the protein product of the NDP gene (300658),
is a secreted protein. One form of FEVR is caused by defects in FZD4, a
presumptive Wnt receptor. Xu et al. (2004) determined that norrin and
FZD4 function as a ligand-receptor pair based on the similarity in
vascular phenotypes caused by norrin and FZD4 mutations in humans and
mice; the specificity and high affinity of norrin-FZD4 binding; the high
efficiency with which norrin induces FZD4- and LRP (see
107770)-dependent activation of the classical Wnt pathway; and the
signaling defects displayed by disease-associated variants of norrin and
FZD4. These data defined a norrin-FZD4 signaling system that plays a
central role in vascular development in the eye and ear, and they
indicated that ligands unrelated to Wnts can act through frizzled
receptors.
Using yeast 2-hybrid assays, Yao et al. (2004) found that PDZ domain 1
of mouse Magi3 (615943) interacted with the C-terminal PDZ-binding
motifs of Fzd4 and Fzd7. PDZ domain 1 also interacted with Ltap (VANGL2;
600533), another planar cell polarity signaling protein. Magi3, Fzd4,
and Ltap independently localized to sites of cell-cell contacts in
epithelial cells, and these 3 proteins interacted in a complex that
required Magi3. Magi3 strongly enhanced Rac (see 602048)-dependent Jnk
(see 601158) activation by Fzd4 and Ltap.
GENE STRUCTURE
Kirikoshi et al. (1999) determined that the FZD4 gene contains 2 exons.
MAPPING
By FISH, Kirikoshi et al. (1999) mapped the FZD4 gene to chromosome
11q14-q21. By positional cloning, Robitaille et al. (2002) mapped the
FZD4 gene to chromosome 11q14.2.
MOLECULAR GENETICS
In affected members of 2 unrelated families with autosomal dominant
familial exudative vitreoretinopathy (EVR1; 133780), Robitaille et al.
(2002) identified 2 different heterozygous deletions in exon 2 of the
FZD4 gene (604579.0001; 604579.0002). Both mutations altered the seventh
transmembrane domain and the intracellular carboxy-terminal tail,
respectively. No mutations in FZD4 were detected in 3 other small
families with FEVR. Robitaille et al. (2002) presented data indicating
that the changes in FZD4 in these families with autosomal dominant FEVR
represented loss-of-function mutations. Following transfection in COS-7
cells, wildtype FZD4 and the FEVR-related FZD4 mutant lacking met493 and
trp494 accumulated at the plasma membrane; however, the mutant
containing the frameshift at leu501 did not.
In an infant with advanced retinopathy of prematurity (see 133780),
MacDonald et al. (2005) identified heterozygosity for a missense
mutation in the FZD4 gene (604579.0006).
GENOTYPE/PHENOTYPE CORRELATIONS
Using a norrin-based reporter assay to analyze the effects of
FEVR-causing mutations, Qin et al. (2008) demonstrated that a nonsense
mutation in FZD4 completely abolished signaling activity, whereas
missense mutations in FZD4 and LRP5 (603506) caused a moderate level of
reduction, and a double missense mutation in both genes caused a severe
reduction in activity, correlating roughly with clinical phenotypes.
Norrin mutants, however, showed variable effects on signal transduction,
and no correlation with clinical phenotypes was observed; norrin mutants
also showed impaired cell surface binding. Qin et al. (2008) concluded
that norrin signaling is involved in FEVR pathogenesis, but suggested
the presence of an unknown parallel pathway at the level of
receptor/ligand binding as evidenced by the moderate and variable signal
reduction lacking a clear genotype/phenotype correlation.
SNORA32
| dbSNP name | rs1944108(A,C) |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 692063 |
| snpEff Gene Name | KIAA1731 |
| EntrezGene Description | small nucleolar RNA, H/ACA box 32 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3558 |
| ESP Afr MAF | 0.235698 |
| ESP All MAF | 0.359413 |
| ESP Eur/Amr MAF | 0.413776 |
| ExAC AF | 0.402 |
MIR1304
| dbSNP name | rs2155248(G,T); rs79462725(G,C) |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 100302240 |
| snpEff Gene Name | KIAA1731 |
| EntrezGene Description | microRNA 1304 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1107 |
| ESP Afr MAF | 0.301487 |
| ESP All MAF | 0.0978 |
| ESP Eur/Amr MAF | 0.008296 |
| ExAC AF | 0.96 |
HEPHL1
| dbSNP name | rs2511403(G,A); rs73568863(G,T); rs7940306(T,A); rs2949865(G,T); rs2949864(T,C); rs1518561(G,A); rs7107851(C,G); rs2460051(C,T); rs2460052(C,T); rs2945633(T,C); rs2462756(A,T); rs2511402(G,A); rs2460053(T,C); rs11020630(C,T); rs2460054(G,A); rs11020631(C,T); rs7944971(G,A); rs4084250(A,G); rs146061757(G,A); rs72966637(A,G); rs1914723(T,C); rs2399749(A,G); rs1518562(C,A); rs10765648(C,G); rs1568259(C,T); rs66538341(G,A); rs11020634(C,A); rs182253093(C,A); rs2460055(G,A); rs117117717(T,A); rs1518563(T,C); rs1518565(C,T); rs1401182(G,C); rs1829371(A,G); rs949452(G,A); rs1518566(G,A); rs1401183(T,G); rs4753115(G,A); rs4753116(T,C); rs4753117(C,T); rs4753118(A,T); rs58116509(C,T); rs2511401(T,C); rs113612050(C,T); rs12362164(T,C); rs16919858(A,G); rs59276869(A,G); rs1945788(A,T); rs11020640(T,C); rs10831159(C,T); rs2511386(A,G); rs67243356(G,A); rs149489030(G,C); rs2460045(T,G); rs113690428(G,A); rs2462755(A,C); rs2462754(A,G); rs4753530(T,C); rs4753120(G,A); rs77717282(C,T); rs1518559(A,T); rs150559512(C,T); rs2462753(T,G); rs1850655(T,C); rs2511379(C,G); rs1984373(G,A); rs1961012(T,C); rs2511378(T,G); rs7945841(G,A); rs2511377(A,C); rs7945945(G,T); rs7946162(G,A); rs2399775(T,C); rs12420636(G,A); rs11020641(G,A); rs11020642(C,T); rs150508311(C,T); rs57953549(T,G); rs182123941(C,T); rs10765649(T,A); rs10831160(T,G); rs7110588(G,A); rs7127348(A,G); rs143031198(C,T); rs10831161(A,G); rs1894167(C,T); rs1401181(G,T); rs2032399(G,A); rs7938136(T,G); rs73551180(C,T); rs4753531(A,G); rs4753532(C,T); rs983328(A,T); rs983327(C,G); rs2460043(T,C); rs1518558(T,C); rs10831162(A,G); rs10831163(C,T); rs2460063(T,C); rs75210572(C,T); rs4753122(T,G); rs1945782(C,T); rs73551201(G,A); rs1945783(A,G); rs1945784(G,A); rs4753534(G,A); rs1894164(T,G); rs11020645(G,A); rs2252036(A,G); rs2511405(A,G); rs10765650(C,T); rs10765651(C,T); rs2511406(A,C); rs76021923(G,C); rs2048980(A,G); rs2511407(A,C); rs10831164(C,T); rs73552910(G,A); rs2511408(A,G); rs2251782(T,G); rs908750(T,A); rs16919902(C,T); rs908751(A,G); rs145542164(G,A); rs73552919(T,C); rs2511409(T,A); rs2460068(A,C); rs7119800(A,T); rs1878799(C,G); rs1878800(T,C); rs148179366(C,A); rs1878801(G,A); rs982543(T,C); rs982544(A,G); rs2176565(G,C); rs7949551(T,C); rs982545(G,A); rs2511410(G,T); rs72968710(C,T); rs115754994(C,T); rs1914725(T,C); rs2949862(C,T); rs75818621(G,A); rs115322931(C,A); rs2945641(A,C); rs16919917(G,A); rs4753123(C,T); rs2226927(T,G); rs116005756(C,T); rs2945637(G,T); rs75302705(C,T); rs2945638(G,A); rs72968720(C,T); rs79449482(G,A); rs79777665(A,C); rs12421996(C,A); rs1401185(G,T); rs2949861(T,C); rs1401186(C,A); rs1356565(G,A); rs2945639(A,G); rs2949860(A,C); rs2945640(G,A); rs150400354(C,A); rs2139093(T,C); rs1829373(G,A); rs3020010(G,A); rs58964858(C,T); rs72968738(G,A); rs112880817(A,G); rs2949858(T,C); rs200450738(G,A); rs2949857(T,G); rs4491178(A,G); rs72968745(A,T); rs2949856(T,C); rs151289653(C,T); rs4753124(C,G); rs74557248(C,T); rs4753535(A,T); rs76900693(T,C); rs145536295(G,A); rs79080786(C,T); rs2949863(T,C); rs138458351(A,G); rs144039313(G,A); rs143082585(C,T); rs375239001(C,T); rs372438222(C,T); rs185488168(C,G); rs4271349(T,G); rs10765652(G,A); rs10831166(A,G); rs10765653(T,C); rs10765654(C,T); rs7942162(A,C); rs7942313(A,T); rs7927016(G,A); rs4408267(G,C); rs142656125(T,C); rs184702288(T,C); rs61905098(G,C); rs146912388(T,C); rs149415595(T,C); rs146065040(A,T); rs79582858(A,T); rs112859892(G,C); rs149931038(C,A); rs16919942(C,T); rs4625415(A,C); rs4531426(T,C); rs7124402(G,C); rs12222234(G,T); rs73554826(A,G); rs138253439(G,A); rs141992470(A,G); rs375940540(C,A); rs10437575(G,T); rs371529327(C,A); rs188335241(T,A); rs146287779(G,T); rs7925817(G,T); rs149715630(A,T); rs139559150(C,T); rs7108501(C,G); rs4644614(A,G); rs151112060(G,C); rs138866382(T,C); rs141998164(G,A); rs116317723(A,C); rs144181517(G,A); rs115539851(C,A); rs145096925(T,C); rs150937433(T,C); rs7116300(G,A); rs115041760(C,A); rs114004842(C,T) |
| ccdsGene name | CCDS44710.1 |
| CosmicCodingMuts gene | HEPHL1 |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 341208 |
| EntrezGene Description | hephaestin-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HEPHL1:NM_001098672:exon7:c.C1294T:p.R432W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9485 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6MZM0 |
| dbNSFP Uniprot ID | HPHL1_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.002163 |
| ESP All MAF | 0.002022 |
| ESP Eur/Amr MAF | 0.001957 |
| ExAC AF | 0.001611 |
FUT4
| dbSNP name | rs7116255(T,C); rs10831240(T,C); rs184210297(C,T); rs10741490(G,A) |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 2526 |
| snpEff Gene Name | PIWIL4 |
| EntrezGene Description | fucosyltransferase 4 (alpha (1,3) fucosyltransferase, myeloid-specific) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06979 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, sensorineural, especially affecting high frequencies
CARDIOVASCULAR:
[Vascular];
Hypertension
GENITOURINARY:
[Kidneys];
Glomerulonephropathy;
Hematuria, gross and microscopic;
Proteinuria;
End-stage renal failure;
Thinning of the glomerular basement membrane (early in the disease);
Thickening of the glomerular basement membrane (later in the disease);
Splitting of the glomerular basement membrane;
Diffuse lamellation of the glomerular basement membrane
LABORATORY ABNORMALITIES:
Hematuria, gross and microscopic;
Proteinuria
MISCELLANEOUS:
Progressive disorder;
Hearing loss is variable
MOLECULAR BASIS:
Caused by mutation in the collagen, type IV, alpha-3 gene (COL4A3,
120070.0009)
OMIM Title
*104230 FUCOSYLTRANSFERASE 4; FUT4
;;ALPHA-3-FUCOSYLTRANSFERASE; FCT3A
OMIM Description
CLONING
In human/mouse myeloid cell hybrids, Geurts van Kessel et al. (1984)
tested for reactivity with monoclonal antibodies with known myelocytic,
monocytic, or myelomonocytic specificity. Twenty antibodies, all of
which bound specifically to the surface of human myeloid cells,
exhibited similar reactivity patterns with the hybrid clones.
Chromosomal analysis showed that the gene or genes involved in
expression of the 1 or more antigens recognized by these antibodies must
be located on human chromosome 11q12-qter. This myeloid-associated
surface antigen was designated CD15 in the CD system.
Tetteroo et al. (1987) found that alpha-3-fucosyltransferase activity
correlated with the presence of human chromosome 11 in human-mouse
myeloid cell hybrids. Also, several other myeloid-associated
carbohydrate antigens, e.g., LeX (CD15), were associated with chromosome
11. Tetteroo et al. (1987) concluded that an alpha-3-fucosyltransferase
gene on chromosome 11 is responsible for synthesis of these antigens.
Couillin et al. (1991) identified an alpha-3-fucosyltransferase on
chromosome 11q, FUT4, that transferred fucose onto H type 2 more
efficiently than onto sialyl-N-acetyllactosamine, suggesting that it is
the myeloid type of alpha-3-fucosyltransferase that makes the
3-fucosyllactosamine epitope (CD15) on polymorphonuclear cells and
monocytes.
Of the fucosyltranstransferases examined by Cailleau-Thomas et al.
(2000), only FUT4 and FUT9 (606865) were expressed during human
embryogenesis; all of the others showed irregular or weak expression. By
Northern blot analysis of 40- to 70-day-old embryos, they found
increasing expression of 6-, 3-, and 2.3-kb FUT4 transcripts. Analysis
of fetal tissues revealed abundant expression in liver, muscle, kidney,
skin, and small intestine, and moderate expression in brain, lung, and
heart. The transcript size varied in different tissues. In adult
tissues, highest expression was found in lung and small intestine, low
expression in kidney, liver, and brain, and no expression in 12 other
tissues tested.
GENE FUNCTION
Nakayama et al. (2001) showed that FUT9 directs CD15 synthesis in
lymphoid cells and mature granulocytes, whereas FUT4 directs CD15
synthesis in promyelocytes and monocytes. FUT9 exhibited stronger
activity for CD15 synthesis than FUT4.
MAPPING
Using human/mouse hybrid cell lines, Couillin et al. (1991) mapped a
human alpha-3-fucosyltransferase, FUT4, to chromosome 11q. Using panels
of somatic cell and radiation hybrids which retained different
rearrangements of chromosome 11, Reguigne et al. (1994) assigned the
FUT4 gene to chromosome 11q21, between D11S388 and D11S919. Using
fluorescence in situ hybridization and a cosmid containing FUT4
sequence, McCurley et al. (1995) confirmed the assignment of the FUT4
gene to chromosome 11q21.
Gersten et al. (1995) demonstrated that the mouse Fut4 gene maps to
chromosome 9 in a region showing syntenic homology with human 11q.
KDM4E
| dbSNP name | rs62617142(A,G); rs138237692(T,A) |
| ccdsGene name | CCDS44713.1 |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 390245 |
| snpEff Gene Name | KDM4DL |
| EntrezGene Description | lysine (K)-specific demethylase 4E |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KDM4E:NM_001161630:exon1:c.A260G:p.H87R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0463 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B2RXH2 |
| dbNSFP Uniprot ID | KD4DL_HUMAN |
| dbNSFP KGp1 AF | 0.010989010989 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0303867403315 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0158311345646 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.00289 |
| ESP All MAF | 0.009198 |
| ESP Eur/Amr MAF | 0.011942 |
| ExAC AF | 0.013 |
SRSF8
| dbSNP name | rs2922090(G,A); rs115139429(G,A); rs1056986(G,A); rs12627(C,A); rs681695(G,C); rs78054640(C,A); rs681134(A,G); rs680673(A,T); rs111245641(T,A); rs77879132(G,T) |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 10929 |
| EntrezGene Description | serine/arginine-rich splicing factor 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)
ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism
LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration
MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)
MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)
OMIM Title
*603269 SPLICING FACTOR, SERINE/ARGININE-RICH, 8; SRSF8
;;SERINE/ARGININE-RICH SPLICING FACTOR 8;;
SPLICING FACTOR, ARGININE/SERINE-RICH, 2B; SFRS2B;;
SPLICING FACTOR, ARGININE/SERINE-RICH, 46-KD; SRp46
OMIM Description
CLONING
The highly conserved SR family contains phosphoproteins that act as both
essential and alternative splicing factors. See 600812. By screening a
genomic library with a fragment of the PR264, or SC35, gene (SFRS2;
600813), Soret et al. (1998) isolated clones of the SRp46 gene. Based on
sequence and gene structure analyses, the authors concluded that SRp46
is likely a processed PR264 pseudogene. Northern and Western blot
analyses revealed that SRp46 is expressed in several human cell lines
and tissues. While monkey cells express SRp46 sequences, mice do not
have an SRp46 homolog. The predicted human SRp46 protein has 282 amino
acids and a calculated molecular mass of 35 kD. However, SRp46 migrated
as a 46-kD protein on Western blots of HeLa cell nuclear extracts; Soret
et al. (1998) noted that SR proteins generally exhibit abnormal gel
mobility, due mainly to extensive phosphorylation of serine residues.
GENE FUNCTION
Soret et al. (1998) demonstrated that SRp46 functions as an essential
splicing factor in vitro. However, SRp46 did not display the same
activity as PR264. Soret et al. (1998) concluded that SRp46 is a novel
member of the SR family that is encoded by a functional retropseudogene.
MAPPING
By fluorescence in situ hybridization, Soret et al. (1998) mapped the
SRp46 gene to chromosome 11q22.
JRKL
| dbSNP name | rs78994203(C,T); rs11549459(G,T); rs4753751(A,G) |
| cytoBand name | 11q21 |
| EntrezGene GeneID | 8690 |
| EntrezGene Description | jerky homolog-like (mouse) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.06612 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Seizures, focal, partial, motor;
Seizures, diurnal partial, rare (in some patients);
Frontal lobe origin;
Nocturnal occurrence, usually during light sleep;
Generalized tonic-clonic seizures (rare);
Vocalizations;
Dystonic posturing;
Hypermotor automatisms;
Seizures occur in clusters;
Status epilepticus (in some);
[Behavioral/psychiatric manifestations];
Behavioral disturbances (in some);
Aggression (in some patients);
Depression (in some patients)
MISCELLANEOUS:
One family has been reported (last curated January 2013);
Onset in childhood;
Seizures may be refractory;
May be misdiagnosed as nightmares, night terrors, parasomnias, or
psychiatric disorders
OMIM Title
*603211 JERKY, MOUSE, HOMOLOG-LIKE; JRKL
;;HHMJG
OMIM Description
CLONING
Zeng et al. (1997) identified a human tonsil cDNA encoding a protein
similar to mouse 'jerky;' see 603210. They designated the predicted
442-amino acid protein HHMJG (human homolog of mouse jerky gene). The
HHMJG and mouse jerky proteins are 35% identical. Northern blot analysis
revealed that HHMJG is abundantly expressed as a 4-kb mRNA in various
tissues. In testis, an additional 2-kb transcript is present.
MAPPING
By fluorescence in situ hybridization, Zeng et al. (1997) mapped the
HHMJG gene to chromosome 11q21.
TMEM133
| dbSNP name | rs515552(A,G); rs471933(C,A); rs535443(T,C); rs488365(G,A); rs17096029(A,G) |
| ccdsGene name | CCDS8309.1 |
| cytoBand name | 11q22.1 |
| EntrezGene GeneID | 83935 |
| EntrezGene Description | transmembrane protein 133 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM133:NM_032021:exon1:c.A57G:p.E19E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3531 |
| ESP Afr MAF | 0.134362 |
| ESP All MAF | 0.18453 |
| ESP Eur/Amr MAF | 0.210233 |
| ExAC AF | 0.315 |
DDI1
| dbSNP name | rs7102675(G,A); rs1052313(G,A); rs2279789(C,T); rs260808(C,A); rs4754098(A,G) |
| ccdsGene name | CCDS31660.1 |
| cytoBand name | 11q22.3 |
| EntrezGene GeneID | 414301 |
| EntrezGene Description | DNA-damage inducible 1 homolog 1 (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DDI1:NM_001001711:exon1:c.G406A:p.G136S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WTU0 |
| dbNSFP Uniprot ID | DDI1_HUMAN |
| dbNSFP KGp1 AF | 0.0851648351648 |
| dbNSFP KGp1 Afr AF | 0.130081300813 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.0157342657343 |
| dbNSFP KGp1 Eur AF | 0.135883905013 |
| dbSNP GMAF | 0.0854 |
| ESP Afr MAF | 0.138965 |
| ESP All MAF | 0.120366 |
| ESP Eur/Amr MAF | 0.11084 |
| ExAC AF | 0.095 |
C11orf87
| dbSNP name | rs7116461(A,G); rs4403771(T,G) |
| cytoBand name | 11q22.3 |
| EntrezGene GeneID | 399947 |
| EntrezGene Description | chromosome 11 open reading frame 87 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3829 |
COLCA1
| dbSNP name | rs11213821(T,C); rs7103178(C,T); rs10891244(G,T); rs4512891(C,T); rs12296076(G,A); rs61764070(C,T); rs147884428(C,T); rs6589218(A,C); rs7944895(C,G); rs10891245(T,G); rs11213822(G,A); rs12273385(C,T) |
| cytoBand name | 11q23.1 |
| EntrezGene GeneID | 399948 |
| snpEff Gene Name | C11orf92 |
| EntrezGene Description | colorectal cancer associated 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2925 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial nerve palsies;
[Eyes];
Ophthalmoplegia;
Optic atrophy (1 patient)
CARDIOVASCULAR:
[Vascular];
Stroke, ischemic;
Stroke, hemorrhagic;
Small-vessel disease;
Polyarteritis nodosa;
Aneurysms;
Stenosis;
Hypertension (in some patients)
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Gastrointestinal pain
GENITOURINARY:
[Kidneys];
Renal artery aneurysms
SKELETAL:
Arthritis;
[Hands];
Ischemic digital necrosis;
[Feet];
Ischemic digital necrosis
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa;
Livedo reticularis;
Erythema nodosum;
Urticarial rash;
Purpura;
HISTOLOGY:;
Vasculitis in the reticular dermis;
Inflammatory infiltrate;
Interstitial neutrophils and macrophages;
Perivascular T lymphocytes;
Leukocytoclastic vasculitis;
Panniculitis
MUSCLE, SOFT TISSUE:
Myalgia
NEUROLOGIC:
[Central nervous system];
Neurologic sequelae of stroke;
Altered mental status;
Hemiplegia;
Headache;
Ataxia;
Agitation;
Cranial nerve dysfunction;
Aphasia;
Lacunar infarcts in the deep-brain nuclei, brainstem, internal capsule
seen on imaging;
[Peripheral nervous system];
Raynaud phenomenon;
Neuropathy
METABOLIC FEATURES:
Fever, recurrent
HEMATOLOGY:
Lupus anticoagulant (in some patients);
Anemia (in some patients);
Thrombocytosis (in some patients)
IMMUNOLOGY:
Immunodeficiency;
Hypogammaglobulinemia (in some patients);
Leukopenia;
Leukocytosis
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Acute-phase reactants during fever
MISCELLANEOUS:
Variable age at onset, usually in first decade, but can occur later;
Variable manifestations;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0001)
OMIM Title
*615693 COLCA1 GENE; COLCA1
;;COLORECTAL CANCER-ASSOCIATED GENE 1
OMIM Description
DESCRIPTION
COLCA1 and COLCA2 (615694) are coregulated genes transcribed from
opposite strands of a region of chromosome 11q23 associated with colon
cancer (CRCS7; 612232) (Peltekova et al., 2014).
CLONING
Peltekova et al. (2014) used microarray-based target selection and
sequencing to interrogate 103 kb of DNA at the chromosome 11q23
colorectal cancer locus (CRCS7) tagged by the SNP dbSNP rs3802842. They
identified COLCA1 and COLCA2, which are arranged on opposite strands of
11q23 and have a shared regulatory region containing variants in high
linkage disequilibrium with dbSNP rs3802842. COLCA1 has multiple
alternative 5-prime noncoding exons and a constant exon encoding a
124-amino acid protein with a signal peptide, a transmembrane domain,
and O-linked glycosylation sites. COLCA1 RNA was expressed in
gastrointestinal and immune tissue, as well as prostate, testis, and
ovary. Immunohistochemical analysis of colon tissues demonstrated COLCA1
expression in lamina propria and eosinophils, but not epithelial cells.
Eosinophils stimulated to differentiate expressed heavily glycosylated
COLCA1, typical of granule-associated proteins. Differential
centrifugation studies showed an association of COLCA1 with membrane
proteins.
GENE FUNCTION
Using Western blot analysis, Peltekova et al. (2014) found that COLCA1
expression was greater in benign adjacent tissues than in colon tumors.
Tissue microarray analysis showed an association of dbSNP rs3803842,
which tags the CRCS7 locus, with lymphocyte density in the lamina
propria and levels of COLCA1 in the lamina propria. Peltekova et al.
(2014) concluded that genetic, expression, and immunohistochemical data
implicate COLCA1 in the pathogenesis of colon cancer.
GENE STRUCTURE
Peltekova et al. (2014) determined that the COLCA1 gene has multiple
alternative 5-prime exons and 1 constant coding exon.
MAPPING
Peltekova et al. (2014) stated that the COLCA1 and COLCA2 genes map to
opposite strands of chromosome 11q23, where they share a regulatory
region.
DIXDC1
| dbSNP name | rs115898460(A,G); rs57753115(G,C); rs1320664(A,G); rs7127153(A,T); rs149116128(G,A); rs138924749(G,T); rs74449703(C,T); rs57483872(A,C); rs35759638(C,G); rs10891301(C,T); rs79090684(A,G); rs76914092(C,T); rs73560062(C,T); rs150113118(G,A); rs145533889(G,A); rs11214048(C,G); rs12225443(A,C); rs80210185(G,A); rs73560065(G,C); rs11214049(A,G); rs4554921(T,C); rs61625528(C,T); rs7945387(C,T); rs35440570(T,C); rs113890495(G,A); rs491535(G,C); rs112622111(G,A); rs111332504(G,A); rs79864540(A,G); rs138811135(C,G); rs141989379(G,C); rs111510375(G,A); rs148416996(G,C); rs186291859(A,G); rs147600086(A,G); rs58970314(A,T); rs145048765(C,A); rs2105619(G,T); rs73560079(C,T); rs12795123(T,G); rs61111688(C,T); rs181785765(T,A); rs192689207(A,G); rs115837286(C,T); rs1784678(G,A); rs60052476(G,A); rs145395551(C,A); rs57670105(A,T); rs116927592(C,T); rs113225469(G,C); rs114492987(C,T); rs57903733(T,C); rs73560089(C,T); rs77905936(C,T); rs73560092(G,C); rs115058855(A,G); rs116266154(G,C); rs150355661(T,C); rs116838775(A,G); rs114431227(C,A); rs78438780(C,T); rs150670145(T,C); rs60241330(T,G); rs3809033(C,A); rs1939528(G,A); rs143529159(G,A); rs10891303(C,T); rs145262774(G,A); rs11821811(C,T); rs144413940(G,T); rs191364649(T,C); rs501932(G,A); rs116837264(C,T); rs531227(C,G); rs116608808(A,G); rs140987896(A,G); rs34575249(A,G); rs10789854(G,C); rs77595475(A,G); rs112682241(T,A); rs6589257(G,C); rs141649815(C,A); rs7926696(T,C); rs479658(A,C); rs2851187(C,T); rs114953862(G,A); rs142288954(T,A); rs4935890(C,T); rs489417(A,G); rs148367662(A,G); rs79715161(C,T); rs7935715(A,T); rs140140857(T,C); rs116468463(A,G); rs10789855(C,G); rs113324773(A,G); rs149184384(A,C); rs60894038(T,C); rs58084586(A,G); rs10891306(G,C); rs58502735(C,T); rs142797842(C,T); rs61196156(A,G); rs57441013(G,A); rs142112426(A,C); rs78621820(C,T); rs57528425(A,C); rs139431732(C,T); rs370201686(A,G); rs524756(G,A); rs189019179(T,A); rs35823624(G,A); rs10789856(C,T); rs59319760(A,T); rs57398568(A,T); rs2081510(T,C); rs2081508(C,T); rs149534010(A,G); rs144986838(G,A); rs140540699(C,T); rs146567773(A,T); rs141303628(G,A); rs113357296(G,A); rs115052354(A,G); rs144826212(A,G); rs187386759(C,T); rs7123284(G,A); rs60745024(T,C); rs650461(C,G); rs476581(C,T); rs79246884(C,T); rs10891310(A,C); rs9971485(G,C); rs606721(G,A); rs1130025(C,T) |
| cytoBand name | 11q23.1 |
| EntrezGene GeneID | 85458 |
| EntrezGene Description | DIX domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DIXDC1:NM_001278542:exon3:c.C92T:p.A31V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.683 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q155Q3 |
| dbNSFP Uniprot ID | DIXC1_HUMAN |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0243902439024 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.021627 |
| ESP All MAF | 0.006986 |
| ESP Eur/Amr MAF | 0.000121 |
| ExAC AF | 0.002402 |
LINC00900
| dbSNP name | rs11215675(G,A); rs141128939(T,C) |
| cytoBand name | 11q23.3 |
| EntrezGene GeneID | 283143 |
| snpEff Gene Name | CTC-774J1.2 |
| EntrezGene Description | long intergenic non-protein coding RNA 900 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06474 |
RNF26
| dbSNP name | rs12797083(T,C); rs12795576(A,G); rs2511841(G,A); rs2248863(G,A); rs2248853(C,T) |
| cytoBand name | 11q23.3 |
| EntrezGene GeneID | 79102 |
| snpEff Gene Name | C1QTNF5 |
| EntrezGene Description | ring finger protein 26 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3251 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps with exercise;
Muscle pain with exercise;
Muscle stiffness with exercise;
Muscle hyperirritability;
Muscle hypertrophy;
Muscle mounding;
Muscle activity is electrically silent on EMG;
Percussion-induced rapid rolling muscle contractions (PIRC);
Decreased caveolin-3 expression on muscle biopsy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Mean age of onset 22 years (range 5-54);
Genetic heterogeneity (see RMD1, 600332);
Autosomal recessive inheritance has been reported (see 601253.0010);
Allelic disorder to limb girdle muscular dystrophy type 1C (LGMD1C,
607801)
MOLECULAR BASIS:
Caused by mutations in the caveolin 3 gene (CAV3, 601253.0001)
OMIM Title
*606130 RING FINGER PROTEIN 26; RNF26
OMIM Description
DESCRIPTION
The RING finger motif is a distinct zinc-chelating domain involved in
mediating protein-DNA and protein-protein interactions. RING finger
proteins are involved in a variety of functions such as oncogenesis,
signal transduction, peroxisome biogenesis, viral infection,
development, transcriptional repression, and ubiquitination. RNF26 is a
member of the C3HC5 RING finger subfamily.
CLONING
By use of a genomic fragment from a chromosome 11q23 contig and EST
database searching, Katoh (2001) cloned an RNF26 cDNA encoding a deduced
433-amino acid protein with an N-terminal leucine zipper domain and a
C-terminal RING finger domain. Its RING finger domain is 49% homologous
to that of CGR19 (606138), another C3HC5 RING finger protein. Northern
blot analysis detected ubiquitous expression of a 3.2-kb transcript in
adult and fetal human tissues. Expression of RNF26 was upregulated in
various human cancer cell lines, including promyelocytic leukemia,
cervical uterine cancer, colorectal cancer, and gastric cancer cell
lines, and in 3 of 6 primary gastric cancers.
MAPPING
By sequence analysis, Katoh (2001) mapped the RNF26 gene to chromosome
11q23.
C1QTNF5
| dbSNP name | rs9640(T,A) |
| cytoBand name | 11q23.3 |
| EntrezGene GeneID | 114902 |
| snpEff Gene Name | MFRP |
| EntrezGene Description | C1q and tumor necrosis factor related protein 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1616 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low weight;
[Other];
Intrauterine growth retardation;
Poor growth
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Deafness, sensorineural;
[Eyes];
Ptosis
SKELETAL:
Delayed bone age;
Osteopenia;
[Hands];
Clinodactyly
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Mental retardation;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Short attention span
LABORATORY ABNORMALITIES:
Increased serum growth hormone;
Decreased serum insulin-like growth factor-1 (IGF1)
MISCELLANEOUS:
Onset in utero
MOLECULAR BASIS:
Caused by mutation in the insulin-like growth factor-1 gene (IGF1,
147440.0001)
OMIM Title
*608752 C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 5; C1QTNF5
;;CTRP5
OMIM Description
DESCRIPTION
The CTRP5 protein is a member of the C1q (see 120550)/tumor necrosis
factor (191160) superfamily, which shows diverse functions including
cell adhesion and basement membrane components (Shapiro and Scherer,
1998).
CLONING
CTRP5 was identified by Agarwal et al. (1995) in a cDNA library enriched
for genes showing expression specific for the retinal pigment epithelium
(RPE). Hayward et al. (2003) determined that the CTRP5 gene encodes a
281-amino acid protein. RT-PCR demonstrated CTRP5 expression in RPE,
liver, lung, placenta, and brain. The 25-kD CTRP5 protein contains an
N-terminal signal domain, followed by a short-chain collagen domain and
a C-terminal C1q domain, which is essential to nucleation of triple
helix formation.
GENE STRUCTURE
Hayward et al. (2003) determined that the CTRP5 gene consists of 3 exons
that generate a 1.8-kb transcript. It is contained within the 3-prime
untranslated region of exon 13 of the MFRP gene (606227). CTRP5 is
present in the same orientation as MFRP, and both genes are expressed as
a bicistronic transcript.
MAPPING
The CTRP5 gene lies within the 3-prime untranslated region of the MFRP
gene, which maps to 11q23 (Katoh, 2001). Hayward et al. (2003)
identified the CTRP5 gene within the 9-Mb region on chromosome 11q23.3
associated with late-onset retinal degeneration (LORD; 605670).
GENE FUNCTION
Hayward et al. (2003) observed that CTRP5 and MFRP interact directly in
a yeast 2-hybrid system. Other observations suggested that CTRP5 is
secreted by the RPE and is a constituent of the Bruch membrane. On the
basis of similarity to COL7A1 (120120) and COL10A1 (120110), Hayward et
al. (2003) hypothesized that CTRP5 may form an extracellular hexagonal
lattice, facilitating the adhesion of basal RPE to Bruch membrane.
MOLECULAR GENETICS
In 7 of 14 families with late-onset retinal degeneration (LORD; 605670),
Hayward et al. (2003) described a proposed founder mutation in the CTRP5
gene that changed a highly conserved serine to arginine (S163R;
608752.0001) in the globular C1q domain of the protein. The mutation
resulted in abnormal high molecular weight aggregate formation, which
may alter the higher order protein structure and interactions of CTRP5.
The authors proposed a novel disease mechanism involving abnormal
adhesion between the RPE and Bruch membrane.
LOC341056
| dbSNP name | rs7933723(G,T); rs1461492(G,C); rs1461493(C,A); rs146417696(C,T); rs140258000(C,G) |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 341056 |
| snpEff Gene Name | RP11-335F8.2 |
| EntrezGene Description | SUMO1 activating enzyme subunit 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1956 |
OR6X1
| dbSNP name | rs74789559(G,C); rs75836681(T,C); rs150562903(A,G); rs12364099(G,T) |
| ccdsGene name | CCDS31695.1 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 390260 |
| EntrezGene Description | olfactory receptor, family 6, subfamily X, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6X1:NM_001005188:exon1:c.C843G:p.P281P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01423 |
| ESP Afr MAF | 0.050863 |
| ESP All MAF | 0.017382 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 4.863e-03,8.132e-06 |
OR6M1
| dbSNP name | rs4936845(G,T); rs76301014(G,A); rs7952150(G,A); rs113975075(G,A); rs78453655(G,A) |
| ccdsGene name | CCDS31696.1 |
| CosmicCodingMuts gene | OR6M1 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 390261 |
| EntrezGene Description | olfactory receptor, family 6, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6M1:NM_001005325:exon1:c.C827A:p.T276K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGM8 |
| dbNSFP Uniprot ID | OR6M1_HUMAN |
| dbNSFP KGp1 AF | 0.240842490842 |
| dbNSFP KGp1 Afr AF | 0.109756097561 |
| dbNSFP KGp1 Amr AF | 0.259668508287 |
| dbNSFP KGp1 Asn AF | 0.281468531469 |
| dbNSFP KGp1 Eur AF | 0.286279683377 |
| dbSNP GMAF | 0.2406 |
| ESP Afr MAF | 0.122616 |
| ESP All MAF | 0.23904 |
| ESP Eur/Amr MAF | 0.298674 |
| ExAC AF | 0.277 |
OR8D4
| dbSNP name | rs17127947(T,G); rs17127950(A,G); rs7926767(G,A); rs10790610(T,C); rs61748875(T,C); rs7942047(T,C); rs7927385(G,A); rs111834679(A,G) |
| ccdsGene name | CCDS31698.1 |
| CosmicCodingMuts gene | OR8D4 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 338662 |
| EntrezGene Description | olfactory receptor, family 8, subfamily D, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8D4:NM_001005197:exon1:c.T164G:p.L55R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGM9 |
| dbNSFP Uniprot ID | OR8D4_HUMAN |
| dbNSFP KGp1 AF | 0.185897435897 |
| dbNSFP KGp1 Afr AF | 0.270325203252 |
| dbNSFP KGp1 Amr AF | 0.157458563536 |
| dbNSFP KGp1 Asn AF | 0.131118881119 |
| dbNSFP KGp1 Eur AF | 0.186015831135 |
| dbSNP GMAF | 0.186 |
| ESP Afr MAF | 0.245459 |
| ESP All MAF | 0.208968 |
| ESP Eur/Amr MAF | 0.190277 |
| ExAC AF | 0.177 |
OR4D5
| dbSNP name | rs142085712(A,T) |
| ccdsGene name | CCDS31699.1 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 219875 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D5:NM_001001965:exon1:c.A524T:p.D175V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0015 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN0 |
| dbNSFP Uniprot ID | OR4D5_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.004314 |
| ESP All MAF | 0.001461 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0004635 |
OR6T1
| dbSNP name | rs12274518(G,A) |
| ccdsGene name | CCDS31700.1 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 219874 |
| EntrezGene Description | olfactory receptor, family 6, subfamily T, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6T1:NM_001005187:exon1:c.C631T:p.L211L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.009642 |
| ESP Afr MAF | 0.036558 |
| ESP All MAF | 0.012383 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.003277 |
OR10S1
| dbSNP name | rs55944888(A,G); rs17686210(T,C); rs17759513(C,T) |
| ccdsGene name | CCDS31701.1 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 219873 |
| EntrezGene Description | olfactory receptor, family 10, subfamily S, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10S1:NM_001004474:exon1:c.T926C:p.V309A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN2 |
| dbNSFP Uniprot ID | O10S1_HUMAN |
| dbNSFP KGp1 AF | 0.125457875458 |
| dbNSFP KGp1 Afr AF | 0.0325203252033 |
| dbNSFP KGp1 Amr AF | 0.17955801105 |
| dbNSFP KGp1 Asn AF | 0.118881118881 |
| dbNSFP KGp1 Eur AF | 0.164907651715 |
| dbSNP GMAF | 0.1253 |
| ESP Afr MAF | 0.075386 |
| ESP All MAF | 0.137363 |
| ESP Eur/Amr MAF | 0.169109 |
| ExAC AF | 0.156 |
OR10G4
| dbSNP name | rs79057843(C,T); rs11219407(A,G); rs1893766(A,G); rs4936880(A,G); rs61908597(G,A) |
| ccdsGene name | CCDS31702.1 |
| CosmicCodingMuts gene | OR10G4 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 390264 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G4:NM_001004462:exon1:c.C26T:p.A9V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN3 |
| dbNSFP Uniprot ID | O10G4_HUMAN |
| dbNSFP KGp1 AF | 0.277014652015 |
| dbNSFP KGp1 Afr AF | 0.193089430894 |
| dbNSFP KGp1 Amr AF | 0.325966850829 |
| dbNSFP KGp1 Asn AF | 0.222027972028 |
| dbNSFP KGp1 Eur AF | 0.349604221636 |
| dbSNP GMAF | 0.2769 |
| ESP Afr MAF | 0.298138 |
| ESP All MAF | 0.383864 |
| ESP Eur/Amr MAF | 0.427774 |
| ExAC AF | 0.401 |
OR10G9
| dbSNP name | rs79715120(C,T); rs77206991(G,T); rs79417294(C,G); rs115910557(A,G); rs61908612(G,A) |
| ccdsGene name | CCDS31703.1 |
| CosmicCodingMuts gene | OR10G9 |
| cytoBand name | 11q24.1 |
| EntrezGene GeneID | 219870 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G9:NM_001001953:exon1:c.C26T:p.A9V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN4 |
| dbNSFP Uniprot ID | O10G9_HUMAN |
| dbNSFP KGp1 AF | 0.122710622711 |
| dbNSFP KGp1 Afr AF | 0.223577235772 |
| dbNSFP KGp1 Amr AF | 0.190607734807 |
| dbNSFP KGp1 Asn AF | 0.145104895105 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.1221 |
| ESP Afr MAF | 0.167651 |
| ESP All MAF | 0.059154 |
| ESP Eur/Amr MAF | 0.003605 |
| ExAC AF | 0.056 |
OR10G8
| dbSNP name | rs75994039(A,G); rs79870106(G,A); rs28711441(T,C); rs75240316(C,T) |
| ccdsGene name | CCDS31704.1 |
| CosmicCodingMuts gene | OR10G8 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 219869 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G8:NM_001004464:exon1:c.A365G:p.Y122C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0013 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN5 |
| dbNSFP Uniprot ID | O10G8_HUMAN |
| dbNSFP KGp1 AF | 0.0796703296703 |
| dbNSFP KGp1 Afr AF | 0.0508130081301 |
| dbNSFP KGp1 Amr AF | 0.165745856354 |
| dbNSFP KGp1 Asn AF | 0.145104895105 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.07989 |
| ESP Afr MAF | 0.043617 |
| ESP All MAF | 0.016615 |
| ESP Eur/Amr MAF | 0.002791 |
| ExAC AF | 0.043 |
OR10G7
| dbSNP name | rs59358830(G,T); rs513591(G,C); rs472442(T,C); rs11827843(G,A); rs3894197(G,C) |
| ccdsGene name | CCDS31705.1 |
| CosmicCodingMuts gene | OR10G7 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 390265 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G7:NM_001004463:exon1:c.C610A:p.L204I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGN6 |
| dbNSFP Uniprot ID | O10G7_HUMAN |
| dbNSFP KGp1 AF | 0.0837912087912 |
| dbNSFP KGp1 Afr AF | 0.0609756097561 |
| dbNSFP KGp1 Amr AF | 0.165745856354 |
| dbNSFP KGp1 Asn AF | 0.152097902098 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.08402 |
| ESP Afr MAF | 0.050682 |
| ESP All MAF | 0.019157 |
| ESP Eur/Amr MAF | 0.003024 |
| ExAC AF | 0.043,1.626e-04 |
OR8G2
| dbSNP name | rs10893172(C,G); rs11219508(T,C); rs2466615(A,C); rs2466614(A,G); rs11825213(C,T); rs2466613(G,A); rs2512268(T,C); rs2466612(G,A) |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 26492 |
| snpEff Gene Name | AP002965.1 |
| EntrezGene Description | olfactory receptor, family 8, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8G2:NM_001291438:exon1:c.C17G:p.S6C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3944 |
| ESP Afr MAF | 0.457784 |
| ESP All MAF | 0.393587 |
| ESP Eur/Amr MAF | 0.325291 |
| ExAC AF | 0.373 |
OR8G5
| dbSNP name | rs2466637(G,A); rs62622834(G,A); rs2512167(G,A); rs2466701(C,T); rs2512166(A,G); rs10893192(A,G) |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 219865 |
| snpEff Gene Name | OR8G7P |
| EntrezGene Description | olfactory receptor, family 8, subfamily G, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8G5:NM_001005198:exon1:c.G21A:p.G7G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4991 |
| ESP Afr MAF | 0.338816 |
| ESP All MAF | 0.482125 |
| ESP Eur/Amr MAF | 0.453776 |
| ExAC AF | 0.485,8.192e-06 |
OR8D1
| dbSNP name | rs4936918(C,T); rs4936919(A,G); rs7107539(A,C); rs6590057(G,A) |
| ccdsGene name | CCDS31706.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 283159 |
| EntrezGene Description | olfactory receptor, family 8, subfamily D, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8D1:NM_001002917:exon1:c.G828A:p.V276V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3398 |
| ESP Afr MAF | 0.213766 |
| ESP All MAF | 0.332692 |
| ESP Eur/Amr MAF | 0.39358 |
| ExAC AF | 0.337 |
OR8D2
| dbSNP name | rs2466620(G,A); rs2512219(C,T); rs61735123(G,A) |
| ccdsGene name | CCDS31707.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 283160 |
| EntrezGene Description | olfactory receptor, family 8, subfamily D, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8D2:NM_001002918:exon1:c.C788T:p.P263L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9GZM6 |
| dbNSFP Uniprot ID | OR8D2_HUMAN |
| dbNSFP KGp1 AF | 0.238095238095 |
| dbNSFP KGp1 Afr AF | 0.455284552846 |
| dbNSFP KGp1 Amr AF | 0.196132596685 |
| dbNSFP KGp1 Asn AF | 0.216783216783 |
| dbNSFP KGp1 Eur AF | 0.133245382586 |
| dbSNP GMAF | 0.2374 |
| ESP Afr MAF | 0.423217 |
| ESP All MAF | 0.241615 |
| ESP Eur/Amr MAF | 0.148639 |
| ExAC AF | 0.206 |
OR8B4
| dbSNP name | rs4057749(A,G); rs7116575(C,A); rs4057750(A,G); rs10750270(T,C) |
| ccdsGene name | CCDS31710.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 283162 |
| EntrezGene Description | olfactory receptor, family 8, subfamily B, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8B4:NM_001005196:exon1:c.T532C:p.C178R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RC9 |
| dbNSFP Uniprot ID | OR8B4_HUMAN |
| dbNSFP KGp1 AF | 0.265567765568 |
| dbNSFP KGp1 Afr AF | 0.506097560976 |
| dbNSFP KGp1 Amr AF | 0.196132596685 |
| dbNSFP KGp1 Asn AF | 0.187062937063 |
| dbNSFP KGp1 Eur AF | 0.201846965699 |
| dbSNP GMAF | 0.2654 |
| ESP Afr MAF | 0.389368 |
| ESP All MAF | 0.283077 |
| ESP Eur/Amr MAF | 0.228658 |
| ExAC AF | 0.238 |
OR8B8
| dbSNP name | rs1893135(G,A); rs4296049(A,G); rs150153041(G,T) |
| ccdsGene name | CCDS8446.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 26493 |
| EntrezGene Description | olfactory receptor, family 8, subfamily B, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8B8:NM_012378:exon1:c.C126A:p.N42K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6459 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q15620 |
| dbNSFP Uniprot ID | OR8B8_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.001 |
| ESP Eur/Amr MAF | 0.001396 |
| ExAC AF | 6.587e-04,8.132e-06 |
OR8B12
| dbSNP name | rs61745407(G,A); rs61746453(C,T) |
| ccdsGene name | CCDS31711.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 219858 |
| EntrezGene Description | olfactory receptor, family 8, subfamily B, member 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8B12:NM_001005195:exon1:c.C821T:p.S274F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGG6 |
| dbNSFP Uniprot ID | OR8BC_HUMAN |
| dbNSFP KGp1 AF | 0.0173992673993 |
| dbNSFP KGp1 Afr AF | 0.0731707317073 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01699 |
| ESP Afr MAF | 0.062699 |
| ESP All MAF | 0.021385 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.005619 |
OR8A1
| dbSNP name | rs55861866(C,G); rs12792184(C,T); rs116716423(G,A) |
| ccdsGene name | CCDS31712.1 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 390275 |
| EntrezGene Description | olfactory receptor, family 8, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR8A1:NM_001005194:exon1:c.C398G:p.T133R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGG7 |
| dbNSFP Uniprot ID | OR8A1_HUMAN |
| dbNSFP KGp1 AF | 0.278846153846 |
| dbNSFP KGp1 Afr AF | 0.0873983739837 |
| dbNSFP KGp1 Amr AF | 0.375690607735 |
| dbNSFP KGp1 Asn AF | 0.284965034965 |
| dbNSFP KGp1 Eur AF | 0.352242744063 |
| dbSNP GMAF | 0.2796 |
| ESP Afr MAF | 0.131304 |
| ESP All MAF | 0.274077 |
| ESP Eur/Amr MAF | 0.347174 |
| ExAC AF | 0.337,8.133e-06 |
TBRG1
| dbSNP name | rs529083(G,T); rs678132(C,A); rs679079(G,A); rs59618270(A,G); rs57209328(C,T); rs9723(G,A); rs2156155(G,A); rs686567(T,C); rs58240213(G,A); rs73622472(C,T); rs2846572(C,T); rs73622475(A,G); rs112561955(A,G); rs4936946(T,A); rs10893279(T,C); rs4936947(C,T); rs4936949(A,G); rs4396300(T,C); rs4411285(G,A); rs79787956(G,A); rs147171432(C,T); rs2156162(A,G); rs4551782(C,A); rs11601766(T,G); rs2187152(A,G); rs76570671(C,T); rs376646498(G,A); rs1047661(A,G); rs2276189(G,T); rs113419576(A,G); rs58908157(G,A); rs73622493(G,T) |
| ccdsGene name | CCDS8448.2 |
| cytoBand name | 11q24.2 |
| EntrezGene GeneID | 84897 |
| EntrezGene Description | transforming growth factor beta regulator 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TBRG1:NM_032811:exon6:c.C751T:p.P251S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5101 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3YBR2-3 |
| ESP Afr MAF | 0.000682 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 6.506e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive;
Growth retardation
CARDIOVASCULAR:
[Vascular];
Postural hypotension
GENITOURINARY:
[Kidneys];
Salt wasting
METABOLIC FEATURES:
Dehydration
ENDOCRINE FEATURES:
Hypoaldosteronism
LABORATORY ABNORMALITIES:
Decreased serum aldosterone;
Increased serum 18-hydroxycorticosterone (18-OHB);
Increased 18-OHB to aldosterone ratio;
Increased serum renin;
Hyponatremia;
Hyperkalemia
MISCELLANEOUS:
Onset in neonatal period;
Infants may have acute life-threatening crises;
Symptoms ameliorate with age;
Adults may be asymptomatic;
Increased frequency among Jewish Iranian individuals from Isfahan;
Allelic disorder to corticosterone methyloxidase type I deficiency
(203400)
MOLECULAR BASIS:
Caused by mutation in the cytochrome P450, subfamily XIB, polypeptide
2 gene (CYP11B2, 124080.0001)
OMIM Title
*610614 TRANSFORMING GROWTH FACTOR-BETA REGULATOR 1; TBRG1
;;TGFB REGULATOR 1;;
NUCLEAR INTERACTOR OF ARF AND MDM2; NIAM
OMIM Description
CLONING
Using the p19(Arf) isoform of mouse Cdkn2a (600160) as bait in a yeast
2-hybrid screen of a mouse embryonic fibroblast cDNA library, followed
by RT-PCR of human pancreas cDNA, Tompkins et al. (2006) cloned mouse
and human TBRG1, which they called NIAM. The deduced human protein
contains 411 amino acids.
Using Northern blot analysis, Babalola and Schultz (1995) detected
expression of Tbrg1, which they called Tb5, in all mouse tissues
examined. Highest expression was in testis.
GENE FUNCTION
Using in vitro and in vivo binding assays, including reciprocal
immunoprecipitation assays, Tompkins et al. (2006) confirmed that NIAM
bound p19(ARF), but not the p16(INK4A) isoform of CDKN2A. NIAM appeared
to function downstream of p19(ARF) in G1-phase growth arrest in both p53
(TP53; 191170)-dependent and p53-independent signaling pathways. NIAM
expression was induced in cells undergoing arrest in response to DNA
damage and TGF-beta-1 (TGFB1; 190180) treatment, suggesting it may also
participate in antiproliferative pathways.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the TBRG1
gene to chromosome 11 (TMAP STS-T95820).
LINC00167
| dbSNP name | rs12805829(C,T); rs4936090(T,C); rs4936091(T,G); rs111707172(C,T); rs73024842(C,T) |
| cytoBand name | 11q24.3 |
| EntrezGene GeneID | 440072 |
| snpEff Gene Name | PRDM10 |
| EntrezGene Description | long intergenic non-protein coding RNA 167 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2084 |
| ExAC AF | 0.058 |
MIR4697HG
| dbSNP name | rs671128(G,A); rs329651(G,T); rs78264560(C,T); rs329652(A,G); rs115412174(C,T); rs329653(G,A) |
| cytoBand name | 11q25 |
| EntrezGene GeneID | 283174 |
| EntrezGene Description | MIR4697 host gene (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01102 |
FOXM1
| dbSNP name | rs28919870(G,A); rs3742076(A,G); rs2215292(T,C); rs28919868(A,G); rs2302257(G,C); rs112316322(A,G); rs11062389(T,C); rs28918672(T,C); rs28990724(T,C); rs114678746(T,C); rs114370307(A,G); rs115836629(G,T); rs58640225(T,C); rs12815029(A,T); rs12815251(A,G); rs188903456(G,A); rs12312865(T,C); rs28990713(G,A); rs149168703(C,T); rs16930048(T,C); rs2074985(G,A); rs28990697(A,T); rs112700697(C,T); rs10848718(C,G); rs11062395(A,T); rs12319562(T,A); rs7294943(C,A); rs11062396(T,C) |
| ccdsGene name | CCDS8515.1 |
| cytoBand name | 12p13.33 |
| EntrezGene GeneID | 100507424 |
| EntrezGene Symbol | LOC100507424 |
| EntrezGene Description | uncharacterized LOC100507424 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | FOXM1:NM_202002:exon10:c.C2132T:p.P711L,FOXM1:NM_001243089:exon8:c.C1970T:p.P657L,FOXM1:NM_001243088:exon8:c.C1973T:p.P658L,FOXM1:NM_202003:exon8:c.C1973T:p.P658L,FOXM1:NM_021953:exon9:c.C2018T:p.P673L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8656 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A8K591 |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.00699300699301 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.002951 |
| ESP All MAF | 0.008073 |
| ESP Eur/Amr MAF | 0.010698 |
| ExAC AF | 0.006245 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Optic atrophy;
Nystagmus
RESPIRATORY:
[Lung];
Pneumonia, recurrent
CHEST:
[External features];
Small chest;
[Ribs, sternum, clavicles, and scapulae];
Anterior cupping of ribs;
Widened anterior ribs
SKELETAL:
Spondylometaphyseal dysplasia;
[Spine];
Mild platyspondyly;
[Pelvis];
Lacy iliac wings;
Narrow sacrosciatic notch;
Irregular proximal femoral metaphyses;
Short femoral necks;
Coxa vara
OMIM Title
*602341 FORKHEAD BOX M1; FOXM1
;;FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 16; FKHL16;;
FORKHEAD BOX M1B TRANSCRIPTION FACTOR; FOXM1B;;
HFH11;;
TRIDENT
OMIM Description
CLONING
The 'forkhead' gene family, originally identified in Drosophila,
comprises transcription factors with a conserved 100-amino acid
DNA-binding motif. One group of factors with the forkhead, or
winged-helix, domain is the hepatocyte nuclear factor-3 family of
proteins, which appears to regulate cell-specific transcription in
hepatocytes and in respiratory and intestinal epithelia. In an attempt
to identify forkhead domain transcription factors involved in intestinal
cell differentiation, Ye et al. (1997) isolated FKHL16, which they
designated HNF3/forkhead homolog-11 (HFH11), from a human colon
carcinoma cell line. On Northern blots, FKHL16 was expressed primarily
in thymus, testis, small intestine, and colon, moderately in ovary, and
at reduced levels in other tissues. Ye et al. (1997) found 2
alternatively spliced FKHL16 mRNAs, yielding predicted proteins of 801
(HFH11A) and 748 (HFH11B) amino acids. Both isoforms contain 2 PEST
regions, associated with rapid protein degradation. Expression studies
in mouse revealed that Fkhl16 is transcribed broadly in embryos, but is
expressed only in adult organs containing proliferating cells involved
in replenishing differentiated cell populations or in response to growth
factors released during injury or repair.
A partial FKHL16 cDNA, called MPP2 (MPM2 reactive phosphoprotein-2) was
isolated by Westendorf et al. (1994), who found it to be one of the
proteins phosphorylated by M-phase kinases.
Independently, Yao et al. (1997) isolated human and rat FKHL16, or WIN,
cDNAs. The predicted rat and human FKHL16 proteins share 81% sequence
identity. Yao et al. (1997) reported that human and rat FKHL16 mRNAs are
differentially spliced within the coding sequence of the winged-helix
DNA-binding domain at sites encoding regions that are important for
directing DNA binding specificity. RNase protection studies indicated
that the alternatively spliced transcripts have different relative
abundances in various tissues, suggesting that the splicing events may
be regulated. Using a PCR-based strategy, the authors determined the DNA
sequences to which rat FKHL16 binds in vitro.
GENE FUNCTION
By analyzing the promoter region of human FKHL16, or TRIDENT, Korver et
al. (1997) found that the 300 bp upstream of the transcription start
site are essential for the cell cycle-specific expression of FKHL16.
They stated that the promoter data in combination with the expression of
FKHL16 in cycling, but not resting, cells indicate that this protein is
likely to play a role in the control of cell proliferation.
By analysis of cDNA microarrays, Ly et al. (2000) showed that diminished
proliferation exhibited by fibroblasts from either elderly patients or
patients with Hutchinson-Gilford progeria (176670) was associated with
reduced expression of cell cycle genes as well as a decline in FOXM1B
(HFH11B) levels. Wang et al. (2001) showed that increased levels of
Foxm1b in regenerating liver of old transgenic mice restored the sharp
peaks in hepatocyte DNA replication and mitosis that are the hallmarks
of young regenerating mouse liver. Restoration of the young regenerating
liver phenotype was associated with increased expression of numerous
cell cycle regulatory genes. Cotransfection assays in the human hepatoma
HepG2 cell line demonstrated that FOXM1B protein stimulated expression
of both the cyclin B1 (123836) and cyclin D1 (168461) promoters,
suggesting that these cyclin genes are a direct FOXM1B transcription
target. The results suggested that FOXM1B controls the transcription
network of genes that are essential for cell division and exit from
mitosis. The results indicated that reduced expression of the FOXM1B
transcription factor contributes to the decline in cellular
proliferation observed in the aging process.
Wang et al. (2002) showed that the FOXM1B transcription factor regulates
expression of cell cycle proteins essential for hepatocyte entry into
DNA replication and mitosis.
Kalinichenko et al. (2004) found that conditionally deleted Foxm1b mouse
hepatocytes failed to proliferate and were highly resistant to
developing chemically induced hepatocellular carcinoma (114550). This
resistance was associated with sustained nuclear levels of the Cdk
inhibitor p27(Kip1) (CDKN1B; 600778) and diminished expression of
M-phase-promoting Cdc25b phosphatase (116949). Overexpression of Foxm1b
in an osteosarcoma cell line enhanced anchorage-independent growth on
soft agar. Kalinichenko et al. (2004) presented evidence that p27(Kip1)
and p19(Arf) (CDKN2A; 600160) interact with Foxm1b and inhibit Foxm1b
transcriptional activity. Furthermore, exposure to a
membrane-transducing synthetic peptide based on N-terminal sequences of
p19(Arf) reduced Foxm1b transcriptional activity and diminished
Foxm1b-induced growth on soft agar.
Laoukili et al. (2005) found that Foxm1-null mouse embryonic fibroblasts
and human osteosarcoma cells treated with FOXM1 interfering RNA were
delayed in G2. There was an increase in cells with 4n or polyploid DNA
content, but no increase in the mitotic index. FOXM1 depletion led to
pleiotropic G2/M defects, including chromosome misalignment, spindle
checkpoint dysfunction, and defects in cytokinesis. Laoukili et al.
(2005) reported that the C terminus of FOXM1 contains a transcriptional
activation domain, and FOXM1 proteins lacking the C terminus behaved in
a dominant-negative manner, causing cell-cycle defects similar to those
observed with FOXM1 RNA interference. Overexpression of FOXM1 caused
increased entry into mitosis. Using high-density human cDNA microarrays,
Laoukili et al. (2005) found that FOXM1 regulated the expression of a
large number of G2/M-specific genes, most importantly cyclin B and CENPF
(600236). Transcriptional activation of cyclin B was essential for
timely mitotic entry, whereas activation of CENPF was required for
sustained activation of the mitotic spindle checkpoint. Laoukili et al.
(2005) concluded that FOXM1 regulates a transcriptional cluster that is
essential for proper mitotic progression.
GENE STRUCTURE
Korver et al. (1997) found that the FKHL16 gene contains 10 exons, which
span approximately 25 kb.
MAPPING
By somatic cell hybrid analysis, radiation hybrid mapping, and
fluorescence in situ hybridization, Korver et al. (1997) localized the
FKHL16 gene to chromosome 12p13, telomeric to the FGF6 gene (134921).
ANIMAL MODEL
Using targeted deletion of the Foxm1 gene in mice, Kim et al. (2005)
found that Foxm1 knockout led to embryonic lethality due to severe
abnormalities in the development of the liver and heart. Foxm1 -/- lungs
displayed severe abnormalities in the development of pulmonary
microvasculature that was associated with diminished pulmonary levels of
Pecam1 (173445), Tgfbr2 (190182), Adam17 (603639), Flk1 (KDR; 191306),
Flt1 (165070), Plk1 (602098), Aurora B kinase (604970), Lama4 (600133),
and Foxf1 (601089). Foxm1 was essential for proliferation of lung
mesenchyme and vascular smooth muscle cells during embryonic lung
development. Cotransfection experiments demonstrated that the Lama4 gene
was a direct transcriptional target for Foxm1. Kim et al. (2005)
concluded that FOXM1 regulates pulmonary genes essential for mesenchyme
proliferation, extracellular matrix remodeling, and vasculogenesis
during lung development.
Cai et al. (2013) generated 2 transgenic mouse models, 1 exhibiting
Foxm1 gain of function and 1 exhibiting Foxm1 loss of function, both
under control of the prostate epithelial-specific probasin promoter. In
the transgenic adenocarcinoma mouse prostate (TRAMP) model that uses
SV40 large T antigen to induce prostate cancer, mice lacking Foxm1 had
decreased tumor growth and metastasis. Decreased prostate tumorigenesis
was associated with decreased tumor cell proliferation and
downregulation of Cdc25b, cyclin B1, Plk1, Lox (153455), and versican
(VCAN; 118661). There was also a decrease in angiogenesis and reduced
Vegfa (192240) expression. Foxm1-deficient prostate tumors and cell
lines had downregulated mRNA and protein expression of Hsd11b2 (614232),
an enzyme important in tumor cell proliferation. ChIP analysis
identified Hsd11b2 as a direct transcriptional target of Foxm1. Without
induction of prostate tumorigenesis, overexpression of Foxm1 alone or in
combination with inhibition of the p19(Arf) tumor suppressor resulted in
epithelial hyperplasia, but not progression to prostate cancer. Cai et
al. (2013) concluded that FOXM1 expression in prostate epithelial cells
is critical for prostate carcinogenesis. They proposed that inhibition
of FOXM1 may be a therapeutic approach for prostate cancer chemotherapy.
TSPAN9
| dbSNP name | rs6489428(T,C); rs73250360(G,A); rs10848783(G,C); rs6489429(G,C); rs7974612(A,G); rs7960511(C,T); rs11611380(A,G); rs10848784(C,T); rs12580314(A,G); rs7314991(A,G); rs12811010(T,C); rs6489430(T,C); rs6489431(C,G); rs59065614(G,A); rs11062491(A,T); rs140719983(C,A); rs10848785(C,G); rs10848786(G,A); rs61589944(A,C); rs3782832(T,G); rs3782831(G,A); rs3782830(G,A); rs3782829(G,A); rs3782828(T,G); rs7965378(T,C); rs10848787(C,T); rs11062494(G,A); rs35896418(C,A); rs933411(A,G); rs10848788(T,C); rs933410(T,C); rs933409(C,A); rs4766042(C,T); rs11062495(C,G); rs11062496(G,A); rs367629550(A,G); rs12371560(A,C); rs10774112(G,A); rs373474452(A,G); rs6489433(T,C); rs6489434(T,C); rs11062497(T,C); rs6489435(C,G); rs113178222(G,T); rs11613213(C,T); rs10848789(G,A); rs74054891(A,G); rs933422(A,G); rs2335341(G,A); rs7295094(T,C); rs2001429(C,A); rs4766043(G,A); rs868882(A,G); rs74054894(C,G); rs12827511(G,A); rs10774114(C,T); rs7969345(A,G); rs1990328(A,G); rs74054898(A,G); rs75180557(G,C); rs1990327(A,G); rs59731950(G,A); rs34685216(G,C); rs11062498(G,C); rs12819399(C,T); rs12820322(A,G); rs12819603(C,T); rs12820016(C,T); rs10848793(A,G); rs12372690(T,C); rs7980216(T,C); rs7980247(T,A); rs7977264(A,G); rs7980334(T,C); rs10848794(G,A); rs10848795(T,G); rs933417(G,A); rs933416(C,A); rs933415(A,G); rs10848796(A,C); rs12833145(A,G); rs12316097(C,A); rs73247323(C,T); rs73247328(A,C); rs73247329(T,C); rs75597551(G,A); rs7965579(A,G); rs7485669(G,A); rs6489436(T,C); rs7489068(T,A); rs6489437(T,C); rs1860430(A,G); rs1860429(T,C); rs12828428(G,T); rs1860428(A,G); rs66707615(C,T); rs10744591(T,C); rs10848797(A,T); rs74057511(A,G); rs56299951(T,C); rs10848798(A,G); rs10744592(C,G); rs7976333(G,A); rs11062499(C,A); rs78910239(C,T); rs57449341(C,T); rs12810695(A,G); rs10848799(C,T); rs933414(C,T); rs73247348(A,G); rs11062500(G,A); rs36044689(C,T); rs35777997(G,T); rs111490848(C,T); rs113587972(A,G); rs139916664(C,T); rs880159(T,C); rs2335343(C,T); rs2335344(A,G); rs2878394(T,G); rs73247355(G,A); rs34868434(T,G); rs10774115(G,T); rs7488689(T,C); rs1122922(C,T); rs7488775(T,C); rs11609275(C,G); rs11611348(A,C); rs7485494(G,C); rs7485657(C,T); rs61916264(A,G); rs73247361(G,A); rs56114238(C,T); rs55908336(G,T); rs4766044(C,T); rs35923805(C,T); rs1000970(C,A); rs10774116(C,A); rs12099765(T,A); rs10774117(C,A); rs10774118(A,G); rs10848800(C,A); rs138004168(A,G); rs11062505(A,G); rs10848801(A,C); rs7972154(C,G); rs10774119(C,T); rs73247363(T,C); rs10848802(A,G); rs4766045(C,A); rs77017491(C,T); rs12099963(G,A); rs4766046(A,C); rs10848803(A,G); rs10848804(A,G); rs10848805(C,G); rs2335345(C,T); rs57449483(C,T); rs57289669(C,T); rs11062506(C,T); rs10848806(T,G); rs7973849(T,A); rs7970946(A,G); rs74057555(C,A); rs10774120(T,C); rs10774121(G,A); rs868087(G,A); rs11837799(T,G); rs11837327(A,G); rs868088(T,C); rs73247368(C,T); rs883594(T,C); rs7304958(G,A); rs144215045(C,T); rs7137113(A,G); rs6489438(A,G); rs6489439(T,C); rs11062510(G,A); rs11062511(C,A); rs139683107(C,T); rs186647746(G,A); rs6416314(C,A); rs6489440(T,G); rs12308222(C,G); rs78461285(G,A); rs78172612(A,G); rs7979152(C,T); rs7484409(G,A); rs57796827(C,T); rs2109206(C,T); rs10735017(T,C); rs2109205(G,T); rs35244030(G,A); rs2109204(C,G); rs7487802(T,A); rs10848807(A,C); rs10848808(G,C); rs488225(A,G); rs576571(A,C); rs12319072(A,G); rs570264(A,G); rs588513(G,A); rs588106(C,G); rs588090(G,A); rs588056(C,T); rs7963344(C,T); rs7977942(A,G); rs7980759(A,G); rs12830084(G,A); rs7955810(T,C); rs73048180(C,T); rs7965820(G,T); rs513374(G,A); rs7956296(T,C); rs34623502(G,A); rs34117451(C,T); rs35096434(C,T); rs483880(C,T); rs666335(G,A); rs61916306(C,T); rs61916308(C,T); rs116983312(G,A); rs73254333(A,G); rs650153(T,G); rs7302492(T,G); rs7314280(C,A); rs142830977(A,C); rs116798717(C,A); rs11062517(C,T); rs79378600(A,G); rs71458035(C,T); rs58860486(G,A); rs576495(A,T); rs35524534(G,A); rs115709274(C,T); rs17695429(T,C); rs71458036(C,A); rs11062519(T,G); rs71458037(T,C); rs71458038(C,G); rs71458039(A,C); rs35886316(T,C); rs34071646(A,G); rs35964281(A,G); rs7134980(A,C); rs12812551(G,A); rs58114618(C,A); rs12812759(G,A); rs34505257(C,G); rs669839(C,T); rs71458040(C,A); rs71458041(A,C); rs71458042(T,C); rs668938(G,A); rs489298(C,T); rs489296(T,G); rs10744594(A,G); rs76350955(G,T); rs10774122(T,C); rs34827888(G,A); rs60370726(T,G); rs7309470(C,G); rs1001214(G,A); rs7308599(G,A); rs7308604(G,C); rs34659927(G,A); rs7312594(C,T); rs7312730(C,T); rs12321327(C,G); rs11610253(T,C); rs2058245(A,G); rs76672046(A,G); rs79365925(C,A); rs11062520(C,T); rs997645(A,T); rs28601814(G,A); rs997646(A,T); rs55774749(T,G); rs11062521(C,T); rs11829766(C,T); rs12311021(G,C); rs11062522(C,T); rs11834197(G,A); rs11062523(C,T); rs7972285(A,G); rs7975449(T,G); rs1894799(A,G); rs11062524(C,G); rs28375006(G,C); rs28662501(G,A); rs56716492(A,G); rs35320745(G,T); rs34152813(G,A); rs4766048(C,T); rs181786718(C,T); rs2159413(A,G); rs7980328(A,C); rs7980339(A,G); rs7964868(G,A); rs59883876(G,C); rs7969052(C,A); rs7969147(C,T); rs9888391(A,G); rs490316(A,G); rs34195345(C,T); rs11613410(C,T); rs2335814(T,C); rs7964595(C,T); rs609667(G,A); rs515245(A,G); rs515127(G,T); rs10744595(A,G); rs11062525(C,T); rs35207554(C,A); rs593025(T,C); rs10848809(A,C); rs10848810(G,A); rs581677(G,A); rs1476802(C,T); rs688362(T,C); rs687448(C,G); rs687436(A,G); rs74425666(G,A); rs11062526(G,A); rs36077100(T,C); rs4766049(C,T); rs7315917(C,T); rs533137(G,A); rs657463(T,C); rs4765713(C,G); rs7973427(T,C); rs7308849(T,C); rs7314045(T,G); rs60277119(C,A); rs7298272(C,T); rs73050153(T,C); rs10848812(C,T); rs7954113(A,G); rs7957389(T,A); rs79328962(G,T); rs7957509(T,C); rs7968220(C,T); rs7968330(C,T); rs10848813(G,A); rs7133793(A,G); rs73050166(A,G); rs11062530(G,C); rs55677084(C,A); rs73050170(G,C); rs73050172(T,C); rs73050175(C,T); rs56255339(G,A); rs56245215(T,C); rs7980107(C,T); rs7972731(T,C); rs12297167(C,T); rs17835270(C,T); rs34885886(C,T); rs7966611(C,T); rs11062533(G,A); rs56036622(T,C); rs76139786(A,G); rs7970750(G,T); rs73243044(A,G); rs4765714(C,G); rs12582837(G,A); rs73051848(C,T); rs2159421(C,T); rs1125020(C,T); rs11062538(G,A); rs4766050(C,A); rs112488493(T,G); rs113855272(T,C); rs113196617(A,G); rs111612598(T,C); rs4766051(C,T); rs146354745(C,G); rs111554292(T,C); rs11836378(G,A); rs10744596(A,G); rs11834261(A,G); rs77115380(C,T); rs73243057(C,T); rs60924546(G,A); rs60986788(A,G); rs4766052(T,C); rs7966730(T,G); rs11062540(A,C); rs11062541(T,C); rs181372195(C,T); rs4766053(A,G); rs115496996(A,G); rs57393570(A,C); rs59270978(T,G); rs114095788(C,T); rs12099733(C,G); rs4765716(A,G); rs12099881(A,G); rs4766056(T,C); rs113451052(T,G); rs112306470(T,C); rs112638380(A,G); rs73243082(T,C); rs73243083(T,A); rs73243085(G,C); rs11062543(T,C); rs58024515(T,C); rs59690907(T,C); rs58645907(T,G); rs4766057(T,C); rs59118579(C,G); rs58472252(A,G); rs58120991(T,C); rs73249028(C,G); rs10848816(A,G); rs79803202(C,T); rs34573223(A,G); rs11062544(G,C); rs73249034(A,C); rs73051870(C,T); rs34791553(T,C); rs11832275(G,C); rs34399892(A,G); rs11832874(G,A); rs7977287(C,T); rs58691260(T,C); rs73249049(A,T); rs11837854(T,C); rs11834909(C,G); rs11837931(T,A); rs73249056(A,G); rs7963153(G,A); rs11062546(G,A); rs35859922(C,T); rs11830854(G,A); rs12370932(C,T); rs2058244(C,T); rs11835694(C,T); rs11831392(G,A); rs11836144(C,T); rs73051875(G,A); rs11829838(T,C); rs61029949(T,G); rs56103839(G,A); rs55838954(G,A); rs10774124(A,G); rs76781668(C,T); rs79050656(A,G); rs55724351(T,A); rs9668437(T,C); rs4766058(C,T); rs11612038(G,C); rs111242560(C,T); rs12810233(T,A); rs11062547(C,T); rs11062548(A,C); rs10774125(T,C); rs10848817(A,T); rs12828899(C,T); rs7967804(C,T); rs7957512(T,A); rs78184637(C,T); rs7314659(C,T); rs148104700(A,G); rs73249077(G,A); rs887362(T,C); rs878962(G,T); rs2002649(G,A); rs876516(G,A); rs879189(C,T); rs879188(G,A); rs4766059(T,C); rs12579294(C,T); rs4766060(T,A); rs58272361(C,T); rs75011552(A,G); rs12315958(G,A); rs12302955(C,T); rs11062553(T,C); rs12311352(A,G); rs11062554(G,A); rs73250802(A,G); rs10744597(A,G); rs4141086(T,C); rs118175286(C,A); rs11062555(G,A); rs7309644(G,A); rs4766061(A,G); rs4766062(T,C); rs4765717(C,T); rs73252610(T,C); rs181549018(T,C); rs10848818(A,G); rs10848819(C,T); rs7965547(A,G); rs116698498(C,T); rs80255493(A,G); rs733851(G,A); rs143607715(C,T); rs2335817(A,C); rs740767(C,T); rs115262646(G,A); rs9788171(T,C); rs113239599(G,T); rs111860325(A,G); rs10848820(A,G); rs113011804(C,T); rs7977649(C,T); rs10848821(G,A); rs10744598(C,T); rs10732596(A,G); rs10744599(C,T); rs7970802(T,A); rs7967815(A,G); rs56902161(C,T); rs7970918(T,C); rs6489443(G,A); rs6489444(A,G); rs887368(T,C); rs758624(G,A); rs758623(A,G); rs758622(T,C); rs758621(A,G); rs758620(A,G); rs758619(C,T); rs758618(G,T); rs758617(G,A); rs7311192(T,C); rs7311195(T,G); rs10774126(T,C); rs10774127(T,C); rs60515876(A,G); rs77916626(G,A); rs10744600(T,C); rs10774128(A,G); rs77391676(A,G); rs11062557(A,G); rs374221207(G,C); rs4766063(A,G); rs4765719(C,T); rs4766064(A,T); rs34512620(C,T); rs7969363(C,T); rs6489445(T,C); rs7955889(A,G); rs7968641(G,A); rs117527144(T,C); rs7969602(C,G); rs7959185(T,C); rs59128562(A,G); rs112059070(T,G); rs116547481(C,T); rs11062560(G,C); rs55897603(G,A); rs11062561(C,A); rs7977968(C,A); rs7974470(A,G); rs7960101(C,T); rs7974684(A,G); rs76237234(C,T); rs2335818(A,G); rs61917910(T,C); rs4765720(C,G); rs740777(C,T); rs740776(C,T); rs740775(C,G); rs71577821(C,A); rs7488997(G,T); rs73252660(C,T); rs11610165(A,T); rs7973920(T,G); rs76435956(A,G); rs77178825(G,A); rs11062564(C,T); rs1860437(T,C); rs11613691(G,A); rs3782824(G,C); rs140784083(A,C); rs2058243(A,G); rs4318042(A,G); rs117495919(C,T); rs117530927(G,A); rs116919662(T,A); rs60273679(G,C); rs76949821(T,C); rs2335665(G,A); rs76127718(C,G); rs2018043(A,C); rs117758120(G,A); rs139855766(G,A); rs78985982(G,A); rs740773(G,A); rs740772(A,G); rs11062565(G,A); rs11062566(C,G); rs740771(G,T); rs149834003(C,T); rs2335666(G,A); rs2878483(C,T); rs2878484(C,T); rs4766070(A,G); rs740770(T,C); rs7297218(C,T); rs9669210(G,A); rs7962280(G,T); rs7977763(A,G); rs7962640(G,A); rs7965587(G,A); rs60302847(C,T); rs11062569(T,C); rs73252686(A,G); rs11062571(C,T); rs11062572(T,C); rs11062573(T,G); rs11062574(A,G); rs61907326(G,A); rs141480177(C,T); rs17779041(A,G); rs73041779(T,C); rs61907327(A,C); rs9669143(T,C); rs9669147(T,C); rs9669160(T,C); rs149869818(A,G); rs7294877(T,C); rs4766073(T,G); rs4766074(A,T); rs4766075(T,C); rs7295115(A,G); rs7310021(C,T); rs7299353(T,C); rs11835656(T,C); rs7965060(A,G); rs12310131(C,G); rs117580414(C,T); rs10848822(T,C); rs10848823(A,G); rs61907328(C,T); rs11833986(C,G); rs9668153(G,A); rs3741949(C,T); rs1468568(A,G); rs3825360(T,C); rs10848824(T,C); rs7312073(T,A); rs887364(C,T); rs3741947(C,T); rs10848825(G,T); rs10848826(G,A); rs887363(C,T); rs10848827(C,T); rs3741946(A,G); rs3741945(T,C); rs3741944(C,G); rs3825359(G,A); rs11062577(G,T); rs7307662(G,A); rs10491966(A,T); rs12426678(G,A); rs73041797(A,G); rs12319149(G,A); rs10774129(A,G); rs79351976(C,G); rs10848828(A,G); rs377080114(G,C); rs10848829(T,C); rs141310333(A,G); rs3741943(A,G); rs112575071(C,T); rs184943543(G,A); rs113566202(C,T); rs56207410(C,T); rs374126756(G,A); rs73254438(A,G); rs4766076(A,C); rs10848831(C,T); rs199776487(T,C); rs113276931(A,G); rs188307292(G,A); rs1002284(C,T); rs9919824(A,T); rs55650465(C,T); rs3825357(A,G); rs143981879(A,G); rs148660493(A,G); rs61907332(C,G); rs2011973(C,T); rs2011873(C,T); rs3782818(A,G); rs3782817(C,T); rs183248206(C,T); rs10848832(C,A); rs148958704(C,T); rs143747485(C,T); rs3782815(A,G); rs3782814(A,G); rs4765721(A,G); rs10774131(T,C); rs61907335(T,C); rs151253415(A,T); rs61907336(G,A); rs12816145(T,G); rs10774132(G,C); rs3782813(C,T); rs3782812(C,G); rs3782810(C,T); rs3782809(G,A); rs10848833(C,T); rs11062585(C,T); rs55679497(C,T); rs6489446(T,C); rs75609718(C,T); rs6489447(T,C); rs10848834(A,G); rs10735018(A,G); rs7301785(A,T); rs11062586(T,G); rs11062587(G,A); rs7139181(C,G); rs4765722(A,G); rs77572543(A,C); rs3782807(A,C); rs1003559(G,C); rs2010581(T,C); rs12316597(G,A); rs3782805(T,C); rs57511254(G,C); rs4766078(A,G); rs11837266(A,G); rs4766079(C,G); rs7963360(C,G); rs7963488(C,T); rs78175639(G,C); rs10774133(A,G); rs3782803(C,T); rs3825356(A,G); rs11062589(A,G); rs3782802(G,T); rs139836890(T,C); rs3782801(C,G); rs3825355(C,T); rs3825354(T,C); rs3825353(G,A); rs77903913(A,G); rs12372121(C,T); rs76065061(T,C); rs3825352(T,C); rs3782800(G,A); rs7296615(A,G); rs74528062(G,C); rs76263864(C,A); rs17835600(G,A); rs74576293(T,C); rs77737253(A,G); rs7979731(C,T); rs76867975(G,T); rs61907355(C,T); rs7953798(G,T); rs2159381(C,T); rs77587(C,G); rs498049(A,G); rs588040(C,T); rs4765723(T,G); rs588873(C,T); rs142242365(A,G); rs600149(G,A); rs601603(G,C); rs602059(G,A); rs602474(C,T); rs7959621(C,T); rs7980313(T,C); rs10848836(C,G); rs615317(T,C); rs615753(G,A); rs616648(A,G); rs75467353(C,G); rs617596(A,G); rs618933(G,C); rs76961464(T,G); rs11062590(C,G); rs631882(G,A); rs631912(C,T); rs632329(G,T); rs479858(A,G); rs61907356(C,T); rs633311(T,C); rs566601(C,A); rs644409(C,T); rs644411(C,T); rs645722(C,T); rs562127(A,G); rs647521(C,T); rs647532(G,A); rs659618(T,C); rs659688(G,A); rs659708(T,G); rs660140(G,C); rs531891(C,A); rs661800(G,A); rs60250999(T,C); rs3782788(T,G); rs116433570(C,T); rs504379(C,T); rs79302180(C,T); rs61907358(C,G); rs503554(C,A); rs502518(A,G); rs676194(T,C); rs79782863(C,T); rs57745580(C,T); rs677991(T,C); rs678022(T,G); rs497878(C,G); rs688882(T,C); rs474942(A,T); rs115998689(A,C); rs74580910(C,G); rs581684(G,C); rs473048(T,G); rs472918(G,A); rs73047059(T,A); rs75303070(C,T); rs76799974(C,T); rs524869(T,C); rs78560707(C,T); rs678112(A,G); rs142751863(G,A); rs11062594(C,G); rs586841(G,C); rs600830(T,G); rs73047065(G,T); rs1860385(C,T); rs116617346(C,T); rs112559202(C,T); rs537136(T,C); rs481136(A,G); rs78278085(C,T); rs614616(G,A); rs3825343(C,T); rs147126982(C,T); rs116685157(A,G); rs74677345(A,G); rs113560223(A,T); rs74584831(C,G); rs643255(A,G); rs644135(A,G); rs78917540(C,G); rs646346(G,A); rs11062595(C,G); rs11062596(A,T); rs11062597(G,A); rs10491967(G,A); rs73047075(G,T); rs11614107(T,C); rs4766080(T,C); rs78646247(G,T); rs12307438(C,A); rs150615342(T,C); rs149808520(G,A); rs1860436(T,C); rs10848837(G,T); rs142655819(G,C); rs3782778(C,T); rs59778971(C,T); rs3825342(T,C); rs3782777(G,A); rs3782776(C,T); rs3782775(G,A); rs3782774(A,G); rs3825341(C,T); rs149862668(G,A); rs11831395(G,A); rs12578221(A,G); rs4766082(G,A); rs4766083(T,C); rs4766085(C,T); rs4766086(A,G); rs4766087(C,T); rs57551718(G,A); rs2878529(A,G); rs758616(C,T); rs740768(T,C); rs373313259(G,A); rs4766088(C,T); rs7296705(T,C); rs151316899(C,T); rs7296720(A,G); rs139421772(G,T); rs11610052(T,C); rs473014(C,T); rs3782772(A,G); rs73048927(G,A); rs12422683(G,A); rs7973548(A,G); rs11615232(A,G); rs114884165(G,C); rs80271086(A,T); rs149395954(G,C); rs3782769(G,A); rs11615775(A,G); rs35201994(C,T); rs34592797(T,C); rs79607888(G,A); rs1978239(C,A); rs3782767(A,G); rs150875021(A,G); rs55952697(A,G); rs670203(A,G); rs3782764(T,G); rs3782763(G,A); rs145250581(G,A); rs683865(G,A); rs12424018(T,C); rs479105(C,T); rs557670(G,C); rs557621(A,C); rs59669701(C,T); rs11062600(G,A); rs527346(T,C); rs521392(A,C); rs187356895(G,A); rs635332(G,A); rs115023342(G,A); rs371119964(C,T); rs648870(G,A); rs650180(C,T); rs571206(A,G); rs651196(C,G); rs651243(C,T); rs16930370(T,C); rs372946603(C,T); rs663134(C,A); rs544668(T,C); rs541015(T,C); rs73048965(G,T); rs10848839(C,T); rs73048966(G,A); rs12580347(T,C); rs678462(G,T); rs142749348(G,A); rs679825(C,T); rs877089(C,T); rs71577836(G,A); rs877090(G,A); rs112543621(C,A); rs66462026(C,T); rs67672535(C,T); rs605613(C,T); rs564247(T,G); rs632887(A,G); rs113502124(C,G); rs634076(C,T); rs1064048(C,T); rs71577823(C,T); rs67551338(C,T); rs12827449(C,T); rs6489451(G,A); rs71577831(G,A); rs537938(T,C); rs11062604(T,G); rs71577850(G,A); rs6869(T,G); rs144544609(A,G) |
| ccdsGene name | CCDS8520.1 |
| cytoBand name | 12p13.32 |
| EntrezGene GeneID | 10867 |
| EntrezGene Description | tetraspanin 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TSPAN9:NM_001168320:exon3:c.C200T:p.T67M,TSPAN9:NM_006675:exon4:c.C200T:p.T67M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.551 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75954 |
| dbNSFP Uniprot ID | TSN9_HUMAN |
| ExAC AF | 4.879e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Masked facies;
[Eyes];
Ocular flutter;
Eye movement disorder;
Oculogyric crises;
[Mouth];
Orolingual dyskinesia
ABDOMEN:
[Gastrointestinal];
Feeding difficulties;
Gastroesophageal reflux;
Constipation
NEUROLOGIC:
[Central nervous system];
Gross motor delay;
Hypokinetic movements;
Hyperkinetic movements;
Lack of speech development;
Chorea;
Parkinsonism;
Dystonia;
Developmental delay, global;
Rigidity;
Tremor;
Bradykinesia;
Truncal hypotonia;
Limb dystonia;
Dyskinesia;
Hypertonicity;
Pyramidal tract signs
LABORATORY ABNORMALITIES:
Increased CSF homovanillic acid (HVA);
Normal CSF 5-hydroxyindoleacetic acid (5-HIAA)
MISCELLANEOUS:
Onset in early infancy;
Progressive disorder;
Decreased life expectancy;
Death often in the teenage years;
Poor response to L-DOPA
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 6 (dopamine neurotransmitter
transporter), member 3 gene (SLC6A3, 126455.0002)
OMIM Title
*613137 TETRASPANIN 9; TSPAN9
;;NEW EST TETRASPAN 5; NET5
OMIM Description
DESCRIPTION
Members of the tetraspanin superfamily, such as TSPAN9, are
characterized by the presence of 4 transmembrane domains. Tetraspanins
associate in large membrane complexes with other molecules, particularly
integrins (see ITGB1; 135630), and function in cell adhesion, migration,
and signaling (summary by Serru et al., 2000).
CLONING
By searching an EST database for tetraspanin-like sequences, followed by
5-prime RACE of a HeLa cell cDNA library, Serru et al. (2000) cloned
TSPAN9, which they called NET5. The deduced 239-amino acid protein
contains 4 transmembrane segments and other characteristics of a
tetraspanin. RT-PCR detected TSPAN9 expression in all human cell lines
examined.
MAPPING
Hartz (2009) mapped the TSPAN9 gene to chromosome 12p13.32 based on an
alignment of the TSPAN9 sequence (GenBank GENBANK AF217967) with the
genomic sequence (GRCh37).
NDUFA9
| dbSNP name | rs2270134(A,G); rs2159352(G,A); rs11063280(A,G); rs35167443(A,G); rs2159351(A,G); rs10744657(G,A); rs11063282(G,A); rs12811453(T,C); rs11063283(G,A); rs2191156(G,C); rs12308883(C,T); rs4147671(T,G); rs11063285(T,C); rs2302247(C,T); rs2302246(G,C); rs4147672(G,A); rs4147673(C,T); rs4147674(A,G); rs147195132(A,T); rs4147675(C,T); rs1990311(C,T); rs12309713(C,T); rs6489557(T,C); rs16931616(A,T); rs4147677(A,C); rs16931620(A,C); rs4147678(C,T); rs4147679(A,T); rs4147680(A,G); rs4147681(T,C); rs4766268(G,A); rs4147682(A,T); rs7972657(A,C); rs7958182(C,T); rs4147683(C,T); rs12318966(A,G); rs7957498(G,A); rs7972920(A,G); rs4147684(C,T); rs4147685(A,C); rs11614014(C,A); rs11614030(C,A); rs61909965(T,A); rs4766269(A,G); rs11610038(G,T); rs2058204(G,T); rs10849115(A,G); rs2267548(G,A); rs2267549(G,A); rs4147687(T,C); rs2267550(T,C); rs77905968(T,C); rs77101172(A,T); rs78389937(G,A); rs7977127(G,A); rs2267551(A,G); rs7306593(T,C); rs59986414(C,T); rs34947765(C,T); rs17701871(C,T); rs68144469(G,A); rs7312558(C,G); rs2240762(A,G); rs1009633(A,G); rs78705685(C,T); rs1009634(A,G); rs2074984(T,G); rs2359252(T,C); rs4147689(G,T); rs10774256(C,T); rs10774257(G,A); rs117797102(C,T); rs7313982(T,G); rs10774258(A,G); rs10774259(T,C); rs7972501(C,G); rs4766270(A,G); rs151018024(C,G); rs10774260(A,G); rs7310700(G,A); rs10083152(G,A); rs10082907(C,G); rs139798190(A,G); rs10128935(G,A); rs115945205(G,A); rs138340246(G,C); rs10732600(G,A); rs10735037(C,A); rs4766271(A,G); rs4766272(G,A); rs6489558(T,G); rs7302268(C,G); rs34214125(C,G); rs4766273(A,T); rs34076756(C,T); rs1029767(C,A); rs2302244(A,G); rs16931634(A,G); rs10849118(T,C); rs2267552(G,A); rs2240761(A,G); rs2240760(A,G); rs7978162(A,G); rs4147693(G,A); rs4147695(G,A) |
| ccdsGene name | CCDS8532.1 |
| cytoBand name | 12p13.32 |
| EntrezGene GeneID | 4704 |
| EntrezGene Description | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NDUFA9:NM_005002:exon9:c.C881T:p.P294L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5396 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q16795 |
| dbNSFP Uniprot ID | NDUA9_HUMAN |
| dbNSFP KGp1 AF | 0.014652014652 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0303430079156 |
| dbSNP GMAF | 0.01469 |
| ESP Afr MAF | 0.004312 |
| ESP All MAF | 0.016761 |
| ESP Eur/Amr MAF | 0.02314 |
| ExAC AF | 0.017 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolonged QT interval on EKG;
Syncope;
Torsade de pointes;
Ventricular fibrillation;
Sudden cardiac death
MISCELLANEOUS:
Association of cardiac events with exercise;
Genetic heterogeneity (see LQT1 192500);
Patients with more severe phenotype have been reported with mutations
in more than 1 LQTS-related gene;
GEI (gene-environment interaction) - association of cardiac events
with drug administration
MOLECULAR BASIS:
Caused by mutation in the sodium channel, voltage-gated, type V, alpha
polypeptide gene (SCN5A, 600163.0001)
OMIM Title
*603834 NADH-UBIQUINONE OXIDOREDUCTASE 1 ALPHA SUBCOMPLEX, 9; NDUFA9
OMIM Description
DESCRIPTION
The NDUFA9 gene encodes a structural accessory subunit of the
multisubunit NADH:ubiquinone oxidoreductase (complex I), which is the
first enzyme complex in the electron transport chain of mitochondria.
NDUFA9 is located in the peripheral part of the complex (summary by van
den Bosch et al., 2012). See also NDUFA2 (602137).
CLONING
Fearnley et al. (1991) isolated the genes encoding the 39- and 42-kD
(603835) subunits of bovine complex I. Both proteins are part of the
hydrophobic protein fraction of the enzyme. However, both are
predominantly hydrophilic, and appear to lie mostly outside the lipid
bilayer. In a heterogeneous nuclear cDNA library of human chromosome 12p
transcribed sequences, Baens et al. (1993) identified CC6, a cDNA
encoding the human homolog of the bovine 39-kD protein. The bovine and
human 39-kD subunits are 78% identical on the amino acid level.
MOLECULAR GENETICS
In a patient, born of consanguineous Kurdish parents, with fatal
neonatal Leigh syndrome due to mitochondrial complex I deficiency
(256000), van den Bosch et al. (2012) identified a homozygous mutation
in the NDUFA9 gene (R321P; 603834.0001). Isolated complex I deficiency
was found in muscle (29% of controls) and fibroblasts (11% of controls).
Gel electrophoresis and Western blot analysis showed a significant
decrease in mature complex I and in NDUFA9 in patient fibroblasts, and
wildtype NDUFA9 restored complex I activity in patient fibroblasts,
confirming that the mutation caused the disorder. The mutation was found
by homozygosity mapping followed by candidate gene analysis. Van den
Bosch et al. (2012) concluded that NDUFA9 plays an important role in
proper complex I function, probably due to its role in maintaining
stability of the complex.
KCNA1
| dbSNP name | rs1048500(T,C); rs2227910(G,C); rs4766309(T,A); rs4766310(G,A); rs4766311(C,T); rs7974459(T,C); rs7974559(A,T); rs73050551(C,T); rs10849174(T,C); rs73050554(C,T); rs12424292(C,T) |
| ccdsGene name | CCDS8535.1 |
| CosmicCodingMuts gene | KCNA1 |
| cytoBand name | 12p13.32 |
| EntrezGene GeneID | 3736 |
| EntrezGene Description | potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia) |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3736&%3Brs=1048500 |
| Annovar Function | KCNA1:NM_000217:exon2:c.T684C:p.C228C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=3736&%3Brs=1048500 |
| dbSNP GMAF | 0.4688 |
| ESP Afr MAF | 0.407172 |
| ESP All MAF | 0.469014 |
| ESP Eur/Amr MAF | 0.499302 |
| ExAC AF | 0.488 |
OMIM Clinical Significance
Neuro:
Ataxia due to posterior column degeneration;
Progressive vibratory and postural sensibility loss;
Muscle stretch reflex losses;
Flexor plantar responses;
Pain and temperature sensations preserved;
No cerebellar or pyramidal tract involvement
Skel:
Scoliosis
Misc:
Age of onset between 19 and 30 years
Inheritance:
Autosomal dominant
OMIM Title
*176260 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER
1; KCNA1
;;MK1, MOUSE, HOMOLOG OF;;
KV1.1
OMIM Description
CLONING
Potassium channels represent the most complex class of voltage-gated ion
channels from both functional and structural standpoints. Present in all
eukaryotic cells, their diverse functions include maintaining membrane
potential, regulating cell volume, and modulating electrical
excitability in neurons. The delayed rectifier function of potassium
channels allows nerve cells to efficiently repolarize following an
action potential. In Drosophila, 4 sequence-related K+ channel
genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been
shown to have a human homolog (Chandy et al., 1990; McPherson et al.,
1991).
By PCR of genomic DNA with primers based on regions conserved between
Drosophila Shaker and a mouse voltage-gated potassium channel, Ramaswami
et al. (1990) isolated fragments of several related human genes. They
used the fragments to screen cDNA libraries and cloned cDNAs encoding
several potassium channels that they designated HuKI (KCNA1), HuKII
(KCNA4; 176266), HuKIV (KCNA2; 176262), and HuKV (KCNA6; 176257). Like
other Shaker-class potassium channels, the predicted 495-amino acid
KCNA1 protein contains 6 hydrophobic segments, a positively charged
region called S4 between hydrophobic segments 3 and 4, and a leucine
zipper. KCNA1 shares 98% amino acid identity with its rat homolog, RCK1.
When expressed in Xenopus oocytes, KCNA1, KCNA4, and KCNA2 exhibited
different voltage dependence, kinetics, and sensitivity to pharmacologic
potassium channel blockers. KCNA1 and KCNA2 were noninactivating
channels and resembled delayed rectifiers, while KCNA4 was rapidly
inactivating.
Glaudemans et al. (2009) demonstrated the presence of Kv1.1 channels in
the superficial cortex of mouse kidney. Using serial kidney sections,
they showed that Kv1.1 channels colocolize with the epithelial magnesium
channel TRPM6 (607009) in the distal convoluted tubule.
MAPPING
Chandy et al. (1990) demonstrated that 3 closely related potassium
channel genes, MK1, MK2, and MK3, are located at separate sites in the
genome of the mouse. These genes, encoding subunits of voltage-dependent
K+ channels, are homologous to the Drosophila Shaker gene. McPherson et
al. (1991) mapped member 1 of the Shaker-related subfamily of K+ channel
genes (the homolog of MK1) to human chromosome 12 by study of somatic
cell hybrids. Curran et al. (1992) mapped the KCNA1 gene to chromosome
12 by use of human-rodent somatic cell panels and narrowed the
localization to the distal short arm by in situ hybridization. Linkage
studies had shown a maximum lod score of 2.72 at a recombination
fraction of 0.05 between KCNA1 and the von Willebrand locus (VWF;
613160). Using interspecific backcrosses between Mus musculus and Mus
spretus, Klocke et al. (1993) mapped the Kcna1, Kcna5 (176267), and
Kcna6 genes to mouse chromosome 6, close to the homolog of TPI1
(190450), which is located on 12p13 in the human. Albrecht et al. (1995)
determined that a 300-kb cluster on chromosome 12p13 contains the human
KCNA6, KCNA1, and KCNA5 genes arranged in tandem.
GENE FUNCTION
Adelman et al. (1995) injected Xenopus oocytes with cDNAs corresponding
to 6 different mutations associated with autosomal dominant myokymia
with episodic ataxia, also known as episodic ataxia type 1 (EA1;
160120). They demonstrated that coassembly of one or more episodic
ataxia subunits with a wildtype subunit can alter channel function,
giving a dominant-negative effect.
Larsson and Elinder (2000) investigated the role of conserved glutamate
at the extracellular end of segment 5 (S5) in slow inactivation by
mutating it to a cysteine (E418C in Shaker). Larsson and Elinder (2000)
could lock the channel in 2 different conformations by disulfide-linking
418C to 2 different cysteines, introduced in the Pore-S6 (P-S6) loop.
Their results suggested that E418 normally stabilizes the open
conformation of the slow inactivation gate by forming hydrogen bonds
with the P-S6 loop. Breaking these bonds allows the P-S6 loop to rotate,
which closes the slow inactivation gate.
Zhou et al. (2001) showed that the central cavity and inner pore of the
Shaker type potassium channel form the receptor site for both the
inactivation gate and small-molecule inhibitors. Zhou et al. (2001)
proposed that inactivation occurs by a sequential reaction in which the
gate binds initially to the cytoplasmic channel surface and then enters
the pore as an extended peptide. This mechanism accounts for the
functional properties of potassium channel inactivation and indicates
that the cavity may be the site of action for certain drugs that alter
cation channel function.
Gu et al. (2003) found that Kv1 axonal targeting required its T1
tetramerization domain. When fused to unpolarized CD4 (186940) or
dendritic transferrin receptor (TFR; 190010), T1 domains from Kv1.1,
Kv1.2, and Kv1.4 promoted their axonal surface expression. Moreover,
mutations in the T1 domain of Kv1.2 that eliminated association with
Kv-beta-2 (601142) compromised axonal targeting, but not surface
expression, of CD4-T1 fusion proteins. The authors concluded that proper
association of Kv-beta with the Kv1 T1 domain is essential for axonal
targeting.
The combinatorial association between distinct alpha and beta subunits
is thought to determine whether Kv channels function as noninactivating
delayed rectifiers or as rapidly inactivating A-type channels. Oliver et
al. (2004) showed that membrane lipids can convert A-type channels into
delayed rectifiers and vice versa. Phosphoinositides, particularly
phosphatidylinositol-4,5-bisphosphate (PIP2), remove N-type inactivation
from A-type channels by immobilizing the inactivation domains.
Conversely, arachidonic acid and its amide anandamide endow delayed
rectifiers with rapid voltage-dependent inactivation. Oliver et al.
(2004) concluded that the bidirectional control of Kv channel gating by
lipids may provide a mechanism for the dynamic regulation of electrical
signaling in the nervous system.
Raab-Graham et al. (2006) found that the mTOR (601231) inhibitor
rapamycin increased the Kv1.1 voltage-gated potassium channel protein in
hippocampal neurons and promoted Kv1.1 surface expression on dendrites
without altering its axonal expression. Moreover, endogenous Kv1.1 mRNA
was detected in dendrites. Using Kv1.1 fused to the photoconvertible
fluorescence protein Kaede as a reporter for local synthesis,
Raab-Graham et al. (2006) observed Kv1.1 synthesis in dendrites upon
inhibition of mTOR or the N-methyl-D-aspartate (NMDA) glutamate receptor
(see 138251). Thus, Raab-Graham et al. (2006) concluded that synaptic
excitation may cause local suppression of dendritic Kv1 channels by
reducing their local synthesis.
BIOCHEMICAL FEATURES
Doyle et al. (1998) determined the atomic structure of the Streptomyces
lividans KcsA potassium channel pore by means of x-ray crystallography.
However, serious doubts were raised concerning whether the prokaryotic
potassium channel pore actually represents those of eukaryotes. Lu et
al. (2001) addressed this issue by substituting the prokaryotic
potassium channel pore into eukaryotic voltage-gated and
inward-rectifier (see 600681) potassium channels. The resulting chimeras
retained the respective functional hallmarks of the eukaryotic channels,
which indicates that the ion conduction pore is indeed conserved among
potassium channels.
Zhou et al. (2001) determined the chemistry of ion coordination and
hydration of the KcsA potassium channel pore at 2-angstrom resolution.
Morais-Cabral et al. (2001) further determined the energetic
optimization by the potassium selectivity filter. Berneche and Roux
(2001) performed molecular dynamics free energy simulations on the basis
of the x-ray structure of the KcsA potassium channel.
Gubitosi-Klug et al. (2005) determined that human Kv1.1 is palmitoylated
at cys243. This palmitoylation modulated voltage sensing by Kv1.1 and
facilitated its dynamic interactions with surrounding lipids during
voltage-induced conformational changes.
In the Shaker potassium channel, mutation of the first charged residue
of the S4 helix to a smaller uncharged residue makes the voltage-sensing
domain permeable to ions ('omega current') in the resting conformation
('S4 down'). Tombola et al. (2007) performed a structure-guided
perturbation analysis of the omega conductance to map its
voltage-sensing domain permeation pathway. Tombola et al. (2007) found
that there are 4 omega pores per channel, which is consistent with 1
conduction path per voltage-sensing domain. Permeating ions from the
extracellular medium enter the voltage-sensing domain at its peripheral
junction with the pore domain, and then plunge into the core of the
voltage-sending domain in a curved conduction pathway. Tombola et al.
(2007) concluded that their results provided a model of the resting
conformation of the voltage-sensing domain.
Cuello et al. (2010) identified the mechanistic principles by which
movements on the inner bundle gate trigger conformational changes at the
selectivity filter, leading to the nonconductive C-type inactivated
state of the KcsA potassium channel. Analysis of a series of KcsA open
structures suggested that, as a consequence of the hinge bending and
rotation of the transmembrane-2 helix, the aromatic ring of phe103 tilts
toward thr74 and thr75 in the pore-helix and toward ile100 in the
neighboring subunit. This allows the network of hydrogen bonds among
trp67, glu71, and asp80 to destabilize the selectivity filter, allowing
entry to its nonconductive conformation. Mutations at position 103 had a
size-dependent effect on gating kinetics: small side-chain substitutions
F103A and F103C severely impaired inactivation kinetics, whereas larger
side-chain substitutions, such as F103W, had more subtle effects. This
finding suggested that the allosteric coupling between the inner helical
bundle and the selectivity filter might rely on straightforward
mechanical deformation propagated through a network of steric contacts.
MOLECULAR GENETICS
Browne et al. (1994) performed mutation analysis of the KCNA1 coding
region in 4 families with myokymia (rippling of muscles) with episodic
ataxia (160120). They found 4 different missense mutations present in
heterozygous state (176260.0001-176260.0004).
For a comprehensive review of episodic ataxia type 1 and its causative
mutations, see Brandt and Strupp (1997).
In a 5-generation Brazilian family segregating autosomal dominant
hypomagnesemia and myokymia mapping to chromosome 12q, Glaudemans et al.
(2009) identified a heterozygous missense mutation in the KCNA1 gene
(N255D; 176250.0015) that segregated with disease and was not found in
100 control chromosomes.
GENOTYPE/PHENOTYPE CORRELATIONS
Eunson et al. (2000) identified 4 families with different neurologic
phenotypes, including seizures and myokymia, isolated myokymia, severe
drug-resistant EA1, and typical drug-responsive EA1, each of which
carried a different heterozygous mutation in the KCNA1 gene
(176260.0008, 176260.0010-176260.0012). Functional expression studies of
the mutations expressed in Xenopus oocytes revealed that the mutations
impaired the channel function via different mechanisms, and Eunson et
al. (2000) concluded that there may be a genotype/phenotype correlation
(see each allelic variant for details).
ANIMAL MODEL
Smart et al. (1998) found that Kcna1-null mice displayed frequent
spontaneous seizures and that these seizures correlated on the cellular
level with alterations in hippocampal excitability and nerve conduction.
The intrinsic passive properties of CA3 pyramidal cells in hippocampal
slices from homozygous Kcna1-null mice were normal; however, antidromic
action potentials were recruited at lower thresholds. In a subset of
slices, mossy fiber stimulation triggered long-latency epileptiform
burst discharges. Axonal action potential conduction was also altered in
the sciatic nerve.
Using homologous recombination, Herson et al. (2003) introduced the
Kcna1 val408-to-ala mutation (V408A; 176260.0001) into mice. In contrast
to Kcna1-null mice, homozygous V408A mice died after embryonic day 3,
consistent with V408A being a homozygous lethal allele. V408A
heterozygous mice showed stress-induced loss of motor coordination that
was ameliorated by acetazolamide, similar to patients with EA1.
Cerebellar Purkinje cells from V408A heterozygous mice showed a greater
frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic
currents than did wildtype. The authors noted that Kcna1 is localized to
GABAergic interneurons in the cerebellum, suggesting that it may be
important for regulating GABA release, and that mutations in the gene
may alter excitability in the cerebellum, leading to clinical symptoms.
Sleep in fruitflies shares many similarities with mammalian sleep; flies
sleep for many hours (9 to 15 hours) and, when sleep deprived, show
sleep rebound and performance impairments. To determine which genes
underlie short sleeping, Cirelli et al. (2005) performed mutagenesis in
Drosophila melanogaster. By screening 9,000 mutant lines, Cirelli et al.
(2005) found 'minisleep' (mns), a line that sleeps for one-third of the
wildtype amount. Mns flies perform normally in a number of tasks, have
preserved sleep homeostasis, and are not impaired by sleep deprivation.
Cirelli et al. (2005) showed that mns flies carry a point mutation in
Shaker, a C-to-T transition in exon 9 resulting in a
threonine-to-isoleucine substitution. This substitution of a polar amino
acid with a highly hydrophobic one occurs at the extracellular end of
S1. The mutated threonine residue is extremely well conserved from
Aplysia to human. After crossing out genetic modifiers accumulated over
many generations, other Shaker null alleles also caused a short-sleeping
phenotype and failed to complement the mns phenotype. Cirelli et al.
(2005) found that short-sleeping Shaker flies have a reduced life span.
Cirelli et al. (2005) concluded that Shaker, which encodes a
voltage-dependent potassium channel controlling membrane repolarization
and transmitter release, may thus regulate sleep need or efficiency.
Beraud et al. (2006) demonstrated that intracerebroventricular infusion
of a specific Kcna1 blocker, BgK-F6A, greatly reduced neurologic
deficits in rats with experimental autoimmune encephalitis, an animal
model of multiple sclerosis (MS; 126200). BgK-F6A increased the
frequency of miniature excitatory postsynaptic currents in cultured rat
hippocampal cells without affecting T-cell activation. Treated rats
showed decreased ventriculomegaly, decreased cerebral injury, and
preservation of brain bioenergetics compared to control rats.
KCNA5
| dbSNP name | rs3741930(C,T); rs1056468(A,T) |
| cytoBand name | 12p13.32 |
| EntrezGene GeneID | 3741 |
| EntrezGene Description | potassium voltage-gated channel, shaker-related subfamily, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.5 |
OMIM Clinical Significance
Neuro:
Ataxia due to posterior column degeneration;
Progressive vibratory and postural sensibility loss;
Muscle stretch reflex losses;
Flexor plantar responses;
Pain and temperature sensations preserved;
No cerebellar or pyramidal tract involvement
Skel:
Scoliosis
Misc:
Age of onset between 19 and 30 years
Inheritance:
Autosomal dominant
OMIM Title
*176267 POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER
5; KCNA5
;;POTASSIUM CHANNEL 1; PCN1;;
POTASSIUM CHANNEL, INSULINOMA AND ISLET CELL;;
HCK1;;
HK2
OMIM Description
See KCNA1 (176260) for a general discussion of potassium voltage-gated
ion channels.
CLONING
Potassium channels play an important role in the regulation of
pancreatic beta cells in response to glucose and the sulfonylurea oral
hypoglycemic agents. Philipson et al. (1991) used a rat brain potassium
channel probe to screen a human insulinoma cDNA library for clones
encoding voltage-gated potassium channels. They isolated a series of
cDNA clones which were then used to isolate and sequence a potassium
channel gene, designated PCN1.
Tamkun et al. (1991) isolated human heart cDNAs encoding PCN1, which
they called HK2, and HK1 (KCNA4; 176266). They reported that the
predicted 605-amino acid HK2 protein shares the characteristics of
voltage-gated potassium channels, with 6 potential membrane-spanning
domains and a positively charged region in the fourth membrane-spanning
domain. Northern blot analysis revealed that HK2 is expressed as a major
2.5- and a minor 1.5-kb mRNA in human atrium and ventricle.
MAPPING
By study of somatic cell hybrids, McPherson et al. (1991) mapped a
Shaker-related potassium voltage-gated channel gene to chromosome 12.
Designated here KCNA5, the gene was identified with probe Kv1 from the
rat. By multipoint linkage analysis of 8 CEPH families, Phromchotikul et
al. (1993) mapped the KCNA5 gene to chromosome 12p and determined its
position relative to 4 DNA markers. Using interspecific backcrosses
between Mus musculus and Mus spretus, Klocke et al. (1993) mapped the
Kcna5 gene to a cluster with the Kcna1 and Kcna6 (176257) genes and the
mouse homolog of TPI1 (190450). Since TPI1 is located on band 12p13 in
the human, the 3 K(+)-channel genes were predicted to be in the same
band. Curran et al. (1992) mapped the KCNA5 gene, which they erroneously
referred to as the KCNA1 gene, to chromosome 12 by use of human-rodent
somatic cell panels and narrowed the localization to the distal short
arm by in situ hybridization. Linkage studies had shown a maximum lod
score of 2.72 at a recombination fraction of 0.05 between KCNA5 and the
von Willebrand locus (VWF; 613160). Albrecht et al. (1995) determined
that a 300-kb cluster on chromosome 12p13 contains the human KCNA6,
KCNA1, and KCNA5 genes arranged in tandem.
GENE FUNCTION
Philipson et al. (1991) microinjected synthetic RNA encoding PCN1 in
order to determine the electrophysiologic characteristics of the
protein. These experiments demonstrated that the PCN1 potassium channel
has the electrophysiologic characteristics of delayed-rectifier type
channels.
MOLECULAR GENETICS
Simard et al. (2005) screened 180 individuals for polymorphisms in the
KCNA5 gene and identified 2 nonsynonymous variants in the C terminus,
pro532 to leu (P532L) and arg578 to lys (R578K). Although the currents
generated by these variants were nearly identical to the current
generated by the wildtype channel, the substitutions resulted in
channels that were much less sensitive to block by the antiarrhythmic
drug quinidine.
Drolet et al. (2005) determined that the P532L variant altered the
secondary structure of the channel, introducing an alpha helix in the C
terminus of KCNA5 that is absent in the wildtype channel. They confirmed
that channels containing the additional alpha helix were drug resistant.
Using a candidate gene approach, Olson et al. (2006) screened 154
unrelated individuals with isolated atrial fibrillation for mutations in
the KCNA5 gene and identified heterozygosity for an E375X mutation
(176267.0001) in 1 individual (see ATFB7, 612240). The mutation
cosegregated with atrial fibrillation in 2 sibs but was not found in 540
control samples.
Yang et al. (2009) analyzed 12 known atrial fibrillation susceptibility
genes in 120 unrelated Chinese families with atrial fibrillation and
identified 3 mutations in KCNA5 in 4 probands (176267.0002-176267.0004),
for an approximate total population prevalence of 3.3%. Two of the
mutations were subsequently also identified in 3 of 256 unrelated
sporadic atrial fibrillation patients.
In 307 Scandinavian patients with early-onset atrial fibrillation,
Christophersen et al. (2013) identified 6 novel heterozygous missense
mutations in 7 patients (see, e.g., 176267.0005 and 176267.0006) as well
as several previously reported missense variants in 12 of the patients.
None of the novel mutations were found in 216 controls. Functional
analysis demonstrated that 3 of the novel mutations were
gain-of-function changes, whereas the other 3 resulted in loss of
function. Christophersen et al. (2013) noted that no other genes had
been reported to have such a high frequency of rare variants associated
with atrial fibrillation, suggesting that KCNA5 is among the most
important genes involved in early-onset atrial fibrillation.
SCARNA10
| dbSNP name | rs714775(T,C) |
| ccdsGene name | CCDS8548.1 |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 692148 |
| snpEff Gene Name | NCAPD2 |
| EntrezGene Description | small Cajal body-specific RNA 10 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1974 |
| ESP Afr MAF | 0.067922 |
| ESP All MAF | 0.144925 |
| ESP Eur/Amr MAF | 0.178805 |
| ExAC AF | 0.180,1.367e-03 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly (+3-5 SD);
[Face];
Frontal bossing;
Prominent chin;
[Eyes];
Hooded eyelids;
Downslanting palpebral fissures;
[Nose];
Broad nasal tip
SKELETAL:
[Skull];
Scaphocephaly;
[Hands];
Fifth finger clinodactyly
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, mild to severe;
Speech deficits;
Seizures (in some patients);
[Behavioral/psychiatric manifestations];
Anxiety;
Repetitive speech;
Stereotyped behaviors
MISCELLANEOUS:
Onset at birth;
Reported in the Ohio Amish Anabaptist community
MOLECULAR BASIS:
Caused by mutation in the kaptin gene (KPTN, 615620.0001)
OMIM Title
*615639 SMALL CAJAL BODY-SPECIFIC RNA 10; SCARNA10
;;snoRNA, U85
OMIM Description
DESCRIPTION
Small nucleolar RNAs (snoRNAs), like SCARNA10, act as guides to direct
posttranscriptional modification of RNAs. SnoRNAs containing a C/D box
associate with fibrillarin (FBL; 134795) and direct 2-prime-O-ribose
methylation of spliceosomal small nuclear RNAs (snRNAs), whereas those
containing an H/ACA box associate with GAR1 (NOLA1; 606468) and direct
pseudouridylation of snRNAs. SCARNA10 contains both C/D and H/ACA boxes
and participates in both 2-prime-O-methylation and pseudouridylation of
U5 snRNA (see RNU5A, 180691) (Jady and Kiss, 2001).
CLONING
By 3-prime terminal sequencing of RNAs purified from HeLa cells,
followed by PCR of genomic DNA, Jady and Kiss (2001) cloned SCARNA10,
which they designated U85. The 330-nucleotide RNA contains conserved
5-prime C box and 3-prime D box motifs, as well as internal C-prime and
D-prime boxes, predicted to form a long hairpin-like structure. A large
region of U85 was predicted to fold into a hairpin-hinge-hairpin
structure similar to box H/ACA snoRNAs, and the 3-prime hairpin of this
H/ACA-like domain contains an additional short hairpin. The H/ACA-like
domain contains a perfect H box and ACA motif. Database analysis
revealed orthologs of U85 in mouse and fruit fly, but not in yeast.
By fluorescent in situ hybridization and fractionation of HeLa cells,
Darzacq et al. (2002) found that U85 colocalized with coilin (COIL;
600272), a Cajal body marker.
GENE FUNCTION
By immunoprecipitation analysis of HeLa cells, Jady and Kiss (2001)
found that human U85 interacted with both GAR1 and fibrillarin. Mutation
analysis revealed that the C and D boxes of U85, but not its H and ACA
boxes, provided metabolic stability following expression in COS-7 cells.
U85 snoRNA directed O-methylation of C45 and pseudouridylation of U46 in
U5 spliceosomal RNA in vitro and following expression in COS-7 cells.
MAPPING
Darzacq et al. (2002) determined that SCARNA10 originates from intron 4
of the NCAPD2 gene.
Hartz (2014) mapped the SCARNA10 gene to chromosome 12p13.31 based on an
alignment of the sequence of its host gene, NCAPD2 (GenBank GENBANK
D63880), with the genomic sequence (GRCh37).
CDCA3
| dbSNP name | rs150858074(A,G) |
| ccdsGene name | CCDS8565.1 |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 83461 |
| EntrezGene Description | cell division cycle associated 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CDCA3:NM_001297604:exon3:c.T130C:p.S44P,CDCA3:NM_001297602:exon3:c.T130C:p.S44P,CDCA3:NM_031299:exon3:c.T130C:p.S44P,CDCA3:NM_001297603:exon3:c.T130C:p.S44P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.1861 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q99618 |
| dbNSFP Uniprot ID | CDCA3_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.001076 |
| ESP Eur/Amr MAF | 0.001628 |
| ExAC AF | 0.004204 |
RPL13P5
| dbSNP name | rs2269358(G,T); rs2269359(G,A); rs12817264(C,G) |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 283345 |
| snpEff Gene Name | LRRC23 |
| EntrezGene Description | ribosomal protein L13 pseudogene 5 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4477 |
DSTNP2
| dbSNP name | rs2269360(A,G); rs11064444(C,T); rs61730383(A,G) |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 171220 |
| snpEff Gene Name | LRRC23 |
| EntrezGene Description | destrin (actin depolymerizing factor) pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3737 |
POU5F1P3
| dbSNP name | rs7315526(G,C); rs11043498(C,T) |
| ccdsGene name | CCDS8590.1 |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 642559 |
| snpEff Gene Name | CLEC4A |
| EntrezGene Description | POU class 5 homeobox 1 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1951 |
ZNF705A
| dbSNP name | rs10770298(T,C) |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 440077 |
| EntrezGene Description | zinc finger protein 705A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4431 |
DDX12P
| dbSNP name | rs10771709(C,T) |
| cytoBand name | 12p13.31 |
| EntrezGene GeneID | 440081 |
| snpEff Gene Name | DDX12 |
| EntrezGene Description | DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 12, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0326 |
| ESP Afr MAF | 0.139451 |
| ESP All MAF | 0.043145 |
| ESP Eur/Amr MAF | 0.001257 |
TAS2R7
| dbSNP name | rs619381(C,T); rs200796127(G,A) |
| ccdsGene name | CCDS8631.1 |
| CosmicCodingMuts gene | TAS2R7 |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 50837 |
| EntrezGene Description | taste receptor, type 2, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R7:NM_023919:exon1:c.G912A:p.M304I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYW3 |
| dbNSFP Uniprot ID | TA2R7_HUMAN |
| dbNSFP KGp1 AF | 0.0695970695971 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0911602209945 |
| dbNSFP KGp1 Asn AF | 0.0961538461538 |
| dbNSFP KGp1 Eur AF | 0.0804749340369 |
| dbSNP GMAF | 0.06933 |
| ESP Afr MAF | 0.02769 |
| ESP All MAF | 0.089574 |
| ESP Eur/Amr MAF | 0.121279 |
| ExAC AF | 0.114 |
TAS2R8
| dbSNP name | rs2537817(T,C); rs1548803(C,T) |
| ccdsGene name | CCDS8632.1 |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 50836 |
| EntrezGene Description | taste receptor, type 2, member 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R8:NM_023918:exon1:c.A922G:p.M308V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYW2 |
| dbNSFP Uniprot ID | TA2R8_HUMAN |
| dbNSFP KGp1 AF | 0.89880952381 |
| dbNSFP KGp1 Afr AF | 0.595528455285 |
| dbNSFP KGp1 Amr AF | 0.944751381215 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.997361477573 |
| dbSNP GMAF | 0.101 |
| ESP Afr MAF | 0.363761 |
| ESP All MAF | 0.126934 |
| ESP Eur/Amr MAF | 0.0055 |
| ExAC AF | 0.958 |
TAS2R9
| dbSNP name | rs3741845(A,G) |
| ccdsGene name | CCDS8633.1 |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 50835 |
| EntrezGene Description | taste receptor, type 2, member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R9:NM_023917:exon1:c.T560C:p.V187A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYW1 |
| dbNSFP Uniprot ID | TA2R9_HUMAN |
| dbNSFP KGp1 AF | 0.576007326007 |
| dbNSFP KGp1 Afr AF | 0.247967479675 |
| dbNSFP KGp1 Amr AF | 0.599447513812 |
| dbNSFP KGp1 Asn AF | 0.702797202797 |
| dbNSFP KGp1 Eur AF | 0.682058047493 |
| dbSNP GMAF | 0.4242 |
| ESP Afr MAF | 0.260554 |
| ESP All MAF | 0.493311 |
| ESP Eur/Amr MAF | 0.387442 |
| ExAC AF | 0.595 |
TAS2R10
| dbSNP name | rs597468(G,A) |
| ccdsGene name | CCDS8634.1 |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 50839 |
| EntrezGene Description | taste receptor, type 2, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R10:NM_023921:exon1:c.C467T:p.T156M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYW0 |
| dbNSFP Uniprot ID | T2R10_HUMAN |
| dbNSFP KGp1 AF | 0.957875457875 |
| dbNSFP KGp1 Afr AF | 0.829268292683 |
| dbNSFP KGp1 Amr AF | 0.983425414365 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.997361477573 |
| dbSNP GMAF | 0.04178 |
| ESP Afr MAF | 0.16856 |
| ESP All MAF | 0.060219 |
| ESP Eur/Amr MAF | 0.00466 |
| ExAC AF | 0.978 |
LOC100129361
| dbSNP name | rs2416548(C,A); rs1047713(C,G); rs8181(C,G); rs8300(G,A); rs34270405(G,A); rs3911800(G,A); rs2416549(G,A); rs2900127(G,A); rs4763637(T,C); rs4763638(C,T); rs61928644(C,T); rs78424527(A,C); rs34590962(C,T); rs144682584(T,A); rs78219648(T,A); rs61928645(C,T); rs61928646(A,G); rs35183723(T,G); rs35119575(C,G) |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 100533464 |
| EntrezGene Symbol | PRH1-PRR4 |
| snpEff Gene Name | PRR4 |
| EntrezGene Description | PRH1-PRR4 readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4265 |
TAS2R42
| dbSNP name | rs1650017(C,G); rs1669411(A,G); rs1669412(C,T); rs1451772(T,C); rs1669413(C,A); rs5020531(A,G); rs1650019(T,C); rs35969491(T,A) |
| ccdsGene name | CCDS31747.1 |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 353164 |
| EntrezGene Description | taste receptor, type 2, member 42 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TAS2R42:NM_181429:exon1:c.G931C:p.A311P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7RTR8 |
| dbNSFP Uniprot ID | T2R42_HUMAN |
| dbNSFP KGp1 AF | 0.670787545788 |
| dbNSFP KGp1 Afr AF | 0.308943089431 |
| dbNSFP KGp1 Amr AF | 0.743093922652 |
| dbNSFP KGp1 Asn AF | 0.86013986014 |
| dbNSFP KGp1 Eur AF | 0.728232189974 |
| dbSNP GMAF | 0.3287 |
| ESP Afr MAF | 0.394235 |
| ESP All MAF | 0.33746 |
| ESP Eur/Amr MAF | 0.2 |
| ExAC AF | 0.835 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Mouth];
Perioral eczema;
Aphthous ulcers
RESPIRATORY:
Recurrent sinusitis
ABDOMEN:
[Gastrointestinal];
Chronic granulomatous colitis;
Diarrhea;
Perianal infections
IMMUNOLOGY:
Recurrent infections;
Neutrophils show defective intracellular NADPH oxidase production
MISCELLANEOUS:
Onset in early childhood;
One patient has been reported (as of May 2011)
MOLECULAR BASIS:
Caused by mutation in the neutrophil cytosolic factor 4 gene (NCF4,
601488.0001)
OMIM Title
*613966 TASTE RECEPTOR, TYPE 2, MEMBER 42; TAS2R42
;;T2R42;;
T2R55
OMIM Description
DESCRIPTION
TAS2R42 belongs to a family of intronless genes that encode highly
related bitter taste receptors (TAS2Rs). TAS2Rs are G protein-coupled
receptors, which are characterized by 7 transmembrane domains (summary
by Fischer et al., 2005). For further information on the TAS2R gene
family, see 604791.
MAPPING
By genomic sequence analysis, Fischer et al. (2005) mapped the TAS2R42
gene, which they called T2R55, to a TAS2R gene cluster on chromosome
12p13.
LOH12CR2
| dbSNP name | rs56895024(T,C); rs6488515(T,C); rs11054841(A,C) |
| cytoBand name | 12p13.2 |
| EntrezGene GeneID | 503693 |
| snpEff Gene Name | LOH12CR1 |
| EntrezGene Description | loss of heterozygosity, 12, chromosomal region 2 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1575 |
RPL13AP20
| dbSNP name | rs10845659(A,G); rs116717562(A,G) |
| cytoBand name | 12p13.1 |
| EntrezGene GeneID | 387841 |
| snpEff Gene Name | RP11-392P7.2 |
| EntrezGene Description | ribosomal protein L13a pseudogene 20 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1768 |
| ExAC AF | 0.836 |
HTR7P1
| dbSNP name | rs1291363(G,C); rs1291362(A,G); rs1291361(G,T); rs73289160(G,C); rs1291360(C,T); rs148865432(T,C); rs376567980(G,A); rs7305778(C,T); rs7305011(G,A); rs141641408(C,T); rs1291359(C,A); rs373881350(C,G); rs115908645(A,G) |
| cytoBand name | 12p13.1 |
| EntrezGene GeneID | 93164 |
| snpEff Gene Name | HEBP1 |
| EntrezGene Description | 5-hydroxytryptamine (serotonin) receptor 7 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4417 |
EMP1
| dbSNP name | rs12368966(C,T); rs58261347(A,G); rs7132172(T,C); rs10845711(T,C); rs11055276(C,T); rs138713317(G,A); rs115502728(T,G); rs10845712(G,A); rs74693998(A,G); rs7299639(T,C); rs7313687(G,C); rs10772630(T,C); rs7303276(T,C); rs75394368(A,G); rs28600283(C,T); rs10772631(A,G); rs10772632(G,T); rs375161714(A,G); rs4763943(G,A); rs4763327(T,C); rs10845713(C,T); rs7305739(C,T); rs4597146(G,A); rs4763944(G,A); rs7295254(A,G); rs7295467(A,C); rs142479208(G,A); rs183321646(A,G); rs191424390(C,T); rs146583593(T,A); rs7955085(C,T); rs76064989(C,G); rs7315940(A,G); rs10845715(G,A); rs3983740(C,T); rs3983741(T,G); rs11612827(C,T); rs7968765(G,A); rs11608741(G,A); rs10845716(A,C); rs80053241(A,G); rs7963748(A,G); rs4763946(A,G); rs147282605(T,G); rs2291061(C,T); rs2291060(A,G); rs3782562(C,T); rs3782561(G,C); rs34412222(G,A); rs2277395(C,T); rs2069086(T,G); rs8885(C,T); rs3191064(A,G) |
| ccdsGene name | CCDS8660.1 |
| CosmicCodingMuts gene | EMP1 |
| cytoBand name | 12p13.1 |
| EntrezGene GeneID | 2012 |
| EntrezGene Description | epithelial membrane protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EMP1:NM_001423:exon2:c.T32G:p.V11G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8031 |
| snpEff Effect | splice_site_donor |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP Uniprot Acc | B4DRR1 |
| ExAC AF | 0.001204 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Optic atrophy;
Nystagmus
RESPIRATORY:
[Lung];
Pneumonia, recurrent
CHEST:
[External features];
Small chest;
[Ribs, sternum, clavicles, and scapulae];
Anterior cupping of ribs;
Widened anterior ribs
SKELETAL:
Spondylometaphyseal dysplasia;
[Spine];
Mild platyspondyly;
[Pelvis];
Lacy iliac wings;
Narrow sacrosciatic notch;
Irregular proximal femoral metaphyses;
Short femoral necks;
Coxa vara
OMIM Title
*602333 EPITHELIAL MEMBRANE PROTEIN 1; EMP1
;;TUMOR-ASSOCIATED MEMBRANE PROTEIN; TMP
OMIM Description
CLONING
Ben-Porath and Benvenisty (1996) cloned a cDNA encoding epithelial
membrane protein-1 (EMP1), named TMP by them, using RT-PCR on human
embryo kidney RNA. Ruegg et al. (1996) independently isolated a cDNA
encoding EMP1, termed B4B by them, using differential display PCR. The
predicted 157-amino acid EMP1 protein contains 4 transmembrane domains
and 2 potential N-linked glycosylation sites in the first extracellular
loop.
Chen et al. (1997) found that EMP1, named CL-20 by them, shares 39%
amino acid identity with peripheral myelin protein-22 (PMP22; 601097);
the conserved amino acids are located predominantly within the
membrane-spanning domains. Using Northern blot analysis, Chen et al.
(1997) detected a 2.8-kb EMP1 transcript in most of the adult tissues
examined, but not in brain, liver, pancreas, or peripheral blood
leukocytes.
Due to the high amino acid sequence homology among PMP22, EMP1, EMP2
(602334), and EMP3 (602335), Ben-Porath and Benvenisty (1996) proposed
that these proteins are members of a novel family. Using RT-PCR,
Ben-Porath and Benvenisty (1996) detected EMP1 expression in embryonic
kidney, brain, and gut, but not in liver and thymus. Based on the
suggested functions of PMP22, they proposed that EMP1 is involved in
cell-cell interactions and the control of cell proliferation.
GENE STRUCTURE
Chen et al. (1997) found that the EMP1 gene contains 5 exons and 4
introns, and they noted that the exon/intron junctions are located at
the same positions as those of PMP22, suggesting that EMP1 and PMP22
arose by duplication of a common ancestral gene.
MAPPING
Marvin et al. (1995) localized the EMP1 gene to chromosome 12 using a
somatic cell hybrid panel. By fluorescence in situ hybridization, Chen
et al. (1997) and Ruegg et al. (1996) mapped the EMP1 gene to 12p12 and
20q12-q13.1, respectively. By FISH, somatic cell hybridization, and
radiation hybrid analysis, Liehr et al. (1999) confirmed assignment of
the EMP1 gene to chromosome 12p12.3. Ben Porath et al. (1998) mapped the
homologous gene in the mouse to chromosome 6.
Gefitinib is a chemotherapeutic agent that competes for the ATP-binding
site on EGF receptor (EGFR; 131550). To study gefitinib resistance in
tumors, Jain et al. (2005) developed a gefitinib-resistant
adenocarcinoma xenograft in nude mice. Acquisition of gefitinib
resistance correlated with surface expression of Emp1. EMP1 expression
also correlated with reduced response to gefitinib in lung cancer
patient samples, as well as with clinical progression to secondary
gefitinib resistance. EMP1 expression and gefitinib resistance were
independent of gefitinib-sensitizing EGFR somatic mutations.
H2AFJ
| dbSNP name | rs2195199(T,C); rs11612057(A,T); rs3748290(C,T); rs6488710(A,G); rs3789999(G,T) |
| cytoBand name | 12p12.3 |
| EntrezGene GeneID | 55766 |
| EntrezGene Description | H2A histone family, member J |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4789 |
SKP1P2
| dbSNP name | rs74574225(G,A); rs35949588(C,T); rs7955087(T,C); rs10744139(G,A) |
| cytoBand name | 12p12.3 |
| EntrezGene GeneID | 728622 |
| snpEff Gene Name | EEF1A1P33 |
| EntrezGene Description | S-phase kinase-associated protein 1 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05464 |
OMIM Clinical Significance
Eyes:
Anterior chamber cleavage disorder;
Iris coloboma
Growth:
Growth retardation
Endocrine:
Congenital hypothyroidism
Ears:
Narrow external auditory meatus
Neuro:
Cerebellar hypoplasia;
Dandy-Walker malformation
Neck:
Short neck
Teeth:
Fusion of 1-2 lower incisors
Thorax:
Shield thorax
Resp:
Tracheal stenosis
Joints:
Hip dysplasia
Hair:
Dense scalp hair
Limbs:
Short feet
GU:
Hypoplasia of penis
Lab:
Growth hormone deficiency
Inheritance:
Autosomal recessive; ? same as Peters-plus syndrome (261540)
OMIM Title
*601435 S-PHASE KINASE-ASSOCIATED PROTEIN 1 PSEUDOGENE 2; SKP1P2
;;S-PHASE KINASE-ASSOCIATED PROTEIN 1B; SKP1B;;
CDK2/CYCLIN A-ASSOCIATED PROTEIN p19B
OMIM Description
CLONING
Demetrick et al. (1996) reported the cloning of a gene, designated
SKP1B, that shared 90% nucleotide identity with SKP1A (601434).
MAPPING
Demetrick et al. (1996) mapped the SKP1B gene to chromosome 12p12 by
fluorescence in situ hybridization.
CAPZA3
| dbSNP name | rs1075421(T,C) |
| cytoBand name | 12p12.3 |
| EntrezGene GeneID | 93661 |
| snpEff Gene Name | PLCZ1 |
| EntrezGene Description | capping protein (actin filament) muscle Z-line, alpha 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3751 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Nose];
Anosmia;
Decreased smell sensation;
[Mouth];
Ageusia;
Decreased taste sensation
CARDIOVASCULAR:
[Vascular];
Orthostatic hypotension
SKIN, NAILS, HAIR:
[Skin];
Anhidrosis
NEUROLOGIC:
[Peripheral nervous system];
Distal sensory loss (all modalities);
Sural nerve biopsy shows marked loss of myelinated fibers;
Less severe loss of unmyelinated fibers;
Axonal degeneration
MISCELLANEOUS:
Adult onset (20 to 50 years)
OMIM Title
*608722 CAPPING PROTEIN, ALPHA-3; CAPZA3
;;CAP PROTEIN, ACTIN, ALPHA-3 SUBUNIT; CAPPA3;;
CP-ALPHA-3
OMIM Description
DESCRIPTION
Dimeric actin capping proteins are made up of an alpha subunit and a
beta subunit. These proteins bind to actin filaments and stabilize the
length of the filaments by inhibiting the addition or loss of actin
monomers. CAPZA3 is an actin capping protein alpha subunit that may play
a role in sperm architecture and male fertility (Miyagawa et al., 2002).
CLONING
By searching a genomic database for sequences similar to mouse Capza3,
followed by PCR and screening a testis cDNA library, Miyagawa et al.
(2002) cloned CAPZA3. The deduced 299-amino acid protein shares 91.3%
identity with mouse Capza3. The C-terminal domain of CAPZA3 contains an
F-actin capping protein alpha subunit signature-2 sequence and a
putative S100 (see 176940) protein-binding site. CAPZA3 also has 2 arg
residues essential for capping protein function. Northern blot analysis
of several human tissues detected a 1.2-kb transcript only in testis.
Western blot analysis detected CAPZA3 at an apparent molecular mass of
33 kD in testis and sperm. Immunohistochemistry showed that CAPZA3
localized predominantly in the neck region of ejaculated sperm, with
moderate and faint signals also in the tail and postacrosome region,
respectively. CAPZA3 colocalized with actin.
GENE STRUCTURE
Miyagawa et al. (2002) determined that CAPZA3 is an intronless gene. The
5-prime flanking region contains 2 consensus sequences for CRE binding,
but it has no TATA box or GC-rich motifs. The mouse Capza3 gene has a
similar structure.
MAPPING
By genomic sequence analysis, Miyagawa et al. (2002) mapped the CAPZA3
gene to chromosome 12p12. They stated that the mouse Capza3 gene maps to
chromosome 6.
MIR4302
| dbSNP name | rs11048315(G,A) |
| cytoBand name | 12p12.1 |
| EntrezGene GeneID | 100422897 |
| EntrezGene Description | microRNA 4302 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09963 |
| ExAC AF | 0.065,7.396e-03 |
BHLHE41
| dbSNP name | rs1048155(C,G); rs76268917(C,T); rs74767697(C,T); rs4963955(T,C); rs76306214(T,C) |
| cytoBand name | 12p12.1 |
| EntrezGene GeneID | 79365 |
| EntrezGene Description | basic helix-loop-helix family, member e41 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4343 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Jerky smooth pursuit
RESPIRATORY:
[Larynx];
Glottic airway narrowing caused by laryngeal abductor paralysis;
Hoarseness;
Laryngeal stridor;
Nocturnal dyspnea
MUSCLE, SOFT TISSUE:
Mild distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Progressive cerebellar ataxia;
Gait ataxia;
Dysmetria;
Limb fasciculations;
Cerebellar atrophy;
EMG shows neurogenic findings
VOICE:
Dysphonia
MISCELLANEOUS:
Onset in adulthood;
May be X-linked
OMIM Title
*606200 BASIC HELIX-LOOP-HELIX FAMILY, MEMBER E41; BHLHE41
;;BASIC HELIX-LOOP-HELIX DOMAIN-CONTAINING PROTEIN, CLASS B, 3; BHLHB3
DIFFERENTIALLY EXPRESSED IN CHONDROCYTES 2; DEC2;;
SHARP1, RAT, HOMOLOG OF; SHARP1
OMIM Description
Basic helix-loop-helix (bHLH) transcription factors (e.g., DEC1, also
called BHLHB2; 604256) are related to Drosophila hairy/enhancer of split
proteins. They are involved in the control of proliferation and
development during differentiation, particularly in neurons.
CLONING
By searching EST databases for sequences similar to DEC1, followed by
5-prime and 3-prime RACE with chondrocyte cDNA, Fujimoto et al. (2001)
obtained cDNAs encoding human and mouse DEC2. The deduced 482-amino acid
human DEC2 protein contains a bHLH domain and an Orange domain that are
highly conserved with those of mouse Dec2 and rat Sharp1. DEC2 also has
a C-terminal alanine/glycine-rich region not seen in DEC1. Northern blot
analysis detected a 3.6-kb DEC2 transcript that was highly expressed in
skeletal muscle and brain, moderately expressed in pancreas and heart,
expressed at low levels in placenta and lung, and expressed at very low
levels in liver and kidney. RT-PCR analysis detected ubiquitous but
variable expression of DEC2. He et al. (2009) noted that DEC2 has a
C-terminal proline-rich region followed by an HDAC-interacting region.
GENE FUNCTION
Using yeast 1-hybrid screens and reporter analysis, Garriga-Canut et al.
(2001) showed that rat Sharp1 binds to the M1 muscarinic acetylcholine
receptor (see CHRM1; 118510) and acts as a transcriptional repressor of
both TATA-containing and TATA-less promoters. Repression occurs either
via the bHLH domain or via a C-terminal domain that is sensitive to the
histone deacetylase inhibitor trichostatin A.
Honma et al. (2002) found that Dec1 and Dec2, basic helix-loop-helix
transcription factors, repress Clock/Bmal1 (601851; 602550)-induced
transactivation of the mouse Per1 (602260) promoter through direct
protein-protein interactions with Bmal1 and/or competition for E-box
elements. Dec1 and Dec2 are expressed in the suprachiasmatic nucleus in
a circadian fashion, with a peak in the subjective day. A brief light
pulse induced Dec1 but not Dec2 expression in the suprachiasmatic
nucleus in a phase-dependent manner. Dec1 and Dec2 are regulators of the
mammalian molecular clock and form a fifth clock gene family.
Toward a system-level understanding of the transcriptional circuitry
regulating circadian clocks, Ueda et al. (2005) identified
clock-controlled elements on 16 clock and clock-controlled genes in a
comprehensive surveillance of evolutionarily conserved cis elements and
measurement of the transcriptional dynamics. Ueda et al. (2005) found
that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the
expression of Per1 (602260), Nr1d2 (602304), Per2 (603426), Nr1d1
(602408), Dbp (124097), Bhlhb2 (604256), and Bhlhb3 transcription
following a repressor-precedes-activator pattern, resulting in delayed
transcriptional activity. RevErbA/ROR (600825)-binding elements
regulated the transcriptional activity of Arntl (602550), Npas2
(603347), Nfil3 (605327), Clock (601851), Cry1 (601933), and Rorc
(602943) through a repressor-precedes-activator pattern as well.
DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3
(603427), Nr1d1, Nr1d2, Rora, and Rorb (601972) through a
repressor-antiphasic-to-activator mechanism, which generates
high-amplitude transcriptional activity. Ueda et al. (2005) suggested
that regulation of E/E-prime boxes is a topologic vulnerability in
mammalian circadian clocks, a concept that had been functionally
verified using in vitro phenotype assay systems.
MAPPING
Fujimoto et al. (2001) mapped the DEC2 gene to chromosome
12p12.1-p11.23, a region associated with tumors and synpolydactyly, by
FISH. They localized the mouse and rat genes to chromosomes 6G2-G3 and
4q43-q44, respectively.
MOLECULAR GENETICS
In a mother and daughter with the short sleep phenotype (612975), He et
al. (2009) identified a heterozygous mutation in the DEC2 gene (P385R;
606200.0001).
Montagner et al. (2012) showed that SHARP1 is a crucial regulator of the
invasive and metastatic phenotype in triple-negative breast cancer
(TNBC; see 114480), one of the most aggressive types of breast cancer.
SHARP1 is upregulated by the p63 metastasis suppressor and inhibits TNBC
aggressiveness through inhibition of hypoxia-inducible factor 1-alpha
(HIF1A; 603348) and HIF2A (603349). SHARP1 opposes HIF-dependent TNBC
cell migration in vitro, and invasive or metastatic behaviors in vivo.
SHARP1 is required, and sufficient, to limit expression of HIF-target
genes. In primary TNBC, endogenous SHARP1 levels are inversely
correlated with those of HIF targets. Mechanistically, SHARP1 binds to
HIFs and promotes HIF proteasomal degradation by serving as the
HIF-presenting factor to the proteasome. This process is independent of
the VHL tumor suppressor (608537), hypoxia, and the ubiquitination
machinery. SHARP1 therefore determines the intrinsic instability of HIF
proteins to act in parallel to, and cooperate with, oxygen levels.
ANIMAL MODEL
He et al. (2009) found that heterozygous P385R-mutant transgenic mice
showed increased activity and less sleep time compared to wildtype mice.
Under sleep deprivation, transgenic mice also showed less compensatory
gain in non-REM sleep compared to wildtype mice, suggesting a role for
Dec2 in sleep homeostasis. There were no differences in circadian rhythm
compared to wildtype mice. The phenotype was not found in Dec2-null
mice, suggesting a dominant effect of the heterozygous P385R mutation
and a dominant increase in the quantity of wakefulness. Similar results
were found in a Drosophila model.
REP15
| dbSNP name | rs929948(C,T); rs929949(A,G); rs12819160(A,T); rs79406438(A,G); rs78669855(A,G); rs74896599(A,T) |
| ccdsGene name | CCDS31762.1 |
| cytoBand name | 12p11.22 |
| EntrezGene GeneID | 387849 |
| EntrezGene Description | RAB15 effector protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | REP15:NM_001029874:exon1:c.C300T:p.S100S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4706 |
| ESP Afr MAF | 0.370177 |
| ESP All MAF | 0.378748 |
| ESP Eur/Amr MAF | 0.38314 |
| ExAC AF | 0.613 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Mitral valve regurgitation
MISCELLANEOUS:
Age-dependent penetrance
OMIM Title
*610848 RAB15 EFFECTOR PROTEIN; REP15
OMIM Description
DESCRIPTION
REP15 is a binding partner of the RAB GTPase family member RAB15 that
facilitates transferrin receptor (TFRC; 190010) recycling from the
endocytic recycling compartment (Strick and Elferink, 2005).
CLONING
Using a RAB15 GTP-bound mutant as bait to screen a yeast 2-hybrid HeLa
cell cDNA library, Strick and Elferink (2005) cloned REP15. The deduced
233-amino acid protein shares 73.8% identity with the predicted mouse
ortholog. By cell fractionation, biochemical, and Western blot analysis,
they localized REP15 to endocytic membrane and cytosolic fractions in
HeLa cells and suggested that REP15 has membrane-binding properties that
involve protein-protein interactions. Confocal microscopy colocalized
REP15 and RAB15 to the perinuclear region of HeLa cells. Sucrose
gradient cell fractionation and organelle-specific immunoprecipitation
experiments showed that REP15 coprecipitated with RAB11 (RAB11A; 605570)
and TFRC but did not associate with early endosomal marker EEA1
(605070). Strick and Elferink (2005) concluded that REP15 localized
specifically to the endocytic recycling compartment (ERC) and excluded
REP15 from sorting endosomes.
GENE FUNCTION
Using yeast 2-hybrid analysis and GST pull-down studies, Strick and
Elferink (2005) showed that REP15 specifically binds to GTP-bound forms
of RAB15. REP15 did not bind GDP-bound or nucleotide-free RAB15 mutant
forms, nor did it bind another GTPase RAB5 (RAB5A; 179512). Yeast
2-hybrid analysis with REP15 deletion mutants and RAB15 showed no
interaction, suggesting that REP15 interaction with RAB15 may require
multiple binding sites or a structural motif requiring full-length
REP15. Overexpression of REP15 in HeLa cells resulted in higher levels
of internalized TFRC with reduction of cell surface TFRC levels, and
siRNA-knockdown of REP15 blocked TFRC recycling from the ERC.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the REP15
gene to chromosome 12 (TMAP RH99304).
H3F3C
| dbSNP name | rs11051595(C,T); rs11051596(T,G); rs3759294(A,C); rs3759295(T,G) |
| cytoBand name | 12p11.21 |
| EntrezGene GeneID | 440093 |
| EntrezGene Description | H3 histone, family 3C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1084 |
RACGAP1P
| dbSNP name | rs73278987(A,G); rs73278989(A,G) |
| cytoBand name | 12q12 |
| EntrezGene GeneID | 83956 |
| snpEff Gene Name | RP11-478B9.1 |
| EntrezGene Description | Rac GTPase activating protein 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.045 |
LINC00938
| dbSNP name | rs888559(T,A) |
| cytoBand name | 12q12 |
| EntrezGene GeneID | 400027 |
| snpEff Gene Name | ARID2 |
| EntrezGene Description | long intergenic non-protein coding RNA 938 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01699 |
AMIGO2
| dbSNP name | rs75018841(C,A); rs35416930(C,T); rs77852114(G,C); rs79435537(T,C); rs11838003(A,T); rs34535517(G,T); rs854889(A,C); rs11836128(C,T); rs2269828(G,A); rs35667451(C,T) |
| cytoBand name | 12q13.11 |
| EntrezGene GeneID | 347902 |
| EntrezGene Description | adhesion molecule with Ig-like domain 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01515 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial nerve palsies;
[Eyes];
Ophthalmoplegia;
Optic atrophy (1 patient)
CARDIOVASCULAR:
[Vascular];
Stroke, ischemic;
Stroke, hemorrhagic;
Small-vessel disease;
Polyarteritis nodosa;
Aneurysms;
Stenosis;
Hypertension (in some patients)
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Gastrointestinal pain
GENITOURINARY:
[Kidneys];
Renal artery aneurysms
SKELETAL:
Arthritis;
[Hands];
Ischemic digital necrosis;
[Feet];
Ischemic digital necrosis
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa;
Livedo reticularis;
Erythema nodosum;
Urticarial rash;
Purpura;
HISTOLOGY:;
Vasculitis in the reticular dermis;
Inflammatory infiltrate;
Interstitial neutrophils and macrophages;
Perivascular T lymphocytes;
Leukocytoclastic vasculitis;
Panniculitis
MUSCLE, SOFT TISSUE:
Myalgia
NEUROLOGIC:
[Central nervous system];
Neurologic sequelae of stroke;
Altered mental status;
Hemiplegia;
Headache;
Ataxia;
Agitation;
Cranial nerve dysfunction;
Aphasia;
Lacunar infarcts in the deep-brain nuclei, brainstem, internal capsule
seen on imaging;
[Peripheral nervous system];
Raynaud phenomenon;
Neuropathy
METABOLIC FEATURES:
Fever, recurrent
HEMATOLOGY:
Lupus anticoagulant (in some patients);
Anemia (in some patients);
Thrombocytosis (in some patients)
IMMUNOLOGY:
Immunodeficiency;
Hypogammaglobulinemia (in some patients);
Leukopenia;
Leukocytosis
LABORATORY ABNORMALITIES:
Abnormal liver enzymes;
Acute-phase reactants during fever
MISCELLANEOUS:
Variable age at onset, usually in first decade, but can occur later;
Variable manifestations;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0001)
OMIM Title
*615690 ADHESION MOLECULE WITH Ig-LIKE DOMAIN 2; AMIGO2
;;AMPHOTERIN-INDUCED GENE AND OPEN READING FRAME 2; AMIGO2;;
ALIVIN 1; ALI1
OMIM Description
DESCRIPTION
AMIGO2 belongs to a family of cell surface transmembrane proteins that
interact with one another. These proteins are predicted to function in
cell adhesion (Kuja-Panula et al., 2003).
CLONING
By searching an EST database for sequences similar to rat Ali1, followed
by PCR of a brain cDNA library, Ono et al. (2003) cloned human AMIGO2,
which they called ALI1. The deduced 522-amino acid protein contains an
N-terminal signal sequence, followed by a cysteine-rich domain, 7
leucine-rich repeats (LRRs), a second cysteine-rich domain, an
immunoglobulin C2-like loop, a transmembrane region, and a C-terminal
intracellular domain. Human ALI1 shares 38% and 32% amino acid identity
with human ALI2 (AMIGO1; 615689) and ALI3 (AMIGO3; 615691),
respectively, and 87% identity with its mouse ortholog. Northern blot
analysis detected Ali1 expression in all 11 rat tissues examined, with
highest expression in lung. Immunohistochemical analysis of rat
cerebellum showed Ali1 localized in somata of cerebellar granule neurons
and Purkinje cells. In rat hippocampus, Ali1 localized in somata of
pyramidal cells between the CA1 and CA3 regions. Fractionation of rat
brain revealed that Ali1 was expressed at the plasma membrane and in
nuclei.
By searching an EST database for sequences similar to AMIGO (AMIGO1;
615689), followed by 5-prime RACE of HT1080 cells, Kuja-Panula et al.
(2003) cloned human AMIGO2. Kuja-Panula et al. (2003) reported that the
AMIGO proteins contain 6 LRRs. The AMIGO protein family shares highest
similarity with the SLIT family of extracellular axon-guiding proteins
(see 603742) and with the NOGO66 receptor (RTN4R; 605566). RT-PCR
analysis detected variable Amigo3 expression in all 12 mouse tissues
examined, with highest expression in cerebellum, retina, liver, and
lung.
GENE FUNCTION
Using cultured embryonic rat cortical and cerebellar neurons, Ono et al.
(2003) found that Ali1 expression was dependent upon neuronal activity.
Upon KCl stimulation, Ali1 transcription was upregulated by calcium
influx through voltage-dependent L-type calcium channels (see 114205).
Expression of Ali1 mRNA was inhibited, and apoptosis was induced, when
spontaneous electrical activity was blocked by tetrodotoxin or an
N-methyl-D-aspartate antagonist. Overexpression of Ali1 in rat
cerebellar neurons inhibited apoptosis induced by low-potassium medium,
a condition that blocks spontaneous activity. Apoptosis was also induced
in rat cerebellar neurons by anti-Ali1 antiserum and recombinant soluble
extracellular domain of Ali1. Ono et al. (2003) concluded that ALI1
expressed at the cell surface is involved in depolarization-dependent
survival of cerebellar granule neurons.
GENE STRUCTURE
Ono et al. (2003) determined that AMIGO2 is an intronless gene. The
3-prime UTR contains 4 copies of the AUUUA destabilization motif and an
mRNA-trafficking motif (UACAAAA).
MAPPING
By radiation hybrid analysis, Ono et al. (2003) mapped the mouse Amigo2
gene to a region of chromosome 15 that shares homology of synteny with
human chromosome 12q13.11.
Hartz (2014) mapped the AMIGO2 gene to chromosome 12q13.11 based on an
alignment of the AMIGO2 sequence (GenBank GENBANK AK091761) with the
genomic sequence (GRCh37).
VDR
| dbSNP name | rs11574139(T,A); rs2853563(C,T); rs2853562(T,A); rs2544043(G,C); rs9729(G,T); rs3858733(T,G); rs739837(G,T); rs202139940(C,T); rs731236(A,G); rs7975232(C,A); rs11574114(C,T); rs11574113(C,G); rs114496626(G,A); rs757343(C,T); rs1544410(C,T); rs11574103(C,G); rs55748765(C,T); rs10783217(A,G); rs2238141(C,T); rs111334502(A,G); rs146470121(C,T); rs2525044(A,G); rs58187695(G,A); rs114558635(A,G); rs376872382(A,G); rs7962898(C,T); rs58789572(C,T); rs7963776(G,A); rs4760732(C,T); rs4760733(A,G); rs7967152(A,C); rs2239185(G,A); rs2239184(G,A); rs7971418(C,A); rs372915749(A,C); rs7975128(G,A); rs77066449(T,G); rs117821874(C,T); rs111325133(G,C); rs11168264(A,G); rs113322950(T,C); rs7296204(G,A); rs11574099(C,T); rs7316602(T,C); rs11168265(C,T); rs7966569(A,G); rs7305032(G,A); rs11574087(C,A); rs11168266(C,T); rs11168267(G,A); rs11168268(G,A); rs11574081(G,A); rs2238140(G,A); rs74085259(T,C); rs367833968(A,G); rs2248098(A,G); rs12370156(C,T); rs987849(G,A); rs2283343(G,A); rs115662557(A,G); rs2239182(T,C); rs2107301(G,A); rs2239181(A,C); rs2239180(C,G); rs79428807(A,G); rs2238139(G,A); rs1540339(C,T); rs11574072(C,T); rs2239179(T,C); rs12717991(C,T); rs7965360(A,G); rs140601173(A,C); rs368427399(C,T); rs111664185(G,A); rs117363307(G,T); rs7308350(C,A); rs114517933(A,T); rs12721370(C,A); rs1808208(G,A); rs73109883(G,A); rs2189480(G,T); rs112971329(C,T); rs2238138(G,A); rs12721395(T,A); rs59707231(A,T); rs3819545(A,G); rs111386341(A,G); rs117572434(T,C); rs117593271(C,T); rs12721396(G,A); rs114098938(A,T); rs114480780(G,A); rs3782905(G,C); rs12721397(A,G); rs80249036(C,A); rs112853820(G,A); rs10735809(G,A); rs10875693(T,A); rs7974353(T,C); rs372908687(G,A); rs7974708(T,C); rs6580642(T,C); rs75358931(G,A); rs11574053(A,G); rs11574052(C,T); rs11168275(T,C); rs11574050(G,A); rs80145821(G,T); rs10783218(G,A); rs2228570(A,G); rs2408876(T,C); rs2254210(G,A); rs2408877(T,A); rs11574044(A,C); rs11574042(C,G); rs11574041(C,T); rs2238136(C,T); rs1989969(A,G); rs2238135(C,G); rs2853564(G,A); rs11168280(T,G); rs7974905(C,T); rs112757594(G,C); rs7965266(T,A); rs7965274(T,C); rs7979131(G,T); rs4760648(C,T); rs4760649(G,A); rs2853561(T,C); rs74085273(C,T); rs10875694(T,A); rs12298585(C,G); rs115517118(A,G); rs2853559(A,G); rs12721375(G,A); rs11168284(A,G); rs7965943(G,T); rs4760650(G,T); rs3922882(C,G); rs11168287(G,A); rs4334089(G,A); rs11574029(T,C); rs11168288(G,A); rs7965397(G,T); rs3890734(G,A); rs3890733(C,T); rs112892098(C,T); rs113389151(C,T); rs111336890(T,C); rs11168290(G,A); rs7302235(T,C); rs58379944(A,G); rs10875695(C,A); rs112884497(A,C); rs11168292(C,G); rs11168293(G,T); rs60556433(G,A); rs4760655(G,A); rs7136534(C,T); rs57946627(T,C); rs12721377(T,C); rs10783219(T,A); rs10083198(T,C); rs7299460(C,T); rs4760658(A,G); rs7979360(A,G); rs11574013(G,A) |
| ccdsGene name | CCDS8757.1 |
| cytoBand name | 12q13.11 |
| EntrezGene GeneID | 7421 |
| EntrezGene Description | vitamin D (1,25- dihydroxyvitamin D3) receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | VDR:NM_001017536:exon10:c.G1259A:p.R420H,VDR:NM_001017535:exon11:c.G1109A:p.R370H,VDR:NM_000376:exon10:c.G1109A:p.R370H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6454 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DRV7 |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 4.879e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Apnea during seizure spells;
Cyanosis
NEUROLOGIC:
[Central nervous system];
Seizures, partial, afebrile;
Secondary generalized tonic-clonic seizures may occur;
Seizures, generalized, afebrile;
Seizures occur in clusters over 1 or several days;
Seizures often begin focally with head and eye deviation;
Hypertonia and rigidity during seizures;
Staring episodes during seizures;
Ictal EEG shows focal onset in central, parietal, or temporal regions;
Normal psychomotor development;
Normal interictal EEG
MISCELLANEOUS:
Average onset 6-10 months (range 3-24);
Seizures easily controlled by medications;
Spontaneous resolution usually after 12 months of age;
Genetic heterogeneity (see BFIC2, 605751);
See also benign familial neonatal-infantile convulsions (BFNIS, 607745),
which shows some phenotypic similarities
OMIM Title
*601769 VITAMIN D RECEPTOR; VDR
;;1,25-@DIHYDROXYVITAMIN D3 RECEPTOR;;
VITAMIN D HORMONE RECEPTOR
OMIM Description
DESCRIPTION
Vitamin D3 (cholecalciferol), which is synthesized in the epidermis in
response to ultraviolet radiation, and dietary vitamin D2
(ergocalciferol), which is synthesized in plants, are devoid of any
biologic activity. Vitamin D hormonal activity is due primarily to the
hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3
(1,25(OH)2D3, or calcitriol). Vitamin D receptor (VDR) is an
intracellular hormone receptor that specifically binds 1,25(OH)2D3 and
mediates its effects (summary by Baker et al. (1988), Liberman and Marx
(2001), and Koren (2006)).
CLONING
Baker et al. (1988) isolated a cDNA corresponding to the human vitamin D
receptor from a human intestinal cDNA library. The deduced 427-amino
acid protein has a calculated molecular mass of 48.3 kD and belongs to
the superfamily of trans-acting transcriptional regulatory factors,
including the steroid and thyroid hormone receptors. The VDR protein
contains a zinc-finger DNA-binding and transcriptional activation domain
and a ligand-binding domain. VDR is closely related to the thyroid
hormone receptors. RNA blot hybridization indicated a single RNA species
of about 4.6 kb.
GENE STRUCTURE
Miyamoto et al. (1997) determined that the VDR gene contains 11 exons
and spans approximately 75 kb. The noncoding 5-prime end of the VDR gene
includes exons 1A, 1B, and 1C, while its translated product is encoded
by 8 additional exons (2-9). Three unique mRNA isoforms are produced as
a result of the differential splicing of exons 1B and 1C. The DNA
sequence upstream to exon 1A is GC-rich and does not contain an apparent
TATA box. Several potential binding sites for the transcription factor
SP1 (189906) and other activators were noted. An intron fragment 3-prime
of exon 1C conferred retinoic acid responsivity when fused to a reporter
gene plasmid.
Exons 2 and 3 of the VDR gene are involved in DNA binding, and exons 7,
8, and 9 are involved in binding to vitamin D (Hughes et al., 1988).
MAPPING
Faraco et al. (1989), who identified an ApaI dimorphism at the VDR
locus, assigned the VDR gene to chromosome 12 by somatic cell hybrid
studies. By study of rat/human somatic cell hybrids, Szpirer et al.
(1991) showed that the VDR gene is located on 12q in the human and
chromosome 7 in the rat. Labuda et al. (1991) assigned the VDR gene to
12q12-q14 by in situ hybridization. No recombination was found between
VDR and COL2A1 (120140; lod = 1.94) or ELA1 (130120; lod = 0.98) on
12q13. The COL2A1 and VDR loci are separated by less than 740 kb, with
VDR distal to COL2A1 (Pedeutour et al., 1994).
GENE FUNCTION
Using mutation analysis, Jurutka et al. (2000) characterized
arg18/arg22, VDR residues immediately N-terminal of the first
DNA-binding zinc finger, as vital for contact with the general
transcription factor IIB (TFIIB; 189963). A natural polymorphic variant
of VDR, termed F/M4 (missing a FokI restriction site), which lacks only
the first 3 amino acids (including glu2), interacted more efficiently
with TFIIB and also possessed elevated transcriptional activity compared
with the full-length (f/M1) receptor. The authors concluded that the
functioning of positively charged arg18/arg22 as part of a VDR docking
site for TFIIB is influenced by the composition of the adjacent
polymorphic N terminus. Increased transactivation by the F/M4 neomorphic
VDR was hypothesized to result from its demonstrated enhanced
association with TFIIB.
Makishima et al. (2002) demonstrated that the vitamin D receptor also
functions as a receptor for the secondary bile acid lithocholic acid,
which is hepatotoxic and a potential enteric carcinogen. The vitamin D
receptor is an order of magnitude more sensitive to lithocholic acid and
its metabolites than are other nuclear receptors. Activation of the
vitamin D receptor by lithocholic acid or vitamin D induced expression
in vivo of CYP3A (124010), a cytochrome P450 enzyme that detoxifies
lithocholic acid in the liver and intestine. Makishima et al. (2002)
suggested a mechanism that may explain the proposed protective effect of
vitamin D and its receptor against colon cancer.
Using retroviral transduction, Palmer et al. (2004) generated human
SW480-ADH colon cancer cells that ectopically express mouse
hemagglutinin-tagged Snai1 (604238) protein (SNAIL-HA). Overexpression
of Snai1 in these cells resulted in lower vitamin D receptor mRNA and
protein expression and inhibited induction of E-cadherin (192090) and
VDR by 1,25(OH)2D3. A 1,25(OH)2D3 analog inhibited tumor growth in
immunodeficient mice injected with mock cells, but not in those injected
with SNAIL-HA cells. In 32 paired samples of normal colon and tumor
tissue from patients undergoing colorectal surgery, Palmer et al. (2004)
found that high SNAI1 expression in tumor tissue correlated with
downregulation of VDR and E-cadherin (p = 0.007 and 0.0073,
respectively). Palmer et al. (2004) concluded that the balance between
VDR and SNAI1 expression is critical for E-cadherin expression, which
influences cell fate during colon cancer progression.
Healy et al. (2005) administered human PTH (168450) over 48 hours to
wildtype mice and observed a 15% reduction in renal VDR levels (p less
than 0.03). When the authors similarly administered PTH to CYP27B1
(609506)-null mice, which are incapable of endogenously producing
vitamin D hormone, they observed a 29% reduction in VDR levels (p less
than 0.001). Healy et al. (2005) concluded that PTH is a potent
downregulator of VDR expression in vivo.
Shah et al. (2006) stated that the signaling and oncogenic activity of
beta-catenin (CTNNB1; 116806) can be repressed by activation of VDR.
Conversely, high levels of beta-catenin can potentiate the
transcriptional activity of 1,25-dihydroxyvitamin D3. Shah et al. (2006)
showed that the effects of beta-catenin on VDR activity are due
interaction between the activator function-2 domain of VDR and the C
terminus of beta-catenin.
Pena et al. (2005) studied the expression and functional correlation of
the SNAI1, E-cadherin (CDH1; 192090), VDR, and ZEB1 (189909) genes and
examined their possible involvement in colon cancer. Their expression
was measured by real-time PCR in 114 patients with colorectal cancer,
and tumor characteristics were analyzed in each patient. SNAI1
expression was associated with downregulation of CDH1 (P = less than
0.001) and VDR (P = less than 0.001) gene products. There was a positive
correlation between CDH1 and VDR expressions, but the association
between SNAI1 and CDH1 was not found in patients with high expression of
ZEB1. There was a correlation between downregulation of: (a) ZEB1 and
presence of polyps in surgical resections; (b) VDR and poor
differentiation; and (c) CDH1 and poor differentiation, vascular
invasion, presence of lymph node metastases, and advanced stages; as
well as a trend toward a correlation between SNAI1 expression in tumors
and vascular invasion. Pena et al. (2005) suggested analyzing these
genes in colon cancer patients for prognostic purposes and for
predicting response to possible therapies with vitamin D or its analogs.
Using DNA microarray and quantitative PCR analyses, Liu et al. (2006)
found that activation of TLR2 (603028) and TLR1 (601194) by a
mycobacterial ligand upregulated expression of VDR and CYP27B1, the
vitamin D 1-hydroxylase that catalyzes the conversion of vitamin D to
its active form, in monocytes and macrophages, but not dendritic cells.
Intracellular flow cytometric and quantitative PCR analyses showed that
treatment of monocytes with vitamin D upregulated expression of CYP24
(CYP24A1; 126065), the vitamin D 24-hydroxylase, and cathelicidin (CAMP;
600474), an antimicrobial peptide, but not DEFB4 (602215). Confocal
microscopy demonstrated colocalization of CAMP with bacteria-containing
vacuoles of vitamin D-treated monocytes, and vitamin D treatment of M.
tuberculosis-infected macrophages reduced the number of viable bacilli.
Ligand stimulation of TLR2 and TLR1 upregulated CYP24 and CAMP in the
presence of human serum, but not bovine serum, and CAMP upregulation was
more efficient in Caucasian than in African American serum, in which
vitamin D levels were significantly lower. Vitamin D supplementation of
African American serum reversed the CAMP induction defect. Liu et al.
(2006) proposed that vitamin D supplementation in African and Asian
populations, which may have a reduced ability to synthesize vitamin D
from ultraviolet light in sunlight, might be an effective and
inexpensive intervention to enhance innate immunity against microbial
infection and neoplastic disease.
In a patient with a form of vitamin D-dependent rickets in which the
vitamin D receptor is intact (VDDR2B; 600785), Chen et al. (2003) found
overexpression of a nuclear response element-binding protein (REBiP)
that interacted with retinoid X receptor (RXR)-VDR heterodimers. Chen et
al. (2006) identified the nuclear protein in that patient as hnRNPC1/C2
(164020), and demonstrated that overexpression of hnRNP C1 and C2 in
vitamin D-responsive cells inhibited VDR-VDRE (vitamin D response
element)-directed transactivation by 23% and 42%, respectively (p less
than 0.005 for both). In contrast, transient expression of an hnRNP
C1/C2 small interfering RNA (siRNA) increased VDR transactivation by 39%
(p less than 0.005). Chromatin immunoprecipitation studies revealed the
presence of REBiP in vitamin D-responsive human cells and indicated that
the normal pattern of 1,25-dihydroxy vitamin D-initiated cyclical
movement of the VDR on and off the VDRE is legislated by competitive,
reciprocal occupancy of the VDRE by hnRNP C1/C2. The temporal and
reciprocal pattern of VDR and hnRNP C1/C2 interaction with the VDRE was
lost in VDDR2B cells overexpressing the hnRNP C1/C2 REBiP. Chen et al.
(2006) suggested that hnRNP C1/C2 may be a key determinant of the
temporal patterns of VDRE occupancy.
Using chromatin immunoprecipitation assays, Zhang et al. (2003) showed
that endogenous Skip (SKIIP; 603055), a putative VDR coactivator,
colocalized with Vdr on VDREs in rat osteosarcoma cells. Crosslinking
and immunoprecipitation experiments showed that endogenous Vdr, Src1
(NCOA1; 602691), and Skip associated with VDREs in the rat Cyp24a1
promoter following treatment with 1,25(OH)2D3. Protein pull-down assays,
followed by SDS-PAGE and mass spectrometry, revealed that human SKIP
interacted with several components of the spliceosome in HeLa cell
nuclear extracts. Expression of a dominant-negative SKIP in COS-7 cells
interfered with proper splicing of transcripts derived from a growth
hormone (GH1; 139250) minigene in response to 1,25(OH)2D3 treatment.
Zhang et al. (2003) concluded that SKIP couples VDR-mediated
transcription to RNA splicing.
In kidney, the level of 1,25(OH)2D3 is controlled by product inhibition,
in which 1,25(OH)2D3 itself, acting through VDR, represses the
1,25(OH)2D3-synthesizing enzyme CYP27B1. Turunen et al. (2007) confirmed
that CYP27B1 was downregulated by 1,25(OH)2D3 via VDR in kidney-derived
HEK293 cells. They showed that inhibition of CYP27B1 by 1,25(OH)2D3 in
HEK293 cells involved interaction of liganded VDR with a negative VDRE
(nVDRE) in the proximal promoter near the CYP27B1 transcriptional start
site and with 2 classical VDREs far upstream of the transcriptional
start site. Both upstream VDREs bound VDR-RXR heterodimers in a
ligand-dependent manner, whereas the nVDRE in the proximal promoter did
not bind VDR-RXR heterodimers directly, but rather bound VDR-interacting
repressor (VDIR, or TCF3; 147141). Turunen et al. (2007) also found that
regulation of CYP27B1 expression in HEK293 cells involved chromatin
looping between the upstream and proximal VDREs.
Chun et al. (2008) reviewed the cellular and molecular mechanisms
associated with vitamin D, including a role for vitamin D in modulating
innate and adaptive immunities. Citing evidence that nonclassic vitamin
D physiology involves localized intracrine modes of action, they
suggested that established models for vitamin D signal transduction
based on endocrine mechanisms are incomplete.
MOLECULAR GENETICS
Uitterlinden et al. (2004) reviewed the genetics of vitamin D receptor
polymorphisms and their associated biologic effects.
- Vitamin D-Dependent Rickets Type 2A
In 2 patients with vitamin D-dependent rickets type 2A (VDDR2A; 277440),
Hughes et al. (1988) identified 2 different mutations in the VDR gene
(601769.0001 and 601769.0002). Hughes et al. (1988) suggested that this
was the first molecular identification of a disease-producing mutation
in a steroid hormone receptor gene. (Mutations were found at about the
same time in the androgen receptor; see 313700.)
Saijo et al. (1991) noted that different mutations in the VDR gene have
been specific for particular ethnic groups: Arabian (601769.0002 and
601769.0003), Haitian (601769.0001), North African (601769.0004), and
Japanese (601769.0005).
Miller et al. (2001) reported a patient with type 2A vitamin D-resistant
rickets who was compound heterozygous for 2 mutations in the VDR gene
(601769.0013, 601769.0014). Similar to patients with mutations in HR
(602302), follicular remnants in this patient's skin appeared to possess
hair follicle stem cells, some of which generated cutaneous cysts. These
and other findings suggested that VDR and HR, which are both zinc finger
proteins, may be in the same genetic pathway that controls postnatal
cycling of the hair follicle.
In the proband of a consanguineous Bedouin family with alopecia and skin
papules, vitamin D-dependent rickets, and deafness, Arita et al. (2008)
identified homozygosity for a missense mutation in the VDR gene
(601769.0015). The mutation was also present in homozygosity in 2
similarly affected sibs from whom DNA was available; the unaffected
parents and 3 unaffected sibs were heterozygous for the change, which
was not found in 100 ethnically matched control chromosomes. Arita et
al. (2008) stated that this was the first reported case of VDDR with
deafness.
- Role in Bone Mineral Density (BMD) and Osteoporosis
Studies on the role of polymorphisms in the VDR gene in the
determination of bone mineral density have been conflicting. Most of the
studies (see below) identified the restriction fragment length
polymorphisms (RFLPs) Bb, Tt, Aa, and Ff, as defined by the
endonucleases BsmI, TaqI, and ApaI, FokI, respectively. The lowercase
allele contains the restriction site, whereas the uppercase allele does
not.
Calcitriol, the active hormonal form of vitamin D, acts through the
vitamin D receptor and a specific vitamin D-responsive element to induce
the synthesis of osteocalcin (BGLAP; 112260), the most abundant
noncollagenous protein in bone. In studies of twins, variation in serum
osteocalcin levels was shown to have a major genetic component (Kelly et
al., 1991) and to be closely correlated with the genetic diversity in
bone density (Pocock et al., 1987). Morrison et al. (1992) presented
evidence suggesting that VDR polymorphisms may influence serum levels of
osteocalcin.
Among 311 healthy women from Sydney, 207 of whom were postmenopausal,
Morrison et al. (1994) found an association between the BB VDR genotype
and lower bone mineral density. However, Hustmyer et al. (1994) found no
relationship between several VDR polymorphisms and bone mineral density
at spine, femur, and forearm among 86 monozygotic and 39 dizygotic adult
female twin pairs. In Korea, Lim et al. (1995) found that no patients
with osteoporosis had the BB genotype. In a study in the northeast of
Scotland, Houston et al. (1996) found that individuals with the BB
genotype had a higher femoral neck bone density than individuals with
the bb genotype, the opposite of the finding in the study of Morrison et
al. (1994). Among 44 patients with severe osteoporosis with vertebral
compression fractures, Houston et al. (1996) found no association with
the VDR genotype.
Garnero et al. (1996) found no relationship between VDR genotype and
bone mass, bone turnover, or bone loss among 268 untreated
postmenopausal women. Ensrud et al. (1999) found no association between
VDR genotype and fracture risk among 9,704 women aged 65 years or older.
Among a group of prepubertal American girls of Mexican descent, Sainz et
al. (1997) found that girls with the aa and bb genotypes had 2 to 3%
higher femoral bone density and an 8 to 10% higher vertebral bone
density than girls with AA and BB genotypes. However, there was no
association between the cross-sectional area of the vertebrae or the
cross-sectional or cortical area of the femur and the vitamin D receptor
genotype. Riggs (1997) quoted a remark by Charles Dent of University
College, London, that 'senile osteoporosis is a pediatric disease.'
Among healthy prepubertal white Australian children aged 7 years, Tao et
al. (1998) found that females homozygous for the t Taq1 allele had lower
BMD than TT homozygotes in certain bone regions; tt homozygotes were
also significantly shorter and lighter. These effects were not observed
in males. The authors suggested that the VDR may play a more important
role in trabecular bone than in cortical bone, and that VDR allelic
variation might be responsible for some of the variation in BMD and
postnatal growth in prepubertal girls.
In a group of men, Ferrari et al. (1999) found that BB homozygotes had
significantly lower BMD only in subjects also carrying the f allele at
the VDR 5-prime polymorphic site (FokI). Serum PTH levels were
significantly higher in the BB genotype at baseline and remained so
under either a low or a high calcium-phosphorus diet. Moreover, on the
low calcium-phosphorus diet, BB subjects had significantly decreased
tubular Pi reabsorptive capacity and plasma Pi levels. The authors
emphasized the importance of identifying multiple single-base mutation
polymorphisms, and suggested a role for environmental/dietary factor
interactions with VDR gene polymorphisms in peak bone mineral mass in
men.
Uitterlinden et al. (2001) found that a haplotype represented by
polymorphisms in the VDR gene and the presence of the COL1A1 gene
Sp1-binding site polymorphism 2046G-T (120150.0051) exhibited a combined
influence on osteoporotic fracture risk, independent of BMD.
Among 426 Italian postmenopausal women, Gennari et al. (1998) found an
association between certain VDR polymorphisms and lumbar spine BMD as
well as the development of osteoporosis. Colin et al. (2003) studied the
combined influence of polymorphisms in both the estrogen receptor gene
(ESR1; 133430) and the VDR gene on the susceptibility to osteoporotic
vertebral fractures in 634 women aged 55 years and older. Three VDR
haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI RFLPs and 3 ESR1
haplotypes (1, 2, and 3) of the PvuII and XbaI RFLPs were identified.
ESR1 haplotype-1 was dose-dependently associated with increased
vertebral fracture risk corresponding to an odds ratio of 1.9 (95% CI,
0.9-4.1) per copy of the risk allele. VDR haplotype-1 was also
overrepresented in vertebral fracture cases. These associations were
independent of BMD.
Nejentsev et al. (2004) studied population differences in
single-nucleotide polymorphisms (SNPs) of the VDR gene. Fang et al.
(2005) determined sequence variation across the major relevant parts of
VDR, including construction of linkage disequilibrium blocks and
identification of haplotype alleles. They analyzed 15 haplotype-tagging
SNPs in relation to 937 clinical fractures recorded in 6,148 elderly
whites over a follow-up period of 7.4 years. Haplotype alleles of the
promoter region and of the 3-prime untranslated region (UTR) was
strongly associated with increased fracture risk. For the 16% of
subjects who had risk genotypes at both regions, their risk increased
48% for clinical fractures (P = 0.0002), independent of age, sex,
height, weight, and bone mineral density. The population-attributable
risk varied between 1% and 12% for each block and was 4% for the
combined VDR risk genotypes. Fang et al. (2005) showed further a 30%
increased mRNA decay in an osteoblast cell line for a construct carrying
the 3-prime-UTR risk haplotype (P = 0.02). This comprehensive candidate
gene analysis demonstrated that the risk allele of multiple VDR
polymorphisms results in lower VDR mRNA levels. This could impact the
vitamin D signaling efficiency and might contribute to the increased
fracture risk observed for these risk haplotype alleles.
In a multicenter large-scale association study of over 26,000
individuals enrolled from 9 European teams, Uitterlinden et al. (2006)
found no association between bone mineral densities at the lumbar spine
and femoral neck or fracture risk and the FokI, BsmI, ApaI, or TaqI VDR
polymorphisms. There was a modest risk reduction (9%) for vertebral
fractures associated with the Cdx2 promoter A allele (dbSNP rs11568820).
Garnero et al. (2005) investigated the relationships between VDR
genotypes and fracture risk. A total of 589 postmenopausal women (mean
age, 62 years) were followed prospectively during a median
(interquartile) of 11 (1.1) years. VDR allele B was significantly and
dose dependently overrepresented in women who fractured, including 34
and 86 women with first incident vertebral and nonvertebral fragility
fractures, respectively. This corresponded to an odds ratio of 1.5 (95%
confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286)
and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers
(BB, n = 90) of the B allele, compared with women with the bb genotype
(n = 213). The authors concluded that VDR genotypes are associated with
the risk of fracture in postmenopausal women independently of BMD, rate
of postmenopausal forearm BMD loss, bone turnover, and endogenous
hormones.
- Role in Height and Overall Growth
Among 589 healthy 2-year-old infants, Suarez et al. (1997) found that
homozygous BB girls had higher length, weight, and body surface area,
and inversely, BB boys had lower weight, body mass index, and body
surface area, than their respective bb counterparts. As a result,
gender-related differences were observed in Bb and bb, but not in BB
populations. These associations with VDR genotype were also observed at
birth and at 10 months of age in the longitudinal analysis of 145
selected full-term babies homozygous for the BsmI polymorphism. The
authors concluded that the VDR genotype may influence intrauterine and
early postnatal growth.
Among 90 healthy Caucasian males, Lorentzon et al. (2000) found that
boys with the BB VDR genotype were shorter at birth and grew less from
birth until after puberty than their Bb and bb counterparts. The BB boys
had lower bone area of the humerus, femur, and total body (p less than
0.05) than the Bb and bb boys; however, the VDR polymorphisms were not
related to BMD at any site. The authors concluded that a prediction
model including parental height, birth height, birth weight, and VDR
alleles could predict up to 39% of the total variation in adult height
in their study population. The VDR allelic variants alone contributed to
8% of the total variation. See STQTL3 (606257).
In a study of 1,873 white subjects from 406 nuclear families, Xiong et
al. (2005) found within-family associations with height at BsmI and TaqI
loci (p = 0.048 and 0.039, respectively). Analyses based on BsmI/TaqI
haplotypes showed linkage (p = 0.05) and association (p = 0.001) with
height. The bT haplotype had the most significant and consistent total
and within-family associations (p = 0.0006 and 0.033, respectively), and
subjects with the bT haplotype were an average of 1% (1.6 cm) taller
than those without it (p = 0.003). The authors noted that this
association might be female-specific and influenced by menstrual status.
Xiong et al. (2005) suggested that VDR may be linked to and associated
with adult height variation in white populations.
D'Alesio et al. (2005) studied the -1521G-C and -1012A-G polymorphisms
located in the VDR promoter region upstream of the transcriptional start
site. A nucleotide change at either SNP led to a dramatic change in
protein-DNA complex formation in nuclear extracts from various cell
lines. Genetic analysis of 185 healthy adolescent girls yielded 3 main
genotypes: homozygous for 1521G/1012A (21.1%), homozygous for
1521C/1012G (17.3%), and heterozygous 1521CG/1012GA (57.3%). Clinical
and biological association studies in the adolescent cohort showed that
girls with a CC/GG genotype had lower circulating levels of
25-dihydroxyvitamin D, with no detectable consequence on calcium
metabolism, lower serum IGF1 (147440) levels, and lower height from 11
years of age to adulthood.
- Role in Hyperparathyroidism
Among 206 Caucasian patients with sporadic primary hyperparathyroidism
(see 145000), Carling et al. (1997) found that the VDR b, a, and T
alleles were overrepresented in 100 menopausal females with sporadic
hyperparathyroidism equivalent. Hyperparathyroidism appeared to be
unrelated to the VDR polymorphisms in patients with hyperparathyroidism
of multiple endocrine neoplasia type I (MEN1; 131100) and patients with
hyperparathyroidism of uremia. By in vitro studies of parathyroid
adenomas, Carling et al. (1997) found an association between
calcium-mediated PTH secretion and inhibition suppression and VDR
genotype. Carling et al. (1998) found that parathyroid tumors from
patients homozygous for the VDR b, a, or T alleles showed significantly
lower VDR and higher PTH mRNA levels than those from patients with BB,
AA, or tt genotypes (p less than 0.0001-0.02), whereas those from
heterozygotes had intermediate values. A similar discrepancy was found
when comparing the baT and non-baT haplotypes (0.042 +/- 0.005 vs 0.064
+/- 0.004 for VDR; 34.4 +/- 3.7 vs 21.6 +/- 2.2 for PTH; both p less
than 0.005). The authors concluded that the lower VDR mRNA levels
associated with the b, a, and T alleles may affect the
calcitriol-mediated control of parathyroid function and thereby
contribute to the development of sporadic primary hyperparathyroidism.
Correa et al. (1999) found no association between the VDR FokI
polymorphism and the development of sporadic primary hyperparathyroidism
among 182 postmenopausal women compared to controls. There were no
significant associations with age, serum calcium, serum PTH, BMD, or
parathyroid tumor weight. The authors concluded that the FokI
polymorphism has at most a minor pathogenic importance in the
development of the disorder.
- Other Disease Associations
Uitterlinden et al. (1997) found overrepresentation of 1 VDR haplotype
and radiographic osteoarthritis and osteophytes at the knee. Adjustment
for bone density at the femoral neck did not change these results,
indicating that the association was not mediated by bone density. The
authors raised the possibility of linkage disequilibrium with the
closely situated COL2A1 gene, which encodes cartilage collagen.
Among 104 Korean patients with psoriasis (177900), Park et al. (1999)
found a significant increase in the frequency of the VDR A polymorphism
compared to controls. This tendency was more marked in early-onset
psoriasis. Derived allele frequencies on the basis of Hardy-Weinberg
equilibrium for A and a were 0.317 and 0.683 in the psoriasis group and
0.168 and 0.832 in the control group, respectively, while in the
early-onset group, A increased to 0.354.
Ban et al. (2000) presented evidence suggesting an association between
the VDR B polymorphism and Japanese patients with Graves disease
(275000).
Motohashi et al. (2003) found a significantly higher frequency of the
VDR B allele among 203 patients with acute onset of type I diabetes
(222100) compared with 222 controls (p = 0.0010).
Selvaraj et al. (2004) presented evidence suggesting that polymorphisms
in the VDR gene may predispose to spinal tuberculosis (TB; see 607948).
Bornman et al. (2004) genotyped the VDR SNPs FokI, BsmI, ApaI, and TaqI
in TB patients, controls, and families in the Gambia, Guinea, and
Guinea-Bissau. By transmission-disequilibrium analysis of family data,
they found a significant global association of TB with the SNP
combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI driven by increased
transmission of the F and A alleles in combination to affected
offspring. Case-control analysis showed no significant association
between TB and VDR variants. Bornman et al. (2004) concluded that there
is a haplotype, rather than a genotype, association between VDR variants
and susceptibility to TB.
ANIMAL MODEL
Yoshizawa et al. (1997) found that VDR-null mice displayed no defect in
development and growth before weaning, irrespective of reduced
expression of vitamin D target genes. After weaning, however, mutants
failed to thrive, with appearance of alopecia, hypocalcemia, and
infertility, and bone formation was severely impaired as a typical
feature of vitamin D-dependent rickets type 2. Unlike humans with this
disease, most of the VDR-null mice died within 15 weeks after birth, and
uterine hypoplasia with impaired folliculogenesis was found in female
reproductive organs. These defects, such as alopecia and uterine
hypoplasia, were not observed in vitamin D-deficient animals. Uterine
hypoplasia was shown to be due to lack of estrogen synthesis in the
mutant ovaries; the uterus in these animals responded normally to
administration of estrogen. Male reproductive organs appeared normal in
VDR-null mice. Uterine hypoplasia, infertility, and early lethality are
not pronounced in patients with vitamin D-dependent rickets type 2,
possibly because of therapy with calcium supplements. The higher content
of calcium in murine milk than in human milk may keep serum calcium
levels normal, thereby ensuring normal growth of VDR-null mice before
weaning. The findings of Yoshizawa et al. (1997) established a critical
role for VDR in growth, bone formation, and female reproduction in the
postweaning stage.
The active metabolite of vitamin D, 1,25(OH)2D3, modulates the immune
response in Th1-related diseases. Using an experimental allergic asthma
model, Wittke et al. (2004) found that, apart from upregulation of 2
Th2-related genes, 1,25(OH)2D3 had no affect on asthma severity in
wildtype mice. Asthma-induced Vdr-deficient mice, however, failed to
develop airway inflammation, airway hyperresponsiveness, or
eosinophilia, despite high IgE concentrations and elevated Th2
cytokines. Wittke et al. (2004) suggested that the vitamin D endocrine
system has an important role in the development of Th2-driven
inflammation in the lung.
During development and postnatal growth of the endochondral skeleton,
proliferative chondrocytes differentiate into hypertrophic chondrocytes,
which subsequently undergo apoptosis and are replaced by bone. Donohue
and Demay (2002) found that Vdr-null mice who developed rickets had
expansion of hypertrophic chondrocytes due to impaired apoptosis of
these cells. Sabbagh et al. (2005) showed that institution of a rescue
diet that restored mineral ion homeostasis in Vdr-null mice prevented
the development of rachitic changes, indicating that mineral ion
abnormalities, not ablation of the Vdr gene, were the cause of impaired
chondrocyte apoptosis. Similarly, 'Hyp' mice with rickets due to
mutation in the Phex gene (300550) also showed impaired apoptosis of
hypertrophic chondrocytes, and the decreased apoptosis was correlated
with hypophosphatemia. Wildtype mice rendered hypercalcemic and
hypophosphatemic by dietary means also developed rickets. In vitro
studies showed that the apoptosis was mediated by caspase-9 (CASP9;
602234). Sabbagh et al. (2005) concluded that hypophosphatemia was the
common mediator of rickets in these mice. The findings indicated that
normal phosphorus levels are required for growth plate maturation and
that circulating phosphate is a key regulator of hypertrophic
chondrocyte apoptosis.
Masuyama et al. (2006) generated mice with conditional inactivation of
Vdr in chondrocytes. Growth-plate chondrocyte development was not
affected by lack of Vdr, but vascular invasion was impaired, and
osteoclast number was reduced in juvenile mice, resulting in increased
trabecular bone mass. Vdr signaling in chondrocytes directly regulated
osteoclastogenesis by inducing Rankl (TNFSF11; 602642) expression.
Mineral homeostasis was also affected in mutant mice. In vivo and in
vitro analysis indicated that Vdr inactivation in chondrocytes reduced
expression of Fgf23 (605380) by osteoblasts and consequently led to
increased renal expression of 1-alpha-hydroxylase (CYP27B1) and
sodium/phosphate cotransporter type IIA (SLC34A1; 182309). Masuyama et
al. (2006) concluded that VDR signaling in chondrocytes is required for
timely osteoclast formation during bone development and for endocrine
action of bone in phosphate homeostasis.
Froicu et al. (2006) compared mice lacking Il10 (124092), which develop
inflammatory bowel disease (IBD; see 266600), with double-knockout (DKO)
mice lacking Il10 and Vdr. They observed normal thymic development and
peripheral T-cell numbers in DKO mice up to 3 weeks of age. However,
following onset of IBD, the thymus became dysplastic with reduced
cellularity and increased apoptosis. Spleen weight increased due to red
blood cell accumulation, but there was a 50% reduction in lymphocytes.
In contrast, mesenteric lymph nodes of DKO mice were enlarged and had
increased lymphocyte numbers. DKO T cells were hyporesponsive. RT-PCR
detected overexpression of inflammatory cytokines (e.g., IL1B; 147720)
in DKO colon. Froicu et al. (2006) concluded that Vdr expression is
required for T-cell control of inflammation in Il10-deficient mice.
Yu and Cantorna (2008) showed that mice lacking Vdr have intrinsically
defective and reduced numbers of invariant natural killer T (iNKT) cells
with diminished responses to alpha-galactosylceramide presented in the
context of CD1d (188410). These iNKT cells also show defective
maturation and reduced thymic expression of CD1d, and lack Tbet
(604895), but not CD122 (IL2RB; 146710), expression.
Quigley et al. (2009) integrated germline polymorphisms with gene
expression in normal skin from a M. musculus x M. spretus backcross to
generate a network view of the gene expression architecture of mouse
skin. They identified expression motifs that contribute to tissue
organization and biologic functions related to inflammation,
hematopoiesis, cell cycle control, and tumor susceptibility. Motifs
associated with inflammation, epidermal barrier function, and
proliferation were differentially regulated in backcross mice
susceptible or resistant to tumor development. The vitamin D receptor
(VDR) was linked to coordinated control of epidermal barrier function,
inflammation, and tumor susceptibility.
HISTORY
Kitagawa et al. (2003) identified a human multiprotein complex that
directly interacts with VDR through WSTF (605681). They designated the
complex WINAC (WSTF-including nucleosome assembly complex) and
determined that it contains as least 13 components. Due to errors
resulting in the failure of several figure panels to report the original
data, the paper of Kitagawa et al. (2003) was retracted (Kitagawa et
al., 2012).
CCDC184
| dbSNP name | rs10783231(A,C); rs73304926(C,T); rs7486941(G,C); rs7485057(T,C); rs7487682(G,T) |
| ccdsGene name | CCDS31785.1 |
| cytoBand name | 12q13.11 |
| EntrezGene GeneID | 387856 |
| EntrezGene Symbol | C12orf68 |
| snpEff Gene Name | C12orf68 |
| EntrezGene Description | chromosome 12 open reading frame 68 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC184:NM_001013635:exon1:c.A420C:p.E140D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q52MB2 |
| dbNSFP Uniprot ID | CL068_HUMAN |
| dbNSFP KGp1 AF | 0.605311355311 |
| dbNSFP KGp1 Afr AF | 0.60162601626 |
| dbNSFP KGp1 Amr AF | 0.538674033149 |
| dbNSFP KGp1 Asn AF | 0.40034965035 |
| dbNSFP KGp1 Eur AF | 0.79419525066 |
| dbSNP GMAF | 0.3944 |
| ESP Afr MAF | 0.332022 |
| ESP All MAF | 0.25485 |
| ESP Eur/Amr MAF | 0.215434 |
| ExAC AF | 0.627 |
OR10AD1
| dbSNP name | rs11168459(A,G); rs11830378(A,C); rs75413005(A,T); rs75531856(C,T); rs17823193(G,A); rs17122812(A,G); rs17224828(A,G) |
| ccdsGene name | CCDS31787.1 |
| CosmicCodingMuts gene | OR10AD1 |
| cytoBand name | 12q13.11 |
| EntrezGene GeneID | 121275 |
| EntrezGene Description | olfactory receptor, family 10, subfamily AD, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10AD1:NM_001004134:exon1:c.T835C:p.Y279H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGE0 |
| dbNSFP Uniprot ID | O10AD_HUMAN |
| dbNSFP KGp1 AF | 0.216575091575 |
| dbNSFP KGp1 Afr AF | 0.25406504065 |
| dbNSFP KGp1 Amr AF | 0.209944751381 |
| dbNSFP KGp1 Asn AF | 0.211538461538 |
| dbNSFP KGp1 Eur AF | 0.199208443272 |
| dbSNP GMAF | 0.2167 |
| ESP Afr MAF | 0.259419 |
| ESP All MAF | 0.230663 |
| ESP Eur/Amr MAF | 0.21593 |
| ExAC AF | 0.184 |
H1FNT
| dbSNP name | rs1471997(G,A); rs2291483(C,T) |
| ccdsGene name | CCDS8762.1 |
| cytoBand name | 12q13.11 |
| EntrezGene GeneID | 341567 |
| EntrezGene Description | H1 histone family, member N, testis-specific |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | H1FNT:NM_181788:exon1:c.G521A:p.R174Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q75WM6 |
| dbNSFP Uniprot ID | H1FNT_HUMAN |
| dbNSFP KGp1 AF | 0.184523809524 |
| dbNSFP KGp1 Afr AF | 0.0914634146341 |
| dbNSFP KGp1 Amr AF | 0.226519337017 |
| dbNSFP KGp1 Asn AF | 0.211538461538 |
| dbNSFP KGp1 Eur AF | 0.204485488127 |
| dbSNP GMAF | 0.185 |
| ESP Afr MAF | 0.103258 |
| ESP All MAF | 0.177821 |
| ESP Eur/Amr MAF | 0.215684 |
| ExAC AF | 0.159 |
WNT1
| dbSNP name | rs114287565(G,A); rs137998844(A,G); rs76398454(C,A) |
| cytoBand name | 12q13.12 |
| EntrezGene GeneID | 7471 |
| EntrezGene Description | wingless-type MMTV integration site family, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmoplantar hyperhidrosis (in some patients);
Fissures of soles (in some patients);
Sensitivity to cold with paresthesias;
[Nails];
Onycholysis of distal nails;
Discoloration of distal nails;
Slowing of nail growth;
Scleronychia (induration and thickening of nails);
Increased transverse curvature in some nails;
Absent lunulae, except on thumbs
MISCELLANEOUS:
Nail changes may be intermittent in some patients
OMIM Title
*164820 WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 1; WNT1
;;ONCOGENE INT1; INT1
MOUSE MAMMARY TUMOR VIRUS INTEGRATION SITE 1, INCLUDED
OMIM Description
DESCRIPTION
The Int oncogenes, including Int1, were first identified as targets for
insertional activation by the mouse mammary tumor virus (MMTV) in
mammary carcinomas. Int2 (see 164950) and Int3 (see 164951) are
fundamentally unrelated genes; the similarity in nomenclature is based
on the criterion of being a target for MMTV insertion mutation.
CLONING
Nusse et al. (1991) proposed that the INT1 gene be termed WNT1
(pronounced 'wint 1'), because it was both an INT gene and a homolog of
the Drosophila 'wingless' gene. The WNTs are a family of secreted
glycoproteins that have been shown to be involved in a variety of
developmental processes in many organisms. The prototype of the family
is the Drosophila protein 'wingless' which acts as a segment polarity
gene during embryogenesis and later participates in pattern formation of
other body parts. Gavin et al. (1990) isolated 7 murine Wnt family
members; Wolda and Moon (1992) isolated 7 Xenopus Wnt family members.
McMahon (1992) discussed the Wnt family of developmental regulators,
with particular reference to mouse mammary gland and the development of
mouse mammary tumors. INT1 has a highly specific (both temporal and
spatial) pattern of expression in fetal brain and spinal cord from 9- to
10-day-old mouse embryos but has been demonstrated to be expressed in
only 1 adult tissue, postmyotic spermatids. The Drosophila homolog of
INT1 is 'wingless,' a segment-polarity gene. Indirect evidence that INT1
is secreted and that the product of 'wingless' is a diffusible gene
product suggests that these proteins are secreted growth factors.
GENE STRUCTURE
By analyzing human genome draft sequence, Kirikoshi et al. (2001)
determined that WNT1 is encoded by 4 exons and is clustered with WNT10B
(601906) in a head-to-head manner within an interval of less than 7 kb.
They discussed possibilities for the origin of WNT gene clusters through
duplication of an ancestral WNT gene cluster.
GENE FUNCTION
Lee et al. (2004) demonstrated that WNT/beta-catenin (116806) signal
activation in emigrating mouse neural crest stem cells had little effect
on the population size and instead regulated fate decisions. Sustained
beta-catenin activity in neural crest cells promoted the formation of
sensory neural cells in vivo at the expense of virtually all other
neural crest derivatives. Moreover, Lee et al. (2004) demonstrated that
WNT is able to instruct early neural crest stem cells to adopt a sensory
neuronal fate in a beta-catenin-dependent manner. Thus, Lee et al.
(2004) concluded that the role of WNT/beta-catenin in stem cells is
cell-type dependent.
Kleber et al. (2005) found that Bmp2 (112261) signaling antagonized the
sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted
synergistically to suppress differentiation and to maintain mouse neural
crest stem cell marker expression and multipotency.
In studies in transgenic mice, Riccomagno et al. (2005) demonstrated
that Wnt3a (606359) and Wnt1 signaling in dorsal regions of the otic
vesicle regulates expression of genes (i.e., Dlx5/6, 600029, 600030;
Gbx2, 601135) necessary for vestibular morphogenesis. In addition, they
found that restriction of the Wnt target genes to the dorsal otocyst is
also influenced by Shh (600725). Riccomagno et al. (2005) suggested that
a balance between Wnt and Shh signaling activities is key in
distinguishing between vestibular and auditory cell types.
Using microarray studies of the mouse presomitic mesoderm transcriptome,
Dequeant et al. (2006) demonstrated that the oscillator associated with
this process, the segmentation clock, drives the periodic expression of
a large network of cyclic genes involved in cell signaling. Mutually
exclusive activation of the Notch (see 190198)-fibroblast growth factor
(FGF) and Wnt pathways during each cycle suggested that coordinated
regulation of these 3 pathways underlies the clock oscillator. Dequeant
et al. (2006) collected presomitic mesoderm samples from 40 mouse
embryos ranging from 19 to 23 somites and used their Lfng (602576)
expression patterns as a proxy to select 17 samples covering an entire
oscillation cycle. Six of the 8 known mouse cyclic genes, Hes1 (139605),
Hes5 (607348), Hey1 (602953), Lfng, Axin2 (604025), and Nkd1 (607851),
were identified with periods of 94, 102, 112, 81, 102, and 112 minutes,
respectively. Two clusters were identified. One cluster contains the
known cyclic genes of the Notch pathway: Hes1, Hes5, and Hey1, as well
as Id1 (600349). This cluster also contains Nrarp, a direct target of
Notch signaling. In the same cluster as the Notch pathway were members
of the FGF-MAPK pathway, including Spry2 (602466) and Dusp6 (602748).
The second cluster of periodic genes contained genes cycling in opposite
phase to the Notch-FGF cluster; in this cluster were a majority of the
cyclic genes associated with Wnt signaling, including Dkk1 (605189),
cMyc (190080), Axin2, Sp5 (609391), and Tnfrsf19 (606122).
Using a combined experimental and computational modeling approach, Sick
et al. (2006) identified Wnt and its inhibitor Dkk as primary
determinants of murine hair follicle spacing. Transgenic Dkk
overexpression reduced overall appendage density. Moderate suppression
of endogenous Wnt signaling forced follicles to form clusters during an
otherwise normal morphogenetic program. Sick et al. (2006) concluded
that their results confirmed predictions of a WNT/DDK-specific
mathematical model and provided in vivo corroboration of the
reaction-diffusion mechanism for epidermal appendage formation.
Ito et al. (2007) demonstrated that after wounding, hair follicles
formed de novo in genetically normal adult mice. The regenerated hair
follicles established a stem cell population, expressed known molecular
markers of follicle differentiation, produced a hair shaft, and
progressed through all stages of the hair follicle cycle. Lineage
analysis demonstrated that the nascent follicles arose from epithelial
cells outside of the hair follicle stem cell niche, suggesting that
epidermal cells in the wound assume a hair follicle stem cell phenotype.
Inhibition of Wnt signaling after reepithelialization completely
abrogated this wound-healing folliculogenesis, whereas overexpression of
Wnt ligand in the epidermis increased the number of regenerated hair
follicles. Ito et al. (2007) concluded that these remarkable
regenerative capabilities of the adult support the notion that wounding
induces an embryonic phenotype in the skin, and that this provides a
window for manipulation of hair follicle neogenesis by Wnt proteins.
By microarray analysis, Hashimi et al. (2009) identified MIR21 (611020)
and MIR34A (611172) among 20 miRNAs that were expressed in a
stage-specific manner during differentiation of cultured human
monocyte-derived dendritic cells (MDDCs). They also found that WNT1 was
a functional target of MIR34A and that JAG1 (601920) was a functional
target of both MIR21 and MIR34A. Inhibition of both MIR21 and MIR34A or
overexpression of WNT1 and JAG1 stalled differentiation of MDDCs and
reduced their endocytic capacity to levels characteristic of immature
DCs. RT-PCR and Western blot analyses revealed that MIR21 and MIR34A
functioned by translational suppression of WNT1 and JAG1.
MAPPING
The INT1 oncogene has been assigned to chromosome 12 by study of somatic
cell hybrids (Nusse et al., 1984). The regional localization is
12pter-q14. The mouse homolog is coded by mouse chromosome 15.
Turc-Carel et al. (1987) mapped INT1 to 12q12-q13 by in situ
hybridization. Turc-Carel et al. (1987) found that the INT1 gene was not
rearranged in a case of myxoid liposarcoma (151900) with
t(12;16)(q13;p11). By in situ hybridization, Arheden et al. (1988)
localized the INT1 gene to 12q13.
MOLECULAR GENETICS
- Osteogenesis Imperfecta, Type XV
By whole-exome sequencing and homozygosity mapping in affected members
of a consanguineous Turkish family segregating OI (OI15; 615220), Keupp
et al. (2013) identified a homozygous 1-bp duplication (c.859dupC;
164820.0001) in the WNT1 gene. Keupp et al. (2013) sequenced the entire
WNT1 coding region in 11 additional families with autosomal recessive OI
for which all known genes affected in OI had been excluded and
identified 4 additional homozygous mutations in 4 families (see, e.g.,
164820.0002-164820.0003). Keupp et al. (2013) demonstrated that the
altered WNT1 proteins failed to activate canonical LRP5-mediated
WNT-regulated beta-catenin signaling. In addition, osteoblasts cultured
in vitro showed enhanced Wnt1 expression with advancing differentiation,
indicating a role of WNT1 in osteoblast function and bone development.
In affected members of 4 consanguineous families segregating a
moderately severe and progressive form of OI, Pyott et al. (2013)
identified 5 different mutations in the WNT1 gene in homozygous or
compound heterozygous state (see, e.g., 164820.0004). In 3 of the
families, the affected individuals also had learning and developmental
delays, and 2 affected individuals from different families had brain
malformations. The mutations in 2 of the families were predicted to
result in nonsense-mediated mRNA decay and the absence of WNT1.
In 4 affected children from 3 unrelated families segregating OI,
Fahiminiya et al. (2013) identified 4 different mutations in the WNT1
gene in homozygous or compound heterozygous state (see, e.g.,
164820.0005-164820.0006). All of those affected had short stature, low
bone density, and severe vertebral compression fractures in addition to
multiple long bone fractures in the first years of life.
In 2 Lao Hmong sisters with a severe form of osteogenesis imperfecta,
Laine et al. (2013) identified a homozygous nonsense mutation in the
WNT1 gene (S295X; 164820.0008). Both parents were heterozygous for the
mutation. The 44-year-old mother had normal bone mineral density (BMD)
on dual-energy x-ray absorptiometry (DXA) and normal spinal radiographs.
The 43-year-old father had normal femoral BMD but had a z score of 1.8
for BMD of the lumbar spine (vertebral bodies L1 through L4). His height
was normal (160 cm). His spinal radiographs showed a mild compression
deformity involving the superior end plate of the L5 vertebral body.
Laine et al. (2013) demonstrated that, in vitro, aberrant forms of the
WNT1 protein showed impaired capacity to induce canonical WNT signaling,
their target genes, and mineralization. Laine et al. (2013) also showed
that mouse Wnt1 was clearly expressed in bone marrow, especially in
B-cell lineage and hematopoietic progenitors; lineage tracing identified
the expression of the gene in a subset of osteocytes, suggesting the
presence of altered cross-talk in WNT signaling between the
hematopoietic and osteoblastic lineage cells in OI type XV and in
osteoporosis.
- Osteoporosis, Early-Onset, Susceptibility to
By whole-exome sequencing of 2 affected individuals from a 4-generation
family segregating early-onset osteoporosis and fractures (BMND16;
615221), Keupp et al. (2013) identified a heterozygous mutation in the
WNT1 gene (R235W; 164820.0007). The mutation segregated with the
phenotype in the family and was not found in over 13,000 alleles listed
in the Exome Variant Server. Also see 164820.0001.
In 10 affected members of a Finnish family segregating severe
early-onset osteoporosis and fractures mapping to chromosome 12, Laine
et al. (2013) identified a heterozygous missense mutation in the WNT1
gene (C218G; 164820.0009).
ANIMAL MODEL
Tsukamoto et al. (1988) generated transgenic mice ectopically expressing
Wnt1 RNA at high levels in mammary and salivary glands of male and
female mice and in male reproductive organs. The mammary glands of males
and virgin females were grossly hyperplastic compared with those of
nontransgenic littermates. Tsukamoto et al. (1988) observed mammary and
(less frequently) salivary adenocarcinomas in these animals at rates
indicating that transcriptional activation of Wnt1 and associated
hyperplasia are initiating events in multistep carcinogenesis.
Thomas and Capecchi (1990) explored the function of int1 in the mouse by
disrupting one of the 2 int1 alleles in mouse embryo-derived stem cells
using positive-negative selection. This cell line was then used to
generate a chimeric mouse that transmitted the mutant allele to its
progeny. Mice heterozygous for the null mutation were normal and
fertile, whereas mice homozygous for the mutation exhibited a range of
phenotypes from death before birth to survival with severe ataxia.
Examination of homozygous mice at several stages of embryogenesis showed
severe abnormalities in the development of the mesencephalon and
metencephalon, indicating a prominent role for the int1 protein in the
induction of the mesencephalon and cerebellum.
The 'swaying' (sw) mouse, first described by Lane (1967), is
characterized by rotational behavior and a severe cerebellar defect that
is also present in some patients with OI. These mice are homozygous for
a spontaneous 1-bp deletion (c.565delG) in the Wnt1 gene that results in
a frameshift beginning at codon 189 and premature termination 10 codons
downstream from the deletion (Thomas et al., 1991). Joeng et al. (2014)
noted that the swaying mutation occurs in the same codon as an OI-linked
nonsense mutation in human WNT1 (E189X; 164820.0003). Joeng et al.
(2014) found that sw/sw mice developed major features of OI, including
spontaneous fractures and severe osteopenia caused by decreased
osteoblast activity. Biomechanical analysis showed that sw/sw bone had
reduced strength compared with wildtype. Spectroscopic analysis
suggested that the matrix of sw/sw bone had reduced mineral and collagen
content compared with wildtype, a finding distinct from bone in
collagen-related forms of OI (see 166200).
DDN
| dbSNP name | rs1054442(A,C); rs3741619(G,A); rs10783299(T,C) |
| cytoBand name | 12q13.12 |
| EntrezGene GeneID | 23109 |
| EntrezGene Description | dendrin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4298 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial weakness;
[Eyes];
Ptosis (less common);
Absence of ophthalmoparesis;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory muscle weakness may occur
MUSCLE, SOFT TISSUE:
Muscle biopsy shows 60-80-nm tubular aggregates arranged in hexagonal
arrays in type 2 fibers
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor milestones (in some);
Proximal muscle weakness due to defect at the neuromuscular junction;
Proximal muscle atrophy;
Distal muscle weakness may also occur;
Easy fatigability;
Muscle cramps;
Gowers sign;
Waddling gait;
Decremental compound motor action potential (CMAP) response to repetitive
nerve stimulation seen on EMG;
Increased jitter seen on single fiber EMG
IMMUNOLOGY:
Absence of acetylcholine receptor (AChR) autoantibodies
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Onset in first decade;
Favorable response to acetylcholinesterase inhibitors;
Distinct disorder from acquired limb-girdle myasthenia (159400)
and congenital limb-girdle myasthenia (254300)
MOLECULAR BASIS:
Caused by mutation in the glutamine:fructose-6-phosphate aminotransferase
1 gene (GFPT1, 138292.0001)
OMIM Title
*610588 DENDRIN; DDN
;;KIAA0749
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1998) cloned dendrin, which they designated
KIAA0749. The 3-prime end of the transcript contains repetitive
elements, and the 678-amino acid protein shares 74.6% amino acid
identity with rat dendrin. RT-PCR ELISA detected highest expression in
brain, skeletal muscle, and kidney, intermediate expression in heart,
testis, and ovary, low expression in liver and spleen, and little to no
expression in lung and pancreas.
By Western blot analysis of fractionated rat brain lysates, Neuner-Jehle
et al. (1996) detected dendrin proteins at about 81 and 89 kD in both
the cytosolic and membrane fractions. Immunohistochemical analysis
detected abundant dendrin expression in hippocampus, notably in apical
dendrites of CA1 pyramidal cells. Dendritic and perikaryal staining was
apparent in neurons of the cerebral cortex, dentate gyrus, subiculum,
amygdala, and preoptic areas. In cortical and hippocampal dendrites,
electron-dense immunoreaction was associated with the endoplasmic
reticulum, the plasma membrane, and spine heads.
GENE FUNCTION
In rat forebrain, Neuner-Jehle et al. (1996) found that DDN expression
was reduced after an extended period of wakefulness. Sleep deprivation
decreased mRNA and protein concentrations of both dendrin isoforms in
subcortical forebrain plus midbrain areas. In the cerebral cortex and
hippocampus, the relative dendrin mRNA levels were unchanged, whereas
the cortical protein concentration was reduced.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the DDN gene
to chromosome 12.
TUBA1A
| dbSNP name | rs1056875(T,C); rs1039225(T,G) |
| ccdsGene name | CCDS8781.1 |
| cytoBand name | 12q13.12 |
| EntrezGene GeneID | 7846 |
| EntrezGene Description | tubulin, alpha 1a |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TUBA1A:NM_001270400:exon3:c.A183G:p.K61K,TUBA1A:NM_001270399:exon3:c.A288G:p.K96K,TUBA1A:NM_006009:exon3:c.A288G:p.K96K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.485347985348 |
| dbNSFP KGp1 Afr AF | 0.605691056911 |
| dbNSFP KGp1 Amr AF | 0.35635359116 |
| dbNSFP KGp1 Asn AF | 0.687062937063 |
| dbNSFP KGp1 Eur AF | 0.316622691293 |
| dbSNP GMAF | 0.4853 |
| ESP Afr MAF | 0.33931 |
| ESP All MAF | 0.442027 |
| ESP Eur/Amr MAF | 0.33 |
| ExAC AF | 0.426 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Ears];
Deafness, sensorineural
GENITOURINARY:
[Kidneys];
Renal salt wasting;
Inability to concentrate urine;
Polyuria;
Decreased glomerular filtration rate;
Renal failure, chronic;
Ultrasound shows hyperechoic kidneys;
Renal biopsy shows tubulointerstitial fibrosis;
Global glomerulosclerosis;
Loss of definition of corticomedullary differentiation
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Hyporeflexia;
Mental retardation;
Motor retardation
METABOLIC FEATURES:
Hypokalemic hypochloremic metabolic alkalosis
ENDOCRINE FEATURES:
Stimulation of the renin/angiotensin/aldosterone axis;
Hyperaldosteronism
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios;
Fetal hydrops;
Fetal polyuria;
[Delivery];
Premature delivery
LABORATORY ABNORMALITIES:
Hypokalemia;
Hyponatremia;
Hypochloremia;
Urinary prostaglandin E;
Increased urinary sodium;
Increased urinary potassium;
Increased urinary chloride
MISCELLANEOUS:
Onset in utero;
Severe volume depletion;
Genetic heterogeneity;
See also antenatal Bartter syndrome type 1 (601678), Bartter syndrome
type 2 (241200), Bartter syndrome 3 (607364), and Bartter syndrome
4b digenic (613090)
MOLECULAR BASIS:
Caused by mutation in the barttin gene (BSND, 606412.0001)
OMIM Title
*602529 TUBULIN, ALPHA-1A; TUBA1A
;;TUBULIN, ALPHA, BRAIN-SPECIFIC;;
B-ALPHA-1;;
TUBA3
OMIM Description
GENE FAMILY
Microtubules tend to be functionally distinct and are involved in
mitosis, cell movement, intracellular movement, and other biologic
processes. The main components of microtubules are different isoforms of
alpha and beta tubulins, which are often cell-type specific.
Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In
humans, this family consists of 15 to 20 dispersed genes, many of which
are processed pseudogenes. The positions of the first 3 introns are
identical between members of the human and rat gene families; in
addition, some human alpha-tubulin genes have a fourth intron, also at
an identical position. Within a vertebrate species, the genes can be
distinguished by their 3-prime untranslated regions (UTRs). Since a
large proportion of the diversity of alpha-tubulins is clustered at the
C-terminal region and is conserved across species, alpha-tubulin genes
can be classified based on homology of their encoded C-terminal motifs
to those of mouse alpha-tubulin genes.
NOMENCLATURE
See Khodiyar et al. (2007) for a revised nomenclature of the
alpha-tubulin gene family.
CLONING
The b-alpha-1 gene, cloned from a human fetal brain cDNA library by
Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By
Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA
is expressed only in brain. They found that the 3-prime UTR of b-alpha-1
is more than 80% homologous to the UTR of the rat brain alpha-tubulin
gene, IL-alpha-T1.
Hall and Cowan (1985) screened a human genomic library with the 3-prime
UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene.
B-alpha-1 encodes a predicted 451-amino acid protein that is 100%
identical to the rat homolog and differs by only 2 and 3 amino acids
from the pig and chicken homologs, respectively. Furthermore, they
observed that the first and largest intron of the b-alpha-1 gene is
homologous to that of the rat gene. Northern blotting showed that
b-alpha-1 expression was restricted to morphologically differentiated
neurologic cells.
By Northern blot analysis and in situ hybridization, Miller et al.
(1987) found that the rat homolog of b-alpha-1, which they called
T-alpha-1, is expressed at high levels during the extension of neuronal
processes.
Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina
cDNA library. One variant had the same sequence as the clone isolated by
Cowan et al. (1983) from fetal brain, and the other had the same
sequence as the brain-specific alpha-tubulin clone isolated by Hall and
Cowan (1985), suggesting that this alpha-tubulin gene is expressed in
both brain and retina.
Poirier et al. (2007) detected high expression of the TUBA1A gene in
human fetal brain. Detailed study of mouse embryos showed expression in
the cortex, hippocampus, cerebellum, brainstem, and rostral migratory
stream. Tuba1a expression was decreased in most neurons at later
postnatal stages and in adulthood.
GENE STRUCTURE
Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4
exons and spans less than 4 kb.
MAPPING
Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on
sequence similarity between the TUBA1A sequence (GenBank GENBANK
AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank
GENBANK AC016125 and GenBank GENBANK AC010173).
Khodiyar et al. (2007) stated that the TUBA1A gene maps to human
chromosome 12q13.12 and mouse chromosome 15F1.
MOLECULAR GENETICS
In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al.
(2007) and Poirier et al. (2007) identified 2 different de novo
heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations
(see, e.g., 602529.0003-602529.0005) in 6 additional patients with a
wide spectrum of brain dysgenesis, ranging from agyria to laminar
heterotopia. Retrospective examination of brain MRI showed defects in
the cerebellum, hippocampus, corpus callosum, and brainstem. Patients
who survived showed mental retardation, seizures, motor delay, and
microcephaly. In general, gyral malformations were more severe in the
posterior than anterior brain regions.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A
gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with
lissencephaly who were negative for mutations in other known
lissencephaly-associated genes. The phenotype ranged from the less
severe perisylvian pachygyria to the more severe posteriorly predominant
pachygyria, which was associated with dysgenesis of the anterior limb of
the internal capsule and mild to severe cerebellar hypoplasia. Patients
with TUBA1A mutations shared a common clinical phenotype consisting of
congenital microcephaly, mental retardation and diplegia/tetraplegia.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations
(see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of
lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545)
mutation. Four of the 5 patients had congenital microcephaly, and all
had dysgenesis of the corpus callosum, cerebellar hypoplasia, and
variable cortical malformations, including subtle subcortical band
heterotopia and absence or hypoplasia of the anterior limb of the
internal capsule.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in
whom mutations in DCX and PAFAH1B1 had been excluded and identified
novel and recurrent TUBA1A mutations in 1% of children with classic
lissencephaly and in 30% of children with lissencephaly with cerebellar
hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of
the corpus callosum and cerebellar hypoplasia without lissencephaly. The
authors demonstrated a wider spectrum of phenotypes than had been
reported and suggested that lissencephaly-associated mutations of TUBA1A
may operate via diverse mechanisms that include disruption of binding
sites for microtubule-associated proteins.
Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A
mutations on tubulin folding, heterodimer assembly, microtubule
dynamics, and stability. The translational yield of each mutant protein
varied across a continuum from an amount similar to that of wildtype for
mutant L286F, to slightly reduced formation for mutants I188L
(602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L
(602529.0005), to significantly diminished amounts for mutants V303G,
L397P, and R402C. Studies of GTP-dependent polymerization and
depolymerization indicated that all the disease-causing TUBA1A mutations
were competent for assembly into microtubules in vitro. However, some of
the mutant proteins showed defects in the tubulin heterodimer assembly
pathway, with deficiencies in the production of intermediates. Mutants
I188L, I238V, L397P and R402C all generated lower yields of
intermediates compared to control TUBA1A; in addition, R402C showed a
time-dependent decay of intermediates, indicating instability. Some of
the mutant proteins (R264C, V303G, and L397P) also showed defective
interaction with assembly chaperone protein TBCB (see, e.g., TBCA,
610058). Tests of heterodimer stability showed that P263T and V303G had
reduced stability, whereas L397P and R402C were highly unstable. P263T
expression resulted in the assembly of heterodimers with a deleterious
effect on microtubule dynamics, whereas the other mutant proteins did
not show defects in microtubule growth. The findings demonstrated that
different TUBA1A mutations result in a variety of tubulin defects, but
also suggested that the mutations may cause compromised interactions
with other interacting proteins essential for proper neuronal migration.
ANIMAL MODEL
Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea
(ENU)-induced mouse mutant with abnormalities in the laminar
architecture of the hippocampus and cortex accompanied by impaired
neuronal migration. Fine mapping and genomic screening identified an
S140G mutation in the Tuba1a gene. Functional studies showed that the
mutation resulted in decreased GTP binding and impaired tubulin
heterodimer formation. However, heterodimers that did form were able to
polymerize and were incorporated into the microtubule network of
cultured cells. Abnormal neuronal migration was manifest as
perturbations in layers II/III and IV of the visual, auditory, and
somatosensory cortices, and a fractured pyramidal cell layer in the
hippocampus. Behavioral studies showed that the mutant mice had impaired
spatial working memory, reduced anxiety, and abnormal nesting,
consistent with a hippocampal deficit. Keays et al. (2007) concluded
that pathogenic mutations in the TUBA1A gene interferes with microtubule
function, thus impairing neuronal migration.
LOC100335030
| dbSNP name | rs7309610(G,A); rs114602392(C,T); rs7488206(C,T); rs7488270(G,A) |
| cytoBand name | 12q13.12 |
| EntrezGene GeneID | 100335030 |
| snpEff Gene Name | SPATS2 |
| EntrezGene Description | FGFR1 oncogene partner 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07805 |
LIMA1
| dbSNP name | rs3184122(A,G); rs9364(G,A); rs1044370(T,C); rs147543382(C,T); rs12426261(A,G); rs4883481(T,C); rs12424335(C,T); rs1862043(G,C); rs138728528(A,G); rs4883482(A,G); rs7315690(C,T); rs7301566(T,C); rs7138420(A,G); rs7138622(C,T); rs10450773(C,T); rs11169306(T,C); rs2358538(G,A); rs11169312(T,A); rs61928263(T,C); rs7300549(G,A); rs10506291(T,C); rs11169314(A,T); rs2004283(T,G); rs2009072(G,A); rs4459386(A,G); rs11169315(A,T); rs10219559(T,C); rs116041065(C,T); rs3861100(A,G); rs2302900(T,C); rs1362984(T,A); rs8181651(C,T); rs11169317(G,T); rs138675367(G,A); rs34825838(T,A); rs78644527(C,T); rs75762455(C,T); rs7308095(G,T); rs1862042(T,C); rs12425705(T,C); rs11169322(C,T); rs8181679(T,C); rs10747572(T,A); rs12424691(G,A); rs12424713(G,A); rs9668955(G,A); rs11169323(A,C); rs73106171(A,C); rs114443045(A,C); rs114567322(T,C); rs115644908(G,A); rs141954955(T,C); rs141256939(A,G); rs1362983(A,G); rs3812825(A,G); rs12811293(G,A); rs79838317(A,T); rs79256223(G,T); rs6580730(C,T); rs7314465(G,A); rs71465002(C,T); rs7136648(G,A); rs12425229(A,C); rs10876013(A,T); rs7308692(C,T); rs10783342(T,C); rs11169331(T,C); rs114392732(C,T); rs11169332(G,A); rs114338688(G,A); rs79934604(T,C); rs79208669(C,T); rs11169335(A,G); rs79157395(C,T); rs17124562(T,C); rs12828340(T,C); rs7957659(T,C); rs7974834(C,T); rs74685854(G,A); rs7979830(C,T); rs79103659(C,T); rs3815671(A,G); rs12423130(A,G); rs7302422(G,A); rs6580732(T,G); rs12809843(A,G); rs7132551(G,A); rs7953953(C,T); rs144118353(T,C); rs76660375(C,T); rs12823506(A,G); rs61928280(A,C); rs2160994(T,C); rs7486747(G,A); rs11169339(T,A); rs35768991(G,A); rs111981506(G,A); rs7309519(G,A); rs10783343(C,G); rs6580734(C,T); rs10783344(T,C); rs1984993(T,C); rs1972611(T,C); rs148177857(G,A); rs141831816(T,C); rs116667672(T,G); rs17274495(C,T); rs10783346(G,A); rs116539721(T,C); rs76034975(G,A); rs116624970(C,T); rs78289454(C,T); rs150776817(G,C); rs11169345(T,C); rs10783347(G,A); rs11169346(T,A); rs11169347(A,G); rs368502395(T,C); rs77101726(G,T); rs6580735(T,C); rs11169348(G,T); rs141346362(G,A); rs75030794(C,T); rs7311378(G,A); rs7311491(G,A); rs143837481(C,A); rs2111988(C,T); rs35535298(G,A); rs11169349(T,C); rs11169350(T,C); rs11169351(C,A); rs7967954(G,A); rs114202366(C,G); rs10876014(C,T); rs736167(C,A) |
| ccdsGene name | CCDS8802.1 |
| cytoBand name | 12q13.12 |
| EntrezGene GeneID | 51474 |
| EntrezGene Description | LIM domain and actin binding 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LIMA1:NM_001243775:exon5:c.G1142A:p.G381D,LIMA1:NM_016357:exon11:c.G2048A:p.G683D,LIMA1:NM_001113547:exon8:c.G1571A:p.G524D,LIMA1:NM_001113546:exon11:c.G2051A:p.G684D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7076 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q59FE8 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 3.415e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Isolated cases
GROWTH:
[Other];
Growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Dysplastic ears;
Low-set ears;
Thick helices;
[Eyes];
Hypertelorism;
Epicanthal folds;
Downslanting palpebral fissures;
[Nose];
Broad flat nose;
[Mouth];
High-arched palate
CARDIOVASCULAR:
[Heart];
Congenital cardiac malformations, variable
RESPIRATORY:
[Nasopharynx];
Velopharyngeal insufficiency
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Learning disabilities;
Mental retardation;
Speech delay
VOICE:
Nasal speech
MISCELLANEOUS:
Contiguous gene duplication syndrome;
Highly variable phenotype, ranging from asymptomatic to severe
MOLECULAR BASIS:
Contiguous gene syndrome caused by duplication (1.5 - 3.0 Mb) of
chromosome 22q11.2
OMIM Title
*608364 LIM DOMAIN AND ACTIN-BINDING PROTEIN 1; LIMA1
;;EPITHELIAL PROTEIN LOST IN NEOPLASM; EPLIN;;
STEROL REGULATORY ELEMENT-BINDING PROTEIN 3; SREBP3
OMIM Description
DESCRIPTION
EPLIN is a cytoskeleton-associated protein that inhibits actin filament
depolymerization and cross-links filaments in bundles (Maul et al.,
2003).
CLONING
By representational difference analysis of normal versus transformed
oral keratinocytes, followed by screening a HeLa cell cDNA library, Maul
and Chang (1999) cloned 2 splice variants of EPLIN, which they
designated EPLIN-alpha and EPLIN-beta. EPLIN-alpha encodes a deduced
600-amino acid protein, and EPLIN-beta encodes a deduced 759-amino acid
protein. Both proteins contain a centrally located LIM domain that is
distantly related to the LIM domain of muscle LIM protein (600824).
Northern blot analysis detected the 2 EPLIN transcripts at about 3.8 kb.
Highest expression was in placenta, followed by kidney, pancreas,
prostate, ovary, spleen, and heart; low expression was detected in all
other tissues. A transcript of about 8 kb was also observed in some
tissues. Western blot analysis detected a major EPLIN-alpha protein at
an apparent molecular mass of 90 kD and a minor EPLIN-beta protein at
about 110 kD in primary mammary, prostate, and oral epithelial cells.
Low levels of EPLIN protein were detected in primary aortic endothelial
cells and dermal fibroblasts, but not in myocardium. The presence of
transcript but not protein in myocardium suggested that EPLIN expression
is tightly regulated. Immunofluorescence analysis detected both EPLIN
isoforms localized to filamentous actin.
GENE FUNCTION
Maul and Chang (1999) found that EPLIN-alpha was either downregulated or
lost in 8 of 8 oral cancer cell lines, 4 of 4 prostate cancer cell
lines, 3 of 3 xenograft tumors, and 5 of 6 breast cancer cell lines
tested. Using an inducible promoter to overexpress EPLIN-alpha and
EPLIN-beta in the U2-OS osteosarcoma cell line, they found that
induction of either isoform altered the morphology of the U2-OS cells
from round polygonal cells with a cobblestone appearance to larger
fusiform cells with spindle cell features and cytoplasmic extensions.
EPLIN overexpression suppressed cell proliferation and increased the
time required for trypsinization, suggesting a change in the cell-matrix
interaction.
Chen et al. (2000) found that endogenous transcription from the
EPLIN-alpha promoter was stimulated by serum, and transcription was
enhanced by activation of RHOA (165390). Transcription from the
EPLIN-beta promoter was unaffected by serum, indicating that expression
of the 2 isoforms can be independently regulated.
Maul et al. (2003) found that overexpression of either EPLIN isoform in
a breast carcinoma cell line increased the number of actin stress
fibers. Using pull-down assays, they established that EPLIN-alpha bound
both actin monomers and purified actin filaments. Using truncation
mutants, they determined that EPLIN-alpha contains at least 2
actin-binding sites, 1 on each side of the central LIM domain. The
stoichiometry of binding showed that 2 actin molecules bind 1 molecule
of EPLIN-alpha. Using fluorescence-labeled actin to monitor
polymerization, they found that EPLIN-alpha did not affect
polymerization, but slowed the rate of depolymerization in a
concentration-dependent manner. EPLIN-alpha did not cap barbed actin
ends, but inhibited branching nucleation of actin filaments by Arp2/3
(604221). Maul et al. (2003) hypothesized that EPLIN-alpha binding to
the sides of actin filaments might prevent secondary activation of
nucleation mediated by Arp2/3, delaying nucleation until polymerization
saturates the filament-binding capacity of EPLIN.
GENE STRUCTURE
Chen et al. (2000) determined that the EPLIN gene contains 11 exons and
spans more than 100 kb. EPLIN-beta mRNA requires all 11 exons, and
EPLIN-alpha mRNA requires exons 4 through 11. ATG initiation codons for
EPLIN-beta and EPLIN-alpha are located in exons 2 and 4, respectively,
and both transcripts share the same TGA stop codon. The EPLIN-alpha
promoter contains a serum response element (SRE), but no TATA box. The
EPLIN-beta promoter has a high GC content and contains several Sp1
(189906) consensus sites, but no TATA boxes.
MAPPING
By genomic sequence analysis, Chen et al. (2000) mapped the LIMA1 gene
to chromosome 12q13.
BIN2
| dbSNP name | rs1044981(C,T); rs3759175(C,T); rs77580094(A,G); rs11835240(G,A); rs4761982(C,T); rs139885911(C,A); rs4761985(G,A); rs6580821(G,T); rs77372820(C,G); rs3847855(C,T); rs7135736(G,A); rs7306875(T,A); rs4761990(A,G); rs4761991(A,C); rs4761994(G,A); rs4761995(G,A); rs74465662(C,T); rs3969069(G,A); rs4991750(G,A); rs4991749(A,G); rs4611251(C,T); rs7954976(T,C); rs4761998(G,A); rs146347748(G,A); rs11169793(C,T); rs12227330(T,A); rs12308997(A,C); rs11838310(G,A); rs117691477(T,C); rs3210837(T,C); rs7306505(T,C); rs7135343(A,T); rs7135840(C,T); rs1362963(T,C); rs2359450(C,A); rs75181075(A,T); rs4762011(G,A); rs4762012(A,G); rs113580494(C,A); rs140244383(C,T); rs7975534(G,C); rs73111045(T,G); rs2288367(G,T); rs111723252(C,T); rs3782468(C,T); rs3782469(A,G); rs7134625(G,A); rs144321166(A,G); rs7955476(A,G); rs7955688(C,T); rs7958762(A,G); rs7973807(T,C); rs149802233(T,A); rs10876160(A,G); rs2288368(G,A); rs10783430(A,G); rs10876161(G,T); rs4762016(G,A); rs4761832(C,T); rs3858637(T,G); rs74093810(C,T); rs7975715(G,A); rs7308177(T,C); rs186765177(G,A); rs68042460(T,A); rs11169798(A,C); rs7316221(T,C); rs2011124(C,G); rs12830766(C,T); rs7316604(T,A); rs143106928(G,A); rs12814917(T,C); rs12228390(C,G); rs57941347(G,A); rs61022955(G,A); rs75478419(T,A); rs74093814(A,T); rs9788096(G,A); rs9788179(T,A); rs71449804(C,T); rs7309232(A,G); rs11832572(G,A); rs11169800(C,A); rs12580302(G,C); rs12580599(C,A); rs74093823(T,C); rs766903(A,G); rs61172662(T,A); rs55901988(T,C); rs76097982(G,C); rs77447697(G,A); rs76025837(G,A); rs74598463(G,A); rs115038997(G,A); rs76447320(T,C); rs77958493(G,T); rs116716523(A,G); rs74518580(A,T); rs4435047(A,G); rs4448733(G,A); rs74093827(A,T); rs4762035(T,C); rs61380773(C,T); rs56869579(T,G); rs55707334(T,A); rs7971409(T,C); rs7306746(T,C); rs60641385(G,A); rs58213562(T,A); rs61570206(C,A); rs80334207(C,T); rs1820617(T,G); rs12581282(C,T); rs186098987(G,T); rs190908775(G,A); rs12370907(C,T); rs4335588(T,C); rs76875296(C,T); rs7138394(T,C); rs4762040(A,G); rs4761843(C,T); rs4761846(C,G); rs4445685(T,A); rs5029067(A,C); rs4762041(T,G); rs4762042(G,T); rs3847857(G,T); rs35854730(T,G); rs4762045(G,A); rs3843650(G,C); rs74093853(C,G) |
| ccdsGene name | CCDS8811.1 |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 51411 |
| EntrezGene Description | bridging integrator 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | BIN2:NM_016293:exon10:c.A1279G:p.S427G,BIN2:NM_001290009:exon9:c.A811G:p.S271G,BIN2:NM_001290008:exon9:c.A1183G:p.S395G,BIN2:NM_001290007:exon10:c.A1105G:p.S369G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6268 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0114468864469 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0145118733509 |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.002043 |
| ESP All MAF | 0.00692 |
| ESP Eur/Amr MAF | 0.009419 |
| ExAC AF | 0.006937 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Bladder];
Urinary urgency (in 44% of patients)
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Rigidity;
Bradykinesia;
Resting tremor;
Asymmetry at onset (74%);
Dystonia at onset (16%);
Postural instability (63%);
Gait impairment (55%);
Hyperreflexia (33%);
Sleep benefit (31%);
Autonomic instability (22%);
Dementia (5%);
[Behavioral/psychiatric manifestations];
Psychiatric disturbances (25%);
Anxiety;
Depression
MISCELLANEOUS:
Early onset (9-48 years, but reported up to 68 years);
Slow progression;
Diurnal fluctuation;
Levodopa-responsive;
Levodopa-induced dyskinesias;
A subset of patients have heterozygous mutations, which may predispose
to disease development
MOLECULAR BASIS:
Caused by mutation in the PTEN-induced putative kinase-1 gene (PINK1,
608309.0001)
OMIM Title
*605936 BRIDGING INTEGRATOR 2; BIN2
OMIM Description
DESCRIPTION
BAR proteins, such as BIN2, which are characterized by a common
N-terminal BAR domain, are adaptor proteins involved in diverse cellular
processes. BIN1 (601248), a member of the BAR family, interacts with and
inhibits the oncogenic properties of MYC (190080) (summary by Ge and
Prendergast, 2000).
CLONING
By searching an EST database for sequences similar to BIN1, followed by
screening a leukocyte phage cDNA library, Ge and Prendergast (2000)
identified a cDNA encoding BIN2. Sequence analysis predicted that the
564-amino acid protein has a BAR motif that is 61% identical to that of
BIN1 and slightly less similar to that of AMPH (600418). BIN2 has acidic
and serine/proline-rich stretches but lacks a C-terminal SH3 domain or a
MYC-interacting region. Northern blot analysis revealed expression of a
major 2.6-kb transcript that was highest in spleen and peripheral blood
leukocytes and also high in thymus, colon, and placenta, suggesting
preferential expression in hematopoietic tissues. Strong expression was
detected in lymphoid and granulocytic cell lines but not other cell
lines. Coimmunoprecipitation and Western blot analyses showed expression
of an 80-kD protein that interacts with the N-terminal portion of the
BAR domain of BIN1 isoforms but not with AMPH. Immunofluorescence
microscopy demonstrated cytosolic expression and lack of
receptor-mediated endocytic function for BIN2. Functional analysis
showed that BIN2 lacks tumor suppressor features.
MAPPING
Using FISH, Ge and Prendergast (2000) mapped the BIN2 gene to 4q22.1.
KRT7
| dbSNP name | rs1902761(A,C); rs7488707(G,T); rs1870209(A,G); rs7135917(C,T); rs11170057(G,T); rs7295280(C,T); rs112216295(A,G); rs12313552(C,T); rs6580870(A,G); rs1902768(A,G); rs12301779(A,G); rs73105198(C,T); rs7300317(A,G); rs55862525(G,A); rs79714737(T,C); rs113301751(C,T); rs12320971(C,T); rs2078201(G,A); rs999665(G,A); rs2243588(T,C); rs999666(A,T); rs1970724(T,C); rs1970725(G,A); rs1970726(A,C); rs4495931(A,G); rs10564(G,A); rs7963792(C,T); rs56082136(C,T); rs2608007(A,G); rs187861526(A,G); rs2608008(C,T); rs2608009(G,C); rs138284704(G,A); rs143540044(G,A); rs74093366(G,A); rs936333(C,T); rs936332(C,T); rs74093369(A,G); rs936331(C,T); rs1317649(C,T); rs1317648(C,A); rs56112415(T,C); rs1870219(C,T); rs1870220(G,A) |
| ccdsGene name | CCDS8822.1 |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 3855 |
| EntrezGene Description | keratin 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT7:NM_005556:exon6:c.C937T:p.R313W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6261 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00686813186813 |
| dbNSFP KGp1 Afr AF | 0.0284552845528 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.036087 |
| ESP All MAF | 0.012302 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.003334 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (less than tenth percentile)
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Round face early in life;
Triangular face later in life;
Long philtrum;
[Ears];
Large, prominent ears;
[Eyes];
Hypertelorism;
Telecanthus;
Long palpebral fissures;
Broad bushy eyebrows;
[Nose];
Anteverted nares;
Hypoplastic alae nasi;
[Teeth];
Macrodontia;
Wide upper central incisors;
Ridged teeth;
Fused incisors;
Oligodontia
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Cervical rib fusion;
Accessory cervical ribs
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Delayed bone maturation;
[Spine];
Vertebral body fusion;
Vertebral arch abnormalities;
Thoracic kyphosis;
[Hands];
Clinodactyly;
Decreased hand length;
Syndactyly
SKIN, NAILS, HAIR:
[Skin];
Simian crease;
[Hair];
Broad, bushy eyebrows;
Low anterior hairline;
Low posterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation
MISCELLANEOUS:
Male to female ratio 21:8
OMIM Title
*148059 KERATIN 7; KRT7
;;K7;;
KERATIN, SIMPLE EPITHELIAL;;
KERATIN, TYPE II, CYTOSKELETAL, 7; K2C7;;
SARCOLECTIN; SCL
OMIM Description
DESCRIPTION
Keratins are proteins that compose the 8-nm intermediate filaments in
epithelial cells. KRT7 is a type II keratin of simple nonkeratinizing
epithelia (Glass et al., 1985).
CLONING
By cross-hybridization with a K6A (148041) cDNA probe, Glass et al.
(1985) cloned KRT7, which they designated K7, from a mesothelial cell
cDNA library. The deduced 489-amino acid protein has a calculated
molecular mass of about 54 kD. K7 contains 4 central alpha-helical
segments with heptad repeats of hydrophobic residues characteristic of a
coiled-coil region. Within this domain, K7 shares 73% homology with
epidermal K6B (148042). The nonhelical N and C termini of K7 are
substantially different in sequence and size from those of K6B and other
epidermal type II keratins. K7 has an isoelectric point of 5.8, which is
more acidic than those of other type II keratins. Northern blot analysis
detected a 1.7-kb transcript in epidermis, bronchus, and mesothelium,
but not in colon, exocervix, or liver.
By screening a genomic library using probes to the 5-prime and 3-prime
K7 cDNA reported by Glass et al. (1985), Glass and Fuchs (1988) isolated
overlapping genomic clones for K7. They identified a 1-bp insertion in
the K7 coding sequence that was inadvertently omitted by Glass et al.
(1985). The change results in a deduced 468-amino acid K7 protein with a
different N terminus than that reported by Glass et al. (1985).
Smith et al. (2002) cloned K7 from human, mouse, and rat kangaroo
libraries. The deduced human K7 protein contains 469 amino acids and has
a calculated molecular mass of 51.4 kD. K7 shares 82% amino acid
identity with mouse K7 and 76% identity with rat kangaroo K7. Western
blot analysis of mouse tissues detected K7 expression in bladder, but
not in epidermis. Smith et al. (2002) found K7 expression restricted to
ducts and specific glands of simple epithelial tissues; examples
included isolated cells in the acini of mammary gland, cells of lung
alveoli and bronchiolar epithelium, kidney collecting duct, and Brunner
glands of the duodenum.
GENE FUNCTION
Glass and Fuchs (1988) determined that expression of endogenous K7 in
rat kangaroo kidney cells was upregulated by retinoic acid, although
retinoic acid did not affect basal K7 expression.
GENE STRUCTURE
Glass and Fuchs (1988) determined that the KRT7 gene contains 8 exons.
The 5-prime upstream region contains a TATA-like sequence and a CCAAT
sequence. The promoter region contains binding sites for SP1 (189906),
AP1 (see 165160), and FOS (164810).
Smith et al. (2002) determined that the KRT7 gene contains 9 exons and
spans more than 15.6 kb. They identified 4 CpG islands conserved in the
human, mouse, and rat kangaroo KRT7 genes. The first island is located
upstream of exon 1, the second is within exon 1, the third, a short
island, is located toward the end of intron 4, and the fourth is
downstream of exon 9.
MAPPING
By Southern blot analysis, Glass et al. (1985) determined that KRT7 is a
single copy gene; however, Glass and Fuchs (1988) presented evidence
that there may be other copies.
Rosenberg et al. (1991) assigned the K7 gene to chromosome 12 using
Southern blot analysis of somatic cell hybrids. They sublocalized the
gene to chromosome 12q12-q14 by in situ hybridization of metaphase
chromosomes. By genomic sequence analysis, Smith et al. (2002)
determined that the human and mouse KRT7 genes map to the periphery of
the type II keratin gene cluster.
KRT75
| dbSNP name | rs61730614(C,T); rs4761794(G,C); rs112764948(T,C); rs10876289(C,G); rs664354(A,G); rs401926(A,G); rs2232402(T,C); rs77737607(A,G); rs1614460(T,C); rs400719(T,G); rs3782486(T,C); rs396831(T,C); rs423949(C,A); rs143063572(A,T); rs199744850(G,A); rs443084(T,A); rs7134582(A,G); rs1798640(G,A); rs187810882(C,T); rs732181(G,A); rs2232388(G,A); rs76652564(G,C); rs67876(C,T); rs2232386(G,C); rs2232385(C,T); rs298109(T,C) |
| ccdsGene name | CCDS8827.1 |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 9119 |
| EntrezGene Description | keratin 75 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT75:NM_004693:exon5:c.T956A:p.I319N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8412 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95678 |
| dbNSFP Uniprot ID | K2C75_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.008852 |
| ESP All MAF | 0.002999 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0009514 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Peripheral retinal cone degeneration;
Visual acuity loss (none to moderate (20/16 to 20/100));
Mild temporal pallor of the optic disc (partial optic atrophy);
Defective color vision in some patients;
Preserved rod function;
Distinctive electroretinogram - focal macular cone ERG is well-preserved;
Relative paracentral scotoma in 2/3 of patients;
Rod-cone perimetry showed normal rod sensitivity, but impaired peripheral
cone sensitivity
MISCELLANEOUS:
3 reported cases, 1 pedigree of affected sibs, neither parent affected
OMIM Title
*609025 KERATIN 75; KRT75
;;KERATIN 6, HAIR FOLLICLE; K6HF
OMIM Description
CLONING
By 5-prime and 3-prime RACE of anagen hair follicle cDNA, Winter et al.
(1998) cloned K6HF. The deduced 551-amino acid protein shares about 80%
homology with cytokeratin KRT5 (148040). In situ hybridization and
indirect immunofluorescence localization showed that K6HF was expressed
exclusively in the companion layer of the hair follicle before KRT17
(148069) and KRT16 (148067).
Wojcik et al. (2001) cloned mouse K6hf. The deduced 551-amino acid
protein shares 84.8% identity with human K6HF.
GENE FUNCTION
Wojcik et al. (2001) found that K6hf assembled into a keratin network
following transfection of kangaroo rat kidney epithelial cells.
GENE STRUCTURE
Rogers et al. (2000) determined that the K6HF gene spans 17.4 kb.
MAPPING
By screening an arrayed PAC DNA library, Rogers et al. (2000) mapped the
K6HF gene to a region of chromosome 12q13 that flanks a series of hair
keratin genes and pseudogenes.
MOLECULAR GENETICS
Winter et al. (2004) identified a nonsynonymous SNP in the KRT75 gene
(A12T; 609025.0001) that was significantly associated with the
development of pseudofolliculitis barbae (612318).
KRT71
| dbSNP name | rs2292505(T,C); rs2292506(C,T); rs2292507(T,C); rs60971309(G,A); rs10747641(A,G); rs10747642(C,T); rs11170171(T,C); rs4761926(A,G); rs11610919(C,T); rs4761927(G,A); rs4761803(A,T); rs4761928(G,A); rs4761929(T,C); rs35988863(T,A); rs3803083(C,T); rs12308719(G,T); rs10876309(C,T); rs3803085(C,T); rs635206(C,T); rs4761930(G,A); rs673916(T,C); rs10747643(T,C); rs10506308(A,T); rs12314106(C,T); rs657870(G,A); rs35919446(T,G); rs4761931(G,A); rs4761932(A,C); rs9325152(C,T); rs663697(G,T); rs17730088(A,G); rs681387(C,G); rs665470(C,T); rs665522(C,T) |
| ccdsGene name | CCDS8831.1 |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 112802 |
| EntrezGene Description | keratin 71 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT71:NM_033448:exon6:c.A1063T:p.I355F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.646 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3SY84 |
| dbNSFP Uniprot ID | K2C71_HUMAN |
| dbNSFP KGp1 AF | 0.00778388278388 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.007805 |
| ESP Afr MAF | 0.034044 |
| ESP All MAF | 0.012148 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 0.003505 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Otosclerosis;
Hearing loss, unilateral or bilateral, conductive , sensorineural,
or mixed
MISCELLANEOUS:
Reduced penetrance
OMIM Title
*608245 KERATIN 71; KRT71
;;KERATIN 6, INNER ROOT SHEATH, 1; KRT6IRS1;;
K6IRS1;;
K71
OMIM Description
DESCRIPTION
KRT71 belongs to a family of type II keratins that are specifically
expressed in the inner root sheath of hair follicles (Langbein et al.,
2003).
CLONING
By searching for sequences similar to mouse K6irs1, followed by PCR and
screening of a human scalp cDNA library, Langbein et al. (2002) cloned
KRT71, which they called K6IRS1. The deduced 523-amino acid protein has
a calculated molecular mass of 57.3 kD. K6IRS1 has a central
alpha-helical rod domain and shares approximately 92% amino acid
identity with mouse K6irs1. In situ hybridization and indirect
immunofluorescence of human hair follicles demonstrated K6IRS1
expression in the Henle and Huxley layers and in the cuticle of the
inner root sheath. In all 3 layers, expression of K6IRS1 began above the
germinative cell pool and terminated higher up in the follicle with the
asynchronous terminal differentiation of each cell layer. K6IRS1 was
also detected in the pseudopods of specialized Huxley cells, termed
'Flugelzellen,' which means 'winged cells.' Along with Henle cells,
Flugelzellen form a continuous desmosomal anchorage to the companion
layer of the outer root sheath.
By in situ hybridization of plucked beard hair follicles, Langbein et
al. (2003) found colocalization of K6IRS1 and K6IRS4 (608248) in broad
and slender foot processes of Flugelzellen above and below the level of
Henle cell differentiation.
Fujimoto et al. (2012) performed double indirect immunofluorescence on
normal human scalp skin sections with anti-K71 and anti-LIPH (607365)
antibodies and observed abundant expression of LIPH in all 3 layers of
the inner root sheath of human hair follicles, which finely overlapped
with K71.
GENE STRUCTURE
Langbein et al. (2002) determined that the KRT71 gene contains 9 exons
and spans about 9.2 kb.
MAPPING
By genomic sequence analysis, Langbein et al. (2003) mapped the KRT71
gene to chromosome 12q13, within a cluster of keratin genes and
pseudogenes.
MOLECULAR GENETICS
In affected members of a 3-generation Japanese family segregating
autosomal dominant woolly hair/hypotrichosis (HYPT13; 615896), Fujimoto
et al. (2012) identified heterozygosity for a missense mutation in the
KRT71 gene (F141C; 608245.0001). Functional analysis showed that the
mutant protein resulted in mislocalization and severely affected
heterodimer formation with type I keratins.
ANIMAL MODEL
Peters et al. (2003) described 'reduced coat-3' (Rco3), a spontaneous
recessive mouse mutation. Heterozygous Rco3 mice appeared normal and
were indistinguishable from wildtype littermates. Homozygous Rco3 mice
were vital and fertile and had a normal life expectancy, but they
developed severe alopecia. Rco3 homozygotes were first identified by
their curly whiskers around 9 days postpartum. All types of hairs in
Rco3 homozygotes were malformed with kinks and twists and could be
plucked without force. Histologic analysis revealed that the hair shaft
malformations were secondary to defective keratinization of the Henle
and Huxley layers of the inner root sheath. Where the wildtype Henle
layer showed keratinization, that of Rco3 homozygotes showed
accumulation of homogeneous, electron-dense type I keratin aggregates
and absence of filament bundles. Peters et al. (2003) identified the
Rco3 mutation as a 10-bp deletion in the K6irs1 gene that caused a
frameshift after 58 codons, resulting in a K6irs1 protein lacking 422
C-terminal amino acids, including the complete alpha-helical rod domain.
Cadieu et al. (2009) performed genomewide association studies of more
than 1,000 dogs from more than 80 domestic breeds to identify genes
associated with canine fur phenotypes (coat growth pattern, length, and
curl). Taking advantage of both inter- and intrabreed variability, they
identified distinct mutations in 3 genes, RSPO2 (610575), FGF5 (165190),
and KRT71, that together account for most coat phenotypes in purebred
dogs in the United States. Thus, Cadieu et al. (2009) concluded that an
array of varied and seemingly complex phenotypes can be reduced to the
combinatorial effects of only a few genes. A SNP in the KRT71 gene is
associated with curly coat in dogs. The combination of mutations in
these 3 genes account for 7 different types of coat phenotype in the
dog.
Shimomura et al. (2010) noted that mutations in the mouse Krt71 gene
have previously been identified in Caracul (Ca) and reduced coat (Rco)
mutant mice. They sequenced the mouse Krt71 gene and identified a
heterozygous mutation in the Caracul-like 4 (Cal4) allele, which is also
characterized by a wavy-coat phenotype.
Hairlessness (hr) in the Sphynx cat is allelic to the curly, or rexoid
(re), coat in the Devon Rex cat. Gandolfi et al. (2010) showed that
these phenotypes result from mutations in the Krt71 gene. The hr
mutation is a G-to-A substitution at position +1 in intron 4 that
affects splicing. The resultant Krt71 protein is truncated and
nonfunctional, with deletion of the majority of the alpha-helical rod
domain. The re mutation is a complex alteration involving deletion of
the last 4 bp of intron 6 and the first 77 bp of exon 7, followed by an
8-bp insertion, and a downstream single-base insertion. These complex
changes disrupt the 3-prime splice site of intron 6, but result in a
functional Krt71 protein with only a 35-amino acid deletion at the
C-terminal end of the alpha-helical rod domain. In addition, 6 Sphynx
cats studied were compound heterozygotes for the hr SNP and the re
deletion. The data suggested that the hr allele is dominant to the re
allele, and both are recessive to wildtype.
KRT72
| dbSNP name | rs73320342(G,C); rs2292502(G,T); rs17116392(T,C); rs612748(A,G); rs12814924(C,G); rs57168304(A,G); rs7310138(A,T); rs7310156(A,C); rs11170184(G,A); rs10747644(A,G); rs681812(C,G); rs675229(C,G); rs76815710(A,G); rs3847847(C,T); rs7958317(G,A); rs34769047(G,C); rs11613547(G,A); rs12824366(A,G); rs73320351(G,A); rs73320352(C,G); rs617820(T,A); rs12833456(T,C); rs10876311(C,T); rs7977909(G,A); rs615265(A,G); rs7953350(G,A); rs11170186(T,G); rs662941(T,C); rs61929565(G,T); rs676126(A,C); rs12821827(C,T); rs12822166(G,A); rs12822038(C,A); rs7295084(C,A); rs6580890(G,A); rs61929567(T,C); rs73320363(G,A); rs595727(T,C); rs4103863(G,T); rs4103862(G,A); rs615235(G,A); rs75992227(A,C); rs11170187(T,C); rs7973012(C,A); rs694714(C,T); rs60157137(T,C); rs7960040(T,G); rs7973356(C,T); rs11170189(T,A); rs61929569(C,T); rs147194175(C,T); rs10876313(T,C); rs61747192(G,A) |
| ccdsGene name | CCDS8833.1 |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 140807 |
| EntrezGene Description | keratin 72 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT72:NM_001146225:exon5:c.C898T:p.R300C,KRT72:NM_080747:exon5:c.C898T:p.R300C,KRT72:NM_001146226:exon5:c.C898T:p.R300C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6394 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0123626373626 |
| dbNSFP KGp1 Afr AF | 0.0406504065041 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.0124 |
| ESP Afr MAF | 0.051521 |
| ESP All MAF | 0.021144 |
| ESP Eur/Amr MAF | 0.005581 |
| ExAC AF | 0.009653 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Otosclerosis;
Hearing loss, unilateral or bilateral, conductive , sensorineural,
or mixed
MISCELLANEOUS:
Reduced penetrance
OMIM Title
*608246 KERATIN 72; KRT72
;;KERATIN 6, INNER ROOT SHEATH, 2; KRT6IRS2;;
K6IRS2
OMIM Description
DESCRIPTION
K6IRS2 belongs to a family of type II keratins that are specifically
expressed in the inner root sheath of hair follicles.
CLONING
By searching an EST database for sequences similar to KRT7 (148509),
Porter et al. (2001) identified K6IRS2, which they designated K6IRS.
They confirmed the mRNA sequence by RT-PCR of human hair mRNA. The
deduced 510-amino acid protein has a calculated molecular mass of about
55.7 kD. The rod domain of K6IRS2 is more closely related to KRT6
keratins (see KRT6A; 148041) than to other type II keratins. The
variable domains V1 and V2, which flank the rod domain, are novel.
RT-PCR of mRNA derived from skin biopsies and from plucked hairs
revealed K6IRS2 expression in both scalp and eyebrow hair follicles and
in palmoplantar epidermis.
Porter et al. (2001) cloned mouse K6irs2. The 524-amino acid mouse
protein has a calculated molecular mass of about 57.3 kD. Mouse and
human K6IRS2 share 70% amino acid identity, including 84% identity in
the rod domain. Most of the interspecies differences are in the V1 and
V2 domains. Immunohistochemical analysis of mouse tissues showed that
K6irs2 is completely specific for the epithelial cells of the inner root
sheath of anagen hair follicles. There appeared to be a sharp
demarcation where expression ended, which was below the region where the
sebaceous gland joins the follicle. The inner root sheath of vibrissae
was also positive for mouse K6irs2. Expression was not detected in the
footpad, in interfollicular epidermis, in any epithelia of internal
organs, mucosal tissues, sebaceous glands, or eccrine sweat glands, or
in epithelial structures of the tongue. Expression was also completely
absent from telogen samples, consistent with the loss of the inner root
sheath during telogen.
Langbein et al. (2003) reported that human K6IRS2 contains 511 amino
acids and has a calculated molecular mass of 55.9 kD. Western blot
analysis detected a single K6IRS2 band in root sheath extracts, but not
in foot sole extracts. Indirect immunofluorescence of human hair
follicles revealed that both K6IRS2 and K6IRS3 (608247) were expressed
in the cuticle of the inner root sheath, but they showed different
onsets of expression. K6IRS3 expression began in the lowermost bulb
region, while K6IRS2 expression began in the apex of the dermal papilla.
GENE STRUCTURE
Porter et al. (2001) determined that the K6IRS2 gene contains 9 exons
and spans almost 16 kb. The promoter region contains a TATA element and
a T-antigen site.
MAPPING
By genomic sequence analysis, Porter et al. (2001) mapped the K6IRS2
gene to chromosome 12q, within a type II keratin gene cluster. Langbein
et al. (2003) localized the cluster to chromosome 12q13.
HOXC11
| dbSNP name | rs116201856(G,A); rs3816153(G,T) |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 3227 |
| EntrezGene Description | homeobox C11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01515 |
| ExAC AF | 0.001427 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Initial loss of central visual acuity and color vision;
Photophobia and epiphora in day light;
Eventual loss of peripheral vision and night blindness;
Marked macular degeneration;
Mild retinal arteriolar constriction;
Mild temporal optic nerve pallor;
Mild peripheral retinal pigmentary changes
LABORATORY ABNORMALITIES:
Electroretinogram is abnormal--rod responses are mildly abnormal and
cone responses are markedly diminished
OMIM Title
*605559 HOMEOBOX C11; HOXC11
OMIM Description
DESCRIPTION
HOXC11 is a member of the Hox C cluster on human chromosome 12 (Scott,
1992) and is homologous to the mouse Hoxc11 gene (previously called
Hox3.7) which is located on chromosome 15. See 142950 for general
information on homeobox genes.
CLONING
Using a yeast 1-hybrid screen designed to identify factors that bind to
a portion of the lactase (LCT; 603202) gene promoter, Mitchelmore et al.
(1998) identified a partial clone of HOXC11. They assembled the
full-length HOXC11 cDNA using database searches and 5-prime RACE. The
HOXC11 cDNA encodes a 304-amino acid protein with a homeodomain and a
C-terminal extension identical to those of mouse Hoxc11. The homeodomain
of HOXC11 is most similar to the homeodomains of mouse Hoxa11, mouse
Hoxd11, and Drosophila Abdominal-B genes. Using Northern blot analysis,
Mitchelmore et al. (1998) detected a 2.1-kb HOXC11 transcript in HeLa
cells. This expression was confirmed by ribonuclease protection assay. A
second, 1.7-kb transcript, hypothesized to encode a protein lacking 114
amino acids at the HOXC11 N-terminal end, was detected in HeLa cells and
Caco-2 intestinal cells. This smaller transcript becomes more abundant
in Caco-2 cells after differentiation. Using RT-PCR, Mitchelmore et al.
(1998) showed that HOXC11 is expressed in fetal tissues, including
kidney, skeletal muscle, and small intestine. The expression in fetal
small intestine was higher than that in small intestine from a
15-year-old subject. Transfection studies using the C-terminal 190 amino
acids of HOXC11 in HeLa cells demonstrated binding with similar affinity
to the LCT promoter and an optimized Abdominal-B binding site. Both the
long and short transcript forms of HOXC11 stimulated HNF1-alpha
(142410)-dependent transcription of LCT in cotransfection experiments.
MIR196A2
| dbSNP name | rs11614913(C,T) |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 406973 |
| snpEff Gene Name | HOXC10 |
| EntrezGene Description | microRNA 196a-2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.388 |
| ESP Afr MAF | 0.189732 |
| ESP All MAF | 0.340583 |
| ESP Eur/Amr MAF | 0.406616 |
| ExAC AF | 0.384 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Normal kidneys
SKELETAL:
[Limbs];
Osteolysis of patellae (bone loss of posterior patella);
[Hands];
Osteolysis of scaphoids (bone loss and fragmentation of scaphoid);
Short fourth metacarpals;
[Feet];
Osteolysis of tali (bone loss and fragmentation of posterior talus)
MISCELLANEOUS:
Onset 13-15 years
OMIM Title
*609687 MICRO RNA 196A2; MIR196A2
;;miRNA196A2;;
MIRN196A2
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs), such as miRNA196, are phylogenetically widespread
18- to 25-nucleotide RNAs found in animals and plants. These small RNAs
can regulate gene expression at the translational level through
interactions with their target mRNAs.
CLONING
Lagos-Quintana et al. (2003) identified miR196 as a 21mer expressed
primarily in ovary.
GENE FUNCTION
Yekta et al. (2004) found that miR196 has extensive evolutionarily
conserved complementarity to messages of HOXB8 (142963), HOXC8 (142970),
and HOXD8 (142985). RNA fragments diagnostic of miR196-directed cleavage
of HOXB8 were detected in mouse embryos. Cell culture experiments
demonstrated downregulation of HOXB8, HOXC8, HOXD8, and HOXA7 (142950)
and supported the cleavage mechanism for miR196-directed repression of
HOXB8. Yekta et al. (2004) concluded that their results point to an
miRNA-mediated mechanism for the posttranscriptional restriction of HOX
gene expression during vertebrate development and demonstrate that
metazoan miRNAs can repress expression of their natural targets through
mRNA cleavage in addition to inhibiting productive translation.
MAPPING
miR196 is encoded at 3 paralogous locations in the A, B, and C mammalian
HOX clusters, with miR196A1 (608632) at the HOXB cluster on chromosome
17q21-q22, miR196A2 at the HOXC cluster on 12q13, and miR196B (609688)
at the HOXA cluster on 7p15-p14.2 (Lagos-Quintana et al., 2003; Lim et
al., 2003).
HOXC-AS1
| dbSNP name | rs56154542(G,C) |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 100874363 |
| snpEff Gene Name | HOXC6 |
| EntrezGene Description | HOXC cluster antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3701 |
LOC100240734
| dbSNP name | rs12308675(T,C); rs35237882(A,G) |
| cytoBand name | 12q13.13 |
| EntrezGene GeneID | 100240734 |
| snpEff Gene Name | RP11-834C11.3 |
| EntrezGene Description | uncharacterized LOC100240734 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3728 |
| ExAC AF | 0.626 |
OR9K2
| dbSNP name | rs12303066(C,T); rs7305779(A,C); rs139105553(G,A); rs7306491(G,A); rs7137261(T,C) |
| ccdsGene name | CCDS31814.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 441639 |
| EntrezGene Description | olfactory receptor, family 9, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR9K2:NM_001005243:exon1:c.C133T:p.R45C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGE7 |
| dbNSFP Uniprot ID | OR9K2_HUMAN |
| dbNSFP KGp1 AF | 0.285714285714 |
| dbNSFP KGp1 Afr AF | 0.406504065041 |
| dbNSFP KGp1 Amr AF | 0.281767955801 |
| dbNSFP KGp1 Asn AF | 0.127622377622 |
| dbNSFP KGp1 Eur AF | 0.328496042216 |
| dbSNP GMAF | 0.286 |
| ESP Afr MAF | 0.386518 |
| ESP All MAF | 0.344456 |
| ESP Eur/Amr MAF | 0.322907 |
| ExAC AF | 0.3 |
OR10A7
| dbSNP name | rs151030005(T,C) |
| ccdsGene name | CCDS31815.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 121364 |
| EntrezGene Description | olfactory receptor, family 10, subfamily A, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10A7:NM_001005280:exon1:c.T421C:p.C141R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0007 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGE5 |
| dbNSFP Uniprot ID | O10A7_HUMAN |
| dbNSFP KGp1 AF | 0.00915750915751 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0197889182058 |
| dbSNP GMAF | 0.009183 |
| ESP Afr MAF | 0.003177 |
| ESP All MAF | 0.01261 |
| ESP Eur/Amr MAF | 0.017442 |
| ExAC AF | 0.011 |
OR6C74
| dbSNP name | rs7301705(A,G); rs11171387(G,A); rs11171388(C,T); rs4522268(C,T); rs11171389(C,T); rs4388990(A,G); rs6581025(G,A); rs73322883(G,A) |
| ccdsGene name | CCDS31816.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 254783 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 74 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C74:NM_001005490:exon1:c.A4G:p.R2G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NCV1 |
| dbNSFP Uniprot ID | O6C74_HUMAN |
| dbNSFP KGp1 AF | 0.207875457875 |
| dbNSFP KGp1 Afr AF | 0.134146341463 |
| dbNSFP KGp1 Amr AF | 0.262430939227 |
| dbNSFP KGp1 Asn AF | 0.0804195804196 |
| dbNSFP KGp1 Eur AF | 0.325857519789 |
| dbSNP GMAF | 0.208 |
| ESP Afr MAF | 0.156222 |
| ESP All MAF | 0.261612 |
| ESP Eur/Amr MAF | 0.315581 |
| ExAC AF | 0.271 |
OR6C6
| dbSNP name | rs7308594(G,A) |
| ccdsGene name | CCDS31817.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 283365 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C6:NM_001005493:exon1:c.C750T:p.Y250Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1846 |
| ESP Afr MAF | 0.106219 |
| ESP All MAF | 0.246001 |
| ESP Eur/Amr MAF | 0.317632 |
| ExAC AF | 0.731 |
OR6C1
| dbSNP name | rs7132431(G,A); rs7132347(C,G); rs7132600(C,T); rs140573862(A,G); rs7132916(G,A) |
| ccdsGene name | CCDS31818.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 390321 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C1:NM_001005182:exon1:c.G389A:p.C130Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96RD1 |
| dbNSFP Uniprot ID | OR6C1_HUMAN |
| dbNSFP KGp1 AF | 0.806776556777 |
| dbNSFP KGp1 Afr AF | 0.810975609756 |
| dbNSFP KGp1 Amr AF | 0.779005524862 |
| dbNSFP KGp1 Asn AF | 0.877622377622 |
| dbNSFP KGp1 Eur AF | 0.763852242744 |
| dbSNP GMAF | 0.1933 |
| ESP Afr MAF | 0.17567 |
| ESP All MAF | 0.202061 |
| ESP Eur/Amr MAF | 0.215581 |
| ExAC AF | 0.768 |
OR6C3
| dbSNP name | rs4318060(C,T); rs73324778(G,T) |
| ccdsGene name | CCDS31819.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 254786 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C3:NM_054104:exon1:c.C206T:p.S69L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NZP0 |
| dbNSFP Uniprot ID | OR6C3_HUMAN |
| dbNSFP KGp1 AF | 0.1163003663 |
| dbNSFP KGp1 Afr AF | 0.20325203252 |
| dbNSFP KGp1 Amr AF | 0.0994475138122 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.155672823219 |
| dbSNP GMAF | 0.1157 |
| ESP Afr MAF | 0.200182 |
| ESP All MAF | 0.176534 |
| ESP Eur/Amr MAF | 0.164419 |
| ExAC AF | 0.13 |
OR6C65
| dbSNP name | rs7971073(A,G) |
| ccdsGene name | CCDS31821.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 403282 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 65 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C65:NM_001005518:exon1:c.A664G:p.T222A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NJZ3 |
| dbNSFP Uniprot ID | O6C65_HUMAN |
| dbNSFP KGp1 AF | 0.784340659341 |
| dbNSFP KGp1 Afr AF | 0.481707317073 |
| dbNSFP KGp1 Amr AF | 0.870165745856 |
| dbNSFP KGp1 Asn AF | 0.914335664336 |
| dbNSFP KGp1 Eur AF | 0.841688654354 |
| dbSNP GMAF | 0.2153 |
| ESP Afr MAF | 0.456877 |
| ESP All MAF | 0.264493 |
| ESP Eur/Amr MAF | 0.16593 |
| ExAC AF | 0.834 |
OR6C76
| dbSNP name | rs6581046(C,T); rs74092310(C,T) |
| ccdsGene name | CCDS31823.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 390326 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 76 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C76:NM_001005183:exon1:c.C84T:p.F28F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2879 |
| ESP Afr MAF | 0.27803 |
| ESP All MAF | 0.364678 |
| ESP Eur/Amr MAF | 0.40907 |
| ExAC AF | 0.635 |
OR6C2
| dbSNP name | rs138582074(C,A); rs74092333(C,T) |
| ccdsGene name | CCDS31824.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 341416 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C2:NM_054105:exon1:c.C492A:p.L164L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.002724 |
| ESP All MAF | 0.003614 |
| ESP Eur/Amr MAF | 0.00407 |
| ExAC AF | 3.627e-03,8.132e-06 |
OR6C70
| dbSNP name | rs60683621(C,G); rs10747756(A,G); rs12313730(G,A) |
| ccdsGene name | CCDS31825.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 390327 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 70 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C70:NM_001005499:exon1:c.G699C:p.K233N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NIJ9 |
| dbNSFP Uniprot ID | O6C70_HUMAN |
| dbNSFP KGp1 AF | 0.274267399267 |
| dbNSFP KGp1 Afr AF | 0.205284552846 |
| dbNSFP KGp1 Amr AF | 0.196132596685 |
| dbNSFP KGp1 Asn AF | 0.484265734266 |
| dbNSFP KGp1 Eur AF | 0.197889182058 |
| dbSNP GMAF | 0.2746 |
| ESP Afr MAF | 0.216069 |
| ESP All MAF | 0.21121 |
| ESP Eur/Amr MAF | 0.208721 |
| ExAC AF | 0.223 |
OR6C68
| dbSNP name | rs7133698(G,A); rs7304753(T,A); rs150231347(C,T); rs12579181(G,T) |
| ccdsGene name | CCDS31826.2 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 403284 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 68 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C68:NM_001005519:exon1:c.G133A:p.A45T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NDL8 |
| dbNSFP Uniprot ID | O6C68_HUMAN |
| dbNSFP KGp1 AF | 0.635989010989 |
| dbNSFP KGp1 Afr AF | 0.493902439024 |
| dbNSFP KGp1 Amr AF | 0.657458563536 |
| dbNSFP KGp1 Asn AF | 0.818181818182 |
| dbNSFP KGp1 Eur AF | 0.580474934037 |
| dbSNP GMAF | 0.3636 |
| ESP Afr MAF | 0.456196 |
| ESP All MAF | 0.420883 |
| ESP Eur/Amr MAF | 0.402791 |
| ExAC AF | 0.608 |
OR6C4
| dbSNP name | rs7313899(A,G); rs58154171(C,T); rs11835716(T,C); rs74093226(A,G); rs57386660(A,G); rs370301670(A,C) |
| ccdsGene name | CCDS31827.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 341418 |
| EntrezGene Description | olfactory receptor, family 6, subfamily C, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6C4:NM_001005494:exon1:c.A109G:p.I37V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGE1 |
| dbNSFP Uniprot ID | OR6C4_HUMAN |
| dbNSFP KGp1 AF | 0.992673992674 |
| dbNSFP KGp1 Afr AF | 0.997967479675 |
| dbNSFP KGp1 Amr AF | 0.994475138122 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.982849604222 |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.01038 |
| ESP Eur/Amr MAF | 0.013953 |
| ExAC AF | 0.992 |
OR2AP1
| dbSNP name | rs61746285(G,A) |
| ccdsGene name | CCDS58241.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 121129 |
| EntrezGene Description | olfactory receptor, family 2, subfamily AP, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2AP1:NM_001258285:exon1:c.G751A:p.G251R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0034 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0714285714286 |
| dbNSFP KGp1 Afr AF | 0.123983739837 |
| dbNSFP KGp1 Amr AF | 0.0883977900552 |
| dbNSFP KGp1 Asn AF | 0.0472027972028 |
| dbNSFP KGp1 Eur AF | 0.0474934036939 |
| dbSNP GMAF | 0.07117 |
| ExAC AF | 0.056 |
OR10P1
| dbSNP name | rs10876838(C,T); rs7970885(G,A) |
| ccdsGene name | CCDS31828.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 121130 |
| EntrezGene Description | olfactory receptor, family 10, subfamily P, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10P1:NM_206899:exon1:c.C263T:p.P88L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGE3 |
| dbNSFP Uniprot ID | O10P1_HUMAN |
| dbNSFP KGp1 AF | 0.319597069597 |
| dbNSFP KGp1 Afr AF | 0.0934959349593 |
| dbNSFP KGp1 Amr AF | 0.422651933702 |
| dbNSFP KGp1 Asn AF | 0.236013986014 |
| dbNSFP KGp1 Eur AF | 0.480211081794 |
| dbSNP GMAF | 0.3196 |
| ESP Afr MAF | 0.147753 |
| ESP All MAF | 0.353529 |
| ESP Eur/Amr MAF | 0.458953 |
| ExAC AF | 0.385 |
CD63
| dbSNP name | rs3138132(G,C) |
| ccdsGene name | CCDS8890.1 |
| cytoBand name | 12q13.2 |
| EntrezGene GeneID | 967 |
| EntrezGene Description | CD63 molecule |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2094 |
OMIM Clinical Significance
Eyes:
Uveal melanoma
Misc:
Most common primary intraocular malignancy;
Frequent loss of chromosome 3 material and additions of chromosome
8
Inheritance:
Autosomal dominant
OMIM Title
*155740 CD63 ANTIGEN; CD63
;;MELANOMA-ASSOCIATED ANTIGEN MLA1; MLA1;;
MELANOMA-ASSOCIATED ANTIGEN ME491;;
GRANULOPHYSIN
OMIM Description
The melanoma-associated antigen ME491 is expressed strongly during early
stages of progression of the tumor. Hotta et al. (1988) cloned the gene
by means of DNA-mediated gene transfer followed by the screening of a
lambda genomic library with human repetitive Alu sequences as a probe.
The cloned DNA, after transcription into mouse L-cells, generated a
protein whose characteristics were indistinguishable in Western blot
analysis from the ME491 antigen expressed by human melanoma cells. The
sequence of the cDNA indicates that the antigen has 237 amino acids
(molecular weight 25,475) with 4 transmembrane regions and 3 putative
N-glycosylation sites. The gene was mapped to 12p12-q13 by somatic cell
hybrid analysis and to 12q12-q14 by in situ hybridization.
Nishibori et al. (1993) used immunofluorescence with anti-CD63 and
anti-granulophysin antibodies to demonstrate deficiency of these
proteins in Hermansky-Pudlak syndrome (HPS; 203300). It appeared that
these antibodies recognized the same protein, and amino-terminal
sequencing over the first 37 amino acids revealed identity of
granulophysin to CD63, melanoma antigen ME491, and pltgp40. This was the
first report of a protein present in platelet dense granules, lysosomes,
and melanocytes, but deficient in a patient with HPS. Clarification as
to whether deficiency in CD63 is the primary defect in HPS will await
molecular characterization of the CD63 gene in patients with this
disorder. That the primary defect resides in the CD63 gene was made
unlikely by the demonstration by Fukai et al. (1995) that the HPS gene
maps to chromosome 10, not chromosome 12.
Gwynn et al. (1996) found that the cDNA encoding mouse CD63 detects 2
closely-related sequences that map to different regions of the mouse
genome. One locus maps to mouse chromosome 10 in a region that shares
linkage homology with chromosome 12 where human CD63 maps. The second
locus maps to mouse chromosome 18 in a region that bears no known human
CD63-related genes. The chromosome 18 locus in the mouse was designated
by the authors Cd63-rs1 (for CD63-related sequence 1). No platelet
storage pool deficiency disorder has been mapped to these regions of
either mouse chromosome 18 or human chromosome 12.
STAT2
| dbSNP name | rs2066808(A,G); rs151302282(T,A); rs12422499(G,C); rs141204874(C,T); rs138681270(G,A); rs2020854(T,C); rs11575236(T,C); rs11575234(C,G); rs187718336(A,G); rs150901100(G,T); rs139433066(C,T); rs11575228(G,C); rs11171812(C,T) |
| ccdsGene name | CCDS8917.1 |
| cytoBand name | 12q13.3 |
| EntrezGene GeneID | 6773 |
| EntrezGene Description | signal transducer and activator of transcription 2, 113kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | STAT2:NM_005419:exon17:c.C1466T:p.P489L,STAT2:NM_198332:exon17:c.C1454T:p.P485L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7394 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3V2M6 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001377 |
| ExAC AF | 2.684e-04,9.759e-05,1.545e-04 |
OMIM Clinical Significance
Growth:
Pre- and postnatal growth retardation
Head:
Microcephaly
Facies:
Distinctive facies
Neuro:
Developmental delay
Heme:
Pancytopenia
Lab:
Normal cellular bone marrow infiltrated with small lymphocytes;
Increased spontaneous chromosome breakage in blood and fibroblasts;
Increased mitomycin C-induced chromosome damage
Inheritance:
Autosomal recessive
OMIM Title
*600556 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2; STAT2
OMIM Description
CLONING
ISGF3 (see ISGF3G; 147574) is a multiprotein transcription factor that
is activated in the cytoplasm after attachment of interferon-alpha (see
IFNA1; 147660) to the cell surface. By screening a human cDNA library
with probes based on peptide sequences of the 113-kD ISGF3 subunit, Fu
et al. (1992) cloned STAT2. The deduced 851-amino acid protein contains
3 major helices in its N-terminal region, followed by heptad leucine
repeats that may form a coiled-coil structure, an SH2-like domain, and a
C-terminal acidic domain. Northern blot analysis detected a 4.8-kb
transcript in HeLa cells.
Sugiyama et al. (1996) cloned full-length mouse Stat2 and 2
alternatively spliced forms that encode the same truncated protein.
RT-PCR detected all 3 variants in several mouse tissues, although the
full-length form was most abundant and was expressed in all tissues
examined. RT-PCR of a human hepatoblastoma cell line revealed
full-length STAT2 and only 1 STAT2 splice variant. The short form of
human STAT2 encodes a protein in which the 231 C-terminal amino acids
are replaced by 32 novel amino acids. It lacks half of the SH2 domain,
the tyrosine phosphorylation site required for dimerization and DNA
binding, and the C-terminal activation domain.
GENE FUNCTION
The STAT proteins have the dual function of signal transduction and
activation of transcription as part of a phosphorylation cascade. The
binding of IFNA1 to its receptor leads to activation of ISGF3, a
DNA-binding complex comprised of STAT1 (600555), STAT2, and p48
(ISGF3G). Bluyssen and Levy (1997) showed that STAT2 forms stable
homodimers which complex with p48 and bind to the interferon-stimulated
response element (ISRE). The authors concluded that assembly of the
ISGF3 complex involves p48 functioning as an adaptor protein to recruit
STAT1 and STAT2 to the ISRE. STAT2 is a potent transactivator in this
complex, but lacks the ability to bind DNA directly.
Banninger and Reich (2004) found that unphosphorylated STAT2
constitutively shuttled in and out of the nucleus in human fibrosarcoma
cell lines. Unphosphorylated STAT2 was imported into the nucleus via
association with IRF9 (ISGF3G), but a STAT2 C-terminal nuclear export
signal directed the return of the STAT2-IRF9 complex to the cytoplasm.
Following tyrosine phosphorylation in response to IFN signaling, STAT2
dimerized with STAT1, resulting in a conformational change that directed
nuclear localization. Banninger and Reich (2004) concluded that STAT2
does not accumulate in the nucleus in the absence of STAT1.
Stimulation of cells by IFNA results in phosphorylation of both STAT1
and STAT2, producing STAT1 homodimers and STAT1/STAT2 heterodimers.
Hartman et al. (2005) identified numerous STAT1 and STAT2 gene targets
on chromosome 22 following IFN stimulation of HeLa cells, and they found
that STAT1/STAT2 heterodimers bound sites not occupied by STAT1
homodimers.
Takeuchi et al. (2003) found that measles virus V protein blocked
IFNA/INF-beta (IFNB1; 147640)-induced antiviral signaling by blocking
STAT1 and STAT2 phosphorylation. V protein had no effect on degradation
of STAT proteins.
Rodriguez et al. (2003) found that Hendra and Nipah virus V proteins
coprecipitated with STAT1 and STAT2, but not STAT3 (102582). Hendra
virus V protein inhibited IFN signaling in transfected human embryonic
kidney cells and altered STAT1 localization to a predominantly
cytoplasmic distribution. Furthermore, Hendra virus V protein prevented
IFN-dependent nuclear redistribution of both STAT1 and STAT2 and caused
sequestration of STAT1 and STAT2 into a 500-kD cytoplasmic complex.
Using single-cell RNA sequencing in mouse bone marrow-derived dendritic
cells (BMDCs) stimulated with lipopolysaccharide (LPS) to investigate
expression variability on a genomic scale, Shalek et al. (2013) observed
extensive and theretofore unobserved bimodal variation in mRNA abundance
and splicing patterns. They found that hundreds of key immune genes are
bimodally expressed across cells, even genes that are very highly
expressed at the population average. Moreover, splicing patterns
demonstrated heterogeneity between cells. Shalek et al. (2013)
identified a module of 137 highly variable yet coregulated antiviral
response genes. Using cells from knockout mice, Shalek et al. (2013)
showed that variability in this module may be propagated through an
interferon feedback circuit, involving the transcriptional regulators
Stat2 and Irf7 (605047). This finding demonstrated that while some of
the observed bimodality could be attributed to closely related, yet
distinct, known maturity states of BMDCs, other portions reflected
differences in the usage of key regulatory circuits.
GENE STRUCTURE
Yan et al. (1995) reported the complete genomic sequence and
characterization of the promoter region and exonic structure of the
human STAT2 gene. It contains 24 exons and has an imperfect ISRE,
consistent with its weak transcriptional induction by IFNA1. In
comparison with STAT1, Yan et al. (1995) found considerable conservation
throughout a 700-amino acid coding region, and the genomic structure is
largely conserved.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the STAT2
gene to chromosome 12 (TMAP RH40514).
APOF
| dbSNP name | rs4996382(C,T); rs4301822(A,G) |
| cytoBand name | 12q13.3 |
| EntrezGene GeneID | 319 |
| snpEff Gene Name | STAT2 |
| EntrezGene Description | apolipoprotein F |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1612 |
OMIM Clinical Significance
Skin:
Xanthomatosis (tuberous, tuberoeruptive, planar and/or tendon)
Cardiac:
Premature coronary disease;
Angina pectoris
Vascular:
Premature peripheral vascular disease
Metabolic:
Abnormal glucose tolerance
Neuro:
APOE*E4 allele associated with late-onset familial and sporadic forms
of Alzheimer disease
Misc:
Primary dysbetalipoproteinemia a monogenic variant (APOE1-HARRISBURG
.0010, APOE3 LEIDEN .0006, APOE2 .0011);
Incompletely dominant type III hyperlipoproteinemia without clinical
manifestations (APOE4-PHILADELPHIA .0013);
Age dependent, rarely evident before the third decade;
Hyperlipidemia exacerbated by carbohydrate, hypothyroidism and obesity
Lab:
Apolipoprotein E;
Increased plasma cholesterol;
Increased triglycerides;
Impaired clearance of chylomicron and VLDL remnants;
Type III hyperlipoproteinemia with some alleles;
Defective apoE3 binding to LDL receptor (APOE LEIDEN .0006, APOE .0008);
Mild hypertriglyceridemia (APOE3-WASHINGTON .0014)
Inheritance:
Autosomal recessive with pseudodominance due to high gene frequency
(e.g. APOE .0009)
OMIM Title
*107760 APOLIPOPROTEIN F; APOF
;;LIPID TRANSFER INHIBITOR PROTEIN; LTIP
OMIM Description
DESCRIPTION
Apolipoprotein F is predominantly associated with low density
lipoprotein and functions as an inhibitory regulator of cholesteryl
ester transfer protein (CETP; 118470) (Wang et al., 1999).
CLONING
Apolipoprotein F, a minor apolipoprotein in human plasma, was isolated
and partially characterized by Olofsson et al. (1978).
By PCR of a human hepatoma cell line cDNA library using primers based on
the N-terminal sequence of purified APOF, Day et al. (1994) cloned
full-length APOF. The deduced 308-amino acid proprotein has a 22-amino
acid N-terminal signal peptide, and its C-terminal half contains the
mature APOF peptide, which is released by proteolytic processing. The
mature 162-amino acid hydrophobic APOF peptide has a calculated
molecular mass of 17.4 kD and contains sites for N- and O-glycosylation.
Northern blot analysis detected a 2.0-kb transcript in human liver only.
Using Western blot analysis, Wang et al. (1999) detected endogenous APOF
in human plasma at an apparent molecular mass of 33 kD.
GENE FUNCTION
Koren et al. (1982) studied the interaction of apoF with other
apolipoproteins and lipids in human plasma. They suggested that
apoF-containing lipoproteins may be involved in transport and/or
esterification of cholesterol.
Wang et al. (1999) found that recombinant APOF secreted from transfected
COS-7 cells suppressed transfer of triglyceride and cholesteryl ester by
CETP in a dose-dependent manner. They suggested that APOF is a regulator
of cholesterol transport between plasma lipoproteins that affects the
sterol content of individual lipoprotein fractions.
MAPPING
By somatic cell hybrid analysis, Day et al. (1994) mapped the APOF gene
to chromosome 12.
Gross (2013) mapped the APOF gene to chromosome 12q13.3 based on an
alignment of the APOF sequence (GenBank GENBANK BC026257) with the
genomic sequence (GRCh37).
GPR182
| dbSNP name | rs35493121(T,C) |
| ccdsGene name | CCDS8927.1 |
| CosmicCodingMuts gene | GPR182 |
| cytoBand name | 12q13.3 |
| EntrezGene GeneID | 11318 |
| EntrezGene Description | G protein-coupled receptor 182 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR182:NM_007264:exon2:c.T1045C:p.C349R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O15218 |
| dbNSFP Uniprot ID | GP182_HUMAN |
| dbNSFP KGp1 AF | 0.131868131868 |
| dbNSFP KGp1 Afr AF | 0.128048780488 |
| dbNSFP KGp1 Amr AF | 0.121546961326 |
| dbNSFP KGp1 Asn AF | 0.166083916084 |
| dbNSFP KGp1 Eur AF | 0.11345646438 |
| dbSNP GMAF | 0.1322 |
| ESP Afr MAF | 0.150023 |
| ESP All MAF | 0.109334 |
| ESP Eur/Amr MAF | 0.088488 |
| ExAC AF | 0.105 |
MYO1A
| dbSNP name | rs17119344(G,A); rs56128678(T,C); rs56354404(T,C); rs755221(C,T); rs1552245(C,T); rs697223(A,C); rs17119352(T,A); rs75249987(A,G); rs117270067(T,C); rs703848(A,G); rs73114452(G,C); rs138851352(C,T); rs58389529(T,C); rs61504157(A,G); rs11615024(G,A); rs61939637(G,A); rs2270739(T,C); rs696216(T,C); rs4143085(C,G); rs138855953(C,T); rs33962952(C,T); rs324009(C,A); rs3858539(A,G); rs3886083(C,T); rs17546153(A,G); rs697222(G,A); rs73114457(T,C); rs73114459(C,T); rs116732460(A,G); rs703847(T,C); rs17119386(T,C); rs78272632(C,T); rs2270737(A,G); rs2270736(A,G); rs3782330(A,C); rs3782329(A,T); rs11613928(T,G); rs17119388(G,T); rs73114468(C,G) |
| ccdsGene name | CCDS8929.1 |
| CosmicCodingMuts gene | MYO1A |
| cytoBand name | 12q13.3 |
| EntrezGene GeneID | 4640 |
| EntrezGene Description | myosin IA |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO1A:NM_005379:exon20:c.G2162A:p.R721Q,MYO1A:NM_001256041:exon21:c.G2162A:p.R721Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5671 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UBC5 |
| dbNSFP Uniprot ID | MYO1A_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 2.44e-05 |
OMIM Clinical Significance
Skel:
Diaphyseal sclerosis of tibia, femur, fibula and radius;
Pain and swelling of lesions
Misc:
Onset usually after puberty;
Usually unilateral or asymmetrically and asynchronously bilateral
Lab:
Osteoblastic activity alone;
Progressive obstruction of haversian systems
Inheritance:
Autosomal recessive
OMIM Title
*601478 MYOSIN IA; MYO1A
OMIM Description
DESCRIPTION
Myosins are molecular motors that, upon interaction with actin
filaments, utilize energy from ATP hydrolysis to generate mechanical
force. Phylogenetic analysis of the myosin motor domains identified 11
distinct classes, 7 of which are expressed in vertebrates. These 7
vertebrate myosin classes include conventional myosin (myosin II) and 6
less well characterized unconventional myosin classes, myosins I, V (see
160777), VI (600970), VII (see 276903), IX, and X (601481). Each myosin
has a conserved N-terminal motor domain (25 to 40% identical at the
amino acid level) that contains both ATP-binding and actin-binding
sequences. Following the motor domain is a light-chain-binding 'neck'
region containing 1-6 copies of a repeat element, the IQ motif, that
serves as a binding site for calmodulin (114180) or other members of the
EF-hand superfamily of calcium-binding proteins. At the C terminus, each
myosin class has a distinct tail domain that serves in dimerization,
membrane binding, protein binding, and/or enzymatic activities and
targets each myosin to its particular subcellular location (review by
Mooseker and Cheney, 1995 and Hasson et al., 1996).
BIOCHEMICAL FEATURES
The ability to sense molecular tension is crucial for a wide array of
cellular processes, including the detection of auditory stimuli, control
of cell shape, and internalization and transport of membranes. Laasko et
al. (2008) showed that myosin I, a motor protein that has been
implicated in powering key steps in these processes, dramatically alters
its motile properties in response to tension. The authors measured the
displacement generated by single myosin I molecules and determined the
actin-attachment kinetics with varying tensions using an optical trap.
The rate of myosin I detachment from actin decreases greater than
75-fold under tension of 2 piconewtons or less, resulting in myosin I
transitioning from a low (less than 0.2) to a high (greater than 0.9)
duty-ratio motor. Laasko et al. (2008) concluded that this impressive
tension sensitivity supports a role for myosin I as a molecular force
sensor.
MAPPING
By interspecific mouse backcross mapping, Hasson et al. (1996) localized
the Myo1a gene to mouse chromosome 10, predicting a location of the
human homolog on 12q13. By fluorescence in situ hybridization, they
demonstrated that the human MYO1A gene is located on 12q13-q15.
MOLECULAR GENETICS
Donaudy et al. (2003) identified a nonsense mutation, a trinucleotide
insertion, and 6 missense mutations in the MYO1A gene in 8 unrelated
patients from central and southern Italy affected by sensorineural
bilateral hearing loss (DFNA48; 607841) of variable degree, usually
ranging from moderate to severe but never profound.
MIR1228
| dbSNP name | rs139262076(C,T) |
| ccdsGene name | CCDS8932.1 |
| cytoBand name | 12q13.3 |
| EntrezGene GeneID | 100302201 |
| snpEff Gene Name | LRP1 |
| EntrezGene Description | microRNA 1228 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.014753 |
| ESP All MAF | 0.005075 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001342 |
MARCH9
| dbSNP name | rs1048691(C,T) |
| cytoBand name | 12q14.1 |
| EntrezGene GeneID | 92979 |
| snpEff Gene Name | CYP27B1 |
| EntrezGene Description | membrane-associated ring finger (C3HC4) 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2654 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Autosomal dominant
HEMATOLOGY:
Increased bleeding after trauma, surgery, or injury;
Hematomas after trauma or injury;
Bleeding defect due to decreased plasminogen activator inhibitor-1;
Decreased euglobin lysis time;
Increased fibrinolysis;
Menorrhagia
MISCELLANEOUS:
Congenital onset;
Spontaneous bleeding is rare;
Favorable management with the fibrinolysis inhibitors (e.g., epsilon-aminocaproic
acid and tranexamic acid)
MOLECULAR BASIS:
Caused by mutation in the serpin peptidase inhibitor, clade E, member
1 gene (SERPINE1, 173360.0001)
OMIM Title
*613336 MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 9; MARCH9
;;MARCH IX
OMIM Description
DESCRIPTION
MARCH9 is a member of the MARCH family of membrane-bound E3 ubiquitin
ligases (EC 6.3.2.19). MARCH enzymes add ubiquitin (see 191339) to
target lysines in substrate proteins, thereby signaling their vesicular
transport between membrane compartments. MARCH9 induces internalization
of several membrane glycoproteins and directs them to the endosomal
compartment (Bartee et al., 2004; Hoer et al., 2007).
CLONING
Poxviruses and gamma-2 herpesviruses express ubiquitin ligases called K3
proteins that inhibit the surface expression of glycoproteins, including
major histocompatibility complex (MHC) class I molecules (see 142800).
By searching a database for sequences similar to the functional domains
of viral K3 proteins, Bartee et al. (2004) identified 9 human MARCH
proteins, including MARCH9. The deduced full-length MARCH9 protein
contains a short N terminus, followed by a RING-CH domain and 2
transmembrane domains. It shares 90% identity with MARCH4 (608208) in
the RING-CH and transmembrane domains. Bartee et al. (2004) also
identified a MARCH9 variant that encodes a protein lacking the RING-CH
domain. Real-time PCR analysis showed that both MARCH9 variants were
expressed in all human tissues examined at variable levels.
Hoer et al. (2007) determined that the short MARCH9 variant, which they
called MARCH9 RINGless, uses a transcription initiation site within
intron 2 of the MARCH9 gene. The deduced protein contains the same 2
C-terminal transmembrane domains as full-length MARCH9, but it has a
unique 57-amino acid N terminus that replaces the RING-CH domain.
Epitope-tagged full-length MARCH9 colocalized with a lysosomal marker.
When overexpressed, it also colocalized with the trans-Golgi network
(TGN).
Using RT-PCR, De Gassart et al. (2008) detected robust MARCH9 expression
in all human cells and cell lines examined, including immature and
mature dendritic cells, HeLa and B-cell lines, and monocytes.
GENE FUNCTION
Using an in vitro ubiquitination assay, Bartee et al. (2004) found that
the isolated RING-CH domain of MARCH9 could not function as an E3
ubiquitin ligase with any E2 ubiquitin-conjugating enzymes tested,
including UBCH2 (UBE2H; 601082), UBCH3 (CDC34; 116948), UBCH5A (UBE2D1;
602961), UBCH6 (UBE2E1; 602916), and UBCH7 (UBE2L3; 603721). Following
transfection into HeLa cells, full-length MARCH9 downregulated the
surface expression of cotransfected CD4 (186940) and endogenous MHC I.
Mutation analysis showed that the RING-CH domain of MARCH9 was essential
for MHC I downregulation, and the MARCH9 isoform lacking the RING-CH
domain did not downregulate MHC I surface expression. MHC I was
internalized to lysosomes via multivesicular bodies, and inhibition of
endosome acidification or expression of a dominant-negative VPS4 (see
609982) mutant abrogated MARCH9-induced MHC I internalization. Deletion
of lysines in the tails of HLA-A2.1 (600642) and CD4 made these proteins
resistant to MARCH9-induced degradation, suggesting that ubiquitination
of these lysines is required for their uptake and degradation.
Hoer et al. (2007) found that overexpression of full-length MARCH9
downregulated the surface expression of ICAM1 (147840), a critical cell
adhesion molecule, and MHC I in transfected HeLa and 293T cells.
Downregulation of ICAM1 involved monoubiquitination of ICAM1 on a
cytoplasmic lysine. Mutation analysis revealed that a critical aspartate
within the transmembrane region of MARCH9 was required for recognition
of MHC I molecules, but not ICAM1. The MARCH9 RINGless isoform
stabilized full-length MARCH9 via heterodimerization, resulting in
enhanced MARCH9-mediated MHC I and ICAM1 downregulation. Full-length
MARCH9 was also able to homodimerize.
GENE STRUCTURE
Hoer et al. (2007) determined that the MARCH9 gene contains 4 exons.
MAPPING
Hartz (2010) mapped the MARCH9 gene to chromosome 12q14.1 based on an
alignment of the MARCH9 sequence (GenBank GENBANK BC009489) with the
genomic sequence (GRCh37).
CYP27B1
| dbSNP name | rs8176351(C,T) |
| cytoBand name | 12q14.1 |
| EntrezGene GeneID | 1594 |
| EntrezGene Description | cytochrome P450, family 27, subfamily B, polypeptide 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0101 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Isolated cases
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Biopsy shows cardiomyocytes with PAS-positive vacuoles;
Increased lysosomal glycogen
MUSCLE, SOFT TISSUE:
Neonatal hypotonia Muscle biopsy shows PAS-positive vacuoles;
Increased lysosomal glycogen;
Biopsy shows deposition of complement proteins C5b-9 of the membrane
attack complex on muscle fibers or in vacuoles;
Normal LAMP2 staining (309060);
Normal alpha-glucosidase or acid maltase activity (GAA, 606800)
NEUROLOGIC:
[Central nervous system];
Developmental delay
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Early lethality;
Overlapping pathologic features with X-linked myopathy with excessive
autophagy (XMEA, 310440)
OMIM Title
*609506 CYTOCHROME P450, SUBFAMILY XXVIIB, POLYPEPTIDE 1; CYP27B1
;;25-@HYDROXYVITAMIN D3-1-ALPHA-HYDROXYLASE;;
1-@ALPHA-HYDROXYLASE;;
P450C1-ALPHA
OMIM Description
DESCRIPTION
Vitamin D3 (cholecalciferol), which is synthesized in the epidermis in
response to ultraviolet radiation, and dietary vitamin D2
(ergocalciferol), which is synthesized in plants, are devoid of any
biologic activity. Vitamin D hormonal activity is due primarily to the
hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3
(1,25(OH)2D3, or calcitriol). The CYP27B1 gene encodes 25-hydroxyvitamin
D3-1-alpha-hydroxylase (1-alpha-(OH)ase), an enzyme in the renal
proximal tubule that catalyzes the hydroxylation of 25-hydroxyvitamin D3
into 1,25(OH)2D3. The active metabolite 1,25(OH)2D3 binds and activates
the nuclear vitamin D receptor (VDR; 601769), with subsequent regulation
of physiologic events such as calcium homeostasis and cellular
differentiation and proliferation (summary by Takeyama et al. (1997),
Liberman and Marx (2001), and Koren (2006)).
CLONING
Takeyama et al. (1997) cloned the mouse gene encoding
25(OH)D3-1-alpha-hydroxylase from mouse kidney. The deduced 507-amino
acid protein has a molecular mass of approximately 55 kD. Biochemical
analysis showed that it has a mitochondrial target sequence and is
homologous to members of the P450 family of enzymes.
Because expression of P450c1-alpha is low in the kidney, Fu et al.
(1997) cloned and sequenced a P450c1-alpha cDNA that was derived from
human keratinocytes, in which expression of P450c1-alpha can be induced.
Northern blot analysis detected a 2.5-kb P450c1-alpha transcript in
keratinocytes. RT-PCR showed expression in human kidney, brain, and
testis. The 508-amino acid P450c1-alpha protein has a predicted topology
that is similar to mitochondrial cytochrome P450 enzymes, with a
putative N-terminal mitochondrial signal sequence and conserved
ferredoxin- and heme-binding sites. Mammalian cells transfected with the
cloned P450c1-alpha cDNA exhibited robust 1-alpha-hydroxylase activity.
Fu et al. (1997) used Southern blotting studies to show that there is
only 1 copy of the P450c1-alpha gene in the human genome.
Human cDNAs encoding the 1-alpha-hydroxylase gene were cloned by St.
Arnaud et al. (1997) and Monkawa et al. (1997).
Kitanaka et al. (1998) isolated the human 1-alpha-hydroxylase gene from
a human kidney cDNA library. The deduced protein shared 82% homology
with the mouse protein. By Northern blot analysis, Kitanaka et al.
(1998) identified a 2.4-kb 1-alpha-hydroxylase mRNA transcript in renal
tissue only.
Diaz et al. (2000) investigated the presence of 25-hydroxyvitamin
D3-1-alpha-hydroxylase gene expression products in cultured human
syncytiotrophoblast. Total RNA was isolated from cultured placental
cells and subjected to Northern blots or RT-PCR by using
1-alpha-(OH)ase-specific primers. The authors concluded that the results
of this study provided evidence for the presence of 1-alpha-(OH)ase in
the human placenta, suggesting that conversion of 25-(OH)D3 to
1,25-dihydroxyvitamin D3 in the trophoblast is most probably attributed
to an enzymatic 1-alpha-hydroxylation reaction.
Using a beta-galactosidase reporter system, Vanhooke et al. (2006) found
no evidence for expression of Cyp27b1 in mouse skin or primary
keratinocytes, although it was expressed in kidney and placenta.
GENE STRUCTURE
Fu et al. (1997) determined that the P450c1-alpha gene contains 9 exons
spanning 5 kb; the entire protein-coding region could be PCR-amplified
as a single 4-kb fragment. The transcriptional start site lies 62 bp
upstream from the ATG translational start codon. Although the gene is
substantially smaller than the human genes for other mitochondrial
enzymes, its intron/exon organization is very similar, especially to
that of P450scc (118485). This indicates that although the mitochondrial
P450 enzymes retain only 30 to 40% amino acid sequence identity, they
all belong to a single evolutionary lineage.
Kitanaka et al. (1998) determined that the human CYP27B1 gene contains 9
exons spanning a region of approximately 4.8 kb.
Kong et al. (1999) determined that the 1-alpha-OHase gene contain 9
exons and spans approximately 6.5 kb and a 1.4-kb 5-prime flanking
region. Promoter analysis characterized the regulatory regions of the
1-alpha-OHase gene and provided insight into the physiologic basis for
regulation of the expression of this gene by PTH and 1,25(OH)2D3.
Turunen et al. (2007) identified VDREs 2.6- and 3.2-kb upstream of the
transcriptional start site in the proximal CYP27B1 promoter. These
upstream elements are located within an intron of the METTL1 gene
(604466).
MAPPING
By somatic cell hybrid analysis, Fu et al. (1997) mapped the
P450c1-alpha gene to chromosome 12, the location where a form of vitamin
D-dependent rickets (VDDR1A; 264700) had been mapped. St. Arnaud et al.
(1997) mapped the CYP27B1 gene to 12q13.1-q13.3 by fluorescence in situ
hybridization.
GENE FUNCTION
Akiba et al. (1980) demonstrated that 25-hydroxyvitamin
D3-1-alpha-hydroxylase activity occurs in the mammalian kidney.
Kawashima et al. (1981), and Kawashima and Kurokawa (1983) demonstrated
the existence of 2 anatomically distinct and independently regulated
25(OH)D-1-alpha-hydroxylase systems in the proximal convoluted tubules
and the proximal straight tubules. Parathyroid hormone (PTH; 168450)
regulated enzyme activity via a cAMP-mediated mechanism in the proximal
convoluted tubule, whereas calcitonin regulated enzyme activity via a
non-cAMP-mediated mechanism in the proximal straight tubule.
Hydroxylation of 25(OH)D in the 1-alpha position is not restricted to
the renal tubular cells. Human placenta decidual cells produce
calcitriol, and the enzyme activity is regulated by feedback mechanisms.
Glorieux et al. (1995) demonstrated that placenta decidual cells
isolated from patients with vitamin D-dependent rickets type 1A (264700)
lacked 25-hydroxyvitamin D-1-alpha-hydroxylase activity, suggesting that
the decidual and renal enzymes are encoded by the same gene.
Takeyama et al. (1997) found that mice lacking the vitamin D receptor
had decreased expression of 1-alpha-hydroxylase. The enzyme was
suppressed by the hormonally active form of vitamin D in homozygous and
heterozygous normal mice but not in homozygous VDR-deficient mice. These
results suggested that the negative feedback regulation of active
vitamin D synthesis is mediated by 1-alpha-hydroxylase through
ligand-bound VDR. Takeyama et al. (1997) cited reports indicating that
this kidney enzyme is inhibited by its end product and activated by
calciotrophic peptide hormones such as calcitonin (114130) and PTH,
which keep serum concentrations of the active hormone constant.
Brenza et al. (1998) studied the DNA flanking the 5-prime sequence of
the mouse 1-alpha-hydroxylase gene. A TATA box was found at -30 bp and a
CCAAT box at -79 bp. The gene's promoter activity was demonstrated by
using a luciferase reporter gene construct transfected into a modified
pig kidney cell line. Parathyroid hormone stimulated this
promoter-directed synthesis of luciferase by 17-fold, whereas forskolin
stimulated it by 3-fold. The action of PTH was concentration- dependent.
The promoter has 3 potential cAMP-responsive element sites, and 2
perfect and 1 imperfect AP-1 sites, while no DR-3 was detected. The
results suggested that PTH, through cAMP, activates the
1-alpha-hydroxylase promoter. Murayama et al. (1998) also characterized
the regulatory regions of the promoter of the CYP27B1 gene. A region
around -4 kb conferred positive responsiveness to PTH and calcitonin,
and a region around -0.5 kb conferred negative responsiveness to the
end-product, 1,25(OH)2D3. The findings confirmed that regulation of the
CYP27B1 gene takes place at the transcriptional level. Shinki et al.
(1999) presented evidence that calcitonin is the major regulator of
CYP27B1 expression in the proximal straight tubule of normocalcemic
rats. The effect of calcitonin was not cAMP-mediated.
By immunohistochemical and Western blot analyses, Zehnder et al. (2001)
detected extrarenal distribution of 1-alpha-hydroxylase in both normal
and diseased tissues. Specific staining for 1-alpha-hydroxylase was
detected in skin (basal keratinocytes, hair follicles), lymph nodes
(granulomata), colon (epithelial cells and parasympathetic ganglia),
pancreas (islets), adrenal medulla, brain (cerebellum and cerebral
cortex), and placenta (decidual and trophoblastic cells). Further
studies also detected overexpression in the dysregulated stratum
spinosum of psoriatic skin.
Using mouse Cyp27b1 with various point mutations, Yamamoto et al. (2005)
found that ser408, which corresponds to thr409 in human CYP27B1,
interacted with the 25-hydroxyl group of the 25(OH)D3 substrate and was
essential for removal of the water molecule during the subsequent
1-alpha hydroxylation reaction. Gln65, which is conserved between mouse
and human CYP27B1, was also involved in substrate binding, but most
mutations of gln65 resulted in expression of Cyp27b1 apoproteins without
heme molecules, suggesting that gln65 is involved in protein folding.
Using DNA microarray and quantitative PCR analyses, Liu et al. (2006)
found that activation of TLR2 (603028) and TLR1 (601194) by a
mycobacterial ligand upregulated expression of VDR and CYP27B1 in
monocytes and macrophages, but not dendritic cells. Intracellular flow
cytometric and quantitative PCR analyses showed that treatment of
monocytes with vitamin D upregulated expression of CYP24 (CYP24A1;
126065), the vitamin D 24-hydroxylase, and cathelicidin (CAMP; 600474),
an antimicrobial peptide, but not DEFB4 (602215). Confocal microscopy
demonstrated colocalization of CAMP with bacteria-containing vacuoles of
vitamin D-treated monocytes, and vitamin D treatment of M.
tuberculosis-infected macrophages reduced the number of viable bacilli.
Ligand stimulation of TLR2 and TLR1 upregulated CYP24 and CAMP in the
presence of human serum, but not bovine serum, and CAMP upregulation was
more efficient in Caucasian than in African American serum, in which
vitamin D levels were significantly lower. Vitamin D supplementation of
African American serum reversed the CAMP induction defect. Liu et al.
(2006) proposed that vitamin D supplementation in African and Asian
populations, which may have a reduced ability to synthesize vitamin D
from ultraviolet light in sunlight, might be an effective and
inexpensive intervention to enhance innate immunity against microbial
infection and neoplastic disease.
Using PCR, Western blot, and immunohistochemical analyses, Schauber et
al. (2007) found that human skin wounding led to upregulation of TLR2,
the TLR coreceptor CD14 (158120), and the vitamin D3 catabolic enzyme
CYP24A1. TLR2 protein expression was detectable on keratinocytes at the
wound edges. Active vitamin D3 (1,25D3) enhanced TLR2 and CD14
expression in cultured keratinocytes. CYP27B1 expression increased in
response to injury, TGFB1 (190180) treatment, or TLR2 activation and
resulted in a corresponding increase in expression of 1,25D3-responsive
genes in a CYP27B1-dependent manner. Keratinocytes stimulated with
1,25D3 displayed enhanced TLR2 function and cathelicidin expression.
Schauber et al. (2007) concluded that vitamin D3 is important in innate
immunity, enabling keratinocytes to recognize and respond to microbes to
protect wounds against infection.
In kidney, the level of 1,25(OH)2D3 is controlled by product inhibition,
in which 1,25(OH)2D3 itself, acting through VDR, represses CYP27B1.
Turunen et al. (2007) confirmed that CYP27B1 was downregulated by
1,25(OH)2D3 via VDR in kidney-derived HEK293 cells. In contrast, CYP27B1
expression in MCF7 breast cancer cells was not affected by 1,25(OH)2D3.
Using chromatin immunoprecipitation (ChIP) analysis, Turunen et al.
(2007) identified 1,25(OH)2D3-responsive regions about 2.6 and 3.2 kb
upstream of the CYP27B1 transcriptional start site, in addition to the
negative vitamin D response element (nVDRE) in the proximal promoter
region. Both upstream sites recruited VDR in a ligand-dependent manner
and reduced CYP27B1 expression in HEK293 cells, but not in MCF7 cells.
Gel shift assays showed that both upstream VDREs directly bound VDR-RXR
(see 180245) heterodimers in a ligand-dependent manner. In contrast, the
nVDRE in the proximal promoter did not bind VDR-RXR heterodimers
directly, but rather bound VDR-interacting repressor (VDIR, or TCF3;
147141). ChIP analysis showed that both the upstream VDREs and nVDRE
associated with different complements of transcriptional regulators and
cofactors in HEK293 cells compared with MCF7 cells. Chromatin
conformation capture analysis of HEK293 cells showed that both far
upstream VDREs directly interacted with nVDRE via chromatin looping
following VDR activation by ligand. MCF7 cells also showed looping
between nVDRE and the VDRE 2.6 kb upstream of the transcriptional start
site, but this looping did not lead to gene repression. Turunen et al.
(2007) concluded that the responsiveness of the CYP27B1 gene to
1,25(OH)D3 is a cell type-selective event that involves different
combinations of multiple VDREs that recruit different transcriptional
regulators.
In a review of their own work on CYP27B1 transcriptional regulation, Kim
et al. (2007) described suppression of CYP27B1 in MCF7 cells by a WSTF
(BAZ1B; 605681)-containing ATP-dependent chromatin remodeling complex
called WINAC. Unliganded VDR interacted with WINAC through WSTF, and the
VDR/WSTF complex interacted with DNA-bound VDIR at nVDRE. Following
recruitment of VDR/WSTF to nVDRE, histones were deacetylated by
recruited histone deacetylases (HDACs; see 601241), and this was
followed by DNA methylation and transcriptional repression.
MOLECULAR GENETICS
- Vitamin D Hydroxylation-Deficient Rickets, Type 1A
Fu et al. (1997) found that primary cultures of human adult and neonatal
keratinocytes exhibited abundant 1-alpha-hydroxylase activity, whereas
those from a patient with vitamin D-dependent rickets type 1A (VDDR1A;
264700) lacked detectable activity. In keratinocyte P450c1-alpha cDNA
from this patient, Fu et al. (1997) identified compound heterozygosity
for 2 null mutations in the CYP27B1 gene (609506.0005 and 609506.0006).
Kitanaka et al. (1998) identified 4 different homozygous missense
mutations in patients with VDDR1A. The parents and 1 sib who were
studied were all heterozygous carriers.
In 19 individuals with VDDR1A from 17 families representing various
ethnic groups (Filipino, white (US), Polish, Chinese, French Canadian,
black (US), Haitian, and Hispanic), Wang et al. (1998) identified 14
different mutations in the CYP27B1 gene. A founder haplotype and
mutation (609506.0007) was identified in several patients from the
French Canadian population. Six families of widely divergent ethnic
backgrounds carried a 7-bp duplication (609506.0008) in association with
4 different microsatellite haplotypes, indicating a mutation hotspot.
Wang et al. (1998) suggested that the disorder should be referred to as
'1-alpha-hydroxylase deficiency.'
Kitanaka et al. (1999) identified mutations in the CYP27B1 gene in 6
unrelated patients with pseudovitamin D deficiency rickets, 5 with
typical clinical manifestations and 1 with milder features (see, e.g.,
609506.0009).
Wang et al. (2002) reported mutations in the CYP27B1 gene in patients
with VDDR type 1A (see, e.g., 609506.0013-609506.0017). In vitro
functional expression studies showed that 2 mutant enzymes (L343F,
609506.0016 and E189G, 609506.0017) retained 2% and 22% of wildtype
activity, respectively. These 2 mutations were found in 2 patients with
mild laboratory abnormalities, including mild hypocalcemia and normal
serum 1,25-(OH)2D concentration, suggesting that such mutations
contribute to the phenotypic variation observed in patients with CYP27B1
deficiency.
Kim et al. (2007) analyzed the CYP27B1 gene in 10 patients with
1-alpha-hydroxylase deficiency (5 from Korea, 2 from the U.S., and 1
each from Argentina, Denmark, and Morocco), all from nonconsanguineous
families. All of the patients had clinical and radiographic features of
rickets, hypocalcemia, and low serum concentrations of
1,25-dihydroxyvitamin D3. Direct sequencing identified the responsible
CYP27B1 mutations on 19 of 20 alleles. Four novel and 4 known mutations
were identified.
- Possible Association with Multiple Sclerosis
By whole-exome sequencing of 43 probands with multiple sclerosis (MS;
126200), each from a family in which 4 or more individuals had MS,
Ramagopalan et al. (2011) failed to find a common loss-of-function or
predicted damaging variant. However, 1 patient had a heterozygous
loss-of-function arg389-to-his (R389H; 609506.0012) substitution (dbSNP
rs118204009) in the CYP27B1 gene that was found to be present in all 4
(100%) affected family members and 33% of genotyped unaffected family
members. This variant was also found to be overtransmitted in an
analysis of 3,046 parent-affected child trios (p = 1 x 10(-5)) and in a
further 422 parent-affected sib pairs (p = 0.046). None of the
individuals had evidence of VDDR1A. Two additional heterozygous
pathogenic variants, E189G (609506.0017) and L343F (609506.0016), were
found to be overtransmitted in the larger trio cohort. None of the
individuals with any of these mutations were of French Canadian origin.
Serum from 1 individual with the R389H mutation showed low calcitriol
levels compared to controls, and 3 of 96 additional MS patients with low
calcitriol levels were found to carry putative pathogenic CYP27B1
variants, suggesting that heterozygosity for loss-of-function alleles
results in lower calcitriol levels. Overall, the findings supported a
causative role for variation in the CYP27B1 gene in MS risk, which
correlates with known latitude gradient that appeared to influence
disease risk.
Ban et al. (2013) found no significant association between the R389H and
L343F variants in the CYP27B1 gene and MS among 495 multiplex families,
2,092 single affected families, and 4,594 patients with the disorder
compared to 3,583 controls. The populations were from the U.K., U.S.,
and Norway. Barizzone et al. (2013) also found no association between
the R389H variant and MS among 2,608 patients and 1,987 controls from
Italy and Belgium. Plasma measurement of 1 MS patient and 1 unaffected
individual, both of whom were heterozygous for the R389H variant, showed
no decrease in 1,25-dihydroxyvitamin D levels. Screening of the CYP27B1
coding sequence in 134 Italian multiplex MS families revealed no
mutations. Ban et al. (2013) and Barizzone et al. (2013) independently
concluded that mutant CYP27B1 alleles do not influence the risk of
developing MS.
ANIMAL MODEL
Panda et al. (2001) developed a mouse model deficient in 1-alpha-(OH)ase
by targeted ablation of the hormone-binding and heme-binding domains of
the Cyp27b1 gene. After weaning, mice developed features similar to
those of human VDDR1: hypocalcemia, secondary hyperparathyroidism,
retarded growth, and skeletal abnormalities characteristic of rickets.
Altered noncollagenous matrix protein expression and reduced numbers of
osteoclasts were also observed in bone. Female mutant mice were
infertile and exhibited uterine hypoplasia and absent corpora lutea.
Furthermore, histologically enlarged lymph nodes in the vicinity of the
thyroid gland and a reduction in CD4- and CD8-positive peripheral T
lymphocytes were observed. Alopecia, reported in vitamin D
receptor-deficient mice and in humans with VDDR type 2 (see 277440), was
not seen. The findings established a critical role for the enzyme in
mineral and skeletal homeostasis as well as in female reproduction and
also pointed to an important role in regulating immune function.
Xue et al. (2005) compared mice with targeted disruption of the Pth
(168450) or Cyp27b1 genes to the double-null mutants. Although Pth-null
and Cyp27b1-null mice displayed only moderate hypocalcemia, Pth/Cyp27b1
double-null mice died of tetany with severe hypocalcemia by 3 weeks of
age. At 2 weeks, Pth-null mice exhibited only minimal dysmorphic
changes, whereas Cyp27b1-null mice showed epiphyseal dysgenesis, and
Pth/Cyp27b1 double-mutants showed severe epiphyseal dysgenesis. Although
reduced osteoblastic bone formation was seen in both mutants, Pth
deficiency caused only a slight reduction in long bone length but a
marked reduction in trabecular bone volume, whereas Cyp27b1 ablation
caused a smaller reduction in trabecular bone volume but a significant
decrease in bone length. The authors concluded that PTH plays a
predominant role in appositional bone growth, whereas 1,25(OH)2D3 acts
predominantly on endochondral bone formation. Although PTH and
1,25(OH)2D3 independently, but not additively, regulate osteoclastic
bone resorption, they do affect the renal calcium transport pathway
cooperatively. Consequently, PTH and 1,25(OH)2D3 exhibited discrete and
collaborative roles in modulating skeletal and calcium homeostasis, and
Xue et al. (2005) hypothesized that loss of the renal component of
calcium conservation may be the major factor contributing to the lethal
hypocalcemia in double mutants.
Vanhooke et al. (2006) found that Cyp27b1-null mice grew normally when
maintained on a balanced diet containing 1,25(OH)2D3, but rapidly
developed rickets when phosphorus and 1,25(OH)2D3 were restricted.
HISTORY
The article by Kim et al. (2009) on DNA demethylation in hormone-induced
transcriptional derepression was retracted.
C12orf61
| dbSNP name | rs10877885(C,T); rs10877886(G,A) |
| cytoBand name | 12q14.1 |
| EntrezGene GeneID | 283416 |
| snpEff Gene Name | MON2 |
| EntrezGene Description | chromosome 12 open reading frame 61 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3545 |
MIR548Z
| dbSNP name | rs17120527(A,G) |
| ccdsGene name | CCDS8969.1 |
| cytoBand name | 12q14.2 |
| EntrezGene GeneID | 100500856 |
| snpEff Gene Name | RASSF3 |
| EntrezGene Description | microRNA 548z |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05647 |
| ESP Afr MAF | 0.176977 |
| ESP All MAF | 0.054563 |
| ESP Eur/Amr MAF | 0.000977 |
| ExAC AF | 0.017 |
MIR6074
| dbSNP name | rs11176006(G,A); rs10878362(C,A) |
| cytoBand name | 12q14.3 |
| snpEff Gene Name | RP11-366L20.4 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1671 |
| ExAC AF | 0.084 |
LOC100130075
| dbSNP name | rs7969876(G,C); rs2120742(C,T) |
| cytoBand name | 12q15 |
| EntrezGene GeneID | 100130075 |
| snpEff Gene Name | MDM2 |
| EntrezGene Description | SUZ RNA binding domain containing 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02938 |
LRRC10
| dbSNP name | rs11177751(A,G); rs7295466(T,C); rs28203(T,C); rs28204(G,A); rs12313819(T,G); rs148566929(C,T); rs374731396(C,T) |
| cytoBand name | 12q15 |
| EntrezGene GeneID | 376132 |
| EntrezGene Description | leucine rich repeat containing 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2084 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Mitral valve regurgitation
MISCELLANEOUS:
Age-dependent penetrance
OMIM Title
*610846 LEUCINE-RICH REPEAT-CONTAINING PROTEIN 10; LRRC10
;;HEART-RESTRICTED LEUCINE-RICH REPEAT PROTEIN; HRLRRP
OMIM Description
CLONING
By EST database analysis to identify cardiac-specific genes, followed by
RT-PCR of mouse E13 embryo cDNA, Nakane et al. (2004) cloned mouse
Lrrc10, which they called Hrlrrp. The deduced 274-amino acid protein has
a predicted molecular mass of 31.2 kD and contains 7 leucine-rich
repeats of 20 to 23 amino acids and 2 possible C-terminal nuclear
localization signals. Northern blot analysis detected a 1.3-kb mouse
Lrrc10 transcript exclusively in heart. PCR analysis confirmed Lrrc10
expression in mouse heart with lower expression detected in skeletal
muscle but not in any other tissues examined. In vitro
transcription/translation of mouse Lrrc10 produced a peptide of
approximately 35 kD. Confocal and fluorescence microscopy localized
transfected Lrrc10 to the nucleus and mitochondria of COS-7 cells.
MAPPING
By genomic sequence analysis, Nakane et al. (2004) mapped the LRRC10
gene to chromosome 12. They mapped the mouse Lrrc10 gene to chromosome
15.
ATXN7L3B
| dbSNP name | rs590352(G,C); rs187952023(C,T); rs625531(T,C); rs2605380(G,A); rs55707513(A,T); rs137952266(G,A); rs200316731(C,T); rs5002508(T,G); rs114397456(A,G); rs1044583(C,G); rs1389488(C,T); rs73190463(C,A); rs1389487(G,A); rs1389486(T,C); rs8744(G,T) |
| ccdsGene name | CCDS53815.1 |
| cytoBand name | 12q21.1 |
| EntrezGene GeneID | 552889 |
| EntrezGene Description | ataxin 7-like 3B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ATXN7L3B:NM_001136262:exon1:c.G267C:p.L89L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3131 |
| ESP Afr MAF | 0.310694 |
| ESP All MAF | 0.379763 |
| ESP Eur/Amr MAF | 0.245129 |
| ExAC AF | 0.658 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation;
Poor postnatal growth
HEAD AND NECK:
[Eyes];
Visual impairment;
Delayed visual-evoked potential
MUSCLE, SOFT TISSUE:
Muscle atrophy;
Hypotonia;
Increased mitochondria seen on muscle biopsy;
Lipid accumulation
NEUROLOGIC:
[Central nervous system];
Intellectual disability, mild;
Tremor;
Dysmetria;
Language delay;
Defects in fine motor skills
METABOLIC FEATURES:
Lactic acidosis
HEMATOLOGY:
Macrocytic anemia (1 patient);
Hypersegmented neutrophils (1 patient);
Variable red blood cell size
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased serum ammonia;
Mitochondrial complex I deficiency in muscle;
Fibroblasts show global defects in multiple mitochondrial respiratory
chain activities
MISCELLANEOUS:
Two unrelated patients have been reported (last curated December 2013);
Variable severity
MOLECULAR BASIS:
Caused by mutation in the sideroflexin 4 gene (SFXN4, 615564.0001)
OMIM Title
*615579 ATAXIN 7-LIKE 3B; ATXN7L3B
OMIM Description
CLONING
Using database analysis to identify genes in a 670-kb region of
chromosome 12 that was deleted in a family with complex
neurodevelopmental and ataxic phenotypes, Rajakulendran et al. (2013)
identified ATXN7L3B.
GENE STRUCTURE
Rajakulendran et al. (2013) determined that ATXN7L3B is a single-exon
gene.
MAPPING
Rajakulendran et al. (2013) stated that the ATXN7L3B gene maps to
chromosome 12q21.
MYF6
| dbSNP name | rs3120(C,A); rs3121(T,C); rs1047183(A,G); rs1047185(A,G) |
| cytoBand name | 12q21.31 |
| EntrezGene GeneID | 4618 |
| EntrezGene Description | myogenic factor 6 (herculin) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1139 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial weakness;
[Mouth];
Tongue fasciculations
RESPIRATORY:
Respiratory insufficiency due to muscle weakness;
Recurrent respiratory infections
ABDOMEN:
[Gastrointestinal];
Difficulty swallowing
SKELETAL:
[Spine];
Scoliosis
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal;
Muscle atrophy;
Gowers sign;
Fasciculations;
Muscle biopsy showed neurogenic atrophy;
EMG shows chronic denervation
NEUROLOGIC:
[Central nervous system];
Normal early psychomotor development;
Difficulty walking;
Frequent falls;
Loss of independent ambulation;
Tremor;
Seizures;
Generalized seizures;
Myoclonic seizures;
3-4 Hz slow sharp waves seen on EEG;
[Peripheral nervous system];
Areflexia
LABORATORY ABNORMALITIES:
Normal serum creatine kinase
MISCELLANEOUS:
Onset of muscle weakness around age 5 years;
Onset of seizures around 7 to 12 years;
Seizures are sensitive to hyperventilation;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the N-acylsphingosine amidohydrolase 1 gene
(ASAH1, 613468.0006)
OMIM Title
*159991 MYOGENIC FACTOR 6; MYF6
;;MUSCLE REGULATORY FACTOR 4; MRF4;;
HERCULIN
OMIM Description
CLONING
Braun et al. (1990) detected the MYF6 gene, a novel member of the human
gene family of muscle determination factors, by its highly conserved
sequence coding for a putative helix-loop-helix domain. This sequence
motif is a common feature of all myogenic factors and other regulatory
proteins.
MAPPING
By a panel of human/rodent somatic hybrid cells lines, Braun et al.
(1990) mapped MYF6 to chromosome 12. In situ hybridization suggested
close localization to MYF5 (159990). When a human genomic library was
screened for the MYF6 gene, 2 of the recombinant lambda-phages isolated
contained all or parts of both MYF6 and MYF5. Restriction analysis
indicated that the MYF6 gene is located upstream of MYF5 in the same
orientation, with a distance of about 6.5 kb separating the genes.
Cupelli et al. (1996) mapped the MYF5/MYF6 gene cluster to 12q21 between
D12S350 and D12S106 by hybridization to YACs. The 2 MYF genes could not
be ordered with respect to each other. This was not surprising since
Braun et al. (1990) found that the 2 genes lie within 6.5 kb of each
other.
Bureau et al. (1995) found that the mouse Myf6 gene is in a region of
mouse chromosome 10 that shows considerable homology of synteny to human
12q15.
MOLECULAR GENETICS
In a boy with myopathy and an increase of muscle fibers with central
nuclei (CNM3; 614408), Kerst et al. (2000) detected a heterozygous
mutation in the MYF6 gene (A112S; 159991.0001). The boy showed the first
signs of myopathy at the age of 9 years when creatine kinase serum
activities were elevated to 300-560 U/l. Three years later, creatine
kinase activities were normal, but he complained of muscle cramps and
weakness in his lower limbs during vigorous exercise. At that time,
histologic muscle analysis showed myopathic changes with ring fibers and
an increased percentage of central nuclei fibers. The boy's father
carried the identical MYF6 mutation as well as an in-frame deletion of
exons 45 to 47 in the dystrophin gene (DMD; 300377). This DMD mutation
is usually associated with a mild to moderate course of Becker muscular
dystrophy (300376), but the father suffered from a severe course of
Becker muscular dystrophy, suggesting MYF6 as a modifier. Mutations,
deletions, and rearrangements within the mitochondrial DNA were ruled
out in the boy and his father. The father presented with cardiomyopathy,
pectus carinatum, and severe muscular dystrophy and was wheelchair-bound
by the age of 21 years. Muscle biopsy studies revealed massive fibrosis
and discontinuous patchy immunostaining of dystrophin. This was said to
be the first observation of a pathogenic defect of an MYF mutation in
man.
NOMENCLATURE
In the mouse, Rhodes and Konieczny (1989) had cloned cDNAs for a 'new'
muscle regulatory factor gene and referred to it as Mrf4. Miner and Wold
(1990) referred to the gene as herculin. The gene was designated MYF6 in
human and Myf6 in the mouse.
ANIMAL MODEL
Observations in Myf knockout mice indicate that MYF4 (159980) and MYF6
are involved in differentiation of myotubes (Yun and Wold, 1996).
Using an allelic series of 3 Myf5 (159990) mutants that differentially
affect the expression of the genetically linked Mrf4 gene,
Kassar-Duchossoy et al. (2004) demonstrated that skeletal muscle is
present in Myf5:Myod (159970) double-null mice only when Mrf4 expression
is not compromised. Kassar-Duchossoy et al. (2004) concluded that their
finding contradicted the widely held view that myogenic identity is
conferred solely by Myf5 and Myod, and identified Mrf4 as a
determination gene. Kassar-Duchossoy et al. (2004) revised the epistatic
relationship of the MRFs, in which both Myf5 and Mrf4 act upstream of
Myod to direct embryonic multipotent cells into the myogenic lineage.
Kassar-Duchossoy et al. (2004) found that Mrf4 can direct embryonic but
not fetal skeletal muscle identity and differentiation in the absence of
Myf5 and Myod. Myod is initially activated by Myf5 and Mrf4, and later
through Pax3 (606597). Mrf4 drives myogenesis in the embryonic trunk and
limbs, but not in embryonic head, or in the fetus.
MIR618
| dbSNP name | rs2682818(A,C) |
| ccdsGene name | CCDS9021.1 |
| cytoBand name | 12q21.31 |
| EntrezGene GeneID | 693203 |
| snpEff Gene Name | LIN7A |
| EntrezGene Description | microRNA 618 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2314 |
| ESP Afr MAF | 0.300702 |
| ESP All MAF | 0.191359 |
| ESP Eur/Amr MAF | 0.143495 |
| ExAC AF | 0.825 |
MKRN9P
| dbSNP name | rs1796320(G,A); rs1675574(C,T); rs7136026(G,A) |
| cytoBand name | 12q21.32 |
| EntrezGene GeneID | 400058 |
| EntrezGene Description | makorin ring finger protein 9, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2011 |
| ExAC AF | 0.756 |
CEP290
| dbSNP name | rs369395574(A,C); rs2468239(G,A); rs2468240(G,A); rs368976110(G,A); rs17015421(T,C); rs11104726(A,G); rs2468241(G,A); rs45477492(G,C); rs7980746(G,T); rs368120021(C,T); rs17418744(T,A); rs369451641(G,A); rs73207072(C,T); rs2468242(A,G); rs2468243(T,A); rs74827643(G,A); rs75562834(T,C); rs115275061(G,A); rs12426625(A,G); rs2471513(C,T); rs73207079(A,T); rs2471512(C,T); rs7963359(T,C); rs138300126(C,T); rs367980361(G,A); rs139198432(G,A); rs149968311(A,G); rs80192319(C,G); rs113143640(G,C); rs7958714(T,C); rs2468244(C,T); rs2471510(T,C); rs2471509(T,G); rs2471508(G,T); rs2471507(T,C); rs66582760(T,C); rs2471506(A,C); rs2471505(T,G); rs73207087(G,A); rs2471504(A,T); rs2471503(T,C); rs375669272(C,T); rs368178426(A,C); rs371960475(T,C); rs141776873(G,A); rs186493578(A,C); rs113094140(T,G); rs142280334(G,A); rs147945852(A,G); rs188434009(A,C); rs6538128(A,G); rs17334396(C,A); rs2471546(G,A); rs17015437(T,A); rs2471544(C,A); rs74996542(C,T); rs74403660(T,G); rs45477793(C,G); rs17015438(T,G); rs2468245(C,T); rs59247112(T,G); rs2468246(A,G); rs367580207(G,T); rs2468247(G,A); rs74688229(C,T); rs78015808(T,C); rs372557655(A,T); rs11104732(T,C); rs17015443(T,A); rs2468248(C,T); rs187085098(C,T); rs2468249(G,A); rs2468250(A,T); rs144040567(G,C); rs2468251(T,C); rs370395204(G,T); rs2468252(G,A); rs77842063(T,C); rs17015450(T,C); rs112112148(G,T); rs2471538(A,T); rs2471537(C,T); rs186485576(G,T); rs11104733(C,T); rs2471535(C,T); rs374224637(T,G); rs149355354(T,A); rs74971832(C,T); rs370933917(G,A); rs11104736(A,G); rs2471534(C,T); rs113754167(G,A); rs10858687(G,C); rs115065875(T,C); rs2471533(C,A); rs2471532(C,G); rs189589490(T,C); rs2471531(C,T); rs2471530(G,A); rs115857364(A,C); rs2471529(T,C); rs2471528(G,T); rs2471527(T,A); rs2471526(G,A); rs2468253(C,G); rs375347376(G,C); rs75013755(G,A); rs75273460(A,C); rs2471523(A,G); rs115837670(A,C); rs2468254(C,T); rs11104739(G,A); rs2468255(T,C); rs78143067(T,A); rs45465996(A,G); rs2468256(T,C); rs374672899(C,A); rs190131546(T,C); rs369674896(A,G); rs2468257(C,T); rs140486997(T,C); rs372664954(T,C); rs138921862(C,T); rs2960425(A,C); rs370895894(G,T); rs76640514(T,C); rs12318967(A,G); rs117938134(G,A); rs2468258(G,C); rs76376809(G,A); rs35601372(C,G); rs2468259(G,A); rs145420876(T,A); rs7294497(C,G); rs116866443(T,C); rs74684367(T,C); rs2468260(A,G); rs2471521(C,T); rs2471520(T,C); rs2468220(C,T); rs45502896(C,G); rs7310461(C,A); rs113132803(A,T); rs115764060(G,A); rs371943060(A,C); rs372382821(C,T); rs377288213(T,C); rs112584743(C,T); rs2960424(T,C); rs376465724(C,A); rs113613226(T,C); rs75934024(C,T); rs74549898(G,A); rs75792793(T,C); rs74747196(C,T); rs377007990(A,C); rs2471517(C,T); rs2468221(C,T); rs45468703(T,C); rs369125023(A,G); rs112756535(T,A); rs2468222(G,A) |
| ccdsGene name | CCDS55858.1 |
| cytoBand name | 12q21.32 |
| EntrezGene GeneID | 80184 |
| EntrezGene Description | centrosomal protein 290kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CEP290:NM_025114:exon38:c.C5125A:p.Q1709K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5732 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O15078 |
| dbNSFP Uniprot ID | CE290_HUMAN |
| ESP Afr MAF | 0.000273 |
| ESP All MAF | 8.4e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 2.452e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, dilated;
Conduction disease, sinoatrial and atrioventricular, progressive;
Ventricular tachyarrhythmia (can result in sudden death)
SKELETAL:
[Hands];
Brachydactyly;
Clinodactyly;
[Feet];
Brachydactyly (more severe than in hands);
Short or absent middle phalanges;
Symphalangism, terminal;
Duplication of bases of second metatarsals;
Extra ossicles;
Syndactyly
MUSCLE, SOFT TISSUE:
Myopathy (rare)
NEUROLOGIC:
[Peripheral nervous system];
Proximal weakness, upper extremities (1 patient)
MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0045)
OMIM Title
*610142 CENTROSOMAL PROTEIN, 290-KD; CEP290
;;ANTIGEN IDENTIFIED BY MONOCLONAL ANTIBODY 3H11; 3H11AG;;
KIAA0373;;
NEPHROCYSTIN 6; NPHP6
OMIM Description
DESCRIPTION
The CEP290 gene encodes a centrosomal protein involved in ciliary
assembly and ciliary trafficking (summary by Coppieters et al., 2010).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned KIAA0373. The deduced protein
contains 1,539 amino acids. RT-PCR detected intermediate expression in
kidney and ovary and low expression in thymus, prostate, and testis.
Little to no expression was detected in other tissues examined.
By proteomic analysis of centrosomes isolated from a human lymphoblastic
cell line, followed by database analysis, Anderson et al. (2003)
identified KIAA0373, which they termed CEP290. The deduced protein
contains 9 coiled-coil domains and has a calculated molecular mass of
290 kD. Fluorescence- and epitope-tagged CEP290 associated with
centrosomes in a transfected human osteoblastoma cell line.
Monoclonal antibody 3H11 binds to cancer cells from various tissues. By
screening a gastric cancer cell line expression library with 3H11,
followed by RACE and nested PCR, Chen and Shou (2001) cloned CEP290,
which they called 3H11 antigen (3H11Ag). The deduced protein contains
589 amino acids. Northern blot analysis detected a 2.3-kb 3H11Ag
transcript. Expression was widespread in cancerous tissues, but was not
detected in corresponding normal tissues. RT-PCR detected expression in
normal embryonic tissues and placenta. Western blot analysis revealed a
70-kD protein.
Sayer et al. (2006) analyzed the deduced CEP290 protein sequence and
described 13 putative coiled-coil domains, a region with homology to SMC
(structural maintenance of chromosomes) chromosome segregation ATPases,
a bipartite nuclear localization signal, 6 RepA/Rep+ protein KID motifs
(KID), 3 tropomyosin homology domains, and an ATP/GTP binding site motif
A (P loop). Using RNA blot analysis, Sayer et al. (2006) demonstrated a
major CEP290 transcript of approximately 8 kb that was expressed
strongly in placenta and weakly in brain. The 290-kD NPHP6 protein
(2,479 amino acid residues) is encoded within the human full-length
CEP290 mRNA of 7,951 nucleotides.
Papon et al. (2010) analyzed CEP290 expression by real-time PCR of human
tissues and found highest expression in neural retina and nasal
epithelium with significant expression in spinal cord, thyroid gland,
testis, heart, lung, bone marrow, cerebellum, and uterus. Weaker
expression was detected in whole brain, fetal brain, and kidney with
very low levels in trachea, thymus, muscle, salivary gland, liver, and
placenta.
GENE STRUCTURE
Sayer et al. (2006) stated that the CEP290 gene, which encodes
nephrocystin-6 (NPHP6), spans 55 exons and 93.2 kb.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the CEP290
gene to chromosome 12. Using a positional cloning strategy, Sayer et al.
(2006) and Valente et al. (2006) identified the CEP290 gene on
chromosome 12q21.32.
GENE FUNCTION
Guo et al. (2004) identified sites for N-glycosylation, tyrosine
sulfation, phosphorylation, N-myristoylation, and amidation in 3H11Ag.
The protein was predicted to have 8 coiled-coil domains and to form
dimeric coiled coils. Transfected COS-7 cells expressed 3H11Ag in the
cytoplasm and nucleus. Extraction experiments suggested that, in the
nucleus, 3H11Ag is a peripheral membrane protein associated with the
nuclear membrane, and 3H11Ag appeared to bind DNA. Truncation
experiments showed that the 150 C-terminal amino acids of 3H11Ag
directed subcellular localization.
To identify direct interaction partners of NPHP6 (CEP290), Sayer et al.
(2006) performed a yeast 2-hybrid screen of a human fetal brain
expression library, showing ATF4 (604064) as a direct interaction
partner of NPHP6. The protein-interaction domains mapped to the
N-terminal third of NPHP6, encoded by exons 2 through 21, and the
C-terminal two-thirds of ATF4. To confirm that NPHP6 and ATF4 interact
physiologically in vivo, Sayer et al. (2006) performed
coimmunoprecipitation experiments using bovine retina extracts.
Immunoblot analysis demonstrated that endogenous ATF4 can be
immunoprecipitated using an antibody to NPHP6 but not using a control
IgG. Reverse coimmunoprecipitation experiments showed that antibody to
ATF4 can also precipitate endogenous NPHP6.
Valente et al. (2006) detected CEP290 expression mostly in proliferating
cerebellar granule neuron populations and showed centrosome and ciliary
localization.
McEwen et al. (2007) provided evidence that CEP290 may mediate G protein
trafficking in certain tissues. Rd16 mice and humans with CEP290
mutations were found to have severe olfactory dysfunction, which in the
mice was characterized by defective ciliary localization of the
olfactory G proteins G-olf (GNAL; 139312) and G-gamma-13 (GNG13; 607298)
in olfactory sensory neurons. Other components of the olfactory
signaling pathway appeared to be unaffected, suggesting that these
components likely enter the cilia independently and assemble within the
cilia.
Using yeast 2-hybrid analysis, Tsang et al. (2008) found that CP110
(609544) interacted with CEP290 from human brain. Both proteins migrated
in a high molecular mass complex in human embryonic kidney cell lysates,
but they did not coelute with a pericentriolar matrix protein. In
G0-phase cells, CP110 localized to the daughter centriole, and CEP290
localized to both the mother and daughter centrioles. Knockdown of
CEP290 suppressed ciliogenesis in differentiating human REP1 retinal
pigment epithelial cells and interfered with localization of the small
GTPase RAB8A (165040) to centrosomes and cilia. Conversely, knockdown of
CP110 resulted in aberrant formation of primary cilia. Tsang et al.
(2008) concluded that CEP290 cooperates with RAB8A to promote
ciliogenesis, and that this function is antagonized by CP110.
By coimmunoprecipitation of proteins from the human TERT-RPE1 cell line,
Kim et al. (2008) found that CEP290 interacted with PCM1 (600299). Both
proteins showed extensive overlap in their localization near centriolar
satellites. Knockdown and biochemical studies revealed that localization
of CEP290 to centriolar satellites was dependent on PCM1 and
microtubules. Conversely, depletion of CEP290 disrupted subcellular
distribution and protein complex formation of PCM1 and caused
disorganization of the cytoplasmic microtubule network. Both CEP290 and
PCM1 were required for ciliogenesis and ciliary targeting of RAB8A, a
small GTPase that promotes ciliogenesis in conjunction with the BBS
protein complex (see BBS1, 209901).
MOLECULAR GENETICS
Coppieters et al. (2010) provided a review of the mutational spectrum of
the CEP290 gene and of the different ciliopathies resulting from these
mutations. No clear genotype/phenotype correlations were apparent.
- Joubert and Senior-Loken Syndromes
Using a positional cloning strategy followed by direct sequencing, Sayer
et al. (2006) detected CEP290 mutations in 1 family with Senior-Loken
syndrome (SLSN6; 610189) and 7 families with Joubert syndrome (JBTS5;
610188). Sayer et al. (2006) identified an identical homozygous nonsense
mutation, 5668G-T (G1890X; 610142.0001) in 2 kindreds. In subsequent
studies they identified 9 distinct CEP290 mutations in 7 families with
JBTS and 1 family with SLSN. All sequence changes were nonsense or
frameshift mutations. In 2 families, they found only 1 heterozygous
mutation in each. All of the affected individuals, with the exception of
1 family with SLSN, showed renal ultrasonographic and clinical features
of JBTS.
Investigating from the neurologic point of view in an international
group studying Joubert syndrome-related disorders, Valente et al. (2006)
identified mutations in the CEP290 gene in 5 families with variable
neurologic, retinal, and renal manifestations. Valente et al. (2006)
found 3 nonsense mutations resulting in premature protein termination, a
1-bp deletion generating a frameshift and a premature stop codon, and a
missense mutation (W7C; 610142.0003).
Joubert syndrome-related disorders (JSRDs) are a group of clinically and
genetically heterogeneous conditions that share a midbrain-hindbrain
malformation, the molar tooth sign (MTS) visible on brain imaging, with
variable neurologic, ocular, and renal manifestations. Mutations in the
CEP290 gene occur in families with the MTS-related neurologic features,
many of which show oculorenal involvement typical of Senior-Loken
syndrome (JSRD-SLS phenotype); see 610142.0004. Brancati et al. (2007)
performed comprehensive CEP290 mutation analysis in 2 nonoverlapping
cohorts of JSRD-affected patients with a proven molar tooth sign. They
identified mutations in 19 of 44 patients with JSRD-SLS. The second
cohort consisted of 84 patients representing the spectrum of other JSRD
subtypes, with mutations identified in only 2 patients. The data
suggested that CEP290 mutations are frequently encountered and are
largely specific to the JSRD-SLS subtype. One patient with mutation
displayed complete situs inversus, confirming the clinical and genetic
overlap between JSRDs and other ciliopathies.
Helou et al. (2007) performed mutation analysis on a worldwide cohort of
75 families with Senior-Loken syndrome, 99 families with Joubert
syndrome, and 21 families with isolated nephronophthisis. Six novel and
6 known truncating mutations, 1 known missense mutation, and 1 novel
3-bp in-frame deletion were identified in a total of 7 families with
Joubert syndrome, 2 families with Senior-Loken syndrome, and 1 family
with isolated nephronophthisis. The mutation in the patient with
isolated nephronophthisis was found in heterozygosity, and it was
suggested that this mutation was not disease-causing in itself but could
be disease-causing in combination with mutations in other genes; it was
classified as a variant 'of unknown significance' in a table.
- Leber Congenital Amaurosis
Den Hollander et al. (2006) ascertained a consanguineous French Canadian
family with 4 sibs affected by Leber congenital amaurosis (LCA10; see
611755). Linkage analysis assigned the gene to 12q21-q22, in a region
containing 15 genes, including CEP290. Joubert syndrome-5, which is due
to mutations in the CEP290 gene, is associated in all patients with
congenital amaurosis or retinitis pigmentosa. An in-frame deletion in
the Cep290 gene was found in association with early onset in the rd16
mouse (Chang et al., 2006). After extensive evaluation, no gross brain
or kidney pathology could be detected in these mice. Because of its
function and the phenotype of the rd16 mice, den Hollander et al. (2006)
considered CEP290 to be an excellent candidate gene for LCA in the
French Canadian family. The authors detected an A-to-G transition 5 bp
downstream of a cryptic exon (2991+1655A-G; 610142.0005) as the cause of
the disorder. To determine whether this mutation could be a common cause
of LCA, den Hollander et al. (2006) screened 76 unrelated patients with
LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients
were found to be homozygous for the mutation, and 12 were heterozygous.
- Meckel Syndrome Type 4
To identify new Meckel syndrome (see MKS1, 249000) loci, Baala et al.
(2007) performed a genomewide linkage scan in 8 families unlinked to
MKS1, MKS2 (603194), or MKS3 (607361) and found linkage to chromosome
12. The interval was narrowed to an 8-Mb region containing the CEP290
gene which, in view of the phenotypic overlap between Joubert syndrome
(213300) and Meckel syndrome, and the finding of Baala et al. (2007) of
allelism of these 2 phenotypes at the MKS3 locus, was considered an
excellent candidate gene. Sequencing of the 53 coding exons revealed
homozygous truncating mutations in 3 families and compound heterozygous
mutations in a fourth family (MKS4; 611134). Sequencing of 20 additional
MKS cases identified 2 additional MKS-affected families with affected
individuals carrying compound heterozygous mutations of CEP290. Baala et
al. (2007) also identified CEP290 mutations in 4 families presenting a
cerebrorenodigital syndrome (see 611134), with a phenotype between that
of Meckel syndrome and Joubert syndrome and thus representing the
continuum of the clinical spectrum between these 2 disorders.
Frank et al. (2008) identified a homozygous mutation in the CEP290 gene
(610142.0012) in 4 fetuses with Meckel syndrome type 4 from 2
consanguineous families of Kosovar origin. Common features included
large cystic, dysplastic kidneys, postaxial polydactyly, occipital
meningoencephalocele, and hepatobiliary ductal plate malformations. No
clear-cut genotype/phenotype correlations were apparent in a review of
CEP290 mutations reported to date.
- Bardet-Biedl Syndrome 14
The identification of mutations in the MKS1 gene (609883) in patients
with clinical diagnoses of Bardet-Biedl syndrome (BBS13; 615990) led
Leitch et al. (2008) to investigate other Meckel syndrome genes as
contributors to the BBS phenotype. Leitch et al. (2008) identified an
individual with Bardet-Biedl syndrome (BBS14; 615991) who was homozygous
for a nonsense mutation in CEP290 (E1903X; 610142.0013) and who also
carried a complex heterozygous mutation in TMEM67 (609884.0012).
NOMENCLATURE
In an analogy to genes previously identified as mutated in
nephronophthisis (NPHP; see 256100), Sayer et al. (2006) referred to the
CEP290 gene as NPHP6, SLSN6, and JBTS6, depending on the predominant
clinical features.
ANIMAL MODEL
Chang et al. (2006) identified an in-frame deletion in the Cep290 gene
in association with a mouse model of early-onset retinal degeneration,
'rd16.' No gross brain or kidney pathology was detected in these mice.
McEwen et al. (2007) found that patients with LCA10 and rd16 mice have
severe olfactory dysfunction. Detailed examination of olfactory cilia
from rd16 mice showed an intact cilia layer and normal localization of
the mutant Cep290 protein to dendritic knobs underlying the cilia.
However, rd16 olfactory sensory neurons showed defective ciliary
localization of the olfactory G proteins Gnal (139312) and Gng13
(607298). Other components of the olfactory signaling pathway appeared
to be unaffected, suggesting that these components likely enter the
cilia independently and assemble within the cilia. The findings
indicated that CEP290 is a mediator of G protein trafficking, and that
the olfactory phenotype is due to defective transport of olfactory G
proteins.
An animal model of autosomal recessive retinitis pigmentosa, designated
rdAc, has been developed in Abyssinian cats. Affected cats have normal
vision at birth, but develop ophthalmic and morphologic changes by 7
months and complete photoreceptor degeneration and blindness at the end
stage, usually at 3 to 5 years of age. Menotti-Raymond et al. (2007)
determined that rdAc is due to a SNP in intron 50 of the Cep290 gene
(IVS50+9T-G) that creates a strong canonical splice donor site,
resulting in a 4-bp insertion and frameshift in the mRNA transcript and
premature termination of the protein.
Schafer et al. (2008) found that depletion of either Nphp5 (IQCB1;
609237) or Nphp6 in zebrafish embryos caused almost identical
abnormalities, including hydrocephalus, developmental eye defects, and
pronephric cysts. Combined knockdown of Nphp5 and Nphp6 synergistically
augmented these phenotypes. Nphp5 directly bound Nphp6 in vitro.
Expression of the Nphp5-binding domain of Nphp6 inhibited neural tube
closure during early Xenopus embryogenesis, and a similar phenotype was
observed after knockdown of Nphp5 in Xenopus oocytes.
Lancaster et al. (2011) found that Cep290-null mouse embryos showed
defective midline fusion of the cerebellum at E16.5, as observed in
Joubert syndrome. Adult Cep290 mutants showed a mild foliation defect,
although the vermis was not statistically smaller than that in controls.
LINC00936
| dbSNP name | rs143045537(G,A); rs7302627(G,A) |
| cytoBand name | 12q21.33 |
| EntrezGene GeneID | 338758 |
| snpEff Gene Name | ATP2B1 |
| EntrezGene Description | long intergenic non-protein coding RNA 936 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
CCER1
| dbSNP name | rs3803099(G,T) |
| cytoBand name | 12q21.33 |
| EntrezGene GeneID | 196477 |
| snpEff Gene Name | C12orf12 |
| EntrezGene Description | coiled-coil glutamate-rich protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2883 |
BTG1
| dbSNP name | rs709222(G,T) |
| cytoBand name | 12q21.33 |
| EntrezGene GeneID | 694 |
| EntrezGene Description | B-cell translocation gene 1, anti-proliferative |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1736 |
OMIM Clinical Significance
Oncology:
B-cell chronic lymphocytic leukemia (CLL)
Inheritance:
Autosomal dominant (13q14)
OMIM Title
*109580 B-CELL TRANSLOCATION GENE 1; BTG1
OMIM Description
CLONING
Rimokh et al. (1991) cloned the breakpoint of a t(8;12) chromosomal
translocation in a case of B-cell chronic lymphocytic leukemia and
isolated a coding sequence mapping to chromosome 12q22. This sequence
detected a 1.8-kb transcript in virtually all tissues tested except in
the brain and muscle where the signal was barely detectable. The
putative gene corresponding to this sequence, termed BTG1 for B-cell
translocation gene 1, was shown to be highly conserved in evolution; a
similar 1.8-kb transcript could be detected in murine and chicken tissue
by using a human BTG1 DNA probe.
Rouault et al. (1992) established the genomic organization of the BTG1
gene. The full-length cDNA isolated from a lymphoblastoid cell line
contained an open reading frame of 171 amino acids. BTG1 expression was
maximal in the G0/G1 phases of the cell cycle and downregulated when
cells progressed throughout G1. Furthermore, transfection experiments
using NIH 3T3 cells indicated that BTG1 negatively regulates cell
proliferation. Rouault et al. (1992) postulated that BTG1 is a member of
a new family of antiproliferative genes.
GENE FUNCTION
Bakker et al. (2004) found increased Foxo3a (602681) expression during
differentiation in a mouse erythroid progenitor cell line, and DNA
microscreens identified Btg1 (109580) as a novel Foxo3a target. Ectopic
expression of Btg1 inhibited the expansion of mouse erythroid progenitor
cells, which was dependent on the protein arginine methyltransferase-1
(HRMT1L2; 602950)-binding domain of Btg1. Bakker et al. (2004) concluded
that the modulation of protein-arginine methylation activity by BTG1 may
be a FOX-dependent mechanism regulating erythroid differentiation.
MAPPING
Rimokh et al. (1991) identified the BTG1 gene on chromosome 12q22, at
the breakpoint of a t(8;12) chromosomal translocation.
NUDT4
| dbSNP name | rs117687080(C,T); rs61934298(C,T); rs11558758(A,G); rs79574264(T,C); rs12597(G,A); rs12819043(C,T) |
| cytoBand name | 12q22 |
| EntrezGene GeneID | 11163 |
| EntrezGene Description | nudix (nucleoside diphosphate linked moiety X)-type motif 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
CEP83-AS1
| dbSNP name | rs73218279(C,T); rs73372226(C,T) |
| cytoBand name | 12q22 |
| EntrezGene GeneID | 144486 |
| EntrezGene Symbol | CCDC41-AS1 |
| snpEff Gene Name | CCDC41 |
| EntrezGene Description | CCDC41 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06612 |
MIR5700
| dbSNP name | rs12314280(T,C); rs17022749(C,T); rs75258105(G,T) |
| cytoBand name | 12q22 |
| EntrezGene GeneID | 100847031 |
| EntrezGene Description | microRNA 5700 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0629 |
| ExAC AF | 0.016 |
MIR7844
| dbSNP name | rs1290910(G,C) |
| cytoBand name | 12q22 |
| EntrezGene GeneID | 57458 |
| EntrezGene Symbol | TMCC3 |
| snpEff Gene Name | TMCC3 |
| EntrezGene Description | transmembrane and coiled-coil domain family 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.365 |
| ExAC AF | 0.582 |
KRT19P2
| dbSNP name | rs2289029(T,C) |
| cytoBand name | 12q22 |
| EntrezGene GeneID | 160313 |
| snpEff Gene Name | MIR492 |
| EntrezGene Description | keratin 19 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05005 |
SLC9A7P1
| dbSNP name | rs11109485(T,A); rs829862(A,G); rs829863(C,T); rs57350646(T,C); rs829864(C,T) |
| cytoBand name | 12q23.1 |
| EntrezGene GeneID | 121456 |
| EntrezGene Description | solute carrier family 9, subfamily A (NHE7, cation proton antiporter 7), member 7 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2378 |
TMPO-AS1
| dbSNP name | rs1439775(G,C); rs1439774(C,T); rs3168521(C,T); rs11768(T,G); rs73136483(A,G) |
| cytoBand name | 12q23.1 |
| EntrezGene GeneID | 100128191 |
| snpEff Gene Name | TMPO |
| EntrezGene Description | TMPO antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0629 |
GNPTAB
| dbSNP name | rs112815421(T,G); rs148901103(T,C); rs76021817(T,A); rs1811338(T,G); rs73392457(G,A); rs75733424(A,G); rs11110995(T,C); rs147981921(G,A); rs6539011(G,A); rs11110997(T,C); rs79493678(G,T); rs7975097(A,C); rs142171235(T,C); rs11110998(T,C); rs61487075(A,G); rs7957655(G,A); rs7957768(G,T); rs730013(A,G); rs11111000(C,T); rs3736475(G,C); rs3736476(A,G); rs141927805(C,T); rs3817305(G,C); rs12371863(C,T); rs11111001(C,T); rs2052829(C,T); rs4589357(G,T); rs150487409(T,C); rs11111002(G,A); rs759935(A,G); rs12368912(T,C); rs10860783(A,T); rs4764813(G,C); rs10778148(T,C); rs76889468(G,A); rs11111007(T,C); rs74389509(A,G); rs149569484(A,G); rs4764814(A,G); rs11111013(T,C); rs12822705(T,G); rs12822003(G,A); rs7963747(C,T); rs10492085(G,A); rs79616536(G,A); rs10745922(T,C); rs17724970(A,G); rs4403858(A,G); rs10778149(G,A); rs61938169(A,T); rs150207620(C,T); rs112139789(T,G); rs11111017(T,C); rs7134161(A,C); rs222511(A,G); rs146240520(G,C); rs1024587(T,C); rs77885533(A,C); rs79721905(G,T); rs80258522(G,T); rs1863907(G,A); rs182962356(T,C); rs919215(G,C); rs145630489(T,C); rs138039531(T,C); rs55829819(T,G); rs55847668(C,T); rs4764815(C,T); rs66621546(T,C); rs76764527(C,T); rs10860784(A,G); rs4764816(T,C); rs1860088(C,T); rs146548259(G,A); rs117080636(G,A); rs11830369(T,C); rs10860785(G,C); rs741645(A,G); rs58474338(G,T); rs11111021(G,A); rs11111022(C,T); rs6539012(C,T); rs73163790(G,A); rs76007709(G,A); rs55764824(C,T); rs2108694(G,A); rs10778150(A,T); rs11830792(T,C); rs11111024(C,A); rs222512(C,T); rs58774153(C,T); rs115312174(C,T); rs975431(T,C); rs369274388(G,A); rs4764652(C,A); rs4764653(C,T); rs7961009(G,A); rs11832844(T,A); rs61938176(A,G); rs10492086(A,G); rs17032014(T,C); rs12322453(C,T); rs7980314(A,G); rs4764654(A,G); rs11609764(C,G); rs11111026(G,T); rs12579766(G,A); rs151337108(G,A); rs11111030(G,A); rs10745924(T,C); rs73183043(T,C); rs138038220(A,G); rs77790583(G,A); rs12311055(G,A); rs10860790(T,G); rs7966774(G,C); rs11111034(C,T); rs4764820(T,C); rs4764821(C,T); rs7309840(G,C); rs66507165(A,G); rs7979041(A,G); rs7133458(C,T); rs55649039(C,A); rs79070432(A,G); rs10778151(C,T); rs7294980(T,C); rs7135718(A,G); rs115328928(C,T); rs140335649(C,T); rs10860791(A,T); rs59947006(T,C); rs2058121(C,T); rs10444509(T,C); rs148901808(C,T); rs4764822(C,T); rs11111045(G,C); rs10860794(C,A); rs10745925(T,C); rs7960795(C,T); rs114895845(T,C); rs4764823(G,A); rs4764824(C,G); rs7964859(C,G); rs10128856(A,G); rs10128858(A,G); rs55700669(C,G); rs7968873(G,C); rs12817362(G,A); rs67155332(C,A); rs61938211(C,T); rs142189441(T,C); rs80212141(G,A); rs4764825(G,A) |
| ccdsGene name | CCDS9088.1 |
| cytoBand name | 12q23.2 |
| EntrezGene GeneID | 79158 |
| EntrezGene Description | N-acetylglucosamine-1-phosphate transferase, alpha and beta subunits |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GNPTAB:NM_024312:exon13:c.C1931T:p.T644I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5424 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3T906 |
| dbNSFP Uniprot ID | GNPTA_HUMAN |
| dbNSFP KGp1 AF | 0.0128205128205 |
| dbNSFP KGp1 Afr AF | 0.030487804878 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.02837 |
| ESP All MAF | 0.017223 |
| ESP Eur/Amr MAF | 0.011512 |
| ExAC AF | 0.015 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Autosomal dominant
SKELETAL:
[Spine];
Kyphoscoliosis;
[Hands];
Claw hand deformities;
[Feet];
Talipes equinovarus
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Proximal muscle involvement may occur;
Areflexia;
Distal sensory impairment;
Normal or mildly reduced motor nerve conduction velocities (NCV) (greater
than 38 m/s);
Loss of myelinated fibers on nerve biopsy;
Axonal regeneration on nerve biopsy;
Pseudo-'onion bulb' formation
MISCELLANEOUS:
Onset before age 3 years;
Onset in feet and legs (peroneal distribution);
Upper limb involvement in first decade;
Severe progression;
Patients with autosomal dominant inheritance and a single GDAP1 mutation
have a less severe course with later onset;
Genetic heterogeneity (see CMT2A 118210);
Allelic disorder to CMT4A (214400)
MOLECULAR BASIS:
Caused by mutation in the ganglioside-induced differentiation-associated
protein-1 gene (GDAP1, 606598.0002)
OMIM Title
*607840 N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, ALPHA/BETA SUBUNITS; GNPTAB
;;GNPTA;;
MGC4170
OMIM Description
DESCRIPTION
UDP-N-acetylglucosamine:lysosomal-enzyme
N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase; EC
2.7.8.17) catalyzes the initial step in the synthesis of the mannose
6-phosphate determinant required for efficient intracellular targeting
of newly synthesized lysosomal hydrolases to the lysosome.
GlcNAc-phosphotransferase is an alpha-2/beta-2/gamma-2 hexameric
complex. The GNPTAB gene encodes both the alpha and beta subunits; the
gamma subunit is encoded by the GNPTG gene (607838).
CLONING
Bao et al. (1996, 1996) determined that bovine GlcNAc-phosphotransferase
is a 54-kD alpha-2/beta-2/gamma-2 hexameric complex. Canfield et al.
(1998) indicated that the alpha and beta subunits are derived from a
single cDNA. The individual subunits are apparently generated by
proteolytic processing at a lys-asp bond following synthesis of an
alpha/beta precursor, generating a 928-amino acid N-terminal alpha
subunit and a 328-amino acid C-terminal beta subunit. The gamma subunit
is encoded by a separate gene (GNPTG; 607838).
By database analysis, Tiede et al. (2005) identified the human GNPTAB
gene. The deduced 1256-amino acid protein has a predicted molecular mass
of 144 kD. Hydrophobicity analysis showed 2 transmembrane domains and 19
potential N-glycosylation sites. Sequence comparisons showed that GNPTAB
has a complex modular structure composed of at least 6 domains including
an N-terminal domain with a putative nucleotide binding site, 2 Notch
repeat-like domains, and a DMAP1 (605077) binding-like domain.
GENE FUNCTION
Canfield et al. (1998) found that in 4 of 4 patients with mucolipidosis
II (ML II; 252500), the 6.2-kb alpha/beta transcript was absent. In 2 of
2 patients with mucolipidosis IIIA (252600), the alpha/beta transcript
was present but greatly reduced. In all patients examined, the gamma
transcript was present at normal levels.
By retroviral transduction of fibroblasts from an individual with
mucolipidosis II, Tiede et al. (2005) demonstrated expression and
localization of GNPTAB in the Golgi apparatus, accompanied by correction
of the hypersecretion of lysosomal enzymes. Tiede et al. (2005)
concluded that GNPTAB encodes a subunit of GlcNAc-phosphotransferase
that is defective in individuals with ML II.
Kudo et al. (2005) cloned the cDNA and genomic DNA encoding the
alpha/beta-subunits precursor gene (GNPTAB). With the cloning of the
gamma-subunit gene (GNPTG; 607838), it could be concluded that
GlcNAc-phosphotransferase is the product of 2 genes, an uncommon
exception to the Garrod-Beadle principle of 1 enzyme-1 gene.
Marschner et al. (2011) found that the alpha/beta subunit of the
N-acetylglucosamine-1-phosphotransferase complex is cleaved by the
site-1 protease (S1P; 603355) that activates sterol regulatory
element-binding proteins in response to cholesterol deprivation.
S1P-deficient cells failed to activate the alpha/beta subunit precursor
and exhibited a mucolipidosis II-like phenotype. Thus, Marschner et al.
(2011) concluded that S1P functions in the biogenesis of lysosomes, and
that lipid-independent phenotypes of S1P deficiency may be caused by
lysosomal dysfunction.
GENE STRUCTURE
By database analysis, Tiede et al. (2005) determined that the GNPTAB
gene contains 21 exons and spans 85 kb.
MAPPING
Vidgoff et al. (1982) found possible linkage of ML II to MN (111300) on
4q, with a lod score of 1.3. Mueller et al. (1987) determined the
chromosome assignment of the structural gene altered in the common forms
of ML II and ML III by linkage analysis, somatic cell hybrids, and gene
dosage. Linkage data with ML II families indicated that the ML II locus
is located between GC (139200) and MNS. The combined data indicated that
GNPTA maps to 4q21-q23.
By genomic sequence analysis, Tiede et al. (2005) mapped the GNPTAB gene
to chromosome 12q23.3.
MOLECULAR GENETICS
In a 47-year-old female who presented with dilated cardiomyopathy and
mild neuropathy and was found to have mucolipidosis III (252600), Steet
et al. (2005) identified a homozygous splice site mutation of the GNPTAB
gene (607840.0001).
In a 14-year-old boy with a mild clinical phenotype of mucolipidosis
III, Tiede et al. (2005) identified homozygosity for an asp407-to-ala
substitution in the GNPTAB gene (607840.0002). The patient was also
homozygous for an ala663-to-gly substitution in the GNPTAB that was
deemed a polymorphism because it was found in 5% of normal alleles. Both
parents were heterozygous for both mutations.
In 3 unrelated Korean girls with mucolipidosis II (252500) and 2
unrelated Korean girls with mucolipidosis IIIA, Paik et al. (2005)
identified compound heterozygosity for 7 different mutations in the
GNPTAB gene (607840.0003-607840.0009).
In 6 patients with clinically and biochemically diagnosed mucolipidosis
II, Tiede et al. (2005) identified homozygosity or compound
heterozygosity for 7 mutations in the GNPTAB gene, all resulting in
premature translational termination (e.g., 607840.0010).
To determine whether mucolipidosis II, or I-cell disease, and
mucolipidosis IIIA, or classic pseudo-Hurler polydystrophy, are caused
by mutations in the gene encoding the alpha/beta-subunits precursor
gene, Kudo et al. (2006) sequenced GNPTAB exons and flanking intronic
sequences and measured GlcNAc-phosphotransferase activity in patient
fibroblasts. They identified 15 different mutations in GNPTAB from 18
pedigrees with one or the other of these 2 diseases and demonstrated
that these 2 diseases are allelic. Mutations in both alleles were
identified in each case, which demonstrated that GNPTAB mutations are
the cause of both diseases. Some pedigrees had identical mutations. A
2-bp deletion (607840.0011), resulting in a frameshift and premature
truncation, predominated and was found in both ML II and ML IIIA. This
mutation was found in combination with severe mutations (i.e., mutations
preventing the generation of active enzyme) in ML II and with mild
mutations (i.e., mutations allowing the generation of active enzyme) in
ML IIIA. Some cases of ML II and ML IIIA were the result of mutations
that cause aberrant splicing. Substitutions were within the invariant
splice site sequence in ML II and were outside it in ML IIIA. When the
mutations were analyzed along with GlcNAc-phosphotransferase activity,
it was possible to distinguish with confidence these 2 related but
distinct disorders.
Bargal et al. (2006) studied GNPTAB mutations in 24 patients. They
suggested that there is a clinical continuum between ML III and ML II,
and the classification of these diseases should be based on the age of
onset, clinical symptoms, and severity.
- Possible Role in Other Disorders
In affected members of a large consanguineous 6-generation Pakistani
family with stuttering (STUT2; 609261) showing linkage to chromosome
12q, Kang et al. (2010) identified a glu1200-to-lys (E1200K) variant in
the GNPTAB gene. Thirteen affected individuals were heterozygous, and 12
were homozygous. However, the variant did not completely segregate with
the disorder: 3 noncarriers were affected, and 2 homozygous E1200K
carriers and 9 heterozygous E1200K carriers were unaffected. Kang et al.
(2010) suggested nonpenetrance in these individuals. The authors
identified 3 additional variants in the GNPTAB gene in 4 additional
unrelated individuals with stuttering. None of the individuals had
features of mucolipidosis. Study of additional families and individuals
identified the E1200K variant in 3 other Pakistani families with
stuttering, in 1 North American patient of Asian Indian ancestry, and in
1 Pakistani control. The E1200K variant was not found in 192 chromosomes
from unaffected Pakistani controls or in 552 chromosomes from North
American controls. By studying other genes in the lysosomal
enzyme-targeting pathway, Kang et al. (2010) identified 3 variants each
in the GNPTG (607838) and NAGPA (607985) genes that were found in 11 of
270 North American/British patients with stuttering but not in 276
controls. Kang et al. (2010) concluded that variations in genes
governing lysosomal metabolism may be susceptibility factors for
nonsyndromic persistent stuttering.
By haplotype analysis of 8 unrelated individuals who were heterozygous
or homozygous for the G1200K variant, Fedyna et al. (2011) determined
that it arose as a founder allele 572 generations, or 14,300 years ago.
Haplotype analysis identified a common 6.67-kb haplotype containing the
variant.
GENOTYPE/PHENOTYPE CORRELATIONS
Otomo et al. (2009) identified 18 GNPTAB mutations, including 14 novel
mutations, among 25 unrelated Japanese patients with ML II and 15
Japanese patients with ML III. The most common mutations were R1189X
(607840.0004), which was found in 41% of alleles, and F374L
(607840.0015), which was found in 10% of alleles. Homozygotes or
compound heterozygotes of nonsense and frameshift mutations contributed
to the more severe phenotype. In all, 73 GNPTAB mutations were detected
in the 80 alleles. In a review of the reported clinical features, most
ML II patients had impairment in standing alone, walking without
support, and speaking single words compared to those with ML III. The
frequencies of heart murmur, inguinal hernia, and hepatomegaly and/or
splenomegaly did not differ between ML II and III patients.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly
Portuguese patients with ML II. Eight of 9 patients had a nonsense or
frameshift mutation, the most common being a 2-bp deletion (607840.0011)
that was found in 45% of the mutant alleles; one patient with ML II was
homozygous for a missense mutation. Three additional patients with a
less severe phenotype consistent with ML III had missense mutations.
Encarnacao et al. (2009) concluded that patients with ML II alpha/beta
are almost all associated with the presence of nonsense or frameshift
mutations in homozygosity, whereas the presence of at least 1 mild
mutation in the GNPTAB gene is associated with ML III alpha/beta.
Cathey et al. (2010) identified 51 pathogenic changes in the GNPTAB
gene, including 42 novel mutations, among 61 probands mostly from the
U.S. with ML II or ML III. Thirty-four probands, including 13 with ML
II, 14 with ML III, and 7 with an intermediate phenotype, were studied
in detail. Those with ML II had a more severe phenotype, with evidence
of craniofacial and orthopedic problems at birth, severe psychomotor
retardation, and enzyme activity of less than 1% of control values.
Growth, speech, ambulation, and cognitive function were impaired. Those
with ML III had enzyme activity of 1 to 10% of control values, minimal
delays in milestones, and later onset of skeletal problems. ML II was
associated with frameshift or truncating mutations, whereas ML III was
associated with hypomorphic mutations. The most common mutation was
3503delTC (607840.0011), found in 18 ML II and 4 ML III patients.
ASCL1
| dbSNP name | rs731682(C,G); rs1391682(T,C); rs2291854(A,G) |
| ccdsGene name | CCDS31886.1 |
| cytoBand name | 12q23.2 |
| EntrezGene GeneID | 429 |
| EntrezGene Description | achaete-scute family bHLH transcription factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ASCL1:NM_004316:exon1:c.C627G:p.V209V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.05831 |
| ESP Afr MAF | 0.201499 |
| ESP All MAF | 0.103926 |
| ESP Eur/Amr MAF | 0.053912 |
| ExAC AF | 0.052 |
OMIM Clinical Significance
Limbs:
Arachnodactyly
Joints:
Joint laxity limited to hands and feet
Skull:
Broad skull
Head:
Brachycephaly;
Micrognathia
Misc:
Normal body proportions
Inheritance:
Autosomal dominant
OMIM Title
*100790 ACHAETE-SCUTE COMPLEX, DROSOPHILA, HOMOLOG OF, 1; ASCL1
;;MAMMALIAN ACHAETE-SCUTE HOMOLOG 1; MASH1;;
HUMAN ACHAETE-SCUTE HOMOLOG 1; HASH1
OMIM Description
CLONING
Basic helix-loop-helix transcription factors of the achaete-scute family
are instrumental in Drosophila neurosensory development and are
candidate regulators of development in the mammalian central nervous
system and neural crest. Ball et al. (1993) isolated and characterized a
human achaete-scute homolog that is highly expressed in 2 neuroendocrine
cancers, medullary thyroid cancer (MTC; 155240) and small cell lung
cancer (SCLC; 182280). The human gene, ASCL1, which was symbolized ASH1
by the authors, was cloned from a human MTC cDNA library. It encodes a
predicted protein of 238 amino acids that shares 95% identity with the
mammalian achaete-scute homolog-1 (Mash1), a rodent basic
helix-loop-helix factor. The proximal coding region of the cDNA contains
a striking 14-copy repeat of the triplet CAG that exhibits polymorphism
in human genomic DNA; thus, ASCL1 is a candidate locus. Northern blot
analysis revealed ASCL1 transcripts in RNA from a human MTC cell line, 2
fresh MTC tumors, fetal brain, and 3 lines of human SCLC. In contrast,
cultured lines of non-SCLC lung cancers and a panel of normal adult
human tissues showed no detectable ASCL1 transcripts.
GENE FUNCTION
Ahmad (1995) found that Mash1 is expressed during development of rat
retina and interacts specifically with an E-box identified in the
promoter for the opsin gene during rod photoreceptor differentiation.
Using retroviral labeling in organotypic slice cultures of the embryonic
human forebrain, Letinic et al. (2002) demonstrated the existence of 2
distinct lineages of neocortical GABAergic neurons. One lineage
expresses DLX1 (600029) and DLX2 (126255) and MASH1 transcription
factors, represents 65% of neocortical GABAergic neurons in humans, and
originates from MASH1-expressing progenitors of the neocortical
ventricular and subventricular zone of the dorsal forebrain. The second
lineage, characterized by the expression of DLX1 and DLX2 but not MASH1,
forms around 35% of the GABAergic neurons and originates from the
ganglionic eminence of the ventral forebrain. Letinic et al. (2002)
suggested that modifications in the expression pattern of transcription
factors in the forebrain may underlie species-specific programs for the
generation of neocortical local circuit neurons and that distinct
lineages of cortical interneurons may be differentially affected in
genetic and acquired diseases of the human brain.
Pattyn et al. (2004) noted that Ascl1 is coexpressed with Nkx2.2
(604612) in the neuroepithelial domain of the hindbrain, which gives
rise to 5-HT neurons. In Ascl1 null mouse embryo brains, Pattyn et al.
(2004) showed that 5-HT neurons were virtually absent from the earliest
stages of differentiation. In the mouse, Ascl1 was essential for the
birth of 5-HT neurons, both as a proneural gene for the production of
postmitotic neuronal precursors and as a determinant of the serotonergic
phenotype for the parallel activation of Gata3 (131320), Lmx1b (602575),
and Pet1 (607150).
Activation of Delta genes, such as Delta1 (DLL1; 606582), by proneural
factors is an evolutionarily conserved step in neurogenesis that results
in activation of Notch (see 190198) signaling and maintenance of an
undifferentiated state in a subset of neural progenitors. Castro et al.
(2006) showed that activation of mouse Delta1 involved cooperative
binding of Mash1 and Brn1 (POU3F3; 602480)/Brn2 (POU3F2; 600494) to an
evolutionarily conserved motif in the Delta1 gene. They identified the
MASH1/BRN-binding motif in several other human, mouse, and rat genes,
suggesting that MASH1 and BRN proteins synergistically regulate genes
that control multiple aspects of the neurogenic program.
Vierbuchen et al. (2010) hypothesized that combinatorial expression of
neural lineage-specific transcription factors could directly convert
fibroblasts into neurons. Starting from a pool of 19 candidate genes,
Vierbuchen et al. (2010) identified a combination of only 3 factors,
Ascl1, Brn2 (600494), and Myt1l (613084), that suffice to rapidly and
efficiently convert mouse embryonic and postnatal fibroblasts into
functional neurons in vitro. These induced neuronal cells express
multiple neuron-specific proteins, generate action potentials, and form
functional synapses.
Pang et al. (2011) showed that POU3F2 (600494), ASCL1, and MYT1L can
generate functional neurons from human pluripotent stem cells as early
as 6 days after transgene activation. When combined with NEUROD1
(601724), these factors could also convert fetal and postnatal human
fibroblasts into induced neuronal cells showing typical neuronal
morphologies and expressing multiple neuronal markers, even after
downregulation of the exogenous transcription factors. Importantly, the
vast majority of human induced neuronal cells were able to generate
action potentials and many matured to receive synaptic contacts when
cocultured with primary mouse cortical neurons. Pang et al. (2011)
concluded that nonneuronal human somatic cells, as well as pluripotent
stem cells, can be converted directly into neurons by
lineage-determining transcription factors.
Caiazzo et al. (2011) identified a minimal set of 3 transcription
factors--Mash1, Nr4a2 (601828), and Lmx1a (600298)--that are able to
generate directly functional dopaminergic neurons from mouse and human
fibroblasts without reverting to a progenitor cell stage. Induced
dopaminergic cells released dopamine and showed spontaneous electrical
activity organized in regular spikes consistent with the pacemaker
activity featured by brain dopaminergic neurons. The 3 factors were able
to elicit dopaminergic neuronal conversion in prenatal and adult
fibroblasts from healthy donors and Parkinson disease (168600) patients.
Yoo et al. (2011) demonstrated that expression of miR9/9* (see 611186)
and miR124 (609327) in human fibroblasts induced their conversion into
neurons, a process facilitated by NEUROD2 (601725). Further addition of
neurogenic transcription factors ASCL1 and MYT1L enhanced the rate of
conversion and the maturation of the converted neurons, whereas
expression of these transcription factors without the aforementioned
microRNAs was ineffective. Yoo et al. (2011) concluded that the genetic
circuitry involving miR9-1 through miR9-3 and miR124 can have an
instructive role in neural fate determination.
The basic helix-loop-helix transcription factors ASCL1, HES1 (139605),
and OLIG2 (606386) regulate fate choice of neurons, astrocytes, and
oligodendrocytes, respectively. These same factors are coexpressed by
neural progenitor cells. Imayoshi et al. (2013) found by time-lapse
imaging that these factors are expressed in an oscillatory manner by
mouse neural progenitor cells. In each differentiation lineage, 1 of the
factors becomes dominant. Imayoshi et al. (2013) used optogenetics to
control expression of Ascl1 and found that, although sustained Ascl1
expression promotes neuronal fate determination, oscillatory Ascl1
expression maintains proliferating neural progenitor cells. Imayoshi et
al. (2013) concluded that the multipotent state correlates with
oscillatory expression of several fate-determination factors, whereas
the differentiated state correlates with sustained expression of a
single factor.
Dyachuk et al. (2014) showed that the parasympathetic system in mice,
including trunk ganglia and the cranial ciliary, pterygopalatine,
lingual, submandibular, and otic ganglia, arises from glial cells in
nerves, not neural crest cells. Dyachuk et al. (2014) further showed
that neurons are recruited from glial progenitors dwelling in cranial
and trunk nerves by a local induction of the Ascl1 gene. The
parasympathetic fate is induced in nerve-associated Schwann cell
precursors at distal peripheral sites. Using multicolor Cre-reporter
lineage tracing, Dyachuk et al. (2014) showed that most of these neurons
arise from bipotent progenitors that generate both glia and neurons.
This nerve origin places cellular elements for generating
parasympathetic neurons in diverse tissues and organs.
MOLECULAR GENETICS
Congenital central hypoventilation syndrome (CCHS; 209880) is a rare
disorder of the chemical control of breathing. The ASCL1--PHOX2A (ABIX;
602753)--PHOX2B (603851) developmental cascade was proposed as a
candidate pathway for this disorder, as well as for Haddad syndrome (see
209880), because the cascade controls the development of neurons with a
definitive or transient noradrenergic phenotype. De Pontual et al.
(2003) identified heterozygosity for mutations in the ASCL1 gene in 2
patients with CCHS (100790.0001-100890.0002) and 1 patient with Haddad
syndrome (100790.0003). The authors also developed an in vitro model of
noradrenergic differentiation in neuronal progenitors derived from the
mouse vagal neural crest. All Ascl1 mutant alleles impaired
noradrenergic neuronal development when overexpressed from adenoviral
constructs.
MAPPING
By analysis of rodent/human somatic cell hybrids, Ball et al. (1993)
assigned the ASCL1 gene to human chromosome 12. Renault et al. (1995)
mapped ASCL1 onto a YAC contig distal to PAH (612349) and proximal to
TRA1 (191175). The authors used fluorescence in situ hybridization to
determine the cytogenetic assignment of 12q22-q23.
ANIMAL MODEL
By homologous recombination in embryonic stem cells, Guillemot et al.
(1993) created a null allele of the Mash1 gene. Homozygous mice died at
birth with apparent breathing and feeding defects. The brain and spinal
cord appeared normal, but the olfactory epithelium and sympathetic,
parasympathetic, and enteric ganglia were severely affected. These
observations suggested that the Mash1 gene, like its Drosophila
homologs, controls a basic operation in development of neuronal
progenitors in distinct neural lineages.
Kokubu et al. (2008) found that Mash1 was highly expressed in mouse
glandular stomach epithelium. At embryonic day 18.5, almost all gastric
neuroendocrine cells were missing in Mash1-null mice, whereas
development of nonneuroendocrine cells appeared normal. Ngn3 (NEUROG3;
604882), which regulates formation of gastrin (GAS; 137250)-, glucagon
(GCG; 138030)-, and somatostatin (SST; 182450)-producing gastric
neuroendocrine cells, was expressed normally in Mash1-null stomach.
Kokubu et al. (2008) concluded that a subset of gastric neuroendocrine
cells requires both NGN3 and MASH1 for their development, while other
neuroendocrine cells require MASH1 alone.
STAB2
| dbSNP name | rs7312553(C,A); rs17034172(G,T); rs11833689(G,A); rs10778266(A,G); rs11111669(A,T); rs115656569(C,T); rs1991436(G,A); rs1582881(A,G); rs17034187(A,T); rs854249(G,A); rs703598(C,A); rs11835948(T,C); rs11836449(T,C); rs55889269(G,C); rs7134377(G,A); rs115677930(G,A); rs10861044(C,T); rs703599(T,C); rs703600(C,G); rs1610202(G,A); rs703601(G,T); rs703602(C,A); rs1610171(C,T); rs703603(T,C); rs7953892(T,C); rs903186(G,A); rs697196(T,C); rs6539085(G,A); rs1593806(A,G); rs12319902(C,A); rs56402195(A,T); rs10861045(A,G); rs10861047(A,G); rs703604(A,G); rs12367313(T,G); rs7979192(C,G); rs7979507(G,A); rs112712099(C,T); rs7979345(C,G); rs7966214(T,C); rs703605(A,G); rs7969320(T,G); rs2100981(G,A); rs2086246(A,T); rs2100980(T,C); rs4015364(C,T); rs703606(A,G); rs11111671(G,A); rs56916543(G,T); rs57650540(C,A); rs58261212(C,G); rs10861048(T,A); rs10861049(G,A); rs74468244(G,A); rs831686(G,A); rs55640603(C,A); rs10861050(A,G); rs146330344(A,C); rs10861051(T,C); rs11111672(G,A); rs831683(C,T); rs2086245(A,C); rs2086244(C,T); rs11111673(A,G); rs11111674(C,T); rs1070073(T,G); rs11111675(A,G); rs2723889(T,C); rs11837998(G,A); rs10861052(G,A); rs79422467(C,T); rs1070075(C,T); rs141172860(C,A); rs1070078(A,T); rs4402400(A,G); rs12307763(C,T); rs703607(A,C); rs7978002(C,T); rs13313235(A,G); rs113390542(G,A); rs6539091(T,C); rs6539092(G,A); rs697197(T,A); rs6539093(A,G); rs17034212(G,A); rs11111680(C,T); rs58318191(G,A); rs703608(G,C); rs12303315(G,A); rs112370828(A,G); rs12303334(C,G); rs703609(T,C); rs17034225(T,C); rs703610(G,A); rs703611(G,T); rs11832217(C,A); rs11111681(G,C); rs697198(C,G); rs113636979(T,C); rs116520145(G,A); rs77334798(T,C); rs3886759(C,T); rs73187882(C,G); rs116159759(C,T); rs79922721(T,C); rs17034229(A,G); rs12310882(C,T); rs78605609(A,T); rs117746666(G,A); rs11111682(C,T); rs10861058(G,A); rs17034234(G,A); rs703612(T,C); rs703613(G,A); rs12315141(G,A); rs12830698(T,G); rs73394074(C,G); rs10861059(G,A); rs703614(C,A); rs12821299(T,G); rs11111683(C,T); rs34689281(A,T); rs703615(T,A); rs11111684(C,G); rs112993553(A,G); rs7133148(T,C); rs703616(T,C); rs831684(T,C); rs703617(A,G); rs703618(G,A); rs703619(G,A); rs1018033(A,G); rs12307028(G,A); rs1427797(T,A); rs1427798(C,A); rs1018034(C,A); rs114326349(G,A); rs703620(A,G); rs10861060(G,T); rs10861061(C,T); rs703621(C,G); rs73394087(T,C); rs1588888(C,T); rs831685(G,T); rs2673654(A,T); rs73394090(C,A); rs186412642(C,T); rs1677979(T,C); rs1993919(G,A); rs2723888(A,G); rs10861062(T,C); rs1826593(T,A); rs1826594(A,T); rs117692512(G,A); rs11111689(C,T); rs831431(C,T); rs11111690(G,A); rs831432(C,T); rs11111691(T,C); rs150530101(C,A); rs59883687(G,A); rs10861063(A,G); rs10861064(G,T); rs1582876(A,G); rs11111693(A,G); rs12317816(G,A); rs61937794(C,T); rs703622(A,G); rs12319476(G,A); rs1650123(C,T); rs117887963(A,G); rs703623(G,T); rs7488859(C,A); rs703624(C,T); rs703625(T,A); rs10861065(G,T); rs144116286(C,T); rs703626(A,G); rs12310140(A,G); rs703627(T,A); rs831433(C,T); rs56077319(G,A); rs10861066(A,G); rs10861067(A,G); rs12319272(G,A); rs11111695(A,T); rs703628(A,G); rs138380193(A,G); rs12580493(A,G); rs11111696(A,G); rs703629(A,G); rs903185(T,C); rs75286248(A,T); rs697199(T,C); rs12829198(G,A); rs150290208(C,T); rs137893264(C,T); rs12303536(G,A); rs10861068(G,A); rs10778270(C,A); rs1032450(A,G); rs11111703(A,G); rs1609860(C,A); rs831425(C,T); rs17034281(C,A); rs703631(G,T); rs831681(C,A); rs703632(G,A); rs75712475(G,A); rs831426(C,A); rs703633(A,G); rs10431413(C,T); rs117039181(G,A); rs7315384(A,C); rs11111705(A,G); rs7959033(C,T); rs7958947(A,G); rs10778272(G,A); rs148397037(G,A); rs10861070(G,C); rs11111707(C,G); rs11111708(A,G); rs4497503(A,G); rs12230501(T,G); rs12229216(G,T); rs10778273(A,G); rs860532(C,A); rs10745977(G,C); rs10745978(C,T); rs4248849(T,C); rs903184(G,C); rs755598(C,A); rs116547375(G,A); rs116123084(T,C); rs1809783(A,G); rs3752879(C,T); rs903182(T,G); rs1582879(A,G); rs831428(C,T); rs7296829(C,T); rs831429(G,A); rs114094795(C,A); rs1965076(T,C); rs59772330(C,T); rs17034333(C,T); rs79030718(A,T); rs17034336(G,A); rs12424164(A,G); rs4981025(A,G); rs148140795(A,T); rs4981024(A,G); rs7977903(G,A); rs76433274(G,A); rs1863877(C,G); rs1863878(G,A); rs703642(G,C); rs10778275(T,C); rs10778276(T,G); rs17034351(G,A); rs11614418(C,T); rs17034360(C,A); rs697200(A,G); rs7973658(G,A); rs697201(A,G); rs142868334(A,T); rs1593809(T,C); rs703646(G,C); rs703647(A,G); rs10861073(C,T); rs10861074(C,G); rs11111710(G,A); rs1101617(G,A); rs12314920(A,G); rs10778277(A,T); rs58605677(C,T); rs7303939(A,G); rs7304095(A,T); rs12368532(C,G); rs74847686(A,G); rs4981017(C,T); rs4981018(C,A); rs11111711(C,T); rs114756096(C,T); rs35682809(A,G); rs696214(T,G); rs11831493(G,A); rs697202(C,A); rs17034372(G,A); rs703648(T,C); rs697203(A,G); rs697204(G,A); rs697205(C,T); rs74574690(G,T); rs11111712(C,T); rs697206(A,G); rs11111713(A,C); rs143036904(G,A); rs118054769(A,G); rs697207(A,G); rs697208(T,C); rs831423(A,G); rs703649(A,G); rs703650(T,C); rs703651(C,T); rs184414492(G,C); rs116465356(T,A); rs703652(A,G); rs77901580(A,T); rs115822114(A,G); rs78416366(G,T); rs17034394(T,C); rs188897650(T,C); rs7136870(A,G); rs697209(A,G); rs146162076(G,A); rs4981031(C,G); rs7312283(T,A); rs7296561(A,G); rs7296691(C,T); rs11111716(A,G); rs6539095(G,A); rs697210(T,C); rs12578430(T,C); rs10778278(A,G); rs113376623(A,G); rs12426734(C,G); rs7309088(C,T); rs1650122(C,G); rs112465042(G,C); rs7303410(G,A); rs697211(A,G); rs11111718(C,A); rs697212(C,T); rs66517507(G,A); rs57416097(G,A); rs6539098(T,C); rs7310585(T,C); rs114612043(T,C); rs11111722(C,T); rs11111723(G,A); rs75727642(T,C); rs116062373(A,G); rs61937834(A,G); rs11111725(C,A); rs116348818(C,T); rs77976636(A,C); rs12307100(C,T); rs10861076(G,T); rs57749959(A,G); rs74524269(C,T); rs117462820(A,G); rs115292245(A,G); rs7138824(C,T); rs10861077(C,G); rs61601185(T,A); rs11111726(C,T); rs10861078(T,C); rs149481529(G,A); rs11111727(C,T); rs111542487(G,A); rs116350784(A,C); rs17583022(C,T); rs11111728(C,T); rs703653(C,A); rs7307204(G,T); rs6539099(A,C); rs147700478(T,G); rs6539100(C,T); rs12306776(G,A); rs7975156(A,G); rs12308764(G,T); rs115879871(C,G); rs703654(A,G); rs12424999(C,T); rs10861080(G,A); rs116515570(T,C); rs59079260(C,T); rs11111732(A,G); rs11111733(T,A); rs703655(A,G); rs11111734(G,A); rs11111735(A,G); rs12370734(G,A); rs74416654(A,G); rs11835383(G,A); rs11837927(T,G); rs10444529(T,C); rs931530(A,G); rs10861081(C,A); rs17034422(T,C); rs79815488(C,A); rs79293963(A,C); rs61937835(G,A); rs12300983(G,A); rs140156766(T,C); rs2118597(G,A); rs79023832(C,T); rs76411186(G,A); rs10861083(A,C); rs10778281(C,T); rs17034433(A,C); rs4981042(A,G); rs115352759(C,T); rs56343453(C,T); rs10861084(G,A); rs10778282(A,G); rs10778283(T,C); rs35285727(A,G); rs74985486(T,G); rs76713321(C,G); rs112518687(C,T); rs11111738(T,C); rs1946820(G,A); rs12296211(A,G); rs1946821(C,A); rs4981030(A,G); rs10778284(A,G); rs17505525(A,G); rs58820268(G,A); rs61413598(A,T); rs60416626(G,A); rs2271640(G,T); rs4143656(T,C); rs10861088(C,T); rs1370785(G,A); rs4981029(G,A); rs113883286(A,G); rs74718119(G,A); rs4015379(G,A); rs17034446(A,G); rs3844213(G,A); rs3851630(T,C); rs10745979(A,G); rs10745980(A,G); rs7301863(T,C); rs7316328(C,G); rs113342313(C,T); rs199578907(G,A); rs11838350(C,A); rs1586986(C,T); rs113007482(G,T); rs2292687(C,T); rs7306642(C,A); rs114610785(G,A); rs78974195(C,G); rs1866297(C,T); rs11111742(C,A); rs113143201(C,T); rs2056128(A,G); rs7979428(G,A); rs115656432(A,G); rs138386227(G,T); rs116797942(T,C); rs199757471(G,A); rs61300396(T,C); rs192632446(G,A); rs11111745(G,A); rs11111746(A,G); rs10431459(G,T); rs116258341(C,T); rs11833263(T,C); rs17505851(G,A); rs189886712(T,C); rs79275061(T,C); rs2374246(A,C); rs2374247(C,T); rs17505884(A,C); rs75991028(T,C); rs34738204(A,T); rs35756765(C,A); rs3751200(G,A); rs3751198(A,G); rs11111747(A,G); rs4981023(C,T); rs11111748(G,A); rs7296626(C,T); rs7313163(T,G); rs4981022(G,A); rs4981021(C,T); rs35585068(C,T); rs11834389(T,C); rs10861091(G,A); rs3763993(T,G); rs4981026(A,G); rs3817303(G,T); rs2271637(C,G); rs12229292(G,T); rs11111750(G,A); rs75343202(G,T); rs11111751(C,T); rs144782506(G,A); rs148572602(C,T); rs75992048(A,G); rs2292682(C,T); rs11111752(C,T); rs10861092(T,C); rs1565773(G,A); rs1976256(G,C); rs7300663(G,C); rs75933662(C,G); rs1973658(C,G); rs61602054(T,C); rs10861093(T,C); rs11111754(G,A); rs11111755(G,A); rs10861094(C,A) |
| ccdsGene name | CCDS31888.1 |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 55576 |
| EntrezGene Description | stabilin 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | STAB2:NM_017564:exon59:c.G6409A:p.E2137K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8067 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WWQ8 |
| dbNSFP Uniprot ID | STAB2_HUMAN |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 8.946e-05 |
MIR3652
| dbSNP name | rs17797090(G,A) |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 100500842 |
| snpEff Gene Name | HSP90B1 |
| EntrezGene Description | microRNA 3652 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06382 |
| ESP Afr MAF | 0.067697 |
| ESP All MAF | 0.082846 |
| ESP Eur/Amr MAF | 0.090602 |
| ExAC AF | 0.067 |
EID3
| dbSNP name | rs11111987(A,G) |
| ccdsGene name | CCDS53822.1 |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 493861 |
| EntrezGene Description | EP300 interacting inhibitor of differentiation 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EID3:NM_001008394:exon1:c.A870G:p.Q290Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4954 |
| ESP Afr MAF | 0.411686 |
| ESP All MAF | 0.492626 |
| ESP Eur/Amr MAF | 0.449392 |
| ExAC AF | 0.526 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Shorter daily total sleep times compared to age-matched controls;
Earlier sleep-offset time (earlier awakening);
Normal sleep-onset time (normal time of falling asleep);
Increased activity period;
Individuals require less sleep in a 24-hour period compared to age-matched
controls
MISCELLANEOUS:
One family has been reported
MOLECULAR BASIS:
Caused by mutation in the basic helix-loop-helix domain-containing
protein class B, 3 gene (BHLHB3, 606200.0001)
OMIM Title
*612986 E1A-LIKE INHIBITOR OF DIFFERENTIATION 3; EID3
;;EP300-INTERACTING INHIBITOR OF DIFFERENTIATION 3;;
NON-SMC ELEMENT 4, S. CEREVISIAE, HOMOLOG OF, B; NSMCE4B;;
NSE4B
OMIM Description
CLONING
By database analysis using EID1 (CRI1; 605894) as query, followed by PCR
of a human testis cDNA library, Bavner et al. (2005) cloned EID3. The
deduced 333-amino acid protein localized to both the nucleus and
cytoplasm. Northern blot analysis of 16 human tissues detected a 2.0-kb
transcript exclusively in testis. SDS-PAGE analysis detected EID3 as a
39-kD band.
By database analysis using EID2 (CRI2; 609773) as query, followed by
screening a human fetal brain cDNA library, Sasajima et al. (2005)
independently identified EID3. By database analysis, Hu et al. (2005)
identified EID3 as a human ortholog of S. cerevisiae Nse4.
GENE FUNCTION
Bavner et al. (2005) showed that EID3 has transcriptional repressor
activity against nuclear repressors SF-1 (NR5A1; 184757), GR (GCCR;
138040), and ER-alpha (ESR1; 133430). Using in vitro and in vivo
studies, they showed that EID3 interacted with CBP (CREBBP; 600140) and
inhibited CBP-dependent transcriptional activity. Chromatin
immunoprecipitation assays demonstrated that EID3 blocked recruitment of
CBP to the endogenous pS2 (113710) promoter.
Sasajima et al. (2005) showed that EID3 has transcriptional repressor
activity, as determined by luciferase assay. EID3 inhibited
serum-induced cellular differentiation in murine C2C12 myoblasts.
Immunoprecipitation studies demonstrated that EID3 interacts with HDAC1
(601241) and HDAC2 (605164). The authors showed that EID3
transcriptional repressor activity was reversed upon treatment with HDAC
inhibitor trichostatin A. In addition, EID3 interacted with itself and
EID2 to form EID3 homodimers and EID3-EID2 heterodimer complexes.
Hu et al. (2005) showed that S. cerevisiae ortholog NSE4 mutants
exhibited arrest occurring after S phase and prior to mitosis in a Rad24
checkpoint-dependent manner, and displayed genome instability and
sensitivity to DNA damage agents. Hu et al. (2005) showed that NSE4 is a
non-SMC element of the Smc5/6 DNA repair complex.
GENE STRUCTURE
Sasajima et al. (2005) determined that the EID3 gene contains 1 exon.
MAPPING
By database analysis, Bavner et al. (2005) mapped the EID3 gene to
chromosome 12q23-q24.1 within the 5-prime end of the TXNRD1 gene
(601112), and they mapped the mouse Eid3 gene to chromosome 10 within
the mouse Txnrd1 gene.
MIR3922
| dbSNP name | rs61938575(G,A) |
| ccdsGene name | CCDS9099.1 |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 100500843 |
| snpEff Gene Name | CHST11 |
| EntrezGene Description | microRNA 3922 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2521 |
| ExAC AF | 0.178 |
APPL2
| dbSNP name | rs2440703(T,A); rs10071(A,G); rs9143(A,G); rs12228948(C,T); rs935241(G,A); rs935240(G,A); rs11112396(T,G); rs11112397(T,C); rs140918264(C,T); rs1196867(G,A); rs1196866(T,C); rs60230439(A,G); rs1196865(A,C); rs10861360(C,T); rs73179990(A,G); rs1196864(A,G); rs1196863(C,G); rs1196862(C,T); rs1196861(A,C); rs12425893(C,G); rs118049128(G,A); rs78494368(T,A); rs11112398(A,G); rs141926126(A,G); rs147363007(C,T); rs115821042(T,C); rs7485364(T,C); rs183484563(G,T); rs1196859(A,G); rs1196858(T,C); rs1196857(G,A); rs4964338(T,A); rs1196856(G,A); rs1196855(T,C); rs148348563(G,C); rs143344429(A,T); rs114147330(G,A); rs1196854(G,A); rs60725801(C,T); rs35672903(C,A); rs35462155(G,A); rs56862143(G,A); rs60835294(T,A); rs1196853(A,T); rs73179994(G,A); rs7978034(A,G); rs935251(G,A); rs935249(C,T); rs2264066(G,T); rs79786821(G,A); rs1196852(A,G); rs1057110(G,C); rs1196851(G,A); rs117788799(A,G); rs73179996(G,A); rs59618886(C,G); rs60732733(T,G); rs2246510(T,G); rs12228093(G,A); rs79661788(G,A); rs2464186(A,T); rs373406559(G,A); rs2464185(A,G); rs2440699(T,C); rs1732379(C,T); rs1732378(G,C); rs73179998(G,C); rs2440698(T,A); rs2440697(G,C); rs2440696(G,A); rs11112403(A,G); rs73180001(T,G); rs1201657(C,T); rs1196742(A,G); rs73395802(T,C); rs1196743(C,T); rs1196744(G,C); rs2257156(G,A); rs74728310(C,T); rs146420641(G,A); rs12303948(G,A); rs76502294(G,A); rs12312965(T,G); rs3829297(G,C); rs78451516(C,T); rs1196745(A,G); rs7964184(T,G); rs1196746(A,G); rs1196747(T,G); rs11112407(G,A); rs1196748(C,G); rs935248(T,C); rs1078420(G,A); rs192389355(A,G); rs11112409(G,A); rs75496623(G,C); rs17036781(G,A); rs3736628(C,T); rs1196749(G,A); rs1196750(G,T); rs58431410(T,G); rs12309135(G,C); rs11112410(C,T); rs4964340(G,A); rs12311156(G,A); rs2293643(G,A); rs1196751(G,A); rs114265761(C,T); rs1196752(G,A); rs1196753(C,A); rs1196754(C,A); rs7132816(T,C); rs1196755(C,T); rs1196756(C,G); rs7302842(C,A); rs1196757(A,C); rs1196758(T,C); rs7971630(C,T); rs10861361(G,A); rs56291025(A,C); rs73397621(A,G); rs1196759(C,T); rs73397624(G,C); rs1196760(G,C); rs1196761(G,A); rs752471(C,T); rs12812433(C,A); rs1196763(C,T); rs750060(G,A); rs1077896(G,C); rs1196764(A,G); rs1196765(T,C); rs11831854(A,T); rs115638499(G,C); rs2440691(T,G); rs74606116(C,A); rs4964342(T,C); rs11112412(G,A); rs1196766(C,T); rs1196767(G,A); rs117421806(A,C); rs7133728(C,A); rs79136735(C,G); rs11112413(A,G); rs11112414(G,A); rs2440715(A,C); rs2464184(C,A); rs60550375(C,T); rs2440708(G,A); rs2440707(G,A); rs2440706(C,T); rs3794227(G,A); rs12304384(C,T); rs12815031(A,G); rs11112415(G,A); rs1196768(G,A); rs881279(C,T); rs78452014(G,A); rs935244(A,G); rs727888(C,G); rs1317955(G,A); rs935245(A,G); rs1196769(C,T); rs1196770(T,C); rs11112416(A,G); rs1196771(T,C); rs2440695(C,T); rs1196772(T,C); rs1196773(A,G); rs17036813(C,T); rs12317804(G,C); rs1470381(C,T); rs60999193(G,T); rs111359512(C,T); rs1317941(A,G); rs880797(T,C); rs12321199(C,T); rs1109432(T,A); rs1109433(T,C); rs1196776(A,G); rs2293644(C,T); rs59593474(G,C); rs3794224(C,T); rs140048709(G,A); rs3794223(T,C); rs57553834(G,T); rs3794222(C,T); rs3829296(T,C); rs59720624(A,G); rs143125800(G,A); rs9634185(C,T); rs12301914(C,T); rs1196777(G,A); rs60294187(A,T); rs1196778(G,A); rs1196779(A,G); rs1196780(T,A); rs1196781(A,G); rs73397654(T,C); rs73397655(T,C); rs73397656(T,G); rs61078684(G,A); rs873119(T,C); rs1196782(T,C); rs12299391(G,C); rs73397659(T,C); rs73397660(T,C); rs73397661(C,T); rs1107757(A,G); rs1107756(A,G) |
| ccdsGene name | CCDS9101.1 |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 55198 |
| EntrezGene Description | adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | APPL2:NM_001251904:exon11:c.C1055T:p.T352M,APPL2:NM_018171:exon11:c.C1037T:p.T346M,APPL2:NM_001251905:exon11:c.C908T:p.T303M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.571 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F8W1P5 |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 3.253e-05,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Atrioventricular septal defect, partial;
Dextrocardia;
Pulmonary atresia;
[Vascular];
Right aortic arch;
Aorta arises from right ventricle
MISCELLANEOUS:
Incomplete penetrance;
Genetic heterogeneity (see 606215)
MOLECULAR BASIS:
Caused by mutations in the cysteine-rich protein with EGF-like domain
1 gene (CRELD1, 607170.0001)
OMIM Title
*606231 ADAPTOR PROTEIN, PHOSPHOTYROSINE INTERACTION, PH DOMAIN, AND LEUCINE
ZIPPER-CONTAINING PROTEIN 2; APPL2
;;ADAPTOR PROTEIN CONTAINING PH DOMAIN, PTB DOMAIN, AND LEUCINE ZIPPER
MOTIF 2;;
DIP13-BETA;;
FLJ10659
OMIM Description
CLONING
Bonaglia et al. (2001) stated that the FLJ10659 gene encodes a 541-amino
acid protein. Northern blot analysis detected a 4-kb transcript in
several tissues, including kidney, brain, heart, and skeletal muscle.
The FLJ10659 transcript was expressed in all central nervous system
samples.
By affinity chromatography and mass spectrometry to identify RAB5
(179512) interactors, followed by RT-PCR using HeLa cell mRNA,
Miaczynska et al. (2004) cloned APPL2. The deduced protein contains 664
amino acids and shares 54% amino acid identity with APPL1 (604299).
APPL2 has an N-terminal BAR domain, a central PH domain, and a
C-terminal PTB domain. Unlike APPL1, APPL2 has a potential nuclear
localization signal.
GENE FUNCTION
Miaczynska et al. (2004) identified a pathway directly linking the small
GTPase RAB5, a key regulator of endocytosis, to signal transduction and
mitogenesis. This pathway operated via APPL1 and APPL2, 2 RAB5 effectors
that reside on a subpopulation of endosomes. In response to
extracellular stimuli such as EGF (131530) and oxidative stress, APPL1
translocated from the membranes to the nucleus, where it interacted with
the nucleosome remodeling and histone deacetylase (NURD) multiprotein
complex, a regulator of chromatin structure and gene expression. Both
APPL1 and APPL2 were essential for cell proliferation, and their
function required RAB5 binding. These findings identified an endosomal
compartment bearing RAB5 and APPL proteins as an intermediate in
signaling between the plasma membrane and the nucleus.
GENE STRUCTURE
Bonaglia et al. (2001) stated that the FLJ10659 gene spans 63 kb and
contains 21 exons. The ATG start codon is located in exon 1, and the
stop codon is located in exon 18.
MAPPING
The APPL2 gene maps to chromosome 12q24.1 (Bonaglia et al., 2001)
CYTOGENETICS
Bonaglia et al. (2001) studied a boy with severe expressive language
delay consistent with the 22q13.3 deletion syndrome (606232). The
patient's karyotype showed a de novo balanced translocation between
chromosomes 12 and 22, t(12;22)(q24.1;q13.3). FISH investigation showed
that the translocation was reciprocal. Further studies located the
chromosome 12 breakpoint in an intron of the FLJ10659 gene and the
chromosome 22 breakpoint within exon 21 of the PSAP2 gene (606230).
Short homologous sequences were found at the breakpoint on both
derivative chromosomes. The authors proposed that disruption of the
PSAP2 gene was likely to be responsible for the clinical disorder.
ASCL4
| dbSNP name | rs11113472(A,G); rs114212068(T,C) |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 121549 |
| EntrezGene Description | achaete-scute family bHLH transcription factor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2107 |
LOC728739
| dbSNP name | rs73193739(T,C) |
| cytoBand name | 12q23.3 |
| EntrezGene GeneID | 728739 |
| snpEff Gene Name | RP11-554D14.2 |
| EntrezGene Description | programmed cell death 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.141 |
MMAB
| dbSNP name | rs11067227(C,T); rs12817689(A,G); rs2241201(C,G); rs35145546(C,G); rs72650177(C,T); rs11067231(C,A); rs877709(G,T); rs877710(C,G); rs11831226(A,C); rs11067232(G,T); rs11067233(C,G); rs148289390(A,C); rs8228(A,G); rs9593(A,T); rs888192(A,G); rs12828717(C,T); rs7312142(T,C); rs7302373(C,T); rs7312275(T,C); rs7302591(C,A); rs2058806(C,A); rs112082462(C,T); rs35072126(G,A); rs142526000(A,G); rs2287183(C,T); rs2287182(C,T); rs7964021(G,C); rs11067250(C,T); rs12580090(C,T); rs11067253(G,A); rs7953014(A,G); rs61940465(C,T); rs57039720(T,C); rs61940466(G,A); rs2058805(T,C); rs78599682(T,C); rs7971853(G,T); rs11067271(T,C); rs12370596(A,G); rs7134594(C,T); rs61940468(C,T); rs12578365(G,A); rs736344(A,G); rs61940470(C,T); rs7970557(C,T); rs61940511(G,A); rs10850379(C,T); rs10850380(A,G); rs7301541(G,A); rs754179(C,T); rs754180(G,T); rs874170(C,T); rs9919738(G,A); rs11836136(A,G); rs12830693(G,T); rs11614986(A,G); rs59227481(A,G); rs80330230(C,T); rs115665182(C,T); rs4499061(G,T); rs115802744(G,A); rs66580225(A,G); rs12322541(A,G); rs2111216(A,G); rs12314392(A,G); rs10774775(C,T) |
| ccdsGene name | CCDS9131.1 |
| cytoBand name | 12q24.11 |
| EntrezGene GeneID | 326625 |
| EntrezGene Description | methylmalonic aciduria (cobalamin deficiency) cblB type |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MMAB:NM_052845:exon2:c.C185T:p.T62M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8805 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96EY8 |
| dbNSFP Uniprot ID | MMAB_HUMAN |
| dbNSFP KGp1 AF | 0.00778388278388 |
| dbNSFP KGp1 Afr AF | 0.0345528455285 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.007805 |
| ESP Afr MAF | 0.021108 |
| ESP All MAF | 0.007227 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.002204 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Abnormal extraocular movements
GENITOURINARY:
[Bladder];
Urinary urgency;
Urinary incontinence;
Sphincter disturbances
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Spastic gait;
Hyperreflexia;
Extensor plantar responses;
Ataxia;
Dystonia;
Dysarthria;
Mental retardation;
Decreased vibratory sense in lower limbs;
Cerebellar atrophy;
Patellar and ankle clonus
MISCELLANEOUS:
Highly variable phenotype
OMIM Title
*607568 MMAB GENE; MMAB
;;COB(I)ALAMIN ADENOSYLTRANSFERASE
OMIM Description
DESCRIPTION
The MMAB gene encodes cob(I)alamin adenosyltransferase (EC 2.5.1.17),
which catalyzes the final step in the synthesis of the coenzyme
adenosylcobalamin (AdoCbl). AdoCbl is a vitamin B12-containing coenzyme
for methylmalonyl-CoA mutase (609058).
CLONING
Dobson et al. (2002) identified MMAB within a bacterial operon
containing MCM and, using the bacterial sequence, identified ESTs and
assembled a full-length human MMAB cDNA. The deduced 250-amino acid
protein has a calculated molecular mass of 27.3 kD. MMAB shares 88%
sequence identity with mouse Mmu. Northern blot analysis revealed
expression of a 1.1-kb transcript, with highest expression in liver and
skeletal muscle.
GENE FUNCTION
MMAB has 45% similarity to PduO, a cob(I)alamin adenosyltransferase, in
Salmonella enterica (Johnson et al., 2001). Dobson et al. (2002)
demonstrated that fibroblasts from 6 MMA patients from the cblB
complementation group had levels of adenosyl-Cbl that were more than 13%
that of control cells, as measured by uptake of radioactive OH-Cbl.
Missense mutations in conserved amino acid residues of MMAB, as well as
splice mutations in the gene among cblB group patients, added further
evidence that the MMAB gene product functions as a cobalamin
adenosyltransferase.
GENE STRUCTURE
Dobson et al. (2002) determined that the MMAB gene consists of 9 exons
extending over 18.87 kb. Exon 9 ends at 2 alternative polyadenylation
sites, and the intron-exon junctions are conserved between man and
mouse. MMAB has a predicted leader sequence and signal cleavage site
consistent with localization to the mitochondria.
MAPPING
By linkage analysis, Dobson et al. (2002) mapped the MMAB gene to
chromosome 12q24.
MOLECULAR GENETICS
Dobson et al. (2002) analyzed fibroblast cell lines from 6 patients with
methylmalonic aciduria of the complementation type cblB patients and
identified 6 mutations in the MMAB gene.
LOC100131138
| dbSNP name | rs115450505(T,C); rs1056618(A,G); rs1056620(C,T) |
| cytoBand name | 12q24.11 |
| EntrezGene GeneID | 100131138 |
| snpEff Gene Name | RP1-46F2.2 |
| EntrezGene Description | uncharacterized LOC100131138 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01561 |
MAPKAPK5-AS1
| dbSNP name | rs3177647(C,T); rs2879603(A,G) |
| cytoBand name | 12q24.12 |
| EntrezGene GeneID | 51275 |
| snpEff Gene Name | MAPKAPK5 |
| EntrezGene Description | MAPKAPK5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2222 |
ADAM1A
| dbSNP name | rs150266565(C,T); rs9971746(C,T); rs11066072(C,T); rs3742000(T,C); rs12321677(G,A) |
| cytoBand name | 12q24.13 |
| EntrezGene GeneID | 8759 |
| snpEff Gene Name | MAPKAPK5 |
| EntrezGene Description | ADAM metallopeptidase domain 1A, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
TBX5-AS1
| dbSNP name | rs61931003(C,A); rs115619914(T,G); rs55727648(T,C); rs16944204(G,C); rs1996821(G,A); rs3803079(A,T); rs59887918(C,T); rs60235778(G,A); rs2948167(C,T); rs2295236(C,T) |
| cytoBand name | 12q24.21 |
| EntrezGene GeneID | 255480 |
| snpEff Gene Name | TBX5 |
| EntrezGene Description | TBX5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1024 |
MIR1178
| dbSNP name | rs74614893(G,A) |
| ccdsGene name | CCDS9192.1 |
| cytoBand name | 12q24.23 |
| EntrezGene GeneID | 100302274 |
| snpEff Gene Name | CIT |
| EntrezGene Description | microRNA 1178 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
| ESP Afr MAF | 0.005674 |
| ESP All MAF | 0.017915 |
| ESP Eur/Amr MAF | 0.024186 |
| ExAC AF | 0.022 |
TRIAP1
| dbSNP name | rs1048830(G,T) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 51499 |
| snpEff Gene Name | COX6A1 |
| EntrezGene Description | TP53 regulated inhibitor of apoptosis 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3145 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial myoclonus
NEUROLOGIC:
[Central nervous system];
Myoclonus, cortical, multifocal;
Frequent falls with preservation of consciousness;
Cerebellar ataxia, mild, late-onset
MISCELLANEOUS:
One Canadian Mennonite family has been reported (last curated November
2012);
Adult onset from second to seventh decade;
Slowly progressive;
Myoclonus triggered by action, sudden movements, and inadvertent somatosensory
stimuli;
Symptoms aggravated by fatigue, exertion, sleep deprivation, emotion,
hunger;
Older patients become wheelchair-dependent
MOLECULAR BASIS:
Caused by mutation in the nucleolar protein-3 gene (NOL3, 605235.0001)
OMIM Title
*614943 TP53-REGULATED INHIBITOR OF APOPTOSIS 1; TRIAP1
;;p53-INDUCIBLE CELL SURVIVAL FACTOR; P53CSV;;
HSPC132
OMIM Description
DESCRIPTION
TRIAP1 is a p53 (TP53; 191170) target gene that is upregulated following
genotoxic stress. TRIAP1 tends to counter the apoptotic function of p53
(Park and Nakamura, 2005).
CLONING
By RT-PCR of CD34 (142230)-positive hematopoietic stem/progenitor cells
from cord blood and adult bone marrow, Zhang et al. (2000) cloned human
TRIAP1, which they called HSPC132. The deduced protein contains 76 amino
acids.
By immunohistochemical analysis of transfected human lung cancer cells,
Park and Nakamura (2005) found that epitope-tagged P53CSV localized to
mitochondria.
GENE FUNCTION
Park and Nakamura (2005) found that expression of P53CSF was upregulated
in HCT116 human colorectal carcinoma cells in a p53-dependent manner
following treatment with the chemotherapeutic agent adriamycin or
ultraviolet radiation. Knockdown of P53CSF via RNA interference
sensitized cells to genotoxic stress. Park and Nakamura (2005) noted
that HSP70 (see 140550) can block apoptosis by binding to APAF1
(602233), thereby preventing formation of a complex between APAF1,
cytochrome c (123970), and caspase-9 (CASP9; 602234).
Coimmunoprecipitation analysis revealed direct interaction of P53CSV
with HSP70 and APAF1, and overexpression of P53CSV inhibited DNA
damage-induced caspase-9 activation.
GENE STRUCTURE
Park and Nakamura (2005) determined that the TRIAP1 gene contains 2
exons and spans 2.4 kb. Exon 2 contains a p53-binding site.
MAPPING
By database analysis, Zhang et al. (2000) mapped the TRIAP1 gene to
chromosome 12q23.
Hartz (2012) mapped the TRIAP1 gene to chromosome 12q24.31 based on an
alignment of the TRIAP1 sequence (GenBank GENBANK F161481) with the
genomic sequence (GRCh37).
HNF1A-AS1
| dbSNP name | rs2254675(G,A); rs113430888(G,A); rs188836859(C,T); rs79710799(G,C); rs6489788(A,C); rs2254779(G,A); rs75965818(T,C) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 283460 |
| EntrezGene Description | HNF1A antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04086 |
HCAR2
| dbSNP name | rs582452(A,G) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 338442 |
| EntrezGene Description | hydroxycarboxylic acid receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2704 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Normal stature
SKELETAL:
[Spine];
Mild platyspondyly;
Irregular vertebral endplates;
Narrow intervertebral disc spaces;
Rectangular lumbar spinal canal;
Accentuated thoracic kyphosis;
Scoliosis;
Elongated vertebrae;
[Pelvis];
Coxa vara;
Irregular, sclerotic acetabulae;
Flattened capital femoral epiphyses;
Narrow iliac wings;
Narrow, short femoral neck;
Prominent trochanter;
Flexion contractures (hip);
[Limbs];
Arthralgia;
Flexion contractures (knee);
Osteochondromatosis (knee);
[Hands];
Short metacarpals (4th-5th);
[Feet];
Hypoplastic or dysplastic toes (3rd, 4th, and 5th);
Hypoplastic metatarsals (3rd and 4th)
MISCELLANEOUS:
Onset of joint pain in childhood;
Waddling gait;
Hip replacement in early adulthood
OMIM Title
*609163 HYDROXYCARBOXYLIC ACID RECEPTOR 2; HCAR2
;;HCA2;;
G PROTEIN-COUPLED RECEPTOR 109A; GPR109A;;
NIACIN RECEPTOR 1; NIACR1;;
HM74A;;
HM74B;;
PROTEIN UPREGULATED IN MACROPHAGES BY IFNG, MOUSE, HOMOLOG OF; PUMAG
OMIM Description
CLONING
By searching for sequences similar to HM74 (GPR109B; 606039), followed
by PCR of a placenta cDNA library, Wise et al. (2003) cloned GPR109A,
which they designated HM74A. The deduced 363-amino acid HM74A protein is
a potential 7 transmembrane-spanning receptor that shares 96% identity
with HM74. Wise et al. (2003) identified Pumag as the mouse ortholog of
HM74A, but they were unable to identify a rodent ortholog of HM74,
suggesting that it arose from a recent duplication event in human.
RT-PCR analysis detected highest HM74A expression in adipose tissue.
Lower expression was detected in spleen and lung, and little to no
expression was detected in all other tissues examined.
In the course of amplifying HM74 from a human spleen cDNA library, Soga
et al. (2003) cloned full-length GPR109A, which they designated HM74B.
RT-PCR detected highest expression in adipose, lung, trachea, and
spleen.
MAPPING
By genomic sequence analysis, Wise et al. (2003) mapped the GPR109A gene
to a region of chromosome 12q24.31 that contains the GPR109B and GPR81
(606923) genes.
GENE FUNCTION
By expression in Xenopus oocytes, Wise et al. (2003) showed that GPR109A
is a Gi (139310)/Go (139311) protein-coupled receptor with a
high-affinity, concentration-dependent response to nicotinic acid.
GPR109A also responded to several nicotinic acid derivatives and analogs
following transfection in Chinese hamster ovary cells.
Using human kidney cells stably expressing mouse, rat, and human
GPR109A, Soga et al. (2003) demonstrated that nicotinic acid and a
compound with a similar pharmacologic profile inhibited
forskolin-stimulated intracellular cAMP accumulation in a dose-dependent
manner. Soga et al. (2003) concluded that GPR109A is an endogenous
receptor for nicotinic acid involving Gi/Go activation.
Tunaru et al. (2003) showed that binding of nicotinic acid to Pumag, the
mouse ortholog of HM74A, resulted in a G protein-mediated decrease in
cAMP levels.
Nicotinic acid has been used for decades as a lipid-lowering agent. Wise
et al. (2003) and Tunaru et al. (2003) identified human HM74A and mouse
Pumag, respectively, as a G protein-coupled receptor that is highly
expressed in adipose tissue and to which nicotinic acid is a
high-affinity ligand. By doing so, they identified the cellular
mechanism by which nicotinic acid exerts its main effect (i.e.,
suppression of lipolysis from adipose tissue). Karpe and Frayn (2004)
discussed the implications of these findings and suggested that research
on signaling through the nicotinic acid receptor might give rise to
novel and more effective methods to interfere with fatty acid metabolism
and a mechanism for the treatment of hyperlipidemia and possibly
insulin-resistant states.
MOLECULAR GENETICS
Zellner et al. (2005) found that many nonsynonymous SNPs listed in
public databases for HM74 and HM74A are artifacts resulting from
extensive homology between these closely linked genes. Zellner et al.
(2005) provided primer sequences that permitted selective amplification
of complete coding regions of HM74 and HM74A. Using these primers, they
showed novel and unique sequence variation in the HM74A gene. Haplotype
analysis suggested that 4 SNPs can define the 5 major haplotypes that
lie within a single haplotype block encompassing these 2 genes.
ANIMAL MODEL
Tunaru et al. (2003) generated mice deficient in Pumag by targeted
disruption. In homozygous knockout mice, the nicotinic acid-induced
decrease in free fatty acid and triglyceride plasma levels was
abrogated, indicating that Pumag mediates the anti-lipolytic and
lipid-lowering effects of nicotinic acid in vivo.
Singh et al. (2014) noted that commensal gut flora and dietary fiber
protect against inflammation and cancer in colon. Butyrate, a
short-chain fatty acid, is a bacterial product from fermentation of
fiber in colon. Niacr1 is a receptor for butyrate, as well as niacin.
Singh et al. (2014) found that mice deficient in Niacr1 had enhanced
susceptibility to colitis and colon cancer, both of which were
suppressed by niacin in a Niacr1-dependent manner. Signaling through
Niacr1 induced dendritic cell-mediated differentiation of regulatory and
Il10 (124092)-producing T cells and expression of Il18 (600953). In the
absence of gut microbiota and dietary fiber, colitis and carcinogenesis
could be inhibited through activation of Niacr1. Singh et al. (2014)
concluded that NIACR1 is a mediator of the antiinflammatory properties
of butyrate.
HCAR3
| dbSNP name | rs113740515(G,A) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 8843 |
| snpEff Gene Name | HCAR1 |
| EntrezGene Description | hydroxycarboxylic acid receptor 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2709 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Gaze-evoked nystagmus;
Saccadic smooth pursuit;
Strabismus (13 to 30% of patients);
Oculomotor apraxia (56% of patients);
Conjunctival telangiectasia (reported in 1 family)
SKELETAL:
[Spine];
Scoliosis (22% of patients);
[Feet];
Pes cavus (less common)
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Distal amyotrophy;
Distal muscle weakness
NEUROLOGIC:
[Central nervous system];
Gait ataxia, progressive;
Limb ataxia, progressive;
Spinocerebellar ataxia;
Dysarthria;
Tremor (57% of patients);
Head tremor (14% of patients);
Dystonic hand posturing (44% of patients);
Dystonia (14% of patients);
Choreic movements (10 to 22% of patients);
Pyramidal signs (21% of patients);
Cerebellar atrophy (96% of patients);
Pontocerebellar atrophy;
[Peripheral nervous system];
Polyneuropathy (98% of patients);
Decreased distal vibration sense;
Decreased distal proprioception (74% of patients);
Decreased distal touch sense (57% of patients);
Areflexia;
Absence of sensory action potentials;
Decreased motor nerve conduction velocity (NCV);
Sural nerve biopsy shows chronic axonal neuropathy;
Sural nerve biopsy shows loss of large myelinated fibers
LABORATORY ABNORMALITIES:
Increased serum alpha-fetoprotein;
Increased serum gamma-globulin;
Increased serum creatine kinase (less common)
MISCELLANEOUS:
Onset usually in mid-teens, average 15 years (range 2 to 20 years);
Progressive disorder;
Variable severity;
High frequency in the French-Canadian population
MOLECULAR BASIS:
Caused by mutations in the senataxin gene (SETX, 608465.0001)
OMIM Title
*606039 HYDROXYCARBOXYLIC ACID RECEPTOR 3; HCAR3
;;HCA3;;
G PROTEIN-COUPLED RECEPTOR 109B; GPR109B;;
CHEMOKINE RECEPTOR HM74; HM74
OMIM Description
CLONING
By PCR using degenerate primers derived from receptors for leukocyte
chemotactic peptides, Nomura et al. (1993) obtained cDNAs encoding HM74.
The predicted 387-amino acid G protein-coupled receptor (GPCR)-type
protein has significant homology to B2 bradykinin receptor (BDKRB2;
113503) and thrombin receptor (F2R; 187930). Northern blot analysis
revealed expression of a 2.3-kb HM74 transcript in peripheral blood
mononuclear cells and neutrophils.
Wise et al. (2003) identified an HM74 EST and cloned the full-length
cDNA from a placenta cDNA library. The HM74 protein is a potential 7
transmembrane-spanning receptor that shares 96% identity with HM74A
(GPR109A; 609163). Wise et al. (2003) identified Pumag as the mouse
ortholog of HM74A, but they were unable to identify a rodent ortholog of
HM74, suggesting that it arose from a recent duplication event in human.
RT-PCR analysis detected highest HM74 expression in spleen, followed by
lymphocytes and adipose tissue. Heart, placenta, prostate, and bone
marrow showed lower expression, and little to no expression was detected
in all other tissues examined.
Using quantitative real-time RT-PCR, Irukayama-Tomobe et al. (2009)
found that expression of GPR109B was nearly 5-fold higher in human
neutrophils than in monocytes. They noted that ESTs and genomic
fragments encoding GPR109B have only been detected in humans and
chimpanzees, suggesting a recent duplication of the GPR109A gene.
GENE FUNCTION
Functional analysis by Nomura et al. (1993) failed to identify ligands
for HM74 that could induce calcium flux.
Tunaru et al. (2003) showed that HM74 is highly expressed in adipose
tissue and is a nicotinic acid receptor. Binding of nicotinic acid to
HM74 resulted in a G protein-mediated decrease in cAMP levels.
By expression in human embryonic kidney cells and Xenopus oocytes, Wise
et al. (2003) showed that HM74 is a Gi (139310)/Go (139311)
protein-coupled receptor with low affinity for nicotinic acid. In
contrast, HM74A showed high affinity for nicotinic acid.
Irukayama-Tomobe et al. (2009) noted that, although GPR109B had been
reported to be a low-affinity receptor for nicotinic acid, the affinity
of nicotinic acid for GPR109B is quite low at millimolar levels. Using
transfected CHO cells, Irukayama-Tomobe et al. (2009) showed that
GPR109B, but not GPR109A or GPR81 (606923), inhibited forskolin-induced
activation of a cAMP response element by the D isomers of phenylalanine,
tryptophan, and kynurenic acid. These amino acids elicited a transient
rise in intracellular Ca(2+) in a dose-dependent manner. Pertussis toxin
abrogated these effects, suggesting that GPR109B couples to the Gi/Go
class of G proteins. In human neutrophils, D-phe and D-trp induced a
transient increase in intracellular Ca(2+) levels and a reduction of
cAMP levels. Small interfering RNA directed against GPR109B inhibited
the D-amino acid-induced decrease of cellular cAMP levels in human
neutrophils. D-phe and D-trp also elicited a chemotactic response in
GPR109B-expressing Jurkat human T cells, but not in mock-transfected
Jurkat cells. Irukayama-Tomobe et al. (2009) concluded that these
aromatic D-amino acids elicit a chemotactic response in human
neutrophils vi activation of GPR109B.
MAPPING
By genomic sequence analysis, Wise et al. (2003) mapped the GPR109B gene
to a region of chromosome 12q24.31 that contains the GPR109A and GPR81
(606923) genes.
MOLECULAR GENETICS
Zellner et al. (2005) found that many nonsynonymous SNPs listed in
public databases for HM74 and HM74A are artifacts resulting from
extensive homology between these closely linked genes. Zellner et al.
(2005) provided primer sequences that permitted selective amplification
of complete coding regions of HM74 and HM74A. Using these primers, they
showed novel and unique sequence variation in the HM74A gene. Haplotype
analysis suggested that 4 SNPs can define the 5 major haplotypes that
lie within a single haplotype block encompassing these 2 genes.
HCAR1
| dbSNP name | rs7313367(A,G); rs7131791(A,G); rs513567(A,G); rs140482291(G,A) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 27198 |
| EntrezGene Description | hydroxycarboxylic acid receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2438 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Teeth];
Dental pulp stones;
Microdontia
SKELETAL:
[Skull];
Narrowed zygomatic arch;
[Hands];
Short fingers;
Distal symphalangism;
Aplastic/hypoplastic middle phalanges (fingers 2-5);
Aplastic/hypoplastic distal phalanges (fingers 2-5);
Cone-shaped epiphyses of middle phalanges;
Absent scaphoid bone;
Absent trapezium bone;
Absent trapezoid bone;
Absent pisiform bone;
[Feet];
Distal symphalangism;
Aplastic/hypoplastic middle phalanges (toes 2-5);
Aplastic/hypoplastic distal phalanges (toes 2-5)
SKIN, NAILS, HAIR:
[Nails];
Absent nails;
Hypoplastic nails
OMIM Title
*606923 HYDROXYCARBOXYLIC ACID RECEPTOR 1; HCAR1
;;HCA1;;
G PROTEIN-COUPLED RECEPTOR 81; GPR81;;
T-CELL ACTIVATION G PROTEIN-COUPLED RECEPTOR; TAGPCR
OMIM Description
DESCRIPTION
G protein-coupled receptors (GPCRs, or GPRs), such as GPR81, contain 7
transmembrane domains and transduce extracellular signals through
heterotrimeric G proteins.
CLONING
Lee et al. (2001) identified GPR81 in a genomic database using sequences
of related GPRs as query. PCR primers were designed to amplify and clone
GPR81 from a genomic library. Full-length GPR81 encodes a deduced
347-amino acid protein that shares 70%, 43%, and 37% sequence identity
in the transmembrane regions with the chemokine receptor HM74 (606039),
GPR31 (602043), and the purinoceptor P2Y1 (601167), respectively.
Northern blot analysis revealed a 1.0-kb transcript in human pituitary
tissue, but not in any other brain region examined.
Using RT-PCR, Wise et al. (2003) found highest GPR81 expression in
adipose tissue. Little to no expression was detected in all other
tissues examined.
By microarray analysis to identify genes coregulated with interleukin-2
(IL2; 147680) in a combination of experiments involving T-cell
activation and other conditions, followed by RT-PCR, Mao et al. (2004)
cloned GPR81, which they called TAGPCR. Real-time PCR analysis indicated
that TAGPCR expression peaked approximately 4 to 6 hours after T-cell
activation.
MAPPING
Lee et al. (2001) mapped the GPR81 gene to chromosome 12q based on
sequence similarity between the GPR81 sequence and a BAC clone (GenBank
GENBANK AC026331) localized to chromosome 12q.
By genomic sequence analysis, Wise et al. (2003) mapped the GPR81 gene
to a region of chromosome 12q24.31 that contains the GPR109A (609163)
and GPR109B (606039) genes.
CCDC62
| dbSNP name | rs839355(A,G); rs60589503(G,A); rs12307038(T,C); rs150571965(C,T); rs12312837(A,G); rs1798563(A,G); rs839352(A,G); rs12302287(C,T); rs11059932(G,A); rs60469279(C,T); rs12305822(C,T); rs1696355(A,T); rs75875275(A,G); rs11059954(C,T); rs55928229(A,G); rs1696320(A,G); rs58131754(C,T); rs115620601(C,T); rs1671679(C,T); rs7967318(C,T); rs2649900(T,G); rs7486414(G,A); rs146975464(C,T); rs6489240(T,C); rs116516249(C,T); rs7311386(G,A); rs7138313(C,T); rs75381856(T,C); rs839363(C,T); rs78935817(C,T); rs80023119(A,C); rs79426485(A,T); rs2649895(A,G); rs75481785(G,A); rs12321100(T,C); rs2649894(T,C); rs2604850(T,C); rs73415535(G,C); rs10744394(G,A); rs115199154(T,C); rs4759393(G,A); rs76762460(C,T); rs60174680(C,T); rs113265587(C,T); rs4759392(C,T); rs7294991(C,T); rs7309225(A,G); rs6489241(C,G); rs73415550(T,G); rs10847749(C,T); rs10847751(C,T); rs967281(A,G); rs11060112(A,C); rs4038080(T,C); rs4038081(G,A); rs73415555(G,A); rs4307760(C,G); rs4424710(T,G); rs3844369(T,C); rs3852535(G,A); rs4426165(T,C); rs7957643(G,A); rs112288169(C,T); rs12817488(G,A); rs7960548(T,C); rs10847771(T,C); rs11060142(G,T); rs10847774(A,G); rs71444563(A,G); rs10773599(A,T); rs4759391(T,A); rs143536297(C,G); rs11060152(G,A); rs10744401(T,G); rs7303973(T,C); rs4038070(C,T); rs1798560(C,G); rs1798561(C,T); rs1696321(G,A); rs1696322(T,G); rs1696323(A,G); rs1798565(A,G); rs7973273(A,T); rs2656814(T,C); rs2649899(T,C); rs2656815(G,A); rs1696316(G,A); rs4759390(C,T); rs2456151(G,A); rs1671683(C,T); rs1671682(T,A); rs11060180(A,G); rs1671681(A,G); rs73415582(C,A); rs1798569(C,A); rs150371247(C,T); rs184670090(T,C); rs7954285(C,T); rs2604851(A,G); rs4759389(A,G); rs1696327(T,C); rs59058900(G,A); rs11060211(T,A); rs7487095(A,G); rs10773627(A,G) |
| ccdsGene name | CCDS9238.1 |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 84660 |
| EntrezGene Description | coiled-coil domain containing 62 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC62:NM_201435:exon11:c.C1964G:p.P655R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6346 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Recurrent skin infections;
Cellulitis
MUSCLE, SOFT TISSUE:
Lymphedema of the lower limbs;
Lymphedema of the hands (in some patients)
MISCELLANEOUS:
Onset in first or second decades;
Females tend to have earlier onset;
Reduced penetrance
MOLECULAR BASIS:
Caused by mutation in the Gap junction protein, gamma-2 gene (GJC2,
608803.0009)
OMIM Title
*613481 COILED-COIL DOMAIN-CONTAINING PROTEIN 62: CCDC62
;;ESTROGEN RECEPTOR-ASSOCIATED PROTEIN, 75-KD; ERAP75
OMIM Description
CLONING
Using serologic identification of antigens by recombinant expression
cloning (SEREX) to immunoscreen a normal testicular cDNA expression
library, Domae et al. (2009) isolated 2 splice variants of CCDC62, which
they called CCDC62-1 and CCDC62-2. The deduced proteins contain 682 and
684 amino acids, respectively. RT-PCR detected both variants in testis
only. Expression of CCDC62-2, but not CCDC62-1, was detected in several
types of tumors.
By yeast 2-hybrid screening of a testis cDNA library using the
ligand-binding domain of human estrogen receptor (ER)-beta (ESR2;
601663) isoform-1 as bait, followed by 5-prime RACE and database
analysis, Chen et al. (2008) cloned 2 splice variants of CCDC62, which
they called ERAP75. Transcript-2, which was identified during the yeast
2-hybrid screen, encodes a deduced 684-amino acid protein with a
calculated molecular mass of 75 kD. It contains 2 N-terminal coiled-coil
motifs and 2 C-terminal LxxLL motifs. Transcript-1 differs from
transcript-2 only in exon 12, which encodes the last 12 or 15 amino
acids of the respective proteins; all other coding regions are
identical. Mouse Erap75 shares 50% homology with human ERAP75. Western
blot analysis of human cell lines showed highest ERAP75 expression in
prostate cancer cell lines, with moderate expression in a lung cancer
cell line and an immortalized benign prostate epithelial cell line, and
low expression in a breast cancer cell line. RT-PCR showed that Erap75
was widely expressed at variable levels in mouse tissues, with highest
expression in prostate. Immunofluorescence analysis revealed
colocalization of ERAP75 and ER-beta in nuclei of LNCaP human prostate
cancer cells. Immunohistochemical analysis of normal human prostate
showed nuclear expression of ERAP75 predominantly in epithelial cells,
but also in stromal cells.
GENE FUNCTION
Estrogens, in combination with androgens, play critical roles in
prostate carcinogenesis. Using yeast 2-hybrid, mammalian 2-hybrid,
protein pull-down, and coimmunoprecipitation analyses, Chen et al.
(2008) found that ERAP75 interacted with ER-alpha (ESR1; 133430).
Mutation analysis revealed that the first LxxLL motif of ERAP75 was
required for the interaction. Interaction between ER-alpha and ERAP75
was induced by 17-beta-estradiol (E2), and addition of ERAP75 led to a
dose-dependent increase in E2-induced ER-alpha transactivation in
transfected COS-1 and human prostate stromal cells. Chen et al. (2008)
concluded that ERAP75 is an ER-alpha coactivator in prostate stromal
cells.
Using mammalian 2-hybrid, protein pull-down, and coimmunoprecipitation
methods, Chen et al. (2009) showed that the ligand-binding domain of
ER-beta interacted with the C terminus of ERAP75. The first LxxLL motif
of ERAP75 was required for the interaction. Electrophoretic mobility
shift assay showed that ERAP75 was recruited by the estrogen response
element-ER complex in the presence of ligand. Chromatin
immunoprecipitation assay demonstrated hormone-dependent recruitment of
ERAP75 to the promoter of the estrogen-responsive gene cyclin D1 (CCND1;
168461). Inhibition of endogenous ERAP75 via small interfering RNA
suppressed ER-beta-mediated activation of a reporter gene and ER target
gene expression in LNCaP cells. Overexpression of ERAP75 enhanced
E2-regulated CCND1 expression and cell growth in LNCaP cells. Chen et
al. (2009) concluded that ERAP75 functions as a coactivator that can
modulate ER-beta transactivation and receptor function in prostate
cancer cells.
GENE STRUCTURE
Independently, Domae et al. (2009) and Chen et al. (2009) determined
that the CCDC62 gene contains 13 exons.
MAPPING
By genomic sequence analysis, Domae et al. (2009) and Chen et al. (2009)
independently mapped the CCDC62 gene to chromosome 12q24.31.
ATP6V0A2
| dbSNP name | rs2250026(G,C); rs12828408(G,C); rs3817309(C,T); rs116676239(G,A); rs66471742(G,A); rs7135267(T,C); rs73420303(A,G); rs35911711(C,T); rs12813346(C,G); rs12813758(C,T); rs67516712(G,A); rs144866718(G,A); rs10734903(C,T); rs150391809(G,C); rs113668123(C,T); rs113239274(G,A); rs6488898(G,A); rs10734904(T,G); rs112918683(C,T); rs10744157(G,A); rs10160842(G,T); rs6488899(C,T); rs6488900(A,G); rs6488901(C,T); rs6488902(G,C); rs7962743(T,A); rs1878077(T,C); rs10160937(G,A); rs149902738(A,G); rs7301641(T,C); rs9788204(C,T); rs9787987(T,C); rs10734905(T,G); rs10734906(A,G); rs7132115(C,T); rs7302708(A,G); rs140953947(A,C); rs139110043(T,C); rs1139789(T,C); rs11837144(C,T); rs59540041(C,T); rs7960403(G,T); rs882563(C,T); rs74783839(T,C); rs1399961(T,C); rs968203(A,G); rs114625715(C,T); rs7311789(C,T); rs7962913(A,G); rs10773026(A,G); rs73219053(G,A); rs7974331(T,C); rs7956751(C,G); rs7398606(A,G); rs7398851(A,G); rs77089692(A,C); rs116957652(G,A); rs2333840(G,A); rs2333839(T,C); rs77639283(T,C); rs111841570(A,G); rs7397240(A,G); rs7398372(C,T); rs7398373(C,T); rs7398384(C,A); rs7397745(T,C); rs7397746(T,C); rs7398641(C,A); rs10744159(T,G); rs2271662(A,G); rs10773029(G,A); rs10734908(C,A); rs10732574(A,G); rs7300721(T,C); rs7300818(T,C); rs10773030(C,T); rs2271661(T,C); rs2271660(T,C); rs2333838(A,C); rs2333837(C,T); rs2333836(C,G); rs2333835(T,C); rs78472946(G,A); rs10846549(C,G); rs10846550(T,G); rs10846551(G,T); rs10773031(G,C); rs1040156(A,G); rs78348348(G,C); rs7295552(T,C); rs73420341(C,T); rs34247974(A,G); rs12580486(T,C); rs7398082(A,C); rs115118771(A,G); rs7399128(G,A); rs10744160(A,G); rs10773032(A,G); rs115871490(T,G); rs181807933(G,T); rs7308398(T,A); rs112769474(G,A); rs7135542(T,C); rs2176152(T,C); rs10773034(A,G); rs73420345(T,C); rs60422087(G,T); rs150865479(A,G); rs7956769(A,G); rs7973463(C,T); rs7309294(C,T); rs59107032(T,C); rs373205804(C,T); rs12827680(A,C); rs73420349(G,A); rs17883456(C,T); rs56862679(T,C); rs112521789(C,T); rs10744162(T,C); rs10846553(C,G); rs77765053(T,A); rs111540619(C,G); rs2333834(G,A); rs73420351(G,A); rs73420352(G,A) |
| ccdsGene name | CCDS9254.1 |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 23545 |
| EntrezGene Description | ATPase, H+ transporting, lysosomal V0 subunit a2 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=23545&%3Brs=17883456 |
| Annovar Function | ATP6V0A2:NM_012463:exon19:c.C2438T:p.A813V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7095 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y487 |
| dbNSFP Uniprot ID | VPP2_HUMAN |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=23545&%3Brs=17883456 |
| dbNSFP KGp1 AF | 0.0169413919414 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0356200527704 |
| dbSNP GMAF | 0.01699 |
| ESP Afr MAF | 0.00749 |
| ESP All MAF | 0.025834 |
| ESP Eur/Amr MAF | 0.035233 |
| ExAC AF | 0.028 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial muscle weakness;
[Eyes];
Ptosis
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy;
Arrhythmia
MUSCLE, SOFT TISSUE:
Delayed motor development;
Muscle weakness, generalized, proximal and distal;
Calf hypertrophy;
Muscle biopsy shows centralized nuclei;
Type 1 fiber predominance;
Minicore-like lesions with mitochondrial depletion and sarcomeric
disorganization;
Disruption of the M-line;
Dystrophic changes occur later
LABORATORY ABNORMALITIES:
Serum creatine kinase may be increased
MISCELLANEOUS:
Muscle involvement shows onset at birth or in infancy;
Cardiac involvement occurs between 5 and 12 years;
Sudden death due to cardiomyopathy
MOLECULAR BASIS:
Caused by mutation in the titin gene (TTN, 188840.0012)
OMIM Title
*611716 ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A2; ATP6V0A2
;;A2V-ATPase
OMIM Description
DESCRIPTION
The multisubunit vacuolar-type proton pump (H(+)-ATPase or V-ATPase) is
essential for acidification of diverse cellular components, including
endosomes, lysosomes, clathrin-coated vesicles, secretory vesicles, and
chromaffin granules, and it is found at high density in the plasma
membrane of certain specialized cells. H(+)-ATPases are comprised of a
peripheral V(1) domain and an integral membrane V(0) domain; ATP6V0A2 is
a component of the V(0) domain (Smith et al., 2003).
CLONING
By screening for secreted immune regulatory proteins, Lee et al. (1990)
cloned Atp6v0a2, which they called J6B7, from a mouse helper T cell
hybridoma cDNA library. The deduced protein has a hydrophobic N terminus
and 3 potential N-glycosylation sites, and it has a calculated molecular
mass of 98.0 kD. Northern blot analysis detected abundant expression in
the T cell hybridoma cells and in mouse thymus, but not in thymoma,
spleen, or liver.
Using flow cytometry and immunofluorescence microscopy, Ntrivalas et al.
(2007) showed that A2V-ATPase was expressed at the cell membrane and
intracellularly in the JEG-3 human choriocarcinoma cell line.
GENE FUNCTION
Lee et al. (1990) found that mouse Atp6v0a2 showed significant
suppression of a mixed lymphocyte reaction in a dose-dependent manner.
Ntrivalas et al. (2007) stated that upon cell stimulation, A2V- ATPase
migrates to the cell membrane as a 50-kD molecule and the remaining
20-kD N-terminal domain is secreted into the extracellular environment.
The authors showed that secretion of IL1B (147720) was increased and
expression of type I and II interleukin receptors IL1R1 (147810) and
IL1R2 (147811) were significantly decreased by the A2V-ATPase N-terminal
domain in human peripheral blood mononuclear cells cocultured with JEG-3
cells.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the
ATP6V0A2 gene to chromosome 12 (TMAP RH92322).
By homozygosity mapping in 15 consanguineous families, Kornak et al.
(2008) identified a critical region for autosomal recessive cutis laxa
(219200) on chromosome 12q24 containing the ATP6V0A2 gene.
MOLECULAR GENETICS
Manifestations in cases of autosomal recessive cutis laxa (ARCL) type II
(Debre type) (ARCL2A; 219200) and wrinkly skin syndrome (WSS; 278250)
include, in addition to excessive congenital skin wrinkling, large
fontanel with delayed closure, typical facial appearance with
downslanting palpebral fissures, a general connective tissue weakness,
and varying degrees of growth and developmental delay and neurologic
abnormalities. Some affected individuals develop seizures and mental
deterioration later in life, whereas the skin phenotype tends to become
milder with age. Because an association of a cutis laxa phenotype with a
congenital disorder of glycosylation had been described and wrinkly skin
observed in an individual with a defect in the conserved oligomeric
Golgi (COG) complex involved in Golgi membrane trafficking, Kornak et
al. (2008) investigated glycosylation of serum proteins isolated from
individuals with ARCL type II. All affected individuals showed a CDG
type II (CDG II) pattern, which corresponds to a defect of
N-glycosylation at the level of processing in the Golgi apparatus. By
homozygosity mapping in 15 consanguineous families, Kornak et al. (2008)
identified a homozygous region on chromosome 12q24 with a maximum lod
score of 3.2 in 12 families. The products of 9 of the genes in the
critical linkage region were part of the Golgi proteome. In 12 families
with diagnoses of either autosomal recessive cutis laxa type II or
wrinkly skin syndrome, Kornak et al. (2008) identified 10 different
loss-of-function mutations in the ATP6V0A2 gene (see, e.g.,
611716.0001-611716.0003). Four were splice site mutations, 3 were
nonsense, and 3 frameshift; 5 mutations led to a premature stop in the
cytoplasmic N terminus, which is thought to mediate interaction with
other ATPase subunits, and the other mutations led to truncations in
transmembrane segments III, VI, and VIII. The mutations resulted in
abnormal glycosylation of serum proteins (CDG II) and caused an
impairment of Golgi trafficking in fibroblasts from affected
individuals. The results indicated that the alpha-2 subunit of the
proton pump has an important role in the Golgi function.
Hucthagowder et al. (2009) determined the molecular defects in ATP6V0A2
in a cohort of 17 patients with autosomal recessive cutis laxa.
Considerable allelic and phenotypic heterogeneity was observed. Abnormal
N- and/or mucin type O-glycosylation was observed in all patients
tested.
In 13 patients with ARCL2, Fischer et al. (2012) identified 17 ATP6V0A2
mutations: 1 mutation of the start codon, 3 missense mutations, 3
nonsense mutations, 3 splice site mutations, 3 in-frame deletions, and 4
frameshift mutations; 14 of the mutations were novel. All mutations but
1 were found in homozygous or compound heterozygous state. A
heterozygous splice site mutation (117+1delG) was detected at the
genomic as well as the cDNA level in a 40-year-old patient (patient 2),
but a pronounced nonsense-mediated decay of the ATP6V0A2 mRNA in
fibroblasts corroborated an ATP6V0A2-related ARCL2. Fischer et al.
(2012) suggested that the second mutation most probably resided in
noncoding regions not included in the mutation screening.
PATHOGENESIS
Hucthagowder et al. (2009) showed that premature stop codon mutations
(see 611716.0001) led to decreased ATP6V0A2 mRNA levels by destabilizing
the mutant mRNA via the nonsense-mediated decay pathway. Loss of
ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in
distended Golgi cisternae, accumulation of abnormal lysosomes and
multivesicular bodies. Immunostaining of ARCL2 cells showed the
accumulation of tropoelastin (ELN; 130160) in the Golgi and in large,
abnormal intracellular and extracellular aggregates. Pulse-chase studies
confirmed impaired secretion and increased intracellular retention of
ELN, and insoluble elastin assays showed significantly reduced
extracellular deposition of mature elastin. Fibrillin-1 (FBN1; 134797)
microfibril assembly and secreted lysyl oxidase (LOX; 153455) activity
were normal in ARCL2 cells. TUNEL staining demonstrated increased rates
of apoptosis in ARCL2 cell cultures. Hucthagowder et al. (2009)
concluded that loss-of-function mutations in ATP6V0A2 lead to ELN
aggregation in the Golgi, impaired clearance of ELN aggregates, and
increased apoptosis of elastogenic cells.
By immunostaining with an antibody against ATP6V0A2, Fischer et al.
(2012) demonstrated localization of ATP6V0A2 at the Golgi-apparatus and
a loss of the mutated ATP6V0A2 protein in the dermal fibroblasts of
patients with ARCL2A. Investigation of brefeldin A-induced Golgi
collapse in dermal fibroblasts as well as in HeLa cells deficient for
ATP6V0A2 revealed a delay, which was absent in cells deficient for the
ARCL-associated proteins GORAB (607983) and PYCR1 (179035). Furthermore,
by detection of P-Smad2, Fischer et al. (2012) demonstrated that
fibroblasts from patients with ATP6V0A2 mutations displayed elevated
TGF-beta signaling and increased TGFB1 (190180) levels in the
supernatant.
THRIL
| dbSNP name | rs1055472(G,A); rs67037258(A,G); rs66836373(A,G); rs67625612(T,C); rs7304738(A,G) |
| cytoBand name | 12q24.31 |
| EntrezGene GeneID | 140707 |
| EntrezGene Symbol | BRI3BP |
| snpEff Gene Name | BRI3BP |
| EntrezGene Description | BRI3 binding protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4674 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Ears];
Otitis media, recurrent;
[Mouth];
Thrush
RESPIRATORY:
Respiratory infections, recurrent
ABDOMEN:
[Gastrointestinal];
Diarrhea;
Gastroenteritis
IMMUNOLOGY:
Primary immunodeficiency;
Recurrent infections, bacterial, viral, and fungal;
Lymphopenia;
Lack of peripheral CD3+ T cells;
Decreased T-cell proliferative responses in vitro;
Normal B cells;
Normal NK cells
MISCELLANEOUS:
Onset in infancy;
Death in infancy without bone marrow transplantation
MOLECULAR BASIS:
Caused by mutation in the CD3 antigen, delta subunit gene (CD3D, 186790.0001)
OMIM Title
*615622 TNF- AND HNRNPL-RELATED IMMUNOREGULATORY LONG NONCODING RNA; THRIL
;;TNF- AND HNRNPL-RELATED IMMUNOREGULATORY lncRNA;;
LONG INTERGENIC NONCODING RNA 1992; LINC1992;;
lincRNA 1992;;
BRI3BP ANTISENSE RNA 1; BRI3BPAS1;;
TCONS_00020260
OMIM Description
DESCRIPTION
THRIL is a widely expressed long noncoding RNA (lncRNA) required for
induction of TNF (191160) expression (Li et al., 2014).
CLONING
Using microarray and RT-PCR analyses, Li et al. (2014) identified THRIL
among 159 lncRNAs whose expression was highly modulated following
stimulation of THP1 macrophages with a synthetic TLR2 (603028)
lipopeptide ligand. By 5-prime and 3-prime RACE, they obtained 2 THRIL
variants that differ only slightly in the first 40 to 50 nucleotides at
the 5-prime end. In vitro translation analysis confirmed that THRIL is a
noncoding RNA. Northern blot analysis of THP1 macrophages detected a 2-
to 2.5-kb transcript, and approximately 8 copies of THRIL were present
per cell. Quantitative RT-PCR of 20 human tissues showed wide expression
of THRIL.
GENE FUNCTION
Li et al. (2014) found that knockdown of THRIL in THP1 macrophages
strongly suppressed TNF induction. Expression of TNF resulted in
decreased expression of THRIL. Knockdown of THRIL also resulted in a 50%
reduction in mRNA levels of BRI3BP (615627), which overlaps THRIL on
chromosome 12, but it had no effect on other nearby genes. Knockdown of
BRI3BP had little effect on TNF expression. Pull-down analysis
identified a specific interaction of THRIL, primarily its 5-prime end,
with HNRNPL (603083). Knockdown of HNRNPL resulted in decreased TNF
production by stimulated THP1 cells. Chromatin immunoprecipitation
analysis revealed binding of HNRNPL to the TNF promoter, and chromatin
isolation by RNA purification assays showed that THRIL was also present
at the TNF promoter. Knockdown of THRIL reduced binding of HNRNPL to the
TNF promoter. Li et al. (2014) concluded that HNRNPL and THRIL form a
ribonucleoprotein complex that stimulates TNF transcription by binding
to its promoter. Additional transcriptome analysis of stimulated cells
showed that THRIL was required for maintenance of expression of numerous
immunity-associated genes, in addition to TNF. By examining RNA samples
from patients with Kawasaki disease (611775), Li et al. (2014) observed
that THRIL expression was significantly lower in the acute phase, when
serum TNF levels are elevated, compared with the convalescent phase.
They proposed that the low levels of THRIL when TNF levels are high in
Kawasaki disease mirrors the negative-feedback loop of THRIL regulation
observed in in vitro experiments and suggested that THRIL may be a
biomarker for immune activation.
MAPPING
Gross (2014) mapped the THRIL gene to chromosome 12q24.31 based on an
alignment of the THRIL sequence (GenBank GENBANK NR_110375) with the
genomic sequence (GRCh37).
By 5-prime and 3-prime RACE analysis, Li et al. (2014) demonstrated that
THRIL is located on the reverse strand of the BRI3BP gene. About 450 bp
of THRIL overlaps with the 3-prime UTR of BRI3BP.
MIR3612
| dbSNP name | rs1683709(G,A) |
| cytoBand name | 12q24.32 |
| EntrezGene GeneID | 100500817 |
| snpEff Gene Name | TMEM132C |
| EntrezGene Description | microRNA 3612 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3081 |
| ExAC AF | 0.119 |
FZD10
| dbSNP name | rs147350994(C,T); rs138051070(G,T); rs4760085(C,G); rs1046890(C,T); rs1046893(G,C); rs1046895(G,A); rs56085810(A,G) |
| ccdsGene name | CCDS9267.1 |
| cytoBand name | 12q24.33 |
| EntrezGene GeneID | 11211 |
| EntrezGene Description | frizzled family receptor 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FZD10:NM_007197:exon1:c.C1609T:p.R537C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7131 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9ULW2 |
| dbNSFP Uniprot ID | FZD10_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 8.946e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps with exercise;
Muscle pain with exercise;
Muscle stiffness with exercise;
Muscle hyperirritability;
Muscle hypertrophy;
Muscle mounding;
Muscle activity is electrically silent on EMG;
Percussion-induced rapid rolling muscle contractions (PIRC);
Decreased caveolin-3 expression on muscle biopsy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Mean age of onset 22 years (range 5-54);
Genetic heterogeneity (see RMD1, 600332);
Autosomal recessive inheritance has been reported (see 601253.0010);
Allelic disorder to limb girdle muscular dystrophy type 1C (LGMD1C,
607801)
MOLECULAR BASIS:
Caused by mutations in the caveolin 3 gene (CAV3, 601253.0001)
OMIM Title
*606147 FRIZZLED, DROSOPHILA, HOMOLOG OF, 10; FZD10
OMIM Description
Drosophila cuticle hairs are arranged in a defined polarity that is
genetically controlled by 'frizzled,' a 7-transmembrane receptor with a
large extracellular N-terminal cysteine-rich domain (CRD). Members of
the FZD family are receptors for secreted WNT glycoproteins (see
602863), which are involved in developmental control. FZD proteins
transmit signals through the beta-catenin (CTNNB1; 116806) or JNK (e.g.,
JNK3; 602897) pathways. The selection of intracellular signaling cascade
may be determined by different C-terminal motifs in FZD proteins.
CLONING
By PCR with degenerate primers based on FZD transmembrane domain
sequences, followed by screening a fetal lung cDNA library, Koike et al.
(1999) obtained a cDNA encoding FZD10. The deduced 581-amino acid
protein, which is 66% identical to FZD9 (601766), contains an N-terminal
CRD; 7 transmembrane domains with 2 cys residues in the second and third
extracellular loops; 2 N-linked glycosylation sites; and a C-terminal
ser/thr-Xxx-val motif, which is a binding site for scaffold proteins
with multiple PDZ domains. Northern blot analysis revealed wide
expression of a 4.0-kb FZD10 transcript, with highest levels in placenta
and fetal kidney, followed by fetal lung and brain. Within adult brain,
expression was relatively high in cerebellum, followed by cerebral
cortex, medulla, and spinal cord.
GENE STRUCTURE
By genomic sequence analysis, Koike et al. (1999) determined that the
FZD10 gene contains a single exon.
MAPPING
By FISH, Koike et al. (1999) mapped the FZD10 gene to 12q24.33.
ZNF605
| dbSNP name | rs12319236(G,A); rs13273(G,A); rs7778(T,G); rs12772(C,T); rs61951590(G,A); rs1278603(G,T); rs2279314(A,G); rs1050225(T,C); rs1278602(G,A); rs116135559(T,C); rs1278601(C,T); rs7953128(G,T); rs2316496(G,A); rs10357(G,T); rs7956834(G,A); rs61951591(A,G); rs2625079(A,G); rs11833667(T,C) |
| cytoBand name | 12q24.33 |
| EntrezGene GeneID | 100289635 |
| EntrezGene Description | zinc finger protein 605 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1501 |
ZNF140
| dbSNP name | rs710945(A,G); rs905226(T,C); rs905225(A,T); rs1025(A,T); rs1026(C,A) |
| ccdsGene name | CCDS9282.1 |
| cytoBand name | 12q24.33 |
| EntrezGene GeneID | 7699 |
| EntrezGene Description | zinc finger protein 140 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF140:NM_003440:exon5:c.A792G:p.Q264Q, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4844 |
| ESP Afr MAF | 0.205856 |
| ESP All MAF | 0.337152 |
| ESP Eur/Amr MAF | 0.404419 |
| ExAC AF | 0.559 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly
NEUROLOGIC:
[Central nervous system];
Megalencephaly;
Ataxia;
Spasticity;
Seizures;
Delay in motor development;
Mild mental retardation;
Diffuse swelling of cerebral white matter;
Large subcortical cysts in frontal and temporal lobes;
Diffuse spongiform leukoencephalopathy;
Vacuolizing myelinopathy
MISCELLANEOUS:
Onset in infancy;
Slow course of functional deterioration compared to severity of MRI
findings
MOLECULAR BASIS:
Caused by mutation in the MLC1 gene (MLC1, 605908.0001)
OMIM Title
*604082 ZINC FINGER PROTEIN 140; ZNF140
OMIM Description
Transcriptional regulatory proteins containing tandemly repeated zinc
finger domains are thought to be involved in both normal and abnormal
cellular proliferation and differentiation. One abundant class of such
transcriptional regulators resembles the Drosophila Kruppel segmentation
gene product due to the presence of repeated Cys2-His2 (C2H2) zinc
finger domains that are connected by conserved sequences, called H/C
links. See ZNF91 (603971) for general information on zinc finger
proteins.
By screening a human insulinoma cDNA library with a degenerate
oligonucleotide corresponding to the H/C linker sequence, Tommerup et
al. (1993) isolated cDNAs potentially encoding zinc finger proteins.
Tommerup and Vissing (1995) performed sequence analysis on a number of
these cDNAs and identified several novel zinc finger protein genes,
including ZNF140. The ZNF140 cDNA predicts a 457-amino acid (GenBank
GENBANK U09368) Kruppel-type zinc finger protein containing an
N-terminal KRAB domain. Vissing et al. (1995) reported that the deduced
ZNF140 protein contains 10 zinc finger domains and both the KRAB A and B
boxes. Northern blot analysis detected ZNF140 expression in all tissues
examined.
Margolin et al. (1994) demonstrated that the KRAB domain of ZNF140
functions as a potent transcriptional repressor domain when fused to the
yeast GAL4 DNA-binding domain.
By FISH, Tommerup and Vissing (1995) mapped the ZNF140 gene to
12q24.32-q24.33.
ANKRD20A9P
| dbSNP name | rs4037527(A,G); rs183071490(G,C); rs117845771(G,A); rs138066041(G,A); rs151015894(G,T); rs111991315(T,C); rs61327291(G,A); rs58329008(G,A); rs140236254(G,A); rs11843093(A,G); rs9510149(C,T); rs11843183(A,G); rs143202364(C,T); rs17206158(A,C); rs192163850(C,A); rs9506851(G,A); rs58708617(C,T); rs55767816(A,G); rs55940363(A,C); rs189887243(G,A); rs150265788(C,T); rs7492279(C,T); rs144734301(C,T); rs141761006(C,A); rs9510181(C,G); rs4412839(A,G); rs2343933(A,G); rs145182783(A,T); rs11617865(G,A); rs147577725(C,T); rs73167583(G,A); rs58986191(C,A); rs2343929(G,C); rs11619532(T,C); rs149331655(C,A); rs17272235(T,G); rs55869047(T,G); rs11148448(A,G); rs11148449(G,T); rs9506864(C,A); rs77069454(C,G); rs9510204(G,C); rs4037795(C,G); rs73167586(A,C); rs11616642(T,G); rs7989701(A,C); rs7990368(G,T); rs192395639(G,T); rs67206049(C,T); rs117126140(C,T); rs12870770(T,C); rs9506883(G,A); rs145580380(C,A); rs1822375(T,G); rs1937748(C,A); rs2440018(G,A); rs150322097(T,C); rs1838122(C,A); rs2440019(C,G); rs9510247(G,T); rs112175968(G,A); rs2586197(A,G); rs7989824(T,A); rs71432302(T,C); rs2586199(C,T); rs17272955(G,A); rs77287079(C,T); rs2801715(C,A); rs2440022(G,A); rs2440012(C,G); rs2440014(C,T); rs66508877(G,C); rs1838123(G,A); rs1838124(A,T); rs139777905(G,A); rs1838126(C,T); rs7317749(C,T); rs9510295(G,A) |
| cytoBand name | 13q11 |
| EntrezGene GeneID | 645626 |
| EntrezGene Symbol | LOC645626 |
| snpEff Gene Name | RHOT1P3 |
| EntrezGene Description | coiled-coil domain containing 29-like |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2842 |
RNU6-52P
| dbSNP name | rs79789225(G,A) |
| cytoBand name | 13q12.11 |
| EntrezGene GeneID | 100873761 |
| snpEff Gene Name | CENPIP1 |
| EntrezGene Description | RNA, U6 small nuclear 52, pseudogene |
| EntrezGene Type of gene | snRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01194 |
GJB2
| dbSNP name | rs7988691(A,G); rs11841182(A,T); rs7623(C,T); rs9237(C,A); rs7329857(G,A); rs7337074(T,A); rs3751385(A,G); rs104894397(A,G); rs9578260(G,A); rs7318163(G,T); rs9578261(C,T); rs9579800(T,A); rs74035963(A,G); rs74035964(T,C); rs74035965(C,T); rs9552098(C,T); rs113089574(T,A); rs73431552(G,A); rs4769974(T,C); rs7994748(G,A) |
| ccdsGene name | CCDS9290.1 |
| cytoBand name | 13q12.11 |
| EntrezGene GeneID | 2706 |
| EntrezGene Description | gap junction protein, beta 2, 26kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GJB2:NM_004004:exon2:c.T229C:p.W77R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9897 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P29033 |
| dbNSFP Uniprot ID | CXB2_HUMAN |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmar telangiectasias (described in 1 family)
NEUROLOGIC:
[Central nervous system];
Cerebral cavernous malformations;
Seizures;
Recurrent headaches;
Hemorrhagic stroke
MISCELLANEOUS:
Genetic heterogeneity (see 116800 for summary);
Sporadic cases often single lesions versus multiple lesions in familial
cases
MOLECULAR BASIS:
Caused by mutation in the CCM2 gene (CCM2, 607929.0001)
OMIM Title
+603324 GAP JUNCTION PROTEIN, BETA-3; GJB3
;;GAP JUNCTION PROTEIN, 31-KD;;
CONNEXIN 31; CX31
DEAFNESS, AUTOSOMAL RECESSIVE, INCLUDED;;
DEAFNESS, AUTOSOMAL DOMINANT, WITH PERIPHERAL NEUROPATHY, INCLUDED
OMIM Description
DESCRIPTION
Gap junctions are conduits that allow the direct cell-to-cell passage of
small cytoplasmic molecules, including ions, metabolic intermediates,
and second messengers, and thereby mediate intercellular metabolic and
electrical communication. Gap junction channels consist of connexin
protein subunits, which are encoded by a multigene family that includes
GJB3 (summary by Richard et al., 1998; Wenzel et al., 1998).
CLONING
Richard et al. (1998) identified 2 expressed sequence tags (ESTs) from
the human EST database by their similarity to mouse Gjb3 and Gjb5. By
radiation hybrid mapping, they placed them in proximity with a sequenced
tag site (STS) that is linked to GJA4 (121012). Comparison of genomic
and cDNA sequence of GJB3 showed an exon-intron organization common to
that of genes encoding connexins. The complete coding sequence was
contained in a single, uninterrupted open reading frame (ORF) of 813
nucleotides preceded by a putative splice junction located 25
nucleotides upstream of the ATG initiation site and followed by the
3-prime untranslated region with a polyadenylation signal at position
1,583. The protein Cx31, of predicted molecular mass 30.8 kD, consists
of 270 amino acids and differs from its rodent homologs at 40 residues
that are confined mainly to the cytoplasmic loop. Protein structure
analysis confirmed a structural organization typical for beta-connexins,
including a conserved arrangement of 3 cysteine residues in each
extracellular loop.
By screening a human genomic library with a mouse Cx31 cDNA, Wenzel et
al. (1998) isolated the CX31 gene. Southern blot analysis of human DNA
showed that CX31 is a single-copy gene. Northern blot analysis of human
keratinocyte cell lines detected approximately 2.2- and 1.8-kb CX31
transcripts. The deduced CX31 protein contains 4 putative transmembrane
domains and 3 potential phosphorylation sites. Human CX31 is 83%
identical to the mouse and rat Cx31 proteins.
Xia et al. (1998) cloned the gene (GJB3) encoding human gap junction
protein beta-3 using homologous EST searching and nested PCR.
MAPPING
By analysis of somatic cell hybrids, Wenzel et al. (1998) mapped the
GJB3 gene to chromosome 1p36-p34. Xia et al. (1998) mapped the GJB3 gene
to 1p35-p33 by fluorescence in situ hybridization.
GENE FUNCTION
Plantard et al. (2003) showed that expression of wildtype CX30.3 (GJB4;
605425) in HeLa cells resulted only in minor amounts of protein
addressed to the plasma membrane. Mutant CX30.3 (605425.0001) was hardly
detectable and disturbed intercellular coupling. In contrast,
coexpression of both wildtype CX30.3 and CX31 proteins led to a large
increase of stabilized heteromeric gap junctions. Coexpressed wildtype
CX30.3 and CX31 coprecipitated, demonstrating a physical interaction.
Inhibitor experiments revealed that this interaction began in the
endoplasmic reticulum.
Using transfected mouse neuroblastoma and HeLa cell lines, Abrams et al.
(2006) found that CX31 channels, like other connexin channels, were
gated by voltage and closed at low pH when exposed to long-chain
alkanols. CX31 channels were relatively nonselective, allowing passage
of both negatively and positively charged dyes. In contrast to mouse
Cx31, human CX31 appeared to form functional heterotypic channels with
all 4 connexins tested: CX26 (GJB2; 121011), CX30 (GJB6; 604418), CX32
(GJB1; 304040), and CX45 (GJA7; 608655).
Liu et al. (2009) found that Cx31 and Cx26 were coexpressed in the mouse
cochlea and coassembled into gap junctions when expressed in HEK293
cells.
MOLECULAR GENETICS
- Erythrokeratodermia Variabilis et Progressiva
Erythrokeratodermia variabilis et progressiva (EKVP; 133200) is a
disorder of keratinization characterized by fixed erythrokeratotic
plaques, associated with migratory erythematous lesions ('variabilis;'
EKV) in some patients. In 4 of 12 families with EKV, Richard et al.
(1998) detected heterozygous missense mutations in the GJB3 gene leading
to substitution of a conserved glycine by charged residues (G12R,
603324.0001; G12D, 603324.0002), or change of a cysteine (C86S;
603324.0003). These mutations were predicted to interfere with normal
Cx31 structure and function, possibly due to a dominant-negative effect.
Thus, the results provided evidence that intercellular communication
mediated by Cx31 is crucial for epidermal differentiation and response
to external factors. Richard et al. (1998) stated that this report was
the first to link mutations in a gene encoding a connexin to a human
skin disorder, and noted that further functional in vitro and in vivo
studies were needed to understand how mutant Cx31 alters differentiation
of the epidermis (hyperkeratosis) and affects the cutaneous
microcapillary system (transient erythema).
Wilgoss et al. (1999) identified heterozygosity for a missense mutation
in the GJB3 gene (R42P; 603324.0008) in affected members of a family
with EKV.
Richard et al. (2000) analyzed the GJB3 gene in 2 families and 3
sporadic patients with EKV and in 2 families and 4 sporadic patients
with the progressive, symmetric form (PSEK) of erythrokeratodermia,
including a family previously described by Macfarlane et al. (1991) in
which 1 sister had features of EKV and the other of PSEK. Richard et al.
(2000) identified 3 heterozygous mutations in GJB3 in EKV patients: in a
sporadic case, they detected a mutation leading to substitution of a
conserved phenylalanine (F137L) in the third transmembrane domain, which
likely interferes with the proper assembly or gating properties of
connexins. In another EKV family, all 3 affected individuals carried 2
distinct mutations on the same GJB3 allele; however, only the R42P
mutation (603324.0008) cosegregated with the disease, whereas a 12-bp
deletion predicted to eliminate 4 amino acid residues in the variable
carboxy-terminal domain of Cx31 was also found in clinically unaffected
relatives but not in 90 unaffected controls. No mutations were detected
in the 6 probands with PSEK. Richard et al. (2000) stated that overall,
they had identified GJB3 mutations in 6 of 17 families with EKV; all of
the mutations presumably affect the cytoplasmic amino-terminal and
transmembrane domains of Cx31. In contrast, 2 mutations linked to
progressive high-tone hearing impairment (DFNA2B; 612644) were located
in the second extracellular domain, suggesting that the character and
position of Cx mutations determine their phenotypic expression in
different tissues.
In a brother and sister from an Israeli family segregating autosomal
recessive EKV, Gottfried et al. (2002) identified homozygosity for a
missense mutation in the GJB3 gene (L34P; 603342.0010). The unaffected
parents were heterozygous for the mutation, which was not found in 208
control chromosomes. Gottfried et al. (2002) suggested that the missense
mutation might not be able to exert a dominant-negative effect in
heterozygous form, thus manifesting itself clinically only in the
homozygote.
In a 4-year-old Dutch boy with the migratory form of EKVP, van Geel et
al. (2002) identified a heterozygous R32W mutation in the GJB3 gene as
well as a homozygous 4-bp deletion (154delGTCT) in the GJB4 gene.
Analysis of unaffected family members revealed that both parents and the
maternal grandfather were heterozygous for the GJB4 deletion, whereas
the mother and maternal grandfather were heterozygous for the GJB3
variant; in addition, the patient's unaffected sister carried the
identical GJB3/GJB4 genotype as the patient, thus excluding either DNA
variation as causative for the disease. Van Geel et al. (2002)
subsequently examined 84 unrelated controls and found 5 heterozygotes
for the GJB4 deletion (allele frequency, 0.03) and 3 for the GJB3
variant (0.02), suggesting that both variations represent normal
polymorphisms in the Dutch population. Van Geel et al. (2002) noted that
the GJB3 variant had previously detected in a family with palmoplantar
keratoderma and hearing defects (see GJB2, 121011) by Kelsell et al.
(2000), who suggested that it might be a polymorphism; analysis of R32W
in Spanish patients and controls by Lopez-Bigas et al. (2001) confirmed
that the variant is a common polymorphism in the Spanish population
(allele frequency, 7.5%).
Di et al. (2002) observed that immunostaining of a skin biopsy taken
from an EKV patient harboring the R42P mutation (603324.0008) revealed
sparse epidermal staining of Cx31 with aberrant perinuclear
localization. Transfection and microinjection studies in keratinocytes
and fibroblast cell lines demonstrated that R42P and 4 other
EKV-associated mutant Cx31 proteins displayed defective trafficking to
the plasma membrane. The deafness/neuropathy-only 66delD (603324.0009)
mutant protein had primarily a cytoplasmic localization, but some
protein was visualized at the plasma membrane in a few transfected
cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly
impaired dye transfer rates compared to wildtype Cx31/EGFP protein. A
high incidence of cell death was observed with the dominant skin disease
Cx31 mutations, but not with wildtype, R32W, or 66delD Cx31 proteins.
Tattersall et al. (2009) reported that in vitro expression of
connexin-31 mutants R42P (603324.0008), C86S (603324.0003), and G12D
(603324.0002), but not wildtype or 66delD (603324.0009), cause elevated
levels of cell type-specific cell death. Their observations did not
support the hypothesis that Cx-associated cell death is related to
abnormal 'leaky' calcium hemichannels. Tattersall et al. (2009) observed
upregulation of components of the unfolded protein response (UPR) in
cells expressing the EKV-associated Cx31 mutants but not wildtype or
66delD. The authors concluded that the endoplasmic reticulum (ER) stress
leading to the UPR may be the main mechanism of mutant Cx31-associated
cell death, and that ER stress may lead to abnormal keratinocyte
differentiation and hyperproliferation in EKV patient skin.
- Deafness
In affected members of 2 Chinese families with autosomal dominant
hearing loss (DFNA2B; 612644), Xia et al. (1998) identified heterozygous
mutations in the GJB3 gene (603324.0004; 603324.0005). Gjb3 expression
was identified in rat inner ear tissue by RT-PCR. It is well known that
age-related hearing impairment is more prevalent in males than in
females. It was noteworthy that, in the 2 families studied by Xia et al.
(1998), female carriers were either subclinically affected or had
undetectable hearing impairment. Noise exposure for male mutation
carriers was not significantly different from their female sibs (as
recalled by the family members).
Following the demonstration that mutations in the GJB3 gene can cause
autosomal dominant nonsyndromic sensorineural deafness, Liu et al.
(2000) screened 25 Chinese families with recessive deafness to determine
whether mutations at this locus can also cause recessive nonsyndromic
deafness. Among the 25 families, 2 contained individuals who were
compound heterozygotes for GJB3 mutations. The 3 affected individuals in
the 2 families were born to nonconsanguineous parents and had an
early-onset bilateral sensorineural hearing loss. In both families,
differing SSCP patterns were observed in affected and unaffected
individuals. Sequence analysis in both families demonstrated an in-frame
3-bp deletion (423-425delATT; 603324.0006) in one allele, which led to
the loss of an isoleucine residue at codon 141; and a 423A-G transition
in the other allele, which created an ile141-to-val missense mutation
(603324.0007). Neither of these mutations was detected in DNA from 100
unrelated control subjects. Both the deletion of isoleucine-141 and its
substitution by valine could alter the structure of the third conserved
alpha-helical transmembrane domain (M3) and impair the function of the
gap junction.
- Deafness With Peripheral Neuropathy
In affected members of a 4-generation Spanish family with mild hearing
impairment and peripheral neuropathy, Lopez-Bigas et al. (2001)
identified a heterozygous 3-bp deletion in the GJB3 gene (603324.0009).
In situ studies in mice demonstrated expression of Gjb3 in the cochlea
and auditory nerve and in the sciatic nerve, similar to the expression
pattern of Gjb1 (connexin-32; 304040).
ANIMAL MODEL
Schnichels et al. (2007) generated a conditional mouse model of EKV
using the human F137L mutation in the Cx31 gene. Although homozygosity
for the mutation was embryonic lethal, heterozygous mice were fertile
and showed no obvious abnormalities. In vitro cellular functional
expression studies showed that the heterozygous mutant channel had
approximately 30% decreased neurobiotin transfer activity, probably due
to a dominant-negative effect. Heterozygous mutant mice showed a
decreased healing time of tail incision wounds by 1 day, similar to mice
with decreased expression of Cx43 (121014) in the epidermis. These
findings suggested again that the Cx31 and Cx43 proteins functionally
interact. No erythema was detected in young mice before 2 weeks of age,
and only about 5% of the skin area of mutant mice showed
hyperproliferation of the stratum germinativum. In addition,
heterozygous Cx31 mutant mice showed normal epidermal expression
patterns and levels of other connexin proteins.
BASP1P1
| dbSNP name | rs9552762(A,C); rs73159100(G,A); rs7489390(A,G); rs117199735(C,T); rs7328194(T,C) |
| cytoBand name | 13q12.12 |
| EntrezGene GeneID | 646201 |
| EntrezGene Description | brain abundant, membrane attached signal protein 1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2925 |
PABPC3
| dbSNP name | rs3002212(C,T); rs148394195(A,G) |
| ccdsGene name | CCDS9311.1 |
| cytoBand name | 13q12.13 |
| EntrezGene GeneID | 5042 |
| EntrezGene Description | poly(A) binding protein, cytoplasmic 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PABPC3:NM_030979:exon1:c.C477T:p.N159N, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.06244 |
| ESP Afr MAF | 0.116659 |
| ESP All MAF | 0.039982 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 0.012 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604680 POLYADENYLATE-BINDING PROTEIN, CYTOPLASMIC, 3; PABPC3
;;POLYADENYLATE-BINDING PROTEIN 3; PABP3;;
POLY(A)-BINDING PROTEIN 3;;
POLYADENYLATE-BINDING PROTEIN-LIKE 3; PABPL3
OMIM Description
DESCRIPTION
Messenger RNA stability and translation initiation are extensively under
the control of poly(A)-binding proteins (PABP). See PABPC1 (604679) for
background information.
CLONING
Using an EST clone of a potentially novel PABP to probe a human testis
cDNA library, Feral et al. (2001) cloned PABPC3. The deduced 631-amino
acid protein has 4 RNA-binding domains, each of which contains 2
ribonucleoprotein consensus motifs, and shares 92.5% sequence identity
with PABPC1. By Northern blot analysis of multiple tissues, Feral et al.
(2001) found testis-specific expression of 2 weak but distinct bands of
2.1 and 2.5 kb. The 2 transcripts may reflect use of one of the 3
alternative polyadenylation signals. In situ hybridization showed that
expression is restricted to round spermatids of the testis. By Western
blot analysis, the protein has an apparent molecular mass of 70 kD.
GENE FUNCTION
Feral et al. (2001) showed that in vitro translated PABPC3 could bind
RNA homopolymers.
GENE STRUCTURE
Feral et al. (2001) determined that PABPC3 is an intronless gene.
Sequence analysis of the promoter region revealed binding sites for AP4,
AP2, and NF1, as well as an myb element and a Gf1 transcriptional
repressor site. By mutation analysis and transfection of
promoter-reporter constructs into a human pluripotent embryonic
carcinoma cell line, Feral et al. (2001) determined that PABPC3 mRNA is
transcribed from a tissue-specific CpG-rich promoter.
MAPPING
Morris and Bodger (1993) found evidence from in situ hybridization that
PABPC1 represents a multigene family with sites on chromosomes 3
(PABPL1; 173865), 12 (PABPL2; 604681), and 13 (PABPL3). Because only a
single 2.9-kb mRNA could be detected in human melanoma cells and a
variety of human leukemia cell lines, they thought that only 1 of the
genes was functional. By amplification of specific DNA fragments from a
human-rodent somatic cell hybrid panel, Feral et al. (1999) mapped the
PABPC3 gene to 13q11-q12.
AMER2
| dbSNP name | rs4329773(C,T); rs28677838(A,G); rs2298073(G,T); rs2298072(C,T); rs2298071(C,G); rs1361569(A,G); rs2298070(C,T); rs1361568(A,G); rs73479448(C,G); rs3803214(T,C); rs74961345(G,A); rs9553545(T,C); rs7335954(A,G); rs7335411(C,T); rs3622(A,G); rs61117529(G,A); rs2282405(A,T); rs140566395(A,G) |
| cytoBand name | 13q12.13 |
| EntrezGene GeneID | 219287 |
| snpEff Gene Name | FAM123A |
| EntrezGene Description | APC membrane recruitment protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1097 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, postnatal
CARDIOVASCULAR:
[Heart];
Left ventricular hypertrophy
ABDOMEN:
[Gastrointestinal];
Poor feeding
GENITOURINARY:
[Kidneys];
Renal tubulopathy
MUSCLE, SOFT TISSUE:
Hypotonia;
Decreased coenzyme Q10;
Decreased activity of complexes II+III
NEUROLOGIC:
[Central nervous system];
Global developmental delay;
Seizures, refractory;
Hypertonia, peripheral Dystonia;
Poor responsiveness;
Cerebral atrophy;
Cerebellar atrophy;
[Peripheral nervous system];
Hyperreflexia
VOICE:
Weak cry
METABOLIC FEATURES:
Lactic acidosis
LABORATORY ABNORMALITIES:
Increased serum lactate
MISCELLANEOUS:
One patient has been reported (last curated May 2012);
This patient died at age 2 years
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae COQ9 gene (COQ9,
612837.0001)
OMIM Title
*614659 FAMILY WITH SEQUENCE SIMILARITY 123, MEMBER A; FAM123A
;;APC MEMBRANE RECRUITMENT PROTEIN 2; AMER2
OMIM Description
DESCRIPTION
FAM123A is an APC (611731)-binding protein that negatively regulates WNT
(see 164820)/beta-catenin (CTNNB1; 116806) signaling (Pfister et al.,
2012).
CLONING
By searching databases for sequences similar to AMER1 (FAM123B; 300647),
followed by RT-PCR of HEK293 cell RNA, Grohmann et al. (2007) cloned
full-length FAM123A, which they called AMER2. The deduced 671-amino acid
protein has 2 predicted APC-binding domains and shares 26% identity with
AMER1. Database analysis revealed an AMER2 splice variant. Epitope- or
fluorescence-tagged AMER2 localized to the plasma membrane of
transfected human MCF7 breast cancer cells.
Pfister et al. (2012) noted that the short isoform of AMER2 contains 552
amino acids and has an in-frame gap in APC-binding domain-1 compared
with full-length AMER2. Both isoforms have 2 lysine-rich domains near
the N terminus that are conserved with AMER1. RT-PCR analysis of 24
adult and fetal tissues revealed widespread expression of AMER2, with
highest levels in adult and fetal brain and in adult spinal cord,
testis, uterus, and placenta. Variable AMER2 expression was detected in
most mammalian cell lines examined.
GENE FUNCTION
Using transfected MCF7 cells, Grohmann et al. (2007) found that AMER2,
like AMER1, recruited APC to the plasma membrane from filamentous
structures, which were likely microtubules.
By mutation analysis, Pfister et al. (2012) confirmed that the putative
APC-binding domains of AMER2 bound APC and that the 2 lysine-rich
domains were required for AMER2 membrane localization.
Coimmunoprecipitation analysis revealed that AMER2 interacted with
beta-catenin and the beta-catenin destruction complex components axin
(AXIN1; 603816) and conductin (AXIN2; 604025), and these interactions
required the APC-binding domains of AMER2. Knockdown of AMER2 in HEK293
cells resulted in upregulated expression of WNT target genes and
stimulated T-cell factor (see 189908)-beta-catenin (CTNNB1;
116806)-dependent reporter gene expression following activation by WNT3A
(606359). Conversely, overexpression of AMER2 reduced reporter activity
stimulated by WNT3A. The short isoform of AMER2 also bound APC and
suppressed T-cell factor-beta-catenin-dependent reporter activity.
MAPPING
By genomic sequence analysis, Grohmann et al. (2007) mapped the FAM123A
gene to chromosome 13. Hartz (2012) mapped the FAM123A gene to
chromosome 13q12.13 based on an alignment of the FAM123A sequence
(GenBank GENBANK BC032653) with the genomic sequence (GRCh37).
ANIMAL MODEL
Pfister et al. (2012) found that Xenopus Amer2 was expressed in early
gastrula stages and that it was prominently expressed in neural tissues.
Morpholino-mediated knockdown of Amer2 in Xenopus oocytes resulted in
massive disruption in neuroectoderm patterning, but not neural
induction. Defects were rescued by expression of a dominant-negative
mutant of Lef1 (153245) that interfered with beta-catenin-dependent
transcription. Pfister et al. (2012) concluded that AMER2 is a negative
regulator of WNT signaling.
GPR12
| dbSNP name | rs73500833(C,T); rs9507782(C,T); rs2441066(T,A); rs2479505(T,G); rs41440549(C,T); rs180753049(G,A); rs191567081(T,C); rs9512372(A,G); rs1927522(A,G) |
| cytoBand name | 13q12.13 |
| EntrezGene GeneID | 2835 |
| EntrezGene Description | G protein-coupled receptor 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01791 |
OMIM Clinical Significance
GU:
Nephrolithiasis uncommon
GI:
Peptic ulcer uncommon;
Pancreatitis
Skin:
Lipomas
Misc:
Neonatal severe primary hyperparathyroidism in homozygotes
Radiology:
Chondrocalcinosis
Lab:
Hypocalciuria;
Hypercalcemia;
Hypermagnesemia;
Parathormone-independent renal tubular calcium reabsorption defect;
Ratio of renal calcium clearance to creatinine clearance usually below
0.01
Inheritance:
Autosomal dominant form not linked to either 19p13.3 or 3q21-q24
OMIM Title
*600752 G PROTEIN-COUPLED RECEPTOR 12; GPR12
OMIM Description
CLONING
A variety of extracellular signals are transmitted into cells through
integral membrane receptors coupled to heterotrimeric G proteins. Such G
protein-coupled receptors are critical for the normal functions of many
cell types: neurons, endocrine cells, cardiac and smooth muscle cells,
and sensory cells for detection of light, taste, and smell. Both
activating and loss-of-function mutations in G protein-coupled receptors
have been found as the cause of human diseases. Song et al. (1995)
isolated cosmids containing human genes for 3 orphan G protein-coupled
receptors, GPR12, GPR6 (600553), and GPR3 (600241), using their rat
homologs as probes. Studies of the mouse and rat cDNAs showed the
receptors to be expressed primarily in brain, but failed to identify
their ligands. The authors found that the 3 receptor proteins of 334,
363, and 330 amino acids, respectively, are encoded by a single exon in
each gene. Excluding the divergent sequences preceding the first
transmembrane domain, they have approximately 60% amino acid identity
with each other.
MAPPING
By fluorescence in situ hybridization, Song et al. (1995) localized the
GPR12 gene to human chromosome 13q12.
LINC00412
| dbSNP name | rs189570612(C,A) |
| cytoBand name | 13q12.2 |
| snpEff Gene Name | RP11-428O18.4 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
ATP5EP2
| dbSNP name | rs2504220(A,C); rs7333200(C,T) |
| cytoBand name | 13q12.2 |
| EntrezGene GeneID | 432369 |
| EntrezGene Description | ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2296 |
| ExAC AF | 0.830,1.631e-05 |
PAN3-AS1
| dbSNP name | rs61260403(G,C); rs78042704(A,G) |
| cytoBand name | 13q12.2 |
| EntrezGene GeneID | 100288730 |
| snpEff Gene Name | PAN3 |
| EntrezGene Description | PAN3 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0551 |
LINC00545
| dbSNP name | rs3747893(A,G) |
| cytoBand name | 13q12.3 |
| EntrezGene GeneID | 100507064 |
| EntrezGene Symbol | TEX26-AS1 |
| snpEff Gene Name | RP11-252M21.1 |
| EntrezGene Description | TEX26 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1699 |
N4BP2L2-IT2
| dbSNP name | rs207629(T,C); rs207630(T,C); rs207631(C,T); rs146864732(A,C); rs76800253(C,T); rs10492398(T,C); rs7331535(G,A); rs9315168(G,C); rs207632(G,C); rs79708624(A,G) |
| ccdsGene name | CCDS45024.1 |
| cytoBand name | 13q13.1 |
| EntrezGene GeneID | 116828 |
| snpEff Gene Name | N4BP2L2 |
| EntrezGene Description | N4BPL2 intronic transcript 2 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3398 |
CSNK1A1L
| dbSNP name | rs945632(G,A); rs1336754(T,G); rs1856028(C,T); rs17773251(C,G); rs111291624(T,C); rs9576175(G,T); rs9576176(G,C); rs9576177(C,T); rs9576178(G,A) |
| cytoBand name | 13q13.3 |
| EntrezGene GeneID | 122011 |
| EntrezGene Description | casein kinase 1, alpha 1-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4674 |
POSTN
| dbSNP name | rs6750(C,G); rs4390468(C,T); rs116088005(A,G); rs9315503(G,A); rs9547955(T,C); rs114134217(C,A); rs114646132(A,T); rs75972397(A,G); rs9547956(C,T); rs9547957(G,A); rs9547959(G,A); rs73182620(A,G); rs75180268(A,T); rs4943522(G,A); rs28407779(T,A); rs78662411(C,T); rs75157793(A,G); rs9603226(G,A); rs4628831(T,C); rs115714760(C,A); rs41306668(C,T); rs9547960(T,C); rs9547961(C,T); rs73452550(C,G); rs9532085(C,T); rs73452553(A,G); rs188437356(G,A); rs73182622(C,T); rs8000073(C,T); rs73182624(C,T); rs73452556(G,A); rs10400597(T,C); rs4512969(A,G); rs8001709(T,A); rs7997479(C,T); rs142973906(G,A); rs7322626(T,G); rs7322993(T,C); rs7323378(T,C); rs73182687(G,A); rs7986347(G,A); rs9315504(T,A); rs9576307(G,C); rs74724324(G,T); rs1041019(T,G); rs112908451(G,A); rs2274082(T,G); rs73182690(T,A); rs17056105(A,T); rs1924285(T,A); rs3794374(C,T); rs6563562(T,C); rs17256386(A,G); rs7320832(G,C); rs9576308(A,G); rs7336560(A,C); rs9576309(G,A); rs4142596(C,T); rs9576310(A,G); rs9576311(T,C); rs1924306(G,A); rs375160545(A,C); rs1006416(G,A); rs9576312(G,A); rs9566234(C,T); rs9603229(T,G); rs7338244(G,C); rs7321492(G,T); rs3923854(C,G); rs4365181(A,C); rs1977278(A,G); rs9576313(G,C); rs2025405(C,T); rs2985158(T,C); rs9576314(G,A); rs17197663(G,A) |
| ccdsGene name | CCDS9364.1 |
| cytoBand name | 13q13.3 |
| EntrezGene GeneID | 10631 |
| EntrezGene Description | periostin, osteoblast specific factor |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POSTN:NM_001286665:exon20:c.T2315C:p.F772S,POSTN:NM_001135934:exon19:c.T2225C:p.F742S,POSTN:NM_006475:exon21:c.T2396C:p.F799S,POSTN:NM_001286666:exon18:c.T2135C:p.F712S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5255 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F5H628 |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0105540897098 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.001816 |
| ESP All MAF | 0.007843 |
| ESP Eur/Amr MAF | 0.01093 |
| ExAC AF | 0.006977 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Nystagmus;
Slow saccades;
Dysmetric saccades;
Impaired smooth pursuit
NEUROLOGIC:
[Central nervous system];
Progressive cerebellar ataxia;
Dysarthria;
Incoordination of trunk and limbs;
Spasticity;
Tremor;
Pyramidal signs;
Hypperreflexia;
Dysphagia;
Cerebellar atrophy;
[Peripheral nervous system];
Sensory neuropathy has been reported
MISCELLANEOUS:
Onset between 18 and 65 years;
SCA8 is caused by bidirectional transcription on chromosome 13q21
involving complementary repeat expansion in ATXN8 (613289) and
ATXN8-opposite strand (603680);
Normal alleles contain 15 to 50 repeats;
Pathogenic alleles contain 71 to 1,300 repeats
MOLECULAR BASIS:
Caused by a trinucleotide repeat expansion (CTG)n in the ataxin 8
opposite strand gene (ATXN8OS, 603680.0001);
Caused by a trinucleotide repeat expansion (CAG)n in the ataxin 8
gene (ATXN8, 613289.0001)
OMIM Title
*608777 PERIOSTIN; POSTN
;;PN;;
OSTEOBLAST-SPECIFIC FACTOR 2; OSF2
OMIM Description
CLONING
Takeshita et al. (1993) cloned mouse Postn, which they designated Osf2.
By screening human placenta and osteosarcoma cDNA libraries with mouse
Postn as probe, they cloned 2 variants of human POSTN. One variant
encodes a deduced 779-amino acid protein with an apparent molecular mass
of 87.0 kD, and the other encodes a deduced 836-amino acid protein with
an apparent molecular mass of 93.3 kD. POSTN contains a typical signal
sequence, followed by a cysteine-rich domain, a 4-fold repeat structure
of about 150 amino acids, and a C-terminal domain. Mouse and human POSTN
share 89.2% amino acid identity overall and 90.1% identity in their
mature forms. Northern blot analysis of a mouse osteoblastic cell line
detected a 3.4-kb Postn transcript. RNA dot blot analysis detected
expression of Postn in primary mouse osteoblasts and in lung, but not in
any other tissues examined.
Gillan et al. (2002) identified a periostin (PN) EST clone encoding a
deduced 782-amino acid protein. RNA dot blot analysis detected PN
expression in a wide range of normal adult tissues, including aorta,
stomach, lower gastrointestinal tract, placenta, uterus, and breast. PN
was expressed at variable levels in all fetal tissues examined. Western
blot analysis detected strong periostin staining in fetal calf serum,
but not in newborn calf serum. Gillan et al. (2002) found that PN was
secreted by cultures derived from epithelial ovarian cancer, but not
from normal ovarian epithelial cells. They identified multiple protein
bands of about 90 kD, as well as a band of about 170 kD, which may
represent a covalently linked multimer. PN was present in 20 of 21
ascites from ovarian cancer patients.
GENE FUNCTION
Gillan et al. (2002) found that purified recombinant PN supported
adhesion of ovarian epithelial cells. Adhesion was inhibited by
antibodies against alpha-V (ITGAV; 193210)/beta-3 (ITGB3; 173470) or
alpha-V/beta-5 (ITGB5; 147561) integrins, but not by antibodies against
beta-1 integrin (ITGB1; 135630). Furthermore, alpha-V/beta-3 integrin,
but not beta-1 integrin, colocalized to the focal adhesion plaques
formed on PN. Cells plated on PN formed fewer stress fibers and were
more motile compared with those plated on fibronectin (135600). Gillan
et al. (2002) concluded that PN functions as a ligand for alpha-V/beta-3
and alpha-V/beta-5 integrins to support adhesion and migration of
ovarian epithelial cells.
Shao et al. (2004) found that periostin was overexpressed by the
majority of human primary breast cancers examined. Transfected tumor
cell lines overexpressing periostin showed accelerated growth and
angiogenesis as xenografts in immunocompromised animals.
Periostin-mediated angiogenesis was derived in part from upregulation of
vascular endothelial growth factor receptor (KDR; 191306) by endothelial
cells through an alpha-V/beta-3 integrin-focal adhesion kinase
(600758)-mediated signaling pathway.
Using gene expression microarrays, Woodruff et al. (2007) found that
CLCA1 (603906), POSTN, and SERPINB2 (PAI2; 173390) were upregulated in
airway epithelial cells of individuals with asthma (see 600807), but not
smokers. Corticosteroid treatment downregulated expression of these 3
genes and upregulated expression of FKBP51 (602623). High baseline
expression of CLCA1, POSTN, and SERPINB2 was associated with a good
clinical response to corticosteroids, whereas high expression of FKBP51
was associated with a poor response. Treatment of airway epithelial
cells with IL13 resulted in increased expression of CLCA1, POSTN, and
SERPINB2, an effect that could be suppressed by corticosteroids.
Kuhn et al. (2007) showed that extracellular periostin induced reentry
of differentiated mammalian cardiomyocytes into the cell cycle.
Periostin stimulated mononucleated cardiomyocytes to go through the full
mitotic cell cycle. Periostin activated alpha-V, beta-1, beta-3, and
beta-5 integrins located in the cardiomyocyte cell membrane. Activation
of phosphatidylinositol-3-OH kinase (see 171833) was required for
periostin-induced reentry of cardiomyocytes into the cell cycle and was
sufficient for cell cycle reentry in the absence of periostin. After
myocardial infarction, periostin-induced cardiomyocyte cell cycle
reentry and mitosis were associated with improved ventricular remodeling
and myocardial function, reduced fibrosis and infarct size, and increase
angiogenesis.
Using immunohistochemical analysis, Snider et al. (2008) showed that
periostin was expressed in pediatric aortic valves in a trilaminar
pattern, with increased expression in fibrosa and spongiosa relative to
ventricularis. Stenotic pediatric bicuspid valves that had lost normal
trilaminar stratification of the extracellular matrix showed greatly
reduced periostin expression. In mice, periostin was expressed
throughout cardiac development in the fibrous cardiac skeleton and
endocardial cushions, but it was absent from cardiomyocytes. Periostin
was detected in all 4 adult mouse valves examined.
Malanchi et al. (2012) demonstrated that a small population of cancer
stem cells is critical for metastatic colonization, i.e., the initial
expansion of cancer cells at the secondary site, and that stromal niche
signals are crucial to this expansion process. The authors found that
periostin, a component of the extracellular matrix, is expressed by
fibroblasts in the normal tissue and in the stroma of the primary tumor.
Infiltrating tumor cells need to induce stromal POSTN expression in the
secondary target organ (in this case the lung) to initiate colonization.
POSTN is required to allow cancer stem cell maintenance, and blocking
its function prevents metastasis. POSTN recruits Wnt ligands and thereby
increases Wnt signaling in cancer stem cells. Malanchi et al. (2012)
suggested that the education of stromal cells by infiltrating tumor
cells is an important step in metastatic colonization and that
preventing de novo niche formation may be a novel strategy for the
treatment of metastatic disease.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the POSTN
gene to chromosome 13 (TMAP STS-H12747).
ANIMAL MODEL
Snider et al. (2008) found that periostin-null mice exhibited variable
cardiac valve disease, with neonatal lethality in 14%. Periostin-null
animals that survived showed truncated leaflets with ectopic
cardiomyocytes and smooth muscle cells, misexpression of the cartilage
proteoglycan aggrecan (ACAN; 155760), disorganized matrix
stratification, and reduced Tgf-beta (TGFB1; 190180) signaling. Those
that died also showed leaflet discontinuities, delamination defects, and
deposition of acellular extracellular matrix. Periostin-deficient
fibroblasts were unable to support normal valve remodeling or establish
a mature cardiac skeleton. Snider et al. (2008) concluded that periostin
is required for TGF-beta-dependent development of noncardiomyocyte
lineages in the heart.
MIR320D1
| dbSNP name | rs181368210(G,A) |
| cytoBand name | 13q14.11 |
| EntrezGene GeneID | 100313896 |
| snpEff Gene Name | MRPS31 |
| EntrezGene Description | microRNA 320d-1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.001594 |
| ESP All MAF | 0.00068 |
| ESP Eur/Amr MAF | 0.000279 |
| ExAC AF | 0.0002399 |
KBTBD6
| dbSNP name | rs184644685(C,A); rs186748139(G,A); rs114564008(T,C); rs1952591(C,A); rs371763483(C,T); rs584594(A,G); rs9566703(A,G) |
| cytoBand name | 13q14.11 |
| EntrezGene GeneID | 89890 |
| EntrezGene Description | kelch repeat and BTB (POZ) domain containing 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
TSC22D1-AS1
| dbSNP name | rs881756(C,G); rs11617024(A,G) |
| cytoBand name | 13q14.11 |
| EntrezGene GeneID | 641467 |
| snpEff Gene Name | TSC22D1 |
| EntrezGene Description | TSC22D1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02112 |
LINC00563
| dbSNP name | rs9567657(T,C); rs729074(G,A) |
| cytoBand name | 13q14.13 |
| EntrezGene GeneID | 100861554 |
| EntrezGene Description | long intergenic non-protein coding RNA 563 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05831 |
LPAR6
| dbSNP name | rs4151550(C,G); rs2227311(A,G); rs116813803(G,T) |
| ccdsGene name | CCDS31973.1 |
| cytoBand name | 13q14.2 |
| EntrezGene GeneID | 10161 |
| EntrezGene Description | lysophosphatidic acid receptor 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0101 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Silver-gray eyelashes;
Silver-gray eyebrows
SKIN, NAILS, HAIR:
[Hair];
Silver-gray hair;
Silver-gray eyelashes;
Silver-gray eyebrows;
Large clumps of pigment irregularly distributed along hair shaft (light
microscopy)
NEUROLOGIC:
No neurologic abnormalities
IMMUNOLOGY:
No immunologic abnormalities
MISCELLANEOUS:
Genetic heterogeneity;
See also Griscelli syndrome, type 1 (214450) for a similar disorder
with characteristic neurologic disease and Griscelli syndrome, type
2 (607624) for a similar disorder with characteristic immunodeficiency/hemophagocytic
syndrome.
MOLECULAR BASIS:
Caused by mutation in the myosin 5a gene (MYO5A, 160777.0004);
Caused by mutation in the melanophilin gene (MLPH, 606526.0001)
OMIM Title
*609239 LYSOPHOSPHATIDIC ACID RECEPTOR 6; LPAR6
;;PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 5; P2RY5;;
P2RY5
OMIM Description
DESCRIPTION
LPAR (P2RY5) belongs to a family of purine and pyrimidine nucleotide
receptors that are coupled to G proteins. Activation results in
mobilization of inositol 1,4,5-trisphosphate-sensitive Ca(2+) stores,
activation of inward plasma membrane currents, and stimulation of
diacylglyceride-dependent protein kinases (Adrian et al., 2000).
CLONING
By PCR using degenerative oligonucleotides to identify novel G
protein-coupled receptors, Herzog et al. (1996) cloned P2RY5. The
deduced 344-amino acid protein shares 82% identity with the chicken
T-cell-specific receptor, including a conserved N-glycosylation site.
GENE FUNCTION
Adrian et al. (2000) analyzed the expression of several purinergic
receptors during differentiation in a promyelocytic leukemia cell line.
Granulocytic differentiation was induced by dimethylsulfoxide, and a
monocytic/macrophage phenotype was induced by phorbol esters. No P2RY5
expression could be detected in undifferentiated cells, and only low
expression was detected in granulocytes. Differentiation to monocytic
cells resulted in marked P2RY5 upregulation. Normal blood leukocytes
showed only low P2RY5 expression.
Pasternack et al. (2008) identified oleoyl-L-alpha-lysophosphatidic acid
(LPA), a bioactive lipid, as a ligand for P2RY5. Homology and studies of
signaling transduction pathways suggested that P2RY5 is a member of a
subgroup of LPA receptors, which also includes LPAR4 (300086) and LPAR5
(606926).
MAPPING
By genomic sequence analysis, Herzog et al. (1996) mapped the P2RY5 gene
to chromosome 13q14.12-q14.2, where it lies in the opposite orientation
within intron 17 of the RB1 gene (614041).
MOLECULAR GENETICS
In affected members of a consanguineous Saudi Arabian family with
hypotrichosis simplex (HYPT8; 278150), Pasternack et al. (2008) detected
homozygosity for a nonsense mutation in the P2RY5 gene (Q155X;
609239.0001). In 2 additional families they identified a second
homozygous truncating mutation in P2RY5 (609239.0002).
Shimomura et al. (2008) identified several Pakistani families that
included consanguineous marriages and multiple individuals with
recessively inherited woolly hair (ARWH1; see 278150) present at birth.
In all cases, they found homozygosity for pathogenic mutations in P2RY5
(see, e.g., 609239.0003; 609239.0004; 609239.0006). P2RY5 is expressed
in both the Henle and the Huxley layers of the inner root sheath of the
hair follicle.
In affected members of 14 Pakistani families segregating autosomal
recessive localized hypotrichosis (HYPT8; 278150), Azeem et al. (2008)
identified 7 different homozygous mutations in the P2RY5 gene (see,
e.g., 609239.0003; 609239.0005; 609239.0006). Three of the mutations had
been reported by Shimomura et al. (2008) in individuals with woolly
hair. However, none of the individuals reported by Azeem et al. (2008)
had the woolly hair phenotype.
In a consanguineous Turkish family with autosomal recessive
hypotrichosis, Nahum et al. (2010) identified homozygosity for a
pro196-to-leu substitution in the LPAR6 gene (609239.0007). Nahum et al.
(2010) noted that mutations in LIPH (607365) result in impaired
signaling through the P2Y5 receptor (LPAR6) and in a phenotype (LAH2;
604379) indistinguishable from that displayed by individuals carrying
mutations in LPAR6.
In 8 Pakistani families with the hypotrichosis/woolly hair phenotype
mapping to LIPH, Khan et al. (2011) identified 4 recurrent homozygous
mutations (see, e.g., 609239.0003-609239.0005); 4 of the families had
features of hypotrichosis, 2 had features of woolly hair with or without
hypotrichosis, and 1 had a mixed phenotype.
CYSLTR2
| dbSNP name | rs56867010(C,T); rs77817181(C,G); rs34494076(C,T); rs912278(A,G) |
| ccdsGene name | CCDS9412.1 |
| cytoBand name | 13q14.2 |
| EntrezGene GeneID | 57105 |
| EntrezGene Description | cysteinyl leukotriene receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CYSLTR2:NM_020377:exon1:c.C900T:p.F300F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.02112 |
| ESP Afr MAF | 0.061053 |
| ESP All MAF | 0.022221 |
| ESP Eur/Amr MAF | 0.002326 |
| ExAC AF | 0.007809 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Macrocephaly;
Brachycephaly;
[Face];
Prominent forehead;
Flat supraorbital ridge;
Wide philtrum;
Malar hypoplasia;
[Ears];
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Anophthalmia;
Sparse eyebrows;
Sparse eyelashes;
Hypertelorism;
Epicanthal folds;
[Nose];
Anteverted nostrils;
Midline nasal appendage;
Elevated nasal bridge;
Short nose;
Proboscis-like nares;
[Mouth];
Downturned mouth;
Cleft palate;
Carp-like mouth;
High-arched palate;
Narrow palate;
[Teeth];
Single maxillary central incisor
GENITOURINARY:
[External genitalia, male];
Hypoplastic genitalia
SKELETAL:
[Skull];
Craniosynostosis;
Asymmetric cranial vault;
[Hands];
Postaxial polydactyly
SKIN, NAILS, HAIR:
[Hair];
Sparse eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Mental retardation;
Encephalocele;
Hypoplastic cerebellar vermis;
Hypoplastic corpus callosum
OMIM Title
*605666 CYSTEINYL LEUKOTRIENE RECEPTOR 2; CYSLTR2
;;CYSLT2
OMIM Description
DESCRIPTION
Cysteinyl leukotrienes (e.g., LTC4; see 246530) mediate anaphylactic
reactions through the cell surface receptors CYSLT1 (300201) and CYSLT2.
CYSLT1 is sensitive to montelukast, zafirlukast, and pranlukast,
antibronchoconstrictive and antiinflammatory drugs used to treat asthma,
whereas CYSLT2 is resistant (summary by Takasaki et al., 2000).
CLONING
By searching a private database for G protein-coupled receptors,
Takasaki et al. (2000) identified a cDNA encoding CYSLT2, which they
initially designated PSEC0146. The deduced 346-amino acid protein is 31%
identical to CYSLT1. Northern blot analysis revealed expression in
heart, placenta, spleen, and peripheral blood leukocytes; no expression
was detected in lung or trachea. RT-PCR analysis, however, detected
expression in lung but not trachea.
Heise et al. (2000) also cloned the CYSLT2 gene, which encodes a
7-transmembrane protein. Northern blot analysis revealed expression in
heart, lymph node, spleen, peripheral blood leukocytes, and several
central nervous system regions. In situ hybridization analysis detected
expression in interstitial lung macrophages, a subpopulation of blood
monocytes, eosinophils, adrenal gland medullary pheochromocytes, and
cardiac Purkinje fiber cells, with much weaker expression in smooth
muscle cells.
GENE FUNCTION
Functional analysis by Takasaki et al. (2000) showed that cysteinyl
leukotrienes (LTC4, LTD4, and LTE4), but not other eicosanoids, induced
significant calcium mobilization in cells expressing CYSLT2 in the
presence or absence of CYSLT1 inhibitors.
MAPPING
By radiation hybrid analysis, Takasaki et al. (2000) and Heise et al.
(2000) mapped the CYSLT2 gene to chromosome 13q14, near a marker for
atopic asthma.
ANIMAL MODEL
By generating Cysltr2-deficient but developmentally normal and fertile
mice Beller et al. (2004) found that Cysltr2 -/- mice developed normally
and were fertile. Compared with wildtype mice, Cysltr2 -/- mice had
significantly reduced vascular permeability associated with
IgE-dependent passive cutaneous anaphylaxis, whereas plasma protein
extravasation in response to zymosan A-induced peritoneal inflammation
was unchanged. Intratracheal injection resulted in reduced alveolar
septal thickening in Cysltr2 -/- mice compared with wildtype mice, but
cysteinyl leukotrienes were not altered. Beller et al. (2004) concluded
that in response to a particular pathobiologic event, CYSLTR2 can
mediate an increase in vascular permeability in some tissues or promote
chronic pulmonary inflammation with fibrosis.
CTAGE10P
| dbSNP name | rs12876820(G,A); rs61747168(A,C); rs61747167(G,A); rs75540113(A,G); rs7331776(G,A); rs35551290(C,T); rs7316930(T,C); rs7338963(A,G); rs12585937(A,C) |
| cytoBand name | 13q14.2 |
| EntrezGene GeneID | 220429 |
| EntrezGene Description | CTAGE family, member 10, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09688 |
UTP14C
| dbSNP name | rs2897964(A,G); rs79730412(T,C); rs1055062(T,C); rs183356568(A,G); rs60572872(C,T) |
| cytoBand name | 13q14.3 |
| EntrezGene GeneID | 9724 |
| snpEff Gene Name | ALG11 |
| EntrezGene Description | UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4412 |
MIR5007
| dbSNP name | rs1572687(T,C) |
| cytoBand name | 13q21.1 |
| EntrezGene GeneID | 100846996 |
| EntrezGene Description | microRNA 5007 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3205 |
| ExAC AF | 0.384 |
CTAGE11P
| dbSNP name | rs564230(G,A); rs565006(A,G); rs555846(G,A); rs147116283(C,T); rs484946(A,G); rs475484(G,A); rs477274(C,A); rs479973(A,C); rs480099(G,A); rs513306(C,T); rs61960513(C,G); rs2876702(T,C); rs61960514(C,A); rs1888257(C,T); rs1888258(A,G) |
| cytoBand name | 13q22.2 |
| EntrezGene GeneID | 647288 |
| EntrezGene Description | CTAGE family, member 11, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4178 |
KCTD12
| dbSNP name | rs6835(A,G); rs9320(T,C); rs75561215(T,C); rs1053433(T,G); rs7705(C,T); rs1053418(T,C); rs6732(T,A); rs41287022(G,T); rs7324963(G,A); rs1053397(C,T); rs41287024(C,G); rs145290769(T,C); rs582752(C,T); rs9318457(C,A) |
| cytoBand name | 13q22.3 |
| EntrezGene GeneID | 115207 |
| EntrezGene Description | potassium channel tetramerization domain containing 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1625 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Eyes];
Optic neuropathy;
Optic atrophy;
Visual impairment
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy (in some patients);
Concentric hypertrophic cardiomyopathy (in some patients);
Patent ductus arteriosus (in some patients);
Patent foramen ovale (in some patients)
RESPIRATORY:
Respiratory failure
ABDOMEN:
[Liver];
Hepatomegaly (in some patients);
[Gastrointestinal];
Poor feeding
MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle weakness;
Rhabdomyolysis;
Ragged red fibers seen on muscle biopsy;
COX-deficient fibers
NEUROLOGIC:
[Central nervous system];
Global developmental delay;
Encephalopathy;
Seizures;
Dystonia;
Cognitive impairment;
Tremor;
Ataxia;
Hypotonia, neonatal;
Reduced brain gyri;
Enlarged ventricles;
Abnormal signals in the thalami seen on MRI;
[Peripheral nervous system];
Axonal sensorimotor neuropathy (in some patients)
METABOLIC FEATURES:
Lactic acidosis
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased serum creatine kinase;
Increased serum ketones;
Increased serum ammonia;
Decreased activity of mitochondrial respiratory complexes I, III,
and IV
MISCELLANEOUS:
Highly variable phenotype
MOLECULAR BASIS:
Caused by mutation in the mitochondrial Ts translation elongation
factor gene (TSFM, 604723.0001)
OMIM Title
*610521 POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 12; KCTD12
;;PREDOMINANTLY FETAL-EXPRESSED T1 DOMAIN; PFET1;;
PFETIN;;
KIAA1778;;
CHROMOSOME 13 OPEN READING FRAME 2; C13ORF2
OMIM Description
CLONING
By subtractive hybridization and differential screening of a fetal
cochlea cDNA library, followed by screening fetal brain and adult
hippocampus cDNA libraries, Resendes et al. (2004) isolated a
full-length cDNA encoding KCTD12, which they called pfetin, or PFET1.
The predicted 325-amino acid human protein is 97% identical to mouse
Pfet1. It contains an N-terminal voltage-gated potassium channel
tetramerization (T1) domain and 4 weakly hydrophobic regions, but no
transmembrane domain. The ORFs of mouse and human PFET1 are 70% GC rich.
Northern blot analysis of human fetal tissues detected a 6.0-kb
transcript expressed strongly in cochlea and brain, moderately in
skeletal muscle, lung, ovary, and eye, and at lower levels in thymus,
tongue, heart, and adrenal gland. In contrast, expression of the 6.0-kb
transcript was barely detectable in adult human tissues, including
spinal cord, cerebrum, cerebellum, skeletal muscle, lung, lymph node,
liver, heart, and kidney. Immunoblot and immunohistochemical analyses
revealed a 35- to 47-kD Pfet1 protein that was expressed in various
cochlear cell classes, notably type I fibrocytes of the spiral ligament,
as well as in type I vestibular hair cells.
GENE FUNCTION
Schwenk et al. (2010) showed by functional proteomics in rat and mouse
that gamma-aminobutyric acid-B (GABA-B) receptors in the brain are high
molecular mass complexes of GABAB1 (137190), GABAB2 (607340), and
members of a subfamily of the KCTD proteins. KCTD proteins 8, 12, 12B,
and 16 (613423) show distinct expression profiles in the brain and
associate tightly with the carboxy terminus of GABAB2 as tetramers. This
coassembly changes the properties of the GABA-B(1,2) core receptor: the
KCTD proteins increase agonist potency and markedly alter the G protein
signaling of the receptors by accelerating onset and promoting
desensitization in a KCTD subtype-specific manner. Schwenk et al. (2010)
concluded that their results established the KCTD proteins as auxillary
subunits of GABA-B receptors that determine the pharmacology and
kinetics of the receptor response.
GENE STRUCTURE
Resendes et al. (2004) determined that the KCTD12 gene is intronless.
MAPPING
By FISH and genomic sequence analysis, Resendes et al. (2004) mapped the
KCTD12 gene to chromosome 13q21. They mapped the mouse gene to
chromosome 14.
BTF3P11
| dbSNP name | rs583970(G,A) |
| cytoBand name | 13q22.3 |
| EntrezGene GeneID | 690 |
| EntrezGene Description | basic transcription factor 3 pseudogene 11 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.124 |
SLITRK1
| dbSNP name | rs1046202(A,T); rs3737193(A,G) |
| cytoBand name | 13q31.1 |
| EntrezGene GeneID | 114798 |
| EntrezGene Description | SLIT and NTRK-like family, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Normal kidneys
SKELETAL:
[Limbs];
Osteolysis of patellae (bone loss of posterior patella);
[Hands];
Osteolysis of scaphoids (bone loss and fragmentation of scaphoid);
Short fourth metacarpals;
[Feet];
Osteolysis of tali (bone loss and fragmentation of posterior talus)
MISCELLANEOUS:
Onset 13-15 years
OMIM Title
*609678 SLIT- AND NTRK-LIKE FAMILY, MEMBER 1; SLITRK1
;;KIAA1910
OMIM Description
DESCRIPTION
Members of the SLITRK family, such as SLITRK1, are integral membrane
proteins with 2 N-terminal leucine-rich repeat (LRR) domains similar to
those of SLIT proteins (see SLIT1; 603742). Most SLITRKs, but not
SLITRK1, also have C-terminal regions that share homology with
neurotrophin receptors (see NTRK1; 191315). SLITRKs are expressed
predominantly in neural tissues and have neurite-modulating activity
(Aruga et al., 2003).
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2001) cloned SLITRK1, which they designated
KIAA1910. The deduced protein contains 760 amino acids. RT-PCR ELISA
detected high expression in adult and fetal brain and in all specific
adult brain regions examined. Expression was intermediate in pancreas
and lung, low in kidney, ovary, heart, and fetal liver, and nearly
undetectable in skeletal muscle, spleen, testis, and adult liver.
Aruga and Mikoshiba (2003) cloned several mouse Slitrk cDNAs, including
Slitrk1. The deduced Slitrk1 protein contains an N-terminal signal
peptide, followed by 2 LRR domains, a C-terminal transmembrane domain,
and a short cytoplasmic tail. Each LRR domain is flanked by
cysteine-rich regions. Northern blot analysis of several mouse tissues
detected high Slitrk1 expression only in brain. In situ hybridization of
developing mouse brain revealed broad Slitrk1 expression, with
significant expression in the subventricular zone, subplate, cortical
plate, thalamus, hypothalamus, ventromedial hypothalamus, the medial
part of periaqueductal gray matter, the pyramidal layer of hippocampus,
and spinal cord. In a rat pheochromocytoma cell line, Slitrk1 localized
in the cell body proximal to the projecting neurites and near the
trans-Golgi network.
By database analysis, Aruga et al. (2003) identified human SLITRK1. The
deduced 696-amino acid protein has a calculated molecular mass of 77.7
kD. It shares more than 95% homology with mouse Slitrk1 and has the same
protein structure. Northern blot analysis detected SLITRK1 transcripts
of 4.3 and 5.6 kb mainly in adult and fetal neural tissues. Highest
expression was in adult cerebral cortex, particularly within the frontal
lobe.
GENE FUNCTION
By overexpression in murine pheochromocytoma and neuroblastoma cell
lines, Aruga and Mikoshiba (2003) found that mouse Slitrk1 induced
neurite outgrowth. Slitrk1 overexpression increased the number of
unipolar-type cells, suggesting that Slitrk1-induced neurites are
qualitatively different from those induced by NGF (see 162030). Neurite
induction by Slitrk1 was additive to induction by NGF.
Using extensive immunohistochemical analyses, Stillman et al. (2009)
found that SLITRK1 is developmentally regulated in the
corticostriatal-thalamocortical circuits in mouse, monkey, and human
brain, starting in embryogenesis. SLITRK1 was transiently expressed in
the striosomal compartment of the striatum, mainly in the direct output
pathway. Developing neocortical expression was prominent in apical
dendrites, whereas in adult brain, expression was localized to cell
bodies of cortical pyramidal neurons and cortical projection neurons.
Striatal staining was not present in adults, except in a few cholinergic
interneurons.
GENE STRUCTURE
Aruga et al. (2003) determined that the SLITRK1 gene contains 1 exon.
MAPPING
By genomic sequence analysis, Nagase et al. (2001) mapped the SLITRK1
gene to chromosome 13. Aruga et al. (2003) mapped the SLITRK1 gene to a
region of chromosome 13q31 that also contains the SLITRK5 (609680) and
SLITRK6 (609681) genes. The intervening sequences between the SLITRK
genes are about 2 Mb. Aruga et al. (2003) mapped the mouse Slitrk1 gene
to a region of chromosome 14E3 that shares homology of synteny with
human chromosome 13q31.
MOLECULAR GENETICS
Abelson et al. (2005) screened the SLITRK1 gene in 174 unrelated
probands with Tourette syndrome (GTS; 137580) and identified 2 different
mutations in 3 probands. One proband, who had GTS and ADHD (143465), had
a single-base deletion in the coding region leading to a frameshift and
a truncated protein (609678.0001). The mutation was also found in the
patient's mother, who had trichotillomania (613229). In 2 other
probands, who had GTS and symptoms of OCD (see 164230), Abelson et al.
(2005) identified a noncoding sequence variant, designated var321
(609678.0002): a single-basepair change in the 3-prime UTR corresponding
to a highly conserved nucleotide within the predicted binding site for
the human micro RNA miR189, 1 of the 2 mature miRNAs derived from the
miR24 precursor (MIRN24-1; 609705). The var321 variant occurred on
different haplotype backgrounds, providing strong evidence that the 2
occurrences arose independently. Var321 replaces a G:U basepair with an
A:U pairing at position +689. The extent of conservation of this G:U
pairing, in both SLITRK1 3-prime UTR and miR189, as well as evidence
that G:U wobble base pairs inhibit miRNA-mediated protein repression to
a greater degree than would be expected on the basis of their
thermodynamic properties alone suggested that var321 might affect
SLITRK1 expression. Mutant SLITRK1 with a var321 mutation showed a
modest but statistically significant and dose-dependent further
repression of luciferase expression compared with that of wildtype.
Abelson et al. (2005) also showed that SLITRK1 and murine miR189
expression colocalizes in mouse brain.
There is controversial evidence about whether or not variation in the
SLITRK1 gene plays a role in Tourette syndrome. Deng et al. (2006) and
Chou et al. (2007) did not find the var321 change or any other
potentially pathogenic changes in the SLITRK1 gene in 82 Caucasian and
160 Taiwanese patients with GTS, respectively. Fabbrini et al. (2007)
also excluded the SLITRK1 as a basis for Tourette syndrome in a large
Italian family. Although Fabbrini et al. (2007) did identify the var321
change in a few family members and 1 spouse, it did not segregate with
the disorder. In addition, a genomewide linkage study by the Tourette
Syndrome Association International Consortium for Genetics (2007) showed
no support for a locus on chromosome 13 in Tourette syndrome.
Zimprich et al. (2008) found no changes in the coding region of the
SLITRK1 gene in 92 Austrian patients with Tourette syndrome. One variant
in the 3-prime untranslated region (3383G-A) was identified in a woman
with Tourette syndrome and OCD and in 2 relatives who had transient tic
symptoms (turning eyes and sniffing). This variant was not identified in
192 control individuals, but Zimprich et al. (2008) questioned the
pathogenicity of the variant, noting that the findings could occur by
chance with a 25% probability.
MIR17HG
| dbSNP name | rs72640333(T,A); rs72640334(C,A); rs111371822(A,G); rs7336610(C,T); rs7318578(C,A); rs1428(C,A) |
| cytoBand name | 13q31.3 |
| EntrezGene GeneID | 407975 |
| snpEff Gene Name | MIR17 |
| EntrezGene Description | miR-17-92 cluster host gene (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09412 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Ptosis, congenital bilateral;
Restrictive partial ophthalmoplegia;
Inability to raise eyes above horizontal midline
LABORATORY ABNORMALITIES:
Balanced/unbalanced chromosomal translocation t(2,13)(q36,q11)
MISCELLANEOUS:
Unbalanced chromosomal translocation carrier have thin body habitus,
shallow orbital ridges, arched eyebrows, exophthalmia, ptosis, bilateral
ophthalmoplegia, thin upper lip, kyphosis, pectus excavatum, and mental
retardation
OMIM Title
*609415 MICRO RNA 17 HOST GENE; MIR17HG
;;MIR17 HOST GENE;;
MIR17-92 CLUSTER HOST GENE;;
MICRO RNA HOST GENE 1; MIRHG1; MIHG1; MIRH1;;
ONCOMIR1 HOST GENE;;
CHROMOSOME 13 OPEN READING FRAME 25; C13ORF25
MIR17-92 CLUSTER, INCLUDED;;
ONCOMIR1, INCLUDED
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs) are small regulatory RNAs that control gene
expression by binding to complementary sites within target mRNAs and
mediating their degradation or translational repression. MIR17HG is the
host gene for the MIR17-92 cluster, which is also called ONCOMIR1, and
encodes a polycistronic primary transcript that yields at least 6 mature
miRNAs: MIR17 (609416), MIR18 (MIR18A; 609417), MIR19A (MIR19A1;
609418), MIR19B (MIR19B1; 609419), MIR20 (MIR20A; 609420), and MIR92
(MIR92A1; 609422). MIR17-92 functions in cell survival, proliferation,
differentiation, and angiogenesis and is the primary target of genomic
amplification of chromosome 13q31 that occurs in several lymphomas and
solid tumors (summary by Olive et al., 2009).
CLONING
Ota et al. (2004) identified MIR17HG, which they called C13ORF25, within
a region of chromosome 13 that is often amplified in hematopoietic
malignancies. RT-PCR detected 2 alternatively spliced transcripts, A and
B, which encode predicted peptides of 32 and 70 amino acids,
respectively, starting from the same ATG codon. Transcript B is
conserved among species and contains 5 precursor microRNAs (pre-miR18,
pre-miR19a, pre-miR19b, pre-miR91, and pre-miR92) and 7 mature microRNAs
(miR17, miR18, miR19A, miR19B, miR20, miR91 (609416), and miR92) in its
3-prime UTR. Northern blot analysis detected a transcript of about 6 kb
and a smeared band above 6 kb in B-cell lymphoma cell lines and diffuse
large B-cell lymphoma patients with 13q31-q32 amplification, but not in
placenta or 2 T-cell lines. Northern blot analysis of several normal
tissues detected weak expression in lung, thymus, and lymph node only.
GENE STRUCTURE
Ota et al. (2004) determined that the MIR17HG gene contains 4 exons.
MAPPING
By FISH and genomic sequence analysis, Ota et al. (2004) mapped the
MIR17HG gene to chromosome 13q31.3.
GENE FUNCTION
De Pontual et al. (2011) examined skeletal preparations of mouse embryos
with homozygous deletion of Mir17hg and observed severe and general
delay of endochondral and membranous ossification at embryonic day 18.5,
with complete absence of the mesophalanx of the fifth digit, presence of
a small mesophalanx of the second digit, and hypoplasia of the first
digital ray. In addition, all embryos presented with fusion of the
cervical vertebrae and microcephaly; other skeletal defects consistently
observed included dysmorphic zeugopods and fusion of the proximal carpal
bones. De Pontual et al. (2011) concluded that MIR17HG plays a
previously unappreciated role in normal growth and skeletal development.
- MIR17-92 Cluster
He et al. (2005) compared B-cell lymphoma samples and cell lines to
normal tissues and found that the levels of the primary or mature
microRNAs derived from the miR17-92 locus were often substantially
increased in the cancers. Enforced expression of the miR17-92 cluster
acted with c-Myc (190080) expression to accelerate tumor development in
a mouse B-cell lymphoma model. Tumors derived from hematopoietic stem
cells expressing a subset of the miR17-92 cluster and c-Myc could be
distinguished by an absence of apoptosis that was otherwise prevalent in
c-Myc-induced lymphomas. Taken together, He et al. (2005) concluded that
noncoding RNAs, specifically microRNAs, can modulate tumor formation,
and that the miR17-92 cluster is a potential human oncogene.
O'Donnell et al. (2005) showed that c-Myc activates expression of a
cluster of 6 miRNAs on human chromosome 13. Chromatin
immunoprecipitation experiments showed that c-Myc binds directly to this
locus. The transcription factor E2F1 (189971) is an additional target of
c-Myc that promotes cell cycle progression. O'Donnell et al. (2005)
found that expression of E2F1 is negatively regulated by 2 miRNAs in
this cluster, miR17-5p (MIR91) and miR20a. O'Donnell et al. (2005)
concluded that their findings expand the known classes of transcripts
within the c-Myc target gene network, and reveal a mechanism through
which c-Myc simultaneously activates E2F1 transcription and limits its
translation, allowing a tightly controlled proliferative signal.
Triboulet et al. (2007) provided evidence for a physiologic role of the
miRNA silencing machinery in controlling HIV-1 replication. Type III
RNAses Dicer (606241) and Drosha (608828), which are responsible for
miRNA processing, inhibited virus replication both in peripheral blood
mononuclear cells from HIV-1-infected donors and in latently infected
cells. In turn, HIV-1 actively suppressed expression of the
polycistronic miRNA cluster miR17-92. This suppression was found to be
required for efficient viral replication and was dependent on the
histone acetyltransferase Tat cofactor PCAF (602303). Triboulet et al.
(2007) concluded that their results highlighted the involvement of the
miRNA silencing pathway in HIV-1 replication and latency.
Bonauer et al. (2009) demonstrated that the miR17-92 cluster is highly
expressed in human endothelial cells and that miR92a, a component of
this cluster, controls the growth of new blood vessels (angiogenesis).
By dividing the oncogenic Mir17-92 miRNA polycistron into subclusters,
Olive et al. (2009) determined that Mir19b was critical in accelerating
Myc-induced B-cell lymphoma in a mouse model. They suggested that Mir19a
may also accelerate Myc-induced lymphomagenesis, since Mir19a and Mir19b
differ by only 1 nucleotide at a region nonessential for target
recognition. Overexpression of Mir19b or the complete Mir17-92
polycistron in Myc-overexpressing cells resulted in highly malignant B
lymphomas with nearly complete penetrance. Mir19b did not enhance cell
proliferation over that induced by Myc alone. The 3-prime UTR of the
human PTEN (601728) transcript contains 2 MIR19-binding sites, and
Mir19b repressed expression of a reporter gene containing the PTEN
sequence. Overexpression of Mir19b downregulated endogenous Pten mRNA
and protein levels in NIH3T3 cells and resulted in activation of the
PI3K (see 601232)-Akt (AKT1; 164730)-Mtor (FRAP1; 601231) antiapoptotic
pathway for cell survival. Olive et al. (2009) concluded that MIR19B has
an essential role in mediating the oncogenic activity of MIR17-92, and
that the oncogenic activity of MIR19B is, at least in part, due to
repression of PTEN expression.
Using expression profiling and antisense oligonucleotides directed
against MIR17 and MIR20A, Inomata et al. (2009) found that CDKN1A
(116899) is likely an essential target of MIR17-92 during human B-cell
lymphomagenesis.
MOLECULAR GENETICS
In 2 probands with skeletal abnormalities consistent with a diagnosis of
Feingold syndrome (FGLDS2; 614326) but who lacked any mutation at the
MYCN locus (164840), de Pontual et al. (2011) identified germline
hemizygous microdeletions at chromosome 13q31.3 that segregated with
disease in both families. The deletion in the first patient spanned 2.89
Mb and encompassed 3 genes, LOC144776, MIR17HG (609415), and GPC5
(602446), whereas the deletion in the second patient spanned 165 kb and
encompassed only MIR17HG and the first exon of GPC5. By searching the
DECIOHER database (Firth et al., 2009), which contained array CGH data
from more than 6,000 individuals with a variety of disorders, they
identified a third proband with features compatible with Feingold
syndrome who had a 180-kb hemizygous 13q31.3 microdeletion encompassing
the entire MIR17HG locus and the first exon of GPC5. Quantitative RT-PCR
on total RNA of white blood cells from the 3 deletion-positive probands
showed that expression of all 6 miRNAs encoded by MIR17HG was
approximately 50% relative to that of controls. De Pontual et al. (2011)
noted that whereas some predicted loss-of-function variants in GPC5 were
listed in databases of genomes of healthy individuals, they identified
no structural variants or polymorphisms directly affecting the miRNAs
encoded by the miR17-92 cluster in those databases. In addition, mice
harboring targeted deletion of the Mir17-92 cluster displayed a
phenocopy of several key features of the human syndrome. De Pontual et
al. (2011) stated that this was the first example of a miRNA gene
responsible for a syndromic developmental defect in humans.
SOX21
| dbSNP name | rs73550479(T,C); rs75993836(T,C) |
| cytoBand name | 13q32.1 |
| EntrezGene GeneID | 11166 |
| EntrezGene Description | SRY (sex determining region Y)-box 21 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03214 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Obesity;
Central fat distribution
GENITOURINARY:
[External genitalia, male];
Precocious puberty, gonadotropin-independent;
[Internal genitalia, female];
Oligomenorrhea;
Infertility
SKIN, NAILS, HAIR:
[Skin];
Acne;
[Hair];
Hirsutism;
Androgenic alopecia (in some patients)
ENDOCRINE FEATURES:
Hyperandrogenism;
Delayed conversion of oral cortisone acetate to plasma cortisol;
Low tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone
(THE) ratio;
Low urinary cortols-to-cortolone ratio;
Low to normal level of cortisol metabolites;
High level of cortisone metabolites;
High to high-normal cortisol secretion rate
MOLECULAR BASIS:
Caused by mutation in the hexose-6-phosphate dehydrogenase gene (H6PD,
138090.0001)
OMIM Title
*604974 SRY-BOX 21; SOX21
;;SRY-RELATED HMG-BOX GENE 21;;
SOX25
OMIM Description
DESCRIPTION
SRY-related HMG-box (SOX) genes encode a family of DNA-binding proteins
containing a 79-amino acid HMG (high mobility group) domain that shares
at least 50% sequence identity with the DNA-binding HMG box of the SRY
protein (480000). SOX proteins are divided into 6 subgroups based on
sequence similarity within and outside of the HMG domain. For additional
background information on SOX genes, see SOX1 (602148).
CLONING
By PCR of human genomic DNA using highly degenerate oligonucleotides
designed to amplify HMG box-related sequences, Cremazy et al. (1998)
identified several novel SOX proteins, including SOX21, which they
designated SOX25. The partial SOX21 sequence encodes a deduced protein
with an HMG box-like domain sharing 63% sequence identity with the SRY
HMG box. Like the HMG box of SRY, the HMG box-like domain of SOX21
contains a putative nuclear localization signal.
By screening a human genomic library with a mouse Sox1 probe, Malas et
al. (1999) isolated the SOX21 gene. SOX21 encodes a 276-amino acid
protein that belongs to subgroup B. The protein is highly homologous to
SOX14 (604747), showing 92% identity within the N-terminal HMG box and
66% identity within a 50-amino acid C-terminal domain. It also shares
89% amino acid sequence identity with the chicken SOX21 protein. By
Northern blot analysis, Malas et al. (1999) showed that SOX21 is
expressed in human embryonic brain as a 5-kb transcript, similar to the
chicken ortholog of SOX21.
GENE FUNCTION
In the chick embryo, Sandberg et al. (2005) found Sox21 promoted
neuronal differentiation by counteracting the activity of Sox1, Sox2
(184429), and Sox3 (313430), which maintains neural cells in an
undifferentiated state. The authors concluded that the balance between
SOX21 and SOX1, SOX2, and SOX3 activities determines whether neural
cells remain as progenitors or commit to differentiation.
MAPPING
By PCR analysis of a rodent/human monochromosomal somatic cell hybrid
panel and by FISH, Malas et al. (1999) mapped the SOX21 gene to
chromosome 13q31-q32. By radiation hybrid mapping, they determined that
SOX21 is located between markers D13S167 and D13S154.
SOX21-AS1
| dbSNP name | rs146229323(T,A); rs7998562(A,T); rs150019881(G,T); rs7997067(G,A); rs1555571(C,G); rs61090007(T,G); rs7982376(A,C); rs7982791(A,T); rs10083267(A,C); rs11617760(T,C); rs10083221(G,A) |
| cytoBand name | 13q32.1 |
| snpEff Gene Name | SOX21 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
DOCK9-AS2
| dbSNP name | rs728981(G,A); rs1927568(T,C); rs913431(G,A); rs913432(A,G); rs1340(T,A) |
| cytoBand name | 13q32.3 |
| snpEff Gene Name | DOCK9 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4729 |
CLYBL-AS2
| dbSNP name | rs10508040(T,C) |
| ccdsGene name | CCDS32002.1 |
| cytoBand name | 13q32.3 |
| EntrezGene GeneID | 100874063 |
| snpEff Gene Name | CLYBL |
| EntrezGene Description | CLYBL antisense RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05372 |
LINC00554
| dbSNP name | rs892251(A,G); rs1347190(A,G); rs1108130(T,A); rs17474781(T,G); rs74411763(C,T) |
| cytoBand name | 13q32.3 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.309 |
ITGBL1
| dbSNP name | rs1572329(A,G); rs9554783(C,T); rs7328708(A,G); rs9557654(A,G); rs9554784(A,T); rs3916910(C,T); rs1034270(C,T); rs7997791(C,T); rs78006473(C,T); rs8000019(T,C); rs71441512(A,G); rs9557656(A,G); rs9585698(C,T); rs9557657(G,C); rs9557658(A,G); rs4772385(T,C); rs9585699(C,T); rs9585700(G,A); rs7323695(G,A); rs2065766(T,G); rs7331689(G,A); rs7336705(A,G); rs9582488(G,T); rs9582489(G,A); rs143955156(C,T); rs9585701(G,C); rs12428334(C,G); rs9585702(G,T); rs7984480(A,C); rs78931378(A,C); rs9585703(G,A); rs9585704(G,A); rs9585705(T,C); rs9585706(C,T); rs9518419(A,T); rs9585707(T,C); rs7996346(A,G); rs4112527(T,C); rs9585708(T,C); rs9300666(A,G); rs80121275(G,C); rs190498233(C,T); rs34320645(T,C); rs116554979(G,T); rs61973748(A,G); rs9585709(T,G); rs1414307(A,C); rs59951861(A,G); rs9300667(T,G); rs7320661(A,G); rs6491623(A,G); rs4555001(C,T); rs112639149(G,A); rs9557661(G,C); rs1591449(G,A); rs1591450(G,T); rs72657124(C,G); rs1577448(G,A); rs4555003(G,A); rs1304406(A,T); rs1304407(A,G); rs2152325(C,T); rs1115028(G,A); rs7491675(G,A); rs34412772(T,C); rs7998526(G,A); rs4617703(T,C); rs4559786(G,C); rs7998783(A,G); rs9557662(T,C); rs9554788(T,G); rs9585710(A,G); rs9557663(A,G); rs9557664(A,G); rs9557665(A,G); rs9557666(T,A); rs9557667(A,G); rs9557668(C,T); rs77254540(T,C); rs1582080(C,T); rs1819556(A,G); rs4586281(T,C); rs4290341(T,C); rs7319700(C,T); rs4566012(G,A); rs4445756(T,G); rs4567576(G,A); rs4329782(A,G); rs9582492(A,G); rs4598762(C,A); rs9585711(C,T); rs116408568(C,T); rs115860514(G,A); rs188397773(C,G); rs112188830(G,T); rs9557669(G,C); rs1115175(T,G); rs76817155(C,T); rs75125547(A,G); rs4133238(G,T); rs1115176(C,A); rs4572249(G,C); rs9557670(G,A); rs4337161(A,T); rs4318072(G,A); rs4624013(C,T); rs4338648(A,G); rs4771398(G,A); rs4772389(A,G); rs4771399(T,A); rs12184572(A,G); rs12874221(G,A); rs12431251(T,G); rs9585712(T,G); rs9554789(G,C); rs9557671(A,G); rs78213048(G,A); rs17623509(T,C); rs9557672(A,T); rs7323294(A,T); rs9557673(A,C); rs7323685(C,A); rs9554790(C,T); rs17680025(G,A); rs2065764(G,T); rs9585713(A,G); rs9582494(T,G); rs7335131(C,T); rs2065765(C,T); rs9582495(C,G); rs6491630(G,C); rs9557674(A,G); rs2152321(G,A); rs35167193(G,A); rs12876937(G,A); rs11069444(T,A); rs146415702(G,A); rs9557675(A,G); rs7319974(C,A); rs9557676(C,T); rs7320334(G,A); rs7325211(G,A); rs7990603(T,C); rs7325543(A,G); rs7325932(C,T); rs7325940(C,T); rs80155155(C,A); rs10851132(C,T); rs10851133(A,G); rs9300668(G,A); rs9300669(C,T); rs74909538(T,C); rs9582496(C,T); rs7998372(T,C); rs79584851(G,A); rs10467272(G,A); rs9300670(A,G); rs16958962(A,G); rs115009486(C,T); rs1335588(T,A); rs1335587(C,T); rs76172027(A,G); rs7337798(C,A); rs6491631(T,A); rs9557677(G,A); rs144784713(T,C); rs9513906(C,G); rs9518422(T,A); rs7327657(A,G); rs9557678(A,G); rs9554791(T,C); rs9585714(C,T); rs4397965(C,T); rs7983201(T,C); rs1335594(T,C); rs57323526(C,G); rs138584313(C,G); rs1335593(G,C); rs8002643(T,C); rs10220217(C,T); rs1335592(C,T); rs12874356(C,T); rs9300671(A,G); rs12856109(G,A); rs1572321(T,C); rs986071(A,G); rs1335591(C,A); rs3916911(A,G); rs113752370(C,T); rs1335590(C,A); rs12870762(A,G); rs1335589(A,G); rs180846307(G,A); rs370509714(A,G); rs114189863(G,A); rs16958977(T,C); rs7323839(A,G); rs146113082(G,A); rs9518425(T,C); rs9513907(C,A); rs4384474(T,G); rs9557682(T,C); rs35125698(G,T); rs55796238(C,T); rs9518426(C,T); rs76018118(G,A); rs2210794(A,T); rs56066406(C,G); rs9585717(T,A); rs9582497(C,T); rs10508068(G,A); rs9582498(C,T); rs9585718(C,G); rs9585719(C,T); rs142097730(A,G); rs9585720(G,A); rs4389006(G,A); rs4497519(G,A); rs2050452(A,G); rs1414313(A,G); rs2152326(A,G); rs117062731(A,G); rs1832093(G,A); rs142948796(G,A); rs9284189(G,A); rs9300673(G,C); rs114981476(T,C); rs74119532(C,T); rs9557683(A,G); rs35524752(T,A); rs79080945(C,T); rs116266660(A,G); rs980882(T,A); rs12586000(C,T); rs12586014(G,T); rs3905239(A,C); rs116000800(C,T); rs7323806(C,G); rs9585722(G,C); rs9582500(C,T); rs2050453(T,C); rs2050454(A,G); rs9582501(G,A); rs875118(C,A); rs875117(C,T); rs875116(G,A); rs9513909(T,C); rs78238191(G,A); rs12853482(T,A); rs9557684(C,T); rs7320478(G,A); rs147962671(A,T); rs147044612(A,C); rs7327264(T,C); rs7326070(A,G); rs12864536(A,G); rs1932263(T,C); rs16959009(A,G); rs34288378(A,G); rs1932264(C,T); rs1932265(A,G); rs1855763(C,T); rs66675776(A,T); rs9582502(A,G); rs55815288(T,C); rs9585723(T,G); rs7339286(C,A); rs1577449(T,C); rs7317529(A,G); rs7336311(T,C); rs9300674(T,C); rs2065763(T,A); rs116080311(A,G); rs9300675(A,G); rs1889700(A,G); rs9300676(G,T); rs9557685(A,G); rs4771400(T,C); rs9300678(G,T); rs9557686(G,A); rs7338092(G,A); rs117113989(A,T); rs7338409(A,G); rs7338776(C,T); rs16959018(T,A); rs9518429(A,C); rs9582503(G,T); rs9300679(A,G); rs1414304(C,T); rs7992333(G,T); rs9554794(A,C); rs113745421(A,G); rs9554795(A,C); rs9518430(G,A); rs16959023(G,C); rs9582504(C,A); rs9518431(A,T); rs1414305(G,A); rs9585724(A,G); rs7988270(C,G); rs9582505(G,A); rs111902328(G,T); rs75528926(C,T); rs9557688(T,C); rs9557689(C,T); rs4772391(A,G); rs9513914(T,C); rs139742737(G,A); rs76576142(T,A); rs9518436(G,A); rs9557695(A,C); rs9557696(G,T); rs7336398(A,G); rs1414312(A,G); rs1414311(A,C); rs9557698(A,G); rs1023304(G,A); rs9518438(G,A); rs57771871(G,A); rs9557699(T,G); rs16959027(A,G); rs9300680(G,T); rs9805348(G,A); rs9518440(T,C); rs112192812(A,G); rs145350386(C,T); rs7317289(G,C); rs74119498(A,G); rs7319118(T,G); rs7324587(T,A); rs9554803(G,T); rs974148(T,G); rs58031393(G,C); rs885304(C,T); rs915343(A,G); rs148350243(T,G); rs6491632(T,C); rs9557700(G,A); rs972367(T,C); rs972366(C,T); rs972365(A,G); rs79197337(G,C); rs12864988(T,C); rs1335603(A,G); rs9513919(T,C); rs9518441(A,G); rs9518442(G,A); rs9513920(A,G); rs112041504(T,C); rs9582507(A,G); rs9554804(A,G); rs7997664(G,T); rs954823(A,T); rs954822(C,T); rs1932266(C,T); rs7988355(A,G); rs74119856(A,G); rs7988693(A,G); rs74455447(G,A); rs9582508(C,A); rs60229376(A,C); rs7985859(G,A); rs9518445(A,G); rs79458558(A,G); rs9518446(C,G); rs9554805(A,G); rs7329282(G,A); rs4400915(C,T); rs4335658(T,G); rs9557702(A,T); rs3899633(G,T); rs12585519(A,C); rs74119857(G,A); rs7989191(C,T); rs7989350(C,T); rs6491633(C,T); rs140928592(T,C); rs62637618(G,A); rs1140605(G,T); rs9554806(G,A); rs67688322(T,C); rs9554807(C,T); rs12585460(A,G); rs28654393(G,A); rs2148168(C,G); rs9518448(C,T); rs1296174(G,A); rs182897774(A,G); rs1572325(A,G); rs1572326(G,T); rs9557703(C,T); rs2243676(G,A); rs1572327(A,G); rs16959094(T,G); rs7358934(T,C); rs9557704(A,T); rs3916912(C,T); rs77039000(T,G); rs75038902(C,T); rs77725167(A,C); rs2765608(T,C); rs7323330(A,G); rs9582509(C,A); rs7982227(G,A); rs113026476(G,A); rs6491634(G,A); rs2148167(G,C); rs9300681(A,G); rs9513921(C,G); rs7337904(C,T); rs8001356(C,T); rs114578048(A,G); rs3918322(A,G); rs17685968(G,A); rs4771403(G,A); rs10467273(A,G); rs4772392(C,T); rs942999(T,G); rs3783210(C,A); rs1925990(T,C); rs943000(C,T); rs1925991(A,G); rs3825513(G,A); rs9518453(C,G); rs17686036(A,T); rs1436269(A,G); rs9518455(A,T); rs9557709(G,T); rs1561118(A,G); rs1561119(G,A); rs116848415(T,C); rs61976184(C,A); rs9557710(C,T); rs57882516(A,G); rs9518459(A,G); rs9554809(G,A); rs6491635(T,C); rs6491636(A,G); rs77542977(C,T); rs74336160(G,A); rs1583526(G,T); rs7338485(G,C); rs9300684(T,C); rs1036435(T,C); rs144019918(G,C); rs4423293(A,G); rs7998449(C,G); rs80092155(G,A); rs7999376(A,G); rs1898202(G,A); rs78770822(T,C); rs1821713(G,T); rs1369883(A,G); rs2117973(G,A); rs34444925(G,A); rs79540689(T,C); rs4772399(T,C); rs4772400(G,T); rs4772401(T,C); rs1540459(G,A); rs66653055(T,A); rs3783213(A,G); rs968939(A,T); rs4144376(A,C); rs1898203(C,G); rs7999749(G,A); rs147153624(A,G); rs78296409(A,G); rs9557712(G,A); rs7320642(C,T); rs9518463(G,A); rs73556023(G,A); rs7139608(C,A); rs996507(A,G); rs34447642(T,C); rs146140743(C,T); rs4772402(G,T); rs4772403(T,C); rs10454530(G,C); rs58393947(G,C); rs7324511(A,G); rs9557713(A,G); rs9557714(A,G); rs56110492(T,C); rs76584962(C,T); rs9582510(C,G); rs16959194(G,A); rs75343618(A,G); rs4238229(T,C); rs1982142(A,G); rs7338172(G,A); rs17624306(C,A); rs1125871(A,C); rs9300686(A,G); rs1125872(A,G); rs9300687(G,C); rs9518464(C,A); rs1925993(C,T); rs16959204(C,T); rs1836843(G,T); rs1436260(A,G); rs4451831(G,A); rs34858299(A,T); rs3783215(C,T); rs61594628(T,G); rs74120603(A,T); rs57359559(A,G); rs9585738(C,T); rs2390632(G,A); rs2893072(T,C); rs67199095(C,A); rs7981106(T,G); rs7982014(T,A); rs7986646(A,G); rs11840251(C,T); rs9554812(C,T); rs7983474(G,A); rs10508069(G,T); rs10508071(C,T); rs6491638(G,T); rs10508072(G,A); rs7995030(C,T); rs16951701(T,C); rs3783216(A,T); rs10508073(T,C); rs16959213(A,G); rs3783217(A,T); rs3783218(T,C); rs74842252(T,C); rs3916913(C,T); rs1436261(C,T); rs9557716(T,C); rs2217902(T,C); rs9554813(A,G); rs77830224(A,C); rs28428809(A,T); rs114413683(T,G); rs79441531(A,G); rs1836844(A,G); rs78194732(C,T); rs17585585(C,T); rs1436262(T,C); rs1469849(G,T); rs16959228(A,C); rs1469850(A,G); rs1469851(A,T); rs16959230(T,G); rs2217903(T,G); rs2196467(T,C); rs16959232(A,G); rs1816544(A,G); rs9518471(C,A); rs1975266(T,C); rs61965080(A,T); rs1036436(G,A); rs75025107(A,G); rs116375819(C,T); rs9585744(T,C); rs1036437(A,T); rs9300689(C,G); rs9585745(C,T); rs9585746(A,G); rs8001658(C,A); rs8001835(C,G); rs66798084(A,G); rs146567438(G,A); rs9585747(C,T); rs9582514(T,C); rs9585748(C,T); rs7990917(G,C); rs9557718(G,A); rs7327971(G,A); rs1898199(G,A); rs1898200(G,A); rs144031122(G,A); rs9513931(G,T); rs1925989(T,C); rs9513932(G,A); rs1898201(C,T); rs114804111(A,G); rs9557719(A,G); rs9585750(A,G); rs9585751(G,A); rs1982143(G,A); rs1982144(C,T); rs57917234(C,T); rs74120610(G,A); rs9554815(T,A); rs7983619(T,C); rs141158346(G,A); rs12428274(C,G); rs9554816(T,C); rs17624462(G,C); rs9518474(A,G); rs9518475(G,A); rs72659162(G,T); rs4772404(A,G); rs143055398(A,G); rs4772405(A,G); rs1025617(T,C); rs9518476(G,A); rs8000425(A,G); rs12873072(A,C); rs5007576(C,T); rs59820645(A,T); rs5007577(C,T); rs4772406(T,C); rs61965088(A,C); rs116325722(A,G); rs1952129(G,A); rs11069452(G,A); rs12584138(A,G); rs9518477(A,G); rs9518478(A,G); rs78902981(C,T); rs9557721(A,T); rs34846342(G,A); rs34676107(A,G); rs12865983(T,C); rs876099(T,C); rs876100(G,C); rs115721050(C,T); rs28589375(G,A); rs7323455(A,G); rs3916914(C,G); rs11843064(A,G); rs7994613(T,C); rs7993068(A,G); rs2082933(C,A); rs112311148(A,G); rs114869443(T,C); rs3916915(G,A); rs7991602(A,G); rs7333553(A,T); rs1595164(T,C); rs3918323(T,C); rs79596802(G,A); rs7323652(G,A); rs6491639(G,A); rs78759175(G,A); rs55735887(T,C); rs114405976(G,A); rs113328330(A,G); rs1436265(A,G); rs6491640(T,A); rs7984264(A,G); rs115182532(G,A); rs61965092(A,T); rs138597361(A,G); rs9582517(T,C); rs114019599(A,G); rs115723411(A,C); rs75669890(C,A); rs3783221(A,G); rs72632687(A,G); rs9518487(C,T); rs9518488(G,A); rs61965093(C,T); rs7998211(C,T); rs9518489(G,A); rs72659178(T,A); rs9554817(A,G); rs80200424(A,T); rs35735050(G,A); rs79811024(G,A); rs1369880(T,G); rs10508074(G,A); rs79403812(T,C); rs2196468(C,T); rs7992107(T,C); rs7992141(T,C); rs148425363(T,C); rs9513939(T,G); rs1436264(G,C); rs4000(T,C); rs9554818(C,G); rs75624120(A,G); rs3783222(A,G); rs2893073(A,G); rs1436263(A,G); rs981073(A,G); rs7995858(C,G); rs9300690(C,T); rs9518494(A,T); rs3783224(T,C); rs1540461(A,G); rs892998(T,C); rs1540460(A,T); rs61094422(A,G); rs74655427(A,G); rs187922675(G,T); rs7993828(C,G); rs1020027(T,C); rs1854306(C,G); rs138712407(T,C); rs9518497(C,T); rs76517578(G,A); rs144373399(C,A); rs56162171(A,G); rs79838492(T,G); rs9300691(G,C); rs7324876(G,T); rs9518498(A,G); rs3783229(T,G); rs9805314(G,C); rs1967335(A,G); rs2031841(T,C); rs114467776(C,T); rs9585757(G,T); rs9582518(T,G); rs1436268(G,C); rs145859125(C,T); rs2296910(G,A); rs2296909(C,A); rs9585758(G,T); rs9585759(G,T); rs2281987(A,G); rs2281989(T,C); rs1436267(G,A); rs17686597(T,C); rs2281991(A,G); rs1469855(T,C); rs1469854(A,G); rs1469853(T,C); rs9582519(C,T); rs1436266(G,T); rs1801803(A,G); rs12583229(C,G); rs9554822(T,A); rs77500159(G,A); rs17624707(T,C); rs17624725(T,C); rs74122650(G,A); rs78851738(G,A); rs61965118(T,C); rs67702854(C,T); rs3825514(T,C); rs76432930(A,G) |
| ccdsGene name | CCDS9499.1 |
| cytoBand name | 13q33.1 |
| EntrezGene GeneID | 9358 |
| EntrezGene Description | integrin, beta-like 1 (with EGF-like repeat domains) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ITGBL1:NM_001271756:exon2:c.G38A:p.G13D,ITGBL1:NM_004791:exon3:c.G317A:p.G106D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5436 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95965 |
| dbNSFP Uniprot ID | ITGBL_HUMAN |
| dbNSFP KGp1 AF | 0.010989010989 |
| dbNSFP KGp1 Afr AF | 0.0447154471545 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.049478 |
| ESP All MAF | 0.016838 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.004668 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Febrile seizures;
Afebrile seizures;
Generalized tonic-clonic seizures;
Absence seizures;
Myotonic seizures;
Atonic seizures
MISCELLANEOUS:
Highly variable phenotype;
Onset of febrile seizures typically between 6 months and 6 years of
age;
Persistence of febrile seizures beyond age 6 years;
Development of afebrile seizures later in childhood;
Incomplete penetrance
MOLECULAR BASIS:
Caused by mutation in the voltage-gated sodium channel, type I, beta
subunit gene (SCN1B, 600235.0001)
OMIM Title
*604234 INTEGRIN, BETA-LIKE 1; ITGBL1
;;TEN BETA-INTEGRIN EGF-LIKE REPEAT DOMAINS; TIED
OMIM Description
CLONING
By screening an EST cDNA database for sequence homology with integrins
(see 147557), Berg et al. (1999) identified overlapping partial-length
cDNA clones from human osteoclastoma, fetal lung, and umbilical vein
endothelial cDNA libraries. A subsequent screening identified a
potential full-length clone from an osteoblast cell cDNA library. The
novel cDNA clone was found to encode a 494-amino acid protein, which the
authors designated TIED (ten beta-integrin EGF-like repeat domains). The
sequence comprised a typical signal peptide, followed by a hydrophilic
471-amino acid domain containing 10 tandem EGF-like repeats strikingly
similar to those found in the cysteine-rich 'stalk-like' structure of
integrin-beta subunits. Northern blot analysis revealed a single RNA
transcript of approximately 2.8 kb. TIED was widely expressed in many
tissues, but readily detectable only in aorta.
MAPPING
By fluorescence in situ hybridization, Berg et al. (1999) mapped the
ITGBL1 gene to human chromosome 13q33.
FGF14-AS2
| dbSNP name | rs2282282(C,T); rs3087647(A,G); rs3168724(A,C) |
| ccdsGene name | CCDS9500.1 |
| cytoBand name | 13q33.1 |
| EntrezGene GeneID | 283481 |
| snpEff Gene Name | FGF14 |
| EntrezGene Description | FGF14 antisense RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3388 |
KDELC1
| dbSNP name | rs9557929(G,C); rs74112432(C,T); rs9514054(T,C); rs78460874(A,G); rs4772500(T,C); rs74112436(A,G); rs76894739(A,T); rs151325582(C,T); rs9514055(T,G); rs138900201(C,G); rs141359230(C,G); rs7322185(A,C); rs3818480(G,A); rs12427768(G,A); rs9585995(T,C); rs56051156(T,C); rs59545971(C,A); rs56085825(A,G); rs7329172(C,A); rs2274387(C,A); rs9514056(T,C); rs9514057(T,C); rs116520888(T,G); rs115528872(C,T); rs143618308(A,G); rs60612408(A,C); rs9557931(G,A); rs77520798(T,C); rs7327400(C,G); rs1047740(T,C); rs12585042(C,T); rs4772501(T,C); rs7334464(A,G); rs75680149(A,T); rs76691546(C,T); rs74109608(A,T); rs74109610(T,C); rs199620095(C,T); rs7994595(T,C); rs7993350(C,A); rs7993381(A,C); rs74109612(T,A) |
| ccdsGene name | CCDS9504.1 |
| cytoBand name | 13q33.1 |
| EntrezGene GeneID | 79070 |
| EntrezGene Description | KDEL (Lys-Asp-Glu-Leu) containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KDELC1:NM_024089:exon1:c.G163A:p.V55M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7501 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6UW63 |
| dbNSFP Uniprot ID | KDEL1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe to profound;
Delayed motor development;
Hypotonia;
Spastic tetraplegia;
Ataxia;
Seizures;
Lissencephaly;
Agyria (posterior-to-anterior gradient);
Pachygyria (posterior-to-anterior gradient);
Polymicrogyria;
Subcortical laminar heterotopia;
Hooked aspect of the frontal horn of the lateral ventricles due to
abnormally shaped basal ganglia;
Ventricular dilatation;
Thin corpus callosum;
Abnormal hippocampus;
Agenesis of the corpus callosum;
Absence or hypoplasia of the anterior limb of the internal capsule;
Hypoplasia of the cerebellar vermis;
Hypoplasia of the brainstem
MISCELLANEOUS:
Most cases occur de novo
MOLECULAR BASIS:
Caused by mutation in the alpha-tubulin 1A gene (TUBA1A, 602529.0001)
OMIM Title
*611613 KDEL MOTIF-CONTAINING 1; KDELC1
;;ENDOPLASMIC RETICULUM RESIDENT PROTEIN 58; EP58
OMIM Description
CLONING
By mouse EST database analysis, followed by PCR of a mouse embryonic
carcinoma cDNA library, Kimata et al. (2000) cloned mouse Kdelc1, which
they called Ep58. The deduced 508-amino acid mouse protein contains an
ER-retention KDEL motif at the extreme C terminus and a predicted
N-terminal signal sequence. Mouse Ep58 shares similarity with the rod
domain of some actin-binding proteins, such as filamin (see FLNA;
300017), and also shares similarity with several bacterial proteins
associated with polysaccharide biosynthesis. Confocal microscopy
localized Ep58 to the endoplasmic reticulum. Endoglycosidase H treatment
determined that Ep58 is N-glycosylated. Mouse Ep58 expressed in COS-7
cell microsomal fractions showed resistance to protease K digestion
unless detergent was added, suggesting that Ep58 is an ER-resident
lumenal protein. RT-PCR analysis of mouse tissues detected strong
expression in placenta, heart, and liver as well as fetal brain, kidney,
intestine, and liver, with moderate or weak expression in all other
adult tissues.
LINC00346
| dbSNP name | rs7334606(T,C); rs9521970(C,G); rs6492320(A,G); rs4773266(A,G); rs4773267(T,C); rs9559896(C,T); rs113966374(T,A); rs2391868(T,A); rs140311766(C,G); rs75710002(T,C); rs7992436(C,T); rs4771714(T,C); rs4771715(T,C); rs9559897(A,G); rs1041182(A,G); rs4285993(T,G); rs927880(A,C); rs927879(T,C); rs9588286(C,T); rs9588287(G,A); rs111765883(G,A); rs2277425(A,G); rs2277424(C,T) |
| cytoBand name | 13q34 |
| EntrezGene GeneID | 283487 |
| snpEff Gene Name | NCRNA00346 |
| EntrezGene Description | long intergenic non-protein coding RNA 346 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1455 |
SOX1
| dbSNP name | rs370809646(G,T); rs3742223(T,C); rs9604188(T,C); rs571564(G,A) |
| cytoBand name | 13q34 |
| EntrezGene GeneID | 6656 |
| EntrezGene Description | SRY (sex determining region Y)-box 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
OMIM Clinical Significance
Neuro:
Essential tremor;
Postural tremor of arms;
Variable tremor of head, legs, trunk, voice, jaw, and facial muscles
Misc:
Aggravated by emotions, hunger, fatigue, and temperature extremes;
Beta-adrenergic blocking agents and primidone partially effective;
Significant side-effects of therapy;
Anticipation suggested in one family
Inheritance:
Autosomal dominant
OMIM Title
*602148 SRY-BOX 1; SOX1
;;SRY-RELATED HMG-BOX GENE 1
OMIM Description
DESCRIPTION
The SRY (480000) and SOX proteins share a DNA-binding domain known as
the HMG box, defined by a 79-amino acid region. All SOX proteins have a
single HMG box and bind linear DNA in a sequence-specific manner,
resulting in the bending of DNA through large angles. Bending causes the
DNA helix to open for some distance, which may affect binding and
interactions of other transcription factors. SOX1, SOX2 (184429), and
SOX3 (313430) show the closest homology to SRY. They share maximum
homology within the HMG domain and are expressed mainly in the
developing nervous system of the mouse (Collignon et al., 1996). These
genes share significant homology outside the HMG box also and are highly
conserved throughout their evolution.
CLONING
Malas et al. (1997) cloned the human SOX1 gene.
MAPPING
Malas et al. (1997) mapped the human SOX1 gene to 13q34 by fluorescence
in situ hybridization. Located in the terminal band of 13q, SOX1 is
proximal to transcription factor DP1 (189902). Malas et al. (1996)
mapped the mouse Sox1 gene to proximal mouse chromosome 8.
GENE FUNCTION
In developing chick spinal cord, Bylund et al. (2003) found that Sox1,
Sox2, and Sox3 were coexpressed in self-renewing progenitor cells and
acted to inhibit neuronal differentiation. Active repression of the Sox
genes promoted neural progenitor cells to initiate differentiation
prematurely. Further studies showed that the ability of the proneural
transcription factor neurogenin-2 (NEUROG2; 606624) to promote neuronal
differentiation was based on its ability to suppress Sox gene
expression, thus showing that neurogenesis is regulated by an interplay
between proneural proteins and inhibitory proteins.
MCF2L-AS1
| dbSNP name | rs2993271(T,C); rs112182717(C,T); rs9549614(T,C); rs3011469(C,T) |
| cytoBand name | 13q34 |
| EntrezGene GeneID | 100289410 |
| snpEff Gene Name | MCF2L |
| EntrezGene Description | MCF2L antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1244 |
LINC00552
| dbSNP name | rs36159814(A,G); rs36147736(T,C); rs139114132(T,G); rs36147237(G,A) |
| cytoBand name | 13q34 |
| EntrezGene GeneID | 100130386 |
| snpEff Gene Name | AC187648.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 552 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4734 |
LINC00565
| dbSNP name | rs60088253(C,T); rs74116296(A,G); rs9604570(A,G) |
| cytoBand name | 13q34 |
| EntrezGene GeneID | 100861555 |
| snpEff Gene Name | RP11-199F6.8 |
| EntrezGene Description | long intergenic non-protein coding RNA 565 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07438 |
OR4Q3
| dbSNP name | rs148505982(C,T); rs12896533(T,C); rs199892896(G,A) |
| ccdsGene name | CCDS32020.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 441669 |
| EntrezGene Description | olfactory receptor, family 4, subfamily Q, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4Q3:NM_172194:exon1:c.C478T:p.Q160X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.0155677655678 |
| dbNSFP KGp1 Afr AF | 0.0691056910569 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01561 |
| ESP Afr MAF | 0.024058 |
| ESP All MAF | 0.00815 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002554 |
OR4M1
| dbSNP name | rs2635535(C,T); rs2815960(G,A) |
| ccdsGene name | CCDS32021.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 441670 |
| EntrezGene Description | olfactory receptor, family 4, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4M1:NM_001005500:exon1:c.C347T:p.T116I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGD0 |
| dbNSFP Uniprot ID | OR4M1_HUMAN |
| dbNSFP KGp1 AF | 0.274267399267 |
| dbNSFP KGp1 Afr AF | 0.0813008130081 |
| dbNSFP KGp1 Amr AF | 0.317679558011 |
| dbNSFP KGp1 Asn AF | 0.295454545455 |
| dbNSFP KGp1 Eur AF | 0.362796833773 |
| dbSNP GMAF | 0.2736 |
| ESP Afr MAF | 0.133227 |
| ESP All MAF | 0.259649 |
| ESP Eur/Amr MAF | 0.324419 |
| ExAC AF | 0.3 |
OR4K2
| dbSNP name | rs74036118(A,T); rs74036119(T,C); rs12883767(A,T) |
| ccdsGene name | CCDS32023.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390431 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K2:NM_001005501:exon1:c.A161T:p.H54L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0025 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGD2 |
| dbNSFP Uniprot ID | OR4K2_HUMAN |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.017476 |
| ESP All MAF | 0.00592 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001765 |
OR4K5
| dbSNP name | rs115414820(A,G); rs77615110(G,A); rs17242341(G,A) |
| ccdsGene name | CCDS32024.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 79317 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K5:NM_001005483:exon1:c.A274G:p.I92V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGD3 |
| dbNSFP Uniprot ID | OR4K5_HUMAN |
| dbNSFP KGp1 AF | 0.0288461538462 |
| dbNSFP KGp1 Afr AF | 0.123983739837 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.02847 |
| ESP Afr MAF | 0.088743 |
| ESP All MAF | 0.030452 |
| ESP Eur/Amr MAF | 0.000582 |
| ExAC AF | 0.008815 |
OR4K1
| dbSNP name | rs2792148(T,C); rs12885778(G,A); rs3916626(G,A); rs74705836(G,A); rs34608158(C,A); rs34394400(C,T); rs2792146(G,A); rs2792145(A,G) |
| ccdsGene name | CCDS32025.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 79544 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K1:NM_001004063:exon1:c.T84C:p.F28F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.27 |
| ESP Afr MAF | 0.110304 |
| ESP All MAF | 0.282101 |
| ESP Eur/Amr MAF | 0.370116 |
| ExAC AF | 0.362 |
OR4K15
| dbSNP name | rs3861512(A,T); rs3861513(T,G); rs2318556(A,C); rs10135246(C,A); rs11158071(C,T) |
| ccdsGene name | CCDS32026.1 |
| CosmicCodingMuts gene | OR4K15 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 81127 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K15:NM_001005486:exon1:c.A335T:p.E112V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH41 |
| dbNSFP Uniprot ID | OR4KF_HUMAN |
| dbNSFP KGp1 AF | 0.18315018315 |
| dbNSFP KGp1 Afr AF | 0.193089430894 |
| dbNSFP KGp1 Amr AF | 0.17955801105 |
| dbNSFP KGp1 Asn AF | 0.115384615385 |
| dbNSFP KGp1 Eur AF | 0.229551451187 |
| dbSNP GMAF | 0.1837 |
| ESP Afr MAF | 0.240127 |
| ESP All MAF | 0.256923 |
| ESP Eur/Amr MAF | 0.265534 |
| ExAC AF | 0.237 |
OR4K14
| dbSNP name | rs12590785(C,T) |
| ccdsGene name | CCDS32027.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 122740 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K14:NM_001004712:exon1:c.G882A:p.E294E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2121 |
| ESP Afr MAF | 0.482978 |
| ESP All MAF | 0.281562 |
| ESP Eur/Amr MAF | 0.16093 |
| ExAC AF | 0.818 |
OR4K13
| dbSNP name | rs17277032(C,T); rs116485278(A,T) |
| ccdsGene name | CCDS32028.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390433 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K13:NM_001004714:exon1:c.G798A:p.S266S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.315 |
| ESP Afr MAF | 0.177485 |
| ESP All MAF | 0.389897 |
| ESP Eur/Amr MAF | 0.498721 |
| ExAC AF | 0.404 |
OR4L1
| dbSNP name | rs1958715(G,A); rs1958716(A,G); rs1959630(G,T); rs1958717(A,G); rs2775253(T,A); rs2775254(G,A); rs1959629(C,T); rs1959628(C,G); rs144249994(G,A) |
| ccdsGene name | CCDS32029.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 122742 |
| EntrezGene Description | olfactory receptor, family 4, subfamily L, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4L1:NM_001004717:exon1:c.G4A:p.D2N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH43 |
| dbNSFP Uniprot ID | OR4L1_HUMAN |
| dbNSFP KGp1 AF | 0.495879120879 |
| dbNSFP KGp1 Afr AF | 0.518292682927 |
| dbNSFP KGp1 Amr AF | 0.530386740331 |
| dbNSFP KGp1 Asn AF | 0.559440559441 |
| dbNSFP KGp1 Eur AF | 0.416886543536 |
| dbSNP GMAF | 0.4968 |
| ESP Afr MAF | 0.487063 |
| ESP All MAF | 0.430867 |
| ESP Eur/Amr MAF | 0.40207 |
| ExAC AF | 0.455,6.621e-05 |
OR4K17
| dbSNP name | rs8005245(G,C); rs9323534(C,T) |
| ccdsGene name | CCDS32030.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390436 |
| EntrezGene Description | olfactory receptor, family 4, subfamily K, member 17 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4K17:NM_001004715:exon1:c.G477C:p.K159N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC6 |
| dbNSFP Uniprot ID | OR4KH_HUMAN |
| dbNSFP KGp1 AF | 0.424908424908 |
| dbNSFP KGp1 Afr AF | 0.298780487805 |
| dbNSFP KGp1 Amr AF | 0.419889502762 |
| dbNSFP KGp1 Asn AF | 0.536713286713 |
| dbNSFP KGp1 Eur AF | 0.424802110818 |
| dbSNP GMAF | 0.4242 |
| ESP Afr MAF | 0.362233 |
| ESP All MAF | 0.398355 |
| ESP Eur/Amr MAF | 0.41686 |
| ExAC AF | 0.426 |
OR11G2
| dbSNP name | rs148846869(C,T); rs45620333(A,G); rs140668031(G,A); rs4981822(T,A); rs4981088(G,A); rs4981823(G,C); rs140982146(T,C); rs141181712(G,A) |
| ccdsGene name | CCDS32032.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390439 |
| EntrezGene Description | olfactory receptor, family 11, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR11G2:NM_001005503:exon1:c.C44T:p.P15L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC1 |
| dbNSFP Uniprot ID | O11G2_HUMAN |
| dbNSFP KGp1 AF | 0.0247252747253 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0331491712707 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0540897097625 |
| dbSNP GMAF | 0.02479 |
| ESP Afr MAF | 0.008852 |
| ESP All MAF | 0.030986 |
| ESP Eur/Amr MAF | 0.042326 |
| ExAC AF | 0.037 |
OR11H6
| dbSNP name | rs10140652(C,A); rs9323693(C,G); rs12891553(T,C); rs17106351(G,A); rs17211285(G,T); rs17277221(T,C); rs61993884(G,C); rs17277228(T,C) |
| ccdsGene name | CCDS32033.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 122748 |
| EntrezGene Description | olfactory receptor, family 11, subfamily H, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR11H6:NM_001004480:exon1:c.C20A:p.S7Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC7 |
| dbNSFP Uniprot ID | O11H6_HUMAN |
| dbNSFP KGp1 AF | 0.0934065934066 |
| dbNSFP KGp1 Afr AF | 0.146341463415 |
| dbNSFP KGp1 Amr AF | 0.0469613259669 |
| dbNSFP KGp1 Asn AF | 0.0926573426573 |
| dbNSFP KGp1 Eur AF | 0.0817941952507 |
| dbSNP GMAF | 0.0932 |
| ESP Afr MAF | 0.096913 |
| ESP All MAF | 0.080501 |
| ESP Eur/Amr MAF | 0.072093 |
| ExAC AF | 0.083 |
OR11H4
| dbSNP name | rs142588807(G,C); rs151288230(G,C); rs17277270(C,G) |
| ccdsGene name | CCDS32034.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390442 |
| EntrezGene Description | olfactory receptor, family 11, subfamily H, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR11H4:NM_001004479:exon1:c.G574C:p.D192H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC9 |
| dbNSFP Uniprot ID | O11H4_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.0005611 |
RPPH1
| dbSNP name | rs3093873(C,T) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 85495 |
| snpEff Gene Name | PARP2 |
| EntrezGene Description | ribonuclease P RNA component H1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2314 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608513 RIBONUCLEASE P, RNA COMPONENT H1; RPPH1
;;H1 RNA; H1RNA
OMIM Description
DESCRIPTION
H1RNA is the RNA component of the RNase P ribonucleoprotein, an
endoribonuclease that cleaves tRNA precursor molecules to form the
mature 5-prime termini of their tRNA sequences (Baer et al., 1989).
CLONING
Bartkiewicz et al. (1989) purified RNase P from HeLa cell extracts and,
using this as template, synthesized and cloned H1RNA cDNA. The deduced
340-nucleotide transcript does not contain a 5-prime cap structure. The
5-prime and 3-prime termini are complementary, and the authors predicted
that they are hydrogen bonded.
Baer et al. (1989) cloned an H1RNA cDNA, including its flanking regions,
from human spleen DNA. In vitro transcription of H1RNA cDNA using S100
and whole HeLa cell extracts confirmed synthesis of a transcript
containing about 340 nucleotides. The mature form of H1RNA did not
appear to be derived from a larger precursor molecule. Inhibitor studies
indicated that H1RNA is transcribed by RNA polymerase (Pol) III (see
606007).
GENE FUNCTION
Following depletion of RNase P from HeLa cell extracts, Reiner et al.
(2006) found a severe deficiency in Pol III-mediated transcription of
tRNA and other small noncoding RNA genes. Targeted cleavage of the H1RNA
moiety of RNase P altered enzyme specificity and diminished Pol III
transcription. Similarly, inactivation of RNase P protein subunits, such
as RPP38 (606116), by small interfering RNA inhibited Pol III function
and Pol III-directed promoter activity in the cell. RNase P exerted its
role in transcription through association with Pol III and chromatin of
active tRNA and 5S rRNA (180420) genes. Reiner et al. (2006) concluded
that RNase P has a role in Pol III transcription and that transcription
and early tRNA processing may be coordinated.
GENE STRUCTURE
Baer et al. (1989) determined that the flanking regions of the H1RNA
gene contain transcriptional control elements characteristic of both RNA
polymerase II and RNA polymerase III.
Myslinski et al. (2001) analyzed the H1RNA promoter region using various
transcription assays on mutant templates and DNA binding assays with
recombinant proteins. They found that the DNA elements required for
H1RNA transcription are typical of vertebrate small nuclear RNA promoter
elements. However, the promoter is unusually compact and is contained
within 100 bp of 5-prime flanking sequences.
MAPPING
By Southern blot analyses, Bartkiewicz et al. (1989) determined that
there are no more than 3 H1RNA genes, and Baer et al. (1989) predicted
that there is only a single gene. Baer et al. (1989) mapped the H1RNA
gene to chromosome 14q just below the centromere by analyzing a panel of
mouse-human hybrid chromosomes and by in situ hybridization.
RNASE10
| dbSNP name | rs79798350(A,G); rs75463308(C,G); rs2067648(G,A) |
| ccdsGene name | CCDS32035.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 338879 |
| EntrezGene Description | ribonuclease, RNase A family, 10 (non-active) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RNASE10:NM_001012975:exon1:c.A91G:p.T31A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0003 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5GAN6 |
| dbNSFP Uniprot ID | RNS10_HUMAN |
| dbNSFP KGp1 AF | 0.0421245421245 |
| dbNSFP KGp1 Afr AF | 0.103658536585 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0422163588391 |
| dbSNP GMAF | 0.04224 |
| ESP Afr MAF | 0.090331 |
| ESP All MAF | 0.045594 |
| ESP Eur/Amr MAF | 0.022674 |
| ExAC AF | 0.031 |
RNASE12
| dbSNP name | rs3827902(G,T) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 493901 |
| EntrezGene Description | ribonuclease, RNase A family, 12 (non-active) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2062 |
| ESP Afr MAF | 0.276668 |
| ESP All MAF | 0.235814 |
| ESP Eur/Amr MAF | 0.214884 |
| ExAC AF | 0.208 |
OR6S1
| dbSNP name | rs17277522(C,T); rs11628297(T,A); rs11627438(A,T); rs11622969(C,T); rs11627574(A,G); rs11622794(G,A) |
| ccdsGene name | CCDS32038.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 341799 |
| EntrezGene Description | olfactory receptor, family 6, subfamily S, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR6S1:NM_001001968:exon1:c.G710A:p.R237H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NH40 |
| dbNSFP Uniprot ID | OR6S1_HUMAN |
| dbNSFP KGp1 AF | 0.526098901099 |
| dbNSFP KGp1 Afr AF | 0.471544715447 |
| dbNSFP KGp1 Amr AF | 0.411602209945 |
| dbNSFP KGp1 Asn AF | 0.725524475524 |
| dbNSFP KGp1 Eur AF | 0.465699208443 |
| dbSNP GMAF | 0.4734 |
| ESP Afr MAF | 0.436677 |
| ESP All MAF | 0.441104 |
| ESP Eur/Amr MAF | 0.443372 |
| ExAC AF | 0.488,8.132e-06 |
RNASE6
| dbSNP name | rs1045922(G,A); rs7156801(T,C); rs60197111(T,C) |
| ccdsGene name | CCDS9558.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 6039 |
| EntrezGene Description | ribonuclease, RNase A family, k6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RNASE6:NM_005615:exon2:c.G266A:p.R89Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q93091 |
| dbNSFP Uniprot ID | RNAS6_HUMAN |
| dbNSFP KGp1 AF | 0.25641025641 |
| dbNSFP KGp1 Afr AF | 0.105691056911 |
| dbNSFP KGp1 Amr AF | 0.273480662983 |
| dbNSFP KGp1 Asn AF | 0.398601398601 |
| dbNSFP KGp1 Eur AF | 0.238786279683 |
| dbSNP GMAF | 0.2567 |
| ESP Afr MAF | 0.133 |
| ESP All MAF | 0.20998 |
| ESP Eur/Amr MAF | 0.249419 |
| ExAC AF | 0.28 |
OMIM Clinical Significance
Growth:
Severe growth failure
GI:
Hepatomegaly;
Diarrhea
Vascular:
Vasculitis
Skel:
Osteoporosis
Immunology:
Immune deficiency
Metabolic:
Zinc deficiency
Skin:
Skin rash
Lab:
Hyperzincemia;
Abnormal zinc metabolism;
Raises liver and muscle Zn and Cu concentrations;
No abnormal liver histology;
Increased liver immunoreactive metallothionein
Inheritance:
? Autosomal dominant
OMIM Title
*601981 RIBONUCLEASE, RNase A FAMILY, 6; RNASE6
;;RNase k6
OMIM Description
CLONING
Rosenberg and Dyer (1996) identified ribonuclease-6, which they referred
to as RNase k6, as an unexpected result of their efforts to trace the
evolutionary history of the ribonuclease gene family. RNASE6 encodes a
150-amino acid polypeptide most closely related to ribonuclease-2
(RNASE2; 131410); these 2 proteins share 47% amino acid sequence
identity. RNASE6 mRNA was detected in all human tissues tested, with
lung representing the most abundant source.
MAPPING
Rosenberg and Dyer (1996) used a PCR-based technique to map the RNASE6
gene to chromosome 14.
ECRP
| dbSNP name | rs10459477(A,G); rs3748340(G,C); rs3748341(G,A) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 643332 |
| snpEff Gene Name | RP11-219E7.4 |
| EntrezGene Description | ribonuclease, RNase A family, 2 (liver, eosinophil-derived neurotoxin) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4201 |
| ExAC AF | 0.677,8.144e-06 |
MIR6717
| dbSNP name | rs117650137(G,A) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 57447 |
| EntrezGene Symbol | NDRG2 |
| snpEff Gene Name | NDRG2 |
| EntrezGene Description | NDRG family member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0202 |
| ESP Afr MAF | 0.010116 |
| ESP All MAF | 0.031756 |
| ESP Eur/Amr MAF | 0.041169 |
| ExAC AF | 0.025 |
OR5AU1
| dbSNP name | rs7145814(T,C); rs45603634(G,T); rs45462402(C,T); rs59120409(G,A); rs7161544(G,A); rs4982419(G,A); rs17102038(T,G); rs17102045(G,A) |
| ccdsGene name | CCDS32042.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 390445 |
| EntrezGene Description | olfactory receptor, family 5, subfamily AU, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR5AU1:NM_001004731:exon1:c.A895G:p.I299V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC0 |
| dbNSFP Uniprot ID | O5AU1_HUMAN |
| dbNSFP KGp1 AF | 0.715201465201 |
| dbNSFP KGp1 Afr AF | 0.85162601626 |
| dbNSFP KGp1 Amr AF | 0.726519337017 |
| dbNSFP KGp1 Asn AF | 0.48951048951 |
| dbNSFP KGp1 Eur AF | 0.791556728232 |
| dbSNP GMAF | 0.2851 |
| ESP Afr MAF | 0.182025 |
| ESP All MAF | 0.201522 |
| ESP Eur/Amr MAF | 0.211512 |
| ExAC AF | 0.743 |
OR10G3
| dbSNP name | rs17792766(G,T); rs28436899(C,T); rs11626669(G,A); rs11626693(G,T); rs45612332(T,C); rs17792778(T,C); rs368210042(C,T) |
| ccdsGene name | CCDS32046.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 26533 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G3:NM_001005465:exon1:c.C666A:p.I222I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1065 |
| ESP Afr MAF | 0.152746 |
| ESP All MAF | 0.151545 |
| ESP Eur/Amr MAF | 0.15093 |
| ExAC AF | 0.112 |
OR10G2
| dbSNP name | rs10146821(G,A) |
| ccdsGene name | CCDS32047.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 26534 |
| EntrezGene Description | olfactory receptor, family 10, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10G2:NM_001005466:exon1:c.C199T:p.L67F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGC3 |
| dbNSFP Uniprot ID | O10G2_HUMAN |
| dbNSFP KGp1 AF | 0.0824175824176 |
| dbNSFP KGp1 Afr AF | 0.0813008130081 |
| dbNSFP KGp1 Amr AF | 0.185082872928 |
| dbNSFP KGp1 Asn AF | 0.0297202797203 |
| dbNSFP KGp1 Eur AF | 0.0738786279683 |
| dbSNP GMAF | 0.08219 |
| ESP Afr MAF | 0.083296 |
| ESP All MAF | 0.074197 |
| ESP Eur/Amr MAF | 0.069535 |
| ExAC AF | 0.087 |
OR4E2
| dbSNP name | rs12717305(A,G); rs2874103(G,A); rs970382(A,G); rs61732411(C,T) |
| ccdsGene name | CCDS41916.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 26686 |
| EntrezGene Description | olfactory receptor, family 4, subfamily E, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4E2:NM_001001912:exon1:c.A120G:p.S40S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4775 |
| ESP Afr MAF | 0.393236 |
| ESP All MAF | 0.468689 |
| ESP Eur/Amr MAF | 0.49544 |
| ExAC AF | 0.475 |
LRP10
| dbSNP name | rs28534929(A,G) |
| ccdsGene name | CCDS9578.1 |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 26020 |
| EntrezGene Description | low density lipoprotein receptor-related protein 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LRP10:NM_014045:exon5:c.A415G:p.M139V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0263 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7Z4F1 |
| dbNSFP Uniprot ID | LRP10_HUMAN |
| dbNSFP KGp1 AF | 0.0178571428571 |
| dbNSFP KGp1 Afr AF | 0.0772357723577 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01745 |
| ESP Afr MAF | 0.05881 |
| ESP All MAF | 0.020378 |
| ESP Eur/Amr MAF | 0.000698 |
| ExAC AF | 6.653e-03,8.133e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, severe to profound
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the TRIO- and F-actin-binding protein (TRIOBP,
609761.0001)
OMIM Title
*609921 LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 10; LRP10
;;LRP9
OMIM Description
CLONING
Sugiyama et al. (2000) cloned mouse Lrp10, which they called Lrp9.
Following cleavage of a 17-amino acid signal sequence, the mature type I
membrane protein contains 696 amino acids and has a calculated molecular
mass of 74.8 kD. It contains 2 N-terminal CUB domains separated by a
single ligand-binding repeat, followed by a cluster of 3 additional
ligand-binding repeats, a central transmembrane domain, and a
proline-rich C-terminal intracellular region. Northern blot analysis
detected abundant Lrp10 expression in mouse liver, kidney, lung, and
heart, with weaker expression in spleen and brain. Northern blot
analysis of human tissues revealed a slightly different expression
pattern, with a 3-kb transcript present in blood leukocytes, lung,
placenta, small intestine, liver, kidney, spleen, thymus, colon,
skeletal muscle, and heart, but not in brain.
GENE FUNCTION
Sugiyama et al. (2000) found that transfection of Chinese hamster ovary
cells with mouse Lrp10 increased cholesteryl ester formation in the
presence of apolipoprotein E (APOE; 107741)-enriched beta-very low
density lipoproteins. They concluded that LRP10 may play a role in the
uptake of APOE-containing lipoproteins.
MAPPING
By radiation hybrid analysis, Sugiyama et al. (2000) mapped the human
LRP10 gene to chromosome 14q11.2. They mapped the mouse Lrp10 gene to a
region of chromosome 14 that shares homology of synteny with human
chromosome 14q11.
MIR4707
| dbSNP name | rs2273626(C,A) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 100616424 |
| snpEff Gene Name | HAUS4 |
| EntrezGene Description | microRNA 4707 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4982 |
| ExAC AF | 0.272 |
PSMB11
| dbSNP name | rs57362684(A,G); rs72684308(T,G); rs11628336(G,A); rs76262327(A,C) |
| cytoBand name | 14q11.2 |
| EntrezGene GeneID | 122706 |
| snpEff Gene Name | CDH24 |
| EntrezGene Description | proteasome (prosome, macropain) subunit, beta type, 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.107 |
| ESP Afr MAF | 0.162886 |
| ESP All MAF | 0.115814 |
| ESP Eur/Amr MAF | 0.092597 |
| ExAC AF | 0.089 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blue/yellow color vision defect;
Red/green color vision defect;
Photophobia;
Night blindness;
Cataract;
Cystoid macular degeneration;
Pigmentary retinopathy (mixed nummular and spicular type in autosomal
dominant cases);
Pigmentary retinopathy (round, irregular clumps of pigment with little
or no evidence of bone spicule formation in autosomal recessive cases);
Three concentric rings of hyperautofluorescence - around the fovea,
along the vascular arcades, and in the far periphery;
Rod-cone dystrophy on ERG (early);
Absent rod-and cone-mediated responses on ERG (late)
MISCELLANEOUS:
Allelic to enhanced S-cone syndrome (268100);
Onset of symptoms age 5-30
MOLECULAR BASIS:
Caused by mutation in the nuclear receptor subfamily 2, group E, member
3 gene (NR2E3, 604485.0006)
OMIM Title
*611137 PROTEASOME SUBUNIT, BETA-TYPE, 11; PSMB11
;;PROTEASOME SUBUNIT, BETA-5 FAMILY, THYMUS-SPECIFIC;;
PROTEASOME SUBUNIT BETA-5T
OMIM Description
DESCRIPTION
Proteasomes generate peptides that are presented by major
histocompatibility complex (MHC) I molecules to other cells of the
immune system. Proteolysis is conducted by 20S proteasomes, complexes of
28 subunits arranged as a cylinder in 4 heteroheptameric rings: alpha-1
to -7, beta-1 to -7, beta-1 to -7, and alpha-1 to -7. The catalytic
subunits are beta-1 (PSMB6; 600307), beta-2 (PSMB7; 604030), and beta-5
(PSMB5; 600306). Three additional subunits, beta-1i (PSMB9; 177045),
beta-2i (PSMB10; 176847), and beta-5i (PSMB8; 177046), are induced by
gamma-interferon (IFNG; 147570) and are preferentially incorporated into
proteasomes to make immunoproteasomes. PSMB11, or beta-5t, is a
catalytic subunit expressed exclusively in cortical thymic epithelial
cells (Murata et al., 2007).
CLONING
By searching databases for proteasome-related genes, followed by PCR of
HeLa cell genomic DNA, Murata et al. (2007) cloned human PSMB11, which
they called beta-5t. The beta-5t protein was most homologous to beta-5
and beta-5i. Northern and Western blot analyses of mouse tissues showed
that beta-5t was expressed exclusively in thymus. Immunohistochemical
analysis detected beta-5t expression in mouse cortical thymic epithelial
cells.
GENE FUNCTION
Using immunoprecipitation analysis, Murata et al. (2007) found that
about 20% of 20S proteasomes in mouse thymus contained beta-5t instead
of beta-5 or beta-5i. Moreover, these beta-5t-containing proteasomes, or
thymoproteasomes, preferentially incorporated beta-1i and beta-2i in
place of beta-1 and beta-2, respectively.
GENE STRUCTURE
Murata et al. (2007) determined that the PSMB11 gene contains 1 exon in
both mice and humans.
MAPPING
By genomic sequence analysis, Murata et al. (2007) mapped the PSMB11
gene to chromosome 14, adjacent to the PSMB5 gene on the opposite
strand.
ANIMAL MODEL
Murata et al. (2007) found that mice deficient in beta-5t had fewer Cd8
(see 186910) single-positive (SP) thymocytes, but normal numbers of Cd4
(186940) SP cells, compared with wildtype mice. They concluded that
PSMB11 plays a pivotal role in development of CD8-positive T cells.
TINF2
| dbSNP name | rs10141326(C,T); rs17102311(G,A); rs17102313(C,T); rs36124829(G,A) |
| ccdsGene name | CCDS41937.1 |
| cytoBand name | 14q12 |
| EntrezGene GeneID | 26277 |
| EntrezGene Description | TERF1 (TRF1)-interacting nuclear factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TINF2:NM_001099274:exon6:c.C721T:p.P241S,TINF2:NM_012461:exon6:c.C721T:p.P241S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7489 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DFJ1 |
| dbNSFP KGp1 AF | 0.00412087912088 |
| dbNSFP KGp1 Afr AF | 0.0162601626016 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.004132 |
| ESP Afr MAF | 0.02406 |
| ESP All MAF | 0.007878 |
| ESP Eur/Amr MAF | 0.00012 |
| ExAC AF | 0.002155 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly (-4 to -7 SD);
[Face];
Low forehead;
Sloping forehead
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Poor speech development;
Poor motor development;
Seizures (variable);
Hypertonia;
Hyperreflexia;
Spastic quadriparesis;
Hemiparesis;
Small brain;
Polymicrogyria;
Pachygyria;
Abnormal gyral pattern;
Simplified gyral pattern;
Lissencephaly;
Schizencephaly;
Thin corpus callosum;
Abnormal corpus callosum;
Heterotopia;
Abnormal neuronal migration;
Relative preservation of the cerebellum;
[Behavioral/psychiatric manifestations];
Impulsivity;
Aggression;
Hyperactivity;
Head banging
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
MISCELLANEOUS:
Variable phenotype, particularly with regard to cortical malformations;
Onset in utero
MOLECULAR BASIS:
Caused by mutation in the WD repeat-containing protein 62 (WDR62,
613583.0001)
OMIM Title
*604319 TRF1-INTERACTING NUCLEAR FACTOR 2; TINF2
;;TIN2
OMIM Description
DESCRIPTION
TINF2 is a subunit of the 6-protein shelterin/telosome complex. This
complex protects telomere ends and cooperates with telomerase (see TERT;
187270) to maintain telomeres. TINF2 plays a central role in the
assembly and function of the shelterin/telosome complex by connecting
the double-stranded DNA-binding proteins TRF1 (TERF1; 600951) and TRF2
(TERF2; 602027) to the single-stranded DNA-binding unit TPP1 (ACD;
609377)/POT1 (606478) (summary by Yang et al., 2011).
CLONING
By interaction cloning using the telomeric DNA-binding protein TRF1, Kim
et al. (1999) isolated a novel human telomere-associated protein that
they named TIN2. The TIN2 protein contains 354 amino acids. A wide
variety of human tissues and cell types expressed a 2.4-kb TIN2
transcript on Northern blot analysis, and expression did not vary with
growth state, immortalization, or transformation. TIN2 colocalized with
TRF1 in nuclei and metaphase chromosomes.
Yang et al. (2011) stated that the 354-amino acid TINF2 protein contains
an N-terminal domain of about 200 amino acids that binds the
shelterin/telosome subunits TPP1 and TRF2, followed by an approximately
20-amino acid TRF1-binding motif.
GENE FUNCTION
Kim et al. (1999) showed that TIN2 interacted with TRF1 in vitro and in
cells. Expression of a TIN2 mutant lacking N-terminal sequences resulted
in elongated human telomeres in a telomerase-dependent manner. Kim et
al. (1999) interpreted the findings as suggesting that TRF1 is
insufficient for control of telomere length in human cells and that TIN2
is an essential mediator of TRF1 function. The mutant TIN2 had the
properties of a dominant-negative mutant. The findings suggested that
wildtype TIN2 is a negative regulator of telomerase length.
Telomere length in humans is partly controlled by a feedback mechanism
in which telomere elongation by telomerase is limited by the
accumulation of the TRF1 complex at chromosome ends. TRF1 itself can be
inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its
interacting partner tankyrase-1 (603303), which abolishes its DNA
binding activity in vitro and removes the TRF1 complex from telomeres in
vivo. Ye and de Lange (2004) reported that the inhibition of TRF1 by
tankyrase is in turn controlled by a second TRF1-interacting factor,
TIN2. Partial knockout of TIN2 by small hairpin RNA in a
telomerase-positive cell line resulted in telomere elongation, which is
typical of reduced TRF1 function. Transient inhibition of TIN2 with
small interfering RNA led to diminished telomeric TRF1 signals. These
and other data identified TIN2 as a PARP modulator in the TRF1 complex
and explained how TIN2 contributes to the regulation of telomere length.
Liu et al. (2004) found that TIN2 was part of a high molecular mass
protein complex in HeLa cells that mediates telomere end-capping and
length control. Other members of this complex are TRF1, TRF2, RAP1
(TERF2IP; 605061), POT1, and TPP1.
Through reconstitution and fractionation experiments, O'Connor et al.
(2006) found that TPP1 and TIN2 were essential mediators of telomeric
complex formation and that TPP1-TIN2 interaction regulated bridging of
TRF1 and TRF2. Overexpression of TPP1 enhanced TIN2-TRF1 association,
and conversely, knockdown of TPP1 reduced the ability of endogenous TRF1
to associate with the TRF2 complex. O'Connor et al. (2006) concluded
that coordinated interaction among TPP1, TIN2, TRF1, and TRF2 is
required for assembly of the telomere complex and ultimately for
telomere maintenance.
Mammalian telomeres are protected by a 6-protein complex, shelterin.
Shelterin contains 2 closely related proteins, TRF1 and TRF2, which
recruit various proteins to telomeres. Chen et al. (2008) dissected the
interactions of TRF1 and TRF2 with their shared binding partner TIN2 and
other shelterin accessory factors. TRF1 recognizes TIN2 using a
conserved molecular surface in its TRF homology domain. However, this
same surface does not act as a TIN2-binding site in TRF2, and TIN2
binding to TRF2 is mediated by a region outside the TRF homology domain.
Instead, the TRF homology domain docking site of TRF2 binds a shelterin
accessory factor, Apollo, also known as SNM1B (609683), which does not
interact with the TRF homology domain of TRF1. Conversely, the TRF
homology domain of TRF1, but not of TRF2, interacts with another
shelterin-associated factor, PINX1 (606505).
MOLECULAR GENETICS
Patients with dyskeratosis congenita (DKC), a heterogeneous inherited
bone marrow failure syndrome, have abnormalities in telomere biology
including very short telomeres. Whereas germline mutations in DKC1
(300126), TERC (602322), and TERT (187270) have been found in DKC
patients, approximately 60% of DKC patients lack an identifiable
mutation. With the very short telomere phenotype and a highly penetrant,
rare disease model, Savage et al. (2008) performed a linkage scan on a
family with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990)
in which affected members did not have mutations in DKC1, TERC, or TERT.
Evidence favoring linkage was found at 14q11.2, which led to the
identification of the TINF2 mutations K280E (604319.0001) in the proband
and her 5 affected relatives. Three additional unrelated DKC probands,
including 1 with Revesz syndrome (268130), carried TINF2 R282H
(604319.0002). A fifth DKC proband had an R282S mutation (604319.0003).
All 3 mutations were in extremely close proximity and near the end of
the TRF1 (600951)-binding domain of the TIN2 protein. This study
provided the first example of a shelterin complex mutation linked to
human disease and confirmed the role of very short telomeres as a
diagnostic test for dyskeratosis congenita.
Walne et al. (2008) identified heterozygous mutations in the TINF2 gene
in 33 (18.9%) of 175 cases of uncharacterized DKC. Of these 33 samples,
21 were found to have a mutation in arg282 in exon 6 (see, e.g., R282H;
604319.0002). The remaining 12 mutations were all in a tight cluster
between residues 280 and 298. No additional mutations were found
elsewhere in the gene. Most of the mutations were de novo. Clinically,
all the DKC patients with a TINF2 mutation had severe disease associated
with shorter telomeres compared to patients with DKC1 mutations.
Yang et al. (2011) found that expression of TIN2 with the K280E, R282H,
or R282S mutation in human cell lines recapitulated the telomere
shortening defect in DKC. These mutations did not affect total
telomerase activity, TIN2 localization at telomeres, telomere end
protection, or expression or stability of other core telomeric proteins.
Despite the clustering of these mutation near the TRF1-binding motif,
they did not affect interaction of TIN2 with TRF1. However, all 3
mutations reduced the level of telomerase activity and the amount of
TERC protein that immunoprecipitated with TIN2. Yang et al. (2011)
concluded that mutation of K280 or R282 in TIN2 results in defective
targeting of telomerase to telomere ends.
The 2 truncating mutations identified by Sasa et al. (2012) in 2
unrelated children with severe DKCA3 (Q269X, 604319.0005 and Q271X,
604319.0007, respectively) both occurred in exon 6, but affected the
more N-terminal region compared to earlier reported mutations and thus
extended the affected segment of the gene to amino acid 269. In vitro
functional expression studies in HEK293 cells showed that the Q269X
mutant protein was markedly impaired in its ability to interact with
TERF1. This was in contrast to R282H (604319.0002), which retained
substantial ability to interact with TERF1. These findings indicated
that disrupted TERF1 binding is not the main factor driving disease
pathogenesis, but may contribute to a more severe phenotype.
Vulliamy et al. (2012) identified 16 new families with mutations in exon
6 of the TINF2 gene ascertained from 224 consecutive patients with
different forms of bone marrow failure, including 46 with criteria
meeting dyskeratosis congenita, 122 with aplastic anemia, and 57 with
some features of DKC. Seven of the 46 patients with DKC carried
mutations, 5 of whom had the R252H mutation (604319.0002). Nine of 57
patients with bone marrow failure and some features of DKC were found to
carry mutations, including 2 with R282H, and 4 with nonsense or
frameshift mutations (see, e.g., 604319.0005 and 604319.0008). Telomere
length was only available for 7 of the mutation carriers, 6 of whom had
shortened telomeres. The seventh patient had a missense variant that was
also found in an asymptomatic individual, and both had normal telomere
lengths, suggesting that this variant was not disease causing. Vulliamy
et al. (2012) concluded that TINF2 mutations can cause a spectrum of
clinical features and that telomere length should be able to distinguish
pathogenic mutations from polymorphic variants in the absence of
functional data. Most of the mutations appeared to occur de novo.
LTB4R
| dbSNP name | rs2224123(T,A); rs2224122(G,C); rs3742510(G,C); rs3742511(T,C); rs4981503(T,G); rs3181384(T,C) |
| cytoBand name | 14q12 |
| EntrezGene GeneID | 1241 |
| snpEff Gene Name | ADCY4 |
| EntrezGene Description | leukotriene B4 receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1869 |
OMIM Clinical Significance
Oncology:
Prostate cancer
Inheritance:
Autosomal dominant form
OMIM Title
*601531 LEUKOTRIENE B4 RECEPTOR; LTB4R
;;LTB4R1;;
CHEMOKINE RECEPTOR-LIKE 1; CMKRL1;;
PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 7; P2RY7;;
PURINOCEPTOR P2Y7; P2Y7;;
LEUKOTRIENE B4 G PROTEIN-COUPLED RECEPTOR; BLTR;;
BLT1;;
G PROTEIN-COUPLED RECEPTOR 16; GPR16
OMIM Description
CLONING
Using degenerate PCR to find cDNAs encoding new G protein
coupled-receptors in human B cells, Owman et al. (1996) identified a
CMKRL1 cDNA which encodes a 352-amino acid polypeptide with a calculated
mass of 43 kD. The nearest homologs of this novel sequence are the
chemoattractant leukocyte receptors, such as the C5a anaphylatoxin
receptor (113995) and the FMLP receptor (136537). Northern blot analysis
revealed transcripts of 5 kb and 7.5 kb in several tissues of the immune
system including spleen, thymus, and lymph node. Owman et al. (1996)
considered the high level of expression in lymphoid tissues suggestive
of the role of CMKRL1 in the regulation of the inflammatory system.
Akbar et al. (1996) used a chicken P2Y3 cDNA to screen a human
erythroleukemia (HEL) cell cDNA library and cloned a purinoceptor cDNA,
which they termed P2Y7. Sequencing revealed an open reading frame coding
for a polypeptide of 352 amino acids having 7 putative transmembrane
domains. The P2Y7 receptor has 23 to 30% identity to other P2Y
receptors, but forms a unique branch within the P2Y family. Northern
blot analysis showed that the P2Y7 gene produced a 1.6-kb transcript
which is expressed at highest levels in human heart, human skeletal
muscle, rat heart, and rat cardiomyocytes and at lower levels in human
brain and human liver. Akbar et al. (1996) noted that its expression in
HEL cells is below the threshold of detection by Northern blot.
Leukotriene B4 (LTB4) is a potent chemoattractant that is primarily
involved in inflammation, immune responses, and host defense against
infection (Samuelsson et al., 1987; Chen et al., 1994). LTB4 activates
inflammatory cells by binding to its cell surface receptor, BLTR. LTB4
can also bind and activate the intranuclear transcription factor
PPAR-alpha (170998), resulting in the activation of genes that terminate
inflammatory processes (Devchand et al., 1996). Yokomizo et al. (1997)
cloned the cDNA encoding a cell surface LTB4 receptor that is highly
expressed in human leukocytes. Two cDNA clones isolated from retinoic
acid-differentiated HL-60 cells contained identical open reading frames
encoding a protein of 352 amino acids and predicted to contain 7
membrane-spanning domains, but different 5-prime untranslated regions.
GENE FUNCTION
Using binding and displacement assays in COS-7 cells, Akbar et al.
(1996) showed that P2Y7 had a high affinity for ATP and much less for
UTP and ADP. The rank order of affinities in the binding series was
distinct from any known for the P2Y1-P2Y6 receptors. Like other P2Y
receptors, P2YR was coupled to phospholipase C and not to adenylate
cyclase. Akbar et al. (1996) speculated that P2Y7 may be the cardiac P2Y
receptor involved in the regulation of cardiac muscle contraction
through modulation of L-type calcium currents.
Yokomizo et al. (1997) found that the putative purinoceptor P2Y7 has a
primary structure identical to that of a BLTR clone, HL-5. To determine
whether BLTR also functions as a purinoceptor, they established stable
transformants of BLTR in glioma cells that possess negligible amounts of
intrinsic purinoceptors. In these cells, up to 300 microM caused no
change in intracellular calcium levels, but significant increases in the
calcium concentrations were induced by exposure to 10 nanoM LTB4. These
results were interpreted to indicate that this receptor is not a
purinoceptor, but a BLTR.
Yokomizo et al. (1997) found that LTB4 induced increases in
intracellular calcium, accumulation of
D-myo-inositol-1,4,5-triphosphate, and inhibition of adenylyl cyclase in
Chinese hamster ovary (CHO) cells stably expressing BLTR. Furthermore,
CHO cells expressing exogenous BLTR showed marked chemotactic responses
toward low concentrations of LTB4 in a pertussis-toxin-sensitive manner.
Using immunohistochemical analysis, Back et al. (2005) found that BLTR
colocalized with markers of smooth muscle cells (SMCs), endothelial
cells, and macrophages in human atherosclerotic lesions. In
nonatherosclerotic internal mammary arteries, BLTR localized in SMCs,
but not in endothelial cells. Exposure of human coronary artery SMCs to
LTB4 increased their whole-cell current about 4-fold in patch-clamp
studies and induced SMC migration in a chemotaxis chamber. Treatment of
human coronary artery SMCs with IL1B (147720) or lipopolysaccharide
resulted in elevated BLTR mRNA and protein levels. SMCs derived from the
intimal thickening of rat carotid arteries subjected to balloon
angioplasty showed elevated Bltr mRNA levels compared with normal medial
SMCs. Bltr expression was upregulated by inducers of NF-kappa-B (see
164011) in rat medial SMCs, and the elevated Bltr expression in rat
intimal SMCs was downregulated by transfection with IKK-beta (IKBKB;
603258). Development of intimal hyperplasia after angioplasty in rats
was reduced by treatment with a Bltr antagonist.
GENE STRUCTURE
By genomic sequence analysis, Kato et al. (2000) determined that BLT1
lacks TATA and CAAT elements but possesses a GC-rich sequence in the
promoter region. Luciferase reporter analysis showed that the region
required for basal transcription, which is activated by SP1, is about 80
bp upstream from the initiator sequence. Southern blot analysis revealed
that the CpG sites of the BLT1 promoter are highly methylated in cells
not expressing BLT1, but are unmethylated in cells expressing BLT1. Kato
et al. (2000) also found that the promoter region of BLT1 is localized
within the open reading frame encoding BLT2 (605773).
MAPPING
Owman et al. (1996) mapped the CMKRL1 gene to 14q11.2-q12 by
fluorescence in situ hybridization.
Akbar et al. (1996) used PCR on a panel of mouse-rodent somatic cell
hybrids to localize the P2RY7 gene to human chromosome 14. Somers et al.
(1997) did sequence tagged site (STS) mapping of the P2RY7 gene using
the National Center for Biotechnology Information (NCBI) database. In
this way, they positioned the P2RY7 gene between D14S283 and D14S264.
ANIMAL MODEL
Shao et al. (2006) generated mice lacking both Blt1 and Blt2 and found
that they lost responsiveness to Ltb4. These mice were completely
protected from collagen-induced arthritis, as were mice lacking Blt1
only. In contrast, wildtype mice developed severe disease, with loss of
joint architecture, inflammation, fibrosis, pannus formation, and bone
erosion. However, serum levels of anticollagen antibodies were similar
in wildtype and mutant mouse strains. Shao et al. (2006) proposed that
BLT1 may be a useful target for antiinflammatory therapy.
By measuring bone mineral content, bone mass, and trabecular bone volume
per tissue volume, Hikiji et al. (2009) found that Blt1 -/- mice were
resistant to bone loss induced by ovariectomy or treatment with
lipopolysaccharide, a potent stimulator of bone resorption. Cultured
wildtype osteoclasts expressed both leukotriene B4 and Blt1, changed
their morphology in response to leukotriene B4 through an inhibitory G
protein (GNAI1; 139310)-Rac1 (602048) signaling pathway, and showed the
ability to resorb calcium. These functions were impaired in osteoclasts
cultured from Blt1 -/- animals. Hikiji et al. (2009) concluded that
leukotriene B4 regulates osteoclast activity via a BLT1-inhibitory G
protein-RAC1 signaling pathway.
GZMH
| dbSNP name | rs17105894(C,G); rs20545(C,T); rs1957526(A,C) |
| cytoBand name | 14q12 |
| EntrezGene GeneID | 2999 |
| EntrezGene Description | granzyme H (cathepsin G-like 2, protein h-CCPX) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Zonular cataract;
Pulverulent cataract;
Stellate cataract;
Nuclear cataract;
Anterior polar cataract;
Perinuclear cataract;
Lamellar cataract
MISCELLANEOUS:
Variable cataract phenotypes within a family;
Cataracts are progressive but may vary between eyes of an individual;
Cataracts variably present at birth
MOLECULAR BASIS:
Caused by mutation in the heat-shock transcription factor 4 (HSF4,
602438.0001)
OMIM Title
*116831 GRANZYME H; GZMH
;;CATHEPSIN G-LIKE 2; CTSGL2;;
CGL2
OMIM Description
This gene is located in a cluster on 14q11.2 (Hanson et al., 1990) with
cathepsin G (116830) and CTSGL1 (123910). A similar cluster of genes in
the mouse is located on chromosome 14 near the T-cell receptor alpha
chain locus (see 186880) (Crosby et al., 1990).
ARHGAP5-AS1
| dbSNP name | rs57278628(T,C) |
| cytoBand name | 14q12 |
| EntrezGene GeneID | 84837 |
| snpEff Gene Name | ARHGAP5 |
| EntrezGene Description | ARHGAP5 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1006 |
CFL2
| dbSNP name | rs9491(C,A); rs41528946(T,C); rs712301(T,A); rs11539496(A,G); rs9789(T,C) |
| cytoBand name | 14q13.1 |
| EntrezGene GeneID | 1073 |
| EntrezGene Description | cofilin 2 (muscle) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2314 |
| ExAC AF | 0.209 |
OMIM Clinical Significance
Limbs:
Rhizomelic short limbs;
Short humeri;
Deformed humeral heads;
Coxa vara
Radiology:
Platyspondyly;
Anomalous segmentation of proximal humeral metaphyses;
Short bowed humeri;
Brachydactyly;
Brachymetacarpalia
Inheritance:
? Autosomal recessive
OMIM Title
*601443 COFILIN 2; CFL2
;;COFILIN, MUSCLE
OMIM Description
DESCRIPTION
Cofilin is a widely distributed intracellular actin-modulating protein
that binds and depolymerizes filamentous F-actin and inhibits the
polymerization of monomeric G-actin in a pH-dependent manner. (Gillett
et al., 1996). Cofilin-2 is a member of the AC group of proteins that
also includes cofilin-1 (CFL1) and destrin (DSTN; 609114), all of which
regulate actin-filament dynamics (Bamburg et al., 1999; Maciver and
Hussey, 2002). The CFL2 gene encodes a skeletal muscle-specific isoform
(Vartiainen et al., 2002) localized to the thin filaments, where it
exerts its effect on actin, in part through interactions with
tropomyosins (Ono and Ono, 2002).
CLONING
By RT-PCR using primers based on murine Cfl2, Thirion et al. (2001)
cloned 4 CFL2 variants from human fetal and adult myoblasts. The
transcripts differ in their 5-prime and 3-prime ends, but have identical
coding regions, due to alternative splicing of the first exon and the
use of alternative polyadenylation signals. The deduced 166-amino acid
CFL2 protein has a calculated molecular mass of 19 kD and shares 99% and
81% identity with mouse Cfl2 and human CFL1 (601442), respectively.
Northern blot analysis detected 2 major CLF2 transcripts that were
highly expressed in heart and skeletal muscle, with weaker expression in
all other tissues examined. Primary human myoblasts and myotubes
expressed transcripts of 1.55, 1.65, and 3.2 kb. Immunohistochemical
analysis of murine and human skeletal muscle localized CFL2 in a uniform
cytoplasmic distribution characteristic of sarcomeric proteins. Western
blot analysis of healthy mouse muscle showed that 30 to 50% of Cfl2 was
phosphorylated.
Agrawal et al. (2012) stated that mouse Cfl2 is expressed as 1.8- and
3.0-kb transcripts that differ in their 3-prime UTRs only and are
alternately expressed during striated muscle development. The 1.8-kb
transcript is expressed at embryonic day 13, peaks in skeletal and
cardiac muscle at birth, and decreases thereafter. The 3.0-kb transcript
is expressed in skeletal muscle only, and its expression increases as
expression of the 1.8-kb transcript decreases.
GENE STRUCTURE
Thirion et al. (2001) determined that the CFL2 gene contains 5 exons,
including alternative first exons (exons 1a and 1b) that encode the
initiating methionine only. Identification of transcription
factor-binding sites upstream of exons 1a and 1b suggested the presence
of 2 promoters. CFL2 has 2 polyadenylation signals.
MAPPING
Gillett et al. (1996) mapped CFL2, the human muscle-type (M-type)
cofilin, to chromosome 14 by analysis of a somatic cell hybrid panel
using an expressed sequence tag (EST) with homology to the mouse
muscle-type cofilin and chicken cofilin.
Agrawal et al. (2012) stated that the CFL2 gene maps to chromosome
14q12.
GENE FUNCTION
By Western blot analysis of 2-dimensional gels, Thirion et al. (2001)
found that expression of Clf2 decreased sharply and that phosphorylated
Cfl2 became undetectable following acute muscle damage in mice. Skeletal
muscle of Duchenne muscular dystrophy (310200) patients and dystrophin
(DMD; 300377)-deficient mdx mice, where continuous muscle degeneration
and regeneration occurs, showed a similar phenomenon.
MOLECULAR GENETICS
Agrawal et al. (2007) used genomic PCR and DNA sequencing to screen the
CFL2 gene in 113 unrelated patients with nemaline myopathy and 58
patients with clinical pathologic diagnoses of other congenital
myopathies. None of the patients had known mutations in previously
identified genes. In 2 sibs with nemaline myopathy (NEM7; 610687) in a
large family of Middle Eastern origin, Agrawal et al. (2007) identified
a homozygous mutation in the CFL2 gene (A35T; 601443.0001). The
proband's muscle contained characteristic nemaline bodies, as well as
occasional fibers with minicores, concentric laminated bodies, and areas
of F-actin accumulation. Cofilin-2 levels were significantly lower in
the proband's muscle, and the mutant protein was less soluble when
expressed in Escherichia coli, suggesting that deficiency of cofilin-2
may result in reduced depolymerization of actin filaments, causing their
accumulation in nemaline bodies, minicores, and, possibly concentric
laminated bodies.
In 2 Iraqi sisters, born of consanguineous parents, with nemaline
myopathy-7, Ockeloen et al. (2012) identified a homozygous missense
mutation in the CFL2 gene (V7M; 601443.0002). The mutation was found by
homozygosity mapping followed by candidate gene sequencing.
ANIMAL MODEL
Agrawal et al. (2012) found that Cfl2 -/- mice were indistinguishable
from wildtype at birth. However, by postnatal day 3, Cfl2 -/- mice
showed reduced size and activity, followed by rapid deterioration and
death by postnatal day 8. Presence of milk in stomachs of Cfl2 -/- mice
at postnatal day 3, but not at postnatal day 7, suggested that the older
animals had lost the ability to suckle. Targeted disruption of Cfl2 to
skeletal or cardiac muscle resulted in a phenotype that was only
modestly less severe. Electron microscopic analysis revealed ballooning
degeneration of skeletal muscle fibers, core-like lesions, extensive
sarcomeric disruption, nemaline bodies, and actin accumulation. Cardiac
muscle fibers did not show evidence of degeneration. Muscle degeneration
and weakness in Cfl2 -/- mice coincided with normal developmental
depletion of Cfl1 in myofibers. Agrawal et al. (2012) hypothesized that
Cfl1 may initiate myofibrillogenesis, whereas Cfl2 is required for
myofiber maintenance.
IGBP1P1
| dbSNP name | rs1967723(T,C); rs185887438(G,A); rs712315(A,T) |
| cytoBand name | 14q13.2 |
| EntrezGene GeneID | 100506157 |
| EntrezGene Symbol | LOC100506157 |
| snpEff Gene Name | RP11-85K15.1 |
| EntrezGene Description | uncharacterized LOC100506157 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3131 |
INSM2
| dbSNP name | rs2296919(T,C) |
| cytoBand name | 14q13.2 |
| EntrezGene GeneID | 84684 |
| snpEff Gene Name | RALGAPA1 |
| EntrezGene Description | insulinoma-associated 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4339 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Angina pectoris
SKIN, NAILS, HAIR:
[Skin];
Eruptive xanthomas;
Palmar xanthomas
LABORATORY ABNORMALITIES:
Hepatic lipase deficiency;
Abnormally triglyceride-rich low and high density lipoproteins and
beta-migrating very low density lipoproteins
MOLECULAR BASIS:
Caused by mutation in the hepatic lipase gene (LIPC, 151670.0001)
OMIM Title
*614027 INSULINOMA-ASSOCIATED 2; INSM2
;;INSULINOMA-ASSOCIATED GENE 6; IA6
OMIM Description
DESCRIPTION
INSM2 belongs to the SNAI1 (604238)/GFI1 (600871)/INSM1 (600010) family
of transcriptional repressors (Cai et al., 2011).
CLONING
By searching an EST database for sequences similar to INSM1, followed by
PCR of a human brain cDNA library, Cai et al. (2011) cloned INSM2. The
deduced 566-amino acid protein contains an SNAI1/GFI1 motif followed by
2 proline-rich sequences in its N-terminal half and 5 C2H2-type zinc
fingers in its C-terminal half. INSM2 shares 51% amino acid identity
with INSM1. Northern blot analysis detected a 4.8-kb INSM2 transcript
that was highly expressed in heart and pancreas, with lower expression
in liver, skeletal muscle, and kidney, and little to no expression in
brain, placenta, and lung. Northern blot analysis of mouse tissues
showed a similar expression profile. Insm2 was detected at all embryonic
mouse stages examined, with highest expression between days 11.5 and
13.5 of whole embryos. In developing mouse brain, expression peaked 2
weeks postnatally and gradually decreased to adult levels. Western blot
analysis detected Insm2 at an apparent molecular mass of 60 kD in mouse
pancreas and brain, mouse MIN6 islet and N2a neuroblastoma cells, and
rat PC12 adrenal pheochromocytoma cells. Immunofluorescence analysis
detected INSM2 in mouse and human pancreatic islet alpha and beta cells,
but not in acinar cells. It was also detected in fetal duodenum and in
deeper layers of mouse adrenal glands, neuronal cells of the cerebral
cortex, Purkinje cells of cerebellum, and CA1 and CA3 regions of the
hippocampus. INSM2 colocalized with NGN3 (NEUROG3; 604882) and NEUROD1
(601724) in human and mouse fetal pancreas.
GENE FUNCTION
Cai et al. (2011) identified 10 putative E boxes (CANNTG) in the 5-prime
region of mouse and human INSM2. They found that the 2 most proximal E
boxes of the mouse Insm2 gene were bound by the basic helix-loop-helix
transcription factors Ngn3 and NeuroD1. Ngn3 and NeuroD1 upregulated
expression of a reporter gene containing these Insm2 E boxes. Activation
of the Insm2 promoter by Ngn3 and NeuroD1 was enhanced by the cofactor
E47 (TCF3; 147141).
MAPPING
By genomic sequence analysis, Cai et al. (2011) mapped the INSM2 gene to
chromosome 14q13.2.
NOMENCLATURE
Although PTPRN (601773) has been referred to as insulinoma-associated
protein-2, or IA2, in the literature, it is distinct from INSM2.
NKX2-1
| dbSNP name | rs10139625(A,T) |
| cytoBand name | 14q13.3 |
| EntrezGene GeneID | 7080 |
| EntrezGene Description | NK2 homeobox 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4614 |
OMIM Clinical Significance
Oncology:
Prolactin-secreting pituitary adenoma;
Prolactinoma
Inheritance:
Familial tendency independent of association with MEN-1
OMIM Title
*600635 NK2 HOMEOBOX 1; NKX2-1
;;THYROID TRANSCRIPTION FACTOR 1; TITF1;;
TTF1;;
THYROID NUCLEAR FACTOR;;
NK2, DROSOPHILA, HOMOLOG OF, A; NKX2A;;
NK2.1, MOUSE, HOMOLOG OF;;
THYROID-SPECIFIC ENHANCER-BINDING PROTEIN; TEBP
OMIM Description
DESCRIPTION
The NKX2-1 gene encodes a transcription factor that is expressed during
early development of thyroid, lung, and forebrain regions, particularly
the basal ganglia and hypothalamus (summary by Thorwarth et al., 2014).
CLONING
The protein referred to as thyroid transcription factor-1 (TTF1) by
Guazzi et al. (1990) is a 38-kD nuclear protein that mediates
thyroid-specific gene transcription. Guazzi et al. (1990) purified the
protein from calf thyroids, obtained partial amino acid sequence and
cloned the cDNA from a calf thyroid cDNA library using degenerate
primers based on the peptide data. The human gene was obtained by Ikeda
et al. (1995) and contains a homeobox domain and a 17-amino acid motif
characteristic of the NKX2 family of transcription factors. TTF1
activates thyroglobulin (TG; 188450) and thyroperoxidase (TPO; 606765)
gene transcription in thyroid adenocarcinomas and is expressed in
epithelial cells of the rat thyroid. TTF1 also activates transcription
of human surfactant protein B (SFTPB; 178640) in the lung.
Ikeda et al. (1995) screened a human genomic DNA cosmid library with the
rat TTF1 cDNA. A subclone from the cosmid containing the gene was
obtained and sequenced. The predicted 371-amino acid protein is 98%
identical to the rat sequence. The predominant 2.4-kb RNA was shown to
be expressed in pulmonary adenocarcinoma cells in addition to thyroid
gland epithelium and the lung. TTF1 protein was detected in fetal lung
as early as the eleventh week of gestation and localized in the nuclei
of epithelial cells of the developing airways. After birth, expression
was seen in type II epithelial cells in the alveoli and in some
bronchiolar epithelial cells. When the 5-prime flanking region of the
gene was placed in front of a luciferase reporter construct, activity
could be measured in pulmonary adenocarcinoma cells.
Hamdan et al. (1998) isolated several NKX2.1 cDNAs from human lung,
which they grouped into 4 distinct classes. All the cDNAs but one encode
a protein identical to that reported by Ikeda et al. (1995). The
remaining cDNA encodes a putative 402-amino acid protein with an
N-terminal extension. Cell-free translation of a transcript encoding the
longer protein resulted in polypeptides with apparent molecular masses
of 44, 40, and 38 kD by SDS-PAGE. Translation of a transcript encoding
the shorter protein resulted in polypeptides of 40 and 38 kD. Hamdan et
al. (1998) hypothesized that the different polypeptides result from the
use of alternate ATG codons.
GENE FAMILY
Holland et al. (2007) stated that the NKX2-1 and NKX2-4 (607808) genes
are collectively orthologous to Drosophila scro and comprise the Nk2.1
gene family.
GENE FUNCTION
Both TTF1 and PAX8 (167415) are thyroid-specific transcription factors
that preferentially bind to the thyroglobulin and thyroperoxidase
promoters, respectively (Acebron et al., 1995).
Zhu et al. (2004) presented evidence that mouse Titf1, which they called
Nkx2.1, is a potential upstream regulator of Bmp4 (112262) expression in
lung. Titf1 and Bmp4 were coexpressed in developing mouse lungs. Using
EMSA and cotransfection assays in mammalian lung epithelial cells, Zhu
et al. (2004) identified functional cis-active Titf1 response elements
in both Bmp4 promoter regions.
Dentice et al. (2005) determined that Titf1 directly controls expression
of the pendrin gene (SLC26A4; 605646) in rat thyroid.
To gain insight into human thyroid development and thyroid
dysgenesis-associated malformations, Trueba et al. (2005) studied the
expression patterns of the PAX8, TITF1, and FOXE1 (602617) genes during
human development. PAX8 and TITF1 were first expressed in the median
thyroid primordium. Interestingly, PAX8 was also expressed in the
thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression
was detected later than in the mouse. PAX8 was also expressed in the
developing central nervous system and kidney, including the ureteric bud
and the main collecting ducts. TITF1 was expressed in the ventral
forebrain and lung. FOXE1 expression was detected in the oropharyngeal
epithelium and thymus. The expression patterns of these genes in human
show some differences from those reported in the mouse; Pax8, Titf1, and
Foxe1 are expressed in the mouse thyroid bud as soon as it
differentiates on the pharyngeal floor. The authors concluded that the
expression patterns of these 3 genes correlate well with the phenotypes
observed in patients carrying mutations of the corresponding gene.
Garcia-Barcelo et al. (2005) localized TITF1 to the myenteric and
submucosa plexuses in adult human colon and to the mesenchyme of
embryonic stomach, where it colocalized with RET (164761). Expression of
TITF1 activated RET transcription via a predicted TITF1-binding site in
the RET promoter region.
Weir et al. (2007) reported a large-scale project to characterize copy
number alterations in primary lung adenocarcinomas. By analysis of 371
tumors using dense single-nucleotide polymorphism arrays, Weir et al.
(2007) identified 57 significantly recurrent events. Weir et al. (2007)
found that 26 of 39 autosomal chromosome arms showed consistent
large-scale copy number gain or loss, of which only a handful had been
linked to a specific gene. They also identified 31 recurrent focal
events, including 24 amplifications and 7 homozygous deletions. Only 6
of these focal events were associated with mutations in lung carcinomas.
The most common event, amplification of chromosome 14q13.3, was found in
about 12% of samples. On the basis of genomic and functional analyses,
Weir et al. (2007) identified NKX2-1, which lies in the minimal 14q13.3
amplification interval and encodes a lineage-specific transcription
factor, as a novel candidate protooncogene involved in a significant
fraction of lung adenocarcinomas.
Taniguchi et al. (2013) followed the development trajectory of
chandelier cells, the most distinct interneurons that innervate the axon
initial segment of pyramidal neurons and control action potential
initiation. Chandelier cells mainly derive from the ventral germinal
zone of the lateral ventricle during late gestation and require the
homeodomain protein Nkx2.1 for their specification. They migrate with
stereotyped routes, and schedule and achieve specific laminar
distribution in the cortex. Taniguchi et al. (2013) concluded that the
developmental specification of this bona fide interneuron type likely
contributes to the assembly of a cortical circuit motif.
GENE STRUCTURE
By genomic sequence analysis, Ikeda et al. (1995) determined that the
TITF1 gene spans approximately 3.3 kb and contains 2 exons.
Hamdan et al. (1998) determined that the TITF1 gene contains 3 exons.
They identified 2 regions that mediate basal promoter activity in lung
epithelial cells, one within the first intron, and the other 5-prime to
the first exon.
MAPPING
Guazzi et al. (1990) mapped the TITF1 gene by in situ hybridization to
mouse chromosome 12C1-C3 and in humans to chromosome 14q12-q21 with most
of the grains localized to 14q13.
PATHOGENESIS
Winslow et al. (2011) modeled human lung adenocarcinoma, which
frequently harbors activating point mutations in KRAS (190070) and
inactivation of the p53 (191170) pathway, using conditional alleles in
mice. Lentiviral-mediated somatic activation of oncogenic Kras and
deletion of p53 in the lung epithelial cells of
Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma
development. Although tumors are initiated synchronously by defined
genetic alterations, only a subset becomes malignant, indicating that
disease progression requires additional alterations. Identification of
the lentiviral integration sites allowed Winslow et al. (2011) to
distinguish metastatic from nonmetastatic tumors and determine the gene
expression alterations that distinguish these tumor types. Cross-species
analysis identified the NK2-related homeobox transcription factor Nkx2-1
as a candidate suppressor of malignant progression. In this mouse model,
Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated
tumors. Gain- and loss-of-function experiments in cells derived from
metastatic and nonmetastatic tumors demonstrated that Nkx2-1 controls
tumor differentiation and limits metastatic potential in vivo.
Interrogation of Nkx2-1-regulated genes, analysis of tumors at defined
developmental stages, and functional complementation experiments
indicated that Nkx2-1 constrains tumors in part by repressing the
embryonically restricted chromatin regulator Hmga2 (600698). Whereas
focal amplification of NKX2-1 in a fraction of human lung
adenocarcinomas had focused attention on its oncogenic function, Winslow
et al. (2011) stated that their data specifically linked Nkx2-1
downregulation to loss of differentiation, enhanced tumor seeding
ability, and increased metastatic proclivity. Winslow et al. (2011)
concluded that the oncogenic and suppressive functions of Nkx2-1 in the
same tumor type substantiate its role as a dual function lineage factor.
MOLECULAR GENETICS
Acebron et al. (1995) reported 3 sibs, a woman and 2 men, with
congenital hypothyroid goiter due to defective thyroglobulin synthesis.
In the sister, Northern blot analysis, RT-PCR, and electrophoretic
mobility shift assays demonstrated virtual absence of TTF1 expression.
She had normal levels of PAX8 mRNA and thyroperoxidase mRNA but very low
levels of thyroglobulin mRNA. Acebron et al. (1995) stated that this was
the first reported evidence of congenital goiter with thyroglobulin
synthesis defect due to low expression of TTF1. The parents were
unaffected and were not known to be related.
In 172 sporadic Chinese patients with Hirschsprung disease (HSCR;
142623), Garcia-Barcelo et al. (2005) identified HSCR-associated RET
(164761) promoter SNPs that were highly correlated with disease. They
determined that the promoter SNPs overlapped a predicted cis-acting
TITF1-binding site. Functional analysis demonstrated that the
HSCR-associated alleles decreased RET transcription. TITF1 expression
activated transcription from the RET promoter, and TITF1-activated RET
transcription was reduced by the HSCR-associated SNPs. The authors
identified a Chinese patient with HSCR who was heterozygous for a
gly322-to-ser (G322S) mutation in the TITF1 gene. The patient did not
harbor a mutation in any of the known HSCR-associated genes. Mutant
TITF1 specifically decreased the function of the TITF1 5E isoform when
assessed on the HSCR-associated RET haplotype.
Garcia-Barcelo et al. (2007) analyzed the TITF1 gene in an additional
102 Chinese and 70 Australian Caucasian HSCR patients and identified a
met3-to-leu (M3L) mutation in 2 of the Australian patients that was not
found in 194 Chinese and 60 Caucasian unrelated controls. In vitro
functional studies showed that M3L completely abolished the activation
of RET by TITF1, irrespective of the HSCR-associated haplotype in the
RET promoter.
- Benign Hereditary Chorea
In affected members of a family with benign hereditary chorea (BHC;
118700), Breedveld et al. (2002) identified a heterozygous 1.2-Mb
deletion including the TITF1 gene. The authors also reported other BHC
families with heterozygous point mutations in the TITF1 gene (see, e.g.,
600635.0001-600635.0004).
- Choreoathetosis and Congenital Hypothyroidism, with or without
Pulmonary Dysfunction
Devriendt et al. (1998) identified deletion of the TTF1 gene in an
infant with choreoathetosis and congenital hypothyroidism with pulmonary
dysfunction (CAHTP; 610978). The infant presented with respiratory
failure, hypotonia, and truncal ataxia. Iwatani et al. (2000) reported
deletion of the gene in 2 sibs with hypothyroidism and respiratory
failure.
In a 6-year-old boy with dyskinesia, neonatal respiratory distress, and
compensated hypothyroidism, Pohlenz et al. (2002) found a heterozygous
mutation in the TITF1 gene (600635.0010). Pohlenz et al. (2002)
concluded that haploinsufficiency of the TITF1 gene results in a
predominantly neurologic phenotype and secondary hyperthyrotropinemia.
In 5 unrelated patients with variable degrees of congenital
hypothyroidism, choreoathetosis, muscular hypotonia, and pulmonary
problems, Krude et al. (2002) identified 5 different heterozygous
loss-of-function mutations in the TTF1 gene: 1 complete gene deletion, 1
missense mutation, and 3 nonsense mutations (see, e.g., 600635.0005 and
600635.0006). The association of symptoms in the patients with TTF1
mutations pointed to an important role of the human gene in the
development and function of the thyroid, basal ganglia, and lung, as had
previously been described in rodents (Kimura et al., 1996). In 1 of the
patients, cytogenetic studies identified an interstitial deletion of
chromosomal region 14q11.2-q13.3, including the TTF1 gene.
Chorioathetosis and respiratory distress were severe, and pulmonary
infections were frequent and severe. Thyroid gland imaging showed
hypoplasia.
Seidman and Seidman (2002) commented on Pohlenz et al. (2002) and Krude
et al. (2002) and noted that haploinsufficiency is often the mechanism
by which transcription factor defects cause disease. They discussed the
diversity of transcription factor haploinsufficiency disorders and
tabulated 32 genes that encode transcription factors and cause disease
through haploinsufficiency.
In 4 affected members of a German family with choreoathetosis,
congenital hypothyroidism, and neonatal respiratory insufficiency, Asmus
et al. (2005) identified a heterozygous mutation in the TITF1 gene
(600635.0008). Two patients had a favorable response to levodopa
treatment.
In a patient with choreoathetosis and congenital hypothyroidism, Carre
et al. (2009) identified a de novo heterozygous pro202-to-leu (P202L)
mutation in the homeodomain of the NKX2-1 gene. Functional analysis of
the P202L mutation revealed loss of transactivation capacity on the
human thyroglobulin (TG; 188450) enhancer/promoter. Deficient
transcriptional activity of the P202L mutant was completely rescued by
cotransfected PAX8 (167415), whereas the synergistic effect was
abolished by 2 other missense mutations (L176V and Q210P).
- Thyroid Cancer
For a discussion of a possible association between variation in the TTF1
gene and thyroid cancer, see 188550 and 188470.
ANIMAL MODEL
Kimura et al. (1996) used homologous recombination to generate mice
lacking the Ttf1 gene, or T/ebp. Heterozygotes developed normally, but
homozygous deficient mice were born dead and lacked lung parenchyma. The
deficient mice lacked a thyroid gland but had a normal parathyroid. In
the brain, multiple defects were found in the ventral region of the
forebrain, and the entire pituitary was missing. In situ hybridization
analysis showed that the T/ebp gene is expressed in normal thyroid, lung
bronchial epithelium, and specific areas of the forebrain during early
embryogenesis. Kimura et al. (1996) concluded that the TTF1 gene is
essential in the embryonic differentiation of the thyroid, lung, ventral
forebrain, and pituitary.
Pohlenz et al. (2002) found that Ttf1 +/- mice demonstrated poor
coordination and increased serum thyrotropin.
NKX2-1-AS1
| dbSNP name | rs35710229(C,A); rs12894724(C,T); rs149861162(G,A); rs8004831(C,G) |
| cytoBand name | 14q13.3 |
| EntrezGene GeneID | 100506237 |
| snpEff Gene Name | NKX2-1 |
| EntrezGene Description | NKX2-1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06244 |
SLC25A21-AS1
| dbSNP name | rs1404(C,T); rs1403(C,A) |
| cytoBand name | 14q13.3 |
| EntrezGene GeneID | 100129794 |
| snpEff Gene Name | SLC25A21 |
| EntrezGene Description | SLC25A21 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04913 |
| ExAC AF | 0.028 |
CLEC14A
| dbSNP name | rs1952562(A,T); rs2812035(G,A) |
| cytoBand name | 14q21.1 |
| EntrezGene GeneID | 161198 |
| EntrezGene Description | C-type lectin domain family 14, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4004 |
LOC100288846
| dbSNP name | rs17109079(A,C); rs12587713(G,C); rs376775224(A,G); rs61739458(C,G) |
| ccdsGene name | CCDS9673.1 |
| cytoBand name | 14q21.1 |
| EntrezGene GeneID | 100288846 |
| snpEff Gene Name | CTAGE5 |
| EntrezGene Description | uncharacterized LOC100288846 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06841 |
FSCB
| dbSNP name | rs75428292(C,T); rs12147557(T,A); rs412408(C,T); rs3825632(A,T); rs11623175(A,G); rs3809430(C,T); rs11629125(T,A); rs78484213(C,T) |
| cytoBand name | 14q21.2 |
| EntrezGene GeneID | 84075 |
| EntrezGene Description | fibrous sheath CABYR binding protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006428 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Retinal arteriolar tortuosity;
Retinal hemorrhage
CARDIOVASCULAR:
[Heart];
Arrhythmias, supraventricular;
[Vascular];
Aneurysms of right internal carotid artery, intracranial segment;
Aneurysm of right middle cerebral artery, horizontal segment;
Raynaud phenomenon
GENITOURINARY:
[Kidneys];
Hematuria, microscopic;
Hematuria, gross (in some patients);
Renal cysts;
Renal failure, mild;
Basement membrane alterations in Bowman capsule, tubules, and interstitial
capillaries, with irregular thickening, splitting into multiple layers,
and electron-lucent areas;
Glomerular basement membrane normal
SKIN, NAILS, HAIR:
[Skin];
ELECTRON MICROSCOPY:;
Basement membrane duplications at dermoepidermal junction;
Dermal arteriole dissociation in vascular smooth muscle cells;
Basement membrane abnormally spread in vascular smooth muscle cells
[Nails];
Capillary tortuosity in nail beds
MUSCLE, SOFT TISSUE:
Muscle cramps
NEUROLOGIC:
[Central nervous system];
Leukoencephalopathy, periventricular;
Microvascular spaces, dilated;
Cerebrovascular accident (in some patients)
LABORATORY ABNORMALITIES:
Creatine kinase, serum, elevated;
Glomerular filtration rate, decreased
MOLECULAR BASIS:
Caused by mutation in the collagen IV, alpha-1 polypeptide gene (COL4A1,
120130.0007)
OMIM Title
*611779 FIBROUS SHEATH CABYR-BINDING PROTEIN
;;C14ORF155
OMIM Description
CLONING
Using coimmunoprecipitation experiments of mouse sperm protein lysates
with an antibody to CABYR (612135), Li et al. (2007) identified a novel
peptide, which they designated Fscb (fibrous sheath CABYR-binding
protein). Antibodies were raised to a truncated version of the mouse
protein, whose full-length version was predicted to be 1,074 amino
acids. By database analysis, Li et al. (2007) identified human FSCB,
which encodes a deduced 825-amino acid protein. Northern blot analysis
of mouse tissues detected a 3.5-kb testis-specific Fscb transcript.
GENE FUNCTION
Li et al. (2007) showed that Fscb is first expressed in the elongating
spermatids during spermatogenesis. Later in spermatogenesis it is found
in the flagellum where it was shown to localize to a cortical layer at
the surface of the ribs and longitudinal columns of the fibrous sheath.
Li et al. (2007) postulated that FSCB may be involved in later stages of
fibrous sheath assembly. Like CABYR, FSCB is a calcium-binding protein,
and both recombinant and native FSCB are phosphorylated by protein
kinase A (PKA; see 176911).
MAPPING
By sequence analysis, Li et al. (2007) mapped the FSCB gene to
chromosome 14q21.3 and the mouse homolog to chromosome 12.
NID2
| dbSNP name | rs74049324(C,T); rs2029984(A,G); rs1497079(G,A); rs1476284(C,T); rs72678187(C,T); rs61971548(G,T); rs4901177(A,G); rs2282346(C,T); rs1151578(G,T); rs1151579(G,A); rs10146989(G,A); rs143519669(C,T); rs1051069(A,G); rs61971549(A,G); rs924185(T,C); rs61971550(T,G); rs55979603(G,A); rs151097007(G,A); rs61971551(C,G); rs1151580(C,T); rs1151581(C,T); rs6572807(A,G); rs10146057(A,G); rs61971552(G,T); rs111370949(T,C); rs946615(C,T); rs17124877(G,A); rs17124880(C,G); rs77529703(C,T); rs17124884(G,A); rs1151582(C,T); rs17124887(C,T); rs1151583(T,C); rs71422049(A,G); rs4901179(G,A); rs74049333(T,C); rs74049334(T,C); rs17124893(G,A); rs74049336(T,C); rs59811471(G,C); rs17124896(C,G); rs58619311(G,A); rs74049337(C,T); rs8007166(G,A); rs77091361(C,T); rs61971553(A,G); rs2516600(T,C); rs17124901(C,T); rs2073626(A,G); rs2073625(C,T); rs28508079(G,A); rs2073624(G,A); rs2073623(C,T); rs2645730(A,G); rs10129648(C,A); rs10137847(C,T); rs112195968(T,C); rs1266398(A,C); rs4901180(G,A); rs11847418(G,A); rs8020559(T,G); rs8019307(A,T); rs56003563(G,T); rs10141373(C,T); rs61971554(A,G); rs1497077(T,C); rs1497076(T,C); rs2516599(T,C); rs61971555(G,A); rs1018085(G,C); rs1018084(G,A); rs2645729(C,T); rs2749870(G,A); rs17124920(T,C); rs11846847(T,A); rs10148284(G,T); rs60511209(G,A); rs144461334(G,A); rs2273429(G,A); rs28663441(G,C); rs77101097(C,T); rs143967858(T,A); rs55874437(C,A); rs2357307(C,T); rs2357308(T,C); rs34006905(G,A); rs11844758(C,A); rs74049344(T,G); rs7144352(C,T); rs58164685(C,T); rs1497088(G,C); rs61971558(G,A); rs1497087(A,C); rs2273430(C,A); rs2273431(C,T); rs8013745(G,T); rs2516598(T,G); rs2645745(A,G); rs2516597(T,C); rs2453950(G,A); rs2453949(C,T); rs78054403(A,G); rs2749871(G,A); rs3825595(A,C); rs3783632(C,A); rs941621(C,T); rs941622(G,A); rs941623(G,C); rs2516595(T,C); rs10133632(T,A); rs74049351(T,A); rs28710170(A,G); rs2073622(G,A); rs2073621(G,A); rs191912985(T,C); rs2749873(A,G); rs2029983(A,G); rs2029982(C,G); rs2173146(A,G); rs2029981(T,C); rs2029980(A,C); rs2029979(C,T); rs77979638(G,C); rs8016169(C,G); rs2645752(A,G); rs2645750(C,A); rs2645749(C,A); rs2516594(T,C); rs2645748(C,T); rs2645747(A,G); rs2516593(T,C); rs2749875(G,A); rs35916258(T,C); rs2516592(T,C); rs2645746(A,G); rs116976987(T,A); rs10143490(G,C); rs55751019(T,G); rs2749876(T,G); rs59520223(T,C); rs2088357(A,G); rs904061(T,C); rs57847444(T,C); rs55889873(G,T); rs753052(A,G); rs753051(A,G); rs753050(A,G); rs2029978(T,A); rs2029977(T,G); rs2029976(C,T); rs12890765(T,A); rs2029975(C,T); rs35931753(G,T); rs10139288(T,C); rs8004226(A,G); rs3825594(G,A); rs74049361(C,G); rs3742536(A,G); rs7148698(G,T); rs61747585(C,A); rs1982963(G,A); rs2273433(G,A); rs56834750(T,C); rs4901186(G,A); rs3818186(T,C); rs115833794(G,C); rs3818187(A,G); rs10137158(C,T); rs10137154(A,G); rs10145619(G,T); rs2749879(C,A); rs11851036(C,G); rs11851063(C,T); rs1266400(A,T); rs111845598(G,C); rs72680315(T,C); rs2645744(G,A); rs67640320(C,G); rs34900091(T,C); rs74049377(C,G); rs1566132(C,T); rs74049379(G,A); rs2645743(C,T); rs74049380(A,G); rs2645741(G,A); rs2645738(G,A); rs2645737(C,T); rs35868721(G,A); rs10400710(C,T); rs10400713(G,A); rs1566131(G,A); rs2516587(C,A); rs1566130(G,A); rs1566129(T,C); rs1566128(A,G); rs147998361(C,G); rs2749881(A,G); rs2645733(C,A); rs2749882(T,G); rs2516586(T,C); rs7359132(A,G); rs7359136(G,A); rs7359137(G,A); rs2749883(A,C); rs2516585(T,C); rs2516584(G,C); rs2645731(C,T); rs2749885(T,G); rs2749886(C,G); rs185564780(T,C); rs1497086(G,C); rs1390968(A,G); rs2173145(T,C); rs730531(A,G); rs730532(G,A); rs904060(A,G); rs1874569(T,C); rs753436(G,A); rs74049394(T,C); rs8019428(T,A); rs2101919(C,T); rs35657569(G,T); rs904059(A,G); rs1497085(G,C); rs1497084(A,T); rs1540702(A,G); rs1540701(C,T); rs1540700(G,A); rs17124972(A,G); rs2029974(C,T); rs971394(A,G); rs2013412(T,C); rs4901188(C,T); rs2132771(T,G); rs2013404(C,T); rs1390967(T,C); rs1826870(G,A); rs1032579(A,G); rs1032578(C,T); rs111860687(C,A); rs1956271(T,A); rs1956274(C,T); rs1476286(A,C); rs1497080(T,C); rs12586602(A,G); rs11157873(A,C); rs975026(G,A); rs754423(C,T); rs754424(T,G); rs931627(C,T); rs17124984(G,T); rs7148490(T,G); rs12886408(T,C); rs1390964(T,C); rs1390965(T,C); rs1390966(A,C); rs72680326(T,C); rs10130626(G,C); rs3783627(C,A); rs3783455(A,T); rs146182298(C,T); rs1497083(C,A); rs12434236(A,T); rs4901189(C,T); rs4901190(A,T); rs979481(A,G); rs2749888(T,C); rs74496147(T,C); rs7145374(C,T); rs75651404(C,G); rs7151874(T,C); rs984051(A,C); rs984050(G,A) |
| ccdsGene name | CCDS9706.1 |
| CosmicCodingMuts gene | NID2 |
| cytoBand name | 14q22.1 |
| EntrezGene GeneID | 22795 |
| EntrezGene Description | nidogen 2 (osteonidogen) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NID2:NM_007361:exon12:c.C2596T:p.R866W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5328 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7EPP3 |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.001922 |
| ESP Eur/Amr MAF | 0.002791 |
| ExAC AF | 0.001439 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Horizontal nystagmus
NEUROLOGIC:
[Central nervous system];
Ataxia;
Delayed motor development;
Dysarthria;
Dysdiadochokinesis;
Broad-based gait;
Cerebellar atrophy
MISCELLANEOUS:
Onset in infancy
OMIM Title
*605399 NIDOGEN 2; NID2
;;OSTEONIDOGEN
OMIM Description
DESCRIPTION
Basement membranes, which are composed of type IV collagens (see
120130), laminins (see LAMC1; 150290), perlecan (HSPG2; 142461), and
nidogen (see NID1; 131390), are thin pericellular protein matrices that
control a large number of cellular activities, including adhesion,
migration, differentiation, gene expression, and apoptosis.
CLONING
By sequencing several overlapping cDNA clones in both directions,
Kohfeldt et al. (1998) obtained a cDNA encoding NID2. Sequence analysis
predicted that the 1,375-amino acid NID2 protein, which is 46% identical
to NID1, contains a 30-residue signal peptide, 49 primarily central cys
residues, 5 potential N-linked glycosylation sites, 2 tyr residues in a
potential O-sulfation sequence, and a YGD rather than an RGD cell
adhesion sequence. Electron microscopy confirmed the presence of 3
deduced globular domains connected by a link and a rod-like region.
Additional predicted structures similar to those found in NID1 include 5
epidermal growth factor (EGF; 131530)-like modules, 2 of which have
potential calcium-binding sequences; 2 thyroglobulin (188450) type I
modules; and 5 low density lipoprotein (LDL) receptor (606945) modules.
SDS-PAGE analysis showed that NID2 is expressed as a 200-kD protein,
larger than the calculated mass of 148 kD, presumably due to
oligosaccharide substitution as indicated by hexosamine analysis.
Northern blot analysis revealed ubiquitous expression of a 5.5-kb NID2
transcript that was strongest in heart and placenta, moderate in
pancreas, kidney, and skeletal muscle, and weakest in brain. Immunoblot
analysis detected expression of NID2 in muscle, heart, placenta, kidney,
skin, and testis, with weaker expression in liver and brain.
Immunofluorescence analysis of mouse tissues showed staining of basement
membranes usually in close colocalization with NID1.
Schymeinsky et al. (2002) cloned mouse Nid2. Northern blot analysis
revealed expression of a 5.5-kb transcript in all tissues examined.
GENE FUNCTION
Binding analysis by Kohfeldt et al. (1998) determined that NID2
interacts with collagens I and IV and perlecan at levels comparable to
NID1, but NID2 failed to bind to fibulins (see FBLN2; 135821). NID2
bound to laminin-1, but only moderately to the epitope on the LAMC1
chain, which promotes high-affinity binding of NID1. In culture, NID2
was at least as active in promoting cell adhesion as NID1.
GENE STRUCTURE
Schymeinsky et al. (2002) determined that the mouse Nid2 gene contains
21 exons. The promoter region contains several putative SP1 (189906) and
CAAT recognition sites, but lacks a TATA box.
MAPPING
By radiation hybrid analysis, Schymeinsky et al. (2002) mapped the mouse
Nid2 gene to chromosome 14.
ANIMAL MODEL
Schymeinsky et al. (2002) developed mice carrying a phenotypic null
mutation in the Nid2 gene. Nid2-deficient mice showed no overt
abnormalities, and their basement membranes appeared normal by
ultrastructural analysis and immunostaining. Nid2 deficiency did not
lead to hemorrhages, and Nid2 did not appear essential for basement
membrane formation or maintenance.
WDHD1
| dbSNP name | rs10140164(A,G); rs28481699(A,T); rs115022805(T,G); rs12147796(C,T); rs8020545(T,A); rs8019390(C,G); rs57622454(C,T); rs7146285(T,C); rs8013521(G,C); rs10129318(G,A); rs144187979(C,T); rs10129802(G,A); rs145557179(G,A); rs7159953(G,A); rs141887223(G,A); rs11629355(C,T); rs146758959(G,A); rs148316043(T,C); rs140515064(T,A); rs8008150(G,T); rs8009997(T,G); rs139790795(T,C); rs143168095(C,T); rs77561506(G,A); rs8012152(T,C); rs8011446(C,G); rs182443894(A,G); rs6572994(C,G); rs28678578(A,C); rs11158029(C,T); rs188359253(C,T); rs146347868(G,C); rs145725165(T,G); rs3783643(A,G); rs3783644(A,G); rs3783645(C,T); rs200882768(T,C); rs9285583(T,C); rs17832269(C,T); rs151246195(G,A); rs8021303(G,A); rs115324363(T,C); rs1187888(T,C); rs181844845(C,T); rs58055971(C,T); rs146554328(T,C); rs141423225(T,C); rs55965693(C,A); rs59323730(C,T); rs4047200(T,A); rs4325453(G,A); rs943914(C,A); rs11846514(A,C); rs7159933(C,A); rs142915719(C,T); rs80067373(G,A); rs57667631(G,A); rs878944(A,G); rs7157085(G,A); rs56335168(C,A); rs75905424(T,C); rs66769866(C,T); rs68065548(C,T); rs28513529(C,T); rs28706216(A,T); rs28406982(G,T); rs67571433(A,G); rs8021370(C,T); rs1187887(C,G); rs1187886(G,C); rs111893223(G,A); rs77810789(G,A); rs56206440(T,C); rs7151670(C,G); rs8018800(A,G); rs10150556(T,C); rs8019220(C,T); rs145429901(T,C); rs140606197(G,A); rs59074935(T,C); rs57922954(C,T); rs17128116(A,G); rs371014811(T,C); rs72715573(C,T); rs111478437(G,A); rs9805952(T,C); rs55704705(G,A); rs10150110(G,T); rs8022049(T,C); rs77333710(A,G); rs1187884(G,C); rs145950468(G,T); rs66820631(T,A); rs148377688(C,T); rs17128119(T,G); rs79201207(G,C); rs190539557(T,G); rs17253633(T,C); rs113695652(C,T); rs2878174(T,C); rs4335711(G,C); rs7153937(A,G); rs28719471(T,C); rs74050278(G,A); rs3783646(T,C); rs2840268(C,G); rs2183085(A,C); rs72715575(G,A); rs189020250(A,T); rs9323275(T,C); rs45459500(A,G); rs17128120(C,T); rs34988865(T,C); rs111864461(C,T); rs6572997(T,C); rs180750268(G,A); rs60028867(C,T); rs10139354(C,T); rs28414866(C,T); rs28693954(A,G); rs28446981(T,C); rs138790271(T,C); rs28489712(A,C); rs11846990(T,C); rs10148100(A,G); rs67395322(G,T); rs140897241(C,T); rs56282786(C,G); rs59645597(A,G); rs1187883(T,C); rs1187882(C,G); rs1187881(G,A); rs113512152(G,A); rs7142626(G,A); rs80066034(A,G); rs116577421(A,T); rs115832415(C,A); rs1209087(C,T); rs1187878(T,C); rs1201378(T,C) |
| ccdsGene name | CCDS9721.1 |
| cytoBand name | 14q22.2 |
| EntrezGene GeneID | 11169 |
| EntrezGene Description | WD repeat and HMG-box DNA binding protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | WDHD1:NM_001008396:exon25:c.A2830C:p.N944H,WDHD1:NM_007086:exon26:c.A3199C:p.N1067H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5802 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F8W7P7 |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.014986 |
| ESP All MAF | 0.005075 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001391 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Dermatitis;
Acrodermatitis enteropathica, transient, seen in breastfed offspring
of affected mothers;
[Hair];
Alopecia, partial
LABORATORY ABNORMALITIES:
Affected mother has reduced zinc levels in breast milk (may be up
to 40% less than normal breast milk);
Affected mother has normal plasma zinc levels and is not zinc-deficient;
Breastfed offspring have transient decrease of plasma zinc levels
MISCELLANEOUS:
Reduced zinc in affected mother's breast milk is unresponsive to oral
zinc supplementation;
Symptoms of zinc deficiency occur only in exclusively breastfed infants;
Dermatitis resolves in offspring after zinc supplementation and/or
weaning;
Zinc deficiency in breastfed offspring resolves after weaning;
Mother who carries the mutation is clinically unaffected
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 30 (zinc transporter),
member 2 gene (SLC30A2, 609617.0001)
OMIM Title
*608126 ACIDIC NUCLEOPLASMIC DNA-BINDING PROTEIN 1, XENOPUS, HOMOLOG OF
;;AND1
OMIM Description
CLONING
Kohler et al. (1997) cloned Xenopus And1. The deduced 1,127-amino acid,
125-kD protein contains 7 WD repeats and a C-terminal HMG box. The HMG
box is typical of some DNA-binding proteins involved in chromatin
assembly, transcription, and replication. And1 also has several putative
nuclear localization signals. And1 localized throughout the entire
interchromatinic space of the interphase nucleoplasm, probably in
homodimeric form. During mitosis, it was transiently dispersed over the
cytoplasm. PCR of human cDNA libraries detected expression in brain,
epidermis, liver, and stomach.
GENE FUNCTION
By DNA affinity chromatography and electrophoretic mobility shift
assays, Kohler et al. (1997) demonstrated that Xenopus And1 bound DNA.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the AND1
gene to chromosome 14 (TMAP RH104447).
RPL13AP3
| dbSNP name | rs2184557(T,C); rs10144431(G,T); rs2152281(C,T); rs56190279(C,T); rs12589473(G,A); rs73272138(A,G); rs11622564(T,C) |
| cytoBand name | 14q22.3 |
| EntrezGene GeneID | 645683 |
| snpEff Gene Name | RP11-813I20.2 |
| EntrezGene Description | ribosomal protein L13a pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3838 |
GPR135
| dbSNP name | rs182656917(C,T); rs1752427(A,G) |
| cytoBand name | 14q23.1 |
| EntrezGene GeneID | 112849 |
| EntrezGene Symbol | L3HYPDH |
| EntrezGene Description | L-3-hydroxyproline dehydratase (trans-) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
SIX1
| dbSNP name | rs78909843(C,G); rs76116881(T,C); rs10144415(G,C); rs147081368(A,C) |
| cytoBand name | 14q23.1 |
| EntrezGene GeneID | 6495 |
| EntrezGene Description | SIX homeobox 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
OMIM Clinical Significance
Eyes:
Anterior polar cataract
Inheritance:
Autosomal dominant
OMIM Title
*601205 SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 1; SIX1
OMIM Description
DESCRIPTION
The vertebrate SIX genes are homologs of the Drosophila 'sine oculis'
(so) gene, which is expressed primarily in the developing visual system
of the fly. Members of the SIX gene family encode proteins that are
characterized by a divergent DNA-binding homeodomain and an upstream SIX
domain, which may be involved both in determining DNA-binding
specificity and in mediating protein-protein interactions. Genes in the
SIX family have been shown to play roles in vertebrate and insect
development or have been implicated in maintenance of the differentiated
state of tissues.
CLONING
Boucher et al. (1996) cloned and sequenced a human SIX1 cDNA and showed
by Northern blotting that it is expressed in adult skeletal muscle. The
cDNA sequence and predicted protein sequence of the human and mouse
genes are highly homologous, with 98% similarity over the entire
predicted amino acid sequence. During mouse limb development at
embryonic day 11.5, Six1 and Six2 are expressed distally over the
posterior and anterior limb regions, respectively. However, by E14.5,
expression of Six1 and Six2 is detected flanking the phalanges in
domains corresponding to the anterior-posterior and dorsoventral axes,
respectively. Six1 is also weakly expressed in skeletal muscles of the
head and body during late development.
Ford et al. (1998) cloned the human SIX1 homeobox gene from late S phase
mammary carcinoma cells and demonstrated that overexpression of SIX1
leads to an abrogation of the DNA damage-induced G2 cell cycle
checkpoint. In addition, they found that overexpression of SIX1 occurs
in a large percentage of mammary carcinomas and correlates strongly with
metastatic breast disease. It appeared that studies of several cancer
cell lines suggested that SIX1 may be overexpressed in multiple types of
tumors. Thus, the studies linked SIX1 to the cell cycle as well as to
tumor progression and provided further evidence that 'master regulators'
involved in development may contribute to tumorigenicity.
GENE FUNCTION
Ridgeway and Skerjanc (2001) induced myogenesis in a mouse pluripotent
stem cell line. Myogenesis was associated with increased expression of
Pax3 (606597), followed by expression of the transcription factor Six1,
its cofactor Eya2 (601654), and the transcription factor Mox1 (600147),
prior to the induction of MyoD (159970) and myogenin (Myog; 159980)
expression.
Yu et al. (2004) established highly and poorly metastatic
rhabdomyosarcoma cell lines derived from a transgenic mouse model
overexpressing Hgf/Sf (142409) and deficient for Ink4a/Arf (600160), in
which skeletal muscle tumors reminiscent of those in embryonic
rhabdomyosarcoma (268210) arise with very high penetrance and short
latency (Sharp et al., 2002). Yu et al. (2004) then used cDNA microarray
analysis of these cell lines to identify a set of genes whose expression
was significantly different between highly and poorly metastatic cells.
Subsequent in vivo functional studies revealed that ezrin, encoded by
Vil2 (123900), and Six1 have essential roles in determining the
metastatic fate of rhabdomyosarcoma cells. VIL2 and SIX1 expression was
enhanced in human rhabdomyosarcoma tissue, significantly correlating
with clinical stage.
Buller et al. (2001) analyzed the functional importance of Eya (EYA1;
601653) domain missense mutations with respect to protein complex
formation and cellular localization. Previously described point
mutations did not alter protein localization; however, 3 mutations
(glu330 to lys, 601653.0009; ser454 to pro, 601653.0012; and leu472 to
arg, 601653.0013) disrupted interactions between Eya and Six1 in both
yeast and mammalian cells. Binding to Six2 (604994) was not impeded.
Grifone et al. (2004) found that among the Six and Eya gene products
expressed in mouse skeletal muscle, Six1 and Eya1 accumulated
preferentially in the nuclei of fast-twitch muscles. Forced coexpression
of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition
to a fast-twitch fiber type, with activation of fast-twitch
fiber-specific genes and a switch toward glycolytic metabolism.
SALL1 (602218) is a transcription factor that has a critical role in
kidney development. Using gel retardation assays, reporter gene assays,
and mutation analysis, Chai et al. (2006) showed that SIX1 directly
bound the SALL1 promoter and induced SALL1 expression in a
dose-dependent manner.
McCoy et al. (2009) found that misexpression of human SIX1 in adult
mouse mammary gland epithelium induced tumors of multiple histologic
subtypes in a dose-dependent manner. Most SIX1-induced tumors underwent
an epithelial-to-mesenchymal transition (EMT) and expressed multiple
targets of activated Wnt (see 164820) signaling, including cyclin D1
(CCND1; 168461). SIX1 promoted a stem/progenitor cell phenotype in mouse
mammary gland and in SIX1-dependent mammary tumors. Coexpression of SIX1
and cyclin D1 was detected in several human breast cancers and was
predictive of poor prognosis.
Independently, Micalizzi et al. (2009) showed that SIX1 overexpression
in human and mouse mammary epithelial cells induced EMT and metastasis,
both of which were dependent on the ability of SIX1 to activate TGF-beta
(TGFB1; 190180) signaling. Breast cancer patients whose tumors
overexpressed SIX1 had a shortened time to relapse and metastasis and an
overall decrease in survival. Similarly, overexpression of SIX1
correlated with adverse outcomes in a number of other cancers, including
brain, cervical, prostate, colon, kidney, and liver. Micalizzi et al.
(2009) concluded that SIX1, acting through TGF-beta signaling and EMT,
is a powerful and global promoter of cancer metastasis.
Delgado-Olguin et al. (2012) found that conditional deletion of Ezh2
(601573) in mouse anterior heart field resulted in right cardiac
hypertrophy and fibrosis after birth. Gene expression profiling of
Ezh2-knockout hearts revealed derepression of Six1, with concomitant
activation of Six1-dependent skeletal muscle-specific genes.
Overexpression of Six1 in cultured neonatal mouse cardiomyocytes
resulted in hypertrophy comparable to that induced by the hypertrophic
agonist endothelin-1 (EDN1; 131240). Knockdown of Six1 in Ezh2-knockout
hearts completely rescued the cardiac phenotype.
EVOLUTION
Gallardo et al. (1999) performed phylogenetic analysis of SIX gene
family members and presented a model for the origin and evolution of SIX
gene clusters.
MAPPING
Using a rodent/human somatic cell hybrid panel, Boucher et al. (1996)
mapped the human SIX1 gene to chromosome 14.
Ruf et al. (2004) located the SIX1, SIX4 (606342), and SIX6 (606326)
genes, which play a role in the EYA-SIX-PAX (see 167411) hierarchy of
regulatory genes for the embryonic development of ear, kidney, and other
organs, within a 33-Mb critical interval on chromosome 14q23.
Oliver et al. (1995) mapped the mouse Six1 gene to the central region of
chromosome 12.
MOLECULAR GENETICS
Branchiootorenal syndrome (see 113650) is an autosomal dominant disorder
characterized by hearing loss, branchial cleft fistulas or cysts, and
renal dysplasia. Branchiootic syndrome (see 602588) is a related
disorder without renal anomalies. Ruf et al. (2003) mapped a locus for
the BOR/BO syndrome (BOS3; 608389) to chromosome 14q23. By direct
sequencing of SIX1 exons, they identified 2 different mutations in the
SIX1 gene in 3 kindreds with BOS3: tyr129 to cys (Y129C; 601205.0001)
and arg110 to trp (R110W; 601205.0002). Both mutations are crucial for
EYA1-SIX1 interaction, and the Y129C mutation, which is within the
homeodomain region, is essential for specific SIX1-DNA binding. In a
member of a fourth family, previously reported by Salam et al. (2000)
with DFNA23 (605192), Ruf et al. (2004) identified a 3-bp deletion in
the SIX1 gene (601205.0003). In addition to deafness, the patient had a
solitary left hypodysplastic kidney with vesicoureteral reflux and
progressive renal failure, suggesting that this family may have BOR/BO
syndrome.
In 7 affected individuals from a large 5-generation Danish family with
branchiootic syndrome, Sanggaard et al. (2007) identified heterozygosity
for a missense mutation in the SIX1 gene (601205.0004).
ANIMAL MODEL
Li et al. (2003) reported that Six1 is required for the development of
murine kidney, muscle, and inner ear and that it exhibits synergistic
genetic interactions with Eya factors. Li et al. (2003) demonstrated
that the Eya family has a protein phosphatase function, and that its
enzymatic activity is required for regulating genes encoding growth
control and signaling molecules, modulating precursor cell
proliferation. The phosphatase function of Eya switches the function of
Six1-Dach (603803) from repression to activation, causing
transcriptional activation through recruitment of coactivators. The
gene-specific recruitment of a coactivator with intrinsic phosphatase
activity provides a molecular mechanism for activation of specific gene
targets, including those regulating precursor cell proliferation and
survival in mammalian organogenesis. Eya1 +/- Six1 +/- double
heterozygous mice had a defect in kidney development, which was not
observed in single heterozygotes for either gene deletion, suggesting
that Six1 and Eya1 act in the same genetic pathway. Notably, there was a
complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double
knockout mice and severe reduction of epaxial muscle, a phenotype
resembling that seen in mice homozygous for deletion of Myog and in
double knockouts for MyoD/Myf5 (159990) and Pax3/Myf5. Interestingly,
although mutation of Six1 or Eya1 has minimal or no effect on pituitary
development, mice with both genes deleted have a pituitary that is
approximately 5- to 10-fold smaller by volume than the wildtype gland.
TMEM30B
| dbSNP name | rs76584614(A,G); rs2351806(G,A); rs1051388(A,G); rs77080549(C,G) |
| cytoBand name | 14q23.1 |
| EntrezGene GeneID | 161291 |
| EntrezGene Description | transmembrane protein 30B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05693 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Deafness, profound, sensorineural
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the radixin gene (RDX, 179410.0001)
OMIM Title
*611029 TRANSMEMBRANE PROTEIN 30B; TMEM30B
;;CDC50, S. CEREVISIAE, HOMOLOG OF, B; CDC50B
OMIM Description
CLONING
By searching databases for homologs of yeast Cdc50 family proteins,
which are involved in polarized cell division, Katoh and Katoh (2004)
identified 3 human CDC50 genes, including TMEM30B, which they called
CDC50B. The predicted CDC50B protein contains 351 amino acids. The human
and yeast CDC50 proteins all have 2 transmembrane domains and an
extracellular loop with 3 cysteines and an N-glycosylation site. In
silico expression analysis revealed that CDC50B was expressed in
pancreatic islet, kidney, and prostate, as well as in lung carcinoid,
parathyroid tumor, bladder tumor, meningioma, and pancreatic cancer.
MAPPING
By genomic sequence analysis, Katoh and Katoh (2004) mapped the TMEM30B
gene to chromosome 14q23.1.
HIF1A-AS2
| dbSNP name | rs994740(T,C); rs6573399(T,G) |
| cytoBand name | 14q23.2 |
| EntrezGene GeneID | 100750247 |
| snpEff Gene Name | HIF1A |
| EntrezGene Description | HIF1A antisense RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.146 |
HSPA2
| dbSNP name | rs1063391(C,T); rs45446693(C,T) |
| ccdsGene name | CCDS9766.1 |
| cytoBand name | 14q23.3 |
| EntrezGene GeneID | 3306 |
| EntrezGene Description | heat shock 70kDa protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HSPA2:NM_021979:exon1:c.C684T:p.D228D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3205 |
| ESP Afr MAF | 0.439174 |
| ESP All MAF | 0.399354 |
| ESP Eur/Amr MAF | 0.316628 |
| ExAC AF | 0.691 |
OMIM Clinical Significance
Cardiac:
Congenital heart malformation;
Hypoplastic left heart syndrome
Inheritance:
Autosomal dominant vs. multifactorial
OMIM Title
*140560 HEAT-SHOCK 70-KD PROTEIN 2; HSPA2
;;HEAT-SHOCK PROTEIN, 70-KD, 2;;
HSP70-2;;
HEAT-SHOCK PROTEIN, 70-KD, 3;;
HSP70-3
OMIM Description
CLONING
Bonnycastle et al. (1994) isolated a genomic clone for HSPA2 and found
that it has a single open reading frame of 1,917 basepairs that encodes
a 639-amino acid protein with a predicted molecular mass of 70,030 Da.
Analysis of the sequence indicated that HSPA2 is the human homolog of
the murine Hsp70-2 gene, with 91.7% identity in the nucleotide coding
sequence and 98.2% in the corresponding amino acid sequence. HSPA2 has
less amino acid homology to the other members of the human HSP70 gene
family. HSPA2 is constitutively expressed in most tissues, with very
high levels in testis and skeletal muscle.
Roux et al. (1994) also cloned the HSPA2 gene, using a genomic probe
derived from one of the HSP genes in the major histocompatibility
complex (MHC) on chromosome 6, which had previously been shown to detect
sequences on chromosome 14 as well. HSPA2 is expressed abundantly in
muscle, heart, esophagus, and brain, and to a lesser extent in testis.
Using Western blot analysis, Son et al. (1999) found significant
expression of a 70-kD HSPA2 protein in testis, but only low expression
in testis with Sertoli cell-only syndrome (see 305700). A small amount
of HSPA2 was detected in breast, stomach, prostate, colon, liver, ovary,
and epididymis. Immunohistochemical analysis of normal testis detected
HSPA2 in spermatocytes and spermatids with normal spermatogenesis,
whereas little to no immunoreactivity was detected in testis with
Sertoli cell-only syndrome.
Huszar et al. (2000) determined that HSPA2 is identical to sperm CKM, a
marker of sperm maturity and function. Immunohistochemical analysis
detected weak expression of HSPA2 in spermatocytes and stronger
expression in spermatids and in the tail of mature sperm.
GENE FUNCTION
During spermiogenesis, both cytoplasmic extrusion and plasma membrane
remodeling, which facilitate the formation of the zona pellucida-binding
site, involve major intrasperm protein transport. Huszar et al. (2000)
noted that immature human sperm, which fail to express HSPA2, show
cytoplasmic retention and lack zona pellucida binding. They suggested
that HSPA2 may be critical to sperm maturation through its role as a
protein chaperone.
Rohde et al. (2005) found elevated expression of HSP70-2 in 5 of 16
(31%) and 4 of 9 (44%) samples from primary and metastatic breast cancer
tissue, respectively, compared with 13 samples from adjacent normal
breast tissue. Cancer cells depleted of HSP70 (HSPA1A; 140550) and
HSP70-2 by small interfering RNA displayed strikingly different
morphologies (detached and round vs flat senescent-like), cell cycle
distribution (G2/M vs G1 arrest), and gene expression profiles.
Concomitant depletion of HSP70 and HSP70-2 had a synergistic
antiproliferative effect on cancer cells.
MAPPING
Several heat-shock protein genes, such as HSPA1, are located in the MHC
on chromosome 6. However, the HSPA2 gene is located on chromosome
14q22-q24 (Harrison et al., 1987). By fluorescence in situ
hybridization, Bonnycastle et al. (1994) mapped a 670-kb YAC containing
HSPA2 to chromosome 14q24.1. Roux et al. (1994) localized HSPA2 to
chromosome 14q22 by study of a somatic cell hybrid panel and by FISH
analysis. Hunt et al. (1993) found that the corresponding gene in the
mouse is located in a region of chromosome 12 homologous to human
chromosome 14.
MOLECULAR GENETICS
For a discussion of a possible association between variation in the
HSPA2 gene and noise-induced hearing loss, see 613035.
ANIMAL MODEL
Dix et al. (1996) showed that female homozygous knockout mice for
Hsp70-2 undergo normal meiosis and are fertile. In contrast, homozygous
male knockout mice lacked postmeiotic spermatids and mature sperm and
were infertile. Hsp70-2 is normally associated with synaptonemal
complexes in the nuclei of meiotic spermatocytes. In the male knockouts,
these structures were abnormal by late prophase. Dix et al. (1996)
observed also a large increase in spermatocyte apoptosis.
MAX
| dbSNP name | rs8181931(A,G); rs73270871(T,C); rs10149182(A,G); rs35410051(A,G); rs55896900(T,G); rs55877000(T,G); rs7145112(A,C); rs7151272(A,G); rs7152879(T,C); rs7152277(G,C); rs12433870(C,T); rs7144259(T,A); rs11626720(C,T); rs7147987(A,G); rs942629(A,G); rs942628(C,G); rs7150646(G,T); rs4899161(G,A); rs7156617(G,A); rs4902357(C,G); rs4902358(A,G); rs1957949(C,T); rs1957948(C,T); rs4902359(G,A); rs45604339(C,T); rs762810(C,A); rs2277500(C,T); rs188570373(T,A); rs12590701(C,T); rs11628938(G,T); rs12588412(T,C); rs12101257(A,G); rs998247(C,T); rs7143495(A,G); rs4902360(A,C); rs11625045(C,T); rs369591376(T,C); rs942627(A,G); rs942626(C,T); rs7159443(T,A); rs141542259(T,G); rs8010213(C,T); rs146979285(T,C); rs7154852(C,A); rs2093989(C,T); rs139333427(T,C); rs55658675(C,T); rs1957947(C,T); rs10143198(C,T); rs8181937(A,C); rs8181938(A,G); rs8181939(G,A); rs7151350(T,C); rs2763887(T,G); rs1953228(G,C); rs1998688(C,G); rs116898180(T,G); rs1256418(A,G); rs7161394(G,T); rs137940321(G,T); rs1256417(C,T); rs1256416(C,T); rs1256415(C,T); rs1271582(T,G); rs1270074(T,C); rs1262269(A,C); rs10151162(T,C); rs2781371(G,C); rs1124752(G,T); rs1124751(C,A); rs2781373(G,A) |
| ccdsGene name | CCDS9774.1 |
| cytoBand name | 14q23.3 |
| EntrezGene GeneID | 4149 |
| EntrezGene Description | MYC associated factor X |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAX:NM_001271068:exon3:c.A172C:p.T58P,MAX:NM_145114:exon4:c.A199C:p.T67P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7316 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96CY8 |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 1.057e-04,3.253e-05 |
OMIM Clinical Significance
Skel:
Skeletal dysplasia;
Severely retarded ossification of epiphyses, pelvis, hands, and feet
Limbs:
Abnormal modeling of bones of hands and feet
Neuro:
No mental retardation
Inheritance:
Autosomal recessive
OMIM Title
*600021 MAX DIMERIZATION PROTEIN 1; MXD1
;;MAD1;;
BHLHC58
OMIM Description
DESCRIPTION
The MXD1 and MXI1 (600020) genes encode proteins that belong to a
distinct subfamily of MAX (154950)-interacting proteins. The MAX protein
specifically interacts with the MYC protein family (190080) by forming
heterodimers mediated by their basic-helix-loop-helix-leucine zipper
(bHLHZ) interaction domains. Binding to MAX is essential for MYC
transcription and transforming activity; MYC homodimers are inactive.
Both MXD1 and MXI1 bind MAX in vitro, forming a sequence-specific
DNA-binding complex similar to the MYC-MAX heterodimer. MXD1 and MYC
compete for binding to MAX. In addition, MXD1 acts as a transcriptional
repressor, while MYC appears to function as an activator. MXI1 also
appears to lack a transcriptional activation domain. Therefore, MXI1 and
MXD1 might antagonize MYC function and are candidate tumor suppressor
genes (Nair and Burley, 2003).
BIOCHEMICAL FEATURES
Nair and Burley (2003) determined the x-ray structures of the bHLHZ
domains of MYC-MAX and MXD1-MAX heterodimers bound to their common DNA
target, the enhancer box (E-box) hexanucleotide
(5-prime-CACGTG-3-prime), at 1.9- and 2.0-angstrom resolution,
respectively. E-box recognition by these 2 structurally similar
transcription factor pairs determines whether a cell will divide and
proliferate (MYC-MAX) or differentiate and become quiescent (MXD1-MAX).
Deregulation of MYC has been implicated in the development of many human
cancers, including Burkitt lymphoma, neuroblastomas, and small cell lung
cancers. Both quasisymmetric heterodimers resemble the symmetric MAX
homodimer, albeit with marked structural differences in the coiled-coil
leucine zipper regions that explain preferential homo- and heteromeric
dimerization of these 3 evolutionarily related DNA-binding proteins. The
MYC-MAX heterodimer, but not its MXD1-MAX counterpart, dimerizes to form
a bivalent heterotetramer, explaining how MYC can upregulate expression
of genes with promoters bearing widely separated E-boxes.
MAPPING
Edelhoff et al. (1994) mapped the human MXD1 and MXI1 genes to
chromosomes 2p13 and 10q25, respectively, by fluorescence in situ
hybridization. The homologous gene in the mouse was mapped to chromosome
6 by interspecific backcross analysis.
Shapiro et al. (1994) confirmed the assignments of the MXD1 and MXI1
genes to chromosomes 2p13-p12 and 10q24-q25, respectively, by somatic
cell mapping and fluorescence in situ hybridization.
NOMENCLATURE
The designation MAD was derived from MAX dimerizer (Eisenman, 1994).
RDH11
| dbSNP name | rs1059238(A,G); rs7765(T,C); rs7410(T,C); rs1018450(A,G); rs77554057(T,C); rs17249649(T,A); rs3784087(G,A); rs8007557(T,C); rs8006772(G,A); rs4902509(C,A); rs4899218(G,A); rs76889275(C,T); rs78495362(T,C); rs11626129(C,T); rs78204770(C,T); rs2273160(C,G); rs111906369(T,C); rs140332452(C,T); rs149663829(C,A); rs10150303(A,G); rs6573792(A,G); rs7147404(C,G); rs56038131(T,C); rs17104587(C,T); rs8017085(G,A); rs55790812(A,G); rs80140987(C,T); rs10135963(C,T); rs147035392(T,C); rs77060049(A,G) |
| ccdsGene name | CCDS32104.1 |
| cytoBand name | 14q24.1 |
| EntrezGene GeneID | 51109 |
| EntrezGene Description | retinol dehydrogenase 11 (all-trans/9-cis/11-cis) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RDH11:NM_016026:exon3:c.G235A:p.E79K,RDH11:NM_001252650:exon3:c.G235A:p.E79K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5388 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DDW0 |
| dbNSFP KGp1 AF | 0.0128205128205 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.024861878453 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.023746701847 |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.003631 |
| ESP All MAF | 0.014686 |
| ESP Eur/Amr MAF | 0.020349 |
| ExAC AF | 0.016 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Autosomal dominant
SKELETAL:
[Spine];
Kyphoscoliosis;
[Hands];
Claw hand deformities;
[Feet];
Talipes equinovarus
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Proximal muscle involvement may occur;
Areflexia;
Distal sensory impairment;
Normal or mildly reduced motor nerve conduction velocities (NCV) (greater
than 38 m/s);
Loss of myelinated fibers on nerve biopsy;
Axonal regeneration on nerve biopsy;
Pseudo-'onion bulb' formation
MISCELLANEOUS:
Onset before age 3 years;
Onset in feet and legs (peroneal distribution);
Upper limb involvement in first decade;
Severe progression;
Patients with autosomal dominant inheritance and a single GDAP1 mutation
have a less severe course with later onset;
Genetic heterogeneity (see CMT2A 118210);
Allelic disorder to CMT4A (214400)
MOLECULAR BASIS:
Caused by mutation in the ganglioside-induced differentiation-associated
protein-1 gene (GDAP1, 606598.0002)
OMIM Title
*607849 RETINOL DEHYDROGENASE 11; RDH11
;;PROSTATE SHORT-CHAIN DEHYDROGENASE/REDUCTASE 1; PSDR1;;
RETINAL REDUCTASE 1; RALR1
OMIM Description
DESCRIPTION
RHD11, a member of the short-chain dehydrogenase/reductase (SDR)
superfamily of oxidoreductases, is expressed at high levels in prostate
epithelium, and its expression is regulated by androgens.
CLONING
Using microarrays, Lin et al. (2001) found that RDH11, which they
designated PSDR1, was upregulated by synthetic androgen in an
androgen-sensitive prostate cancer cell line. By database analysis and
screening of a prostate cDNA library, they cloned full-length RDH11. The
deduced protein contains 318 amino acids, and the transcript contains 2
potential polyadenylation signals. RDH11 shares conserved motifs with
the SDR family of oxidoreductases, including an N-terminal
coenzyme-binding motif, which binds NAD(H) or NADP(H), and a C-terminal
catalytic domain. RDH11 shares about 25% sequence identity with other
SDR family members. Northern blot and RNA dot blot analyses detected a
2.5-kb transcript expressed at a high level in prostate and at low
levels in other tissues, including spleen, thymus, testis, ovary, small
intestine, colon, peripheral blood leukocytes, kidney, adrenal gland,
and fetal liver. Testis expressed an additional transcript of about 0.9
kb. In situ hybridization of normal prostate detected RDH11 expression
in basal and luminal epithelial cells, but not in fibromuscular stromal
cells, endothelial cells, or infiltrating lymphocytes. Primary prostate
adenocarcinoma cells were uniformly positive for RDH11 expression.
Kedishvili et al. (2002) determined that RDH11, which they called RALR1,
localized to the endoplasmic reticulum when transfected into COS-7
cells.
Moore et al. (2002) cloned mouse Rdh11. The deduced 316-amino acid
protein shares 85% identity with human RDH11. Northern blot analysis
detected highest expression in testis and liver, where there were 2
Rdh11 isoforms. RNA dot blot analysis detected expression in all tissues
examined, with highest expression in testis.
GENE FUNCTION
Kedishvili et al. (2002) characterized the substrate specificity of
recombinant RDH11 expressed in sf9 insect cells. They determined that
RDH11 had oxidoreductase activity toward retinoids but not steroids. It
also showed a preference for NADP+ and NADPH versus NAD+ and NADH as
cofactors. The enzyme was about 50-fold more efficient in the reduction
of all-trans-retinal than in the oxidation of all-trans-retinol. RDH11
reduced all-trans-retinal in the presence of a 10-fold molar excess of
cellular retinol-binding protein-1 (180260), which was believed to
sequester all-trans-retinal from nonspecific enzymes.
GENE STRUCTURE
Lin et al. (2001) determined that the RDH11 gene contains 7 exons and
spans about 18.9 kb. The promoter region contains a TATA box and
putative androgen, progesterone, and interleukin-6 (IL6; 147620)
response elements.
MAPPING
By radiation hybrid analysis, Lin et al. (2001) mapped the RDH11 gene to
chromosome 14q23-q24.3. Moore et al. (2002) mapped the mouse Rdh11 gene
to chromosome 12 in a region that shows homology of synteny to human
chromosome 14q23-q24.3.
By genomic sequence analysis, Haeseleer et al. (2002) mapped the RDH11
and RDH12 (608830) genes within about 30 kb of each other.
CCDC177
| dbSNP name | rs7494244(A,T); rs116803661(A,C); rs7140978(C,T); rs117298196(C,G); rs4899302(A,G) |
| CosmicCodingMuts gene | C14orf162 |
| cytoBand name | 14q24.1 |
| EntrezGene GeneID | 56936 |
| snpEff Gene Name | C14orf162 |
| EntrezGene Description | coiled-coil domain containing 177 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.770146520147 |
| dbNSFP KGp1 Afr AF | 0.619918699187 |
| dbNSFP KGp1 Amr AF | 0.834254143646 |
| dbNSFP KGp1 Asn AF | 0.797202797203 |
| dbNSFP KGp1 Eur AF | 0.816622691293 |
| dbSNP GMAF | 0.2296 |
| ESP Afr MAF | 0.406792 |
| ESP All MAF | 0.256242 |
| ESP Eur/Amr MAF | 0.190761 |
| ExAC AF | 0.719 |
LOC100289511
| dbSNP name | rs3809399(C,T) |
| cytoBand name | 14q24.2 |
| EntrezGene GeneID | 100289511 |
| snpEff Gene Name | SRSF5 |
| EntrezGene Description | uncharacterized LOC100289511 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09229 |
ADAM21P1
| dbSNP name | rs150958502(T,G); rs12586570(A,G); rs117006186(C,T) |
| cytoBand name | 14q24.2 |
| EntrezGene GeneID | 145241 |
| snpEff Gene Name | RP11-486O13.1 |
| EntrezGene Description | ADAM metallopeptidase domain 21 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1198 |
| ExAC AF | 0.08 |
MAP3K9
| dbSNP name | rs8006539(G,T); rs8006424(A,G); rs10140478(T,A); rs3742848(C,T); rs10134761(C,T); rs7156271(A,G); rs17108442(C,T); rs11625206(C,T); rs12879569(C,T); rs117382165(A,G); rs2286053(C,T); rs150460336(G,A); rs1476610(T,G); rs11621251(A,C); rs56118372(C,T); rs11844774(C,T); rs75902769(T,C); rs200148074(G,A); rs3829955(G,A); rs141180334(C,A); rs6573978(T,C); rs45600331(C,G); rs34322726(T,C); rs17108454(A,C); rs10146889(C,T); rs4899367(C,T); rs4141095(C,T); rs1859465(T,C); rs79402258(C,G); rs76828553(G,A); rs8010714(G,C); rs8011047(G,A); rs7153601(C,T); rs12590343(T,C); rs11628333(T,C); rs58162675(A,T); rs61359483(C,A); rs2286052(G,A); rs8008802(G,A); rs144836040(G,A); rs12435875(C,T); rs74762543(G,A); rs189963382(C,T); rs4899368(A,G); rs4902843(C,A); rs111729880(C,T); rs10483834(A,G); rs4902844(T,C); rs2269946(T,C); rs8011507(G,A); rs61988426(C,T); rs61988427(A,G); rs2332455(T,C); rs8018294(T,C); rs2332456(A,G); rs2332457(T,G); rs79588155(T,G); rs10129495(G,A); rs79518608(T,C); rs11622989(C,T); rs8015238(T,C); rs8014356(G,T); rs8014624(A,T); rs67446674(T,C); rs61990472(T,G); rs12437256(T,A); rs34307438(T,C); rs4902846(G,A); rs117787708(C,T); rs75142804(C,T); rs4902847(G,A); rs142200590(A,G); rs4902848(G,A); rs10873240(A,G); rs7161415(T,C); rs112095593(C,T); rs8007131(C,A); rs1476609(G,A); rs2877693(T,C); rs116058487(T,A); rs150386984(G,A); rs6573979(T,C); rs6573980(G,A); rs7147731(T,A); rs71425216(G,C); rs8015636(C,T); rs74669594(C,T); rs3814872(A,C); rs11621281(G,A); rs145731692(T,C); rs34817530(T,C); rs9323548(A,C); rs60417730(C,T); rs12886990(G,A); rs886600(C,G); rs28420983(T,G); rs77275949(C,T); rs150752821(T,C); rs12589737(A,T); rs35506365(C,T); rs12888427(G,T); rs10873241(T,C); rs73285177(T,C); rs61990476(A,G); rs4902849(A,T); rs55941560(C,T); rs8019261(C,T); rs6573981(T,C); rs8019448(A,G); rs4902852(C,T); rs138870042(G,A); rs2332458(C,T); rs8005459(C,G); rs10873242(A,G); rs17108492(C,T); rs17176971(G,A); rs75800609(G,A); rs1548585(T,C); rs1548584(T,C); rs184685773(A,G); rs12433469(C,T); rs78839467(T,C); rs7154907(C,G); rs17176985(G,A); rs7160912(C,A); rs12897648(C,T); rs368076417(G,A); rs10143748(G,A); rs56801523(G,A); rs142610045(G,A); rs17108504(C,T); rs17177014(T,C); rs7152516(T,G); rs7151405(C,T); rs55727545(A,G); rs17108510(C,G); rs12895576(A,C); rs61212719(T,G); rs58270240(C,T); rs17766512(T,A); rs72721934(T,C); rs112283475(A,G); rs74461437(C,T); rs8022333(C,T); rs8022803(G,A); rs8022401(A,C); rs11620710(A,G); rs7140653(C,T); rs35438375(A,C); rs12883087(C,T); rs12883244(C,T); rs2107666(G,C); rs2158531(T,C); rs2158530(T,C); rs11158881(T,C); rs4902854(T,C); rs11621269(T,C); rs10141804(C,T); rs55717811(C,G); rs17108530(G,A); rs17108533(C,T); rs115106865(C,T); rs11852001(G,C); rs34632954(C,G); rs11621236(A,T); rs10131177(G,A); rs8006715(G,A); rs10131364(G,C); rs17766551(G,C); rs57843652(T,C); rs61990481(C,T); rs11622867(G,C); rs11622833(A,C); rs55912635(G,A); rs17177097(C,T); rs8019513(T,C); rs61990514(A,G); rs1987652(C,T); rs59858521(G,A); rs60533515(G,A); rs17108537(C,A); rs1034769(C,A); rs4902855(C,T); rs7146255(C,T); rs17108539(A,G); rs17108540(G,C); rs11626707(G,T); rs34857523(G,A); rs12590049(G,A); rs8020663(G,A); rs12437037(A,G); rs12437113(C,G); rs17108546(A,G); rs57284652(C,T); rs2107665(C,T); rs2158529(G,T); rs10143031(C,T); rs17108548(T,C); rs12883168(G,A); rs12586899(T,C); rs4528504(G,A); rs71425385(C,T); rs67164415(T,C); rs61990518(G,A); rs61990519(T,C); rs8018972(C,T); rs17766621(T,C); rs75372759(G,A); rs61990520(C,G); rs2051857(C,T); rs17108554(G,C); rs17108555(A,G); rs61990521(A,G); rs8021260(G,C); rs8020852(A,G); rs55725720(C,T); rs10083428(G,A); rs8022269(A,G); rs11624934(A,G); rs8022621(C,T); rs116987310(A,C); rs4902857(C,T); rs116824824(G,A); rs7151024(G,C); rs4899371(A,G); rs36025596(A,C); rs61990523(C,T); rs74408905(A,G); rs76342619(C,A); rs2023955(T,G); rs731571(T,C); rs2023954(A,G); rs4902858(G,A); rs4902859(C,T); rs10873243(T,A); rs7155910(G,T); rs11158882(C,G) |
| ccdsGene name | CCDS32112.1 |
| cytoBand name | 14q24.2 |
| EntrezGene GeneID | 4293 |
| EntrezGene Description | mitogen-activated protein kinase kinase kinase 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAP3K9:NM_001284231:exon11:c.C2065T:p.R689W,MAP3K9:NM_001284230:exon11:c.C2737T:p.R913W,MAP3K9:NM_033141:exon12:c.C2779T:p.R927W,MAP3K9:NM_001284232:exon10:c.C1936T:p.R646W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.584 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3V4P9 |
| ExAC AF | 4.067e-05 |
OMIM Clinical Significance
Eyes:
Retinitis pigmentosa
Inheritance:
Autosomal recessive (6p)
OMIM Title
*600136 MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 9; MAP3K9
;;MIXED-LINEAGE KINASE 1; MLK1
OMIM Description
CLONING
Using the polymerase chain reaction to study mRNA expressed in human
epithelial tumor cells, Dorow et al. (1993) identified a member of a new
family of protein kinases. The catalytic domain of these kinases had
amino acid sequence similarity to both the tyr-specific and the
ser/thr-specific kinase classes. Dorow et al. (1993) isolated clones
representing 2 members of this new family from a human colonic
epithelial cDNA library. The predicted amino acid sequence revealed
that, in addition to their unusual nature of the kinase catalytic
domains, they contain 2 leu/ile-zipper motifs and a basic sequence near
their C-termini. Because they possess domains associated with proteins
from 2 distinct functional groups, these kinases were referred to as
mixed-lineage kinases (MLK) 1 and 2. MLK1 mRNA was found to be expressed
in epithelial tumor cell lines of colonic, breast, and esophageal
origin. The similarity score with MLK1 varied from 73 down to 61 for the
following tyr PKs; ROS (165020), ABL (189980), EGFR (131550), SRC
(190090), TRK (191315), PDGFR (173410, 173490), INSR (147670). The
similarity score with MLK1 was 63 for RAF (164760) and 52 for MOS
(190060).
MAPPING
By study of rodent/human somatic cell hybrids and isotopic in situ
hybridization, Dorow et al. (1993) mapped the MAP3K9 gene to chromosome
14q24.3-q31.
MOLECULAR GENETICS
Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic
mutations in metastatic melanoma. Focusing on the mitogen-activated
protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012)
found that 24% of melanoma cell lines have mutations in the
protein-coding regions of either MAP3K5 (602448) or MAP3K9. Structural
modeling predicted that mutations in the kinase domain may affect the
activity and regulation of these protein kinases. The position of the
mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and
67% of melanoma samples, respectively, together suggested that the
mutations are likely to be inactivating. In in vitro kinase assays,
MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity.
Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the
phosphorylation of downstream MAP kinases. Attenuation of MAP3K9
function in melanoma cells using siRNA led to increased cell viability
after temozolomide treatment, suggesting that decreased MAP3K pathway
activity can lead to chemoresistance in melanoma.
GENE FAMILY
While protein kinases vary widely in their primary structures, each
contains a catalytic domain of 250 to 300 amino acids, which includes 11
highly conserved motifs or subdomains separated by sequences of amino
acids with reduced conservation. The presence of these motifs within a
newly characterized sequence is, therefore, strongly predictive of PK
activity. Furthermore, specificity of a PK for phosphorylation of either
tyr or ser/thr can be predicted by the sequence of 2 of the motifs (VIb
and VIII) in which different residues are conserved in each class. PKs
with similar substrates or modes of activation cluster into families,
whose members share a higher degree of catalytic-domain sequence
identity with each other than with other members of the same PK
specificity class. Hanks (1991) described 10 families of ser/thr PKs and
11 families of tyr PKs.
LOC145474
| dbSNP name | rs191457798(T,A); rs14030(A,C); rs12127(T,C); rs3088206(C,A) |
| cytoBand name | 14q24.2 |
| EntrezGene GeneID | 145474 |
| snpEff Gene Name | SIPA1L1 |
| EntrezGene Description | uncharacterized LOC145474 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
PAPLN
| dbSNP name | rs3742826(T,A); rs3742825(G,A); rs3742824(T,G); rs3742823(C,T); rs148561768(G,A); rs59781702(T,G); rs2242603(G,A); rs78371326(C,T); rs2242604(C,T); rs177407(T,C); rs145486339(T,C); rs125505(T,C); rs2242606(A,G); rs74916401(T,C); rs1008245(A,C); rs177406(G,A); rs177405(T,A); rs74828683(C,T); rs2280792(A,G); rs2280793(G,A); rs2280794(G,T); rs2242608(G,T); rs12895249(T,C); rs177404(G,C); rs12883707(C,G); rs144111866(G,A); rs112556267(G,A); rs177396(A,G); rs139532071(C,T); rs177394(G,A); rs2293792(C,T); rs2293793(T,C); rs177393(G,A); rs17182237(T,C); rs12432062(G,A); rs147672782(G,A); rs2242610(A,G); rs8017581(G,A); rs8017937(G,A); rs11159011(G,A); rs2242611(G,A); rs17126331(A,C); rs4346152(C,T); rs2079319(G,C); rs74426878(C,T); rs177392(C,T); rs2293796(G,A); rs17126354(C,T); rs11628713(C,T); rs2242614(A,G); rs7493181(G,A); rs11845511(A,C); rs177391(A,T); rs76501718(A,G); rs6574115(A,G); rs7160247(A,G); rs2293797(C,A); rs2293801(T,C); rs177389(T,G); rs12880103(G,C); rs177385(C,A); rs1145948(A,G); rs45574438(C,T); rs177383(C,G); rs375796432(C,T); rs150619831(G,C); rs61745771(G,A); rs909216(A,G); rs878869(A,G); rs4903104(C,T); rs1980413(G,C); rs1980414(G,T); rs140030387(C,T); rs2269967(G,A); rs11848550(A,G); rs117634003(T,C); rs41310938(G,A); rs11849947(G,A); rs932256(C,G) |
| ccdsGene name | CCDS32114.1 |
| cytoBand name | 14q24.2 |
| EntrezGene GeneID | 89932 |
| EntrezGene Description | papilin, proteoglycan-like sulfated glycoprotein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PAPLN:NM_173462:exon23:c.G3259A:p.A1087T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6009 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95428-6 |
| dbNSFP KGp1 AF | 0.00595238095238 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.00699300699301 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.004844 |
| ESP Eur/Amr MAF | 0.006628 |
| ExAC AF | 0.005766 |
C14orf169
| dbSNP name | rs3813563(T,C) |
| ccdsGene name | CCDS9815.2 |
| cytoBand name | 14q24.3 |
| EntrezGene GeneID | 399671 |
| EntrezGene Symbol | HEATR4 |
| snpEff Gene Name | HEATR4 |
| EntrezGene Description | HEAT repeat containing 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4463 |
| ESP Afr MAF | 0.351908 |
| ESP All MAF | 0.492368 |
| ESP Eur/Amr MAF | 0.44047 |
| ExAC AF | 0.515 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic (episodes last from hours to days);
Weakness;
Dysarthria;
Vertigo;
Normal interictal neurologic examination
MISCELLANEOUS:
Onset before age 20 years;
Symptoms precipitated by exercise and excitement;
Episode frequency is monthly to yearly, and decreases with age
OMIM Title
*611919 MYC-ASSOCIATED PROTEIN WITH JMJC DOMAIN
;;MAPJD;;
NUCLEOLAR PROTEIN, 66-KD; NO66;;
CHROMOSOME 14 OPEN READING FRAME 169; C14ORF169
OMIM Description
CLONING
By searching databases for homologs of Xenopus No66, Eilbracht et al.
(2004) identified human NO66. The deduced 641-amino acid protein has a
calculated molecular mass of 71.1 kD. It contains a JmjC domain, 2
putative nuclear localization signals, and several potential
phosphorylation sites. Northern blot analysis detected a 2.3-kb
transcript expressed at variable levels in all human tissues examined
and in the MCF-7 human breast cancer cell line. Immunohistochemical
analysis showed that NO66 localized to different subnuclear compartments
in different cell lines. In most cell lines, NO66 was enriched in the
granular part of nucleoli and in distinct nucleoplasmic granules, where
it colocalized with replicating chromatin. Western blot analysis of
cultured human cells detected a 79-kD NO66 protein. Homologs of NO66
were detected in cell lines from diverse species, but the sizes of the
proteins differed from that of human NO66, primarily due to different
lengths of the N-terminal end.
GENE FUNCTION
Eilbracht et al. (2004) found that the nuclear distribution of NO66
changed during the cell cycle in MCF-7 cells: it localized to
perichromosomal cytoplasm in metaphase and early anaphase, to
chromosomes in late anaphase, and to prenucleolar bodies in late
telophase. In Xenopus oocyte and human cell nuclear extracts, NO66
associated with large preribosomal particles and coimmunoprecipitated
with the nucleolar proteins NO38 (NPM1; 1640440) and nucleolin (NCL;
164035). Eilbracht et al. (2004) concluded that NO66 associates with
preribosomes through several stages of maturation and may be involved in
assembly and processing of ribosomal subunits.
Using a cDNA microarray, Suzuki et al. (2007) found that expression of
MAPJD was elevated at least 3-fold in more than half of non-small cell
lung carcinomas examined. RT-PCR detected high MAPJD expression in 27 of
30 lung cancer cell lines, but MAPJD was only weakly expressed in normal
airway epithelia and other normal tissues. Downregulation of MAPJD in
lung cancer cell lines by small interfering RNA (siRNA) increased the
number of apoptotic cells and the number of cells in sub-G1 phase.
Transfection of MAPJD in mouse fibroblasts increased their growth rate.
Among 53 candidate genes whose expression decreased in accordance with
siRNA-mediated downregulation of MAPJD, Suzuki et al. (2007) identified
4 genes, SBNO1 (614274), TGFBRAP1 (606237), RIOK1, and RASGEF1A
(614531), that were most significantly induced by MAPJD expression in
lung cancer cells. The promoter regions of these 4 genes contain several
E boxes, which bind MYC (190080). Chromatin immunoprecipitation and
reporter gene assays revealed that MAPJD and MYC interacted at the
promoter region of these genes and increased their expression.
Furthermore, TRRAP (603015) and trimethylated histone H4 were recruited
to these promoters in MAPJD-transfected cells. Suzuki et al. (2007)
concluded that the MAPJD-MYC complex binds E boxes and recruits
chromatin-modifying factors to upregulate expression of target genes.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the MAPJD
gene to chromosome 14 (TMAP SHGC-56451).
PNMA1
| dbSNP name | rs8949(G,T); rs7182(C,T); rs61117767(C,T); rs116398549(G,C); rs35585529(T,G) |
| cytoBand name | 14q24.3 |
| EntrezGene GeneID | 9240 |
| snpEff Gene Name | C14orf43 |
| EntrezGene Description | paraneoplastic Ma antigen 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1221 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly
NEUROLOGIC:
[Central nervous system];
Megalencephaly;
Ataxia;
Spasticity;
Seizures;
Delay in motor development;
Mild mental retardation;
Diffuse swelling of cerebral white matter;
Large subcortical cysts in frontal and temporal lobes;
Diffuse spongiform leukoencephalopathy;
Vacuolizing myelinopathy
MISCELLANEOUS:
Onset in infancy;
Slow course of functional deterioration compared to severity of MRI
findings
MOLECULAR BASIS:
Caused by mutation in the MLC1 gene (MLC1, 605908.0001)
OMIM Title
*604010 PARANEOPLASTIC MA ANTIGEN 1; PNMA1
;;PARANEOPLASTIC ANTIGEN MA1; MA1;;
NEURON- AND TESTIS-SPECIFIC PROTEIN 1
OMIM Description
DESCRIPTION
The PNMA1 gene encodes a proapoptotic protein inducing an antineuronal
antibody (anti-Ma) present in patients with paraneoplastic neurologic
disorders (Dalmau et al., 1999; Chen and D'Mello, 2010).
Some paraneoplastic syndromes affecting the nervous system are
associated with antibodies that react with neuronal proteins and the
causal tumor (onconeuronal antigens). Several of these antibodies are
markers of specific neurologic syndromes associated with distinct types
of cancer. The presence of some antibodies is so specific that disorders
previously identified by brain biopsy or at autopsy can be diagnosed
serologically. The expression of neuronal proteins by the tumor appears
to be a crucial step that breaks the immune tolerance for otherwise
normal neuronal proteins. The identity of most onconeuronal antigens was
established by probing human cDNA expression libraries with serum
containing antineuronal antibodies (summary by Dalmau et al., 1999).
CLONING
Dalmau et al. (1999) performed serologic studies of 1,705 sera from
patients with suspected paraneoplastic neurologic disorders and
identified 4 patients with antibodies that reacted with 37- and 40-kD
(see MA2; 603970) neuronal proteins, which they referred to as anti-Ma
antibodies. Three patients had brainstem and cerebellar dysfunction, and
1 had dysphagia and motor weakness. Autopsy of 2 patients showed loss of
Purkinje cells, Bergmann gliosis, and deep cerebellar white matter
inflammatory infiltrates. Extensive neuronal degeneration, gliosis, and
infiltrates mainly composed of CD8+ T cells were also found in the
brainstem of 1 patient. In normal human and rat tissues, the anti-Ma
antibodies reacted exclusively with neurons and with testicular germ
cells; the reaction was mainly with subnuclear elements (including the
nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also
reacted with cancers (breast, colon, and parotid) available from 3
anti-Ma patients, but not with 66 other tumors of varying histologic
types. Preincubation of tissues with any of the anti-Ma sera abrogated
the reactivity of the other anti-Ma immunoglobulins. Probing of a human
cDNA library with anti-Ma serum resulted in the cloning of a gene that
encodes a novel 37-kD, 330-amino acid protein, which Dalmau et al.
(1999) called MA1. Recombinant MA1 was specifically recognized by the 4
anti-Ma sera but not by 337 control sera, including those from 52 normal
individuals, 179 cancer patients without paraneoplastic neurologic
symptoms, 96 patients with paraneoplastic syndromes, and 10 patients
with non-cancer-related neurologic disorders. Northern blot analysis
showed that expression of MA1 mRNA was highly restricted to the brain
and testis as an approximately 2.7-kb transcript. Subsequent analysis
suggested that MA1 is likely to be a phosphoprotein.
Schuller et al. (2005) corrected the DNA and protein sequences of PNMA1.
The corrected protein contains 353 amino acids rather than 330 amino
acids, as reported by Dalmau et al. (1999).
By RT-PCR analysis, Chen and D'Mello (2010) found that Pnma1 expression
in rats peaked in the perinatal period, when developmentally regulated
neuronal death occurs. In day-7 postnatal rat brain, Pnma1 expression
was highest in striatum, followed by midbrain, hippocampus, and
cerebellum, with little expression in cortex and olfactory bulb. There
was little to no expression in mature rat brain. Immunofluorescence
microscopy demonstrated cytoplasmic expression of Pnma1 in cultured rat
cerebellar granule neurons (CGNs).
MAPPING
Gross (2014) mapped the PNMA1 gene to chromosome 14q24.3 based on an
alignment of the PNMA1 sequence (GenBank GENBANK AF037364) with the
genomic sequence (GRCh37).
GENE FUNCTION
The brain and testis are immunologically privileged by the existence of
a blood-tissue barrier. In addition to this physical barrier, the
MA1-expressing cells of these organs (neurons and germ cells) lack
expression of the MHC class I and II antigens needed for the
presentation of surface or intracellular proteins to the immune system.
These findings indicated that the expression by a tumor of proteins
normally restricted to immunoprivileged tissues (brain or testis) is a
crucial step in the development of an immune response that may result in
neurologic disease. In keeping with this model, a group of
'cancer/testis' antigens, such as melanoma-associated antigen-1 (MAGE1;
300016) and melanoma-associated antigen-3 (MAGE3; 300174), were
originally identified because of their ability to elicit immune
responses, usually T cell-mediated. Dalmau et al. (1999) questioned
whether patients with anti-Ma antibodies also develop immunopathologic
abnormalities in the testis. The only male patient in their study was
lost to follow-up.
Using RT-PCR and Western blot analysis, Chen and D'Mello (2010) found
that Pnma1 expression increased in cultured rat CGNs induced to die by
low potassium and in cultured rat cortical neurons treated with
homocysteic acid (HCA). Pnma2 (603970), Pnma3 (300675), and Moap1
(609485) showed no change in rat CGNs following low potassium treatment,
whereas Pnma5 (300916) expression was also elevated in CGNs under these
conditions. However, Pnma5 showed no change in cortical neurons
following HCA treatment. Treatment of CGNs with short hairpin RNA
against Pnma1 inhibited low potassium-induced cell death, as did
overexpression of Bcl2 (151430). Induction of cell death required the
N-terminal BH3-like domain of Pnma1. Chen and D'Mello (2010) concluded
that PNMA1 functions to promote neuronal death.
ANIMAL MODEL
Chen and D'Mello (2010) detected increased expression of Pnma1 in
striatum of R6/2 transgenic mice, a model of Huntington disease (HD;
143100), compared with wildtype mice. They also detected increased Pnma1
expression in striatum of wildtype mice administered a succinate
dehydrogenase (see 600857) inhibitor, which produces HD-like pathology,
including striatal neurodegeneration and movement deficits. Chen and
D'Mello (2010) proposed that elevated PNMA1 expression may contribute to
neurodegenerative disorders.
LTBP2
| dbSNP name | rs74384554(T,C); rs73296215(T,C); rs1052939(G,A); rs7569(G,A); rs77015988(C,T); rs116738303(T,C); rs2286412(C,T); rs73296217(C,T); rs139932140(A,G); rs144967693(C,T); rs11159087(C,T); rs10146812(A,T); rs11846588(T,C); rs112413542(C,T); rs116317911(T,C); rs3815329(A,G); rs189939559(C,T); rs7160756(A,G); rs12898083(C,T); rs1005154(G,A); rs1005153(A,T); rs2530399(G,C); rs2530398(A,G); rs862057(C,T); rs862056(T,C); rs862055(T,C); rs862054(C,T); rs862053(G,T); rs862052(T,C); rs862051(C,T); rs862050(C,G); rs862049(C,T); rs862048(A,G); rs862046(G,T); rs2530397(T,C); rs63395061(C,G); rs862045(A,G); rs4899518(G,A); rs862039(A,G); rs4899520(G,A); rs146190354(C,T); rs699370(T,C); rs699371(T,C); rs79459845(G,A); rs862037(G,A); rs862036(C,T); rs862035(C,G); rs862034(A,G); rs862033(T,C); rs3784030(G,A); rs862031(A,G); rs862030(T,C); rs3815328(C,T); rs699374(A,G); rs699375(A,C); rs699372(A,C); rs699373(A,G); rs3784029(C,T); rs201838800(G,A); rs12886662(G,T); rs7149562(G,A); rs117826491(G,T); rs6574180(C,T); rs6574181(C,T); rs6574182(G,T); rs6574183(T,G); rs6574184(G,A); rs862027(G,T); rs186372023(C,A); rs862026(G,A); rs862025(C,T); rs1860106(C,T); rs12882065(T,C); rs3742794(G,T); rs4899522(G,A); rs4903234(T,C); rs4899523(C,T); rs7155637(C,A); rs12894581(T,G); rs12893681(G,A); rs7156894(C,T); rs10138237(G,A); rs12588574(A,G); rs12588688(G,T); rs2358796(A,G); rs2358797(C,T); rs2358798(T,C); rs67507466(C,A); rs10873268(C,T); rs10873269(A,G); rs10873270(A,G); rs10873271(G,A); rs7140170(T,G); rs2028377(C,T); rs2165199(T,C); rs2884550(G,C); rs934997(G,A); rs140160042(C,T); rs1992302(C,T); rs76637487(G,A); rs1992303(A,G); rs11159088(G,T); rs12100463(C,G); rs3825711(G,C); rs7148461(T,C); rs1982216(G,A); rs2359141(A,G); rs2196861(T,C); rs2289387(G,A); rs2289388(G,A); rs67358575(G,C); rs1992304(T,C); rs934998(T,C); rs934999(G,C); rs55971017(A,G); rs11625990(A,G); rs376917789(G,A); rs61738025(C,T); rs11622992(T,C); rs111850609(A,G); rs61980881(A,T); rs61980882(C,T); rs73297910(T,C); rs10136102(G,A); rs55927952(G,A); rs2304707(G,T); rs57176747(A,G); rs61980885(G,T); rs10142206(A,G); rs55762670(A,G); rs113785923(C,A); rs7148764(C,T); rs7150659(T,C); rs3784028(C,T); rs11159089(A,G); rs61654245(C,T); rs3729502(G,T); rs1008007(G,A); rs28627652(G,A); rs10144559(T,C); rs116068314(C,T); rs11624211(C,T); rs11624291(G,T); rs12895882(T,C); rs61980888(G,C); rs2196863(T,G); rs61980889(C,T); rs2196864(G,C); rs4903239(T,C); rs11622583(A,G); rs11159090(C,T); rs61980890(G,C); rs11622806(C,A); rs6574186(A,G); rs10149616(T,C); rs3825710(A,C); rs3784027(T,C); rs3784025(G,A); rs11626424(A,G); rs11627650(C,T); rs11623580(T,C); rs10150499(G,A); rs10150419(C,T); rs11624818(T,C); rs10140101(T,C); rs10150950(A,G); rs61980907(T,C); rs8006916(G,C); rs11629289(T,C); rs11624749(C,T); rs61980909(C,G); rs10139746(A,G); rs28651311(C,G); rs10142883(C,G); rs8006807(A,T); rs61980910(G,A); rs10146172(A,G); rs4903242(C,T); rs3825709(C,T); rs61980911(A,C); rs4903243(C,A); rs10133124(C,T); rs3784024(A,G); rs4903244(G,C); rs61980912(A,G); rs4903245(T,G); rs56365335(A,C); rs59242728(G,A); rs74065450(T,C); rs7150223(A,T); rs8014087(T,C); rs36063013(A,G); rs73297968(G,A); rs182838847(G,A); rs10400787(G,C); rs11625386(T,C); rs115510427(A,G); rs117096840(C,T); rs12435481(T,C); rs183579087(G,A); rs374436252(C,T); rs59706456(A,G); rs181044395(G,A); rs4544177(C,A); rs61578021(A,T); rs57784746(T,C); rs58569871(A,G); rs61980917(C,T); rs11626065(T,G); rs7148701(A,T); rs7150149(T,A); rs61980918(T,C); rs377393605(C,T); rs8004866(T,C); rs58052725(T,C); rs60411104(G,A); rs7158922(G,A); rs60328208(T,A); rs72732149(A,G); rs4899524(C,T); rs3742793(G,C); rs61980921(C,T); rs8006778(C,T); rs935000(C,T); rs61980922(G,C); rs61980923(T,G); rs2043948(C,T); rs4903246(T,C); rs78821336(A,C); rs4899525(C,T); rs4903247(A,G); rs7141062(G,A); rs11159091(G,A); rs8009788(G,T); rs7147181(C,G); rs1866628(C,T); rs1866629(A,G); rs61056974(A,G) |
| ccdsGene name | CCDS9831.1 |
| CosmicCodingMuts gene | LTBP2 |
| cytoBand name | 14q24.3 |
| EntrezGene GeneID | 4053 |
| EntrezGene Description | latent transforming growth factor beta binding protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LTBP2:NM_000428:exon33:c.T4769C:p.V1590A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7117 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14767 |
| dbNSFP Uniprot ID | LTBP2_HUMAN |
| dbNSFP KGp1 AF | 0.00457875457875 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0105540897098 |
| dbSNP GMAF | 0.004591 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.007151 |
| ESP Eur/Amr MAF | 0.00907 |
| ExAC AF | 0.007709 |
OMIM Clinical Significance
Skin:
Capillary hemangiomas
Misc:
Most sporadic as single lesions
Inheritance:
Autosomal dominant type;
High penetrance
OMIM Title
*602090 LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 3; LTBP3
;;LTBP2, FORMERLY
OMIM Description
DESCRIPTION
Transforming growth factors (TGFs) beta-1 (190180), beta-2 (190220),
beta-3 (190230), and others have both stimulatory and inhibitory effects
on the growth of different cell types and play a role in the production
and degradation of the extracellular matrix. TGF-beta molecules are
secreted in the form of latent large molecular mass complexes that
contain other proteins, such as latent TGF-beta-1 binding protein
(LTBP1; 150390). There is evidence that these binding proteins modulate
TGF-beta bioavailability.
See Oklu and Hesketh (2000) for a review of the LTBP gene family.
CLONING
Yin et al. (1995) cloned a novel mouse gene, designated Ltbp3, isolated
because of structural similarities to fibrillin (134797). Its 4.6-kb
transcript was found to encode a protein sequence related to LTBP1.
MAPPING
Li et al. (1995) assigned the human and mouse LTBP3 loci (called LTBP2
and Ltbp2 by them) to regions of conserved synteny on human chromosome
11 and mouse chromosome 19. By PCR analysis of somatic cell hybrid DNA
and fluorescence in situ hybridization (FISH), the genes were mapped to
human 11q12 and mouse chromosome 19B.
Sawicki et al. (1997) identified the sequence of the human LTBP3 gene on
a transcript map encompassing the locus for MEN I (MEN1; 131100) on
chromosome 11q13.
MOLECULAR GENETICS
In affected members of a consanguineous Pakistani family with selective
tooth agenesis (STHAG6; 613097), Noor et al. (2009) identified a
homozygous nonsense mutation in the LTBP3 gene (Y744X; 602090.0001). Two
affected males were examined in detail. The phenotype was characterized
by absence of many of the permanent teeth, as well as apparent increased
bone density in the spine and skull base. The findings suggested an
important role for LTBP3-mediated transcription in development of the
axial skeleton.
NOMENCLATURE
The official designation for the gene mapped to human chromosome 11 by
Li et al. (1995) is LTBP3. An LTBP gene mapped to chromosome 14 and
previously designated LTBP3 in the literature is symbolized LTBP2; see
602091.
ANIMAL MODEL
Dabovic et al. (2002) created an Ltbp3-null mutation in the mouse by
gene targeting. Mice homozygous for the mutation developed craniofacial
malformations by day 10. At 2 months, there was a pronounced rounding of
the cranial vault, extension of the mandible beyond the maxilla, and
kyphosis. Between 6 and 9 months of age, mutant mice also developed
osteosclerosis and osteoarthritis. The pathologic changes were
consistent with perturbed TGF-beta signaling in the skull and long
bones.
Using direct lineage tracing and loss-of-function studies in zebrafish,
Zhou et al. (2011) demonstrated that Ltbp3 transcripts mark a field of
cardiac progenitor cells with defining characteristics of the anterior
second heart field in mammals. Specifically, Ltbp3+ cells differentiate
in pharyngeal mesoderm after formation of the heart tube, elongate the
heart tube at the outflow pole, and give rise to 3 cardiovascular
lineages in the outflow tract and myocardium in the distal ventricle. In
addition to expressing Ltbp3, a protein that regulates the
bioavailability of TGF-beta ligands, zebrafish second heart field cells
coexpress nkx2.5 (600584), an evolutionarily conserved marker of cardiac
progenitor cells in both fields. Embryos devoid of ltbp3 lacked the same
cardiac structures derived from ltbp3+ cells due to compromised
progenitor proliferation. Furthermore, small molecule inhibition of
TGF-beta signaling phenocopied the ltbp3-morphant phenotype whereas
expression of a constitutively active TGF-beta type I receptor rescued
it. Zhou et al. (2011) concluded that their results uncovered a
requirement for ltbp3-TGF-beta signaling during zebrafish second heart
field development, a process that serves to enlarge the single
ventricular chamber in this species.
FOXN3-AS2
| dbSNP name | rs243196(C,A); rs243197(A,C) |
| cytoBand name | 14q32.11 |
| EntrezGene GeneID | 29018 |
| snpEff Gene Name | FOXN3 |
| EntrezGene Description | FOXN3 antisense RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1598 |
MOAP1
| dbSNP name | rs149552910(C,T); rs1128801(G,C); rs113142191(C,T); rs15837(C,T); rs1046099(A,G) |
| cytoBand name | 14q32.12 |
| EntrezGene GeneID | 64112 |
| snpEff Gene Name | C14orf109 |
| EntrezGene Description | modulator of apoptosis 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Short philtrum;
Thick philtrum;
Maxillary hypoplasia;
[Ears];
Low-set ears;
Thick earlobes;
[Eyes];
Telecanthus;
Megalocornea;
Blue sclerae;
Corneal ulcer;
Downslanting palpebral fissures;
Ptosis;
High-arched, dense eyebrows;
Curled eyelashes;
Synophrys;
[Nose];
Prominent nasal bridge;
Broad nasal bridge;
Bulbous nasal tip;
[Mouth];
Full lips;
Everted lower lip;
[Neck];
Short neck
CHEST:
[Breasts];
Widely spaced nipples
ABDOMEN:
[Gastrointestinal];
Hirschsprung disease (in most patients)
SKELETAL:
[Hands];
Tapered fingers;
Clinodactyly;
Small hands
SKIN, NAILS, HAIR:
[Hair];
Sparse hair
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Pachygyria;
Polymicrogyria;
Thin corpus callosum;
Brainstem hypoplasia
MISCELLANEOUS:
Prenatal onset;
Additional developmental abnormalities may be seen in some patients
MOLECULAR BASIS:
Caused by mutation in the KIAA1279 gene (KIAA1279, 609367.0001)
OMIM Title
*609485 MODULATOR OF APOPTOSIS 1; MOAP1
;;MAP1;;
PARANEOPLASTIC MA ANTIGEN FAMILY, MEMBER 4; PNMA4;;
PARANEOPLASTIC ANTIGEN-LIKE PROTEIN 4
OMIM Description
CLONING
Using amino acids 1 to 171 of mouse Bax (600040) in a yeast 2-hybrid
screen of a human brain cDNA library, followed by screening of a
cerebellum cDNA library, Tan et al. (2001) cloned MAP1. The deduced
351-amino acid protein has a calculated molecular mass of 39 kD. MAP1
contains a central BH3-like motif that is similar to the BH3-B domain of
BID (601997). Northern blot analysis detected a 2.8-kb MAP1 transcript
in all tissues examined, with highest expression in heart and brain.
GENE FUNCTION
Tan et al. (2001) found that overexpression of MAP1 in a breast
carcinoma cell line induced apoptosis, which was abrogated by inclusion
of a broad-spectrum caspase (see 147678) inhibitor. MAP1 formed
homodimers, and it associated with BAX, BCL2 (151430), and BCLXL
(BCL2L1; 600039) in vitro and in transfected human embryonic kidney
cells. MAP1 did not bind other members of the BCL2 family. Mutation
analysis indicated that the BH3-like domain of MAP1 was required to
mediate apoptosis and for binding of MAP1 to BAX, but not to BCLXL. All
3 BH domains of BAX were required for binding with MAP1.
Baksh et al. (2005) found that MAP1 interacted with RASSF1A (605082)
following TNF-alpha (191160) stimulation. Mutation analysis determined
that a basic stretch in MAP1 mediated the interaction with RASSF1A, and
the BH3-like domain of MAP1 was dispensable for RASSF1A/MAP1
interaction. In the absence of RASSF1A, MAP1 appeared to exist in an
inactive closed conformation in which the BH3-like domain was
unavailable for interaction with BAX. RASSF1A binding relieved the
inhibitory interaction, allowing MAP1 to bind BAX. RASSF1A/MAP1
interaction was required for conformational change in BAX, mitochondrial
membrane insertion, and maximal apoptosis in response to death receptor
stimulation. RASSF1A and MAP1 were recruited to both the TNF-alpha and
TRAIL (603598) receptor complexes in response to their respective
cognate ligands.
MAPPING
Gross (2014) mapped the MOAP1 gene to chromosome 14q32.12 based on an
alignment of the MOAP1 sequence (GenBank GENBANK AF305550) with the
genomic sequence (GRCh37).
LINC00341
| dbSNP name | rs17111964(A,C); rs1129498(A,G); rs3168818(G,A); rs1599965(T,C); rs1047403(C,G); rs3742345(C,T); rs3742344(C,G) |
| cytoBand name | 14q32.13 |
| EntrezGene GeneID | 79686 |
| snpEff Gene Name | NCRNA00341 |
| EntrezGene Description | long intergenic non-protein coding RNA 341 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1341 |
SNHG10
| dbSNP name | rs3742339(A,G); rs140287656(G,T); rs3825546(T,C); rs749742(G,C); rs8013240(C,T) |
| cytoBand name | 14q32.13 |
| EntrezGene GeneID | 283596 |
| snpEff Gene Name | GLRX5 |
| EntrezGene Description | small nucleolar RNA host gene 10 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4467 |
RTL1
| dbSNP name | rs11623267(C,G); rs6575805(A,G); rs61993320(C,T); rs3825569(T,C) |
| ccdsGene name | CCDS53910.1 |
| cytoBand name | 14q32.2 |
| EntrezGene GeneID | 388015 |
| EntrezGene Description | retrotransposon-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RTL1:NM_001134888:exon1:c.G2542C:p.E848Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PKS8 |
| dbNSFP KGp1 AF | 0.237637362637 |
| dbNSFP KGp1 Afr AF | 0.0853658536585 |
| dbNSFP KGp1 Amr AF | 0.171270718232 |
| dbNSFP KGp1 Asn AF | 0.358391608392 |
| dbNSFP KGp1 Eur AF | 0.277044854881 |
| dbSNP GMAF | 0.2378 |
| ExAC AF | 0.177 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
RESPIRATORY:
Recurrent respiratory infections due to impaired ciliary motility;
[Lung];
Bronchiectasis
ABDOMEN:
Situs inversus (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Male fertility remains intact
LABORATORY ABNORMALITIES:
Cilia show nonflexible and hyperkinetic beating of axonemes;
Cilia may also be static, with slow activity;
Axonemes show normal structure
MOLECULAR BASIS:
Caused by mutation in the dynein axonemal heavy chain 11 gene (DNAH11,
603339.0001)
OMIM Title
*611896 RETROTRANSPOSON-LIKE GENE 1; RTL1
;;PATERNALLY EXPRESSED GENE 11; PEG11
OMIM Description
DESCRIPTION
The retrotransposon-derived mouse gene Rtl1 (retrotransposon-like-1),
also known as Peg11 (paternally expressed-11) is a paternally expressed
imprinted gene highly expressed at the late fetal stage in both the
fetus and placenta. Rtl1 has an overlapping maternally expressed
antisense transcript, Rtl1 antisense (Rtl1as, also known as anti-Peg11),
which contains several microRNAs (miRNAs) targeting the Rtl1 transcript
through an RNA interference (RNAi) mechanism (Seitz et al., 2003; Davis
et al., 2005).
GENE FUNCTION
Sekita et al. (2008) produced 2 different types of knockout mice: mice
with no Rtl1 expression upon paternal transmission of the knockout
allele, and those with 2.5 to 3.0 times overexpression of Rtl1 as a
result of deficiency of Rtl1as upon maternal transmission of the
knockout allele. They demonstrated that Rtl1 is essential for
maintenance of the fetal capillaries and that both its loss and its
overproduction cause late fetal and/or neonatal lethality in mice. The
observations contributed to the understanding of the formation and
maintenance of the eutherian chorioallantoic placenta, and how the
feto-maternal interface is maintained.
Kagami et al. (2008) studied 8 individuals with a paternal uniparental
disomy for chromosome 14 (upd(14)pat)-like phenotype and 3 with a
upd(14)mat-like phenotype in the absence of upd(14) and identified
various deletions and epimutations affecting the imprinted region. The
results implied that the intergenic differentially methylated region
(IG-DMR) has an important cis-acting regulatory function on the
maternally inherited chromosome and that excessive and decreased RTL1
expression contribute to the upd(14)pat-like and upd(14)mat-like
phenotypes, respectively.
MAPPING
The human RTL1 and RTL1as genes are located in the 14q32.2 region
between maternally expressed gene 3 (MEG3; 605636) and maternally
expressed gene 8 (MEG8) (Kagami et al., 2008). The homologous mouse gene
is located in a large imprinted region on distal chromosome 12.
SNORD114-7
| dbSNP name | rs72700530(G,C) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 767583 |
| snpEff Gene Name | AL132709.5 |
| EntrezGene Description | small nucleolar RNA, C/D box 114-7 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1309 |
| ESP Afr MAF | 0.057078 |
| ESP All MAF | 0.195152 |
| ESP Eur/Amr MAF | 0.255902 |
| ExAC AF | 0.172 |
MIR300
| dbSNP name | rs12894467(C,T) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 100126297 |
| snpEff Gene Name | MIR376C |
| EntrezGene Description | microRNA 300 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4265 |
| ESP Afr MAF | 0.421875 |
| ESP All MAF | 0.468058 |
| ESP Eur/Amr MAF | 0.419877 |
| ExAC AF | 0.509 |
MIR323B
| dbSNP name | rs56103835(T,C) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 574410 |
| snpEff Gene Name | MIR134 |
| EntrezGene Description | microRNA 323b |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3049 |
| ESP Afr MAF | 0.046556 |
| ESP All MAF | 0.157573 |
| ESP Eur/Amr MAF | 0.20617 |
| ExAC AF | 0.270,8.158e-06 |
MIR412
| dbSNP name | rs61992671(A,G) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 574433 |
| snpEff Gene Name | MIR377 |
| EntrezGene Description | microRNA 412 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2342 |
| ESP Afr MAF | 0.110332 |
| ESP All MAF | 0.368447 |
| ESP Eur/Amr MAF | 0.481435 |
| ExAC AF | 0.348 |
MIR656
| dbSNP name | rs58834075(C,T) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 724026 |
| snpEff Gene Name | MIR369 |
| EntrezGene Description | microRNA 656 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.073 |
| ESP Afr MAF | 0.155612 |
| ESP All MAF | 0.064563 |
| ESP Eur/Amr MAF | 0.024707 |
| ExAC AF | 0.049 |
DIO3OS
| dbSNP name | rs17100344(A,G); rs60082567(G,C); rs12147061(A,C); rs12147069(C,A); rs34929738(C,T); rs117528223(C,T) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 64150 |
| EntrezGene Description | DIO3 opposite strand/antisense RNA (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1272 |
| ExAC AF | 0.11 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous
MISCELLANEOUS:
One report of mother and son (last curated August 2012)
OMIM Title
*608523 DIO3, OPPOSITE STRAND; DIO3OS
OMIM Description
DESCRIPTION
The mouse and human DIO3OS and DIO3 (601038) genes overlap and are
transcribed in opposite directions. The mouse Dio3 gene is imprinted
from the paternal allele during fetal development, suggesting that
DIO3OS is a noncoding gene that may have a role in maintaining
monoallelic expression of DIO3 (Hernandez et al., 2004).
CLONING
During characterization of the promoter region of the DIO3 gene,
Hernandez et al. (2004) identified DIO3OS as being transcribed in the
antisense direction. By searching EST databases and 3-prime and 5-prime
RACE of several tissues, they cloned DIO3OS. Complex alternative
splicing results in at least 13 DIO3OS transcripts. Hernandez et al.
(2004) cloned mouse Dio3os, which also encodes several splice variants.
They identified a 408-nucleotide ORF in 1 human DIO3OS cDNA, and no ORFs
were found in the mouse cDNAs, suggesting that DIO3OS is a noncoding
gene. Northern blot analysis detected widespread expression in human
tissues. The most prominent bands were approximately 4.8, 3.7, 2.6, and
1.4 kb, with highest abundance in testis, adrenal cortex, prostate,
bladder, uterus, placenta, and fetal lung. Several other transcripts,
including some that were very small and some that appeared to be
doublets, were also detected. A transcript of about 8.0 kb was expressed
weakly in fetal lung.
GENE STRUCTURE
The human and mouse DIO3OS genes contain at least 6 exons and have 2
alternate polyadenylation sites. Although the exon-intron structure is
conserved in mouse and human DIO3OS, the exonic sequences share less
than 60% homology, except for exon 1, which is located in the highly
conserved GC region flanking the DIO3 gene. The mouse and human DIO3OS
promoters contain 2 regions of homology. One region contains a putative
AP1 (165160) site and serum-response elements, and the other contains a
putative TATA box.
MAPPING
By genomic sequence analysis, Hernandez et al. (2004) mapped the DIO3OS
gene to chromosome 14q32. Exon 1 of DIO3OS is located within a GC-rich
region 1 kb upstream of the DIO3 gene. The mouse Dio3os gene maps to
chromosome 12F1, and exon 1 of Dio3os overlaps with exon 1 of the Dio3
gene.
DIO3
| dbSNP name | rs113370931(G,T); rs945006(T,G); rs149804060(A,C) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 1735 |
| EntrezGene Description | deiodinase, iodothyronine, type III |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
OMIM Clinical Significance
Limbs:
Absent/hypoplastic tibia. Bowed radius and ulna. Postaxial polydactyly
of hands. Postaxial polydactyly of feet. Preaxial polydactyly of feet.
Clubfoot.
Mouth:
Cleft lip.
Thorax:
Absent diaphragm.
Neuro:
Posterior fossa cyst. Choroid plexus cyst.
Inheritance:
Autosomal recessive.
OMIM Title
*601038 DEIODINASE, IODOTHYRONINE, TYPE III; DIO3
;;THYROXINE DEIODINASE, TYPE III; TXDI3;;
IODOTHYRONINE DEIODINASE, PLACENTAL TYPE
OMIM Description
CLONING
Thyroid hormone is critical to the normal development of the human
central nervous system. Salvatore et al. (1995) noted that, despite the
presence of thyroxine (T4) and thyroid follicles in the fetal thyroid by
10 to 12 weeks of gestation, as well as the potential availability of
maternal thyroid hormone, the free concentration of the active thyroid
hormone T3 is less than half that of maternal levels up to the time of
delivery. The physiologic rationale for this circumstance is not well
understood, but the authors suggested that it is possible that 'normal'
circulating T3 concentrations could have deleterious effects on immature
tissues or could enhance the metabolic requirements of the fetus. There
are 2 principal mechanisms by which the circulating fetal T3
concentration is maintained at low levels. One is that the type I
iodothyronine deiodinase (147892) in fetal liver is expressed at lower
levels relative to those in adult life. This reduces the extra thyroidal
T3 supply from this source. The second important factor in maintaining
low serum T3 concentrations is the expression of high levels of the type
III deiodinase in placenta of all species examined. Type III
iodothyronine deiodinase catalyzes the conversion of T4 and T3 to
inactive metabolites. Salvatore et al. (1995) cloned human placental
type III iodothyronine deiodinase (which they referred to as D3). It is
a selenoenzyme, as evidenced by (1) the presence of an in-frame UGA
codon at position 144; (2) the synthesis of a 32-kD (75)Se-labeled
protein in D3 cDNA transfected cells; and (3) the presence of a
selenocysteine insertion sequence element in the 3-prime untranslated
region of an mRNA that is required for its expression. The authors
stated that the D3 selenocysteine insertion sequence element is more
potent than that found in the type I deiodinase or glutathione
peroxidase (138320) gene, suggesting a high priority for selenocysteine
incorporation into this enzyme. The conservation of this enzyme from
Xenopus laevis tadpoles to humans implies an essential role for
regulation of thyroid hormone inactivation during embryologic
development.
By Northern blot analysis, Hernandez et al. (2004) detected several DIO3
transcripts. A 2.1-kb transcript was highly expressed in placenta, fetal
liver, and uterus, and a 3.2-kb transcript predominated in testis,
bladder, and uterus. A 4.8-kb transcript was detected in heart and
skeletal muscle, but it hybridized only with the most 5-prime region of
the DIO3 cDNA, suggesting that it is not a true coding transcript. Some
or all of these transcripts were also present in adrenal cortex,
thyroid, prostate, stomach, pancreas, and fetal lung.
GENE FUNCTION
Huang et al. (2000) reported the case of a 3-month-old infant with
massive hepatic hemangiomas and primary hypothyroidism who needed very
high doses of thyroid hormone to restore euthyroidism and normal
thyrotropin secretion. This finding suggested that the rate of
degradation of thyroid hormone was accelerated. They subsequently
identified high levels of type III iodothyronine deiodinase activity in
the hemangioma tissue. Normally present in the brain and placenta, this
selenoenzyme catalyzes the conversion of thyroxine to reverse
triiodothyronine and the conversion of triiodothyronine to
3,3-prime-diiodothyronine, both of which are biologically inactive. They
then retrospectively analyzed other patients with hemangiomas and
identified additional patients with similar histories and other
hemangiomas with type III iodothyronine deiodinase activity.
GENE STRUCTURE
Hernandez et al. (2004) determined that, like the mouse Dio3 gene, the
coding region and 3-prime UTR of human DIO3 are contained within a
single exon. In both mouse and human, the promoter elements are located
immediately upstream and are extremely GC rich (80% of the sequence).
MAPPING
By FISH, Hernandez et al. (1998) mapped the human DIO3 gene to 14q32 and
the mouse Dio3 gene to 12F1. See also DIO1 (147892) and DIO2 (601413).
Hernandez et al. (2004) noted that mouse Dio3 is imprinted and
preferentially expressed from the paternal allele during fetal
development. They determined that exon 1 of the DIO3OS gene (608523),
which is transcribed in the opposite orientation of the DIO3 gene, maps
to a region 1 kb upstream of the DIO3 transcription start site and
within the DIO3 GC-rich promoter region.
ANIMAL MODEL
By targeted inactivation of the Dio3 gene in mouse embryonic stem cells,
Hernandez et al. (2006) generated Dio3-knockout mice, which demonstrated
neonatal thyrotoxicosis followed later by persistent central
hypothyroidism. Early in life, the mutant mice had delayed T3 clearance,
markedly elevated serum T3 levels, and overexpression of T3-inducible
genes in the brain. From postnatal day 15 to adulthood, Dio3-knockout
mice exhibited central hypothyroidism, with low serum levels of T4 and
T3, and modest or no increase in TSH (see 118850) concentration;
peripheral tissues were also hypothyroid. Hypothalamic T3 was decreased,
whereas thyrotropin-releasing hormone (TRH; 613879) expression was
elevated. Hernandez et al. (2006) concluded DIO3 plays a critical role
in the maturation and function of the thyroid axis.
MIR4309
| dbSNP name | rs12879262(G,C) |
| cytoBand name | 14q32.31 |
| EntrezGene GeneID | 100422954 |
| EntrezGene Description | microRNA 4309 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07392 |
| ExAC AF | 0.058 |
AMN
| dbSNP name | rs2295828(T,C); rs2295829(G,C); rs138106067(G,A); rs1190226(T,C); rs148867699(A,G); rs1190228(A,G); rs1190229(A,G); rs1190230(T,C); rs28548211(T,C); rs1190231(T,C); rs13379138(G,A); rs1190232(T,G); rs1190233(G,C) |
| ccdsGene name | CCDS9977.1 |
| cytoBand name | 14q32.32 |
| EntrezGene GeneID | 81693 |
| EntrezGene Description | amnion associated transmembrane protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AMN:NM_030943:exon2:c.G130A:p.A44T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5449 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BXJ7 |
| dbNSFP Uniprot ID | AMNLS_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000681 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001222 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Nails];
Longitudinal angular ridges;
Reddish dome-shaped prominence at origin of ridges (in some nails);
Thinning of nail plate;
Free margin notched or split;
Lunulae poorly developed or absent;
Platonychia (in some nails);
Koilonychia (in some nails)
MISCELLANEOUS:
Most patients have involvement of all nails, with more severe changes
in the nails of the thumbs and great toes
OMIM Title
*605799 AMNIONLESS, MOUSE, HOMOLOG OF; AMN
OMIM Description
DESCRIPTION
The Amn gene, mutant in the 'amnionless' mouse, encodes a type I
transmembrane protein that is expressed exclusively in the
extraembryonic visceral endoderm layer during gastrulation.
CLONING
Fate-mapping experiments in the mouse have revealed that the primitive
streak can be divided into 3 functional regions: the proximal region
gives rise to the germ cells and the extraembryonic mesoderm of the yolk
sac; the distal region generates cardiac mesoderm and node-derived axial
mesendoderm; and the middle streak region produces the paraxial,
intermediate, and lateral plate mesoderm of the trunk. To gain insight
into the mechanisms that mediate the assembly of the primitive streak
into these functional regions, Kalantry et al. (2001) cloned and
functionally identified the gene disrupted in the amnionless mouse,
which has a recessive embryonic lethal mutation that interferes
specifically with the formation and/or specification of the middle
primitive streak region during gastrulation. The extracellular region of
the Amn protein contains a cysteine-rich domain with similarity to bone
morphogenetic protein (BMP)-binding cysteine-rich domains in chordin
(603475), its Drosophila homolog 'short gastrulation' (Sog), and
procollagen IIA (120140). Alignment of the predicted amino acid
sequences of the Drosophila, human, and mouse genes indicate that the
N-terminal portion, together with the cysteine-rich module, is the most
conserved segment of AMN. Amn acts in the visceral endoderm to affect
cell behaviors in the adjacent epiblast. The apical location of Amn
places it on the opposite side of the visceral endoderm from the
epiblast; therefore, Amn is unlikely to interact directly with epiblast
cells. Kalantry et al. (2001) proposed that AMN modulates a BMP
signaling pathway within the visceral endoderm to direct the production
of a set of gene products that interact directly with epiblast cells and
influence their behavior. Unlike chordin and Sog, AMN is
transmembrane-bound. This indicates that AMN might modulate BMP receptor
function by serving as an accessory or coreceptor that, through its
cysteine-rich domain, facilitates or hinders BMP binding.
The human AMN gene is predicted to encode a 454-amino acid protein
(Kalantry et al., 2001).
Dunn and Hogan (2001) discussed the work of Kalantry et al. (2001) in
the context of the role of extraembryonic signals in embryonic
patterning.
GENE STRUCTURE
Tanner et al. (2003) determined that the AMN gene comprises 12 exons
encoding at least 5 protein products.
GENE FUNCTION
Fyfe et al. (2004) showed that cubilin (CUBN; 602997), a protein that
recognizes intrinsic factor (IF)-cobalamin and various other proteins to
be endocytosed in the intestine and kidney, respectively, and AMN
colocalize in the endocytic apparatus of polarized epithelial cells and
copurify as a tight complex during IF-cobalamin affinity and
nondenaturing gel filtration chromatography. In transfected cells
expressing either AMN or a truncated IF-cobalamin-binding cubilin
construct, neither protein alone conferred ligand endocytosis. Other
studies indicated that cubilin and AMN are subunits of a novel
cubilin/AMN (cubam) complex, where AMN binds to the N-terminal third of
cubilin and directs subcellular localization and endocytosis of cubilin
with its ligand. Fyfe et al. (2004) concluded that mutations affecting
either of the 2 proteins may abrogate function of the cubam complex and
cause Imerslund-Grasbeck syndrome (261100).
MAPPING
Kalantry et al. (2001) assembled an EST contig corresponding to the
human AMN gene. By sequence identity between this contig and a BAC clone
(GenBank GENBANK AL133455), they mapped the human AMN gene to 14q32. AMN
resides between TRAF3 (601896) and CDC42BPB (614062), in the same
transcriptional orientation as TRAF3.
MOLECULAR GENETICS
Autosomal recessive hereditary megaloblastic anemia (MGA1; 261100) was
described simultaneously in Norway by Imerslund (1960) and in Finland by
Grasbeck et al. (1960). Aminoff et al. (1999) showed that MGA1 is caused
in Finnish cases by homozygous mutations of the CUBN gene, which encodes
a receptor for the intrinsic factor-vitamin B12 complex. Unexpectedly,
however, Norwegian individuals showing the MGA1 phenotype did not have
mutations in CUBN. Using samples from these Norwegian families, Tanner
et al. (2003) carried out a genomewide search, established linkage to
14q, and narrowed the critical region to that containing the AMN gene.
AMN emerged as a clear candidate because of its high expression in the
kidney. Tanner et al. (2003) screened the AMN gene in 5 families and
identified homozygosity for one or another of 3 AMN mutations in all 11
affected individuals, with heterozygosity in the 5 parents available for
study.
It is a paradox that homozygous inactivation of Amn causes an embryonic
lethal condition in mice, whereas homozygous mutations in human AMN
cause only the mild MGA1 phenotype. As all mutations resulting in MGA1
occurred toward the N-terminal end of the gene, this part of the gene
might not be essential for embryonic development but might be for
vitamin B12 uptake. By in vitro protein expression analysis, Tanner et
al. (2003) showed that the AMN gene encodes at least 5 protein products.
Further studies confirmed that the MGA1 mutations allowed truncated AMN
translation. The authors postulated that the truncated AMN products are
important for embryonic development and thereby preclude a lethal
phenotype as seen in the amnionless mouse.
Evidence of mutations in a single gene, such as AMN, causing 2 or more
distinct phenotypes is an exception to the dogma of 1 gene, 1 protein, 1
function. Thus, AMN/Amn can be added to the short list of 'moonlighting
proteins' (Jeffery, 1999). Other examples include laminin A/C (LMNA;
150330), mutations in which cause related phenotypes that suggest a
common mechanism; a notable example is ERCC2 (126340), which apparently
has 2 distinct functions in DNA repair and transcription and causes 3
distinct diseases (Lehmann, 2001) when mutated.
ANIMAL MODEL
The mouse mutation 'amnionless' was originally so named because on some
genetic backgrounds homozygotes lack the amnion (Wang et al., 1996;
Tomihara-Newberger et al., 1998). More striking, however, is that Amn
mutants lack a trunk. Embryos that survive to the tenth day of
gastrulation have headfolds, a beating heart, and abundant posterior
mesoderm; however, in between these tissues is none of the mesoderm that
produces the limb buds, dermis, muscle, vertebrae, and other organs of
the trunk (Tomihara-Newberger et al., 1998). Analysis of marker genes
expressed regionally indicates that the phenotype originates from
mispatterning of epiblast cells in the middle levels so that they
acquire a more posterior fate. The Amn mouse has an insertional mutation
generated by the integration of a human CD8-alpha transgene into distal
mouse chromosome 12, downstream from the 3-prime end of Traf3 (601896).
By in situ hybridization analysis of wildtype blastocysts and early
postimplantation-stage embryos, Kalantry et al. (2001) demonstrated that
Amn is first transcribed in the primitive endoderm at embryonic day 4.5.
Amn expression was specifically in the visceral endoderm at all
subsequent stages of gastrulation examined. The Amn protein is localized
to the apical surface of the visceral endoderm cells at embryonic day
6.0 and 7.5. A similar distribution of Amn was detected at embryonic day
5.5; in particular, Amn is expressed throughout the visceral endoderm
and is not localized to either the posterior or anterior side of the
embryo. The expression pattern indicates that Amn functions exclusively
in the visceral endoderm to direct epiblast growth and assembly of the
middle primitive streak.
LINC00605
| dbSNP name | rs3742452(T,C); rs115204691(G,A); rs183502188(C,T); rs2763529(G,T) |
| cytoBand name | 14q32.32 |
| EntrezGene GeneID | 100131366 |
| snpEff Gene Name | AL161669.2 |
| EntrezGene Description | long intergenic non-protein coding RNA 605 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1295 |
RD3L
| dbSNP name | rs1187447(T,C); rs35337422(A,C) |
| ccdsGene name | CCDS9987.2 |
| cytoBand name | 14q32.33 |
| EntrezGene GeneID | 647286 |
| snpEff Gene Name | TDRD9 |
| EntrezGene Description | retinal degeneration 3-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03719 |
ZBTB42
| dbSNP name | rs10141867(G,A); rs4983387(G,A); rs3803300(T,C); rs62902662(G,T) |
| ccdsGene name | CCDS45174.1 |
| CosmicCodingMuts gene | ZBTB42_ENST00000342537 |
| cytoBand name | 14q32.33 |
| EntrezGene GeneID | 100128927 |
| EntrezGene Description | zinc finger and BTB domain containing 42 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZBTB42:NM_001137601:exon2:c.G570A:p.L190L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2282 |
| ESP Afr MAF | 0.308526 |
| ESP All MAF | 0.287127 |
| ESP Eur/Amr MAF | 0.277778 |
| ExAC AF | 0.218 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
HEAD AND NECK:
[Face];
Loss of subcutaneous adipose tissue from face;
Sunken face;
'Progeroid' expression
GENITOURINARY:
[Kidneys];
Membranoproliferative glomerulonephritis (26%);
Nephrotic syndrome
MUSCLE, SOFT TISSUE:
Loss of subcutaneous adipose tissue from face, progressive;
Loss of subcutaneous adipose tissue from upper limbs and trunk
IMMUNOLOGY:
Frequent infections;
Decreased serum C3;
Presence of C3 nephritic factor autoantibody
LABORATORY ABNORMALITIES:
Hematuria;
Proteinuria
MISCELLANEOUS:
Onset in first or second decade;
More common in females (male:female ratio 4:1);
Variable phenotype;
No family history;
Association with autoimmune diseases
OMIM Title
*613915 ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 42: ZBTB42
;;ZNF925
OMIM Description
CLONING
Using RT-PCR, Devaney et al. (2011) cloned human ZBTB42 from skeletal
muscle RNA. The deduced protein has a calculated molecular mass of about
47 kD and contains an N-terminal POZ domain and 4 C-terminal C2H2-type
zinc fingers. Database analysis revealed ZBTB42 orthologs in several
vertebrate species. Mouse and human ZBTB42 share 75% amino acid
identity. Western blot analysis detected ZBTB42 proteins with apparent
molecular masses of 47 and 36 kD in human skeletal muscle. In mouse, the
47-kD protein was highly expressed in skeletal muscle and ovary, with
lower expression in brain, lung, spleen, liver, and heart, and no
expression in kidney or intestine. The 36-kD protein was highly
expressed in mouse skeletal muscle and liver, but was not detected in
other tissues. Immunohistochemical analysis of human skeletal muscle
showed that ZBTB42 localized to nuclei of myofibers and interstitial
connective tissue cells. Confocal microscopy of mouse skeletal muscle
localized Zbtb42 within the nucleoplasm of myofiber nuclei, and Zbtb42
was highly enriched in subsynaptic nuclei at the neuromuscular junction.
GENE STRUCTURE
Devaney et al. (2011) determined that the ZBTB42 gene contains 2 exons.
MAPPING
Hartz (2011) mapped the ZBTB42 gene to chromosome 14q32.33 based on an
alignment of the ZBTB42 sequence (GenBank GENBANK AK125003) with the
genomic sequence (GRCh37).
LINC00638
| dbSNP name | rs2498790(A,G); rs55961253(C,T); rs12894160(C,T); rs10138512(G,A) |
| cytoBand name | 14q32.33 |
| EntrezGene GeneID | 196872 |
| snpEff Gene Name | RP11-477I4.3 |
| EntrezGene Description | long intergenic non-protein coding RNA 638 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
CRIP2
| dbSNP name | rs149070182(T,C) |
| cytoBand name | 14q32.33 |
| EntrezGene GeneID | 1397 |
| EntrezGene Description | cysteine-rich protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002296 |
OMIM Clinical Significance
Muscle:
Congenital muscular dystrophy;
Generalized muscle weakness;
Facial weakness;
Axial and limb muscle weakness
Neuro:
Severe psychomotor retardation
Misc:
Infantile onset of weakness
Radiology:
Ventriculomegaly;
Severe cerebral and cerebellar atrophy
Lab:
Progressive muscle infiltration with fat cells;
Variable expression of merosin (156225);
Hypomyelination;
Myopathic potentials on EMG;
Markedly decreased motor nerve conduction velocities;
Isoelectric central evoked potentials;
Almost complete absence of large diameter fibers but no signs
of degeneration on sural nerve biopsy
Inheritance:
Autosomal recessive
OMIM Title
*601183 CYSTEINE-RICH INTESTINAL PROTEIN 2; CRIP2
;;CYSTEINE-RICH PROTEIN 2; CRP2;;
LIM DOMAIN PROTEIN ESP1/CRP2
OMIM Description
CLONING
By low stringency screening of a human small intestine cDNA library with
a rat cysteine-rich intestinal protein (CRIP1; 123875) cDNA, Karim et
al. (1996) isolated a cDNA encoding CRIP2, which they called ESP1/CRP2.
The cDNA predicts a 208-amino acid protein containing 2 LIM domains.
CRIP2 shares 93% amino acid sequence identity with its rat homolog,
called Esp1 or Crp2. Northern blot analysis showed widespread tissue
expression of the 1.3-kb CRIP2 mRNA, with the highest level of
expression found in heart. In testis, a second 1.7-kb mRNA was also
detected.
Tsui et al. (1996) cloned a human heart cDNA encoding CRIP2, which they
called CRP2. CRIP2 is 38% and 35% identical to the CSRP1 (123876) and
CSRP3 (600824) proteins, respectively.
MAPPING
Tsui et al. (1996) mapped the CRIP2 gene to 14q32 using fluorescence in
situ hybridization (FISH). By somatic cell hybrid analysis and FISH,
Karim et al. (1996) mapped the CRIP2 gene to 14q32.3.
LINC00226
| dbSNP name | rs11160942(A,G) |
| cytoBand name | 14q32.33 |
| EntrezGene GeneID | 338004 |
| snpEff Gene Name | IGHV3-25 |
| EntrezGene Description | long intergenic non-protein coding RNA 226 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | IG_V_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4357 |
LOC646214
| dbSNP name | rs111948233(T,C); rs4983761(G,A); rs59089552(G,A); rs1996583(T,C); rs4984139(G,A); rs8040953(C,T); rs4984123(G,A); rs58100517(A,G); rs8043454(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 646214 |
| snpEff Gene Name | RP11-32B5.1 |
| EntrezGene Description | p21 protein (Cdc42/Rac)-activated kinase 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03857 |
OR4N3P
| dbSNP name | rs111333174(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 390539 |
| EntrezGene Description | olfactory receptor, family 4, subfamily N, member 3 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| ExAC AF | 0.007878 |
HERC2P2
| dbSNP name | rs60002889(C,T); rs417713(T,C) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 400322 |
| snpEff Gene Name | AC091565.1 |
| EntrezGene Description | hect domain and RLD 2 pseudogene 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01607 |
MKRN3
| dbSNP name | rs2239669(C,T) |
| ccdsGene name | CCDS10013.1 |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 7681 |
| EntrezGene Description | makorin ring finger protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MKRN3:NM_005664:exon1:c.C663T:p.P221P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2204 |
| ESP Afr MAF | 0.180209 |
| ESP All MAF | 0.264878 |
| ESP Eur/Amr MAF | 0.308256 |
| ExAC AF | 0.281 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolonged QT interval on EKG;
Syncope;
Torsade de pointes;
Ventricular fibrillation;
Sudden cardiac death
MISCELLANEOUS:
Association of cardiac events with exercise;
Genetic heterogeneity (see LQT1 192500);
Patients with more severe phenotype have been reported with mutations
in more than 1 LQTS-related gene;
GEI (gene-environment interaction) - association of cardiac events
with drug administration
MOLECULAR BASIS:
Caused by mutation in the sodium channel, voltage-gated, type V, alpha
polypeptide gene (SCN5A, 600163.0001)
OMIM Title
*603856 MAKORIN 3; MKRN3
;;ZINC FINGER PROTEIN 127; ZNF127; ZFP127
OMIM Description
CLONING
Jong et al. (1999) characterized 2 genes, termed ZNF127 (MKRN3) and
ZNF127AS (603857), which are encoded in the complex imprinted locus on
15q11-q13. The ZNF127 gene encodes a 507-amino acid protein with a RING
(C3HC4) zinc finger motif and multiple C3H zinc finger motifs, the
former being closely related to a protein from variola major virus, the
smallpox etiologic agent. These motifs predict ribonucleoprotein
function for the ZNF127 polypeptide. Northern blot analysis revealed
that the intronless ZNF127 gene is expressed ubiquitously as an
approximately 3-kb transcript; however, the entire coding sequence and
5-prime CpG island overlap a second gene, ZNF127AS, which is transcribed
from the antisense strand with a different transcript size and pattern
of expression. Allele-specific analysis showed that the ZNF127 gene is
expressed only from the paternal allele. Consistent with this expression
pattern, in the brain, the ZNF127 5-prime CpG island is completely
unmethylated on the paternal allele but methylated on the maternal
allele. Analysis of adult testis, sperm, and fetal oocytes demonstrated
a gametic methylation imprint with unmethylated paternal germ cells.
Other work indicated that the ZNF127 gene is part of a coordinately
regulated imprinted domain affected in Prader-Willi syndrome (PWS;
176270) patients with imprinting mutations (Nicholls et al., 1998).
Therefore, ZNF127 and ZNF127AS are novel imprinted genes that may be
associated with some of the clinical features of the polygenic
Prader-Willi syndrome.
Jong et al. (1999) characterized the murine ZNF127 ortholog, termed
Zfp127, which encodes a homologous putative zinc finger polypeptide. The
mouse and human ZNF127 polypeptide sequences share similar structural
motifs, including all 5 putative zinc finger motifs, and they have an
overall identity of 69% at the amino acid level. Using RT-PCR across an
in-frame hexamer tandem repeat and RNA from an interspecific F1 cross,
Jong et al. (1999) showed that the Zfp127 gene is expressed only from
the paternal allele in brain, heart, and kidney. Similarly, Zfp127 was
expressed in differentiated cells derived from androgenetic embryonic
stem cells and normal embryos but not those from parthogenetic embryonic
stem cells. Jong et al. (1999) hypothesized that the gametic imprint may
be set, at least in part, by the transcriptional activity of Zfp127 in
pre- and postmeiotic male germ cells. They concluded that Zfp127 is a
novel imprinted gene that may play a role in the imprinted phenotype of
mouse models of PWS.
GENE FUNCTION
The hypothalamic arcuate nucleus is the site of expression of several
genes known to be important for puberty, including Kiss1 (603286) and
Tac2 (TAC3; 162330). Abreu et al. (2013) performed quantitative
real-time PCR to assess Mkrn3 mRNA levels in the arcuate nucleus of
mice, and observed in both male and female mice that levels were highest
on postnatal days 10 and 12, began to decline on day 15, and reached a
nadir by days 18 to 22, at which time Mkrn3 expression was 10 to 20% of
the levels detected at 10 days. The timing of the decline in Mkrn3
expression correlated with the ages at which arcuate Kiss1 and Tac2 have
been shown to increase, heralding the onset of puberty.
MOLECULAR GENETICS
Abreu et al. (2013) performed whole-exome sequencing in 40 members of 15
families with central precocious puberty (CPPB2; 615346) and identified
heterozygosity for 3 frameshift mutations and 1 missense mutation in the
MKRN3 gene (603856.0001-603856.0004) in affected individuals from 5 of
the families. Sanger sequencing confirmed the mutations, and there was
complete cosegregation with the phenotype in each of the families. All
affected family members inherited their mutations from their fathers,
consistent with a paternally expressed imprinted gene; the 1
heterozygous carrier known to have inherited his mutation from his
mother was unaffected.
MAGEL2
| dbSNP name | rs8920(A,T); rs9785(G,T); rs2233070(G,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 54551 |
| EntrezGene Description | MAGE-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2723 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Bilateral sensorineural deafness;
[Eyes];
Arched eyebrows;
Synophrys;
Wide-eye appearance;
Optic atrophy (rare);
Macrophthalmia (in some patients);
Blue sclerae (in some patients);
Tilted optic discs (in some patients);
[Mouth];
Prominent philtrum;
Cleft palate (rare);
[Teeth];
Microdontia;
Talon cusps;
Midline diastema;
Narrow lower alveolar ridge;
Lobulated anterior palatine rugae (rare)
SKELETAL:
[Hands];
Soft tissue syndactyly;
Short, abducted thumbs;
Clinodactyly (fingers II-V);
Functional symphalangism;
Short metacarpals;
Hyperphalangism;
Preaxial brachydactyly;
Phalangeal duplication;
Carpal fusion;
Radioulnar synostosis (rare);
[Feet];
Lateral deviation of the halluces;
Short metatarsals;
Tarsal fusion
MOLECULAR BASIS:
Caused by mutation in the carbohydrate synthase 1 gene (CHSY1, 608123.0001)
OMIM Title
*605283 MAGE-LIKE 2; MAGEL2
;;NECDIN-LIKE 1; NDNL1
OMIM Description
DESCRIPTION
The MAGEL2 gene encodes a ubiquitin ligase enhancer that is required for
endosomal protein recycling (summary by Schaaf et al., 2013).
CLONING
Boccaccio et al. (1999) reported the characterization of the MAGEL2
(MAGE-like-2) gene, which they identified within the critical region for
Prader-Willi syndrome (PWS; 176270). By RT-PCR analysis of fibroblast
and total brain RNA from normal individuals and patients with Angelman
(105830) and Prader-Willi syndromes, they demonstrated that MAGEL2 is
transcribed only from the paternal allele.
Lee et al. (2000) independently cloned and characterized the MAGEL2
gene, also known as NDNL1 (necdin-like-1). The MAGEL2 gene encodes a
529-amino acid protein with 51% sequence similarity to necdin (NDN;
602117). As shown by Northern blot analysis, the 4.5-kb MAGEL2
transcript is expressed predominantly in brain, the primary tissue
affected in PWS, and in several fetal tissues. MAGEL2 is imprinted with
monoallelic expression in control brain, and with paternal-only
expression in the central nervous system, as demonstrated by its lack of
expression in brain from a PWS-affected individual. The orthologous
mouse gene, Magel2, is imprinted with paternal-only expression and is
expressed predominantly in late developmental stages and adult brain as
shown by Northern blot analysis, RT-PCR, and whole-mount RNA in situ
hybridization. Magel2 distribution partially overlaps that of Ndn, with
strong expression being detected in the central nervous system in
midgestation mouse embryos by in situ hybridization. Lee et al. (2000)
hypothesized that, although loss of necdin expression may be important
in the neonatal presentation of PWS, loss of MAGEL2 may be critical to
abnormalities in brain development and dysmorphic features in
individuals with PWS.
GENE FUNCTION
Lee et al. (2005) demonstrated that necdin and Magel2 bound to and
prevented proteasomal degradation of Fez1 (604825), which is implicated
in axonal outgrowth and kinesin-mediated transport, and also bound to
BBS4 (600374) protein in cotransfected cells. The interactions among
necdin, Magel2, Fez1, and BBS4 occurred at or near centrosomes.
Centrosomal or pericentriolar dysfunction has previously been implicated
in BBS (209900) and may also be important in features of PWS that
overlap with BBS, such as learning disabilities, hypogonadism, and
obesity.
GENE STRUCTURE
Boccaccio et al. (1999) determined that the MAGEL2 gene is intronless.
MAPPING
Boccaccio et al. (1999) identified the MAGEL2 gene within the PWS
deletion region on chromosome 15q11-q13. The mouse Magel2 gene resides
on chromosome 7C, within a region of conserved synteny with human
15q11-q13.
Lee et al. (2000) determined that the MAGEL2 gene is located 41 kb
distal to the necdin gene (NDN; 602117). The mouse Magel2 gene is
located within 150 kb of Ndn.
MOLECULAR GENETICS
In 4 unrelated boys with Prader-Willi-like syndrome (PWLS; 615547),
Schaaf et al. (2013) identified 4 different de novo heterozygous
truncating mutations in the MAGEL2 gene (605283.0001-605283.0004). All
mutations occurred on the paternal allele. Because the maternal allele
is not normally expressed, the findings were consistent with a loss of
MAGEL2 function. The mutation in the first patient was found by clinical
whole-exome sequencing. Based on these results, a research database of
1,248 whole-exome sequencing cases were reviewed, and the 3 remaining
cases were identified.
ANIMAL MODEL
Mammalian circadian rhythms of activity are generated within the
suprachiasmatic nucleus (SCN). Transcripts from the imprinted,
paternally expressed MAGEL2 gene, which maps to the chromosomal region
associated with PWS, are highly enriched in the SCN. Kozlov et al.
(2007) found that in mice the Magel2 message is circadianly expressed
and peaks during the subjective day. Mice deficient in Magel2 expression
entrain to light cycles and express normal running-wheel rhythms, but
with markedly reduced amplitude of activity and increased daytime
activity. These changes are associated with reductions in food intake
and male fertility. Levels of orexin (602358) levels and orexin-positive
neurons in the lateral hypothalamus are substantially reduced,
suggesting that some of the consequences of Magel2 loss are mediated
through changes in orexin signaling. The robust rhythmicity of Magel2
expression in the SCN and the altered behavioral rhythmicity of null
mice revealed Magel2 to be a clock-controlled circadian output gene
whose disruption results in some of the phenotypes characteristic of
PWS.
Bischof et al. (2009) found that Magel2-null mice showed features
similar to those of Prader-Willi syndrome in humans. There was reduced
embryonic viability associated with loss of Magel2. Magel2-null mice
showed neonatal growth retardation, excessive weight gain after weaning,
and increased adiposity with altered metabolism, including increased
fasting insulin and elevated cholesterol, in adulthood. Mutant mice also
showed abnormalities in the circadian pattern of feeding behavior. The
findings implicated loss of the Magel2 gene in hypothalamic dysfunction.
NDN
| dbSNP name | rs2192206(G,A) |
| ccdsGene name | CCDS10014.1 |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 4692 |
| EntrezGene Description | necdin, melanoma antigen (MAGE) family member |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NDN:NM_002487:exon1:c.C858T:p.D286D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2103 |
| ESP Afr MAF | 0.04498 |
| ESP All MAF | 0.158895 |
| ESP Eur/Amr MAF | 0.217245 |
| ExAC AF | 0.215 |
OMIM Clinical Significance
GU:
Tubulointerstitial nephropathy;
Progressive renal failure
GI:
Cholestatic liver disease
Radiology:
Segmental irregularities and narrowing of intrahepatic bile ducts on endoscopic retrograde cholangiopancreatography
Lab:
Elevated liver enzymes;
Histologic sclerosing glomeruli and atrophic tubules;
Renal interstitium fibrotic and infiltrated by lymphocytes;
Liver histology shows enlarged portal triads, mild proliferation and inflammation of bile ducts, and fibrosis
Inheritance:
Autosomal recessive
OMIM Title
*602117 NECDIN; NDN
OMIM Description
CLONING
Reasoning that additional imprinted genes may lie within the
Prader-Willi syndrome (PWS; 176270) deletion interval 15q11-q13,
MacDonald and Wevrick (1997) searched for transcribed sequences in the
region between the 2 imprinted genes ZNF127 (MKRN3; 603856) and SNRPN
(182279). An EST showed 99% sequence identity to the 3-prime end of a
GenBank sequence (GENBANK U35139), defined as 'a human necdin-related
protein mRNA.' Mouse necdin (Ndn) was originally identified by Maruyama
et al. (1991) as a protein encoded by a neural differentiation-specific
mRNA, derived from embryonal carcinoma cells. The necdin protein was
localized to the nuclei of postmitotic neurons and was expressed in
almost all postmitotic neurons in the CNS from the beginning of neural
differentiation and into adult life. MacDonald and Wevrick (1997)
demonstrated that expression of the Ndn mouse gene and the NDN human
gene is limited to the paternal allele, with highest levels of
expression in brain and placenta. They suggested that loss of necdin
gene expression may contribute to the disorder of brain development in
individuals with PWS.
Jay et al. (1997) likewise cloned a human cDNA with close similarities
to the mouse necdin gene. NDN displayed several characteristics of an
imprinted locus, including allelic DNA methylation and an asynchronous
DNA replication. Jay et al. (1997) found a complete lack of NDN
expression in PWS brain and fibroblasts, indicating that the gene is
expressed exclusively from the paternal allele in these tissues and
suggesting a possible role of this gene in PWS.
Necdin is a growth suppressor expressed in virtually all postmitotic
neurons in the brain. Nakada et al. (1998) isolated and characterized
the human NDN gene and its promoter region. They found that NDN encodes
a protein of 321 amino acids, 4 residues shorter than the mouse protein.
Watrin et al. (1997) demonstrated paternal-specific expression of the
Ndn gene in mouse CNS and showed that paternal alleles display a
differential methylation profile in the coding region.
Tcherpakov et al. (2002) found that necdin was expressed as a
cytoplasmic protein in a rat neural precursor cell line.
GENE FUNCTION
Tcherpakov et al. (2002) found that the intracellular domain of nerve
growth factor receptor (NGFR; 162010) interacted with necdin and Mageh1
(300548) in rodent neural tissue, and the interaction was enhanced by
ligand stimulation. Rat neural precursor cells transfected with necdin
or Mageh1 exhibited accelerated differentiation in response to NGF (see
162030).
Necdin and Magel2 (605283) are related proteins inactivated in PWS. Lee
et al. (2005) demonstrated that necdin and Magel2 bound to and prevented
proteasomal degradation of Fez1 (604825), which is implicated in axonal
outgrowth and kinesin-mediated transport, and also bound to BBS4
(600374) protein in cotransfected cells. The interactions among necdin,
Magel2, Fez1, and BBS4 occurred at or near centrosomes. Centrosomal or
pericentriolar dysfunction has previously been implicated in BBS
(209900) and may also be important in features of PWS that overlap with
BBS, such as learning disabilities, hypogonadism, and obesity.
Miller et al. (2009) showed that necdin was not expressed in an
immature, migratory gonadotropin-releasing hormone (GNRH1; 152760)
neuronal cell line (GN11), but high levels were present in a mature GNRH
neuronal cell line (GT1-7). Furthermore, overexpression of necdin
activated GNRH transcription through cis elements bound by the
homeodomain repressor Msx1 (142983) that were located in the enhancer
and promoter of the GNRH1 gene, and knockdown of necdin expression
reduced GNRH gene expression. Overexpression of Necdin relieved Msx
repression of GNRH transcription through these elements and necdin
coimmunoprecipitated with Msx from GNRH neuronal cells, indicating that
necdin may activate GNRH gene expression by preventing repression of
GNRH gene expression by Msx. Necdin was necessary for generation of the
full complement of GNRH neurons during mouse development and extension
of GNRH axons to the median eminence. As the NDN gene maps to the
Prader-Willi syndrome candidate region and is highly expressed in mature
hypothalamic neurons, Miller et al. (2009) hypothesized that lack of
necdin during development may contribute to the hypogonadotrophic
hypogonadal phenotype in individuals with PWS.
GENE STRUCTURE
MacDonald and Wevrick (1997) determined that the mouse Ndn gene contains
a single exon. Consistent with the observation that imprinted genes have
few and small introns (Hurst et al., 1996), human NDN is contained
within a single exon, like its mouse ortholog.
Nakada et al. (1998) identified CpG islands in a region of NDN extending
from the proximal 5-prime flanking sequence to the protein-coding
region. The 5-prime flanking sequence, which lacks canonical TATA and
CAAT boxes, possessed a promoter activity in postmitotic neurons derived
from murine embryonal carcinoma P19 cells. Methylation in vitro of HhaI
CpG sites in the promoter region reduced transcriptional activity. These
results suggested that the necdin gene is silenced through methylation
of the CpG island encompassing its promoter region.
MAPPING
MacDonald and Wevrick (1997) concluded that the NDN gene is a single
locus in proximal 15q, as determined by radiation hybrid mapping,
localization of the appropriate PCR-amplified fragments to overlapping
YACs, and absence in other YACs from the PWS deletion region. The mouse
Ndn gene was mapped to chromosome 7 in a region of conserved synteny
with human 15q11-q13 by MacDonald and Wevrick (1997) using genetic
mapping in an interspecific backcross panel.
Jay et al. (1997) mapped the NDN gene to 15q11-q13 by fluorescence in
situ hybridization (FISH), and confirmed the location by PCR analysis of
DNA extracted from a panel of hamster/human somatic cell hybrids. Both
approaches suggested that the NDN gene maps to 15q11-q13 but that a
homologous gene or pseudogene maps to 12q21. Jay et al. (1997) also
mapped NDN by hybridization to a YAC contig covering the PWS critical
region. They suggested that NDN is located approximately 100 kb distal
to ZNF127 and 1 to 1.5 Mb proximal to SNRPN.
By fluorescence in situ hybridization, Nakada et al. (1998) localized
the NDN gene to chromosome 15q11.2-q12.
Watrin et al. (1997) established the localization of the mouse necdin
gene in the region of mouse chromosome 7 showing conserved synteny to
the human PWS region. By FISH, they demonstrated an asynchronous pattern
of replication at the Ndn locus.
ANIMAL MODEL
Tsai et al. (1999) prepared a null mutation in the mouse by deleting the
coding region for Ndn, and transmitted the deletion to the germline.
Mice with paternal deficiency and homozygous mice were viable. Northern
blot analysis showed absence of Ndn expression in brain and liver of
mice heterozygous for paternal deficiency. Mice of all genotypes were
recovered at the predicted mendelian ratios at weaning following matings
between heterozygotes. Mice of all genotypes, including homozygotes,
were fertile and did not develop obesity up to 10 months of age.
Behavioral studies had not yet been done; thus, any potential
relationship to the mental retardation of PWS remained unknown.
To determine the possible contribution of Ndn to the Prader-Willi
syndrome phenotype, Gerard et al. (1999) generated Ndn mutant mice.
Heterozygous mice inheriting the mutated maternal allele were
indistinguishable from their wildtype littermates. On the other hand,
mice carrying a paternally inherited Ndn deletion allele demonstrated
early postnatal lethality. Gerard et al. (1999) claimed this was the
first example of a single gene being responsible for phenotypes
associated with PWS.
Nicholls (1999) commented on the work of Gerard et al. (1999), which he
called 'the latest episode of a seat-gripping saga.' He noted the
discrepancy between the findings of Tsai et al. (1999) and those of
Gerard et al. (1999). He further discussed other 'suspicious
characters,' i.e., other genes that may be implicated in PWS, and
suggested that several genes in the PWS region may affect the
failure-to-thrive phenotype. He suggested that this aspect of the PWS
story resembles the plot of 'Murder on the Orient Express' by Agatha
Christie. The famed train transported a number of suspects, all of whom
were eventually found to have had a part in the crime.
Muscatelli et al. (2000) produced mice deficient for necdin and
suggested that postnatal lethality associated with loss of the paternal
gene may vary depending on the strain. Viable necdin mutants showed a
reduction in both oxytocin (167050)-producing and luteinizing
hormone-releasing hormone (LHRH; 152760)-producing neurons in the
hypothalamus; increased skin scraping activity; and improved spatial
learning and memory. The authors proposed that underexpression of necdin
is responsible for at least a subset of the multiple clinical
manifestations of PWS.
Lee et al. (2005) demonstrated that morphologic abnormalities in axonal
outgrowth and fasciculation manifested in several regions of the nervous
system in Ndn-null mouse embryos, including axons of sympathetic,
retinal ganglion cell, serotonergic, and catecholaminergic neurons. Lee
et al. (2005) concluded that necdin mediates intracellular processes
essential for neurite outgrowth and that loss of necdin may impinge on
axonal outgrowth, and further suggested that loss of necdin may
contribute to the neurologic phenotype of PWS. They speculated that
codeletion of necdin and the related protein Magel2 (605283) may explain
the lack of single gene mutations in PWS.
PWRN2
| dbSNP name | rs376609094(G,A); rs76911601(C,T); rs1133615(G,A); rs1133614(T,A); rs1806581(C,T); rs28533394(C,T); rs1054983(A,G); rs7173213(C,T); rs1806580(G,C); rs117615705(C,T); rs2354068(A,T); rs2354069(A,G); rs11161409(T,C); rs11161410(G,A); rs11632379(C,T); rs28442895(T,C); rs28676818(A,C); rs6576676(G,A); rs12914643(C,A); rs12899240(G,T); rs137856372(A,G); rs4989967(A,G); rs7168221(G,A); rs11635057(C,G); rs145045387(G,T); rs4778415(C,T); rs17118408(G,C); rs4448891(T,C); rs55718621(C,A); rs5022358(G,A); rs4451909(G,C); rs150751469(C,T); rs143492012(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 791115 |
| EntrezGene Description | Prader-Willi region non-protein coding RNA 2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Brachycephaly;
Low posterior hair line;
Extra frontal hair whorl;
[Face];
Bulging midface (in some patients);
Smooth philtrum;
Long philtrum;
Parotid gland dysfunction (in some patients);
Micrognathia, mild (in some patients);
[Ears];
Hearing loss, sensorineural;
Low-set ears;
Ear anomalies;
Preauricular skin tags (in some patients);
[Eyes];
Severe hypertelorism;
Laterally sparse eyebrows;
Myopia, progressive severe;
[Nose];
Absence or dysfunction of nasolacrimal structures;
Broad nasal bridge;
Pointed nasal tip;
Anteverted nostrils;
[Mouth];
High-arched palate;
Thin upper vermilion border;
Wide mouth;
[Teeth];
Loss of lamina dura;
Thin or hypoplastic enamel;
Worn-out teeth (in some patients);
Malocclusion (in some patients);
Hypodontia (in some patients);
[Neck];
Pterygium colli;
Sloping shoulders
CARDIOVASCULAR:
[Heart];
Intraventricular conduction delay;
Patent ductus arteriosus, small (in some patients);
Mitral regurgitation (in some patients);
Atrial septal defect (in some patients);
Atrioventricular canal, total (in some patients)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum (in some patients)
ABDOMEN:
[Gastrointestinal];
Swallowing difficulties (in some patients)
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
Cryptorchidism;
Absent gonad activity
SKELETAL:
Generalized osteopenia;
[Skull];
Craniosynostosis (in some patients);
[Pelvis];
Hip dysplasia;
[Limbs];
Long bone fractures;
[Hands];
Thumb deviation;
Ectopic finger creases;
Long fingers;
Short index finger;
Syndactyly (in some patients);
Tapering fingers (in some patients);
Clinodactyly of fifth finger;
[Feet];
Long toes (in some patients)
SKIN, NAILS, HAIR:
[Hair];
Low posterior hair line;
Extra frontal hair whorl
NEUROLOGIC:
[Central nervous system];
Psychomotor retardation, moderate
VOICE:
Unclear speech
ENDOCRINE FEATURES:
Hypoparathyroidism
HEMATOLOGY:
Anemia, microcytic hypochromic
MOLECULAR BASIS:
Caused by mutation in the Iroquois homeobox protein-5 gene (IRX5,
606195.0001)
OMIM Title
*611217 PRADER-WILLI REGION NONCODING RNA 2; PWRN2
OMIM Description
CLONING
By searching for genes in the Prader-Willi syndrome (PWS; 176270) region
on chromosome 15, followed by database analysis and RT-PCR of testis,
Buiting et al. (2007) obtained several PWRN2 transcripts. The
transcripts differed due to alternative splicing and polyadenylation,
and all appeared to be noncoding. RT-PCR detected PWRN2 expression in
testis only.
GENE STRUCTURE
Buiting et al. (2007) determined that the PWRN2 gene contains 3 exons
and spans 7.2 kb.
MAPPING
By genomic sequence analysis, Buiting et al. (2007) mapped the PWRN2
gene to chromosome 15q11-q13. In addition to the expressed gene, this
region contains 5 partial duplications of PWRN2.
NPAP1
| dbSNP name | rs116262912(C,T); rs3784246(T,C); rs7165533(A,G); rs3742950(C,G); rs60574723(C,T); rs12902137(T,C); rs12902295(T,C); rs112526219(G,A); rs79981954(G,A) |
| ccdsGene name | CCDS10015.1 |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 23742 |
| snpEff Gene Name | C15orf2 |
| EntrezGene Description | nuclear pore associated protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NPAP1:NM_018958:exon1:c.C543T:p.S181S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.023831 |
| ESP All MAF | 0.00815 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.002505 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
RESPIRATORY:
Respiratory distress, severe, neonatal;
Respiratory failure, neonatal;
Tachypnea;
Dyspnea;
Apnea;
[Lung];
Alveolar proteinosis;
Alveoli filled with granular or foamy surfactant protein exudate;
Alveoli contain desquamated type II pneumocytes and macrophages;
Desquamative interstitial pneumonitis;
Type II pneumocyte hyperplasia;
Type II pneumocytes contain abnormal lamellar bodies;
Desquamative interstitial pneumonitis;
Interstitial thickening;
Radiograph shows granular, hazy, ground-glass interstitial opacifications;
Surfactant deficiency
MISCELLANEOUS:
Genetic heterogeneity;
Onset at birth;
Occurs in full-term infants;
Most affected infants die in the first month of life
MOLECULAR BASIS:
Caused by mutation in the ATP-binding cassette, subfamily A, member
3 gene (ABCA3, 601615.0001)
OMIM Title
*610922 NUCLEAR PORE ASSOCIATED PROTEIN 1; NPAP1
;;CHROMOSOME 15 OPEN READING FRAME 2; C15ORF2
OMIM Description
CLONING
By sequencing YAC clones containing a CpG island in the Prader-Willi
syndrome (PWS; 176270) critical region on chromosome 15, followed by
database analysis and PCR and 3-prime RACE of a human testis cDNA
library, Farber et al. (2000) cloned C15ORF2. The deduced protein
contains 1,156 amino acids. Northern blot analysis detected a 7.5-kb
transcript in adult testis, but not in fetal testis or in any other
adult or fetal tissues examined. Southern blot analysis detected C15ORF2
in several primates, but not in any other mammalian or avian species
examined. The primate sequences share between 97 and 99% identities.
GENE FUNCTION
Farber et al. (2000) found that a CpG island associated with C15ORF2 was
methylated in all tissues tested except for germ cells. Although C15ORF2
maps between the imprinted genes MAGEL2 (605283) and SNRPN (182279),
they demonstrated that C15ORF2 was biallelically expressed in adult
testis.
Buiting et al. (2007) found that C15ORF2 was monoallelically expressed
in fetal brain.
GENE STRUCTURE
Farber et al. (2000) determined that C15ORF2 is an intronless gene with
its start codon imbedded within a CpG island.
MAPPING
By genomic sequence analysis, Farber et al. (2000) mapped the C15ORF2
gene to chromosome 15q11-q13. Southern blot analysis indicated that
C15ORF2 is a single-copy gene.
PWARSN
| dbSNP name | rs147166106(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 347746 |
| snpEff Gene Name | SNRPN |
| EntrezGene Description | Prader Willi/Angelman region RNA, SNRPN neighbor |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04637 |
PWAR5
| dbSNP name | rs75101221(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 8123 |
| snpEff Gene Name | SNURF |
| EntrezGene Description | Prader Willi/Angelman region RNA 5 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02709 |
SNORD116-4
| dbSNP name | rs188061923(C,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033416 |
| snpEff Gene Name | SNORD116-3 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-4 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 2.575e-05 |
SNORD116-5
| dbSNP name | rs7402542(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033417 |
| snpEff Gene Name | SNORD116-4 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-5 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02847 |
| ExAC AF | 0.961 |
SNORD116-11
| dbSNP name | rs139502181(A,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033423 |
| snpEff Gene Name | SNORD116-10 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-11 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006887 |
| ESP Afr MAF | 0.032534 |
| ESP All MAF | 0.009941 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002796 |
SNORD116-12
| dbSNP name | rs114762959(T,A) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033424 |
| snpEff Gene Name | SNORD116-10 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-12 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.025685 |
| ESP All MAF | 0.007848 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001958 |
SNORD116-13
| dbSNP name | rs17115176(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033425 |
| snpEff Gene Name | SNORD116-10 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-13 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03214 |
| ESP Afr MAF | 0.126712 |
| ESP All MAF | 0.050924 |
| ESP Eur/Amr MAF | 0.017579 |
| ExAC AF | 0.029 |
SNORD116-15
| dbSNP name | rs150163917(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033427 |
| snpEff Gene Name | SNORD116-12 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-15 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.025114 |
| ESP All MAF | 0.007674 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001957 |
SNORD116-18
| dbSNP name | rs3803328(T,A) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033430 |
| snpEff Gene Name | SNORD116-15 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-18 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3444 |
| ESP Afr MAF | 0.187215 |
| ESP All MAF | 0.305895 |
| ESP Eur/Amr MAF | 0.358112 |
| ExAC AF | 0.624 |
SNORD116-19
| dbSNP name | rs151016158(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 727708 |
| snpEff Gene Name | SNORD116-16 |
| EntrezGene Description | small nucleolar RNA, C/D box 116-19 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03076 |
| ESP Afr MAF | 0.136986 |
| ESP All MAF | 0.042204 |
| ESP Eur/Amr MAF | 0.000502 |
| ExAC AF | 0.011 |
PWAR1
| dbSNP name | rs7342623(C,A); rs17115286(T,C); rs2249378(G,A) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 145624 |
| snpEff Gene Name | UBE3A-AS1 |
| EntrezGene Description | Prader Willi/Angelman region RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | ncrna_host |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1873 |
SNORD115-2
| dbSNP name | rs200514049(T,C) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033437 |
| snpEff Gene Name | SNORD115-1 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-2 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| ESP Afr MAF | 0.001142 |
| ESP All MAF | 0.001047 |
| ESP Eur/Amr MAF | 0.001006 |
| ExAC AF | 0.001046 |
SNORD115-4
| dbSNP name | rs72546369(C,A) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033441 |
| snpEff Gene Name | SNORD115-2 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-4 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008264 |
| ESP Afr MAF | 0.017694 |
| ESP All MAF | 0.009944 |
| ESP Eur/Amr MAF | 0.006533 |
| ExAC AF | 0.007617 |
SNORD115-9
| dbSNP name | rs34859712(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033442 |
| EntrezGene Symbol | SNORD115-5 |
| snpEff Gene Name | SNORD115-3 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-5 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1768 |
| ESP Afr MAF | 0.300799 |
| ESP All MAF | 0.146124 |
| ESP Eur/Amr MAF | 0.077968 |
| ExAC AF | 0.112 |
SNORD115-8
| dbSNP name | rs2011153(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033445 |
| snpEff Gene Name | SNORD115-6 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-8 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2571 |
| ESP Afr MAF | 0.416096 |
| ESP All MAF | 0.238311 |
| ESP Eur/Amr MAF | 0.086181 |
| ExAC AF | 0.145 |
SNORD115-11
| dbSNP name | rs146068240(G,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033448 |
| snpEff Gene Name | SNORD115-10 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-11 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004591 |
| ESP Afr MAF | 0.000571 |
| ESP All MAF | 0.00436 |
| ESP Eur/Amr MAF | 0.006027 |
| ExAC AF | 0.005908 |
SNORD115-13
| dbSNP name | rs7172888(A,G) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033450 |
| snpEff Gene Name | SNORD115-11 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-13 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3163 |
| ESP Afr MAF | 0.27968 |
| ESP All MAF | 0.294908 |
| ESP Eur/Amr MAF | 0.107735 |
| ExAC AF | 0.179 |
SNORD115-17
| dbSNP name | rs113138331(G,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033458 |
| EntrezGene Symbol | SNORD115-19 |
| snpEff Gene Name | SNORD115-16 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-19 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02617 |
| ESP Afr MAF | 0.091324 |
| ESP All MAF | 0.028098 |
| ESP Eur/Amr MAF | 0.000251 |
| ExAC AF | 0.007347 |
PWAR4
| dbSNP name | rs376077674(G,A); rs36042159(G,A); rs182518819(G,A); rs73362147(C,A) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 692218 |
| EntrezGene Symbol | SNORD115@ |
| snpEff Gene Name | SNORD115-21 |
| EntrezGene Description | small nucleolar RNA, C/D box 115 cluster |
| EntrezGene Type of gene | other |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| ESP Afr MAF | 0.000571 |
| ESP All MAF | 0.000174 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0001463 |
SNORD115-40
| dbSNP name | rs2719918(T,G); rs72546400(C,T) |
| cytoBand name | 15q11.2 |
| EntrezGene GeneID | 100033814 |
| snpEff Gene Name | SNORD115-38 |
| EntrezGene Description | small nucleolar RNA, C/D box 115-40 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | snoRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2117 |
| ESP Afr MAF | 0.33105 |
| ESP All MAF | 0.224799 |
| ESP Eur/Amr MAF | 0.029382 |
| ExAC AF | 0.088 |
TRPM1
| dbSNP name | rs11070718(C,T); rs17227989(T,C); rs3784588(C,T); rs13380059(C,T); rs17227996(T,G); rs76312270(G,T); rs10162919(A,C); rs144004866(C,A); rs116346195(C,T); rs12913397(C,T); rs148993933(A,G); rs372000987(C,T); rs142326880(C,T); rs7161796(A,G); rs7167074(T,C); rs148049513(T,C); rs7182571(G,A); rs113153992(C,T); rs7166214(C,T); rs72710454(G,A); rs28805322(A,G); rs142441096(A,G); rs116243599(A,G); rs61997145(A,G); rs185773327(C,T); rs76461935(T,C); rs2113946(A,G); rs145471900(G,A); rs7179234(G,A); rs7164939(C,G); rs116924272(G,A); rs4559875(C,T); rs4344701(G,A); rs12441456(A,G); rs12913087(T,A); rs73368444(A,T); rs78802665(G,A); rs964925(C,T); rs36042462(C,T); rs35891405(G,A); rs12905872(A,G); rs58083498(G,A); rs16956455(T,C); rs142755559(G,A); rs183699657(A,G); rs12911930(C,T); rs187010995(G,A); rs12898815(C,T); rs12898829(C,T); rs139372775(A,G); rs141503723(C,T); rs35208656(G,A); rs114743193(C,T); rs146506021(G,A); rs12442333(C,A); rs6493387(T,C); rs6493388(A,G); rs7172375(G,C); rs12915504(C,T); rs12901022(T,C); rs17815726(G,C); rs12902573(C,A); rs28435882(G,A); rs2911855(A,G); rs7177217(A,G); rs7175354(G,C); rs147579766(A,G); rs192279275(C,G); rs28487996(T,C); rs72712214(T,C); rs28697571(G,T); rs7182143(G,A); rs7161812(A,G); rs372080865(C,T); rs16956460(A,G); rs7165798(C,T); rs28583849(G,A); rs60293970(C,G); rs13380246(C,T); rs138846375(C,G); rs72712216(C,G); rs7172938(G,A); rs61997150(G,A); rs79134010(C,T); rs10519726(G,A); rs3784590(A,G); rs2042613(T,C); rs9806389(G,C); rs16956469(T,C); rs2113945(G,A); rs2162070(A,T); rs151104706(C,T); rs140679710(C,T); rs138228219(C,T); rs16956471(A,G); rs78808124(C,T); rs28668219(A,G); rs28592627(G,A); rs1991214(T,G); rs186989078(G,C); rs2911854(G,A); rs12914747(G,A); rs2911853(G,T); rs2959041(T,C); rs28480303(C,T); rs2959042(A,G); rs2959043(T,C); rs375558307(C,G); rs2911852(G,A); rs12911350(G,A); rs181153432(T,G); rs2288242(A,G); rs12913672(A,G); rs2911851(C,T); rs12917026(G,C); rs12917058(G,A); rs28449259(A,T); rs12908432(T,C); rs12708421(C,A); rs2911850(C,G); rs2911849(C,G); rs7179304(A,G); rs28535333(C,T); rs186459994(C,T); rs181881666(T,A); rs2338835(C,G); rs12148242(A,G); rs7167823(G,A); rs185168470(A,G); rs4779808(G,A); rs190952106(C,T); rs7173932(G,C); rs143929587(G,A); rs7174338(G,A); rs2338834(G,A); rs12907509(T,G); rs34969393(G,A); rs11636071(A,G); rs11636121(A,C); rs3743234(A,G); rs185790878(G,C); rs146227265(G,A); rs11070764(T,C); rs7173280(T,C); rs10851487(G,A); rs2288241(C,T); rs10162957(C,T); rs3784594(C,T); rs3784595(A,G); rs17815780(A,T); rs1035705(C,T); rs1035706(A,G); rs7179148(G,A); rs10162706(C,T); rs10162731(A,G); rs10162727(C,T); rs4779809(T,C); rs4779810(T,C); rs4779811(C,T); rs73372445(G,C); rs7174872(T,G); rs4779501(C,T); rs4779812(G,T); rs62038928(A,T); rs112426277(A,G); rs183039560(C,G); rs28792740(G,A); rs8041204(T,G); rs8037421(A,G); rs149430774(C,T); rs4779813(T,C); rs62038930(C,T); rs78655970(A,G); rs7165995(G,A); rs11070765(A,G); rs62038931(T,C); rs11853585(C,T); rs11070767(T,C); rs143944675(G,A); rs144210379(C,T); rs77759817(C,T); rs115489373(C,T); rs12902840(C,T); rs2278133(A,G); rs16956506(C,A); rs57299770(C,T); rs7166431(T,C); rs7166442(T,C); rs4779814(T,C); rs16956509(C,T); rs3784596(C,A); rs3784597(T,C); rs3784598(T,C); rs919001(A,G); rs3825950(G,A); rs62038939(G,A); rs142072609(C,A); rs8039189(G,T); rs3784599(T,G); rs149338863(A,G); rs3784600(C,T); rs12910514(G,A); rs28545730(T,A); rs141344896(T,C); rs12915986(G,A); rs78722554(C,T); rs28587177(G,A); rs28624489(G,A); rs7181834(C,G); rs144480940(G,A); rs7182134(C,A); rs10400821(G,A); rs10400832(C,T); rs2241493(C,T); rs34491369(A,G); rs17815804(G,A); rs11638753(A,T); rs56242510(T,C); rs11633683(C,T); rs8038324(C,T); rs28878478(A,G); rs71399740(A,G); rs4779815(C,T); rs28846507(A,G); rs28861698(A,T); rs28878543(T,C); rs28632121(T,C); rs28427283(A,G); rs116894076(T,A); rs28428641(C,T); rs28679758(A,T); rs114808972(T,C); rs141571937(G,A); rs16956517(T,A); rs150352906(C,T); rs2241494(A,G); rs2241495(G,T); rs2241496(T,C); rs74010765(A,T); rs2241497(C,G); rs4779816(A,G); rs4779817(C,T); rs4779818(C,T); rs4779819(C,T); rs75616103(T,C); rs148586410(T,G); rs7180591(G,A); rs8042645(A,T); rs140968522(C,T); rs55821493(T,C); rs890158(G,A); rs28451564(T,G); rs2338863(A,G); rs4779503(G,A); rs4779504(T,C); rs144404525(C,T); rs114663804(G,A); rs151036343(G,A); rs74010766(T,C); rs117015562(A,T); rs116471383(C,T); rs11070796(A,G); rs11634362(G,A); rs12441329(C,T); rs9944230(G,A); rs12909039(C,T); rs12909383(C,T); rs59335451(G,C); rs11853640(C,T); rs11853491(G,C); rs10438315(G,T); rs10438316(C,T); rs150944765(A,G); rs12911889(A,C); rs147105383(C,T); rs111348554(T,C); rs12910418(G,T); rs12910440(G,C); rs73374070(G,A); rs6493450(G,C); rs9302157(T,A); rs114877218(A,G); rs57961794(G,C); rs76973158(G,A); rs6493451(C,G); rs11855260(G,T); rs12917436(C,G); rs58628755(C,T); rs10152647(C,T); rs1035707(G,A); rs55840077(G,C); rs55989345(G,C); rs112304295(C,T); rs78484588(A,G); rs187033153(A,G); rs79060403(G,A); rs77512536(G,A); rs140472016(G,A); rs60796519(G,A); rs56751906(C,T); rs28825085(A,G); rs113363806(G,A); rs111974529(C,T); rs28676696(A,G); rs28446900(A,G); rs11632661(G,C); rs79384439(C,T); rs12914420(G,A); rs17228129(G,A); rs28613966(A,G); rs8039170(G,A); rs8040406(C,T); rs138935382(C,A); rs73374092(C,T); rs28615582(C,T); rs28695741(G,T); rs17228136(T,C); rs28453275(G,A); rs11070808(G,C); rs11070810(G,T); rs10851488(T,C); rs375802051(C,T); rs10851489(T,C); rs58740340(C,G); rs3784601(C,T); rs6493454(C,T); rs11070811(C,T); rs3809579(C,T); rs3809578(G,A); rs4779820(A,T); rs7182946(G,T); rs28441327(C,T); rs3826030(C,G); rs28456199(G,A); rs12906564(C,A); rs16956543(G,A); rs148953314(T,C); rs8033330(G,A); rs112943435(T,A); rs147000482(A,C); rs117866215(A,G); rs117351706(T,C); rs17815839(G,C); rs11635657(T,C); rs8040166(G,A); rs8024324(G,A); rs8025698(C,T); rs8030968(T,C); rs35267463(T,C); rs11630011(A,C); rs11630017(A,C); rs11636012(C,G); rs11635797(G,A); rs73375923(G,A); rs62038946(C,G); rs11636102(C,T); rs112365407(C,A); rs12592518(T,A); rs73375932(G,A); rs7179254(T,G); rs374153560(G,A); rs55901714(G,A); rs12916281(A,G); rs56880154(C,T); rs79346978(C,A); rs34359249(C,A); rs28415473(C,A); rs4779824(T,C); rs11635677(A,G); rs6493461(T,C); rs6493462(T,C); rs113203164(G,A); rs6493463(G,A); rs75062601(C,T); rs71474644(A,C); rs7170825(A,G); rs12907809(C,T); rs79259282(G,A); rs4041971(A,T); rs77499079(G,C); rs116325205(A,G); rs2338859(G,A); rs4779825(G,A); rs73375940(A,T); rs2338858(T,C); rs75725053(T,C); rs12913202(A,T); rs2338856(G,C); rs2338855(C,G); rs2338854(T,C); rs115933157(A,T); rs2338853(A,G); rs11070816(T,A); rs11853267(T,C); rs11070818(G,A); rs74644889(C,T); rs12909468(T,C); rs7165641(G,C); rs10851490(T,C); rs112440406(C,T); rs115474638(C,T); rs2879275(C,T); rs148152809(A,C); rs11630489(T,C); rs11070819(C,A); rs11070820(G,A); rs4779826(A,T); rs149755421(G,A); rs10467995(G,T); rs71474646(G,T); rs10467996(C,T); rs10467997(G,A); rs376764975(G,C); rs369917632(A,T); rs35472543(G,A); rs35572544(G,C); rs147592472(A,G); rs8032212(A,T); rs1346043(T,C); rs10467999(A,G); rs10467922(T,G); rs12324335(A,G); rs11070823(T,C); rs12324831(C,G); rs12915482(A,G); rs141325010(C,T); rs4779827(G,A); rs377182958(T,G); rs4779505(A,G); rs60936148(A,G); rs56999411(G,A); rs78836167(A,C); rs11631401(C,G); rs34209379(G,C); rs8038801(T,C); rs8038969(T,C); rs8034628(C,A); rs74010779(G,T); rs1816161(A,G); rs57700167(G,A); rs8040946(A,G); rs8039120(G,A); rs8039270(G,A); rs12902091(T,C); rs79296466(C,T); rs12915948(G,A); rs55664007(A,G); rs4779829(A,G); rs8031038(G,A); rs8037337(T,C); rs74010797(T,G); rs12902544(G,A); rs12903013(G,A); rs34231231(G,A); rs4779830(C,T); rs11070830(C,A); rs4779831(T,C); rs7172292(A,G); rs783023(C,T); rs783024(G,A); rs783025(C,G); rs803533(C,T); rs16956564(G,A); rs783026(T,C); rs7178742(C,T); rs151244347(G,A); rs783028(C,T); rs783029(C,T); rs2081455(A,G); rs2004777(G,A); rs2077321(C,T); rs752048(A,G); rs34567587(T,C); rs34081950(T,C); rs783033(A,G); rs11638121(C,T); rs6493475(C,G); rs783034(G,A); rs4779832(C,T); rs148901592(G,A); rs73377615(T,G); rs11853276(C,T); rs8028220(A,G); rs8031296(G,A); rs803534(T,C); rs2338807(G,C); rs796715(T,C); rs16956578(C,T); rs79894101(G,A); rs72714642(A,G); rs115646475(C,T); rs72714643(G,T); rs72714645(C,T); rs113862103(C,T); rs73377624(C,T); rs55905993(C,T); rs8026274(A,G); rs8035325(T,G); rs112355246(C,T); rs112800152(G,A); rs56403436(A,G); rs55888834(A,G); rs61068131(T,C); rs56292023(G,C); rs74936000(T,C); rs73377629(A,T); rs67485529(G,A); rs12148297(T,C); rs12148622(G,A); rs8033503(T,G); rs8031783(G,A); rs58001248(A,T); rs146703062(C,T); rs59071841(G,A); rs12148459(T,A); rs12148879(C,T); rs12148567(T,G); rs12148889(C,A); rs813299(A,C); rs73377636(G,T); rs7162049(G,T); rs7163512(C,T); rs1672407(C,T); rs12902517(T,C); rs8030503(T,G); rs1672408(A,G); rs8030823(T,C); rs1672409(G,A); rs1223880(G,A); rs79214024(T,C); rs112530209(G,T); rs4779509(G,A); rs1580141(A,G); rs113212812(C,T); rs374253059(C,A); rs8035624(A,C); rs8040097(T,A); rs141288021(C,T); rs1378847(C,T); rs1236524(G,A); rs8025178(G,A); rs113185788(C,T); rs11631001(C,A); rs12910070(A,G); rs12913209(G,A); rs59799200(G,A); rs12899902(G,A); rs12906081(T,C); rs75638145(G,A) |
| ccdsGene name | CCDS10024.2 |
| cytoBand name | 15q13.3 |
| EntrezGene GeneID | 4308 |
| EntrezGene Description | transient receptor potential cation channel, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TRPM1:NM_002420:exon20:c.C2611G:p.L871V,TRPM1:NM_001252020:exon20:c.C2728G:p.L910V,TRPM1:NM_001252024:exon21:c.C2677G:p.L893V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9015 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ExAC AF | 2.448e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary urgency;
Urinary incontinence;
Sphincter disturbances
SKELETAL:
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Atrophy of shins
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Upper limb spasticity (in some patients);
Spastic gait;
Hyperreflexia;
Extensor plantar responses;
Degeneration of the lateral corticospinal tracts;
[Peripheral nervous system];
Decreased vibratory sense in the lower limbs
MISCELLANEOUS:
Adult onset (18 to 60 years);
Insidious onset;
Progressive disorder;
Severe phenotype
MOLECULAR BASIS:
Caused by mutation in the KIAA0196 gene (KIAA0196, 610657.0001)
OMIM Title
*603576 TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 1;
TRPM1
;;MELASTATIN 1; MLSN1
OMIM Description
DESCRIPTION
TRPM1 is the founding member of the melastatin-related transient
receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation
channels localized predominantly to the plasma membrane. The structural
machinery of TRPM channels includes intracellular N and C termini, 6
transmembrane segments, and a pore region between segments 5 and 6. The
N-terminal domain has a conserved region, and the C-terminal domain
contains a TRP motif, a coiled-coil region, and, in some TRPM channels,
an enzymatic domain (review by Farooqi et al., 2011).
CLONING
Duncan et al. (1998) used differential display PCR to identify an RNA
sequence that was downregulated in highly metastatic mouse melanoma
cells compared with poorly metastatic cells. They cloned the
corresponding mouse cDNA, termed melastatin. Northern blot analysis of
mouse tissues and cell lines revealed that melastatin was expressed as a
2.8-kb mRNA in normal eye and in 4 melanoma cell lines; its expression
in each of the 4 cell lines was inversely proportional to metastatic
potential. In 45 human melanocytic primary neoplasms examined by in situ
hybridization, the loss of melastatin expression correlated with the
thickness of the melanomas.
Hunter et al. (1998) cloned the human melastatin cDNA from a retina cDNA
library. The gene encodes a 1,533-amino acid polypeptide with homology
to members of the TRP family of calcium channels (see TRPC1; 602343).
Using differential display analysis, Fang and Setaluri (2000) identified
TRPM1 among genes overexpressed in pigmented metastatic human melanoma
cells treated with the differentiation inducer hexamethylene
bisacetamide (HMBA). Multiple short transcripts, from both the 5-prime
and 3-prime ends of TRPM1, were present in melanocytes and pigmented
metastatic melanoma cell lines. The full-length 5.4-kb transcript was
only found in melanocytes.
By RT-PCR of cDNA libraries derived from normal human melanocytes,
retina, brain, and melanoma cell lines, Oancea et al. (2009) cloned 5
variants of TRPM1 that differ in their use of 5-prime exons and start
codons. The deduced proteins contain 1,516 to 1,643 amino acids and
differ only in the lengths of their N termini. The TRPM1 exons involved
in alternative splicing are conserved across several mammalian species.
Koike et al. (2010) cloned a long form of mouse Trpm1, which they
designated Trpm1l. The deduced 1,622-amino acid protein contains 6
transmembrane domains, a pore region, and a TRP domain. Northern blot
analysis detected both Trpm1l and the short form of Trpm1, Trpm1s, in
retina, but only Trpm1s was detected in skin. Trpm1 expression was not
detected in other mouse tissues examined. Immunohistochemical analysis
of mouse retina at postnatal day 14 revealed diffuse Trpm1l expression
in bipolar cells. At 1 month of age, Trpm1l localized to dendritic tips
in the outer plexiform layer. Trpm1l colocalized with Go-alpha (GNAO1;
139311) and Mglur6 (GRM6; 604096) in ON bipolar cells, but it did not
colocalize with OFF bipolar cell markers.
GENE STRUCTURE
Oancea et al. (2009) determined that the TRPM1 gene contains 29 exons,
including the alternatively spliced exons 0 and 1-prime.
Hunter et al. (1998) cloned the mouse melastatin genomic region and
found that the promoter contains 4 consensus binding sites for the
microphthalmia-associated transcription factor (MITF; 156845). One of
these binding sites is an M box, a motif shared by the tyrosinase
pigmentation genes (see TYRP1; 115501).
MAPPING
Hunter et al. (1998) used a radiation hybrid panel to map the human
MLSN1 gene to chromosome 15q13-q14. They used interspecific backcrosses
to map the mouse gene to chromosome 7.
GENE FUNCTION
Xu et al. (2001) found that TRPM1 mediated Ca(2+) entry when expressed
in HEK293 cells. They found that a short form of TRPM1 interacted
directly with and suppressed the activity of full-length TRPM1, possibly
by inhibiting translocation of the full-length form to the plasma
membrane.
Using Northern blot and RT-PCR analyses, Fang and Setaluri (2000)
demonstrated that HMBA treatment upregulated expression of full-length
TRPM1 and a 5-prime short form of TRPM1.
Oancea et al. (2009) showed that a nonselective, outwardly rectifying
current measured in mouse melanoma cells was reduced by introducing a
microRNA targeting Trpm1. The current was also blocked by lanthanum, a
nonspecific blocker of many TRP channels. By transfection into melanoma
cells, Oancea et al. (2009) showed that TRPM1 isoforms containing 1,625
or 1,643 amino acids functioned as nonselective ion channels with a
slight preference for Na+ over Ca(2+). TRPM1 mRNA abundance in human
epidermal melanocytes correlated with melanin content. Melanocytes from
dark-pigmented skin showed higher TRPM1 content than melanocytes
obtained from light-pigmented skin. The complement of TRPM1 splice
variants also differed between melanocytes from dark- and
light-pigmented skin and between normal melanocytes and melanoma cell
lines.
Van Genderen et al. (2009) reacted transverse sections of normal human
retina with antibodies to TRPM1 and presynaptic and cone terminal
markers and observed dense TRPM1 puncta closely aligned with cone
photoreceptor terminals, with weaker TRPM1 staining in the inner nuclear
layer, associated with bipolar cell bodies. Staining for TRPM1 was
closely associated with but did not overlap presynaptic labeling in
large cone and small rod terminals. Van Genderen et al. (2009) concluded
that, like nyctalopin (NYX; 300278), TRPM1 is localized on rod ON
bipolar cell dendrites in the outer plexiform layer of the retina, and
suggested that in humans, TRPM1 is the cation channel gated by the GRM6
(604096) signaling cascade, which results in the light-evoked response
of ON bipolar cells.
Koike et al. (2010) found that expression of the mouse Trpm1l isoform in
Chinese hamster ovary cells resulted in constitutively active inward
currents. Coexpression of Trpm1l with Go-alpha resulted in currents that
were inhibited by Go-alpha activation, and expression of Mglur6 in
addition to Trpm1l and Go-alpha resulted in channels that were inhibited
by glutamate. Currents were recorded with all extracellular cations
examined, suggesting that Trpm1l is a constitutively active nonselective
cation channel.
MOLECULAR GENETICS
In a consanguineous family of South Asian ethnicity with complete
congenital stationary night blindness (CSNB1C; 613216), Li et al. (2009)
analyzed the candidate gene TRPM1 (603576) and identified homozygosity
for a splice site mutation (603576.0001) in the affected mother; the
father was heterozygous for the mutation. Li et al. (2009) screened the
TRPM1 gene in 9 families that were negative for mutation in the NYX and
GRM6 genes and identified compound heterozygosity for a 1-bp deletion
and a nonsense mutation and 2 missense mutations, respectively, in 2
families of Caucasian European descent (see, e.g.,
603576.0002-603576.0003). None of the mutations were found in 192
control individuals.
Audo et al. (2009) analyzed the TRPM1 gene in 38 clinically diagnosed
CSNB patients and identified homozygosity or compound heterozygosity for
14 causative mutations in 10 unrelated patients, including missense,
splice site, deletion, and nonsense mutations (see, e.g.,
603576.0004-603576.0005). Audo et al. (2009) proposed that the complete
CSNB phenotype in these patients was due to the absence of functional
TRPM1 in retinal ON bipolar cells.
In 6 of 8 female probands of European ancestry with complete CSNB, who
were negative for mutation in GRM6 and NYX, van Genderen et al. (2009)
identified mutations in TRPM1. Five probands carried either homozygous
or compound heterozygous mutations (see, e.g., 603576.0005-603576.0007),
and in 1 proband, only a single heterozygous mutation was found.
In 3 unrelated Japanese patients with CSNB, Nakamura et al. (2010)
identified compound heterozygosity for 5 different mutations (see, e.g.,
603576.0008-603576.0010).
ANIMAL MODEL
The appaloosa coat spotting pattern in horses is caused by a single
incomplete dominant gene, designated 'LP,' homozygosity for which is
directly associated with CSNB in Appaloosa horses. Bellone et al. (2008)
analyzed the relative expression of 5 candidate genes located in the
6-cM LP region on horse chromosome 1 and found markedly reduced
expression of TRPM1 in the retina and pigmented and unpigmented skin of
homozygous LP/LP Appaloosa horses compared to non-Appaloosa lp/lp horses
(p = 0.001 for all). Bellone et al. (2008) concluded that decreased
expression of TRPM1 in the eye and skin might alter bipolar cell
signaling as well as melanocyte function, thus causing both CSNB and LP
in horses.
Koike et al. (2010) found that Trpm1 -/- mice were indistinguishable
from wildtype littermates in appearance, including coat color. However,
whole-cell recording of retinal bipolar cells in retinal slices showed
that light stimulated an inward current in wildtype rod and cone ON
bipolar cells, but not in Trpm1 -/- ON bipolar cells.
GOLGA8A
| dbSNP name | rs4984228(A,G); rs7727(G,T); rs8631(A,G); rs8043502(G,A); rs3169217(T,C); rs2644237(C,T); rs74323336(C,G); rs3889892(T,G); rs2644233(G,T); rs2644232(T,C); rs76358577(C,T); rs113283603(C,A); rs80263932(C,T); rs7168232(A,C); rs4082583(T,C); rs2554786(C,G); rs34960231(C,G); rs11634235(T,C); rs116878443(T,C); rs349633(C,T); rs349632(C,A); rs2339438(C,T); rs1967143(T,G); rs1971525(C,G); rs1971524(C,T); rs349631(T,C); rs56962987(T,C); rs149121332(C,T); rs142814904(C,T); rs349629(C,T); rs113798775(G,C); rs8032401(C,T); rs79307273(C,A); rs74007822(T,C); rs138941581(C,T); rs117784984(G,A); rs59708025(C,G); rs1874378(A,G); rs114505481(G,A); rs8037742(C,A); rs74183679(G,A); rs1874377(T,C); rs74196569(C,T); rs79171960(G,T); rs117628820(T,C); rs59026480(G,C); rs2114262(C,G); rs56746941(T,C); rs115056228(C,T); rs349628(C,G); rs74203734(C,A) |
| cytoBand name | 15q14 |
| EntrezGene GeneID | 23015 |
| EntrezGene Description | golgin A8 family, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0932 |
GOLGA8B
| dbSNP name | rs3538(A,G); rs3200769(C,T); rs11558446(T,A); rs115263952(G,A); rs1059887(A,G); rs36106641(T,C); rs1059885(C,A); rs16954481(C,T); rs115999474(C,T); rs3866558(G,C); rs76906643(C,T); rs71464878(A,C); rs36110558(C,T); rs186940191(C,T); rs62006255(C,A); rs58595349(G,A); rs117364787(T,C); rs115262233(T,C); rs62006257(C,G); rs59195538(G,C); rs28543018(G,C); rs1863497(C,T); rs1863496(A,G); rs148940709(G,T); rs62004905(C,G); rs8039675(A,T); rs12593366(T,C); rs8039908(C,T); rs6495686(T,C); rs6495687(A,G); rs2879515(A,G); rs2339594(T,C); rs138119978(A,G); rs7179402(G,A); rs7182249(A,G); rs4633683(C,T); rs74205237(G,C); rs890389(A,G); rs1808501(C,T); rs1808500(C,T); rs1808499(G,C); rs2002870(G,C); rs144851039(C,A); rs74196431(C,G); rs6495689(C,T); rs62004935(T,C); rs62004936(A,G) |
| cytoBand name | 15q14 |
| EntrezGene GeneID | 440270 |
| EntrezGene Description | golgin A8 family, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4605 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature, disproportionate
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural;
[Eyes];
Retinal detachment
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Cupped ribs
SKELETAL:
[Spine];
Platyspondyly;
Anterior beaking of vertebrae;
Increased lumbar lordosis;
Scoliosis;
End-plate irregularities;
[Pelvis];
Small iliac wings;
Pubic punctate calcification (stippling);
Narrow sacrosciatic notch;
Flattened acetabular roof;
Hypoplastic pubic bones;
[Limbs];
Upper limb mesomelic shortening;
Distal ulnar epiphyseal calcifications (stippling);
Short tubular bones;
Megaepiphyses;
[Hands];
Brachydactyly;
Delayed carpal ossification;
Enlarged metacarpal epiphyses;
Enlarged phalangeal epiphyses;
Cone-shaped epiphyses;
[Feet];
Short feet;
Broad toes;
Pes planus
OMIM Title
*609619 GOLGI AUTOANTIGEN, GOLGIN SUBFAMILY A, 8B; GOLGA8B
;;GOLGIN 67;;
KIAA0855
OMIM Description
CLONING
By database analysis with the sequence of the Golgi complex autoantigen
golgin-95/golgin-130 (GOLGA2; 602580) as probe, Eystathioy et al. (2000)
identified a novel Golgi autoantigen, golgin-67. Using overlapping cDNAs
and RACE, Eystathioy et al. (2000) constructed a full-length clone
encoding a 459-amino acid protein with numerous alpha-helical
coiled-coils. Golgin-67 shares 4 regions with sequence identity to
golgin-95, ranging between 42% and 60%. Golgin-67 is identical to the
KIAA0855 clone identified by Nagase et al. (1998) from a human brain
cDNA library.
Of 84 human anti-Golgi sera, Eystathioy et al. (2000) identified 5 (6%)
containing autoantibodies to golgin-67. Two of these sera, from patients
with Sjogren syndrome (270150) and rheumatoid arthritis (180300), bound
to a protein of 67 kD on Western blots. Anti-golgin-67 human sera and
affinity purified rabbit antibody to the recombinant protein gave
predominant Golgi staining.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the GOLGA8B
gene to chromosome 15 (TMAP RH48788).
ANP32AP1
| dbSNP name | rs2589529(G,T) |
| cytoBand name | 15q14 |
| EntrezGene GeneID | 723972 |
| EntrezGene Description | acidic (leucine-rich) nuclear phosphoprotein 32 family, member A pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04178 |
ANKRD63
| dbSNP name | rs12440450(G,T) |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 100131244 |
| EntrezGene Description | ankyrin repeat domain 63 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ANKRD63:NM_001190479:exon1:c.C1113A:p.T371T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3632 |
| ExAC AF | 0.092 |
CHST14
| dbSNP name | rs582736(G,A) |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 113189 |
| snpEff Gene Name | BAHD1 |
| EntrezGene Description | carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1313 |
| ESP Afr MAF | 0.27054 |
| ESP All MAF | 0.145471 |
| ESP Eur/Amr MAF | 0.081395 |
| ExAC AF | 0.101 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Respiratory insufficiency due to muscle weakness (in some patients)
CHEST:
[Ribs, sternum, clavicle, and scapulae];
Scapular winging
SKELETAL:
Joint contractures (in some patients);
[Spine];
Rigid spine (in some patients)
MUSCLE, SOFT TISSUE:
Pelvic girdle muscle weakness (occurs earlier);
Difficulty running and jumping;
Shoulder girdle muscle weakness;
Distal muscle weakness occurs later;
Proximal and distal muscle atrophy;
Respiratory muscles may be involved (more common in juvenile-onset);
EMG shows myopathic changes;
Biopsy shows myopathic and dystrophic changes;
Increased fiber size variability;
Central nuclei;
Enlarged nuclei with central pallor;
Filamentous inclusions in muscle fibers;
Abnormal Z bands;
Rimmed vacuoles;
Autophagic vacuoles;
Increased connective tissue;
Increased mitochondria with rare paracrystalline inclusions
NEUROLOGIC:
[Central nervous system];
Delayed walking, mild (in some patients);
Abnormal gait due to muscle weakness
LABORATORY ABNORMALITIES:
Serum creatine kinase may be normal or elevated
MISCELLANEOUS:
Clinical variability;
Variable progression;
Juvenile-onset (before 15 years of age);
Adult-onset in third to fourth decade;
Some patients may become wheelchair-bound;
One large Spanish family and 1 unrelated patient have been reported
(last curated June 2014)
MOLECULAR BASIS:
Caused by mutation in the transportin 3 gene (TNPO3, 610032.0001)
OMIM Title
*608429 CARBOHYDRATE SULFOTRANSFERASE 14; CHST14
;;DERMATAN-4-SULFOTRANSFERASE 1; D4ST1;;
N-ACETYLGALACTOSAMINE 4-0 SULFOTRANSFERASE
OMIM Description
DESCRIPTION
The CHST14 gene encodes dermatan-4-sulfotransferase-1 (D4ST1), which
catalyzes the 4-O-sulfation of N-acetylgalactosamine (GalNAc) residues
in dermatan sulfate, a stereoisomeric form of chondroitin sulfate that
contains varying proportions of iduronic acid in place of glucuronic
acid (summary by Mikami et al., 2003).
CLONING
By searching a database for sequences similar to CHST10 (606376),
followed by PCR and 3-prime RACE of a brain cDNA library, Evers et al.
(2001) cloned CHST14, which they termed D4ST1. The deduced 376-amino
acid protein has a calculated molecular mass of 43 kD. D4ST1 is a type
II membrane protein with an N-terminal transmembrane region, binding
sites for 3-prime-phosphoadenosine-5-prime-phosphosulfonate (PAPS), and
2 potential N-glycosylation sites. D4ST1 shares significant similarity
with other sulfotransferases. The N-terminal regions are most variable.
Northern blot analysis detected a 2.4-kb transcript in heart, placenta,
liver, and pancreas, with significantly lower levels in skeletal muscle
and kidney. RNA dot blot analysis detected at least modest expression of
D4ST1 in all tissues examined with highest expression in pituitary,
placenta, uterus, thyroid, fetal lung, and a colorectal adenocarcinoma
cell line. Evers et al. (2001) also cloned mouse D4st1 by PCR of mouse
lung and kidney cDNA libraries. Mouse D4st1 is 92.7% identical to human
D4ST1.
GENE STRUCTURE
Evers et al. (2001) determined that CHST14 is an intronless gene. A CpG
island extends from 620 bp upstream to 880 bp downstream of the D4ST1
start codon.
MAPPING
By genomic sequence analysis, Evers et al. (2001) mapped the CHST14 gene
to chromosome 15q14.
GENE FUNCTION
Evers et al. (2001) examined the sulfotransferase activity of D4ST1
following transfection in Chinese hamster ovary cells. They noted that,
although D4ST1 is predicted to be a transmembrane protein, most activity
was released into the culture medium and only 3% was retained within the
transfected cells. D4ST1 showed dermatan-specific
GalNAc-4-O-sulfotransferase activity. The specificity of D4ST1 suggested
that the addition of sulfate to GalNAc occurred immediately after the
epimerization of glucuronic acid to iduronic acid.
Mikami et al. (2003) found that, unlike other sulfotransferases, D4ST1
transferred sulfate to GalNAc flanked on both sides by iduronic acid
residues more efficiently than to GalNAc flanked by glucuronic acid.
They also found that partially desulfated dermatan sulfate also served
as a sulfate acceptor.
MOLECULAR GENETICS
In 4 families with adducted thumbs, clubfeet, and progressive joint and
skin laxity mapping to chromosome 15q15 (EDSMC1; 601776), Dundar et al.
(2009) sequenced the candidate gene CHST14 and identified homozygous
mutations that segregated with disease in each family
(608429.0001-608429.0004) and were not found in controls. The mutations
abolished or decreased D4ST1 activity by early protein truncation and
altered intracellular protein processing, resulting in a decrease of
dermatan sulfate and an increase of chondroitin sulfate in patient
fibroblasts and in culture medium. Dundar et al. (2009) stated that this
was the first disorder caused by a defect specific to dermatan sulfate
biosynthesis, producing a generalized involvement of organs and
revealing roles for dermatan sulfate in human development and the
extracellular matrix.
In 2 probands from unrelated consanguineous Japanese families with
bilateral thumb adduction, clubfeet, and progressive joint and skin
laxity, Miyake et al. (2010) identified homozygosity for the same
missense mutation in both patients (P281L; 608429.0005). Genetic
analysis of 4 more unrelated Japanese probands with similar features
revealed compound heterozygosity for the P281L mutation and respective
missense and nonsense mutations (608429.0004; 608429.0006-608429.0007).
In 2 Turkish sisters and an Indian girl with the musculocontractural
form of Ehlers-Danlos syndrome, Malfait et al. (2010) identified
homozygosity for a 1-bp deletion (608429.0001) and a 20-bp duplication
(608429.0008) in the CHST14 gene, respectively.
In 2 sisters with the musculocontractural type of Ehlers-Danlos
syndrome, born of first-cousin parents of Afghan descent,
Mendoza-Londono et al. (2012) identified homozygosity for a missense
mutation in the CHST14 gene (R274P; 608429.0009).
RAD51-AS1
| dbSNP name | rs2619679(T,A) |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 100505648 |
| snpEff Gene Name | RAD51 |
| EntrezGene Description | RAD51 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4247 |
INO80
| dbSNP name | rs9796(A,T); rs7175438(C,T); rs76495904(G,A); rs151117314(G,A); rs113407733(A,G); rs4924531(G,C); rs7173954(T,G); rs11855248(G,A); rs4609821(C,G); rs142357383(T,C); rs2305656(T,A); rs74014730(C,T); rs936220(C,T); rs79429037(A,T); rs10438298(C,T); rs28501589(G,A); rs12905314(C,T); rs12905926(G,A); rs12910027(A,T); rs137995065(T,C); rs4924532(T,C); rs192059455(G,T); rs75277301(C,T); rs3101436(A,G); rs11854924(G,C); rs3101440(A,G); rs4924533(T,C); rs74014734(G,T); rs7162992(T,C); rs78395142(G,A); rs3100807(G,A); rs28473405(C,T); rs373468443(G,A); rs3101435(A,G); rs13329511(T,C); rs140432217(C,T); rs8034461(C,T); rs11070319(A,G); rs6492976(G,C); rs144765100(G,A); rs6492977(A,G); rs2927061(C,T); rs2927062(G,A); rs144987034(T,A); rs28423980(C,A); rs2925342(A,G); rs2925343(T,C); rs2925344(C,T); rs7169375(T,C); rs72735699(G,A); rs3101437(C,T); rs2925345(T,C); rs7174513(G,A); rs28550294(G,A); rs58617586(C,G); rs3214068(C,G); rs3101438(T,G); rs7171437(G,A); rs12148744(T,C); rs2925346(G,A); rs6492978(T,C); rs9920619(A,G); rs191049824(A,T); rs79498877(C,A); rs193156509(G,C); rs4923891(G,C); rs2412598(G,A); rs4924534(C,T); rs28581803(G,A); rs2927065(G,A); rs56829576(G,A); rs12912131(G,A); rs4468583(A,G); rs2925348(A,G); rs2927066(G,T); rs1009913(C,T); rs7173146(A,G); rs7178326(C,T); rs2013359(C,G); rs1962410(T,C); rs2927067(T,C); rs2925349(G,A); rs8042088(T,C); rs4923894(C,T); rs4923895(G,T); rs3101441(A,C); rs11630905(A,G); rs12903676(A,G); rs11070320(C,T); rs11856572(T,C); rs11856577(T,C); rs72737713(G,A); rs111364472(G,A); rs4924535(A,G); rs2899010(T,C); rs2306083(G,A); rs2412599(A,G); rs2412600(C,T); rs7179681(A,T); rs141618851(C,T); rs61203391(C,G); rs12101934(C,T); rs114130636(G,A); rs12148862(G,A); rs11854472(G,A); rs16971454(C,T); rs373425392(T,C); rs544744(G,C); rs28516832(G,A); rs1717200(A,G); rs11853192(G,A); rs112751747(C,T); rs79677411(T,C); rs11856848(C,T); rs143145426(G,A); rs28510775(G,A); rs1983400(T,C); rs2947493(G,A); rs2947494(C,T); rs516156(A,G); rs3101442(T,G); rs145473172(T,C); rs145751950(C,T); rs691830(A,G); rs476633(C,G); rs28896021(A,C); rs6492982(C,T); rs28664602(G,A); rs2928148(G,A); rs66818965(G,A); rs28613002(T,C); rs28688742(G,A); rs692155(A,G); rs61648937(C,T) |
| ccdsGene name | CCDS10071.1 |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 54617 |
| EntrezGene Description | INO80 complex subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | INO80:NM_017553:exon36:c.C4666T:p.R1556W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.587 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9ULG1 |
| dbNSFP Uniprot ID | INO80_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Dolichostenomelia (uncommon)
HEAD AND NECK:
[Face];
Micrognathia;
Retrognathia;
[Eyes];
Hypertelorism;
Exotropia;
Blue sclerae;
Proptosis;
[Mouth];
Bifid uvula;
Cleft palate (uncommon)
CARDIOVASCULAR:
[Heart];
Atrial septal defect (uncommon);
Bicuspid aortic valve (uncommon);
Bicuspid pulmonary valve (rare);
Mitral valve prolapse (uncommon);
Quadricuspid pulmonary valve (rare);
[Vascular];
Arterial tortuosity, generalized;
Patent ductus arteriosus;
Ascending aortic aneurysm;
Ascending aortic dissection;
Pulmonary artery aneurysm;
Descending aortic aneurysm (uncommon);
Cerebral aneurysm (uncommon)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus deformity
ABDOMEN:
[External features];
Umbilical hernia (rare);
Inguinal hernia (rare)
SKELETAL:
Joint laxity;
Osteoporosis (in some patients);
Low-impact fractures (in some patients);
[Skull];
Craniosynostosis (uncommon);
Malar hypoplasia;
[Spine];
Scoliosis;
[Hands];
Arachnodactyly;
Camptodactyly;
Postaxial polydactyly (rare);
Brachydactyly;
Syndactyly (rare);
Absent distal phalanges (rare);
Contractures;
[Feet];
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Velvety texture;
Translucent skin
NEUROLOGIC:
[Central nervous system];
Mental retardation (uncommon);
Developmental delay (uncommon);
Chiari malformation (uncommon);
Hydrocephalus (uncommon)
MISCELLANEOUS:
Genetic heterogeneity (see 609192);
Uncommon and rare features seen in the most severely affected patients
MOLECULAR BASIS:
Caused by mutation in the transforming growth factor, beta receptor
II, 70-80kD gene (TGFBR2, 190182.0008)
OMIM Title
*610169 INO80 COMPLEX HOMOLOG 1; INOC1
;;INO80, S. CEREVISIAE, HOMOLOG OF; INO80
OMIM Description
DESCRIPTION
INOC1 is the human homolog of S. cerevisiae Ino80, the catalytic ATPase
subunit of the INO80 chromatin remodeling complex (Shen et al., 2000;
Bakshi et al., 2004). INOC1 defines a subfamily of SWI2/SNF2 chromatin
remodeling proteins; see SMARCA (600014) for background information.
CLONING
Using in silico analysis, Bakshi et al. (2004) identified novel members
of the SNF2/SWI2 gene family, including the human homolog of yeast
Ino80. The deduced 1,556-amino acid INOC1 protein has a predicted
molecular mass of 177 kD (Bakshi et al., 2006). The protein contains the
conserved 7-motif SNF2 helicase domain, which is dispersed over 700
amino acids rather than the typical 400. It has a typical GxGK[S/T]
sequence in SNF domain motif-1, a DEAQ, rather than a DExH/D, pattern in
motif-2, and a 126-amino acid domain, termed DBINO (DNA-binding domain
of INO80), that is conserved in members of the INO80 subfamily and is
located upstream of the SNF2 helicase domain. INOC1 contains both
N-terminal and C-terminal nuclear localization signals (Bakshi et al.,
2004; Bakshi et al., 2006).
By PCR analysis with 3 primer sets mapping across different exons of
INOC1, Bakshi et al. (2006) detected ubiquitous expression of the mouse
Inoc1 in all 3; in cDNA from human tissues, ubiquitous expression was
seen in 2, but the transcript spanning the SNF2 ATPase domain was
expressed only in brain, liver, and pancreas. Using immunoprecipitation
and Western blot analysis, Bakshi et al. (2006) detected a 76-kD protein
band in embryonic kidney (HEK293) cells and suggested that this may
represent an alternative splice product. Bakshi et al. (2006) localized
INOC1 to the nucleus by immunofluorescence microscopy in HEK293 cells.
GENE FUNCTION
Using histidine-tagged, recombinant INOC1 containing the ATPase domain,
Bakshi et al. (2006) demonstrated that INOC1 displayed ATPase activity
specific to double-stranded DNA and exhibited activity on isolated human
mononucleosomes. ATP hydrolysis of double-stranded DNA occurred in a
linear time course with a calculated Km of 167 microM, similar to that
of other ATPases of the SNF2/SWI2 family. Using an electrophoretic
mobility shift assay and fluorescence spectroscopy, Bakshi et al. (2006)
demonstrated that the INOC1 DBINO domain has DNA-binding activity.
GENE STRUCTURE
The INOC1 gene contains 36 exons and spans approximately 135 kb (Bakshi
et al., 2004).
MAPPING
By sequence analysis, Bakshi et al. (2004) mapped the INOC1 gene to
chromosome 15q14. Bakshi et al. (2006) stated that the INOC1 gene maps
to 15q15.1.
EHD4
| dbSNP name | rs1048175(C,G); rs1048166(T,C); rs12441018(T,G); rs1113333(T,C); rs148466470(G,A); rs9920406(C,T); rs11636923(T,C); rs11636960(T,C); rs1648812(C,T); rs1648813(C,T); rs8041458(G,C); rs117792352(G,A); rs1704386(A,G); rs7172468(G,A); rs1704388(T,C); rs28478297(G,A); rs10518741(T,C); rs28550631(C,A); rs8039061(G,A); rs1704389(A,G); rs9920696(G,A); rs890500(T,C); rs28547280(T,C); rs1648814(C,T); rs1704391(A,C); rs1648815(A,G); rs78416710(A,G); rs62002147(A,G); rs890502(A,G); rs17686769(G,A); rs34051765(G,A); rs67310386(G,A); rs112824870(C,T); rs6493011(A,G); rs2412652(C,T); rs1648818(T,C); rs1704393(G,A); rs2555557(T,C); rs1820506(T,C); rs1704394(G,T); rs4923919(G,A); rs1648819(T,C); rs1648820(A,T); rs1704395(T,C); rs1704396(A,G); rs1704397(T,C); rs1648821(C,T); rs4924588(A,G); rs1648822(T,C); rs34282406(T,G); rs142151041(G,T); rs76024922(G,C); rs1704398(C,G); rs12101334(A,T); rs74777346(A,G); rs78150752(C,T); rs1648811(A,G); rs1704401(A,G); rs55809667(A,T); rs8034944(G,A); rs74587848(T,C); rs35651471(C,A); rs11634233(G,A); rs6493013(T,C); rs58367666(C,T); rs6493014(C,T); rs139736022(C,T); rs6493015(G,T); rs1426890(G,A); rs4286082(C,T); rs78647939(G,A); rs7171846(T,G); rs79712585(T,C); rs2114477(T,C); rs12913835(C,T); rs11638621(C,T); rs1648857(C,G); rs16972296(C,T); rs4924589(C,T); rs17687755(G,C); rs10518743(C,T); rs12101888(C,T); rs1426889(C,T); rs117874072(A,G); rs115420849(C,T); rs17687882(C,T); rs11070354(C,T); rs4924590(T,A); rs1648856(C,T); rs2665213(T,G); rs17739125(T,C); rs62004265(C,T); rs28660334(C,G); rs367607858(A,T); rs17687976(A,G); rs28479572(T,A); rs17739167(A,G); rs11631075(G,A); rs141695670(T,C); rs12909773(G,T); rs75978546(C,T); rs1648855(C,G); rs1648854(T,C); rs16972308(G,A); rs72726023(G,A); rs4244586(T,G); rs1614170(T,C); rs8035074(C,T); rs148590584(C,T); rs72726025(T,C); rs74403139(C,T); rs57556178(G,A); rs58818261(G,A); rs1704405(G,A); rs113877402(C,T); rs11638953(G,A); rs28634033(T,A); rs77469137(G,C); rs60772450(G,C); rs35796146(G,A); rs57614850(C,T); rs36018108(G,A); rs72726027(T,C); rs59114612(T,C); rs1704407(A,G); rs72726030(T,A); rs4924591(C,T); rs113250378(C,T); rs112035122(C,T); rs72726031(C,A); rs76177165(C,T); rs34899815(C,T); rs2598469(T,C); rs201882614(A,T); rs74909248(A,T); rs1868831(C,T); rs111969880(C,G); rs72726034(C,A); rs7183879(A,G); rs189893570(G,T); rs2250635(T,C); rs1002774(G,A); rs59271769(C,A) |
| ccdsGene name | CCDS10081.1 |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 30844 |
| EntrezGene Description | EH-domain containing 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EHD4:NM_139265:exon3:c.A437G:p.N146S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8308 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A8K9B9 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001306 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Muscle fatigue
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated serum N,N-dimethylglycine (DMG);
Elevated urinary N,N-dimethylglycine (DMG);
Dimethylglycine dehydrogenase (DMGDH) deficiency
MISCELLANEOUS:
Fishy body odor
MOLECULAR BASIS:
Caused by mutation in the dimethylglycine dehydrogenase gene (DMGDH,
605849.0001)
OMIM Title
*605892 EH DOMAIN-CONTAINING 4; EHD4
OMIM Description
CLONING
By screening a human fetal brain cDNA library with exons derived from a
BAC mapping to the 19q13.3 glioma tumor suppressor candidate region,
Pohl et al. (2000) identified 3 novel genes, designated EHD2 (605890),
EHD3 (605891), and EHD4, which are homologous to human EHD1 (605888).
The deduced protein identities between EHD1 and EHD2, between EHD1 and
EHD3, and between EHD1 and EHD4, are 71%, 86%, and 76%, respectively.
All contain multiple conserved regions that include a nucleotide-binding
consensus site at the N terminus, a bipartite nuclear localization
signal, and an eps15 homology (EH) protein-binding domain with an
EF-hand motif at the C terminus. EHD4 encodes a deduced 482-amino acid
protein. Northern blot analysis detected expression of 4 mRNA species of
approximately 2.0, 2.7, 3.2, and 3.6 kb. All of the transcripts are
highly expressed in pancreas, and the 2.7- and 3.6-kb transcripts are
highly expressed in heart. Only weak expression is found in other
tissues.
MAPPING
By radiation hybrid analysis, Pohl et al. (2000) mapped the EHD4 gene to
chromosome 15q11.1.
CAPN3
| dbSNP name | rs16973175(A,G); rs28364372(T,C); rs8026177(A,T); rs8026198(A,C); rs8027800(T,C); rs114914004(G,C); rs114559229(G,T); rs80240985(G,A); rs113945208(G,A); rs112669731(G,C); rs113731627(A,G); rs75246910(G,C); rs728508(T,C); rs139083274(C,T); rs728509(C,T); rs728510(G,A); rs113168375(T,C); rs1359003(C,T); rs1359004(C,G); rs112099103(G,T); rs12441700(C,T); rs79269514(C,T); rs111452548(C,T); rs112229812(T,C); rs113032324(T,C); rs16973177(G,A); rs3850774(A,G); rs74682480(G,A); rs8035332(G,A); rs8035521(G,A); rs141980670(T,C); rs138881559(T,C); rs116381153(T,C); rs2407707(G,A); rs16973182(A,G); rs116127972(C,T); rs114810264(A,G); rs77978790(T,A); rs111234891(C,T); rs8038771(T,C); rs8038967(T,C); rs76812490(A,G); rs79989453(G,A); rs111873324(G,T); rs113374390(C,G); rs143392843(C,T); rs114507770(T,C); rs115373982(G,A); rs78679324(A,G); rs7166785(C,G); rs74538882(T,C); rs116777709(A,C); rs78920810(A,G); rs16973184(A,G); rs8033108(A,T); rs8033734(G,A); rs114018038(A,G); rs8033882(G,A); rs8033960(A,G); rs147184467(C,G); rs140931459(G,A); rs8040129(A,C); rs8040726(G,T); rs8024452(A,G); rs16973188(A,G); rs5029919(G,A); rs4516202(C,T); rs4486855(C,T); rs142833389(G,A); rs4307925(T,G); rs28364383(A,G); rs80240204(A,G); rs113829250(A,G); rs75085290(G,A); rs77526692(C,G); rs77192344(C,A); rs114501512(T,C); rs146646992(T,C); rs4924674(T,C); rs74996094(A,G); rs146132903(G,T); rs74577756(G,T); rs79701537(A,C); rs115599778(G,T); rs114186601(G,C); rs56702977(G,A); rs151297043(G,A); rs57347762(G,A); rs7167683(A,C); rs76684467(C,T); rs145736785(A,G); rs111917515(C,T); rs111812815(A,G); rs116539294(C,T); rs116001184(G,T); rs116346045(G,A); rs111331616(C,T); rs116109811(G,A); rs113455092(C,T); rs181846492(A,G); rs12438369(T,C); rs28364388(G,A); rs143117834(A,G); rs28364389(G,C); rs28364390(T,A); rs16973200(A,G); rs185604837(T,A); rs28364395(G,A); rs28364399(G,T); rs12438453(A,G); rs28364401(T,C); rs16973206(G,A); rs7168709(C,A); rs28364407(G,A); rs751572(T,C); rs17593(T,C); rs7174880(A,G); rs28364416(C,T); rs28364417(C,T); rs1801449(G,A); rs78369269(G,A); rs28364427(C,T); rs28364430(C,G); rs28364432(C,T); rs150436147(C,T); rs3115876(A,G); rs28364440(G,A); rs12324205(C,G); rs28364442(A,G); rs28364445(T,A); rs28364446(A,G); rs28364447(T,C); rs28364448(G,A); rs28364450(C,T); rs28364453(G,A); rs28364457(C,A); rs8024113(G,C); rs28364459(A,C); rs7168121(A,G); rs28364462(A,G); rs112253071(T,C); rs28364465(C,T); rs28364466(C,T); rs3115877(A,G); rs16973233(C,G); rs28364467(A,G); rs3803342(A,G); rs28364472(G,A); rs28364473(G,T); rs28745872(C,T); rs8042603(T,G); rs7182281(G,A); rs141594816(A,G); rs28745878(C,T); rs28745879(G,T); rs28745880(A,G); rs3743003(C,G); rs3743002(G,A); rs28364475(C,T); rs28364476(T,C); rs28364479(G,A); rs28364482(C,T); rs28364485(G,A); rs28364491(T,C); rs2241827(T,C); rs138857720(G,A); rs28364495(G,A); rs28364496(G,A); rs28364498(G,C); rs17764849(C,T); rs7163986(A,T); rs28364500(G,T); rs28364501(A,C); rs2412711(C,G); rs28364508(C,T); rs28364509(G,A); rs28364511(A,G); rs3115881(A,G); rs28364513(T,A); rs28364516(T,A); rs28364519(C,T); rs77946392(T,G); rs28364522(C,G); rs28364524(G,A); rs28364526(G,C); rs16952474(A,G); rs2289293(G,A); rs3115882(G,C); rs28364532(C,T); rs3115883(T,C); rs28364536(G,C); rs28364540(G,C); rs116852089(G,A); rs28364541(C,G); rs3115884(T,C); rs28364543(T,C); rs28364544(C,T); rs3098423(C,T) |
| ccdsGene name | CCDS45246.1 |
| CosmicCodingMuts gene | CAPN3 |
| cytoBand name | 15q15.1 |
| EntrezGene GeneID | 825 |
| EntrezGene Description | calpain 3, (p94) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CAPN3:NM_173087:exon12:c.G1441A:p.A481T,CAPN3:NM_173088:exon2:c.G49A:p.A17T,CAPN3:NM_000070:exon13:c.G1585A:p.A529T,CAPN3:NM_024344:exon13:c.G1585A:p.A529T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6073 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
Limbs:
Camptodactyly;
Proximal interphalangeal finger joint contractures
Joints:
Knee-joint subluxation
Misc:
Fifth finger most frequently affected
Lab:
Associated taurinuria
Inheritance:
Autosomal dominant
OMIM Title
*114240 CALPAIN 3; CAPN3
;;CALPAIN, LARGE POLYPEPTIDE L3;;
CALPAIN III, LARGE SUBUNIT; CANPL3;;
CALCIUM-ACTIVATED NEUTRAL PROTEASE 3, MUSCLE-SPECIFIC, LARGE SUBUNIT;
CANP3;;
p94
OMIM Description
DESCRIPTION
The CAPN3 gene encodes calpain-3. The calpains, or calcium-activated
neutral proteases (EC 3.4.22.17), are nonlysosomal intracellular
cysteine proteases. Mammalian calpains are heterodimers composed of a
ubiquitous 80-kD large subunit (e.g., CAPN1, 114220 and CAPN2, 114230)
and a common small 30-kD subunit (CAPNS1; 114170). CAPN3 is a
muscle-specific large subunit (Sorimachi et al., 1989).
CLONING
Sorimachi et al. (1989) isolated a clone corresponding to a novel member
of the CAPN (symbolized CANP by them) large subunit family from human
and rat skeletal muscle cDNA libraries. The deduced protein (p94),
corresponding to CAPN3, contains 821 amino acid residues, has a
molecular mass of 94 kD, and shows significant sequence homology with
other large subunits. The protein could be divided into 4 domains (I to
IV) as reported for the CANP large subunit family. Domains II and IV are
potential cysteine protease and calcium-binding domains, respectively,
and have sequences homologous to the corresponding domains of other CANP
large subunits. However, domain I of p94 is significantly different from
others. In addition, p94 contains 2 unique sequences of 62 and 77
residues in domains II and III, respectively. In contrast to the
ubiquitous expression of other large subunits, Northern blot analysis
detected a p94 mRNA in skeletal muscle.
Richard et al. (1995) identified the CAPN3 gene by positional cloning of
a region on chromosome 15q containing the gene for limb-girdle muscular
dystrophy type 2A (LGMD2A; 253600). CAPN3 gene was a particularly
attractive candidate because of its functional role in muscle. Richard
et al. (1995) reported a gene sequence that differed slightly from that
reported by Sorimachi et al. (1989).
Blazquez et al. (2008) identified 4 different CAPN3 mRNA transcripts in
human white blood cells. Sequence analysis showed that exon 15 was
always absent, whereas exons 6 and 16 could be present or not. There was
only 1 transcript detected in muscle.
Richard and Beckmann (1996) found that the mouse Capn3 gene encodes an
mRNA of a size similar to the human CANP3 mRNA. The mouse gene directs
the synthesis of an 821-amino acid protein.
GENE STRUCTURE
Richard et al. (1995) demonstrated that the CAPN3 gene contains 24 exons
and extends over 40 kb.
MAPPING
Ohno et al. (1989) mapped the CAPN3 gene to chromosome 15.
By somatic cell hybridization, Richard and Beckmann (1996) localized the
mouse Capn3 gene to either chromosome 2 or chromosome 4. The results did
not allow distinction between these 2 chromosomes, since all hybrids
carrying mouse chromosome 2 also carried chromosome 4. The fact that
isolated murine YACs amplified a sequence tagged site (STS) for the
TYRO3 gene (600341), which maps to human chromosome 15, suggested to
Richard and Beckmann (1996) that the 2 genes are adjacent in the mouse.
Homology between mouse chromosome 2 and human chromosome 15 is well
established by a number of examples of synteny; no homology of synteny
has been demonstrated between human 15 and mouse 4.
GENE FUNCTION
In COS-1 cells, Huang et al. (2008) demonstrated that calpain-3 and
AHNAK (103390) colocalize at the I-band near the A-I junction in
skeletal muscle, that calpain-3 cleaves AHNAK, and that this cleavage
results in decreased levels of AHNAK. Studies of AHNAK fusion protein
constructs showed that calpain-3 can cleave AHNAK at 2 sites in the N
terminus and 3 sites in the C terminus, but not at the central M region.
Cleavage of AHNAK disrupted its binding to dysferlin (DYSF; 603009) and
myoferlin (FER1L3; 604603). Skeletal muscle from 4 patients with LGMD2A
(253600) due to CAPN3 mutations showed increased levels of AHNAK at the
sarcolemma and blood vessels. Huang et al. (2008) concluded that CAPN3
plays a role in the dysferlin protein complex and that disruption of
CAPN3 function may affect muscle membrane repair and remodeling.
Sarparanta et al. (2010) found that C-terminal domains of the
muscle-specific protein myospryn (CMYA5; 612193) interacted with
calpain-3. Myospryn appeared to stabilize full-length calpain-3 against
proteolytic autoactivation, and active calpain-3 used myospryn as a
substrate.
MOLECULAR GENETICS
By a mutation screen in LGMD2A families (253600), Richard et al. (1995)
identified 15 nonsense, splice site, frameshift, or missense CAPN3
mutations cosegregating with the disease (see, e.g., 114240.0001,
114240.0002, and 114240.0003). Six of the mutations were found within an
inbred population on Reunion Island, and haplotype analysis suggested
the existence of at least 1 more mutation in the group. The occurrence
of multiple independent mutations in the isolated population on Reunion
Island rather than the finding of an expected founder mutation was
referred to as the 'Reunion paradox' by Richard et al. (1995). They
suggested that LGMD2A, instead of being a monogenic disorder, might have
a more complex inheritance pattern in which expression of calpain
mutations is dependent on genetic background, either nuclear or
mitochondrial; see MOLECULAR GENETICS section in 253600.
Richard et al. (1997) studied 21 LGMD2 pedigrees of various origins:
France, Israel, Lebanon, Switzerland, United States, Italy, and Turkey.
Nine of the 23 families showed linkage to chromosome 15, whereas such
linkage was excluded in 10 and was inconclusive in 4. A search for CAPN3
mutations uncovered 19 novel mutations in addition to the 16 described
previously (see, e.g., 114240.0004; 114240.0005). A survey of clinical
features showed great variability. All patients showed elevated serum
creatine kinase in a range of 7 to 84 times the upper limit of normal,
marked intra- and interfamilial phenotypic variability in age of onset
(range 2.5 to 40 years), and loss of ambulation. For example, affected
individuals in 1 family presented with a very mild phenotype, with onset
at ages 30 and 40 years, and were still ambulatory at ages 54 and 66
years, respectively. In contrast, 2 Lebanese sibs had onset at age 6
years and had loss of independent walking at ages 13 years and 15 years.
Fanin et al. (2005) identified mutations in the CAPN3 gene in 70 (33%)
of 214 patients with limb-girdle muscular dystrophy in Italy. The
prevalence of LGMD2A was estimated at 9.47 per million inhabitants in
northeastern Italy. Two founder mutations were identified (500delA,
114240.0009; R490Q, 114240.0010). Todorova et al. (2007) identified
mutations in the CAPN3 gene in 20 (42%) of 48 unrelated Bulgarian
patients with muscular dystrophy. Three novel and 6 recurrent mutations
were identified. Forty percent of the patients were homozygous for the
500delA mutation, and 70% carried it on at least 1 allele.
By high-throughput denaturing HPLC, Piluso et al. (2005) scanned the
CAPN3 gene in 530 individuals with different grades of symptoms
consistent with LGMD. They found 141 LGMD2A patients carrying 82
different CAPN3 mutations, of which 45 were novel. Females had a more
favorable course than males. In 94% of the most severely affected LGMD2A
patients, the defect was also discovered in the second allele. CAPN3
mutations were found in 35.1% of patients with classic LGMD phenotypes,
18.4% of atypical patients, and 12.6% of patients with high serum
creatine kinase levels. Piluso et al. (2005) broadened the spectrum of
LGMD2A phenotypes and set the carrier frequency at 1:103.
Among 46 European patients suspected to have LGMD2A based on Western
blot results, Duno et al. (2008) found that 16 patients had mutations in
the CAPN3 gene identified by both direct genomic sequencing and cDNA
analysis. Both mutant alleles were demonstrated in 10 patients. A total
of 16 mutations were identified, including 5 novel mutations. Only 3 of
the genetically confirmed LGMD2A patients were of Danish origin,
indicating a 5- to 6-fold lower prevalence in Denmark compared to other
European countries.
- Molecular Mechanism of Disease
Prior to the identification of CAPN3 as the defective gene in LGMD2A,
all identified molecular mechanisms in muscular dystrophies had involved
structural components of muscle. CAPN3 appears to have a very rapid
turnover mediated by autocatalysis, possibly reflecting the need for
precise regulation of its activity. Furthermore, CAPN3 shows a nuclear
localization, possibly mediated by the nuclear translocation signal in
the IS2 region. Richard et al. (1995) favored the idea that the CAPN3
protein is involved in the control of gene expression by regulating the
turnover or activity of transcription factors or of their inhibitors.
Ono et al. (1998) constructed 9 CAPN3 missense point mutations and
analyzed the unique properties of the resultant protein product. All
mutants completely or almost completely lost proteolytic activity
against a potential substrate, fodrin. However, some of the mutants
still possessed autolytic activity and/or connectin/titin (TTN;
188840)-binding ability, indicating that these properties are not
necessary for the LGMD2A phenotype. These results provided strong
evidence that LGMD2A results from the loss of proteolysis of substrates
by p94, suggesting a novel molecular mechanism leading to muscular
dystrophies.
Zatz and Starling (2005) reviewed the roles of calpains in disease with
specific reference to the etiologic role of mutations in CAPN3 in
LGMD2A.
In many patients with LGMD2A, loss-of-function mutations cause enzymatic
inactivation of calpain-3 while protein quantity remains normal. Because
the diagnosis of calpainopathy is obtained by identifying calpain-3
protein deficiency or mutations in the CAPN3 gene, the identification of
such patients is difficult. Fanin et al. (2007) used a functional in
vitro assay to test calpain-3 autolytic function in a large series of
muscle biopsy specimens from patients with unclassified LGMD/hyperCKemia
who had been shown to have normal calpain-3 protein quantity. Of 148
muscle biopsy specimens tested, 17 (11%) had lost normal autolytic
function. The CAPN3 gene mutations were identified in 15 of the 17
patients (88%), who accounted for about 20% of the total patients with
LGMD2A diagnosed in their series.
ANIMAL MODEL
Tagawa et al. (2000) created transgenic mice that expressed an inactive
mutant of p94, in which the active site cys129 is replaced by ser
(p94:C129S). Transgenic mice expressing p94:C129S mRNA showed
significantly decreased grip strength. Sections of soleus and extensor
digitorum longus (EDL) muscles of the aged transgenic mice showed
increased numbers of lobulated and split fibers, respectively, which are
often observed in limb-girdle muscular dystrophy muscles. Centrally
placed nuclei were also frequently found in the EDL muscle of the
transgenic mice, whereas wildtype mice of the same age had almost none.
More p94 protein was produced in aged transgenic mice muscles, and the
protein showed significantly less autolytic degradation activity than
that in wildtype mice. The authors hypothesized that accumulation of
p94:C129S protein caused these myopathy phenotypes.
The giant protein titin (188840) serves a primary role as a scaffold for
sarcomere assembly; one potential mediator of this process is calpain-3.
To test the hypothesis that calpain-3 mediates remodeling during
myofibrillogenesis, Kramerova et al. (2004) generated Capn3-knockout
(C3KO) mice. The mice were atrophic, with small foci of muscular
necrosis. Myogenic cells fused normally in vitro, but lacked
well-organized sarcomeres, as visualized by electron microscopy. Titin
distribution was normal in longitudinal sections from the C3KO mice;
however, electron microscopy of muscle fibers showed misaligned A-bands.
In vitro studies revealed that calpain-3 can bind and cleave titin and
that some mutations that are pathogenic in human muscular dystrophy
result in reduced affinity of calpain-3 for titin. Kramerova et al.
(2004) suggested a role for calpain-3 in myofibrillogenesis and
sarcomere remodeling.
Kramerova et al. (2005) showed that the rates of atrophy and growth were
decreased in C3KO mouse muscles under conditions promoting sarcomere
remodeling. In wildtype mice, ubiquitinated proteins accumulated during
muscle reloading, possibly reflecting removal of atrophy-specific and
damaged proteins. The increase in ubiquitination correlated with an
increase in calpain-3 expression. There was upregulation of heat shock
proteins in C3KO muscles following challenge with a physiologic
condition that required highly increased protein degradation. Old C3KO
mice showed evidence of insoluble protein aggregate formation in
skeletal muscles. Kramerova et al. (2005) suggested that accumulation of
aged and damaged proteins may lead to cellular toxicity and a cell
stress response in C3KO muscles, and that these characteristics may be
pathologic features of LGMD2A.
Huebsch et al. (2005) generated CAPN3 overexpressing transgenic (C3Tg)
and C3KO mice and showed that overexpression of CAPN3 exacerbated mdm
disease, leading to a shorter life span and more severe muscular
dystrophy. However, C3KO/mdm double-mutant mice showed no change in the
progression or severity of disease, indicating that aberrant CAPN3
activity is not a primary mechanism in this disease. The authors
examined the treadmill locomotion of heterozygous +/mdm mice and
detected a significant increase in stride time with a concomitant
increase in stance time. These altered gait parameters were completely
corrected by CAPN3 overexpression in C3Tg/+/mdm mice, suggesting a
CAPN3-dependent role for the N2A domain of TTN in the dynamics of muscle
contraction.
Kramerova et al. (2009) reported both morphologic and biochemical
evidence of mitochondrial abnormalities in C3KO mouse muscles, including
irregular ultrastructure and distribution of mitochondria. The
morphologic abnormalities in C3KO muscles were associated with reduced
in vivo mitochondrial ATP production. Mitochondrial abnormalities in
C3KO muscles also correlated with the presence of oxidative stress;
increased protein modification by oxygen free radicals and an elevated
concentration of the antioxidative enzyme Mn-superoxide dismutase (SOD2;
147460) were observed in C3KO muscles. The activity of the
beta-oxidation enzyme, VLCAD (ACADVL; 609575), was decreased in C3KO
mitochondrial fractions compared with wildtype, suggestive of a general
mitochondrial dysfunction. Kramerova et al. (2009) suggested that
mitochondrial abnormalities leading to oxidative stress and energy
deficit may be important pathologic features of calpainopathy and
possibly represent secondary effects of the absence of calpain-3.
STARD9
| dbSNP name | rs12910030(A,G); rs12911561(T,C); rs116809323(G,C); rs2241998(A,G); rs7164196(T,G); rs144084975(G,T); rs186959564(T,C); rs144343572(C,T); rs116577253(A,C); rs138113203(C,G); rs115827874(C,T); rs80347429(A,G); rs9783683(C,A); rs7168835(T,C); rs79158309(A,G); rs876992(T,C); rs186697829(C,A); rs138430407(C,G); rs143440000(G,A); rs115532536(C,T); rs138770997(C,G); rs10163179(G,C); rs116088885(G,A); rs11070376(G,T); rs78263141(G,T); rs12904010(G,A); rs74714963(C,T); rs11637248(C,G); rs149335396(T,G); rs77171961(G,C); rs148022476(G,A); rs139999040(C,T); rs79147516(A,G); rs6493053(G,A); rs6493054(G,A); rs17767264(C,T); rs76465418(C,A); rs181996302(T,C); rs78898799(G,A); rs72711771(A,T); rs1705360(G,A); rs1667493(C,T); rs184997894(G,A); rs115044157(C,T); rs183580304(T,C); rs75891360(A,C); rs9652417(T,G); rs4923949(A,G); rs479519(T,C); rs74670147(G,A); rs79044457(G,T); rs78366241(C,T); rs114743946(T,C); rs62019322(T,C); rs13379865(C,T); rs17767270(C,T); rs138246348(C,T); rs2899060(G,T); rs78594152(G,A); rs141930037(C,G); rs115058341(A,T); rs138717526(T,C); rs1197546(A,G); rs79994978(T,C); rs11632169(G,A); rs74715782(G,A); rs16973384(T,A); rs4447398(A,C); rs1197547(G,T); rs185003255(G,A); rs630620(T,C); rs115420503(A,T); rs374353102(A,G); rs9972577(C,T); rs9972600(T,C); rs6493055(A,G); rs6493056(G,A); rs114539185(T,G); rs60753136(G,A); rs672054(T,C); rs71474496(A,G); rs11638835(A,G); rs113567591(G,C); rs1705356(T,C); rs142075513(G,A); rs114191253(T,A); rs34117505(C,T); rs7342639(C,T); rs16956932(A,G); rs3099758(T,C); rs623271(A,G); rs1197548(A,G); rs1197549(T,C); rs59881302(G,A); rs10162939(T,A); rs1197550(A,T); rs150192451(C,T); rs145872164(T,G); rs1197551(A,T); rs114793100(A,T); rs1212814(G,C); rs12911585(T,C); rs12594951(A,C); rs35006192(G,A); rs116719583(T,G); rs73406601(T,C); rs34070722(G,A); rs12594855(G,A); rs12594858(G,A); rs12324838(C,T); rs2136903(A,G); rs9920163(G,T); rs12324135(C,T); rs115134206(A,G); rs28736688(G,A); rs73408611(C,T); rs56839966(G,T); rs28699522(G,C); rs62019357(C,T); rs8043143(A,G); rs8043472(A,G); rs73408619(G,C); rs4924690(C,G); rs4924691(T,C); rs4924692(G,A); rs150729042(C,G); rs10400824(C,T); rs71474497(T,C); rs28798437(A,C); rs28823029(G,C); rs28811114(C,T); rs7166373(C,T); rs938047(A,G); rs57298545(A,G); rs7178483(A,G); rs8039711(G,A); rs8039765(C,A); rs8024902(T,G); rs8023743(C,G); rs144819529(A,G); rs34603230(A,G); rs28537072(C,A); rs4545789(A,C); rs149026782(C,T); rs12438056(G,A); rs4923950(A,G); rs2175370(G,A); rs16957011(T,C); rs55651630(A,G); rs9944270(A,T); rs28479391(A,G); rs187495317(G,A); rs16957020(T,C); rs9944248(A,G); rs35738819(G,A); rs73408701(T,A); rs16957031(G,C); rs74012616(A,G); rs12914570(A,G); rs16957037(C,T); rs12323990(C,T); rs7163030(T,C); rs7169202(G,C); rs78994161(C,A); rs16957043(G,A); rs77245532(A,G); rs6493059(A,C); rs28680600(A,G); rs74475031(A,G); rs76594962(T,G); rs16957052(C,T); rs115067542(G,A); rs16957055(C,T); rs115794149(A,G); rs28744617(A,G); rs8030587(G,A); rs8031218(C,T); rs3742995(A,G); rs74009205(C,G); rs3742993(A,G); rs3742992(C,G); rs111336295(C,G); rs16957061(A,G); rs16957063(A,G); rs61750914(C,T); rs58237318(G,T); rs61746531(C,T); rs61753412(A,T); rs78906041(C,T); rs8039346(G,C); rs8039217(C,A); rs113103629(C,T); rs7163324(C,T); rs6493061(C,A); rs78373841(A,G); rs61192504(C,A); rs2136899(A,G); rs145878659(T,C); rs4924694(T,A); rs12592374(A,G); rs113915421(C,T); rs61122145(G,A); rs2136900(A,G); rs2136901(G,A); rs77922743(C,G); rs8028699(T,C); rs8028365(C,T); rs4334272(T,C); rs60723187(C,T); rs12902830(C,T); rs12102055(T,A); rs73410923(C,T); rs116417375(A,G); rs28562951(T,C); rs141270837(A,G); rs8036733(G,T); rs149348057(A,G); rs7176860(G,A); rs12594696(A,G); rs7183487(T,A); rs7182479(G,A); rs12594725(C,G); rs12594724(A,G); rs77336982(C,T); rs7162040(T,C); rs116032750(T,G); rs146410393(C,A); rs73410927(A,G); rs75988797(G,A); rs74477058(C,G); rs35616173(T,C); rs59900882(C,G); rs78562640(A,G); rs57258642(A,T); rs34191150(A,G); rs58938096(G,T); rs12903762(C,A); rs73410937(T,G); rs116360099(G,A); rs9806648(G,A); rs12591415(C,T); rs2412740(T,C); rs28431056(C,T); rs67470909(T,C); rs73410940(G,A); rs2280048(C,A); rs9919994(G,T); rs1058846(C,T); rs3199486(T,C); rs9269(A,G); rs1995939(A,G); rs78325423(G,C); rs8028863(T,G) |
| ccdsGene name | CCDS53935.1 |
| cytoBand name | 15q15.2 |
| EntrezGene GeneID | 57519 |
| EntrezGene Description | StAR-related lipid transfer (START) domain containing 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | STARD9:NM_020759:exon23:c.C10403G:p.P3468R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5696 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9P2P6 |
| dbNSFP Uniprot ID | STAR9_HUMAN |
| dbNSFP KGp1 AF | 0.0105311355311 |
| dbNSFP KGp1 Afr AF | 0.0426829268293 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0101 |
| ESP Afr MAF | 0.020231 |
| ESP All MAF | 0.006135 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.00203 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Photosensitivity;
Freckling;
Telangiectasia;
Dry skin
LABORATORY ABNORMALITIES:
Cells show defective transcription-coupled nucleotide excision repair
(TC-NER) after UV irradiation;
Increased cellular sensitivity to UV light
MISCELLANEOUS:
Onset in infancy;
No predisposition to skin tumor development
MOLECULAR BASIS:
Caused by mutation in the UV-stimulated scaffold protein A gene (UVSSA,
614632.0001)
OMIM Title
*614642 START DOMAIN-CONTAINING PROTEIN 9; STARD9
;;KIAA1300
OMIM Description
DESCRIPTION
STARD9 belongs to the kinesin-3 family of ATPases (see KIF1A; 601255)
involved in transporting vesicles and organelles (Torres et al., 2011).
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned STARD9, which they designated
KIAA1300. The deduced protein contains 1,820 amino acids. RT-PCR ELISA
detected highest STARD9 expression in adult lung. Moderate expression
was detected in all other adult and fetal tissues and adult brain
regions examined except skeletal muscle, which showed low STARD9
expression.
Halama et al. (2006) determined that the 1,820-amino acid STARD9 protein
contains a START lipid-binding domain. By database analysis, they
identified a STARD9 splice variant lacking exon 8. Database analysis
revealed STARD9 orthologs in mammals, chicken, and pufferfish.
By characterizing proteins that copurified with polymerized microtubule
asters and that were required for mitotic progression in HeLa cells,
Torres et al. (2011) identified STARD9. The deduced full-length protein
contains 4,614 amino acids and has a calculated molecular mass of 506.7
kD. The N terminus of full-length STARD9 has a motor domain and an FHA
domain, and the C terminus has a coiled-coil region and a START domain.
The motor domain of STARD9 shares highest similarity with the motor
domains of KIF16B and KIF1A. Torres et al. (2011) identified 2
additional isoforms of STARD9. One, a 323-amino acid protein, lacks 84
N-terminal amino acids of full-length STARD9 that are essential for
ATPase activity. The other, a 292-amino acid protein, is nearly
identical to the N-terminal end of full-length STARD9, but it lacks part
of the motor domain. Torres et al. (2011) found that STARD9 was
expressed at low levels in all tissues examined. Immunohistochemical
analysis of HeLa cells detected STARD9 throughout the nucleus and
cytoplasm in interphase and localized to daughter centrioles from
prophase to late anaphase. STARD9 was not detected during cytokinesis.
Orthologs of STARD9 were found in vertebrates only.
GENE FUNCTION
Torres et al. (2011) found that the isolated motor domain of STARD9
showed ATPase activity and bound microtubules. Mutation analysis
revealed a critical role for thr110 in STARD9 ATPase activity and for
arg223 within the switch-1 region in STARD9 microtubule binding. Both
residues were involved in localization of the motor domain to
centrosomes. Knockdown of STARD9 in HeLa cells via small interfering RNA
led to fragmentation and dissociation of the pericentriolar material,
multipolar spindles, activation of the spindle assembly checkpoint,
mitotic arrest, and apoptosis. Overexpression of the STARD9 motor domain
partially rescued fragmentation of pericentriolar material following
STARD9 depletion. Knockdown of STARD9 had little effect on mitotic
progression or apoptosis in normal cells and in a significant subset of
tumor cell lines. Chemical inhibition of the mitotic regulators CDK1
(116940), PLK1 (602098), and kinesin-5 (KIF11; 602821) and
nocodazole-dependent depolymerization of microtubules reduced
fragmentation of pericentriolar material in STARD9-knockdown cells.
Nocodazole also eliminated localization of STARD9 to centrioles. Torres
et al. (2011) hypothesized that STARD9 stabilizes pericentriolar
material under microtubule-mediated tension during bipolar spindle
assembly and may form a link between the daughter centriole and
pericentriolar material.
GENE STRUCTURE
Halama et al. (2006) determined that the STARD9 gene contains 11 exons.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the STARD9
gene to chromosome 15. Halama et al. (2006) mapped the STARD9 gene to
chromosome 15q15 by genomic sequence analysis.
LCMT2
| dbSNP name | rs7048(A,C); rs514438(T,C); rs3742969(A,G) |
| cytoBand name | 15q15.3 |
| EntrezGene GeneID | 9836 |
| EntrezGene Description | leucine carboxyl methyltransferase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08494 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Limbs];
Ankle contractures
MUSCLE, SOFT TISSUE:
Muscle amyotrophy
NEUROLOGIC:
[Central nervous system];
Delayed motor development (in some patients);
[Peripheral nervous system];
Proximal and distal asymmetric muscle weakness of the upper and lower
limbs;
Gait difficulties;
Frequent falls;
Areflexia;
Decreased motor nerve conduction velocities;
Decreased nerve amplitudes;
Sural nerve biopsy shows axonal loss;
Thinly myelinated nerve fibers;
Onion bulb formation;
De- and remyelination;
Distal sensory impairment
MISCELLANEOUS:
Onset usually in early childhood;
Adult onset may occur;
Variable severity;
Motor impairment more significant than sensory impairment;
Progressive disorder;
Some patients may become wheelchair-bound;
Trauma may accelerate symptoms
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae Fig4 gene (FIG4,
609390.0001)
OMIM Title
*611246 LEUCINE CARBOXYL METHYLTRANSFERASE 2; LCMT2
;;tRNA-WYBUTOSINE-SYNTHESIZING PROTEIN 4, S. CEREVISIAE, HOMOLOG OF;
TYW4;;
tRNA-YW-SYNTHESIZING PROTEIN 4, S. CEREVISIAE, HOMOLOG OF;;
KIAA0547
OMIM Description
DESCRIPTION
Wybutosine (yW) is a hypermodified guanosine at the 3-prime position
adjacent to the anticodon of phenylalanine tRNA that stabilizes
codon-anticodon interactions during decoding on the ribosome. LCMT2 is
the human homolog of a yeast gene essential for yW synthesis (Noma and
Suzuki, 2006).
CLONING
By sequencing clones obtained from a brain cDNA library, Nagase et al.
(1998) cloned LCMT2, which they designated KIAA0547. The transcript
contains several repetitive elements in its 3-prime UTR, and the deduced
protein contains 686 amino acids. RT-PCR detected LCMT2 expression in
kidney only. In vitro-translated LCMT3 had an apparent molecular mass of
61 kD by SDS-PAGE.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the LCMT2 gene
to chromosome 4. However, Hartz (2013) mapped the LCMT2 gene to
chromosome 15q15.3 based on an alignment of the LCMT2 sequence (GenBank
GENBANK AF265443) with the genomic sequence (GRCh37).
HYPK
| dbSNP name | rs12702(T,C); rs143593239(T,G); rs482124(A,G) |
| ccdsGene name | CCDS10104.1 |
| cytoBand name | 15q15.3 |
| EntrezGene GeneID | 100529067 |
| EntrezGene Symbol | SERF2-C15ORF63 |
| snpEff Gene Name | C15orf63 |
| EntrezGene Description | SERF2-C15orf63 readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | HYPK:NM_016400:exon4:c.T313C:p.S105P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NX55 |
| dbNSFP Uniprot ID | HYPK_HUMAN |
| dbNSFP KGp1 AF | 0.212454212454 |
| dbNSFP KGp1 Afr AF | 0.319105691057 |
| dbNSFP KGp1 Amr AF | 0.187845303867 |
| dbNSFP KGp1 Asn AF | 0.304195804196 |
| dbNSFP KGp1 Eur AF | 0.0857519788918 |
| dbSNP GMAF | 0.213 |
| ESP Afr MAF | 0.262511 |
| ESP All MAF | 0.151709 |
| ESP Eur/Amr MAF | 0.095044 |
| ExAC AF | 0.134 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Iris hypoplasia, partial;
[Teeth];
Defective enamel development
MUSCLE, SOFT TISSUE:
Muscular hypotonia;
Myopathy, nonprogressive
HEMATOLOGY:
Hemolytic anemia, autoimmune;
Thrombocytopenia
IMMUNOLOGY:
Recurrent bacterial infections;
Susceptibility to infection with human herpesvirus;
Lymphadenopathy;
Impaired T cell activation;
Impaired T cell proliferative response;
Normal lymphocyte counts;
Normal serum immunoglobulin levels;
Impaired seroconversion of immunoglobulins in response to vaccination;
Decreased T cell production of cytokines
METABOLIC FEATURES:
Intermittent fever
NEOPLASIA:
Kaposi sarcoma (1 patient)
MISCELLANEOUS:
One family with 3 patients and 1 patient with sporadic disease have
been reported (last curated June 2011)
MOLECULAR BASIS:
Caused by mutation in the stromal interaction molecule 1 gene (STIM1,
605291.0001)
OMIM Title
*612784 HUNTINGTIN-INTERACTING PROTEIN K
;;HUNTINGTIN YEAST 2-HYBRID PROTEIN K; HYPK
OMIM Description
CLONING
Huntington disease (HD; 143100) is caused by expansion of a CAG
trinucleotide repeat encoding an N-terminal polyglutamine region in
huntingtin (HTT; 613004) to more than 34 units. Using N-terminal domains
of HTT containing 58 or 62 glutamines in a yeast 2-hybrid assay of a
testis cDNA library, Faber et al. (1998) obtained a partial HYPK clone.
By PCR of a Burkitt B-cell lymphoma cell line, Raychaudhuri et al.
(2008) cloned full-length HYPK.
GENE FUNCTION
By coexpressing human proteins in a mouse neuroblastoma cell line,
Raychaudhuri et al. (2008) showed that HYPK interacted with the isolated
N-terminal region of human huntingtin containing either 16 (H16) or 40
(H40) glutamines. Coexpression of HYPK reduced H40 aggregate formation
and H40-induced apoptosis. Purified recombinant HYPK showed
chaperone-like activity in vitro against temperature-induced protein
aggregates and in vivo against heat-denatured proteins. In cells
expressing HYPK and H40, the chaperone-like activity of HYPK against
other protein substrates was reduced compared with cells expressing HYPK
and H16, apparently due to interaction of HYPK with H40 protein
aggregates.
MAPPING
Hartz (2009) mapped the HYPK gene to chromosome 15q15.3 based on an
alignment of the HYPK sequence (GenBank GENBANK AF049613) with the
genomic sequence (build 36.1).
GATM-AS1
| dbSNP name | rs7164602(A,G); rs12441971(A,T) |
| cytoBand name | 15q21.1 |
| EntrezGene GeneID | 145663 |
| snpEff Gene Name | GATM |
| EntrezGene Description | GATM antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | upstream |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4605 |
FLJ10038
| dbSNP name | rs28534445(T,C); rs28715646(T,C); rs1645(G,A); rs6493430(T,C); rs75175518(T,G); rs192288316(A,T); rs526045(G,T); rs78137202(A,T); rs526952(G,A) |
| cytoBand name | 15q21.2 |
| EntrezGene GeneID | 55056 |
| snpEff Gene Name | GABPB1 |
| EntrezGene Description | uncharacterized protein FLJ10038 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1455 |
GABPB1-AS1
| dbSNP name | rs504781(T,C); rs12903381(C,T); rs79608599(G,C); rs535648(T,C); rs79817635(C,T); rs12440601(G,T); rs489345(A,G) |
| cytoBand name | 15q21.2 |
| EntrezGene GeneID | 100129387 |
| snpEff Gene Name | GABPB1 |
| EntrezGene Description | GABPB1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2828 |
MIR4712
| dbSNP name | rs145291446(G,A) |
| cytoBand name | 15q21.2 |
| EntrezGene GeneID | 100616396 |
| snpEff Gene Name | GABPB1 |
| EntrezGene Description | microRNA 4712 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01423 |
| ExAC AF | 0.002699 |
USP8
| dbSNP name | rs62016939(A,G); rs7174015(G,A); rs34659874(T,C); rs114284805(A,G); rs62016940(A,G); rs12593481(T,C); rs7164347(T,C); rs2414045(T,C); rs150688202(T,C); rs4775883(A,T); rs62016942(G,A); rs74808657(A,C); rs4775884(C,T); rs77350454(G,C); rs11637111(C,T); rs62016943(C,T); rs72738959(C,T); rs4775885(G,T); rs4775886(C,T); rs144452093(T,C); rs62016944(G,A); rs934636(C,G); rs28698226(A,G); rs11070774(C,T); rs77610324(C,A); rs62016947(T,C); rs72738960(T,C); rs11632823(C,G); rs116762390(G,C); rs11070775(T,C); rs145377993(T,C); rs140893062(A,T); rs114633178(T,C); rs2414044(A,G); rs8041096(C,T); rs2414043(G,A); rs185864874(A,T); rs111400168(C,A); rs79359532(T,G); rs4318151(A,G); rs28582911(G,A); rs61565615(A,G); rs8034080(T,A); rs8032743(A,G); rs3131575(T,G); rs11632697(G,C); rs11632708(C,T); rs11633765(A,G); rs62019075(G,A); rs62019076(A,G); rs62019077(A,G); rs62019078(G,A); rs62019079(T,C); rs78203651(G,A); rs62019080(G,A); rs11070776(G,A); rs113143102(C,T); rs7182980(T,C); rs7182569(G,A); rs114863477(T,C); rs8026653(G,C); rs11070777(G,A); rs11070778(G,A); rs189412966(T,C); rs112357967(G,A); rs111436258(T,C); rs3098203(A,G); rs3131574(C,A); rs115038379(A,G); rs116749090(C,T); rs28642809(A,G); rs3098205(G,T); rs8037446(G,A); rs11634832(G,T); rs115427652(C,G); rs11070779(A,G); rs4774569(A,G); rs4774570(A,G); rs4774571(A,G); rs114535846(T,C); rs62019082(A,C); rs4775888(C,T); rs56396299(G,T); rs138813527(C,G); rs72738970(G,A); rs17519466(T,G); rs149503531(G,A); rs7165464(T,C); rs112886078(C,T); rs3098167(T,C); rs3098168(T,C); rs113853662(A,G); rs138826675(C,T); rs3131572(C,G); rs151267564(C,T); rs62019084(G,A); rs112025890(G,C); rs3098169(G,A); rs75098660(C,G); rs11631351(C,G); rs11631398(C,T); rs7168783(G,A); rs7169778(T,C); rs7170114(T,G); rs3131570(C,T); rs115560072(A,G); rs10519276(C,G); rs11070780(G,A); rs11070781(G,A); rs3131568(C,T); rs3131567(A,T); rs11070784(T,C); rs3131566(T,C); rs11637104(A,G); rs4380013(G,A); rs115175485(A,G); rs28840973(C,G); rs62019085(G,A); rs12440152(G,C); rs139096022(G,C); rs3131565(A,C); rs17597852(C,T); rs59818085(T,C); rs8035522(C,T); rs8035874(C,T); rs11638198(G,A); rs3131563(A,T); rs62019087(C,T); rs140140027(C,T); rs141726541(G,A); rs12439248(G,A); rs11633624(A,G); rs76391301(T,C); rs188511320(C,T); rs11070785(T,G); rs17645209(T,C); rs3098171(C,G); rs11630309(C,T); rs182359233(A,T); rs11070786(A,G); rs11070787(C,T); rs11070788(C,T); rs77598376(A,T); rs3131562(C,T); rs3098172(A,G); rs78169455(G,A); rs8030373(A,T); rs12050594(A,T); rs75527469(A,G); rs17597915(T,C); rs56398519(A,G); rs3131561(G,A); rs115970610(G,A); rs11633608(G,A); rs145427358(T,C); rs3131560(T,C); rs140614522(A,G); rs10220843(T,C); rs4775889(A,G); rs76646760(A,G); rs149289926(T,C); rs7494907(G,A); rs3098174(C,T); rs62019112(G,A); rs3131559(C,A); rs138748971(C,T); rs3098176(T,A); rs79805520(T,C); rs2289108(G,A); rs116672818(T,C); rs11638390(A,G); rs77448434(C,G); rs72738977(T,G); rs3098177(G,A); rs115404312(G,A); rs114424214(C,T); rs28648524(A,T); rs12903031(T,G); rs3784300(A,G); rs17598061(T,G); rs16963744(T,G); rs17645290(T,C); rs62019113(C,T); rs143062357(G,A); rs3098179(T,G); rs3098180(T,G); rs11637031(A,G); rs10519278(A,T); rs8037553(A,G); rs62019114(G,T); rs62019115(A,G); rs139134291(A,G); rs75814199(C,G) |
| ccdsGene name | CCDS53944.1 |
| cytoBand name | 15q21.2 |
| EntrezGene GeneID | 373509 |
| EntrezGene Symbol | USP50 |
| snpEff Gene Name | USP50 |
| EntrezGene Description | ubiquitin specific peptidase 50 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | USP50:NM_203494:exon7:c.G962C:p.G321A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6843 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0284552845528 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.020613 |
| ESP All MAF | 0.006581 |
| ESP Eur/Amr MAF | 0.000122 |
| ExAC AF | 1.706e-03,1.641e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Strabismus
NEUROLOGIC:
[Central nervous system];
Axial hypotonia;
Psychomotor retardation;
Areflexia;
Seizures;
Ataxia
HEMATOLOGY:
Factor XI deficiency
LABORATORY ABNORMALITIES:
Elevated serum transaminases during infections;
Abnormal isoelectric focusing of serum transferrin (type 1 pattern);
Dolichyl-P-Glc:Man(9)GlcNAc(2)-PP-dolichyl glucosyltransferase deficiency;
Decreased serum cholesterol;
Decreased factor XI;
Decreased antithrombin III;
Decreased protein C
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae Alg6 gene (ALG6,
604566.0001)
OMIM Title
*603158 UBIQUITIN-SPECIFIC PROTEASE 8; USP8
;;DEUBIQUITINATING ENZYME HUMORF8; HUMORF8
USP8/PIK3R2 FUSION GENE, INCLUDED
OMIM Description
CLONING
During analysis of randomly sampled human coding sequences from the
myeloid cell line KG-1, Nomura et al. (1994) identified a novel cDNA,
which they referred to as KIAA0055, that was related to the tre2
oncogene. Janssen et al. (1998) found that HUMORF8 encodes a putative
deubiquitinating enzyme.
GENE FUNCTION
- Fusion Gene
Janssen et al. (1998) analyzed DNA from a patient with chronic
myeloproliferative disorder. They identified an oncogenic fusion of the
5-prime end of p85-beta (603157) with the 3-prime end of HUMORF8.
MOLECULAR GENETICS
For discussion of a possible association between variation in the USP8
gene and spastic paraplegia, see 603158.0001.
MYO5C
| dbSNP name | rs4776016(G,A); rs4776017(G,A); rs4776018(G,T); rs62016465(G,A); rs11639108(A,T); rs62016466(G,A); rs4776019(C,T); rs3794548(C,T); rs16964770(T,C); rs79420691(C,T); rs11070884(G,A); rs74940475(A,G); rs11070885(A,G); rs11632189(G,C); rs11632174(A,G); rs8031893(A,T); rs11638716(T,C); rs1011050(C,T); rs1011051(G,A); rs34276836(T,C); rs2278295(T,C); rs2278296(C,T); rs35277595(A,G); rs3751608(C,T); rs3794550(A,G); rs4238388(A,G); rs3794551(T,C); rs3794552(G,A); rs71472930(G,A); rs6493546(C,T); rs11636051(T,G); rs4145158(T,G); rs34212289(T,G); rs3751609(C,T); rs4774612(C,T); rs28408301(A,G); rs28454152(T,C); rs192746979(G,C); rs4405491(G,A); rs4405492(G,T); rs115170131(T,C); rs12915773(T,C); rs11070886(C,A); rs11070887(A,C); rs11070888(T,C); rs28730328(C,T); rs12906784(C,T); rs10851509(G,A); rs11631002(T,A); rs4776022(C,G); rs62623565(C,T); rs12148073(G,A); rs8042218(A,T); rs8023465(T,C); rs8043150(G,A); rs3794553(C,T); rs7180204(C,T); rs4371107(C,T); rs6493547(G,A); rs114559587(C,T); rs8030407(G,A); rs8030428(G,A); rs8031357(G,A); rs8031089(A,G); rs6493549(T,C); rs8031858(G,C); rs77927485(G,A); rs2001857(G,A); rs2001858(C,T); rs58097559(A,G); rs4776023(G,C); rs4776024(A,C); rs7183588(G,A); rs17707007(T,C); rs11635028(A,G); rs59941481(A,G); rs4776025(C,T); rs62014635(C,T); rs4776026(G,A); rs4774613(T,C); rs4774614(G,T); rs4774615(G,A); rs35350036(T,A); rs3751631(G,A); rs7165256(T,G); rs116354172(C,T); rs55850227(A,G); rs10152383(G,A); rs4774616(G,A); rs10152377(C,T); rs56066716(T,A); rs6493550(T,C); rs8042385(A,G); rs41504447(A,C); rs10163109(C,T); rs55870025(C,A); rs4600419(G,C); rs7168434(C,T); rs4776027(C,T); rs4776028(G,A); rs142375939(T,G); rs11070889(A,G); rs139233116(T,C); rs9920688(A,G); rs77015977(T,C); rs4238389(T,C); rs4316698(C,T); rs3751630(T,G); rs117867197(A,C); rs7182505(A,T); rs7165320(G,C); rs74455958(C,T); rs4776029(C,T); rs4776030(G,A); rs79134753(A,C); rs4627279(T,C); rs113440839(C,T); rs8043194(A,G); rs4145157(C,G); rs186605169(A,G); rs8034613(C,T); rs4257157(T,C); rs4278685(A,C); rs10851510(G,A); rs7172236(T,A); rs11638448(C,G); rs4496072(C,A); rs4497629(C,G); rs75932126(G,A); rs4774617(C,T); rs7169177(T,C); rs4776031(C,A); rs11070890(A,G); rs10851511(C,A); rs4776032(A,G); rs4776033(T,C); rs4448882(T,C); rs7171825(T,C); rs7172026(T,A); rs7175945(C,T); rs9646201(C,T); rs11070891(T,C); rs11637680(T,C); rs7169271(T,A); rs3751629(T,C); rs4608282(C,T); rs113477375(C,T); rs6493551(T,C); rs7165061(T,C); rs111608590(C,T); rs4776034(C,G); rs61058363(C,T); rs66714926(T,A); rs55763365(T,C); rs11854890(G,A); rs3751626(T,A); rs28714255(C,T); rs79129232(C,G); rs17650694(C,G); rs8024131(T,A); rs16964849(C,G); rs79585796(C,T); rs78359326(G,A); rs7161988(C,T); rs7162691(G,A); rs7162229(A,C); rs75976000(C,G); rs17650718(C,G); rs7175663(G,A); rs7175545(C,T); rs191237689(A,G); rs8040562(A,C); rs3751624(C,T); rs79170904(T,C); rs79748106(G,A); rs28523395(T,G); rs116379066(T,C); rs28776010(T,C); rs62015972(A,G); rs149615780(G,A); rs76373107(A,T); rs148748000(T,C); rs75653920(G,C); rs77524459(G,A); rs79043101(G,A); rs78695709(G,A); rs12907952(C,T); rs12592927(T,C); rs78325121(C,T); rs28714155(C,A); rs12898879(G,A); rs73406657(A,G); rs12904985(G,A); rs142158145(G,A); rs11070892(G,A); rs35982476(C,T); rs146454988(C,T); rs76536089(G,A); rs4238390(A,T); rs7178838(G,T); rs61036537(T,G); rs4442751(C,G); rs116257540(A,G); rs78175543(C,G); rs5002319(A,G) |
| ccdsGene name | CCDS42036.1 |
| cytoBand name | 15q21.2 |
| EntrezGene GeneID | 55930 |
| EntrezGene Description | myosin VC |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO5C:NM_018728:exon10:c.C1199T:p.A400V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6281 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NQX4 |
| dbNSFP Uniprot ID | MYO5C_HUMAN |
| dbNSFP KGp1 AF | 0.0114468864469 |
| dbNSFP KGp1 Afr AF | 0.0508130081301 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.028292 |
| ESP All MAF | 0.009336 |
| ESP Eur/Amr MAF | 0.00024 |
| ExAC AF | 0.002629 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Pancreas];
Islet cell hyperplasia, diffuse
NEUROLOGIC:
[Central nervous system];
Loss on consciousness due to hypoglycemia;
Seizures, hypoglycemic
ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia
LABORATORY ABNORMALITIES:
Hypoglycemia;
Hyperinsulinemia;
Exercise-induced hyperinsulinism;
Pyruvate-induced insulin secretion
MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 16, member 1 gene
(SLC16A1, 600682.0003)
OMIM Title
*610022 MYOSIN VC; MYO5C
OMIM Description
CLONING
Using EST database analysis followed by PCR amplification of human
pancreas cDNA, Rodriguez and Cheney (2002) identified a new myosin V
family member that they named MYO5C. The MYO5C gene encodes a
1,742-amino acid protein with a predicted molecular mass of 203 kD that
shares approximately 50% identity with family members MYO5A (160777) and
MYO5B (606540). The MYO5C protein consists of a motor domain followed by
6 IQ motifs, a coiled-coil region, and a C-terminal globular domain.
MYO5C contains a serine residue conserved among all 3 class V myosins
whose phosphorylation in MYO5A regulates melanosome binding; however,
MYO5C does not contain the PEST region present in MYO5A and MYO5B.
Northern and dot blot analyses showed expression of an 8.7-kb MYO5C
transcript in salivary gland, stomach, colon, pancreas, lung, thyroid,
prostate, and mammary gland. Immunolocalization in mouse tissues
detected abundant Myo5c protein expression in pancreas, colon, and
stomach. Myo5c was found specifically in the apical regions of
intestinal epithelial cells and in exocrine pancreas.
GENE FUNCTION
Rodriguez and Cheney (2002) demonstrated, by overexpression of a
dominant-negative MYO5C tail construct in HeLa cells, that MYO5C
colocalizes with and perturbs a membrane compartment containing the
transferrin receptor (TFRC; 190010) and RAB8 (165040). Pulse-chase
experiments showed that overexpression of MYO5C also disrupts TFRC
trafficking.
GENE STRUCTURE
Using genomic sequence analysis, Rodriguez and Cheney (2002) determined
that the MYO5C gene consists of at least 39 exons and spans more than
100 kb.
MAPPING
Rodriguez and Cheney (2002) mapped the MYO5C gene to chromosome 15q21,
immediately adjacent to MYO5A, by genomic sequence analysis.
PRTG
| dbSNP name | rs12595448(G,C); rs617137(T,C); rs530798(G,A); rs74017540(T,C); rs12905395(A,G); rs3910565(T,C); rs491014(T,C); rs28523366(T,C); rs28607098(T,C); rs115376600(T,C); rs183155454(T,C); rs541656(T,C); rs956840(T,C); rs766865(A,T); rs9920740(C,T); rs2579033(G,A); rs2251001(T,C); rs4307895(G,A); rs16976432(T,C); rs7173180(G,T); rs1659301(C,T); rs77957184(C,T); rs72748421(C,T); rs111640775(G,A); rs62017965(G,C); rs654844(C,G); rs12591646(T,G); rs11639131(G,A); rs28657920(C,T); rs140054441(T,G); rs7165971(T,C); rs28379390(G,T); rs34646495(G,C); rs79553549(C,T); rs16976436(C,T); rs576113(G,A); rs35675847(T,C); rs581287(T,C); rs636050(G,A); rs638786(T,C); rs4774796(G,A); rs71476736(T,C); rs71476737(C,T); rs77020617(T,C); rs4453409(G,A); rs4601983(T,C); rs4238317(G,C); rs7182068(T,G); rs7180772(C,T); rs12917213(G,A); rs1659297(T,C); rs558290(T,C); rs7164393(C,T); rs59647323(T,G); rs28515086(T,A); rs113411227(G,C); rs72748427(A,G); rs28398229(T,C); rs720509(C,T); rs489672(A,T); rs11638787(C,G); rs181724879(T,C); rs4561398(T,C); rs2576934(T,C); rs1659296(C,G); rs1550326(G,T); rs12902393(T,C); rs145306396(C,T); rs28512199(G,C); rs28399707(C,T); rs601062(C,T); rs72748431(T,A); rs12903208(G,A); rs71476738(G,C); rs8027131(G,A); rs13380218(G,C); rs7176818(A,G); rs8037501(G,A); rs113282697(T,C); rs73421398(T,C); rs74482405(A,G); rs183566555(C,T); rs79066867(G,C); rs934886(A,G); rs78176351(C,A); rs8038564(A,T); rs8038744(A,G); rs2414423(C,G); rs62017992(T,C); rs674899(C,T); rs4774797(G,C); rs492363(A,G); rs572531(G,A); rs9920076(T,A); rs9920246(A,G); rs9920262(C,A); rs7165778(A,T); rs7166952(C,A); rs74360451(G,C); rs7171318(A,C); rs7171683(C,T); rs7171522(A,G); rs7171834(C,T); rs9920546(C,T); rs7178379(G,A); rs1438918(T,C); rs28557162(C,T); rs79523867(T,C); rs10851589(C,T); rs11071200(C,A); rs4774798(T,A); rs7164032(G,A); rs4774799(C,T); rs4774800(C,T); rs12438177(A,G); rs56233400(T,A); rs10518817(A,T); rs113659285(T,C); rs7162504(T,A); rs8027291(A,T); rs148075284(C,T); rs8034113(G,C); rs115830288(C,T); rs79776102(C,T); rs76656344(A,C); rs2053335(G,A); rs4337238(T,A); rs12903822(T,C); rs73423329(C,T); rs28576513(C,T); rs4392003(A,C); rs16976450(A,G); rs8032175(G,C); rs73423335(A,T); rs76847262(A,C); rs73408312(T,C); rs2196774(C,T); rs4774219(C,T); rs4774220(G,A); rs7167185(A,G); rs114661974(T,C); rs589335(C,T); rs7167804(A,T); rs4412917(G,A); rs28556884(T,C); rs62043869(T,C); rs6493805(T,G); rs79485212(C,A); rs8025445(C,A); rs529451(C,T); rs189609172(C,T); rs8030790(A,G); rs2118781(T,C); rs12373006(G,A); rs143800886(G,T); rs11854213(A,G); rs137887360(G,A); rs145317541(T,C); rs7179697(A,T); rs116430831(A,G); rs28620386(A,G); rs576456(A,G); rs16976466(T,C); rs34303822(T,G); rs147402073(T,A); rs16976467(T,C); rs11852298(A,G); rs28621834(C,T); rs75842275(T,C); rs143863174(G,A); rs78081590(A,C); rs28481986(C,T); rs74399124(C,T); rs73408332(C,T); rs28428526(A,C); rs62043871(C,T); rs77735641(A,G); rs16976472(G,C); rs7162879(T,A); rs142831024(C,T); rs1014551(T,C); rs1344957(G,C); rs1986012(T,C); rs66810538(T,C); rs573005(C,T); rs112310748(A,G); rs11852746(T,C); rs12899976(A,C); rs687128(A,C); rs1550330(C,T); rs9920680(T,C); rs1011061(A,G); rs8026215(T,C); rs368148702(G,A); rs59820715(A,G); rs16976479(A,G); rs75577582(T,C); rs8031192(G,A); rs28664233(C,T); rs10851590(C,T); rs1530087(G,A); rs72750515(G,A); rs76302043(G,A); rs149682916(A,G); rs79231255(G,A); rs74406062(T,G); rs7162071(T,G); rs75265381(A,G); rs76472232(T,G); rs8043521(C,T); rs117572622(C,T); rs1657953(A,C); rs12594642(T,C); rs149601382(A,T); rs1371056(T,G); rs689571(G,A); rs74365454(G,A); rs79265627(C,T); rs9672390(A,T); rs3985768(A,T); rs151047948(C,T); rs11857453(G,T); rs12908813(C,T); rs11857467(C,G); rs11858195(A,C); rs7178114(G,C); rs28534646(T,C); rs2414424(C,T); rs4774802(T,C); rs62043872(C,T); rs9673006(G,A); rs146432276(T,C); rs9673000(C,T); rs7164194(T,C); rs2263952(C,A); rs77837244(C,T); rs12907892(T,C); rs10851591(A,G); rs6493809(A,G); rs8042029(G,A); rs74365936(C,A); rs28637460(C,T); rs190684422(A,G); rs77360292(A,G); rs2414426(C,G); rs2414427(T,A); rs116360825(T,C); rs75576399(T,C); rs12439011(C,T); rs8032300(C,A); rs2008336(C,T); rs2250529(T,C); rs144600072(T,C); rs138532811(G,A); rs2414428(T,C); rs141587717(T,C); rs999303(T,C); rs80005828(T,C); rs2433761(G,A); rs715321(A,T); rs12908232(A,G); rs2917839(C,T); rs28524503(A,C); rs2576936(G,C); rs143465394(A,C); rs16976489(T,C); rs2917840(A,G); rs28489760(C,T); rs7161967(G,T); rs62043904(T,C); rs4774803(T,A); rs28626962(G,A); rs56190205(C,A); rs144258555(C,T); rs8034414(C,T); rs146632322(T,A); rs55874929(T,C); rs56220110(G,A); rs12903239(T,C); rs2556571(T,C); rs2912800(T,A); rs149046382(T,C); rs12442165(T,C); rs2246271(A,G); rs4377101(T,C); rs150923499(C,T); rs4774806(T,A); rs8028880(T,C); rs149524464(C,A); rs12915423(C,T); rs12901963(T,C); rs79539321(T,C); rs76925378(T,C); rs12592192(G,A); rs147782215(G,C); rs6493810(G,T); rs6493811(G,A); rs6493812(C,T); rs75761038(C,T); rs7181212(A,C); rs9919969(C,T); rs12591246(T,C); rs6493813(C,T); rs11071203(T,C); rs144298027(C,T); rs8037136(C,T); rs7180112(T,C); rs8023911(T,C); rs11630141(G,T); rs28575567(C,T); rs77995643(C,G); rs11853533(C,T); rs80329464(G,T); rs77511927(C,A); rs11857271(T,C); rs12907772(T,C); rs28485308(T,C); rs4774222(T,C); rs2414431(T,G); rs11071204(A,G); rs6493814(G,A); rs12442771(A,G); rs57782071(T,C); rs10152116(G,A); rs76058251(G,A); rs77118243(G,A); rs7182733(G,A); rs12438394(G,A); rs12905693(T,C) |
| ccdsGene name | CCDS42040.1 |
| cytoBand name | 15q21.3 |
| EntrezGene GeneID | 283659 |
| EntrezGene Description | protogenin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRTG:NM_173814:exon8:c.C1256T:p.P419L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8399 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2VWP7 |
| dbNSFP Uniprot ID | PRTG_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Achromatic retinal patches;
Retinal astrocytoma;
Optic gliomas;
[Mouth];
Pitted dental enamel;
Gingival fibroma
CARDIOVASCULAR:
[Heart];
Wolf-Parkinson-White syndrome;
Cardiac rhabdomyoma
RESPIRATORY:
[Lung];
Lymphangiomyomatosis, rare
GENITOURINARY:
[Kidneys];
Renal cysts;
Tumors of the kidney (may progress to malignancy in less than 2%)
SKELETAL:
Cystic areas of bone rarefaction, esp. phalanges
SKIN, NAILS, HAIR:
[Skin];
Facial angiofibroma (adenoma sebaceum);
White ash leaf-shaped macules;
Shagreen patch;
Subcutaneous nodules;
Cafe-au-lait spots;
Subungual fibromata
NEUROLOGIC:
[Central nervous system];
Hamartomatous lesions of the brain;
Subependymal nodules;
Cortical tubers;
Infantile spasms;
Seizures;
Mental retardation (30%);
Learning difficulties;
Intracranial calcification by x-ray or CT;
[Behavioral/psychiatric manifestations];
Attention deficit disorder;
Hyperactivity;
Autism
ENDOCRINE FEATURES:
Precocious puberty;
Hypothyroidism
NEOPLASIA:
Myocardial rhabdomyoma;
Multiple bilateral renal angiomyolipoma;
Ependymoma;
Renal carcinoma;
Giant cell astrocytoma;
Chordoma;
Benign tumors of the eye, heart, and lungs
LABORATORY ABNORMALITIES:
Increased frequency of premature centromere disjunction (PCD) in cultured
fibroblasts, esp. chromosome 3;
Allelic loss on 16p13.3 in angiomyolipoma, cardiac rhabdomyoma, cortical
tuber, and giant cell astrocytoma
MISCELLANEOUS:
Genetic heterogeneity (see 191100);
Many studies have reported that the phenotype of tuberous sclerosis-2
(TSC2) is more severe than that of tuberous sclerosis-1 (e.g., lower
IQ, more seizures, more macules, cust-like cortical tubers);
Highly variable phenotype;
One-third of cases are familial;
Majority of cases are sporadic;
Prevalence of 1 in 6,000 to 1 in 10,000;
Frequent new mutations (~60%) and/or gonadal mosaicism in TSC2
MOLECULAR BASIS:
Caused by mutation in the tuberin gene (TSC2, 191092.0001)
OMIM Title
*613261 PROTOGENIN, CHICKEN, HOMOLOG OF; PRTG
OMIM Description
CLONING
Toyoda et al. (2005) cloned chicken protogenin and identified the mouse
and human orthologs by database analysis. Chicken protogenin contains
1,187 amino acids and has an extracellular domain, followed by 4
immunoglobulin domains and 5 fibronectin type III domains. In situ
hybridization showed that expression of chicken protogenin was prominent
between embryonic days 1 and 3 and subsequently declined. Transcripts
localized to early mesodermal cells, the neuroepithelial cell layer of
brain and trunk neural tube, the neural layer of retina, and in the
epithelial somite and dermomyotome.
MAPPING
By genomic sequence analysis, Toyoda et al. (2005) mapped the human PRTG
gene to chromosome 15q21.3. They mapped the mouse Prtg gene to a region
of chromosome 9C that shares homology of synteny with human chromosome
15q21.3.
HSP90AB4P
| dbSNP name | rs2052804(A,C); rs2052805(A,G); rs7179724(G,C); rs7161889(G,C); rs7163162(T,A); rs12437998(G,C); rs12437955(C,T); rs139846838(A,G); rs4774310(T,G); rs112635599(G,A); rs112565809(C,T) |
| ccdsGene name | CCDS10167.1 |
| cytoBand name | 15q21.3 |
| EntrezGene GeneID | 664618 |
| snpEff Gene Name | AC091046.1 |
| EntrezGene Description | heat shock protein 90kDa alpha (cytosolic), class B member 4, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2787 |
FOXB1
| dbSNP name | rs62013139(G,C); rs75582291(G,A) |
| cytoBand name | 15q22.2 |
| EntrezGene GeneID | 27023 |
| EntrezGene Description | forkhead box B1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1809 |
MIR8067
| dbSNP name | rs148376400(G,C) |
| cytoBand name | 15q22.2 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
| ExAC AF | 0.0007463 |
FBXL22
| dbSNP name | rs3934552(T,G); rs3934553(G,A) |
| cytoBand name | 15q22.31 |
| EntrezGene GeneID | 283807 |
| EntrezGene Description | F-box and leucine-rich repeat protein 22 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3531 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEMATOLOGY:
High blood oxygen saturation of hemoglobin (10% higher mean than the
lowest values of population studied)
OMIM Title
*609088 F-BOX AND LEUCINE-RICH REPEAT PROTEIN 22; FBXL22
;;FBL22
OMIM Description
DESCRIPTION
Members of the F-box protein family, such as FBXL22, are characterized
by an approximately 40-amino acid F-box motif. SCF complexes, formed by
SKP1 (601434), cullin (see CUL1; 603134), and F-box proteins, act as
protein-ubiquitin ligases. F-box proteins interact with SKP1 through the
F box, and they interact with ubiquitination targets through other
protein interaction domains (Jin et al., 2004).
CLONING
Jin et al. (2004) reported that the FBXL22 protein contains an F-box in
its N-terminal half and 3 tandem leucine-rich repeats in its C-terminal
half.
MAPPING
Jin et al. (2004) stated that the FBXL22 gene maps to chromosome 15q22.1
and the mouse Fbxl22 gene maps to chromosome 9C.
KBTBD13
| dbSNP name | rs12901617(T,C); rs2946643(C,T); rs12905499(A,G) |
| cytoBand name | 15q22.31 |
| EntrezGene GeneID | 390594 |
| snpEff Gene Name | RASL12 |
| EntrezGene Description | kelch repeat and BTB (POZ) domain containing 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3701 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
Contractures, late-onset;
[Spine];
Lumbar lordosis
MUSCLE, SOFT TISSUE:
Muscular dystrophy, limb-girdle;
Proximal muscle weakness;
Generalized muscle weakness;
Muscle atrophy;
Gowers sign;
Difficulty climbing stairs, running, jumping;
Muscle biopsy shows dystrophic features
NEUROLOGIC:
[Central nervous system];
Delayed motor development
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset in early childhood;
Rapid progression in adolescence;
Adults may lose ability to walk
MOLECULAR BASIS:
Caused by mutation in the plectin 1 gene (PLEC1, 601282.0010)
OMIM Title
*613727 KELCH REPEAT AND BTB/POZ DOMAINS-CONTAINING PROTEIN 13; KBTBD13
OMIM Description
CLONING
By searching a region of chromosome 15 linked to nemaline myopathy
(NEM6; 609273), followed by RT-PCR of skeletal muscle RNA, Sambuughin et
al. (2010) cloned KBTBD13. The deduced 458-amino acid protein has a
calculated molecular mass of 49 kD. KBTBD13 has an N-terminal BTB/POZ
domain, followed by a central alpha-helical linker region and a
C-terminal Kelch repeat domain that contains 5 repeats and is predicted
to form a beta-propeller structure. Northern blot analysis detected a
3.5-kb KBTBD13 transcript in skeletal muscle. RT-PCR of mouse tissues
detected Kbtbd13 in skeletal muscle, heart, and lung, with very low
expression in other tissues examined. Epitope-tagged KBTBD13 localized
in a punctate cytoplasmic distribution in transfected C2C12 mouse
myotubes and embryonic mouse cardiomyocytes.
GENE STRUCTURE
Sambuughin et al. (2010) determined that the KBTBD13 gene contains a
single exon.
MAPPING
By genomic sequence analysis, Sambuughin et al. (2010) mapped the
KBTBD13 gene to chromosome 15q22.31.
MOLECULAR GENETICS
In affected members of 4 unrelated families with nemaline myopathy-6
(NEM6; 609273), Sambuughin et al. (2010) identified heterozygous
mutations in the KBTBD13 gene (613727.0001 and 613727.0002). Another
patient with sporadic disease carried a third heterozygous mutation
(613727.0003).
SNAPC5
| dbSNP name | rs73471759(G,A); rs62011877(C,T); rs35596743(G,A); rs12594835(T,C); rs537(C,T); rs60178804(C,T); rs144457652(A,G); rs12909581(C,T); rs12909967(G,A); rs114398553(T,C); rs143176301(T,A); rs151153879(C,T) |
| ccdsGene name | CCDS10217.1 |
| cytoBand name | 15q22.31 |
| EntrezGene GeneID | 10302 |
| EntrezGene Description | small nuclear RNA activating complex, polypeptide 5, 19kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SNAPC5:NM_006049:exon1:c.G34A:p.E12K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5208 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75971 |
| dbNSFP Uniprot ID | SNPC5_HUMAN |
| ExAC AF | 8.620e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CHEST:
[Ribs and sternum];
Pectus carinatum;
Pectus excavatum
SKELETAL:
[Limbs];
[Hands];
Preaxial polydactyly;
Bifid thumb;
Triphalangeal thumb;
Soft tissue syndactyly between all fingers (in 1 family);
[Feet];
Soft tissue syndactyly between all toes (in 1 family);
Preaxial polydactyly
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate (in 1 patient)
MISCELLANEOUS:
Variable phenotype;
F syndrome (102510) has many overlapping features;
Two families reported (last curated September 2012)
OMIM Title
*605979 SMALL NUCLEAR RNA-ACTIVATING PROTEIN COMPLEX, POLYPEPTIDE 5; SNAPC5
;;SMALL NUCLEAR RNA-ACTIVATING PROTEIN COMPLEX, 19-KD SUBUNIT; SNAP19
OMIM Description
DESCRIPTION
SNAPC5 encodes a subunit of the snRNA-activating protein complex
(SNAPc), which is required for transcription of both RNA polymerase II
and III snRNA genes (see SNAPC1, 600591) (Henry et al., 1998).
CLONING
By microsequence analysis of a 19-kD polypeptide present in SNAPC,
followed by EST database searching and RT-PCR analysis, Henry et al.
(1998) obtained a cDNA encoding SNAPC5, which they termed SNAP19.
Sequence analysis predicted that the 98-amino acid protein contains a
leucine zipper motif at its N terminus and a 10-residue glutamate
stretch at its C terminus.
GENE FUNCTION
Using supershift and immunoblot analyses, Henry et al. (1998) confirmed
the existence of SNAPC5 in the complex with the proximal sequence
element (PSE) of snRNA promoters and that it is required for snRNA gene
transcription by both pol II and pol III. Immunoprecipitation analysis
of cotranslated SNAP genes suggested that SNAPC4 (602777) forms a
backbone on which SNAPC2 (605076) and SNAPC5 assemble. The latter is
essential for the subsequent assembly of SNAPC1 with SNAPC4, which is
followed by the assembly of SNAPC3 (602348) with SNAPC1. Henry et al.
(1998) reconstituted SNAPC from the 5 recombinant subunits and showed
that this core complex binds to the PSE and directs both RNA pol II and
pol III snRNA transcription.
MAPPING
Gross (2014) mapped the SNAPC5 gene to chromosome 15q22.31 based on an
alignment of the SNAPC5 sequence (GenBank GENBANK AF093593) with the
genomic sequence (GRCh37).
ANP32A-IT1
| dbSNP name | rs62008191(A,G); rs11639228(G,T); rs113944041(C,T); rs182451453(G,C); rs28474727(C,A); rs28599719(T,C); rs2958405(G,A); rs1470901(G,T); rs1470902(A,C); rs1470903(T,C); rs188727798(T,C); rs3743090(C,T); rs7176388(G,A); rs148072475(T,G); rs4238419(G,C) |
| ccdsGene name | CCDS45292.1 |
| cytoBand name | 15q23 |
| EntrezGene GeneID | 80035 |
| snpEff Gene Name | ANP32A |
| EntrezGene Description | ANP32A intronic transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3659 |
HEXA-AS1
| dbSNP name | rs4777505(T,C); rs4777506(A,G); rs4777507(C,T) |
| cytoBand name | 15q23 |
| EntrezGene GeneID | 80072 |
| snpEff Gene Name | HEXA |
| EntrezGene Description | HEXA antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1896 |
NPTN-IT1
| dbSNP name | rs2509(T,A); rs8037836(G,A); rs16958019(A,G); rs75418437(C,T); rs11856313(A,G); rs80137767(C,T) |
| ccdsGene name | CCDS10249.1 |
| cytoBand name | 15q24.1 |
| EntrezGene GeneID | 101241892 |
| snpEff Gene Name | NPTN |
| EntrezGene Description | NPTN intronic transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3893 |
LOC101929221
| dbSNP name | rs72743342(G,A) |
| cytoBand name | 15q24.1 |
| EntrezGene GeneID | 101929221 |
| EntrezGene Description | uncharacterized LOC101929221 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01515 |
ISLR2
| dbSNP name | rs113881001(G,A); rs3743207(T,C) |
| cytoBand name | 15q24.1 |
| EntrezGene GeneID | 57611 |
| EntrezGene Description | immunoglobulin superfamily containing leucine-rich repeat 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
ABDOMEN:
[Biliary tract];
Ductal plate malformation;
Persistent of bile duct remnants
GENITOURINARY:
[Kidneys];
Renal cysts
SKELETAL:
[Hands];
Postaxial polydactyly;
[Feet];
Postaxial polydactyly
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple
NEUROLOGIC:
[Central nervous system];
Anencephaly (1 patient);
Occipital encephalocele
MISCELLANEOUS:
Two fetuses have been reported (as of August 2011)
MOLECULAR BASIS:
Caused by mutation in the B9 domain-containing protein 2 gene (B9D2,
611951.0001)
OMIM Title
*614179 IMMUNOGLOBULIN SUPERFAMILY CONTAINING LEUCINE-RICH REPEAT 2; ISLR2
;;LEUCINE-RICH REPEAT DOMAIN- AND IMMUNOGLOBULIN DOMAIN-CONTAINING AXON
EXTENSION PROTEIN; LINX;;
KIAA1465
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated human fetal brain
cDNA library, Nagase et al. (2000) obtained a partial ISLR2 clone, which
they designated KIAA1465. The transcript contains a repetitive element
in its 3-prime end. The deduced 642-amino acid partial sequence contains
2 leucine-rich repeats (LRRs), an LRR C-terminal domain, and an
immunoglobulin domain. RT-PCR ELISA detected relatively low ISLR2
expression in fetal and adult brain, testis, and heart, with little to
no expression in other tissues examined. Within adult brain, expression
was detected in amygdala, corpus callosum, cerebellum, caudate nucleus,
hippocampus, and subthalamic nucleus, but not in substantia nigra,
thalamus, or spinal cord.
Mandai et al. (2009) cloned mouse Islr2, which they called Linx. The
deduced 745-amino acid protein has an N-terminal signal sequence,
followed by 5 tandem LRRs flanked by cysteine-rich LRR N-terminal and
C-terminal domains, an immunoglobulin domain, a transmembrane domain,
and a short C-terminal cytoplasmic tail. Immunohistochemical analysis of
mouse embryos showed that Linx was highly expressed in ventral spinal
cord, dorsal and ventral roots of dorsal root ganglion (DRG), and
sympathetic chain ganglia, but not in DRG soma. Expression of Linx in
DRG sensory neurons gradually decreased between embryonic day 14.5 and
postnatal day 7.
GENE FUNCTION
By coimmunoprecipitation analysis, Mandai et al. (2009) showed that
mouse Linx interacted with Trka (NTRK1; 191315), Trkc (NTRK3; 191316)
Ret (164761), and p75(Ntr) (NGFR; 162010) following expression in 293T
cells. Linx also formed homomultimers. Mutation analysis revealed that
Linx and Trka interacted via their extracellular domains.
MAPPING
By PCR of a human-rodent hybrid panel, Nagase et al. (2000) mapped the
ISLR2 gene to chromosome 15. Hartz (2011) mapped the ISLR2 gene to
chromosome 15q24.1 based on an alignment of the ISLR2 sequence (GenBank
GENBANK AB040898) with the genomic sequence (GRCh37).
ANIMAL MODEL
Mandai et al. (2009) found that Linx -/- mice died shortly after birth.
Linx -/- embryos showed deficits in sensory and motor neuron axonal
projections similar to but milder than those found in Ngf (see NGFB;
162030), Trka, and Ret mutant mice. The phenotype of Linx -/- mice was
enhanced by deleting a single copy of the Ret gene. Cultured Linx -/-
sensory and motor neurons showed a deficit in Ngf and Gdnf
(600837)-dependent axonal outgrowth. Mandai et al. (2009) concluded that
Linx has a role in NGF-TRKA and GDNF-RET signaling during development of
peripheral nervous system projections.
IMP3
| dbSNP name | rs4886724(C,T); rs13737(G,T) |
| cytoBand name | 15q24.2 |
| EntrezGene GeneID | 55272 |
| EntrezGene Description | IMP3, U3 small nucleolar ribonucleoprotein, homolog (yeast) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003673 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Micrognathia;
Malar hypoplasia;
[Ears];
Conductive hearing loss;
Anotia;
Rudimentary ear;
External auditory canal atresia;
External auditory canal stenosis;
[Eyes];
Ptosis, bilateral congenital;
Downward-slanting palpebral fissures;
[Teeth];
Malocclusion
SKELETAL:
[Hands];
Camptodactyly (4th and 5th fingers)
SKIN, NAILS, HAIR:
[Nails];
Hypoplastic nails (5th toes)
OMIM Title
*608259 INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 3; IGF2BP3
;;IGF2 mRNA-BINDING PROTEIN 3; IMP3;;
KH DOMAIN CONTAINING PROTEIN OVEREXPRESSED IN CANCER; KOC1;;
VICKZ3
OMIM Description
CLONING
From a pancreatic cancer tumor screen, Mueller-Pillasch et al. (1997)
identified a novel cDNA, which they termed KOC. The deduced 580-amino
acid protein has a molecular mass of approximately 65 kD and contains 4
K-homologous (KH) domains. The transcript was highly overexpressed in
pancreatic cancer cell lines and in pancreatic cancer tissue compared to
normal pancreas and chronic pancreatitis tissue, as well as in tissues
of other human tumors. Mueller-Pillasch et al. (1997) noted that the KH
domain has been shown to be involved in the regulation of RNA synthesis
and metabolism.
By Northern blot analysis, Monk et al. (2002) detected expression of a
4.4-kb IMP3 transcript in placenta and limb fetal tissue. PCR showed
that IMP3 is expressed ubiquitously during fetal development and in
multiple adult tissues, suggesting a role in normal growth and
development. Imprinting studies showed that IMP3 is biallelically
expressed.
Nielsen et al. (1999) noted that the IMP3 protein contains 2 functional
RNA recognition motifs (RRM) in addition to the 4 KH domains. By
Northern blot analysis, they found that IMP3 is expressed in multiple
fetal tissues in both humans and mice, with a burst of expression at
embryonic day 12.5 followed by a decline towards birth. IMP3 mRNA was
not detected in several adult mouse tissues.
GENE STRUCTURE
Monk et al. (2002) determined that the IGF2BP3 gene contains 15 exons.
MAPPING
By FISH analysis, Monk et al. (2002) mapped the IGF2BP3 gene to human
chromosome 7p15. They mapped the mouse Igf2bp3 gene to a region of
chromosome 6 that shares homology of synteny with human chromosome 7p15.
GENE FUNCTION
Nielsen et al. (1999) found that the IMP3 protein associates
specifically with the 5-prime UTR of the human 6.0-kb insulin-like
growth factor II (IGF2; 147470) leader-3 mRNA, suggesting a role for
IMP3 in the physiologic regulation of IGF2 production.
Jiang et al. (2006) found that IMP3 tumor expression was greatly was
associated with metastasis in clear cell renal cell carcinoma (RCC;
144700). Among 371 patients with localized clear cell renal cell
carcinoma, those with IMP3 tumor expression had a much lower 5-year
metastasis-free survival than those with IMP3-negative tumors (44% vs
98% for stage I; 41% vs 94% for stage II; and 16% vs 62% for stage III).
IMP3 expression was also associated with reduced 5-year overall
survival. These findings were replicated by Hoffmann et al. (2008) who
studied 716 clear cell RCC specimens and found that 213 (29.8%) of 716
tumors expressed IMP3, which was associated with advanced stage and
grade of primary tumors as well as other adverse features, including
coagulative tumor necrosis and sarcomatoid differentiation. After
multivariate adjustment, positive IMP3 expression was still associated
with a 42% increase in the risk of death from RCC. Among those with
initially localized disease, positive IMP3 expression was associated
with a 4.71-fold increased risk of distant metastases.
Jiang et al. (2008) found that 40 (12%) of 334 RCCs, including 254
papillary and 80 chromophobic tumors, expressed IMP3. Positive IMP3
expression was significantly associated with later tumor stage and
higher tumor grade. An analysis of patient outcomes showed that 28 of
317 with initially localized disease progressed to metastasis. Fifteen
(45.5%) of the 33 patients with IMP3-positive tumors developed
metastases compared to only 13 (4.6%) of the 284 patients with
IMP3-negative tumors. Statistical analysis showed that those with
initially localized IMP3-positive tumors were over 10 times more likely
to have metastasis (risk ratio of 11.38; p less than 0.001), and were
nearly twice as likely to die compared to patients with localized
IMP3-negative tumors. The 5-year metastasis-free and overall survival
rates were 64% and 58% for patients with IMP3-positive localized
papillary and chromophobe RCCs compared to 98% and 85% for patients with
IMP3-negative tumors, respectively. Jiang et al. (2008) concluded that
IMP3 expression can be used as a prognostic biomarker for metastasis in
all subtypes of renal cell carcinoma.
MOLECULAR GENETICS
- Exclusion Studies
Although the location and putative function of IMP3 suggested a possible
role in Silver-Russell syndrome (180860), Monk et al. (2002) found no
IMP3 mutations in 25 affected patients.
NOMENCLATURE
The IMP3 gene described here is distinct from the IMP3 gene described in
608238.
LOC91450
| dbSNP name | rs28470811(C,A); rs72732535(G,T); rs7167778(A,G); rs144387080(G,T) |
| cytoBand name | 15q24.3 |
| EntrezGene GeneID | 91450 |
| snpEff Gene Name | TBC1D2B |
| EntrezGene Description | uncharacterized LOC91450 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06428 |
C15orf37
| dbSNP name | rs2733101(A,T); rs34172478(T,C); rs2115534(A,G) |
| cytoBand name | 15q25.1 |
| EntrezGene GeneID | 283687 |
| snpEff Gene Name | MTHFS |
| EntrezGene Description | chromosome 15 open reading frame 37 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.36 |
FAH
| dbSNP name | rs1370277(A,T); rs116213732(C,T); rs113519661(G,A); rs17217997(G,T); rs112699321(G,A); rs28561542(C,T); rs112028224(G,T); rs12593724(T,C); rs12593746(T,C); rs76852381(G,C); rs114370360(C,T); rs112704674(G,T); rs1370276(T,C); rs1370275(G,A); rs62006328(A,T); rs62006330(G,A); rs1370274(T,C); rs1370273(G,A); rs75782446(C,G); rs78223708(G,A); rs733679(T,G); rs8027913(G,T); rs11856427(T,C); rs8027831(A,G); rs17218165(A,G); rs2114716(T,C); rs4778583(A,T); rs2162552(C,T); rs7164048(C,A); rs1963890(A,G); rs1963889(C,G); rs72630428(G,A); rs141027126(C,A); rs8036972(C,G); rs68167475(G,T); rs72740004(C,T); rs1545119(A,G); rs145389125(G,A); rs7166889(G,A); rs8033974(A,G); rs7179137(G,A); rs13329170(T,C); rs28465485(T,G); rs73481166(A,G); rs28462237(C,T); rs3752693(G,A); rs3752692(G,A); rs4778758(A,G); rs28670686(C,T); rs2278205(C,T); rs11072883(A,G); rs79745256(G,C); rs1863768(G,T); rs60181128(C,T); rs1978816(C,T); rs6495477(A,G); rs6495478(C,T); rs2114706(T,G); rs1978817(C,T); rs8043254(C,T); rs8043131(A,T); rs144978559(C,T); rs10152142(T,C); rs2162550(G,A); rs57043393(T,A); rs67650837(G,A); rs2866591(A,G); rs2866592(C,T); rs186061473(G,A); rs12591114(C,T); rs12591184(G,T); rs2866593(A,G); rs1030865(C,T); rs58626166(C,T); rs141996799(C,A); rs7180267(C,T); rs2043692(T,C); rs2043691(C,A); rs1801374(C,T); rs56104030(C,A); rs61128916(T,C); rs11633719(C,T); rs2866594(C,T); rs28665646(G,A); rs57370807(T,C); rs148480017(C,T); rs60797290(A,G); rs74027255(T,C); rs55639808(G,A); rs115774369(T,C); rs12594576(A,G); rs11637869(C,T); rs7177977(A,G); rs78139854(T,C); rs74027257(A,G); rs80195303(C,T); rs116460382(C,T); rs8039712(G,A); rs62006336(C,T); rs12898575(G,A); rs12898576(G,A); rs1049194(T,C); rs75212096(T,A) |
| ccdsGene name | CCDS10314.1 |
| cytoBand name | 15q25.1 |
| EntrezGene GeneID | 2184 |
| EntrezGene Description | fumarylacetoacetate hydrolase (fumarylacetoacetase) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FAH:NM_000137:exon7:c.G565A:p.V189I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7231 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P16930 |
| dbNSFP Uniprot ID | FAAA_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.00227 |
| ESP All MAF | 0.000769 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0004717 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
RESPIRATORY:
Respiratory insufficiency, progressive;
Respiratory failure;
Weak cry;
Apneic episodes
CHEST:
Decreased chest wall compliance due to muscular hypertonicity
SKELETAL:
Contractures (variable)
MUSCLE, SOFT TISSUE:
Muscle hypertonicity;
Rigidity;
Stiffness;
EMG shows increased insertion activity and fibrillation;
Muscle biopsy shows dystrophic changes;
Endomysial fibrosis;
Eosinophilic inclusions;
Z-band streaming;
Granular deposits in the sarcomeres
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset in first 8 weeks of life;
Rapidly progressive;
Death usually in the first 2 years of life
MOLECULAR BASIS:
Caused by mutation in the alpha-B crystallin gene (CRYAB, 123590.0005)
OMIM Title
*613871 FUMARYLACETOACETATE HYDROLASE; FAH
;;FUMARYLACETOACETASE
OMIM Description
DESCRIPTION
The enzyme fumarylacetoacetate hydrolase (FAH; EC 3.7.1.2) is the last
enzyme in the catabolic pathway of tyrosine (summary by Tanguay et al.,
1990).
CLONING
Phaneuf et al. (1991) isolated human FAH cDNA clones by screening a
liver cDNA expression library with specific antibodies and plaque
hybridization with a rat FAH cDNA probe. From transient expression in
transfected mammalian cells, a single polypeptide chain encoded by the
FAH gene appeared to contain all the genetic information required for
functional activity, indicating that the dimer found in vivo is a
homodimer.
Grompe et al. (1993) stated that Fah is predominantly expressed in liver
and kidney in mice.
MAPPING
By in situ hybridization, Berube et al. (1989) assigned the FAH gene to
chromosome 15q23-q25. Using in situ hybridization, Tanguay et al. (1990)
confirmed the assignment to chromosome 15 by analysis of rodent-human
hybrid cells.
By study of somatic cell hybrids and by in situ hybridization using the
FAH cDNA, Phaneuf et al. (1991) demonstrated that the gene maps to
chromosome 15q23-q25.
GENE FUNCTION
Jorquera and Tanguay (2001) reported that a subapoptogenic dose of
fumarylacetoacetate, the mutagenic metabolite accumulating in hereditary
type I tyrosinemia, induced spindle disturbances and segregational
defects in both rodent and human cells. A sustained activation of the
extracellular signal-regulated protein kinase (ERK; see MAPK1, 176948)
was also observed. Primary skin fibroblasts derived from type I
tyrosinemia patients not exogenously treated with fumarylacetoacetate
showed similar mitotic-derived alterations and ERK activation.
Replenishment of intracellular glutathione (GSH) with GSH monoethylester
abolished ERK activation and reduced the chromosomal instability induced
by fumarylacetoacetate by 80%. The authors speculated that this
tumorigenic-related phenomenon may rely on the biochemical/cellular
effects of fumarylacetoacetate as a thiol-reacting and organelle/mitotic
spindle-disturbing agent.
MOLECULAR GENETICS
Tanguay et al. (1990) analyzed the FAH in livers of unrelated patients
with tyrosinemia type I (TYRSN1; 276700) using mRNA levels,
immunoreactive protein, and enzyme activity. They demonstrated a
missense mutation in the FAH gene in cDNA from 1 patient with normal FAH
mRNA but without immunoreactive protein or enzymatic activity. In the
full article of this work (Phaneuf et al., 1992) stated that the
mutation was an asn16-to-ile (N16I) substitution (613871.0001) in a
French Canadian patient.
Grompe et al. (1994) found that 100% of tyrosinemia type I patients from
the Saguenay-Lac-Saint-Jean region of Quebec and 28% of TYRSN1 patients
from other regions of the world carry a splice donor site mutation in
intron 12 of the FAH gene (613871.0003). Of 25 patients from the
Saguenay-Lac-Saint-Jean region, 20 were homozygous. The frequency of
carrier status, based on screening of blood spots from newborns, was
about 1 per 25 in that region of Quebec and about 1 per 66 overall in
Quebec. Using cDNA probes for the FAH gene, Demers et al. (1994)
identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes from the
French Canadian population. Among 29 children with hereditary
tyrosinemia, haplotype 6 was found to be strongly associated with
disease, at a frequency of 90% as compared with approximately 18% in 35
control individuals. This frequency increased to 96% in the 24 patients
originating from the Saguenay-Lac-Saint-Jean region. Most patients were
found to be homozygous for a specific haplotype in this population.
Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of
approximately 52% for haplotype 6, suggesting a relatively high
association worldwide.
Hahn et al. (1995) reviewed 7 previously reported mutations in
tyrosinemia type I and added 2 more identified in a compound
heterozygote.
Timmers and Grompe (1996) reported 6 new mutations in the FAH gene in
patients with hereditary tyrosinemia type I: 2 splice mutations, 3
missense mutations, and 1 nonsense mutation.
Rootwelt et al. (1996) classified 62 hereditary tyrosinemia type I
patients of various ethnic origins clinically into acute, chronic, or
intermediate phenotypes and screened for the 14 published causal
mutations in the FAH gene. Restriction analysis of PCR-amplified genomic
DNA identified 74% of the mutated alleles. The IVS12+5G-A mutation
(613871.0003), which is predominant in French Canadian tyrosinemia type
I patients, was the most common mutation being present in 32 alleles in
patients from Europe, Pakistan, Turkey, and the United States. The
IVS6-1G-T mutation (613871.0010), encountered in 14 alleles, was common
in central and western Europe. There was an apparent 'Scandinavian'
1009G-to-A combined splice and missense mutation (12 alleles), a
'Pakistani' 192G-to-T splice mutation (11 alleles), a 'Turkish' D233V
mutation (6 alleles), and a 'Finnish' or northern European W262X
(613871.0009) mutation (7 alleles). Rootwelt et al. (1996) commented
that some of the mutations seemed to predispose for acute and others for
more chronic forms of tyrosinemia type I, although no clear-cut
genotype/phenotype correlation could be established.
ANIMAL MODEL
Grompe et al. (1993) found that Fah -/- mice exhibited a phenotype
significantly different from that of humans with null mutations in FAH.
Fah -/- mice appeared normal at birth, but they rapidly developed
hypoglycemia and liver dysfunction and died within 12 hours of birth.
Fah -/- mice were not tyrosinemic. Electron microscopy revealed
disruption of the endoplasmic reticulum in liver of Fah -/- mice.
Wuestefeld et al. (2013) noted that lethality in Fah -/- mice can be
prevented by continuous treatment with the drug nitisinone (NTBC). Using
short hairpin RNA screening, they found that stable knockdown of Mkk4
(601335) countered lethality in Fah -/- mice following NTBC withdrawal.
Knockdown of Mkk4 robustly increased the regenerative capacity of
hepatocytes and reduced the number of apoptotic hepatocytes in FAH -/-
mice following NTBC withdrawal, as well as in mouse models of acute and
chronic liver failure.
MESDC1
| dbSNP name | rs74525494(C,G); rs7169370(C,G) |
| cytoBand name | 15q25.1 |
| EntrezGene GeneID | 59274 |
| EntrezGene Description | mesoderm development candidate 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04637 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly;
[Ears];
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Epicanthal folds;
Hypertelorism;
Hypotelorism;
[Nose];
Broad nose;
[Mouth];
Cleft lip;
Cleft palate
GENITOURINARY:
[External genitalia, male];
Small penis;
Hypospadias;
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
[Skull];
Hypoplastic frontal bones;
Craniosynostosis (reported in 1 patient);
[Hands];
Ectrodactyly;
Syndactyly;
[Feet];
Ectrodactyly;
Syndactyly
NEUROLOGIC:
[Central nervous system];
Lobar holoprosencephaly;
Hypotonia, neonatal;
Psychomotor retardation, severe;
Vermian hypoplasia;
Agenesis of the corpus callosum
ENDOCRINE FEATURES:
Gonadotropin deficiency;
Diabetes insipidus
LABORATORY ABNORMALITIES:
Hypernatremia
MOLECULAR BASIS:
Caused by mutation in the fibroblast growth factor receptor 1 gene
(FGFR1, 136350.0030)
OMIM Title
*615466 MESODERM DEVELOPMENT CANDIDATE 1; MESDC1
OMIM Description
CLONING
Wines et al. (2001) cloned mouse Mesdc1, and by database analysis, they
identified the human ortholog. The deduced 362-amino acid mouse protein
was predicted to be globular and to have a nuclear localization signal
near the N terminus. The predicted mouse and human MESDC1 proteins share
98% identity. Northern blot analysis of mouse tissues detected abundant
expression of an approximately 1.5-kb transcript in liver only. Weak
expression of an approximately 3-kb transcript was detected in mouse
embryos and in all adult tissues examined. EST database analysis
revealed expression of MESDC1 in various human and rat tissues and in
Xenopus oocytes.
GENE FUNCTION
Tatarano et al. (2012) found that expression of MESDC1 was downregulated
by the microRNA MIR574-3p (615469). Knockdown of MESDC1 or
overexpression of MIR574-3p in 2 bladder cancer cell lines reduced cell
proliferation, migration, and invasion and induced apoptosis.
MAPPING
By radiation hybrid analysis and sequencing of a BAC contig, Wines et
al. (2001) mapped the MESDC1 gene to chromosome 15q23-q25. They mapped
the mouse Mesdc1 gene to a region of chromosome 7 that shares homology
of synteny with human chromosome 15q23-q25.
MEX3B
| dbSNP name | rs11073028(G,A) |
| cytoBand name | 15q25.2 |
| EntrezGene GeneID | 84206 |
| EntrezGene Description | mex-3 RNA binding family member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.045 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, acquired
ABDOMEN:
[Gastrointestinal];
Poor feeding
NEUROLOGIC:
[Central nervous system];
Jerking movements;
Posturing;
Seizures, intractable;
Hypertonia;
Psychomotor retardation;
Brain imaging shows generalized atrophy;
Hypoplastic cerebellar vermis
LABORATORY ABNORMALITIES:
Decreased plasma serine;
Decreased plasma glycine;
Decreased CSF serine;
Decreased CSF glycine
MISCELLANEOUS:
Onset in infancy;
Treatment with serine and glycine replacement may alleviate features
if started at birth;
Lack of treatment results in early death
MOLECULAR BASIS:
Caused by mutation in the phosphoserine aminotransferase-1 gene (PSAT1,
610936.0001)
OMIM Title
*611008 MEX3, C. ELEGANS, HOMOLOG OF, B; MEX3B
;;RING FINGER- AND KH DOMAIN-CONTAINING PROTEIN 3; RKHD3
OMIM Description
CLONING
C. elegans Mex3 is a regulator of translation that specifies posterior
blastomere identity in the early embryo and contributes to the
maintenance of germline totipotency. By database analysis and RT-PCR,
Buchet-Poyau et al. (2007) cloned a family of 4 human genes homologous
to C. elegans Mex3, including RKHD3, which they called MEX3B. Like the
other human MEX3 proteins, the deduced 569-amino acid MEX3B protein has
an N-terminal nuclear export signal (NES), 2 heterogeneous nuclear
ribonucleoprotein K (HNRNPK; 600712) homology (KH) domains, and a
C-terminal RING finger domain. The KH domains are present in C. elegans
Mex3, but not the RING domain. MEX3B also has an N-terminal nuclear
localization signal. RT-PCR detected variable expression of MEX3B in
human tissues and cell lines, with highest levels in fetal brain,
testis, thymus, and salivary gland. Immunohistochemical analysis showed
MEX3B expression in goblet cells of adult intestinal epithelium.
GENE FUNCTION
Using Western blot analysis of transfected human embryonic kidney cells
and kinase assays, Buchet-Poyau et al. (2007) showed that MEX3A
(611007), MEX3B, and MEX3C (611005) were phosphoproteins. RNA
homopolymer-binding assays and immunoprecipitation analysis revealed
that MEX3A, MEX3B, and MEX3C bound RNA via their KH domains in vitro and
in vivo. Immunofluorescence analysis of transfected breast cancer cells
showed that MEX3A, MEX3B, and MEX3C shuttled between the nucleus and
cytoplasm in an NES-dependent manner. MEX3A and MEX3B colocalized with
DCP1A (607010) decapping factor and argonaute proteins (e.g., AGO1;
606228) in processing (P) bodies, which are centers for mRNA turnover.
Buchet-Poyau et al. (2007) proposed that MEX3 proteins may function in
maintenance of pluripotent cells, i.e., stem cells.
GENE STRUCTURE
Buchet-Poyau et al. (2007) determined that the RKHD3 gene contains 2
exons.
MAPPING
By genomic sequence analysis, Buchet-Poyau et al. (2007) mapped the
MEX3B gene to chromosome 15q25.2.
LOC338963
| dbSNP name | rs4513065(C,G); rs11852808(A,G) |
| cytoBand name | 15q25.2 |
| EntrezGene GeneID | 338963 |
| snpEff Gene Name | AP3B2 |
| EntrezGene Description | epididymal protein pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1047 |
ASB9P1
| dbSNP name | rs7164758(T,C); rs77582277(C,G); rs79319943(T,A); rs75197417(C,T); rs28575385(A,T); rs112182809(G,T); rs113878460(A,G); rs77053281(A,G) |
| cytoBand name | 15q26.1 |
| EntrezGene GeneID | 728619 |
| snpEff Gene Name | FAM174B |
| EntrezGene Description | ankyrin repeat and SOCS box containing 9 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2599 |
| ExAC AF | 0.197 |
MIR3175
| dbSNP name | rs1439619(T,G); rs114901994(A,G) |
| ccdsGene name | CCDS10374.2 |
| cytoBand name | 15q26.1 |
| EntrezGene GeneID | 100422995 |
| snpEff Gene Name | CHD2 |
| EntrezGene Description | microRNA 3175 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3912 |
| ExAC AF | 0.246 |
LOC440311
| dbSNP name | rs3803490(T,C); rs114588302(G,C); rs11631624(G,A) |
| cytoBand name | 15q26.2 |
| EntrezGene GeneID | 440311 |
| snpEff Gene Name | CTD-2576F9.1 |
| EntrezGene Description | glioma tumor suppressor candidate region gene 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1997 |
HSP90B2P
| dbSNP name | rs6598229(A,C); rs139912132(C,T); rs7162949(G,A); rs1976589(T,C); rs78117606(G,T) |
| ccdsGene name | CCDS10380.1 |
| cytoBand name | 15q26.3 |
| EntrezGene GeneID | 123355 |
| EntrezGene Symbol | LRRC28 |
| snpEff Gene Name | LRRC28 |
| EntrezGene Description | leucine rich repeat containing 28 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3733 |
PRKXP1
| dbSNP name | rs967467(G,A); rs967466(T,A); rs12910735(A,G); rs12910448(C,A); rs77355140(C,T); rs112280213(G,A); rs4965314(T,G); rs76517034(C,T); rs12915921(C,T); rs12901344(T,C); rs28589374(A,G); rs28497263(A,C); rs1972053(G,A); rs28685143(C,T); rs56311864(C,T); rs140264925(C,T); rs28605780(A,G); rs73477754(C,A); rs4965316(T,C); rs12442898(A,T); rs111870044(T,C); rs4965674(G,T); rs4965675(T,C); rs62037117(C,T); rs28538762(T,A); rs62037118(A,G); rs11634945(C,T); rs35852295(C,T); rs28628432(C,G); rs12904590(A,G); rs55954859(G,A); rs116072471(C,T) |
| cytoBand name | 15q26.3 |
| EntrezGene GeneID | 441733 |
| snpEff Gene Name | CERS3 |
| EntrezGene Description | protein kinase, X-linked, pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4775 |
OR4F6
| dbSNP name | rs401632(G,A); rs147056953(C,G) |
| ccdsGene name | CCDS32341.1 |
| cytoBand name | 15q26.3 |
| EntrezGene GeneID | 390648 |
| EntrezGene Description | olfactory receptor, family 4, subfamily F, member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4F6:NM_001005326:exon1:c.G108A:p.V36V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03949 |
| ESP Afr MAF | 0.174535 |
| ESP All MAF | 0.060895 |
| ESP Eur/Amr MAF | 0.002674 |
| ExAC AF | 0.018 |
OR4F15
| dbSNP name | rs142759394(G,A); rs144039449(G,A) |
| ccdsGene name | CCDS32342.1 |
| cytoBand name | 15q26.3 |
| EntrezGene GeneID | 390649 |
| EntrezGene Description | olfactory receptor, family 4, subfamily F, member 15 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4F15:NM_001001674:exon1:c.G62A:p.R21Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0005 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGB8 |
| dbNSFP Uniprot ID | O4F15_HUMAN |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.000681 |
| ESP All MAF | 0.003767 |
| ESP Eur/Amr MAF | 0.005349 |
| ExAC AF | 3.351e-03,8.132e-06,8.132e-06 |
HBM
| dbSNP name | rs78153988(G,C) |
| ccdsGene name | CCDS32347.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 3042 |
| EntrezGene Description | hemoglobin, mu |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HBM:NM_001003938:exon1:c.G84C:p.L28L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.020757 |
| ESP All MAF | 0.007018 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.002482 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Teeth];
Neonatal teeth
GENITOURINARY:
[External genitalia, male];
Phimosis, secondary to epidermolysis
SKELETAL:
[Hands];
Pseudosyndactyly;
Tapered distal phalanges;
[Feet];
Widely spaced toes
SKIN, NAILS, HAIR:
[Skin];
Progressive generalized skin erosions;
Cutis aplasia;
HISTOLOGY:;
Suprabasal clefting;
Acantholysis;
ELECTRON MICROSCOPY:;
Disconnection of keratin intermediate filaments from desmosomes;
[Nails];
Nail loss;
[Hair];
Universal alopecia
MISCELLANEOUS:
Neonatal death
MOLECULAR BASIS:
Caused by mutation in the desmoplakin gene (DSP, 125647.0008).
OMIM Title
*609639 HEMOGLOBIN MU
;;HBM
OMIM Description
CLONING
Using postgenomic approaches to examine the transcriptional profiles of
human reticulocytes, Goh et al. (2005) characterized a previously
undefined transcript representing an unrecognized globin gene that
showed homology to the pseudo-HbA2 region within the alpha-globin locus
(see 141800) on chromosome 16p13.3. Cloning and sequencing of that
transcript, named hemoglobin (Hb) mu (HBM), revealed an insert with a
423-nucleotide open reading frame. The predicted protein demonstrated a
high level of homology with the avian alpha-D globin. In addition, the
heme- and globin-binding amino acids of mu-globin and avian alpha-D
globin were largely conserved. Using quantitative real-time PCR,
mu-globin was detected at a level of approximately 0.1% of that measured
for alpha-globin in erythroid tissues. Erythroid-specific expression was
detected by Northern blot analysis, and maximal expression during the
erythroblast terminal differentiation was also detected. Despite this
highly regulated pattern of mu-globin gene transcription, mu-globin
protein was not detected by mass spectrometry. These results suggested
that the human genome encodes a previously unrecognized globin member of
the avian alpha-D family that is transcribed in a highly regulated
pattern in erythroid cells.
GENE FUNCTION
Goh et al. (2005) commented that it is curious that mu-globin is not the
only gene in the human alpha-globin cluster that lacks a detectable
hemoglobin product. The downstream region of the alpha locus contains an
unusual gene named theta-globin (HbQ1; 142240) that generates no
detected globin protein in humans. Theta-globin gene transcription is
regulated, and the transcripts contain no obvious defects to explain the
lack of detectable protein in erythroid tissues. Both the HBM and HbQ1
genes are well conserved at the genomic level, and both have a highly
regulated pattern of transcription in erythroid cells. It was uncertain
whether the HBM gene is evolving toward becoming a pseudogene; Goh et
al. (2005) raised the possibility that instead, this ancient globin has
a function for which high-level protein expression is not required.
GENE STRUCTURE
Goh et al. (2005) determined that the HBM gene has a 3-exon structure
similar to that of other human hemoglobin alpha genes.
MAPPING
The HBM gene maps to the alpha-globin region on chromosome 16p13.3,
overlapping the pseudo-Hb2 gene (Goh et al., 2005).
HBA2
| dbSNP name | rs2541640(A,G) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 3040 |
| EntrezGene Description | hemoglobin, alpha 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005969 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Jaundice;
Cyanosis
HEMATOLOGY:
Alpha polypeptide hemoglobin chain;
Alpha-thalassemia silent carrier (3 normal genes);
Alpha-thalassemia with microcytosis (2 normal genes);
Alpha-thalassemia with microcytosis and hemolysis, Hb H disease (1
normal gene);
Alpha-thalassemia with fatal Hb Bart's hydrops fetalis (No normal
gene);
Polycythemia (e.g. Hb Chesapeake 141800.0018);
Unstable hemoglobin (e.g. Hb Contaldo 141800.0022);
Hemolysis (e.g. Hb Koelliker 141800.0083);
Methemoglobinemia (e.g. Hb M Boston 141800.0092);
Amelioration of SS disease (e.g. Hb Memphis 141800.0096);
Congenital Heinz body anemia (e.g. Hb Toyama 141800.0152)
LABORATORY ABNORMALITIES:
Decreased heme-heme interaction (e.g. Hb Kanagawa 141800.0169);
Increased oxygen affinity (e.g. Hb Nunobiki 141800.0109);
Reduced oxygen affinity (e.g. Hb Thionville 141800.0168);
Decreased reversible oxygen-binding capacity (e.g. Hb L (Bombay) 141800.9999)
MISCELLANEOUS:
Two alpha-globin genes - 5-prime or alpha-2 and 3-prime or alpha-1
OMIM Title
*141850 HEMOGLOBIN--ALPHA LOCUS 2; HBA2
;;5-PRIME @ALPHA-GLOBIN GENE;;
ALPHA-GLOBIN LOCUS, SECOND;;
MAJOR ALPHA-GLOBIN LOCUS
OMIM Description
Since at least as early as 1970, 2 alpha loci have been known to exist
in some humans (Brimhall et al., 1970): hemoglobins G (Pest) and J
(Buda) showed the existence of at least 2 alpha chains in the Hungarians
studied (141800.0041, 141850.0008), whereas hemoglobin J (Tongariki)
indicated that in Melanesians only 1 alpha locus exists (141800.0077).
The alpha locus is apparently double in Chinese (Kan, 1974), whereas in
American blacks, chromosomes with single or double alpha loci are about
equally frequent (Huisman, 1974). Rucknagel and Dublin (1974) estimated
that a chromosome with a single alpha locus has a frequency of about
0.27 in American blacks and about 0.36 in African blacks. Rucknagel and
Rising (1975) studied an American black family in which of 5 persons
heterozygous for hemoglobin G (Philadelphia), an alpha-chain mutant, 3
had about 30% Hb G and 2 had 40%. They suggested that the former persons
have 2 alpha hemoglobin loci and the latter persons 1 such locus. Three
members of a Hungarian family had 2 alpha-chain variants (Hb J Buda and
Hb G Pest), each variant accounting for 25% of hemoglobin, the rest
being Hb A (Brimhall et al., 1974). From studies of hemoglobin G
(Philadelphia), Baine et al. (1976) also concluded that there is
variability in the number of alpha-chain genes in the American black
population. In heterozygotes the proportion of Hb G (Philadelphia) was
trimodally distributed with modes at about 20%, 30%, and 40%. The
workers concluded that gene dosage accounts for this: 1 G gene out of 4
alpha genes leads to 20% Hb G; 1 G gene out of 3 alpha genes leads to
30% Hb G; 1 G gene out of 2 alpha genes or 2 G genes out of 4 alpha
genes leads to 40% Hb G. In Melanesians, Eng et al. (1974) observed
homozygous Hb Constant Spring and Hb A. The products of the 2
alpha-chain genes appear to have the same primary structure. Although
there is no direct proof, they are probably closely linked
(Politis-Tsegos et al., 1976). Unequal crossingover may be responsible
for the type of alpha-thalassemia with deleted alpha loci. From study of
Hb J(Mexico) in an Algerian family, Trabuchet et al. (1977) also
concluded that the alpha gene was duplicate in some chromosomes and
single in others. Two types of deletional alpha-plus-thalassemia are
identified by molecular genetic studies. One, termed leftward, shows a
deletion of 4.2 kb and removes the entire alpha-2 gene; the other,
termed rightward, has a deletion of 3.7 kb and gives rise to a hybrid
alpha-2/alpha-1 gene. The 3.7-kb rightward deletion can also remove the
entire alpha-1 gene and is 'possibly the most common mutation known to
produce a genetic disorder' (Bowden et al., 1987). It is prevalent in
most tropical and subtropical populations that have been studied,
including African and American blacks, Mediterraneans, Southeast Asians,
and some Pacific Island populations. In contrast, the 4.2-kb deletion of
the alpha-2 gene is very rare in African blacks and Mediterraneans. The
leftward one was found only in Asian cases until the report of a case in
East Sicily (Troungos et al., 1984).
El-Hazmi (1986) found several persons with the leftward deletion
alpha-thalassemia in Saudi Arabia, including homozygotes and
heterozygotes. Remarkably, in north coastal Papua New Guinea, the 4.2-kb
deletion is found in more than 80% of the population and appears to be
going to fixation (Oppenheimer et al., 1984). From comparison of the
level of hemoglobin Bart's at birth in homozygotes for each of the 2
deletions, Bowden et al. (1987) demonstrated that the alpha-2 gene, when
alone on the chromosome, reduces more alpha-globin than does the alpha-1
gene. (Since hemoglobin Bart's (142309) is a tetramer of gamma chains,
the level of this hemoglobin reflects in an inverse manner the amount of
alpha chains produced.) In a case of alpha-thalassemia, Whitelaw and
Proudfoot (1986) showed that the mutation in the 3-prime poly(A) site
leads to transcription of the mutant alpha-2 globin gene through into
the intergenic sequence past the normal termination site. They
interpreted these results as demonstrating that transcriptional
termination and 3-prime end processing of mRNA are coupled events for
the alpha-2 globin gene. Liebhaber et al. (1986) studied 8 separate
alpha-globin mutants mapped to the alpha-1 or the alpha-2 locus and
demonstrated that the alpha-2 gene encodes 2- to 3-fold more protein
than the alpha-1 gene. These results suggested that the human
alpha-globin cluster contains a major and a minor locus and that
deletions in the alpha-2 gene are more significant in the generation of
the alpha-thalassemia phenotype than are deletions in the alpha-1 gene.
Straub et al. (2012) reported a model for the regulation of nitric oxide
(NO) signaling by demonstrating that hemoglobin alpha, encoded by the
HBA1 (141800) and HBA2 genes, is expressed in human and mouse arterial
endothelial cells and enriched at the myoendothelial junction, where it
regulates the effects of NO on vascular reactivity. Notably, this
function is unique to hemoglobin alpha and is abrogated by its genetic
depletion. Mechanistically, endothelial hemoglobin alpha heme iron in
the Fe(3+) state permits NO signaling, and this signaling is shut off
when hemoglobin alpha is reduced to the Fe(2+) state by endothelial
cytochrome b5 reductase 3 (CYB5R3; 613213). Genetic and pharmacologic
inhibition of CYB5R3 increased NO bioactivity in small arteries. Straub
et al. (2012) concluded that their data revealed a mechanism by which
the regulation of the intracellular hemoglobin alpha oxidation state
controls nitric oxide synthase (NOS; see 163729) signaling in
nonerythroid cells. The authors suggested that this model may be
relevant to heme-containing globins in a broad range of NOS-containing
somatic cells.
N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2
is involved have been arbitrarily listed under HBA1 (141800).
PDIA2
| dbSNP name | rs115506610(A,G); rs432925(G,C); rs11647490(G,A) |
| ccdsGene name | CCDS42089.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 64714 |
| EntrezGene Description | protein disulfide isomerase family A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PDIA2:NM_006849:exon2:c.A277G:p.M93V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0013 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0228937728938 |
| dbNSFP KGp1 Afr AF | 0.0934959349593 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.0225 |
| ESP Afr MAF | 0.068773 |
| ESP All MAF | 0.023385 |
| ESP Eur/Amr MAF | 0.000354 |
| ExAC AF | 0.006264 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Ears];
Low-set ears;
Otitis media, multiple episodes;
[Nose];
Narrow, pointy nose
RESPIRATORY:
Recurrent respiratory tract infections (upper and lower);
[Lung];
Pneumonia;
Restrictive lung disease;
Interstitial fibrosis
SKELETAL:
Spondylometaphyseal dysplasia;
[Spine];
Platyspondyly;
Irregular vertebral endplates;
[Limbs];
Sclerotic, irregular metaphyses (distal radii and ulnae, distal femurs,
proximal fibulae)
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmented macules;
Hypopigmented skin patches on arms (vitiligo);
[Hair];
Normal hair shaft morphology
NEUROLOGIC:
[Central nervous system];
Normal intelligence
ENDOCRINE FEATURES:
Hypothyroidism (autoimmune)
HEMATOLOGY:
Idiopathic thrombocytopenic purpura (ITP)
IMMUNOLOGY:
Combined humoral and cellular immunodeficiency;
Recurrent infections (pneumonia, sinusitis, fulminant varicella);
Autoimmune disorders (i.e., ITP, juvenile rheumatoid arthritis (JRA),
hypothyroidism, Crohn disease);
Decreased T cell response to mitogens;
Decreased numbers of circulating T cells;
Decreased specific antibodies;
Normal to elevated IgG;
Lymphadenopathy
MISCELLANEOUS:
Onset in infancy or childhood
OMIM Title
*608012 PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 2; PDIA2
;;PROTEIN DISULFIDE ISOMERASE, PANCREATIC; PDIP
OMIM Description
DESCRIPTION
Protein disulfide isomerases (EC 5.3.4.1), such as PDIP, are endoplasmic
reticulum (ER) resident proteins that catalyze protein folding and
thiol-disulfide interchange reactions (Desilva et al., 1996).
CLONING
Desilva et al. (1996) cloned PDIP from an insulinoma subtraction cDNA
library. The deduced 511-amino acid protein has a calculated molecular
mass of about 56.6 kD and contains 2 thioredoxin (187700)-like catalytic
sites, a C-terminal ER retention sequence (KEEL), and 3 potential
N-glycosylation sites. PDIP shares about 46% identity with bovine,
mouse, rabbit, and human PDIs (176790). Northern blot analysis detected
a 2.0-kb transcript expressed exclusively in pancreas.
GENE FUNCTION
Desilva et al. (1996) determined that recombinant PDIP, expressed in E.
coli, catalyzed the reductive cleavage of radiolabeled insulin and
reactivated reduced RNase A.
MAPPING
By somatic cell hybrid analysis and FISH, Desilva et al. (1996) mapped
the PDIP gene to chromosome 16p13.3.
C16orf13
| dbSNP name | rs34560623(C,T) |
| ccdsGene name | CCDS42090.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 84326 |
| snpEff Gene Name | Z84479.1 |
| EntrezGene Description | chromosome 16 open reading frame 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C16orf13:NM_001040160:exon5:c.G565A:p.A189T,C16orf13:NM_001040165:exon4:c.G505A:p.A169T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0114 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F6TF62 |
| dbNSFP KGp1 AF | 0.014652014652 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0356200527704 |
| dbSNP GMAF | 0.01469 |
| ESP Afr MAF | 0.007951 |
| ESP All MAF | 0.024381 |
| ESP Eur/Amr MAF | 0.032791 |
| ExAC AF | 0.027,3.254e-05 |
JMJD8
| dbSNP name | rs6597(T,G) |
| ccdsGene name | CCDS10419.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 339123 |
| snpEff Gene Name | RHBDL1 |
| EntrezGene Description | jumonji domain containing 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07943 |
HAGHL
| dbSNP name | rs1054788(G,C) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 84264 |
| snpEff Gene Name | NARFL |
| EntrezGene Description | hydroxyacylglutathione hydrolase-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1791 |
| ExAC AF | 0.208 |
SSTR5
| dbSNP name | rs4988483(C,A); rs169068(C,T); rs642249(A,G); rs2076421(A,G) |
| ccdsGene name | CCDS10429.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 6755 |
| EntrezGene Description | somatostatin receptor 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SSTR5:NM_001053:exon1:c.C142A:p.L48M,SSTR5:NM_001172560:exon2:c.C142A:p.L48M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0246 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P35346 |
| dbNSFP Uniprot ID | SSR5_HUMAN |
| dbNSFP KGp1 AF | 0.025641025641 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0386740331492 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0514511873351 |
| dbSNP GMAF | 0.02571 |
| ESP Afr MAF | 0.011494 |
| ESP All MAF | 0.040229 |
| ESP Eur/Amr MAF | 0.054804 |
| ExAC AF | 0.035 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Cerebrovascular ischemic attacks;
Cerebrovascular hemorrhagic attacks;
Hypertension
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa (usually on trunk and/or lower extremities);
Erythematous, irregular netlike pattern of vessels;
HISTOLOGY:;
Intimal proliferation of small arteries;
Occlusion of small arteries
NEUROLOGIC:
[Central nervous system];
Cerebrovascular ischemic attacks, transient (proceed secondary neurologic
findings);
Headaches;
Visual changes;
Hemiplegia;
Dysarthria;
Facial palsy;
Seizures;
Tremor;
Cognitive decline
LABORATORY ABNORMALITIES:
Associated with serum anti-phospholipid antibodies in about 50% of
patients
MISCELLANEOUS:
Incidence of 4 per million per year;
Secondary features include arterial hypertension and renal involvement;
Women are more often affected;
Onset in young adulthood;
Progressive disorder;
One family with confirmed CECR1 mutation has been reported (last curated
August 2014)
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0010)
OMIM Title
*182455 SOMATOSTATIN RECEPTOR 5; SSTR5
OMIM Description
DESCRIPTION
The cyclic tetradecapeptide somatostatin (SST; 182450) is widely
distributed throughout the body and is an important regulator of
endocrine and nervous system function. It exerts its biologic actions by
binding to specific high-affinity receptors on the cell surface.
Somatostatin receptors are a group of structurally related proteins that
are members of the 7 transmembrane-spanning family of G protein-coupled
receptors.
CLONING
Yamada et al. (1993) cloned human somatostatin receptor-4 (SSTR4;
182454) and SSTR5 and determined their functional expression and
pharmacologic characteristics. Moldovan et al. (1998) cloned the mouse
Sstr5 cDNA.
GENE FUNCTION
Somatostatin and dopamine are 2 major neurotransmitter systems that
share a number of structural and functional characteristics.
Somatostatin receptors and dopamine receptors are colocalized in
neuronal subgroups, and somatostatin is involved in modulating
dopamine-mediated control of motor activity. Using photobleaching
fluorescence resonance energy transfer (FRET), Rocheville et al. (2000)
demonstrated that the receptors SSTR5 and D2R (126450) interact
physically through heterooligomerization to create a novel receptor with
enhanced functional activity. The neurotransmitter for either receptor
promoted heterodimerization, but the presence of both ligands did not
produce an additive or synergistic interaction (Milligan, 2000). The
results of Rocheville et al. (2000) provided evidence that receptors
from different G protein-coupled receptor families interact through
oligomerization. Such direct intramembrane association defines a new and
more complex level of molecular crosstalk between related G
protein-coupled receptor subfamilies.
Zatelli et al. (2001) determined that the human medullary thyroid
carcinoma cell line TT (characterized by the presence of a mutation
involving exon 11 of RET, 164761.0012), expresses all SSTR subtypes;
that SSTR2 (182452) activation inhibits DNA synthesis and cell
proliferation, whereas SSTR5 activation increases DNA synthesis; and
that an SSTR2 preferential agonist can antagonize SSTR5-selective
agonist action, and vice versa. These findings suggest a tissue-specific
function and a tissue-specific interaction between the 2 receptors.
Ardjomand et al. (2003) investigated the distribution of SSTR2, SSTR3
(182453), and SSTR5 in uveal melanomas and their diagnostic and possible
therapeutic value. All 25 uveal melanomas studied were positive for
SSTR2: SSTR2A was expressed in 15 of 25; SSTR2B in 23 of 25; SSTR3 in 7
of 25; and SSTR5 in 13 of 25. A Kaplan-Meier survival curve showed a
significantly better ad vitam prognosis for patients with tumors
expressing high levels of SSTR2. Because a melanoma cell proliferation
assay showed an inhibitory effect of up to 36% +/- 6% using octreotide
or vapreotide, somatostatin analogs might be beneficial in the treatment
of patients with ocular melanomas.
Normal pancreatic beta cells express SSTRs. Bertherat et al. (2003)
determined the prevalence of SSTR expression in vitro and characterized
SSTR subtype binding in insulinomas and its correlation with in vivo
SSTR scintigraphy. Semiquantitative RT-PCR of SSTR mRNA was performed
for 20 insulinomas. SSTR2 and SSTR5 were expressed in 70%, SSTR1
(182451) in 50%, and SSTR3 and SSTR4 subtypes only in 15 to 20% of the
tumors. Displacement experiments with ligands of higher affinity for
each of the SSTRs revealed significant binding with the SSTR2 and SSTR5
ligands in 72%, SSTR3 in 44%, SSTR1 in 44%, and SSTR4 in 28% of cases.
The authors concluded that loss of expression of SSTR2/SSTR5 in a third
of insulinomas may be involved in beta-cell dysfunction.
Using an SSTR2-selective antagonist, Ren et al. (2003) showed that both
SSTR2 and SSTR5 participate in the suppression of GH (139250) by
somatostatin (182450) in the human fetal pituitary. The results
demonstrated that either SSTR2 or STR5 may independently suppress GH
secretion from the pituitary. Activation of both SSTR2 and SSTR5 induced
a functional, synergistic association of the receptor subtypes that
resulted in enhanced suppression of G secretion.
Palmitoylation of cysteine residues within intracellular C-terminal
tails of G protein-coupled receptors creates an additional intracellular
loop important for efficient coupling of the receptor to G proteins and
is believed to target receptors to lipid rafts. Using rat Sstr5 as bait
to screen a mouse brain expression library, and by immunoprecipitation
analysis of transfected HEK293 cells, Kokkola et al. (2011) showed that
Sstr5 interacted directly with the palmitoyl acyltransferase Zdhhc5
(614586). Deletion analysis revealed that the first 2 transmembrane
domains of Zdhhc5 were required to interact with the Sstr5 C-terminal
tail. Overexpression of Zdhhc5 increased palmitoylation of Sstr5, and
small interfering RNA-mediated knockdown of ZDHHC5 inhibited Sstr5
palmitoylation.
MAPPING
Takeda et al. (1995) mapped the SSTR5 gene to chromosome 16 on the basis
of its segregation in a panel of reduced human/rodent somatic cell
hybrid cell lines. Takeda et al. (1995) localized the SSTR5 gene to
16p13.3 by fluorescence in situ hybridization. By interspecific
backcross analysis, Brinkmeier and Camper (1997) mapped the Sstr5 gene
to mouse chromosome 17.
EVOLUTION
- Conservation
The 400-Mb genome of the Japanese pufferfish, Fugu rubripes, is
relatively free of repetitive DNA and contains genes with small introns
at high density. Sandford et al. (1996) demonstrated that the genes that
are mutant in polycystic kidney disease-1 (PKD1; 601313) and tuberous
sclerosis-2 (TSC2; 191092) are conserved in the Fugu genome where they
are tightly linked. In addition, sequences homologous to the SSTR5 gene
were identified 5-prime to PKD1, defining a larger syntenic region. As
in genomes of mouse and human, the Fugu TSC2 and PKD1 genes are adjacent
in a tail-to-tail orientation.
MOLECULAR GENETICS
Ballare et al. (2001) reported a mutation in the SSTR5 gene
(182455.0001) that abrogated the antiproliferative action of
somatostatin and activated mitogenic pathways in a patient with
acromegaly (102200) resistant to somatostatin analog octreotide who also
carried an activating GNAS (R201C; 139320.0008) mutation.
NME3
| dbSNP name | rs2575328(T,C) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 4832 |
| snpEff Gene Name | MAPK8IP3 |
| EntrezGene Description | NME/NM23 nucleoside diphosphate kinase 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003214 |
OMIM Clinical Significance
Cardiac:
Protective effect on CAD
Lab:
Elevated serum bilirubin
Inheritance:
Major gene effect in 11.5% of persons analyzed
OMIM Title
*601817 NONMETASTATIC CELLS 3, PROTEIN EXPRESSED IN; NME3
;;DR-NM23;;
NONMETASTATIC PROTEIN 23, HOMOLOG OF; NM23H3
OMIM Description
CLONING
Chronic myelogenous leukemia evolves in 2 clinically distinct stages: a
chronic phase and a blast crisis phase. Venturelli et al. (1995)
identified a cDNA clone, called DR-nm23 by them, which was
differentially expressed in a blast-crisis cDNA library. The sequence
shares approximately 70% similarity with the putative metastatic
suppressor genes, nm23-H1 (NME1; 156490) and nm23-H2 (NME2; 156491). The
gene encodes a 168-amino acid polypeptide with a predicted molecular
mass of 18 kD.
Using Northern blot analysis, Martinez et al. (1997) analyzed the level
of NME3 mRNA in several human tumor cell lines. Abundant expression was
detected in all solid tumor cell lines and in erythromyeloid cell lines.
Lower expression was detected in lymphoid and monocytic cell lines.
Fluorescence-tagged NME3 showed a cytoplasmic punctate localization
following transfection in osteosarcoma cells.
Masse et al. (2002) cloned mouse Nme3, which they called nm23-M3. The
deduced 169-amino acid protein shares 88% identity with human NME3.
Northern blot analysis of several mouse tissues detected a 0.9-kb
transcript expressed at highest levels in liver and kidney, with
moderate levels in heart, brain, spleen, and lung. Little to no
expression was detected in other mouse tissues examined. In situ
hybridization of 15-day postcoitum mouse embryos showed expression in
nervous tissue and thymus.
GENE FUNCTION
Venturelli et al. (1995) found that DR-nm23 mRNA was preferentially
expressed at early stages of myeloid differentiation of highly purified
CD34(+) cells. Its constitutive expression in a myeloid precursor line,
which is growth-factor dependent for both proliferation and
differentiation, resulted in inhibition of granulocytic differentiation
induced by granulocyte colony-stimulating factor (138970) and caused
apoptotic cell death. Venturelli et al. (1995) considered the results
consistent with a role for the NME3 gene in normal hematopoiesis and
raised the possibility that its overexpression contributes to
differentiation arrest, a feature of blastic transformation in chronic
myelogenous leukemia.
GENE STRUCTURE
Martinez et al. (1997) determined that the NME3 gene contains 6 exons.
The promoter region is GC rich and has a pyrimidine-rich initiator (Inr)
element, but no TATA or CAAT boxes. There are putative binding sites for
Sp1 (189906), AP2 (107580), MYB (189990), ETS (164720), GATA (see
305371) and HOX1 (see 142950). However, only AP2 was able to
transactivate the promoter and to interact with 2 putative AP2 sites.
Masse et al. (2002) determined that the mouse and human NME3 genes
contain 5 exons and span about 1.0 kb. Their promoters, like those of
other NME genes, contain several binding sites for AP2, NF1 (613113),
Sp1, LEF1 (153245), and response elements to glucocorticoid receptors
(138040). Masse et al. (2002) stated that NME3 has no pyrimidine-rich
Inr sequences.
MAPPING
By screening human-rodent hybrid cells lines and FISH, Martinez et al.
(1997) mapped the NME3 gene to chromosome 16q13.
SNHG9
| dbSNP name | rs1133099(C,T); rs1054003(C,T) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 735301 |
| snpEff Gene Name | NDUFB10 |
| EntrezGene Description | small nucleolar RNA host gene 9 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2195 |
PGP
| dbSNP name | rs26852(A,G); rs26851(C,T); rs12918530(C,T); rs112972541(G,A); rs11403(A,G); rs114996223(C,T); rs1126(G,C); rs112511919(C,T); rs26849(A,G); rs160545(C,T); rs26848(A,G) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 283871 |
| snpEff Gene Name | MLST8 |
| EntrezGene Description | phosphoglycolate phosphatase |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4288 |
OMIM Clinical Significance
Heme:
Hemolytic anemia
Misc:
Interaction of 6PGL deficiency with G6PD variant
Lab:
6-Phosphogluconolactonase deficiency
Inheritance:
Autosomal dominant
OMIM Title
*172280 PHOSPHOGLYCOLATE PHOSPHATASE; PGP
OMIM Description
This enzyme (EC 3.1.3.18) may have an important regulatory influence on
oxygen transport in man by indirectly affecting the level of red cell
2,3-diphosphoglycerate. (The spellings 'phosphoglycolate' and
'phosphoglycollate' have been used interchangeably, but the former is
preferred.) Barker and Hopkinson (1978) devised a method for detecting
PGP isozymes after starch-gel electrophoresis. They are present in all
human tissues, with highest activities in skeletal and cardiac muscle.
Six different electrophoretic phenotypes were identified. Family studies
showed that these are determined by 3 alleles at an autosomal locus. In
a sample of Europeans, the frequency of the alleles were PGP(1), 0.826;
PGP(2), 0.129; PGP(3), 0.045. The 3-banded isozyme pattern in
heterozygotes suggested that the enzyme is dimeric.
The phosphoglycolate phosphatase locus was assigned to chromosome 16 by
Donald et al. (1979) and by Blankenstein-Wijnen et al. (1979). Family
data suggested that PGP is not close to 16qh or alpha-haptoglobin (Povey
et al., 1980). The most likely regional assignment was considered to be
16p13 or 16p12, but a site on 16q could not be excluded (Povey et al.,
1980). Koeffler et al. (1981) assigned the PGP locus to 16p by mouse-man
somatic cell hybridization. Bale et al. (1984) suggested the existence
of recombination heterogeneity in the linkage with haptoglobin. Reeders
et al. (1986) showed that the PGP locus is, like the alpha-globin locus,
close to the adult polycystic kidney disease locus (maximum lod = 8.21,
theta = 0.00). PGP versus the 3-prime-HVR (hypervariable region 3-prime
to the alpha-globin locus) gave a maximum lod score of 11.61 at theta =
0.00. Thus, PGP, HBA, and APCKD are all close together on 16p. Mulley et
al. (1990) assigned the PGP gene to 16p13.3 by electrophoretic detection
of enzymes from a human/mouse somatic cell panel, the members of which
carried portions of human chromosome 16 with precisely defined
breakpoints. Eiberg et al. (1993) reported a suggestion of linkage
between manic-depressive illness (125480) and PGP; a maximum lod score
of 2.20 at 0% recombination was found in a single large family. A second
family was uninformative.
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
SRRM2
| dbSNP name | rs3112680(T,A); rs3112681(C,T); rs3112682(G,A); rs2240145(C,A); rs2107321(C,T); rs3094779(G,T); rs3094778(C,T); rs76786072(G,A); rs2285879(T,G); rs2285878(C,G); rs2240144(A,C); rs2240143(A,G); rs2240142(C,T); rs2240141(A,G); rs2240140(C,A); rs147634161(C,G); rs3094775(G,A); rs3094773(A,C); rs2301802(T,C); rs3094792(T,G); rs72768767(G,A); rs1050134(G,T) |
| ccdsGene name | CCDS32373.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 23524 |
| EntrezGene Description | serine/arginine repetitive matrix 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SRRM2:NM_016333:exon11:c.C3527G:p.A1176G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5008 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UQ35 |
| dbNSFP Uniprot ID | SRRM2_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.003867 |
| ESP All MAF | 0.001385 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 4.961e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Gaze-evoked nystagmus;
Saccadic smooth pursuit;
Strabismus (13 to 30% of patients);
Oculomotor apraxia (56% of patients);
Conjunctival telangiectasia (reported in 1 family)
SKELETAL:
[Spine];
Scoliosis (22% of patients);
[Feet];
Pes cavus (less common)
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Distal amyotrophy;
Distal muscle weakness
NEUROLOGIC:
[Central nervous system];
Gait ataxia, progressive;
Limb ataxia, progressive;
Spinocerebellar ataxia;
Dysarthria;
Tremor (57% of patients);
Head tremor (14% of patients);
Dystonic hand posturing (44% of patients);
Dystonia (14% of patients);
Choreic movements (10 to 22% of patients);
Pyramidal signs (21% of patients);
Cerebellar atrophy (96% of patients);
Pontocerebellar atrophy;
[Peripheral nervous system];
Polyneuropathy (98% of patients);
Decreased distal vibration sense;
Decreased distal proprioception (74% of patients);
Decreased distal touch sense (57% of patients);
Areflexia;
Absence of sensory action potentials;
Decreased motor nerve conduction velocity (NCV);
Sural nerve biopsy shows chronic axonal neuropathy;
Sural nerve biopsy shows loss of large myelinated fibers
LABORATORY ABNORMALITIES:
Increased serum alpha-fetoprotein;
Increased serum gamma-globulin;
Increased serum creatine kinase (less common)
MISCELLANEOUS:
Onset usually in mid-teens, average 15 years (range 2 to 20 years);
Progressive disorder;
Variable severity;
High frequency in the French-Canadian population
MOLECULAR BASIS:
Caused by mutations in the senataxin gene (SETX, 608465.0001)
OMIM Title
*606032 SERINE/ARGININE REPETITIVE MATRIX PROTEIN 2; SRRM2
;;SERINE/ARGININE-RICH SPLICING FACTOR-RELATED NUCLEAR MATRIX PROTEIN,
300-KD;;
SR-RELATED NUCLEAR MATRIX PROTEIN, 300-KD; SRM300;;
SRL300
OMIM Description
DESCRIPTION
The 300-kD nuclear matrix antigen SRM300 forms a complex with the 160-kD
serine/arginine (SR)-related nuclear matrix protein SRM160 (605975)
known as the SRM160/300 splicing coactivator. This complex functions in
splicing by promoting critical interactions between splicing factors
bound to pre-mRNA, including snRNPs and SR family proteins (summary by
Blencowe et al., 2000).
CLONING
By biochemical purification, micropeptide sequence analysis, EST
database searching, and screening a monocytoid cDNA library, Blencowe et
al. (2000) isolated a cDNA encoding SRM300. Like SRM160, the deduced
2,296-amino acid SRM300 protein is rich in serine (S), arginine (R), and
proline (P), has numerous SR dipeptides and 2 long polyserine domains,
and lacks an RNA recognition domain. A portion of the SRM300 protein is
identical to a partial protein, KIAA0324, identified by Nagase et al.
(1997). By RT-PCR analysis, Nagase et al. (1997) detected ubiquitous
expression of KIAA0324. Using immunoblot and immunoprecipitation
analyses and confocal microscopy, Blencowe et al. (2000) confirmed that
SRM300 associates with SRM160 and pre-mRNA and is localized in nuclear
speckles. Reconstitution of SRM160/SRM300-depleted splicing reactions
with recombinant SRM160 restored splicing activity, suggesting that
SRM160 is the more important component of the complex.
By screening a cDNA library for RNA ligands, Sawada et al. (2000)
identified a cDNA encoding SRM300, which they termed SRL300. The deduced
2,752-amino acid protein has multiple R, S, and P residues, numerous
phosphorylation sites, and a predicted molecular mass of 300 kD,
suggesting that it may be the full-length protein. Immunoblot analysis
detected GST fusion proteins of greater than 300 kD in human and rat
cells. Northern blot analysis revealed expression of a 9.0- to 10.0-kb
SRL300 transcript in all tissues and cell lines tested.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the SRM300
gene, or KIAA0324, to chromosome 16. By genomic sequence analysis,
Blencowe et al. (2000) mapped the SRM300 gene to chromosome 16.
PRSS21
| dbSNP name | rs2074907(A,G); rs200208957(G,A); rs11076844(T,C); rs10641(G,A) |
| ccdsGene name | CCDS10478.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 10942 |
| EntrezGene Description | protease, serine, 21 (testisin) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRSS21:NM_001270452:exon4:c.G355A:p.V119I,PRSS21:NM_144957:exon4:c.G361A:p.V121I,PRSS21:NM_144956:exon4:c.G355A:p.V119I,PRSS21:NM_006799:exon4:c.G361A:p.V121I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.564 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y6M0 |
| dbNSFP Uniprot ID | TEST_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0002277 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Isolated cases
HEAD AND NECK:
[Head];
Microcephaly, acquired;
[Face];
Mask-like facies;
Expressionless facial appearance;
Bitemporal narrowing;
Frontal bossing, mild;
Prominent glabella;
Maxillary hypoplasia;
Retrognathia;
Long, smooth philtrum;
[Ears];
Abnormal ear configuration;
Triangular-shaped ears;
Prominent antihelices;
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Short palpebral fissures;
Blepharophimosis;
Hypertelorism;
Sparse eyelashes;
Sparse eyebrows;
[Nose];
Flat, broad nasal bridge;
Short nose;
Large, anteverted nasal tip;
[Mouth];
Small mouth;
Long, everted upper lip;
Thin upper lip;
High-arched palate;
[Teeth];
Abnormal dentition;
Curved incisors;
[Neck];
Short neck;
Broad neck
CHEST:
[External features];
Laterally displaced nipples;
Hypoplastic nipples
GENITOURINARY:
[External genitalia, male];
Small penis;
[Internal genitalia, male];
Cryptorchidism;
[External genitalia, female];
Hypoplastic labia
SKELETAL:
Joint contractures;
[Skull];
Asymmetric skull;
Craniosynostosis;
[Hands];
Camptodactyly;
Clinodactyly;
Tapering fingers
SKIN, NAILS, HAIR:
[Skin];
Tight, glistening facial skin;
[Hair];
Upswept frontal hair pattern;
Low anterior hairline;
Sparse hair;
Unruly hair;
Sparse eyebrows;
High-arched eyebrows;
Misaligned eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Developmental delay;
[Behavioral/psychiatric manifestations];
Happy demeanor
OMIM Title
*608159 PROTEASE, SERINE, 21; PRSS21
;;EOSINOPHIL SERINE PROTEASE 1; ESP1;;
TESTISIN
OMIM Description
DESCRIPTION
PRSS21 is a membrane-type serine protease that shows highest expression
in premeiotic testicular germ cells.
CLONING
By PCR of an eosinophil cDNA library using degenerate primers based on
the active site of serine proteases, followed by 5-prime and 3-prime
RACE, Inoue et al. (1998) cloned PRSS21, which they called ESP1. The
deduced 314-amino acid ESP1 precursor protein has a calculated molecular
mass of 33.1 kD, and the 273-amino acid active form has a calculated
molecular mass of 30.6 kD. ESP1 contains an N-terminal signal peptide, a
propeptide, an active site catalytic triad of conserved his, asp, and
ser residues, and a hydrophobic C terminus, which suggests that ESP1 is
a membrane-type serine protease. ESP1 shares about 41% amino acid
identity with prostasin (PRSS8; 600823). Northern blot analysis detected
a 1.2- to 1.4-kb transcript in HeLa cells. RT-PCR detected high
expression of ESP1 in testis and prostate, moderate expression in lung,
pancreas, and spleen, and low expression in thymus, colon, and
peripheral blood leukocytes. No expression was detected in kidney and
skeletal muscle. Western blot analysis of transfected human embryonic
kidney cells showed that ESP1 has an apparent molecular mass of 35 kD.
Using PCR, Hooper et al. (1999) cloned PRSS21, which they designated
testisin, from a HeLa cell cDNA library. They identified 3 putative
N-glycosylation sites and 10 conserved cysteine residues in the PRSS21
protein. By analogy to other serine proteases, Hooper et al. (1999)
concluded that 8 of these cysteines likely form disulfide bridges within
the catalytic region, while the remaining 2 probably link the propeptide
and catalytic regions. PRSS21 shares 26 to 38% amino acid identity with
hepsin (142440), acrosin (102480), chymotrypsin (see 118890), and PSA
(176820). Hooper et al. (1999) identified a PRSS21 splice variant that
encodes a 312-amino acid precursor lacking 2 residues near the catalytic
histidine. Northern blot analysis of several human tissues detected a
1.4-kb transcript only in testis. RNA dot blot analysis detected
abundant expression in testis and weak expression in salivary gland,
bone marrow, lung, and trachea. Immunostaining of normal testicular
tissue showed PRSS21 expression in the cytoplasm and on the plasma
membrane of premeiotic germ cells. No staining was detected in 8 germ
cell-derived testicular tumors.
GENE STRUCTURE
Inoue et al. (1999) and Hooper et al. (2000) determined that the PRSS21
gene contains 6 exons and spans 4.5 to 4.6 kb. Using a reporter plasmid,
Inoue et al. (1999) identified a GC-rich 5-prime flanking region
containing an AP1 (see 165160)/SP1 (189906)-binding site as the minimum
promoter for expression in HeLa cells. Hooper et al. (2000) determined
that the promoter region lacks a TATA consensus sequence but contains a
CCAAT box and a CpG island, as well as binding sites for several
testis-specific elements. They noted that the PRSS21 gene has a
structure similar to that of the PRSS8 gene, which maps to chromosome
16p11.2, near PRSS21, suggesting that the 2 genes may have evolved
through gene duplication.
MAPPING
By FISH, Hooper et al. (1999) mapped the PRSS21 gene to chromosome
16p13.3, a region associated with allelic imbalance and loss of
heterozygosity in sporadic testicular tumors. Inoue et al. (1999) mapped
the PRSS21 gene to chromosome 16p13.3 by radiation hybrid analysis and
FISH.
PRSS30P
| dbSNP name | rs149650281(G,A); rs12598686(G,C); rs9925374(A,G); rs17854132(G,A); rs12596044(C,G); rs11859372(C,G); rs11860210(C,G); rs3810801(C,A); rs8064026(A,G) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 124221 |
| EntrezGene Description | protease, serine, 30, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
CLDN9
| dbSNP name | rs2227269(C,T) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 9080 |
| snpEff Gene Name | CLDN6 |
| EntrezGene Description | claudin 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2062 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Nose];
White spongy plaques of nasal mucosa;
[Mouth];
White spongy plaques on the buccal, labial, and soft palatal mucosa
and gingiva
RESPIRATORY:
[Nasopharynx];
White spongy plaques on the pharyngeal mucosa
ABDOMEN:
[Gastrointestinal];
White spongy plaques on the esophageal mucosa;
White spongy plaques on the rectal mucosa
GENITOURINARY:
[Internal genitalia, female];
White spongy plaques on the vaginal mucosa
SKIN, NAILS, HAIR:
[Skin];
Asymptomatic soft white spongy mucosal plaques with thick folded surfaces
HISTOLOGY:;
Epithelial thickening;
Hyperparakeratosis;
Acanthosis;
Intracellular edema of spinous layer;
Basket-weave appearance of spinous layer;
Cell-within-a-cell appearance of spinous layer;
Perinuclear condensation;
Narrow intercellular spaces between vacuolated cells;
Orderly appearance of basal cell layer;
Mild chronic inflammatory cell infiltrate of lymphocytes in submucosal
connective tissue
MOLECULAR BASIS:
Caused by mutation in the keratin-13 gene (KRT13, 148065.0001)
OMIM Title
*615799 CLAUDIN 9; CLDN9
OMIM Description
DESCRIPTION
Members of the claudin family, such as CLDN9, form tight junctions and
regulate permeability of epidermal sheets. Claudins have 2 extracellular
loops responsible for permeability barrier formation and ion
selectivity, 4 transmembrane regions, and a cytoplasmic C-terminal tail
that anchors the claudin to the cytoskeleton (summary by Zheng et al.,
2007).
CLONING
Using real-time PCR, Zheng et al. (2007) found that CLDN9 was highly
expressed in human peripheral blood mononuclear cells, with lower
expression in liver and hepatocarcinoma cell lines.
GENE FUNCTION
Zheng et al. (2007) found that CLDN6 (615798) and CLDN9 functioned as
receptors for entry of hepatitis C virus (HCV; see 609532) in
HCV-permissive human hepatocellular carcinoma cells. Real-time PCR
showed that overexpression of either claudin in nonpermissive 293T cells
conferred susceptibility to HCV entry. Mutation analysis revealed that
val32, asn38, val45, and glu48 in extracellular loop-1 of CLDN9 were
required for HCV infection.
MAPPING
Hartz (2014) mapped the CLDN9 gene to chromosome 16p13.3 based on an
alignment of the CLDN9 sequence (GenBank GENBANK A1791760) with the
genomic sequence (GRCh37).
CLDN6
| dbSNP name | rs8064223(C,T); rs2257295(T,C); rs367945835(G,A); rs2269911(G,A); rs2717701(G,C); rs2717702(G,A); rs2717703(A,G) |
| ccdsGene name | CCDS10488.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 9074 |
| EntrezGene Description | claudin 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN6:NM_021195:exon2:c.C314T:p.T105I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.804 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P56747 |
| dbNSFP Uniprot ID | CLD6_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0002114 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Nose];
White spongy plaques of nasal mucosa;
[Mouth];
White spongy plaques on the buccal, labial, and soft palatal mucosa
and gingiva
RESPIRATORY:
[Nasopharynx];
White spongy plaques on the pharyngeal mucosa
ABDOMEN:
[Gastrointestinal];
White spongy plaques on the esophageal mucosa;
White spongy plaques on the rectal mucosa
GENITOURINARY:
[Internal genitalia, female];
White spongy plaques on the vaginal mucosa
SKIN, NAILS, HAIR:
[Skin];
Asymptomatic soft white spongy mucosal plaques with thick folded surfaces
HISTOLOGY:;
Epithelial thickening;
Hyperparakeratosis;
Acanthosis;
Intracellular edema of spinous layer;
Basket-weave appearance of spinous layer;
Cell-within-a-cell appearance of spinous layer;
Perinuclear condensation;
Narrow intercellular spaces between vacuolated cells;
Orderly appearance of basal cell layer;
Mild chronic inflammatory cell infiltrate of lymphocytes in submucosal
connective tissue
MOLECULAR BASIS:
Caused by mutation in the keratin-13 gene (KRT13, 148065.0001)
OMIM Title
*615798 CLAUDIN 6; CLDN6
OMIM Description
DESCRIPTION
Members of the claudin family, such as CLDN6, form tight junctions and
regulate permeability of epidermal sheets. Claudins have 2 extracellular
loops responsible for permeability barrier formation and ion
selectivity, 4 transmembrane regions, and a cytoplasmic C-terminal tail
that anchors the claudin to the cytoskeleton (summary by Zheng et al.,
2007).
CLONING
Using real-time PCR, Zheng et al. (2007) found that CLDN6 was expressed
at variable levels in human liver, peripheral blood mononuclear cells,
and hepatocarcinoma cell lines.
GENE FUNCTION
Zheng et al. (2007) found that CLDN6 and CLDN9 (615799) functioned as
receptors for entry of hepatitis C virus (HCV; see 609532) in
HCV-permissive human hepatocellular carcinoma cells. Real-time PCR
showed that overexpression of either claudin in nonpermissive 293T cells
conferred susceptibility to HCV entry.
MAPPING
Hartz (2014) mapped the CLDN6 gene to chromosome 16p13.3 based on an
alignment of the CLDN6 sequence (GenBank GENBANK AF125306) with the
genomic sequence (GRCh37).
ANIMAL MODEL
Troy et al. (2005) stated that homozygous mice overexpressing Cldn6 in
epidermis exhibit defective permeability barrier function, causing
dehydration and death within 48 hours of birth. They found that
heterozygous transgenic mice were also born with an incomplete epidermal
permeability barrier, but that they survived and progressively acquired
barrier function and normal hydration by postnatal day 12. Transgenic
heterozygotes displayed hyperkeratosis, concomitant with atypical
patterns of claudin and keratin expression, including uncoupling of Krt5
(148040) and Krt14 (148066). Heterozygous transgenic animals also showed
abnormalities in hair-type distribution.
TNFRSF12A
| dbSNP name | rs13209(T,C) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 51330 |
| snpEff Gene Name | HCFC1R1 |
| EntrezGene Description | tumor necrosis factor receptor superfamily, member 12A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1855 |
| ExAC AF | 0.177 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Bladder];
Urinary urgency (in 44% of patients)
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Rigidity;
Bradykinesia;
Resting tremor;
Asymmetry at onset (74%);
Dystonia at onset (16%);
Postural instability (63%);
Gait impairment (55%);
Hyperreflexia (33%);
Sleep benefit (31%);
Autonomic instability (22%);
Dementia (5%);
[Behavioral/psychiatric manifestations];
Psychiatric disturbances (25%);
Anxiety;
Depression
MISCELLANEOUS:
Early onset (9-48 years, but reported up to 68 years);
Slow progression;
Diurnal fluctuation;
Levodopa-responsive;
Levodopa-induced dyskinesias;
A subset of patients have heterozygous mutations, which may predispose
to disease development
MOLECULAR BASIS:
Caused by mutation in the PTEN-induced putative kinase-1 gene (PINK1,
608309.0001)
OMIM Title
*605914 TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 12A; TNFRSF12A
;;TYPE I TRANSMEMBRANE PROTEIN FN14; FN14;;
TWEAK RECEPTOR; TWEAKR
OMIM Description
CLONING
Using a differential display approach to isolate cDNA fragments
representing fibroblast growth factor-1 (FGF1; 131220)-inducible genes,
Meighan-Mantha et al. (1999) isolated a mouse cDNA encoding, Tnfrsf12a,
which they called Fn14. They characterized Fn14 as an immediate-early
response gene. By searching an EST database with the mouse sequence,
Feng et al. (2000) identified cDNAs encoding human TNFRSF12A. The
predicted 129-amino acid FN14 protein, which shares 82% amino acid
identity with the mouse sequence, contains a signal peptide, an
extracellular domain, a membrane-anchoring domain, and a cytoplasmic
domain. Northern blot analysis detected increased FN14 expression in
response to FGF1, calf serum, or phorbol ester stimulation of human
quiescent fibroblasts in vitro. A 1.2-kb FN14 transcript was expressed
at high levels in heart, placenta, and kidney, at intermediate levels in
lung, skeletal muscle, and pancreas, and at low levels in brain and
liver. In addition, elevated FN14 expression was found in human liver
cancer cell lines and hepatocellular carcinoma specimens. Expression of
mouse Fn14 was upregulated in hepatocellular carcinoma nodules that
develop in 2 different transgenic mouse models of hepatocarcinogenesis.
Rapid induction of Fn14 expression occurred during mouse liver
regeneration after partial hepatectomy. Feng et al. (2000) concluded
that FN14 may play a role in hepatocyte growth control and liver
neoplasia.
Using expression cloning and panning of an endothelial cell cDNA library
with the C-terminal receptor-binding domain of TWEAK (TNFSF12; 602695)
as the probe, followed by slide binding analysis, Wiley et al. (2001)
isolated a cDNA encoding FN14, which they termed TWEAKR. Sequence
analysis predicted that TWEAKR has a single extracellular cysteine-rich
region that is homologous to those observed in TNFRSF1A (191190) and
some other TNFR family members. TWEAKR also has a cytoplasmic TRAF (see
TRAF2; 601895)-binding site. Different binding analyses indicated a
physiologically relevant affinity between TWEAK and TWEAKR. GST-binding
analysis showed an interaction of the TWEAKR cytoplasmic region with
TRAF1 (601711), TRAF2, and, to a lesser extent, TRAF3 (601896), but not
with other TRAFs tested. Northern blot analysis revealed expression of a
1.2-kb Tweakr transcript in rat aortic smooth muscle cells. Tweakr
expression could be upregulated by a number of growth factors. Blocking
of TWEAKR signaling inhibited the migration of renal microvascular cells
in vitro, indicating that endogenous TWEAK regulates endothelial cell
wound closure rates. Wiley et al. (2001) concluded that TWEAKR is a
fully functional receptor for TWEAK and that the TWEAK-TWEAKR system
plays a role in endothelial cell growth and migration.
MAPPING
Using FISH, Feng et al. (2000) mapped the TNFRSF12A gene to chromosome
16p13.3. Meighan-Mantha et al. (1999) mapped the mouse Tnfrsf12a gene to
chromosome 17.
GENE FUNCTION
Using Western blot and immunocytochemistry, Jain et al. (2009)
demonstrated high relative expression of Fn14 in cardiomyocytes, 3-fold
greater than the overall tissue mean, with the level of expression
second only to bronchial epithelial cells, smooth muscle cells,
colorectal adenocarcinoma, and placenta. In mice, Fn14 expression was
noted in ventricular cardiomyocytes at embryonic day 12.5, with little
expression in atrial cells.
OR1F1
| dbSNP name | rs1834026(T,C); rs2075851(T,C) |
| ccdsGene name | CCDS10496.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 4992 |
| EntrezGene Description | olfactory receptor, family 1, subfamily F, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1F1:NM_012360:exon1:c.T224C:p.F75S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O43749 |
| dbNSFP Uniprot ID | OR1F1_HUMAN |
| dbNSFP KGp1 AF | 0.445970695971 |
| dbNSFP KGp1 Afr AF | 0.29674796748 |
| dbNSFP KGp1 Amr AF | 0.488950276243 |
| dbNSFP KGp1 Asn AF | 0.548951048951 |
| dbNSFP KGp1 Eur AF | 0.444591029024 |
| dbSNP GMAF | 0.4458 |
| ESP Afr MAF | 0.311334 |
| ESP All MAF | 0.395798 |
| ESP Eur/Amr MAF | 0.438953 |
| ExAC AF | 0.462 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Severe myopia (> -6.00 diopters);
Detached retina
MISCELLANEOUS:
Genetic heterogeneity
OMIM Title
*603232 OLFACTORY RECEPTOR, FAMILY 1, SUBFAMILY F, MEMBER 1; OR1F1
;;OLFMF
OMIM Description
CLONING
During genomic sequencing and exon trapping in the chromosomal region
around the familial Mediterranean fever locus (MEFV; 608107), the French
FMF Consortium (1997) identified a novel gene encoding an olfactory
receptor, which they designated OLFMF. OLFMF encodes a deduced 312-amino
acid polypeptide.
GENE STRUCTURE
The French FMF Consortium (1997) determined that the OR1F1 gene contains
a single exon. The authors also noted that another exon in this
chromosomal region has homology to the olfactory receptors but is likely
to be a pseudogene.
MAPPING
The French FMF Consortium (1997) mapped the OR1F1 gene to chromosome
16p13, telomeric to the marenostrin gene (MEFV).
OR1F2P
| dbSNP name | rs2550401(A,G) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 26184 |
| snpEff Gene Name | AJ003147.1 |
| EntrezGene Description | olfactory receptor, family 1, subfamily F, member 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4642 |
| ExAC AF | 0.474,1.195e-03 |
OR2C1
| dbSNP name | rs1218762(G,A); rs1228348(A,G); rs1218763(C,G); rs62000973(G,A); rs11643487(A,G); rs11648783(G,A) |
| ccdsGene name | CCDS10502.1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 4993 |
| EntrezGene Description | olfactory receptor, family 2, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR2C1:NM_012368:exon1:c.G46A:p.G16S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95371 |
| dbNSFP Uniprot ID | OR2C1_HUMAN |
| dbNSFP KGp1 AF | 0.257783882784 |
| dbNSFP KGp1 Afr AF | 0.373983739837 |
| dbNSFP KGp1 Amr AF | 0.254143646409 |
| dbNSFP KGp1 Asn AF | 0.141608391608 |
| dbNSFP KGp1 Eur AF | 0.271767810026 |
| dbSNP GMAF | 0.258 |
| ESP Afr MAF | 0.345926 |
| ESP All MAF | 0.298907 |
| ESP Eur/Amr MAF | 0.274884 |
| ExAC AF | 0.263 |
MTRNR2L4
| dbSNP name | rs9937267(C,T); rs9921152(A,G); rs9921169(A,T); rs72776357(C,A); rs9929549(G,A); rs8053830(T,C); rs9940125(C,G) |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 100463285 |
| EntrezGene Description | MT-RNR2-like 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2461 |
TRAP1
| dbSNP name | rs8047251(G,A); rs150401264(C,A); rs710891(C,T); rs6500548(C,G); rs1024573(A,T); rs7200737(G,A); rs377509192(G,A); rs144965528(G,A); rs76345172(A,G); rs143557692(A,G); rs149420453(G,C); rs117577706(G,A); rs75484539(C,G); rs75377947(G,A); rs4786427(A,G); rs10852637(T,C); rs3794699(T,C); rs74005843(G,A); rs11646287(C,T); rs28464270(A,G); rs138319534(A,G); rs114467413(T,A); rs115064695(C,A); rs56373045(G,A); rs1136948(G,C); rs144279281(T,C); rs12925683(C,G); rs12444804(C,A); rs12929402(G,T); rs13926(G,C); rs2074805(A,T); rs8050400(A,G); rs2074801(T,G); rs4786429(C,T); rs7197794(C,T); rs73489734(G,A); rs3829541(C,G); rs3794701(A,G); rs115548635(C,A); rs67081976(G,A); rs149874326(G,C); rs77388305(G,C); rs8048647(G,A); rs191124026(C,T); rs28697882(A,G); rs113458195(G,A); rs112526911(G,A); rs61758086(C,T); rs7202449(G,C); rs28699119(A,G); rs6500549(T,G); rs79848897(T,C); rs1468608(C,A); rs2158962(A,G); rs2108430(C,T); rs78763112(C,G); rs2072379(C,T); rs2072380(T,G); rs2270186(C,T); rs9923245(G,T); rs72778152(A,T); rs2008344(G,A); rs8050069(T,G); rs8050794(T,C); rs11646456(C,G); rs4786432(C,G); rs12925310(C,G); rs72760803(C,T); rs11862646(T,C); rs75712687(G,A); rs13333291(A,T); rs6500550(C,T); rs1635404(G,T); rs1639150(C,T); rs111432642(G,A); rs8048452(G,A); rs116252659(T,G); rs8055172(T,C); rs8050376(C,T); rs11646280(C,T); rs11645975(G,C); rs112767262(C,T); rs13335243(T,C); rs117914665(C,T); rs1639151(G,C); rs7191949(G,A); rs117025072(G,A); rs7199019(T,A); rs60049641(T,C); rs76170454(T,C); rs4260059(A,G); rs4260060(A,G); rs4786434(T,G); rs142406029(T,C); rs116870791(C,T); rs7201881(T,C); rs188335951(G,A); rs34167944(C,T); rs6500552(T,C); rs117897135(G,A); rs9972684(A,G); rs17136481(C,A); rs67264850(C,T); rs129987(T,A); rs129989(C,T); rs38025(T,C); rs43223(C,A); rs79639764(T,C); rs72760814(C,A); rs186746790(A,G) |
| ccdsGene name | CCDS10508.1 |
| CosmicCodingMuts gene | TRAP1 |
| cytoBand name | 16p13.3 |
| EntrezGene GeneID | 10131 |
| EntrezGene Description | TNF receptor-associated protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TRAP1:NM_001272049:exon3:c.G224A:p.R75H,TRAP1:NM_016292:exon4:c.G383A:p.R128H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6921 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000455 |
| ESP All MAF | 0.001462 |
| ESP Eur/Amr MAF | 0.001977 |
| ExAC AF | 3.326e-03,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Tall stature;
[Other];
Normal to accelerated growth
HEAD AND NECK:
[Head];
Dolichocephaly;
Macrocephaly;
[Face];
Asymmetric face;
Prominent brow;
Maxillary prognathism, mild;
Pointed chin;
Small chin;
[Ears];
Prominent ears;
Dysplastic ears;
Simple ears;
Hearing impairment;
[Eyes];
Ptosis;
Epicanthal folds;
[Nose];
Saddle nose;
Bulbous nasal tip
ABDOMEN:
[Gastrointestinal];
Feeding difficulties, neonatal
SKELETAL:
[Hands];
Large, fleshy hands
SKIN, NAILS, HAIR:
[Skin];
Tendency to overheat;
Lack of perspiration;
[Nails];
Dysplastic toenails
MUSCLE, SOFT TISSUE:
Hypotonia, neonatal
NEUROLOGIC:
[Central nervous system];
Global developmental delay;
Delayed motor development;
Absent or delayed speech development;
Compromised expressive language development, severe;
Mental retardation, moderate to severe;
Generalized hypotonia;
Seizures;
[Peripheral nervous system];
Increased tolerance to pain;
Hyporeflexia, neonatal;
Abnormal reflexes;
[Behavioral/psychiatric manifestations];
Inappropriate chewing behavior;
Autistic features;
Poor social interaction;
Poor communication;
Aggressive behavior
MISCELLANEOUS:
Wide phenotypic variation;
Some patients do not have dysmorphic features;
Heterozygous deletion of the terminal band 22q13.3 including SHANK3
(606230)
MOLECULAR BASIS:
A contiguous gene syndrome caused by deletion (160kb to 9Mb) of 22q13.3
OMIM Title
*606237 TRANSFORMING GROWTH FACTOR-BETA RECEPTOR-ASSOCIATED PROTEIN 1; TGFBRAP1
;;TGFBR-ASSOCIATED PROTEIN 1; TRAP1
OMIM Description
Members of the transforming growth factor-beta (TGFB) family (e.g.,
TGFB1; 190180) act through type II membrane receptor serine-threonine
kinases (e.g., TGFBR2; 190182), which then recruit and
transphosphorylate type I receptor serine-threonine kinases (e.g.,
TGFBR1; 190181). This leads to the activation of downstream targets
involved in the regulation of physiologic and pathologic processes.
CLONING
Using TGFBR1 carrying leu193-to-ala, pro194-to-ala, and thr204-to-asp
mutations, which were designed to activate the molecule and eliminate
FKBP1A (186945) binding, as bait in a yeast 2-hybrid screen of a
lymphocyte cDNA library, followed by probing a heart cDNA library and
5-prime RACE, Charng et al. (1998) isolated cDNAs encoding TRAP1 and
TRAP2. Binding analysis indicated that TRAP1 interacted with activated
TGFBR1 (i.e., TGFBR1 with the thr204-to-ala mutation) but not with
wildtype, inactive TGFBR1. TRAP2 only interacted with activated TGFBR1
that also had the leu193-to-ala and pro194-to-ala mutations, which
removed FKBP1A binding. The deduced 860-amino acid TRAP1 protein
contains multiple phosphorylation and myristoylation sites. Northern
blot analysis revealed ubiquitous expression of 4.4- and 6.0-kb TRAP1
transcripts, with lower abundance in lung and liver. Functional analysis
suggested that a partial TRAP1 cDNA could act as an inhibitor of TGFB
signaling.
GENE FUNCTION
By immunoprecipitation and Western blot analyses with full-length TRAP1,
Wurthner et al. (2001) showed that TRAP1 associates with the TGFBR
complex and that its primary binding partner is TGFBR2. Strongest
binding was found to occur with kinase-deficient receptors. Mutation
analysis indicated that TRAP1 has TGFBR2-binding sites in its N and C
termini and in its central portion. Immunoblot analysis determined that
TRAP1 interacts with SMAD4 (MADH4; 600993) but not with a panel of other
SMADs. This interaction was transient and could be disrupted by
activated SMAD2 (MADH2; 601366).
GENE STRUCTURE
Wurthner et al. (2001) reported that the TRAP1 gene contains 11 exons.
MAPPING
Wurthner et al. (2001) stated that the TRAP1 gene maps to chromosome 2.
MIR548X
| dbSNP name | rs7501294(G,A) |
| cytoBand name | 16p13.2 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4412 |
PRM3
| dbSNP name | rs438289(G,A); rs429744(C,T); rs35598356(G,C) |
| cytoBand name | 16p13.13 |
| EntrezGene GeneID | 58531 |
| snpEff Gene Name | PRM2 |
| EntrezGene Description | protamine 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRM3:NM_021247:exon1:c.C310T:p.R104X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03719 |
| ESP Afr MAF | 0.10837 |
| ESP All MAF | 0.041035 |
| ESP Eur/Amr MAF | 0.005424 |
| ExAC AF | 0.973 |
PRM1
| dbSNP name | rs737008(G,T); rs35262993(C,T) |
| ccdsGene name | CCDS10547.1 |
| CosmicCodingMuts gene | PRM1 |
| cytoBand name | 16p13.13 |
| EntrezGene GeneID | 5619 |
| EntrezGene Description | protamine 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRM1:NM_002761:exon2:c.C139A:p.R47R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4899 |
| ESP Afr MAF | 0.456076 |
| ESP All MAF | 0.350931 |
| ESP Eur/Amr MAF | 0.297209 |
| ExAC AF | 0.595 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial asymmetry;
Long philtrum;
[Ears];
Transverse earlobe creases;
Low-set ears;
[Eyes];
Strabismus;
Narrow palpebral fissure, unilateral;
Ptosis, unilateral
SKELETAL:
[Skull];
Decreased orbital diameter, unilateral;
Thin zygomatic arch, unilateral
NEUROLOGIC:
[Central nervous system];
Delayed speech development;
Decreased IQ (some patients);
Learning disability
OMIM Title
*182880 SPERM PROTAMINE P1; PRM1
OMIM Description
CLONING
Protamines are small, arginine-rich, nuclear proteins that replace
histones (e.g., 142709) late in the haploid phase of spermatogenesis and
are believed essential for sperm head condensation and DNA
stabilization. Mice, humans, and certain fish have 2 or more different
protamines, whereas the sperm of bull, boar, rat, rabbit, guinea pig,
and ram have one form of protamine. The 2 human protamines are denoted
P1 and P2 (PRM2; 182890). The amino acid sequence of both has been
determined (Ammer et al., 1986). Of the 50 amino acid residues of P1, 24
are arginines and 6 are cysteines. Ammer et al. (1986) found 2 forms of
P2 that differ by the presence in one of 3 additional amino acids at the
N terminus. Of the 57 residues of the longer form, 27 are arginines and
5 are cysteines. The nucleotide sequence of the 2 mouse protamine cDNAs
predict markedly different amino acid sequences, a conclusion in
agreement with data on amino acid composition and on electrophoretic
mobility.
GENE STRUCTURE
Krawetz et al. (1989) showed that there is a single copy of the human P1
protamine gene, that the mRNA is approximately 450 bases long, and that
the gene contains an intron.
Domenjoud et al. (1990) showed that both PRM1 and PRM2 have a single
intron, consisting of 91 and 163 bp, respectively. Both genes were found
to contain typical TATAA and CAAT boxes at conventional distances from
the transcription start points which, by use of primary extension
experiments, were assigned to nucleotides -91 and -110 for PRM1 and
PRM2, respectively.
GENE FUNCTION
Choudhary et al. (1995) referred to the linear array of PRM1, which they
stated is located on 16p13.2, as a multigenic locus. To study the
mechanisms that govern expression in the male gamete, they constructed a
transgenic mouse model. A segment of human chromosome 16 harboring the
PRM1--PRM2--TNP2 gene cluster was introduced into fertilized mouse eggs.
This 40,255-bp fragment contained sufficient information to express
faithfully all the members of this multigene family in a copy
number-dependent but position-independent manner in the heterologous
system. A DNase I-sensitive domain of approximately 28.5 kb encompassing
the human gene cluster was bounded by an array of topoisomerase II
consensus sites. These results established that, like somatic cells, the
genes transcribed by the male gamete are organized at specific loci as
functional domains. The concept that transcriptionally competent
chromatin assumes an altered nuclear structure had been validated for
somatic cells when it was shown that the beta-globin gene (141900)
acquired a DNase I-sensitive conformation within cells in which it was
expressed. Choudhary et al. (1995) found that the 28.5-kb segment
containing the 3 genes integrated into independent chromosomal sites
while maintaining its fidelity of transcription. All members of the
cluster were expressed in proportion similar to those in human testis.
Furthermore, DNase I sensitivity established that in sperm the gene
domain is bounded by an array of nuclear matrix-associated topoisomerase
II (126430) consensus sites. This was the first description of a
multigenic male gamete-specific domain as a fundamental gene regulatory
unit.
Protamines, the major DNA-binding proteins in the nucleus of sperm in
most vertebrates, package the DNA in a volume less than 5% of a somatic
cell nucleus. Many mammals have one protamine, but a few species,
including humans and mice, have 2. Cho et al. (2001) used gene targeting
to determine if the second protamine provides redundancy to an essential
process, or if both protamines are necessary. They disrupted the coding
sequence of 1 allele of either Prm1 or Prm2 in embryonic stem (ES) cells
derived from 129-strain mice, and injected them into blastocysts from
C57BL/6-strain mice. Male chimeras produced 129-genotype sperm with
disrupted Prm1 or Prm2 alleles, but failed to sire offspring carrying
the 129 genome. They also found that a decrease in the amount of either
protamine disrupted nuclear formation, processing of protamine-2, and
normal sperm function. Their studies indicated that both protamines are
essential and that haploinsufficiency caused by a mutation in 1 allele
of either gene prevents genetic transmission of both mutant and wildtype
alleles.
MAPPING
From studies of hamster/mouse hybrids, Hecht et al. (1986) found that
both of the protamines of mice are coded by chromosome 16. Perhaps the
synteny permits coordinate regulation. These may be genes that are
expressed in the haploid state.
Reeves et al. (1987, 1987) also found that the protamine-1 locus is on
chromosome 16 of the mouse. By linkage studies, Reeves et al. (1987,
1989) showed that Prm1 is located near the proximal end of mouse
chromosome 16. No recombinants between Prm1 and Prm2 were found. In the
Chinese hamster, furthermore, probes specific for Prm1 and Prm2
hybridized to the same restriction fragment after digestion of hamster
genomic DNA with any of 5 different restriction endonucleases.
By studies in rodent/human cell hybrids, Reeves et al. (1987, 1989)
demonstrated that PRM1 is located on chromosome 16 in humans.
Krawetz et al. (1989) mapped the human PRM1 gene to chromosome 16q21 by
a combination of somatic cell hybrid studies and in situ hybridization.
By in situ hybridization, Engel (1990) found that PRM1 and PRM2 are in
the same 4.8-kb fragment and map to 16p13.3. Viguie et al. (1990) found,
also by in situ hybridization, that both PRM1 and PRM2 map to 16p13.3.
MOLECULAR GENETICS
Iguchi et al. (2006) analyzed the PRM1 gene in 30 unrelated infertile
men and 10 men of pregnancy-proven fertility. In 3 of the infertile men,
they identified heterozygosity for a 197G-T SNP, predicted to result in
an arg34-to-ser (R34S) substitution in a highly conserved arginine
cluster. The authors noted that this appeared to be an uncommon SNP, as
it was not found in 522 men from previous studies (270 fertile, 226
sterile, and 26 unselected) nor in 220 individuals from 2 SNP databases.
Kichine et al. (2008) screened 361 infertile and 672 fertile men for the
197G-T SNP, which they designated 102G-T, and found 3 heterozygotes, 2
from the fertile group and 1 who had obstructive infertility (agenesis
of the vas deferens). Another SNP in the PRM1 gene, a -107G-C
transversion, was not found in any of the 672 fertile men but in 2 of
192 infertile men, both of sub-Saharan African origin; however, in a
screening of unselected samples from similar regions, 3 of 95 Comorian
men and 12 of 67 Congolese men were found to be 107C carriers. Kichine
et al. (2008) concluded that neither SNP has a significant effect on
male fertility.
ANIMAL MODEL
Okada et al. (2007) used a loss-of-function approach to demonstrate that
the mouse H3K9me2/1-specific demethylase Jhdm2a (611512) is essential
for spermatogenesis. They showed that Jhdm2a-deficient mice exhibit
postmeiotic chromatin condensation defects, and that Jhdm2a directly
binds to and controls the expression of transition nuclear protein-1
(TNP1; 190231) and PRM1 genes, the products of which are required for
packaging and condensation of sperm chromatin. Thus, Okada et al. (2007)
concluded that their work uncovered a role for JHDM2A in spermatogenesis
and revealed transition nuclear protein and protamine genes as direct
targets of JHDM2A.
MYH11
| dbSNP name | rs2242549(G,T); rs4781680(T,C); rs4781681(C,T); rs881803(C,T); rs9746950(G,T); rs12443661(C,T); rs67006130(G,T); rs4781682(C,T); rs11075278(A,G); rs78796084(A,G); rs10521101(T,C); rs55871015(G,A); rs2242548(G,T); rs141973181(T,C); rs1050163(C,T); rs1050162(C,T); rs72772021(G,A); rs11646134(G,T); rs17284411(G,A); rs375253455(C,A); rs144592555(C,T); rs2075512(C,T); rs137934837(C,T); rs141830488(C,G); rs2384933(T,C); rs145503391(C,G); rs11641598(G,A); rs8047068(G,C); rs2075511(A,C); rs11130(G,A); rs16967510(A,G); rs7185993(C,T); rs2018109(G,C); rs72772024(G,A); rs62029310(T,C); rs117161826(C,T); rs62029312(G,T); rs11862588(A,C); rs57066595(G,C); rs4781683(G,C); rs76320617(A,G); rs80225998(A,G); rs2272555(G,A); rs62029314(C,G); rs138438263(T,A); rs116692213(A,G); rs191313777(A,T); rs7186708(G,T); rs72772025(C,T); rs142683189(A,C); rs2075510(G,C); rs13335203(G,A); rs62029315(C,T); rs2384934(G,C); rs1050113(G,A); rs8045110(C,G); rs2293736(G,A); rs880071(G,A); rs76699771(G,A); rs6498570(G,A); rs373362818(G,A); rs79295535(G,A); rs77466193(C,T); rs4781684(T,C); rs4781685(G,C); rs13330959(C,T); rs138091450(T,C); rs4781686(T,C); rs62029316(T,G); rs116925582(A,G); rs62029317(G,C); rs62029318(C,G); rs12102743(T,G); rs62029319(C,T); rs62029320(T,C); rs2272554(A,G); rs147497974(G,A); rs2280764(C,G); rs73504420(C,A); rs142024469(G,T); rs142148967(T,G); rs60150942(G,A); rs932233(C,G); rs115364997(A,G); rs35382676(A,G); rs72772041(T,A); rs2384936(A,G); rs4444362(C,G); rs4781687(C,A); rs79379911(G,C); rs72772042(C,A); rs16967478(G,A); rs17213271(T,C); rs16967475(A,G); rs112740394(G,A); rs11865503(T,C); rs74341835(C,T); rs13333923(G,A); rs8059739(A,G); rs35288467(C,A); rs11641649(T,C); rs56374730(T,G); rs1569301(T,C); rs8059855(C,T); rs12149912(G,A); rs4781690(G,A); rs12922040(C,T); rs2075516(T,C); rs2072619(T,C); rs34341838(A,G); rs57038077(A,G); rs11075280(G,A); rs112653462(A,G); rs4541094(C,T); rs72772049(G,T); rs1569300(G,A); rs4262965(G,A); rs4482303(C,T); rs113841182(G,A); rs112536681(T,C); rs58081475(A,G); rs10852375(A,T); rs57379392(A,G); rs10852376(G,A); rs2075515(G,A); rs2075514(A,G); rs11644832(G,T); rs11645883(G,A); rs62030562(A,G); rs55801716(G,A); rs8048077(C,T); rs11075281(G,A); rs147676087(T,A); rs7201553(A,G); rs11866891(C,T); rs62030564(C,T); rs58476672(G,A); rs2075513(T,C); rs13332091(C,T); rs8060975(C,T); rs62030565(G,T); rs72772056(G,A); rs72772057(T,G); rs8045778(C,T); rs113646446(A,G); rs8051703(A,G); rs6498573(C,T); rs9936350(G,A); rs62030567(G,A); rs62030568(G,A); rs9929598(A,G); rs112560110(A,G); rs56041951(G,A); rs11645301(A,G); rs113989508(C,T); rs9924070(G,A); rs62030572(G,A); rs74009429(T,A); rs66459930(A,G); rs72772064(G,A); rs72772068(T,C); rs17214007(T,C); rs9941314(A,G); rs62030574(A,G); rs72772070(G,A); rs77197376(C,T); rs12599111(G,A); rs4781693(T,C); rs59996655(T,C); rs144762096(C,G); rs8051319(T,C); rs114258721(C,T); rs117537739(G,A); rs62030576(A,G); rs7193613(C,T); rs9923303(A,G); rs6498574(T,C); rs6498575(T,G); rs6498576(T,C); rs13335794(C,G); rs141144031(G,A); rs8054007(A,G); rs8054219(A,C); rs9926287(A,G); rs9936196(C,T); rs9926301(A,T); rs8063887(C,T); rs909079(G,T); rs7186608(T,C); rs13339360(A,G); rs13333967(G,C); rs62030580(G,A); rs17286649(T,C); rs12325569(C,A); rs9929067(A,G); rs74449435(T,A); rs8064077(T,C); rs35773266(G,C); rs74923788(C,G); rs7185312(A,G); rs8050382(T,C); rs147065499(G,C); rs116411193(T,A); rs35982068(A,G); rs741715(C,T); rs9302519(A,G); rs1109418(T,G); rs9929886(T,G); rs1109420(C,T); rs1109419(G,C); rs9673727(T,C); rs75713692(A,G); rs9972711(A,T); rs9284324(G,A); rs62030621(T,C); rs11075282(T,C); rs11866783(G,A); rs8048256(C,T); rs8058223(T,A); rs11647019(T,C); rs79205960(T,C); rs4780581(C,T); rs7206453(T,C); rs8059018(C,T); rs7206892(T,C); rs8044595(A,G); rs7200660(G,A); rs188574457(C,T); rs11648603(G,A); rs12919510(T,G); rs62030623(G,T); rs8044708(G,A); rs62030626(T,C); rs76517844(C,T); rs80125178(A,T); rs62030627(A,G); rs62030628(A,G); rs12691049(C,A); rs8057345(T,C); rs8056900(C,T); rs62030629(C,A); rs6498577(A,G); rs6498578(G,A); rs6498579(T,G); rs8057655(C,T); rs11641501(G,T); rs3915501(A,G); rs3915500(A,C); rs3915499(G,A); rs62030630(A,C); rs17214768(G,A); rs66931955(G,A); rs78908227(C,T); rs78243093(A,G); rs62030632(G,C); rs7205443(G,T); rs58037351(C,T); rs3915425(T,C); rs11645494(G,A); rs11645539(G,A); rs12926894(T,C); rs12921616(G,A); rs78060868(C,T); rs77204060(T,C); rs77081170(G,A); rs12923560(C,T); rs62030634(C,T); rs74009441(G,A); rs62030635(G,C); rs62030636(C,T); rs9630619(T,C); rs9630620(T,A); rs9630621(C,T); rs12931560(G,A); rs216152(A,G); rs7192541(T,C); rs216153(C,A); rs216154(T,C); rs216155(G,T); rs11864608(T,C); rs11863857(A,G); rs12920280(C,T); rs216156(A,C); rs2272553(G,A); rs1050111(G,A); rs2272552(T,C); rs62031666(A,C); rs216157(A,G); rs201005747(C,A); rs2633505(A,G); rs2733855(C,T); rs216159(G,A); rs141213345(G,C); rs62031667(A,G); rs2733854(T,G); rs2633506(G,A); rs216160(A,G); rs62031668(T,C); rs216161(G,A); rs13337059(C,A); rs216162(A,T); rs216163(C,T); rs216164(C,T); rs7184125(C,T); rs7184472(C,T); rs216165(T,C); rs112630627(G,A); rs78964369(A,C); rs216166(C,A); rs62031669(G,A); rs3851699(G,C); rs3888687(G,T); rs216167(T,C); rs140457801(G,A); rs114508697(A,G); rs216168(G,T); rs34488124(A,G); rs216169(A,G); rs215594(T,C); rs215593(T,C); rs62031671(A,G); rs215591(G,A); rs215590(C,A); rs35776041(C,A); rs215589(A,G); rs215588(T,C); rs139089839(G,A); rs215587(C,T); rs62031672(G,A); rs71378208(C,T); rs75835245(G,A); rs215586(T,C); rs7199924(C,T); rs215585(A,G); rs215584(G,T); rs28691806(G,A); rs215583(G,A); rs8048670(C,T); rs58145782(C,T); rs374313783(G,C); rs215582(A,G); rs215581(T,C); rs34518997(C,A); rs8045271(A,G); rs9923459(C,T); rs28594849(C,T); rs9923628(C,A); rs61611600(T,C); rs9925218(G,T); rs215580(G,T); rs6498583(A,T); rs215579(C,T); rs112871124(C,T); rs77787719(C,T); rs215578(A,G); rs182101367(C,T); rs6498584(A,G); rs6498585(T,C); rs55771154(T,C); rs215577(G,A); rs215576(C,G); rs215575(C,T); rs62031676(T,G); rs7196606(A,G); rs7202009(T,G); rs7196358(C,T); rs7202176(T,C); rs215574(T,C); rs75949369(G,A); rs72773915(C,T); rs215573(A,C); rs215572(C,T); rs112545672(T,G); rs8045448(C,G); rs372179315(G,A); rs62031677(G,A); rs66834422(G,A); rs112593261(C,T); rs215571(C,T); rs215570(C,T); rs79351746(C,T); rs145059492(C,T); rs147561726(G,A); rs7188829(T,C); rs13335548(A,G); rs9933091(A,G); rs9922682(C,T); rs374305900(C,T); rs112930612(C,A); rs140704052(C,A); rs13331604(G,A); rs13335449(C,T); rs11860621(T,C); rs74855305(A,C); rs13335286(G,A); rs9933130(C,G); rs9932525(G,T); rs9933232(C,G); rs146098678(G,A); rs9932695(G,A); rs9925632(T,A); rs9933417(C,T); rs59940497(C,T); rs9925813(T,G); rs78802015(C,T); rs9935015(G,A); rs34332406(C,G); rs72773921(C,G); rs3851702(T,C); rs80205263(C,T); rs3851703(G,A); rs3851704(A,G); rs13338347(C,T); rs13334610(T,C); rs35309286(T,G); rs202232358(C,A); rs200246498(C,A); rs72773927(T,G); rs3851706(G,A) |
| ccdsGene name | CCDS10566.1 |
| cytoBand name | 16p13.11 |
| EntrezGene GeneID | 54820 |
| EntrezGene Symbol | NDE1 |
| EntrezGene Description | nudE neurodevelopment protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYH11:NM_022844:exon33:c.G4604A:p.R1535Q,MYH11:NM_001040114:exon34:c.G4625A:p.R1542Q,MYH11:NM_002474:exon33:c.G4604A:p.R1535Q,MYH11:NM_001040113:exon34:c.G4625A:p.R1542Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7469 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B1PS43 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000455 |
| ESP All MAF | 0.001616 |
| ESP Eur/Amr MAF | 0.002209 |
| ExAC AF | 0.002334 |
OMIM Clinical Significance
Eyes:
Severe myopia;
Detached retina
Neuro:
Superior intelligence
Inheritance:
Autosomal dominant form
OMIM Title
*160745 MYOSIN, HEAVY CHAIN 11, SMOOTH MUSCLE; MYH11
;;MYOSIN, SMOOTH MUSCLE, HEAVY CHAIN 11; SMHC;;
SMOOTH MUSCLE MYOSIN HEAVY CHAIN; SMMHC
MYH11/CBFB FUSION GENE, INCLUDED
OMIM Description
CLONING
Matsuoka et al. (1991, 1993) isolated a smooth muscle myosin heavy-chain
gene from a human cDNA library. They confirmed it as a smooth muscle MHC
gene by Northern blot hybridization and a partial DNA sequence analysis.
MAPPING
Deng et al. (1993) mapped the MYH11 gene to the middle of the short arm
of chromosome 16 by fluorescence in situ hybridization. Southern blots
of a panel of hybrids containing different portions of human chromosome
16 localized the gene to 16p13.13-p13.12. Studies of DNA from a
CHO/mouse hybrid clone mapping panel showed that the gene was located on
mouse chromosome 16.
GENE FUNCTION
- MYH11/CBFB FUSION GENE
The pericentric inversion inv(16)(p13q22) is a characteristic
abnormality associated with acute myeloid leukemia, most commonly of the
M4Eo subtype. Liu et al. (1993) pinpointed the 16p and 16q breakpoints
by yeast artificial chromosome and cosmid cloning and identified the 2
genes involved in the inversion. On 16p, the MYH11 gene was interrupted;
on 16q, the inversion occurred near the end of the coding region for
CBF-beta (121360), also known as PEBP2-beta, a subunit of a
heterodimeric transcription factor regulating genes expressed in T
cells. In all of 6 inv(16) patients tested, an in-frame fusion messenger
RNA was demonstrated that connected the first 165 amino acids of CBFB
with the tail region of MYH11. The repeated coiled coil of MYH11 may
result in dimerization of the CBFB fusion protein, which in turn would
lead to alterations in transcriptional regulation and contribute to
leukemic transformation.
Castilla et al. (1999) showed that the fusion Cbfb-MYH11 blocks myeloid
differentiation in mice and predisposes the mice to acute myelomonocytic
leukemia when exposed to N-ethyl-N-nitrosourea (ENU), a potent DNA
alkylating mutagen.
Huang et al. (2004), who referred to MYH11 as smooth muscle myosin heavy
chain (SMMHC), investigated the molecular basis for the dominant
inactivation of RUNX1 (151385) by the leukemogenic inversion of
chromosome 16. They showed that, in the PEBP2-beta-SMMHC chimeric
protein, the second heterodimerization domain is created by the fusion
junction, enabling the chimeric protein to interact with RUNX1 at far
greater affinity than PEBP2-beta and inactivate the RUNX1 function. To
explain how heterozygous chimeric protein can inactivate homozygous
RUNX1 near to completion, Huang et al. (2004) proposed a model for the
chimeric protein that consists of a Y-shaped dimer with unpaired
N-terminal halves followed by a coiled-coil for the C-terminal region.
MOLECULAR GENETICS
Familial clustering of common (isolated) thoracic aortic aneurysm/aortic
dissection (TAAD), one of the most severe cardiovascular conditions in
adults, is heterogeneous, with 1 locus having been mapped to chromosome
16p13.1-p12.2 (AAT4; 132900). The MYH11 gene is located in the critical
linkage region for AAT4. Zhu et al. (2006) performed systematic mutation
screening, which showed 2 heterozygous mutations affecting the same
allele of MYH11 in the French kindred reported by Khau Van Kien et al.
(2004, 2005). The first was a substitution at the splice donor site of
intron 32 and the second was a missense mutation in exon 37, R1758Q
(160745.0001). Both mutations were identified in all subjects carrying
the disease haplotype, but neither was found in 340 normal chromosomes.
A similar mutation analysis in an American family with a combination of
thoracic aortic aneurysm and patent ductus arteriosus (Glancy et al.,
2001) showed a mutation in the MYH11 gene, a deletion of 72 nucleotides
within exon 28 (160745.0002). Zhu et al. (2006) suggested that the
position of the mutations observed in the French and American kindreds
may affect the coiled-coil structure of smooth muscle myosin heavy chain
(SM-MHC) and the assembly of myosin thick filaments. Abnormal
immunologic recognition of SM-MHC and the colocalization of wildtype and
mutant rod proteins in smooth muscle cells in conjunction with
differences in their coimmunoprecipitation capacities strongly suggested
a dominant-negative effect of the mutations.
The ascending aorta is placed under major mechanical stress during each
cardiac cycle. Khau Van Kien et al. (2005) showed in the French kindred
that individuals bearing the disease haplotype showed altered aortic
stiffness parameters: notably, aortic compliance, which serves as an
early marker of the disease. Zhu et al. (2006) extended this study to
49-first degree relatives, showing that aortic diameter was generally
similar in those with and without the mutation, but that the carriers of
the mutation had a lower aortic compliance (66% decrease) and a higher
pulse wave velocity (73% increase; both p less than 0.001). Young
asymptomatic mutation carriers already had aortic indices similar to
those of symptomatic mutation carriers and significantly different from
those of normal relatives of the same age. Thus, Zhu et al. (2006)
concluded that MYH11 heterozygous mutation leads to an early and severe
decrease in the elasticity of the aortic wall consistent with the role
of smooth muscle cells in maintaining the mechanical properties of the
thoracic aorta.
Alhopuro et al. (2008) identified somatic mutations in the MYH11 gene in
56 (56%) of 101 samples of colorectal cancer (114500) tissue showing
microsatellite instability. All mutations were within a mononucleotide
repeat of 8 cytosines (C8) in the last exon of the MYH11 SM2 isoform,
which is susceptible to mutations under microsatellite instability, and
were predicted to lead to a frameshift and elongation of the protein.
All mutations were found within epithelial cells. Analysis of
microsatellite stable tumors identified 2 somatic mutations in the same
tumor that were not in the C8 repeat. Functional expression studies of
the mutant proteins showed unregulated actin-activated motor activity.
Among 32 patients with Peutz-Jeghers syndrome (PJS; 175200) and 66
patients with unspecified hamartomatous polyposis, Alhopuro et al.
(2008) identified 1 PJS patient with a heterozygous germline 1-bp
insertion in the C8 repeat of the MYH11 gene. This mutation was also
identified in the somatic state in a colorectal tumor from an unrelated
patient, but not in 1,015 controls. The patient had a cystic astrocytoma
at age 13 years. At age 23 years, he developed intussusception and was
diagnosed with typical PJS. His unaffected father also carried the
mutation. There was no family history of the disorder, and the patient
did not have a STK11 (602216) mutation. Based on a zebrafish phenotype
(see ANIMAL MODEL), Alhopuro et al. (2008) postulated autosomal
recessive inheritance and the presence of a second unidentified MYH11
mutation.
Pannu et al. (2007) sequenced the MYH11 gene in 3 probands from 3 TAAD
families in which 1 or more members had patent ductus arteriosus (PDA)
and in 93 probands from unrelated TAAD families without PDA, and
identified 2 closely linked missense mutations in 1 of the 3 TAAD/PDA
families (160745.0003 and 160745.0004) and a different missense mutation
in another of the 3 TAAD/PDA families (160745.0005). Analysis of aortic
sections and explanted smooth muscle cells from mutation-positive
individuals from both families revealed upregulation of insulin-like
growth factor-1 (IGF1; 147440) but no increase in transforming growth
factor-beta (TGFB; 190180) or downstream targets. Enhanced expression
levels of angiotensin-converting enzyme (ACE; 106180) and markers of
angiotensin II (106150) vascular inflammation, e.g., macrophage
inflammatory proteins 1-alpha (MIP1A; 182283) and 1-beta (MIP1B;
182284), were also found.
ANIMAL MODEL
Major changes in the structure and composition of the ductus arteriosus
occur before and after delivery, and these changes require smooth muscle
cells to migrate, proliferate, differentiate, and contract (Slomp et
al., 1997). Homozygous MYH11 -/- mice deficient in SM-MHC have delay in
closure of the ductus arteriosus (Morano et al., 2000). The
SM-MHC-deficient mice also presented a giant thin-walled bladder and
abnormal intestinal movement. No symptoms of this type were observed in
the affected members with AAT4.
The autosomal recessive Zebrafish meltdown (mlt) lethal phenotype is
characterized by cystic expansion of the posterior intestine as a result
of stromal invasion of nontransformed epithelial cells. Using positional
cloning, Wallace et al. (2005) determined that the mlt phenotype
resulted from a mutation in the Myh11 gene that causes constitutive
activation of the Myh11 ATPase and disruption of smooth muscle cells
surrounding the posterior intestine. The findings implicated an
essential role for smooth muscle signaling in the maintenance of
epithelial architecture.
ABCC6
| dbSNP name | rs3902401(C,T); rs212097(T,C); rs212098(T,C); rs2238473(G,C); rs74950025(G,A); rs6498604(G,C); rs8051720(G,A); rs8057863(A,G); rs8058210(A,G); rs115207771(A,G); rs9932935(A,T); rs143745078(A,C); rs58760581(C,T); rs2066738(G,A); rs57695665(C,T); rs12598559(C,G); rs78867067(G,A); rs169845(C,G); rs58260876(G,A); rs3896244(G,A); rs58694313(C,T); rs2238472(C,T); rs150468(T,G); rs116580094(T,A); rs2239329(G,A); rs2239328(C,T); rs62030282(G,C); rs114619510(T,C); rs2238470(C,T); rs4781730(C,T); rs144288355(A,T); rs169844(A,G); rs77898856(A,G); rs3851721(T,G); rs2376957(C,T); rs3213470(G,A); rs3213471(A,G); rs145517426(C,T); rs187645110(C,T); rs143353478(G,A); rs117521357(T,C); rs140741199(G,A); rs3213472(C,T); rs3213473(T,G); rs16967441(C,A); rs117686059(C,T); rs56672286(G,A); rs212067(A,G); rs9922834(G,A); rs149211430(A,G); rs2283509(T,C); rs11860746(G,A); rs73525748(A,G); rs7198216(C,T); rs6498606(C,T); rs9635506(C,T); rs8057824(A,G); rs8056307(G,T); rs11862458(C,T); rs11644902(C,T); rs9931948(C,T); rs11644687(G,C); rs11863504(C,T); rs7205522(C,T); rs7205901(C,T); rs11864636(C,T); rs13336520(C,T); rs78296281(G,A); rs77368860(G,A); rs2644994(G,C); rs2644993(G,T); rs4781732(G,A); rs4781733(A,T); rs4781734(G,A); rs143256321(C,A); rs2644991(C,A); rs6498607(G,C); rs7194043(G,A); rs2856585(G,A); rs7201980(T,C); rs6498608(A,G); rs8057956(G,A); rs8043704(T,G); rs8060029(A,G); rs8043862(T,C); rs7500840(A,G); rs6498609(A,G); rs7498292(T,C); rs6498610(C,T); rs6498611(G,A); rs6498612(G,T); rs112166910(C,A); rs2856586(G,C); rs56246088(T,G); rs2856587(A,C); rs73509111(G,A); rs11866320(A,G); rs2644985(G,A); rs7188967(A,G); rs4577106(A,G); rs2644987(C,T); rs116002649(A,C); rs212618(C,A); rs212619(G,A); rs212620(A,G); rs7405025(A,G); rs117766129(C,G); rs212621(G,A); rs212622(A,G); rs2239325(C,A); rs6498614(T,C); rs6498615(C,T); rs3784870(T,C); rs212623(C,T); rs74907776(A,G); rs6416668(T,C); rs9924755(G,A); rs6498616(C,T); rs212624(C,T); rs73524021(C,T); rs2283508(G,A); rs7500834(T,C); rs12934421(G,T); rs150465(C,T); rs212069(G,A); rs212070(C,G); rs73524024(C,T); rs75143325(G,A); rs112038079(T,C); rs73524029(G,A); rs2283507(G,A); rs73524031(G,A); rs73524035(G,A); rs73524038(C,T); rs59757815(T,A); rs150466(C,T); rs28572220(C,T); rs28588983(G,C); rs117109895(G,A); rs149442873(G,A); rs28504242(A,G); rs73524045(G,A); rs79731312(G,C); rs73524046(C,T); rs73524048(G,A); rs78172764(C,T); rs212072(G,A); rs146052037(C,G); rs115095230(G,A); rs212073(C,T); rs57018726(C,A); rs114734073(C,T); rs57314310(T,G); rs2239324(C,T); rs2239323(A,T); rs139145602(C,T); rs8058694(G,T); rs8058696(G,C); rs115990368(G,A); rs41278182(C,T); rs8060117(C,A); rs150467(G,C); rs212074(C,T); rs212075(G,A); rs212076(T,A); rs7191300(C,T); rs212077(G,C); rs7192265(C,T); rs7192961(A,G); rs8056103(T,C); rs12931472(A,G); rs4369696(C,A); rs3851722(G,A); rs2238469(C,T); rs55707615(G,A); rs2239322(T,C); rs7193932(C,T); rs8057689(G,T); rs6498617(C,T); rs11643893(G,T); rs73524066(G,A); rs9932889(C,T); rs7206048(G,C); rs76470239(C,T); rs6498618(G,C); rs59683222(C,T); rs7201601(C,T); rs56299644(G,T); rs6498619(A,G); rs8044613(C,A); rs11643423(G,T); rs7403832(G,A); rs11862259(G,A); rs7184822(G,A); rs7186376(C,T); rs7187235(A,G); rs7186601(C,T); rs7192303(A,T); rs72777666(A,T); rs8056397(T,C); rs9925057(T,C); rs9927246(T,C); rs62030313(G,A); rs7199104(A,G); rs4781735(A,G); rs4780597(G,A); rs4780598(C,T); rs4780599(C,T); rs4780600(A,G); rs6498620(A,T); rs8062992(A,G); rs12929319(G,A); rs58394656(G,C); rs12934253(G,A); rs138087831(G,A); rs2283503(G,A); rs4780614(G,T); rs372585916(G,A); rs2007413(C,T) |
| ccdsGene name | CCDS10568.1 |
| cytoBand name | 16p13.11 |
| EntrezGene GeneID | 368 |
| EntrezGene Description | ATP-binding cassette, sub-family C (CFTR/MRP), member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCC6:NM_001171:exon28:c.G3980A:p.G1327E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6946 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95255 |
| dbNSFP Uniprot ID | MRP6_HUMAN |
| dbNSFP KGp1 AF | 0.00778388278388 |
| dbNSFP KGp1 Afr AF | 0.0325203252033 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.007805 |
| ESP Afr MAF | 0.011607 |
| ESP All MAF | 0.004002 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.001197 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)
ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism
LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration
MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)
MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)
OMIM Title
*603234 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ABCC6
;;ANTHRACYCLINE RESISTANCE-ASSOCIATED PROTEIN; ARA;;
MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 6; MRP6
OMIM Description
DESCRIPTION
ABCC6 belongs to the multidrug resistance-associated protein (MRP)
subfamily of ATP-binding cassette (ABC) transmembrane transporters. MRPs
are involved in drug resistance, particularly in association with cancer
chemotherapy. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum
(PXE; see 264800), a heritable connective tissue disorder characterized
by calcification of elastic fibers in skin, arteries, and retina (Bergen
et al., 2000; Le Saux et al., 2000; Ringpfeil et al., 2000).
CLONING
Multidrug resistance in cancer cells has been attributed to the
overexpression of certain membrane proteins, several of which are
members of the ATP-binding cassette (ABC) superfamily. Examples include
MRP (158343) and MDR1 (171050). Longhurst et al. (1996) screened an
E1000 leukemia cell cDNA library using an MRP probe. They cloned a novel
cDNA encoding a 453-amino acid polypeptide that was similar to the
C-terminal half of MRP. Whereas MRP contains 2 ABC domains and 12
transmembrane domains, the ARA protein contains 1 ABC domain and 5
transmembrane domains. Northern blot analysis showed that ARA was
expressed as a 2.2-kb mRNA in an E1000 leukemia cell line, but not in
the untransformed parental CEM cell line. Southern blot analysis
revealed that, like MRP, the ARA gene was amplified in the genomic DNA
of the E1000 cell line. The ABCC6 protein consists of 1,503 amino acids
with a molecular mass of 165 kD, is located in the plasma membrane, and
probably has 17 membrane-spanning helices grouped into 3 transmembrane
domains (Le Saux et al., 2000). The 4.5-kb ABCC6 mRNA is expressed in
several secretory tissues, but primarily in kidney and liver. By RT-PCR
analysis using RNA isolated from tissues frequently affected by PXE,
Bergen et al. (2000) detected expression of ABCC6 in retina, skin, and
vascular tissue, although the highest level of expression was in the
liver.
By Western blot analysis of transfected Chinese hamster ovary (CHO)
cells, Belinsky et al. (2002) found that MRP6 migrated at the predicted
molecular mass of about 152 kD and at 182 kD, which likely represents a
glycosylated form.
Sinko et al. (2003) found that human ABCC6, when expressed by retroviral
transduction in polarized mammalian cells (MDCKII), is exclusively
localized to the basolateral membrane. In contrast to the in vitro
translated protein, ABCC6 was glycosylated in MDCK cells. Limited
proteolysis of the fully glycosylated and underglycosylated forms,
followed by immunodetection with region-specific antibodies, indicated
that asn15, located in the extracellular N-terminal region of ABCC6, is
the only N-glycosylated site in the protein.
By in situ hybridization and immunohistochemical analysis, Beck et al.
(2005) detected ABCC6 mRNA and protein in a wide range of epithelial
cells of exocrine and endocrine tissues such as acinar cells in the
pancreas, mucosal cells of the intestine, and follicular epithelial
cells of the thyroid. Enteroendocrine G cells of the stomach showed
strong immunostaining. In addition, ABCC6 mRNA and protein were present
in most neurons of the brain, in alveolar macrophages in the lung, in
lymph node lymphocytes, in hepatocytes, and in keratinocytes and
epithelial cells of the ducts of sweat glands.
Using PCR, Matsuzaki et al. (2005) found that Abcc6 expression was
highest in mouse liver and lower in kidney and small intestine.
Second-round nested PCR revealed much weaker expression in brain,
tongue, stomach, and eye. Subcloning and sequencing of distinct PCR
products indicated that the 3-prime end is subject to aberrant splicing,
resulting in each case in a premature termination codon. PCR analysis of
cultured human cells revealed similar splice variations in the 3-prime
end resulting in the skipping of exons 24 and 30 in epidermal
keratinocytes, and exons 24, 26, and 28 in dermal fibroblasts. In
fibroblasts, a minor PCR product represented alternative splicing of
exon 7.
GENE STRUCTURE
Kool et al. (1999) determined that the human ABCC6 gene contains 31
exons.
Ratajewski et al. (2008) found that the 5-prime upstream region of the
ABCC6 gene contains a major Alu element of over 4.5 kb.
GENE FUNCTION
Belinsky and Kruh (1999) and Klein et al. (1999) suggested that ABCC6
function may be related to cellular detoxification rather than drug
resistance. Bergen et al. (2000) commented that the molecules presumably
transported by ABCC6 may be essential for extracellular matrix
deposition or turnover of connective tissue at specific sites in the
body. Given the high expression of ABCC6 in liver and kidney, ABCC6
substrates may be transported into the blood. A deficiency of specific
ABCC6 substrates may affect a range of connective tissue sites
throughout the body and specifically elastic fiber assembly.
By assaying membrane vesicles obtained from ABCC6-expressing insect
cells, Ilias et al. (2002) found ABCC6 specifically bound MgATP and
actively transported glutathione conjugates, including leukotriene-C4
and N-ethylmaleimide S-glutathione (NEM-GS), in an MgATP-dependent
manner. 17-Beta-estradiol-17-beta-D-glucuronide was a weak transport
substrate. The organic anions probenecid, benzbromarone, and
indomethacin specifically inhibited ABCC6-mediated NEM-GS transport, and
orthovanadate, a phosphotyrosine phosphatase inhibitor, completely
inhibited NEM-GS transport.
Using similar substrates to those used by Ilias et al. (2002), Belinsky
et al. (2002) found that MRP6 expressed in CHO cell membranes could
transport glutathione conjugates but not glucuronate conjugates.
Transfected cells also showed enhanced resistance to several anticancer
agents. The highest levels of resistance were observed for the
inhibitors of topoisomerase II (126430) etoposide and teniposide,
followed by the anthracyclines doxorubicin and daunorubicin.
MRP6-expressing CHO cells accumulated less etoposide compared with
control transfected cells, indicating that MRP6 functions as a drug
efflux pump.
Using a luciferase reporter gene construct, Jiang et al. (2006) examined
the 2.6-kb human ABCC6 promoter. An NF-kappa-B (see NFKB1, 164011)-like
sequence conferred strong expression in HepG2 hepatoma cells, but much
weaker expression in cell lines of other tissue origin. Injection of the
construct into mouse tail vein confirmed liver-specific expression.
Testing of selected cytokines revealed that TGF-beta (190180)
upregulated, while TNF-alpha (191160) and interferon-gamma (IFNG;
147570) downregulated, the promoter activity in HepG2 cells. The
responsiveness to TGF-beta resided primarily within an SP1 (189906)/SP3
(601804) binding site. The expression of the ABCC6 promoter was markedly
enhanced by SP1. Jiang et al. (2006) concluded that the expression of
ABCC6 can be modulated by proinflammatory cytokines.
Using the ABCC6 promoter region in reporter gene assays in the HepG2
hepatoma cell line, Ratajewski et al. (2006) showed that all-trans
retinoic acid caused significant induction of ABCC6 activity. They found
9-cis retinoic acid (9cRA), a specific RXR (see RXRA, 180245) receptor
agonist, induced the ABCC6 promoter in a concentration-dependent manner.
9cRA also induced the expression of endogenous ABCC6 in HepG2 cells. The
binding of RXR to the endogenous ABCC6 promoter was confirmed by
chromatin immunoprecipitation experiments. Occupancy of the ABCC6
promoter by RXR was relatively high in unstimulated cells and increased
further in 9cRA-treated cells.
Using the ABCC6 reporter construct described by Ratajewski et al. (2006)
in a screen for ABCC6-regulating factors, Ratajewski et al. (2008) found
that GATA3 (131320) repressed ABCC6 activity, and that SP1, PLAG1
(603026), and PLAGL1 (603044) induced ABCC6 activity. They identified 2
putative PLAG-binding sites on the reverse strand of the ABCC6 proximal
promoter. Reporter gene assays, electrophoretic mobility shift assays,
and chromatin immunoprecipitation analysis showed that the more proximal
site was bound and activated by PLAG1 and PLAGL1. Furthermore,
overexpression of PLAG1 resulted in enhanced ABCC6 transcription in
transfected human embryonic kidney cells.
MAPPING
Kuss et al. (1998) used fluorescence in situ hybridization to map the
ARA gene to human chromosome 16p13.1. The gene order in this region is
telomere--MYH11(160745)--MRP--ARA--centromere. The MRP and ARA genes are
located within 9 kb of each other and are transcribed in opposite
directions. Both MRP and ARA are deleted in a subgroup of inv(16)
leukemias, and both are expressed in normal hematopoietic precursor
cells.
- Pseudogenes
Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences
highly homologous to the 5-prime end of the ABCC6 gene.
MOLECULAR GENETICS
- Pseudoxanthoma Elasticum
Simultaneously and independently, Bergen et al. (2000), Le Saux et al.
(2000), and Ringpfeil et al. (2000) identified missense, nonsense, and
splice site mutations as well as deletions and insertions in the ABCC6
gene causing pseudoxanthoma elasticum (264800). Mutations appeared to
represent autosomal recessive (Le Saux et al., 2000) and autosomal
dominant (177850) (Bergen et al., 2000) modes of inheritance, and
sporadic cases. By SSCP and heteroduplex analysis using genetic DNA from
a cohort of 17 unrelated PXE patients, Le Saux et al. (2000) screened
109 exons within 5 PXE candidate genes in the chromosome 16p13.1 region
for mutations. By screening the 31 exons of ABCC6 by SSCP, Le Saux et
al. (2000) identified 6 mutations that were responsible for PXE in 10 of
17 patients. They identified a C-to-T substitution within exon 24 at
nucleotide 3421, resulting in an arg-to-stop substitution at codon 1141
(R1141X; 603234.0001) in 6 unrelated families with autosomal recessive
PXE. Bergen et al. (2000) identified mutations in ABCC6 causing
autosomal dominant, autosomal recessive, and sporadic PXE. Bergen et al.
(2000) found the R114X mutation in 2 families with autosomal dominant
PXE. One patient had a large de novo deletion of chromosome 16
(603234.0010). Ringpfeil et al. (2000) reported a total of 8
pathogenetic mutations in the ABCC6 gene in 8 kindreds with PXE. They
referred to the gene as MRP6 (multidrug resistance-associated
protein-6). Examination of clinically unaffected family members in 4
multiplex families identified heterozygous carriers, consistent with an
autosomal recessive inheritance pattern.
Le Saux et al. (2001) performed a mutation analysis of the ABCC6 gene in
122 unrelated patients with PXE, the largest cohort of patients studied
to that time. They characterized 36 mutations, 28 of which were novel.
Twenty-one were missense variants, 6 were small insertions or deletions,
5 were nonsense, 2 were alleles likely to result in aberrant mRNA
splicing, and 2 were large deletions involving ABCC6. Although most
mutations appeared to be unique variants, 2 disease-causing alleles
occurred frequently in apparently unrelated individuals. Arg1141 to ter
(R1141X; 603234.0001) was found in this patient cohort at a frequency of
18.8% and was preponderant in European patients. Deletion of nucleotides
23-29 (603234.0016) occurred at a frequency of 12.9% and was prevalent
in patients from the United States. Putative disease-causing mutations
were identified in approximately 64% of the 244 chromosomes studied, and
85.2% of the 122 patients were found to have at least 1 disease-causing
allele. The results suggested that a fraction of the undetected mutant
alleles could be either genomic rearrangements or mutations occurring in
noncoding regions of the ABCC6 gene. A cluster of disease-causing
variants was observed within exons encoding a large C-terminal
cytoplasmic loop and in the C-terminal nucleotide-binding domain.
While implementing a strategy to screen for PXE by complete mutation
analysis of the ABCC6 gene, Germain (2001) found evidence for the
existence of at least 1 pseudogene highly homologous to the 5-prime end
of ABCC6. Sequence variants in this ABCC6-like pseudogene could be
mistaken for mutations in the ABCC6 gene and consequently lead to
erroneous genotyping results in pedigrees affected with PXE.
Germain et al. (2001) identified a heterozygous missense mutation in
exon 7 of the ABCC6 gene in a female PXE patient whose parents were
second cousins. Despite complete scanning of the gene, no further
mutation was evident. A heterozygous profile was also found in the
proband's unaffected children. However, haplotype homozygosity was
confirmed at chromosome 16p13.1, using both extragenic microsatellites
and intragenic polymorphisms located 3-prime from the mutation, in
agreement with the known consanguinity in the family. Taken together,
the data indicated that PCR products of exon 7 of the ABCC6 gene were
amplified from more than 2 genomic copies. This supported the existence
of one or more ABCC6 pseudogenes highly homologous to the 5-prime end
(exons 1-9) of the ABCC6 gene.
Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences
highly homologous to the 5-prime end of the ABCC6 gene. Nucleotide
differences in flanking introns between these 2 pseudogenes and ABCC6
allowed them to design allele-specific primers that eliminated the
amplification of both pseudogene sequences by PCR and provided reliable
amplification of ABCC6-specific sequences only. The use of
allele-specific PCR revealed 2 novel 5-prime-end PXE mutations.
In 59 unrelated Dutch patients with PXE, Hu et al. (2003) identified 17
different mutations, including 11 novel mutations, in the ABCC6 gene in
65 alleles. The R1141X mutation was by far the most common mutation,
identified in 19 (32.2%) patients; the second most common mutation,
which results in the deletion of exons 23-29 (603234.0016), was
identified in 11 (18.6%) patients. In 20 patients, only 1 mutation in 1
allele was detected. Combined with previous mutation data, Hu et al.
(2003) concluded that approximately 80% of the PXE mutations occur in
the cytoplasmic domains of the predicted ABCC6 protein, especially the 2
nucleotide-binding fold (NBF) domains (NBF1 and NBF2) and the eighth
cytoplasmic loop between the fifteenth and sixteenth transmembrane
regions.
Hu et al. (2004) described an efficient molecular diagnostic strategy
for ABCC6 in PXE. The 2 most frequent mutations, R1141X (603234.0001)
and deletion of exons 23 through 29 (603234.0016), as well as a core set
of mutations, were identified by restriction enzyme digestion and size
separation on agarose gels. In the remaining patient group in which only
1 or no mutant allele was found, the complete coding sequence was
analyzed using DHPLC. All variations found were confirmed by direct DNA
sequencing. Finally, Southern blot was used to investigate the potential
presence of small or large deletions. Twenty different mutations,
including 2 novel mutations in the ABCC6 gene, were identified in 80.3%
of the 76 patients, and 58.6% of the 152 ABCC6 alleles analyzed.
Chassaing et al. (2005) commented that mutations had been identified in
PXE in most of the 31 ABCC6 exons and that no correlation between the
nature or the location of the mutations and phenotype severity had been
established.
Trip et al. (2002), Van Soest et al. (1997), and Bacchelli et al. (1999)
emphasized the carriage of a sole ABCC6 mutation as a cardiovascular
risk factor. Sherer et al. (2001) described limited phenotypic
expression of PXE in parents of affected offspring.
Miksch et al. (2005) performed a mutation screen in ABCC6 using
haplotype analysis in conjunction with direct sequencing to achieve a
mutation detection rate of 97%. Their mutational analysis confirmed an
earlier haplotype-based analysis and conclusions regarding a
recessive-only mode of inheritance in PXE (Cai et al., 2000) through the
identification of 2 mutated alleles in all individuals with PXE who
appear in either consecutive or alternating generations of the same
family. Their study demonstrated that the full phenotypic expression of
the disorder requires 2 defective allelic copies of ABCC6 and that
pseudodominance is the mode of transmission in presumed autosomal
dominant families (i.e., the second parental disease allele 'marries
into' the family). The apparent frequency of this mechanism was
approximately 7.5% in their family cohort. Miksch et al. (2005) stated
that in their families no heterozygote for a large deletion showed any
apparent clinical sign of PXE according to category I diagnostic
criteria.
Chassaing et al. (2005) provided a comprehensive catalog of ABCC6
mutations identified in PXE.
Pfendner et al. (2007) collected mutation data on an international case
series of 270 patients with PXE (239 probands, 31 affected family
members). In 134 patients with a known phenotype and both mutations
identified, genotype-phenotype correlations were assessed. In total, 316
mutant alleles in ABCC6, including 39 novel mutations, were identified
in 239 probands. Mutations clustered in exons 24 and 28, corresponding
to the second nucleotide-binding fold and the last intracellular domain
of the protein. Together with the recurrent R1141X (603234.0001) and
del23-29 (603234.0016) mutations, these mutations accounted for 71.5% of
the total individual mutations identified. Genotype-phenotype analysis
failed to reveal a significant correlation between the type of mutations
identified or their predicted effect on the expression of the protein
and the age of onset and severity of the disease.
Using multiplex ligation-dependent probe amplification (MLPA) to analyze
35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing,
Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon
deletions and were thus able to characterized 25% of the unidentified
disease alleles. The findings illustrated the instability of the ABCC6
genomic region and stressed the importance of screening for deletions in
the molecular diagnosis of PXE.
- Generalized Arterial Calcification of Infancy 2
In a 28-year-old French man with PXE, who had a younger brother who died
of generalized arterial calcification of infancy (GACI1; 614473) at age
15 months, Le Boulanger et al. (2010) identified compound heterozygosity
for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026),
which were also found in heterozygosity in each of his unaffected
parents, respectively. No disease-causing mutations were found in the
known GACI1 (208000)-related gene, ENPP1 (173335). Although no DNA
material was available from the deceased younger brother, his disease
was presumed to be related to the familial ABCC6 mutations. Le Boulanger
et al. (2010) concluded that GACI may represent an atypical and severe
end of the vascular phenotypic spectrum of PXE.
Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from
25 unrelated families who were negative for mutation in the ENNP1 gene,
as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had
been detected. They identified homozygosity or compound heterozygosity
for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g.,
603234.0001, 603234.0002, 603234.0006, and 603234.0027-603234.0028). In
6 patients from 5 unrelated families, only 1 mutation was detected in
ABCC6; the authors noted that there was no phenotypic difference between
these patients and those with biallelic mutations in ABCC6, and stated
that mutations in regulatory untranslated regions of ABCC6 might not
have been detected by their approach. No mutation in the ABCC6 gene was
found in 16 patients from 14 unrelated families, including the 2
patients who were known to carry monoallelic mutations in ENNP1.
Overall, 13 different ABCC6 mutations were identified in GACI patients,
all but 2 of which had been previously identified in typical PXE
patients who had a much milder phenotype than the GACI patients. Based
on the considerable overlap of phenotype and genotype of GACI and
pseudoxanthoma elasticum, Nitschke et al. (2012) suggested that GACI and
PXE represent 2 ends of a clinical spectrum of ectopic calcification and
other organ pathologies rather than 2 distinct disorders.
POPULATION GENETICS
The Afrikaner population of South Africa is of Dutch, German, and French
Huguenot descent and has its origin in the first European immigrant
settlements at the Cape of Good Hope during the 17th century. Torrington
and Viljoen (1991) proposed that the basis for the high prevalence of
PXE in the Afrikaner population is a founder effect. An initial
genealogic study traced the ancestry of 20 Afrikaner families with PXE
back to potentially only 4 individuals, suggesting that this disorder is
most likely derived from these original founders in South Africa. To
study this possibility further, Le Saux et al. (2002) performed
haplotype and mutation analyses in 17 of the 20 originally analyzed
Afrikaner families, and identified 3 common haplotypes and 6 different
disease-causing variants. Three of these mutant alleles were missense
variants, 2 were nonsense mutations, and 1 was a single-basepair
insertion. The most common variant, arg1339 to cys (R1339C;
603234.0017), accounted for 53% of the PXE alleles, whereas other mutant
alleles appeared at lower frequencies ranging from 3 to 12%. Haplotype
analysis of the Afrikaner families showed that the 3 most frequent
mutations were identical by descent, indicating a founder origin of PXE
in this population.
Chassaing et al. (2005) suggested that the proposed prevalence of PXE of
1 in 25,000 may be an underestimation. Consequently, the prevalence of
heterozygous carriers, and the prevalence of different organ involvement
in carriers of 1 or 2 ABCC6 mutations, are not precisely known.
PATHOGENESIS
Since the ABCC6 gene is expressed primarily, if not exclusively, in the
liver and kidneys, Ringpfeil et al. (2001) suggested that PXE is a
primary metabolic disorder with secondary involvement of elastic fibers,
a situation comparable to the secondary involvement of connective tissue
elements in homocystinuria (236200) and alkaptonuria (203500).
ABCC6 is a member of the large ATP-dependent transmembrane transporter
family. Chassaing et al. (2005) commented that the association of PXE to
ABCC6 efflux transport alterations raised a number of pathophysiology
hypotheses, among them, the idea that PXE is a systemic metabolic
disease resulting from lack or accumulation over time in the bloodstream
of molecules interacting with the synthesis, turnover, and/or
maintenance of extracellular matrix (ECM).
Since ABCC6 is expressed primarily in the liver, Jiang and Uitto (2006)
likewise supported the notion that PXE is a metabolic disease.
In an investigation of the functional relationship between ABCC6
deficiency and elastic fiber calcification, Le Saux et al. (2006)
speculated that ABCC6 deficiency in PXE patients induces a persistent
imbalance in circulating metabolite(s) which impairs the synthetic
abilities of normal elastoblasts or specifically alters elastic fiber
assembly. They found that PXE fibroblasts cultured with normal human
serum expressed and deposited increased amounts of proteins, but
structurally normal elastic fibers. Normal and PXE fibroblasts as well
as normal smooth muscle cells deposited abnormal aggregates of elastic
fibers when maintained in the presence of serum from PXE patients. The
expression of tropoelastin (see 130160) and other elastic
fiber-associated genes was not significantly modulated by the presence
of PXE serum. These results indicated that certain metabolites present
in PXE sera interfered with the normal assembly of elastic fibers in
vitro and suggested that PXE is a primary metabolic disorder with
secondary connective tissue manifestations.
ANIMAL MODEL
To elucidate the pathogenesis of PXE, Klement et al. (2005) generated a
transgenic mouse by targeted ablation of the mouse Abcc6 gene.
Abcc6-null mice were negative for expression of Mrp6 in the liver, and
necropsies revealed profound mineralization of several tissues including
skin, arterial blood vessels, and retina, while heterozygous animals
were indistinguishable from the wildtype mice. Particularly striking was
the mineralization of vibrissae, as confirmed by von Kossa and alizarin
red stains. Electron microscopy revealed mineralization affecting both
elastic structures and collagen fibers. Mineralization of vibrissae was
noted as early as 5 weeks of age and was progressive with age in Abcc6
-/- mice but was not observed in heterozygous or wildtype mice up to 2
years of age. Total body computerized tomography scan of Abcc6 -/- mice
showed mineralization in skin and subcutaneous tissue as well as in
kidneys. These data demonstrated aberrant mineralization of soft tissues
in PXE-affected organs, and consequently, these mice recapitulated
features of this complex disease.
Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and
electron microscopy that Abcc6 -/- mice spontaneously developed
calcification of elastic fibers in blood vessel walls and in Bruch
membrane in the eye. No clear abnormalities were seen in the dermal
extracellular matrix. Calcification of blood vessels was most prominent
in small arteries in the cortex of the kidney, but in old mice, it
occurred also in other organs and in the aorta and vena cava. Monoclonal
antibodies against mouse Abcc6 localized the protein to the basolateral
membranes of hepatocytes and the basal membrane in renal proximal
tubules, but failed to show the protein at the pathogenic sites. Abcc6
-/- mice developed a 25% reduction in plasma HDL cholesterol and an
increase in plasma creatinine levels, which may be due to impaired
kidney function. No changes in serum mineral balance were found. Gorgels
et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares
calcification of elastic fibers with human PXE pathology, and supports
the hypothesis that PXE is a systemic disease.
To characterize the mineralization process in PXE, Jiang et al. (2007)
examined a PXE animal model, the Abcc6 -/- mouse, with respect to
specific proteins serving as inhibitors of mineralization. The levels of
calcium and phosphate in serum of these mice were normal, but the Abcc6
-/- serum had less ability to prevent the mineral deposition induced by
inorganic phosphate in a cell culture system. Addition of fetuin-A
(138680) to the culture system prevented the mineralization. The
calcium-phosphate product was markedly elevated in the mineralized
vibrissae of Abcc6 -/- mice, an early biomarker of the mineralization
process, consistent with histopathologic findings. Levels of fetuin-A
were slightly decreased in Abcc6 -/- serum, and positive immunostaining
for matrix-Gla-protein (MGP; 154870), fetuin-A, and ankylosis protein
(ANK; 605145) as well as alkaline phosphatase activity were strongly
associated with the mineralization process. In situ hybridization
demonstrated that the genes for MGP and Ank were expressed locally in
vibrissae, whereas fetuin-A was expressed highly in the liver. These
data suggested that the deposition of the bone-associated proteins
spatially coincides with mineralization and actively regulates this
process locally and systemically.
In the Dyscalc1 mouse model of dystrophic cardiac calcification (DCC),
Meng et al. (2007) studied 2 intercrosses and identified Abcc6 as the
causative gene, which was confirmed by transgenic complementation. The
authors noted that myocardial calcification has not been reported as a
phenotype associated with human PXE or mouse Abcc6-knockout models.
In all mouse strains positive for DCC, Aherrahrou et al. (2008)
identified a missense mutation at the 3-prime border of exon 14 of the
Abcc6 gene that created an additional donor splice site. The alternative
transcript lacked the last 5 nucleotides of exon 14, resulting in
premature termination at codon 684, and leading to Abcc6 protein
deficiency in DCC-susceptible mice.
Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin
onto the back of Abcc6-knockout mice resulted in abnormal mineralization
of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout
mouse muzzle skin onto wildtype mice did not. The data implied that PXE
does not result from localized defect based on resident cellular
abnormalities but from a change of metabolite(s) in serum. These
findings implicate circulatory factors as a critical component of the
mineralization process and supported the notion that PXE is a secondary
mineralization of connective tissues. In addition, the findings
suggested that the abnormal mineralization process could possibly be
countered or even reversed by changes in the homeostatic milieu.
ITPRIPL2
| dbSNP name | rs11074362(C,T); rs3210530(G,A); rs59357034(G,A); rs16971597(G,A); rs11859503(C,A); rs138934648(G,A); rs56381208(T,C); rs76116733(A,C); rs61265966(G,A); rs141301863(G,A); rs55809104(G,T); rs57236534(A,G); rs3743955(A,C); rs3743956(T,C) |
| ccdsGene name | CCDS32395.1 |
| cytoBand name | 16p12.3 |
| EntrezGene GeneID | 162073 |
| EntrezGene Description | inositol 1,4,5-trisphosphate receptor interacting protein-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ITPRIPL2:NM_001034841:exon1:c.C1564T:p.P522S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0004 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3MIP1 |
| dbNSFP Uniprot ID | IPIL2_HUMAN |
| dbNSFP KGp1 AF | 0.0434981684982 |
| dbNSFP KGp1 Afr AF | 0.130081300813 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.00524475524476 |
| dbNSFP KGp1 Eur AF | 0.032981530343 |
| dbSNP GMAF | 0.04362 |
| ESP Afr MAF | 0.11015 |
| ESP All MAF | 0.059566 |
| ESP Eur/Amr MAF | 0.033721 |
| ExAC AF | 0.032 |
LOC554206
| dbSNP name | rs79771466(T,C); rs11074669(G,A); rs7498149(A,G) |
| cytoBand name | 16p12.1 |
| EntrezGene GeneID | 554206 |
| EntrezGene Description | leucine carboxyl methyltransferase 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02388 |
| ExAC AF | 0.003542 |
C16orf82
| dbSNP name | rs185409807(C,T); rs114049498(G,C); rs115398674(T,C); rs12446622(A,C); rs113551573(G,A); rs114570071(C,G); rs115982912(A,G); rs115695246(C,T); rs191967871(G,A); rs115622223(C,G); rs116780507(A,G); rs114407423(C,T); rs114065546(T,C); rs114167428(T,C); rs2280183(C,A); rs141209928(T,C); rs115791444(T,C); rs116245283(G,A); rs11823(G,A) |
| cytoBand name | 16p12.1 |
| EntrezGene GeneID | 162083 |
| EntrezGene Description | chromosome 16 open reading frame 82 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C16orf82:NM_001145545:exon1:c.C229T:p.P77S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01837 |
| ExAC AF | 0.005569 |
APOBR
| dbSNP name | rs151233(C,T); rs61748351(G,A); rs142080760(T,C); rs180744(A,G); rs201285042(G,A); rs61753940(A,G); rs40831(A,G); rs40832(T,C) |
| ccdsGene name | CCDS58442.1 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 55911 |
| EntrezGene Description | apolipoprotein B receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | APOBR:NM_018690:exon2:c.C66T:p.L22L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09045 |
| ESP Afr MAF | 0.108329 |
| ESP All MAF | 0.127729 |
| ESP Eur/Amr MAF | 0.136696 |
| ExAC AF | 0.122 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature (of varying degrees);
[Other];
Poor growth in infancy;
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
[Ears];
Low-set ears;
Dysmorphic ears;
[Eyes];
Hypertelorism;
Strabismus;
Epicanthal folds;
Narrow palpebral fissures;
Downslanting palpebral fissures;
Thick eyebrows;
Synophrys;
Long eyelashes (in some patients);
[Nose];
Broad nose;
[Mouth];
Thin upper lip;
High-arched palate;
Cupid's bow, exaggerated (in some patients)
ABDOMEN:
[Gastrointestinal];
Constipation (in some patients)
SKELETAL:
Delayed bone age (in some patients);
[Hands];
Short fingers;
Fifth finger clinodactyly;
Short middle phalanges;
Tapering fingers (in some patients);
[Feet];
Short toes
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple (in some patients);
[Hair];
Thick eyebrows;
Hairy elbows;
Hypertrichosis, patchy (in some patients);
Hypertrichosis, generalized (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia;
Slim, muscular build (in some patients);
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures (1 patient);
Wide-based gait;
Speech delay;
[Behavioral/psychiatric manifestations];
Aggressive behavior;
Autistic features
MISCELLANEOUS:
Hairy elbows become apparent in infancy and regress during adolescence;
Facial appearance becomes more apparent with age
MOLECULAR BASIS:
Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia
gene (MLL, 159555.0001)
OMIM Title
*605220 APOLIPOPROTEIN B RECEPTOR; APOBR
;;APOLIPOPROTEIN B48 RECEPTOR; APOB48R
OMIM Description
DESCRIPTION
APOB48R is a macrophage receptor that binds to the apolipoprotein B48
(107730) of dietary triglyceride (TG)-rich lipoproteins (summary by
Brown et al., 2000).
CLONING
Brown et al. (2000) cloned a full-length APO48R cDNA from a THP-1 cDNA
library. TG-rich lipoprotein uptake by this receptor rapidly converted
macrophages and APOB48R-transfected Chinese hamster ovary cells in vitro
into lipid-filled foam cells, as seen in atherosclerotic lesions. The
APOB48R cDNA encodes a 1,088-amino acid protein with no known homologs.
Its mRNA of approximately 3.8 kb is expressed primarily by
reticuloendothelial cells: monocytes, macrophages, and endothelial
cells. It was expressed in all but skeletal muscle, with highest
expression in lung and placenta and least in brain and heart. By
immunohistochemistry, Brown et al. (2000) showed that the APOB48
receptor is in foam cells of human atherosclerotic lesions. Normally,
the receptor may provide essential lipids to reticuloendothelial cells.
If overwhelmed, foam cell formation, endothelial dysfunction, and
atherothrombogenesis may ensue, a mechanism for cardiovascular disease
risk of elevated triglycerides.
MAPPING
By fluorescence in situ hybridization, Brown et al. (2000) mapped the
APOBR gene to chromosome 16p11. They confirmed its localization by
demonstrating near identity to a sequence found in a BAC clone at
16p11.2.
C16orf54
| dbSNP name | rs79758803(T,C); rs7199164(A,C); rs76901882(C,A); rs7205278(T,C); rs9940387(C,T); rs112368680(C,T); rs112310246(A,G) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 283897 |
| EntrezGene Description | chromosome 16 open reading frame 54 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1313 |
PRRT2
| dbSNP name | rs11150573(T,C); rs141436390(C,A); rs1045968(G,T); rs10204(T,C) |
| ccdsGene name | CCDS10654.1 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 112476 |
| EntrezGene Description | proline-rich transmembrane protein 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRRT2:NM_001256443:exon2:c.T751C:p.L251L,PRRT2:NM_145239:exon2:c.T751C:p.L251L,PRRT2:NM_001256442:exon2:c.T751C:p.L251L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.027322 |
| ESP All MAF | 0.009238 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.998 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Glomerulonephritis
SKIN, NAILS, HAIR:
[Skin];
Photosensitive skin rashes
IMMUNOLOGY:
Systemic lupus erythematosus;
Dermatomyositis;
Anaphylactoid purpura;
Vasculitis
LABORATORY ABNORMALITIES:
Absent CH50 activity in complete C4 deficiency
MISCELLANEOUS:
Two loci control synthesis of C4, C4A (120810) and C4B (120820);
Patients with total C4 deficiency are homozygous for double null C4
haplotype;
Prevalence of homozygous c4A deficiency in SLE 10-15x higher than
general population
MOLECULAR BASIS:
Caused by mutation in the complement component 4A gene (C4A, 120810.0001)
OMIM Title
*614386 PROLINE-RICH TRANSMEMBRANE PROTEIN 2; PRRT2
OMIM Description
CLONING
Chen et al. (2011) identified PRRT2 within a region of chromosome 16
linked to the paroxysmal kinesigenic dyskinesia locus (EKD1; 128200).
The deduced 340-amino acid protein has a proline-rich domain in its
N-terminal half and 2 transmembrane domains in its C-terminal half.
RT-PCR of mouse tissues detected high Prrt2 expression in brain and
spinal cord, with negligible expression in all other tissues examined.
Prrt2 expression in mouse was low prior to embryonic day 16, after which
it increased, peaked at postnatal day 14, and declined in adult. RT-PCR
and in situ hybridization of postnatal day-14 mouse brain revealed high
Prrt2 expression in cerebral cortex, hippocampus, and cerebellum, with
enrichment in cortical layers of cerebral cortex, as well as in granule
cells and Purkinje cell layers of cerebellum. Fluorescence-tagged PRRT2
was expressed in the membrane of transfected COS-7 cells.
Heron et al. (2012) found that Prrt2 was widely expressed in the mouse
brain, with high expression in the cerebral cortex and lower expression
in the basal ganglia.
GENE STRUCTURE
Chen et al. (2011) determined that the PRRT2 gene contains 4 exons, the
first of which is noncoding.
MAPPING
Chen et al. (2011) stated that the PRRT2 gene maps to chromosome
16p11.2.
GENE FUNCTION
In HEK293T cells and brain extracts from mice, Lee et al. (2012)
demonstrated that the PRRT2 protein interacted with SNAP25 (600322), a
synaptosomal membrane. After transfection of PRRT2 into rat hippocampal
cells, PRRT2 was detected in thin axonal processes exiting from the
neuron cell bodies.
MOLECULAR GENETICS
In affected members of 8 unrelated Han Chinese families with episodic
kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified 3
different heterozygous truncating mutations in the PRRT2 gene
(614386.0001-614386.0003). The first mutation was found by exome
sequencing of a large 4-generation family with 17 affected individuals.
Expression of a truncated form of PRRT2 in COS-7 cells showed loss of
membrane targeting and localization of the truncated protein in the
cytoplasm, suggesting interruption of protein function.
Using a combination of exome sequencing and linkage analysis in 2 large
Han Chinese families with EKD1, Wang et al. (2011) independently and
simultaneously identified 2 different heterozygous truncating mutations
in the PRRT2 gene (649dupC, 614386.0001 and Q163X, 614386.0009,
respectively) that completely segregated with the phenotype in each
family. Two patients in each family also had infantile convulsion and
choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han
Chinese families with EKD1 revealed that 2 carried the 649dupC mutation
and 1 had a different PRRT2 mutation (614386.0010).
Heron et al. (2012) identified heterozygous mutations in the PRRT2 gene
(see, e.g., 614386.0001 and 614386.0004-614386.0006) in 14 (82%) of 17
families with benign familial infantile seizures-2 (BFIS2; 605751), and
in 5 (83%) of 6 families with familial infantile convulsions with
paroxysmal choreoathetosis, a familial syndrome in which infantile
seizures and an adolescent-onset movement disorder, paroxysmal
kinesigenic choreoathetosis (EKD1), cooccur. The 649dupC mutation
(614386.0001) was the most common mutation, found in affected members of
12 families with BFIS2 and in 3 families with ICCA. Overall, the 649dupC
mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2
studied. The families were of different ethnic origin, including
Australasian of western European heritage, Swedish, and Israeli
Sephardic-Jewish, and there was no evidence of a common haplotype among
these families, indicating a mutation hotspot. These findings
demonstrated that mutations in PRRT2 cause both epilepsy and a movement
disorder, with obvious pleiotropy in age of expression.
Lee et al. (2012) also identified heterozygous mutations in the PRRT2
gene (see, e.g., 614386.0007 and 614386.0008) in affected members of
families with ICCA. The mutations were identified by whole-genome
sequencing of 6 well-characterized families. The findings were confirmed
by the identification of PRRT2 mutations in 24 of 25 additional families
with the disorder. The 649dupC mutation was the most common mutation.
Sanger sequencing of a third cohort of 78 probands with a less clear
clinical diagnosis found that 10 patients with familial disease and 17
with sporadic disease had the common 649dupC mutation; 1 additional
patient had a different truncating PRRT2 mutation. None of the
pathogenic alleles were found in over 2,500 control chromosomes. There
was intrafamilial variability of the phenotype. In vitro functional
expression assays showed that the mutant truncating proteins were not
expressed and did not exert dominant-negative effect on the wildtype
protein, suggesting haploinsufficiency as the pathologic mechanism.
Meneret et al. (2012) identified heterozygous mutations in the PRRT2
gene (see, e.g., 614386.0001; 614386.0011-614386.0012) in 22 (65%) of 34
patients of European descent with EKD1 or ICCA. Mutations were found in
13 (93%) of 14 familial cases and in 9 (45%) of 20 sporadic cases. There
was evidence for incomplete penetrance. The most common mutation was
649dupC, which was found in 17 of the 22 patients with PRRT2 mutations,
although this was not due to a founder effect. Compared to patients
without PRRT2 mutations, those with mutations had a slightly earlier age
at onset (median age of 15 years and 9 years, respectively), but
otherwise there were no phenotypic differences between the 2 groups.
Most of the mutations caused premature termination, leading Meneret et
al. (2012) to suggest that the disorders result from PRRT2
haploinsufficiency.
Schubert et al. (2012) identified a heterozygous 649dupC mutation in the
PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with
sporadic occurrence of the disorder (77% of index cases). Three
additional heterozygous PRRT2 mutations (see, e.g., 614386.0013;
614386.0014) were found in 3 other families with the disorder. The
patients were of German, Italian, Japanese, and Turkish origin. Some of
the families had previously been reported by Striano et al. (2006) and
Weber et al. (2004). The 649dupC mutation, which occurs in an unstable
DNA sequence of 9 cytosines, arose independently in families of
different origin. Some unaffected family members also carried the
mutation, indicating incomplete penetrance.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese
families with EKD1, some of whom also had ICCA, and in 2 Japanese
families with BFIS2. The mutation was shown to occur de novo in at least
1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and
BFIS2 segregated with the mutation even within the same family. The
findings indicated that all 3 disorders are allelic and are likely
caused by a similar mechanism.
GENOTYPE/PHENOTYPE CORRELATIONS
Heron and Dibbens (2013) reviewed the role of PRRT2 in 3 common
neurologic disorders, EKD1, ICCA, and BFIS2, noting that there are no
clear genotype/phenotype correlations.
HIRIP3
| dbSNP name | rs56183743(C,T) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 8479 |
| snpEff Gene Name | TAOK2 |
| EntrezGene Description | HIRA interacting protein 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09917 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmar telangiectasias (described in 1 family)
NEUROLOGIC:
[Central nervous system];
Cerebral cavernous malformations;
Seizures;
Recurrent headaches;
Hemorrhagic stroke
MISCELLANEOUS:
Genetic heterogeneity (see 116800 for summary);
Sporadic cases often single lesions versus multiple lesions in familial
cases
MOLECULAR BASIS:
Caused by mutation in the CCM2 gene (CCM2, 607929.0001)
OMIM Title
*603365 HIRA-INTERACTING PROTEIN 3; HIRIP3
OMIM Description
CLONING
The HIRA (600237) protein shares sequence similarity with the S.
cerevisiae Hir1p and Hir2p corepressors, which appear to act together on
chromatin structure to control gene transcription. Lorain et al. (1998)
stated that HIRA, like Hir1p, contains 7 N-terminal WD repeats and
probably functions as part of a multiprotein complex. Using a yeast
2-hybrid screen with HIRA as bait, these authors identified HeLa cell
cDNAs encoding HIRA-interacting proteins, or HIRIPs. The predicted
partial protein sequence of HIRIP3 contained 20% acidic and 21% basic
amino acids, including several stretches of lysine and arginine
residues.
GENE FUNCTION
Lorain et al. (1998) found in in vitro studies that HIRIP3 interacted
with HIRA and with H2B and H3 core histones (see 142711), suggesting to
Lorain et al. (1998) that a HIRA-HIRIP3-containing complex could
function in some aspects of chromatin and histone metabolism.
MAPPING
Gross (2012) mapped the HIRIP3 gene to chromosome 16p11.2 based on an
alignment of the HIRIP3 sequence (GenBank GENBANK AJ223349) with the
genomic sequence (GRCh37).
ZNF768
| dbSNP name | rs3751847(A,G); rs10871453(C,G) |
| ccdsGene name | CCDS10681.2 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 79724 |
| EntrezGene Description | zinc finger protein 768 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF768:NM_024671:exon2:c.T789C:p.C263C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4747 |
| ESP Afr MAF | 0.112426 |
| ESP All MAF | 0.302139 |
| ESP Eur/Amr MAF | 0.39907 |
| ExAC AF | 0.577 |
ZNF785
| dbSNP name | rs148651854(G,A); rs9934806(G,A); rs74015016(C,G); rs35974081(C,T) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 146540 |
| EntrezGene Description | zinc finger protein 785 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
SRCAP
| dbSNP name | rs2972803(A,C); rs77949246(C,T); rs35969813(T,C); rs67456513(A,T); rs138829955(G,A); rs7197770(T,C); rs75449882(A,G); rs72793372(C,T); rs139339184(G,A); rs4889500(G,T); rs4889501(C,T); rs80323213(G,A); rs11150593(T,C); rs6565198(G,C); rs6565199(T,C); rs8058578(C,T); rs374597482(C,T); rs1348039(G,A); rs111395501(C,T); rs367948915(C,A); rs111513754(T,G); rs7204278(A,G); rs4436794(T,C); rs4616297(G,A); rs10153105(G,C); rs1470129(C,G); rs4889502(C,A); rs75941883(A,G); rs72793375(G,A); rs11150594(A,G); rs2289442(T,C); rs2053426(T,C); rs9934046(A,G); rs9928572(C,T); rs369595841(C,G); rs7198250(C,A); rs6565201(C,T); rs148311339(A,C) |
| ccdsGene name | CCDS10689.2 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 10847 |
| EntrezGene Description | Snf2-related CREBBP activator protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SRCAP:NM_006662:exon12:c.G1559A:p.S520N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5286 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6ZRS2-3 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000455 |
| ESP All MAF | 0.001 |
| ESP Eur/Amr MAF | 0.001279 |
| ExAC AF | 0.0008051 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Mild hearing impairment (13%);
[Eyes];
Nystagmus, horizontal, mild (44%)
GENITOURINARY:
[Bladder];
Urinary urgency (57%)
SKELETAL:
[Spine];
Scoliosis (35%)
NEUROLOGIC:
[Central nervous system];
Cerebellar ataxia;
Ataxic gait;
Spasticity;
Hyperreflexia;
Dysarthria (74%);
Dystonia (57%);
Dysmetria;
Cognitive impairment, mild (44%);
Cerebellar atrophy;
Cortical atrophy (43%);
Nonspecific leukoencephalopathy (52%)
MISCELLANEOUS:
Variable age at onset (range 2 to 59 years, mean 24 years);
High intrafamilial and interfamilial variability;
High frequency among French-Canadians;
About 50% of patients become wheelchair-bound at an average age of
37 years
MOLECULAR BASIS:
Caused by mutation in the methionyl-tRNA synthetase 2 gene (MARS2,
609728.0001)
OMIM Title
*611421 SNF2-RELATED CBP ACTIVATOR PROTEIN; SRCAP
;;SWR1, S. CEREVISIAE, HOMOLOG OF; SWR1;;
KIAA0309
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned SRCAP, which they designated
KIAA0309. RT-PCR detected low to moderate expression in most tissues
examined.
Using the transcription coactivation domain of CBP (CREBBP; 600140) as
bait in a yeast 2-hybrid of a HeLa cell cDNA library, followed by
screening a human SKN plasmid library, Johnston et al. (1999) cloned
SRCAP. The deduced 2,971-amino acid protein has a calculated molecular
mass of 315 kD. It has a highly charged N-terminal domain, a central
CBP-binding domain, a second charged domain, and a putative C-terminal
DNA-binding domain. A complete ATPase domain, consisting of 7 highly
conserved regions, are dispersed over the length of the protein.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the SRCAP gene
to chromosome 16.
GENE FUNCTION
Johnston et al. (1999) showed that SRCAP increased transcription of a
reporter plasmid when it was cotransfected with the transcription
activation domain of CBP. Endogenous SRCAP immunoprecipitated from
nuclear extracts of a human lung epithelial cell line had ATPase
activity, and the C-terminal half of SRCAP enhanced the ability of CBP
to activate transcription. Adenovirus protein E1A blocked the ability of
CBP to function as a coactivator for a number of transcription factors.
Johnston et al. (1999) showed that binding of E1A to CBP excluded
binding of SRCAP to CBP, suggesting a means by which E1A represses the
coactivator function of CBP.
Adenovirus DNA-binding protein (Dbp) is a multifunctional protein
involved in several aspects of the adenovirus life cycle, including an
ability to modulate transcription. Xu et al. (2001) showed that in
vitro-translated Dbp and SRCAP proteins interacted and that Dbp
inhibited SRCAP transcriptional activity in a dose-dependent manner.
Monroy et al. (2003) stated that SRCAP is found in multiprotein
complexes that include proteins found in SWI/SNF (see SMARCA2; 600014)
chromatin remodeling complexes. They demonstrated that SRCAP enhanced
phosphoenolpyruvate carboxykinase (see PCK1; 261680) promoter
transcription induced by glucocorticoids. SRCAP also enhanced
glucocorticoid receptor (GCCR; 138040)-mediated transcription of a
simple promoter containing only 2 glucocorticoid response elements.
SRCAP served as a coactivator of the androgen receptor (313700) and
exhibited synergistic activation with nuclear receptor coactivators and
functionally interacted in vivo with glucocorticoid receptor-interacting
protein-1 (NCOA2; 601993) and coactivator-associated arginine
methyltransferase-1 (CARM1; 603934). Monroy et al. (2003) proposed that
SRCAP, by virtue of its ability to interact with CBP, functions as a
coactivator to regulate transcription initiated by several signaling
pathways.
Eissenberg et al. (2005) stated that the SRCAP homolog in Drosophila is
the domino (Dom) gene. They showed that human SRCAP complemented
recessive domino-mutant phenotypes, and the rescue depended on an intact
ATPase homology domain. SRCAP colocalized with Dom on Drosophila
polytene chromosomes and was recruited to sites of active transcription,
such as steroid-regulated loci, but not to activated heat shock loci.
SCCAP recruited Drosophila Cbp to ectopic chromosomal sites, suggesting
that SRCAP and Cbp interacted directly or indirectly on chromosomes.
They showed that Dom is a Notch (190198) pathway activator in Drosophila
and that wildtype SRCAP, but not an ATPase domain mutant, substituted
for Dom in Notch-dependent wing development. SRCAP also potentiated
Notch-dependent gene activation in HeLa cells.
By chromatin immunoprecipitation analysis of a human lung carcinoma cell
line, Wong et al. (2007) found that SRCAP was recruited to both active
and inactive promoters, with highest levels of SRCAP on the active SP1
(189906), G3BP (608431), and FAD synthetase (FLAD1; 610595) promoters.
The sites of SRCAP recruitment on these promoters overlapped or occurred
adjacent to the sites of deposition of H2AZ (142763) and acetylated
H2AZ. Knockdown of SRCAP expression resulted in decreased deposition of
H2AZ and acetylated H1AZ and decreased levels of SP1, G3BP, and FAD
synthetase mRNA. Wong et al. (2007) concluded that SRCAP mediates in
vivo deposition of H2AZ.
MOLECULAR GENETICS
In 13 unrelated patients with Floating-Harbor syndrome (FLHS; 136140),
Hood et al. (2012) identified heterozygosity for 5 different truncating
mutations in the SRCAP gene (see, e.g., 611421.0001-611421.0003), all of
which were located in the final exon (exon 34) and were not represented
in dbSNP131, the 1000 Genomes Project, or the National Heart, Lung, and
Blood Institute Exome Variant Server. The mutations were shown to be de
novo in all 6 instances in which parental DNA was available. Hood et al.
(2012) stated that given the structure of SRCAP, the nonrandom
clustering of truncating mutations seen in these patients was strongly
suggestive of a dominant-negative disease mechanism due to loss of one
or more critical domains.
By whole-exome sequencing followed by Sanger sequencing, Le Goff et al.
(2013) identified heterozygous de novo mutations in exon 34 of the SRCAP
gene in 6 of 9 patients with Floating-Harbor syndrome (see, e.g.,
611421.0001, 611421.0002, and 611421.0004). Le Goff et al. (2013) noted
that these findings confirmed exon 34 as a mutation hotspot, and that
the absence of an SRCAP mutation in 3 patients fulfilling all the
characteristics of Floating-Harbor syndrome suggested genetic
heterogeneity, although partial intragenic deletions or mutations in the
introns or promoter region could not be excluded.
MIR4519
| dbSNP name | rs897984(T,C) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 100616231 |
| snpEff Gene Name | BCL7C |
| EntrezGene Description | microRNA 4519 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4178 |
| ExAC AF | 0.273 |
FBXL19-AS1
| dbSNP name | rs141694151(C,G); rs9319588(C,T); rs7199908(T,G); rs73526645(A,C); rs149139746(A,G); rs12930657(C,T); rs7184263(C,T); rs77088799(A,T); rs150202164(G,A) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 283932 |
| snpEff Gene Name | FBXL19 |
| EntrezGene Description | FBXL19 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02755 |
HSD3B7
| dbSNP name | rs12443627(G,C); rs9938550(A,G); rs34212827(T,C); rs2305880(T,C) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 80270 |
| snpEff Gene Name | SETD1A |
| EntrezGene Description | hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4151 |
| ExAC AF | 0.491 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Apnea during seizure spells;
Cyanosis
NEUROLOGIC:
[Central nervous system];
Seizures, partial, afebrile;
Secondary generalized tonic-clonic seizures may occur;
Seizures occur in clusters over 1 or several days;
Seizures often begin focally with head and eye deviation;
Rigidity during seizures;
Staring episodes during seizures;
Ictal EEG shows focal onset, often posterior region of brain;
Normal psychomotor development;
Normal interictal EEG
MISCELLANEOUS:
Onset ranges from 2 days to 7 months (most at 2-3 months);
Seizures are easily controlled by medications;
Spontaneous resolution by 12 months of age with no recurrence later
in life;
See also benign familial infantile convulsions (BFIC1, 601764);
See also benign neonatal epilepsy (EBN1, 121200)
MOLECULAR BASIS:
Caused by mutation in the alpha-1-subunit of the voltage-gated type
II sodium channel gene (SCN2A, 182390.0002)
OMIM Title
*607764 3-@BETA-HYDROXY-DELTA-5-C27-STEROID OXIDOREDUCTASE; HSD3B7
;;C27-3-BETA-HSD
OMIM Description
CLONING
Schwarz et al. (2000) used expression cloning to isolate cDNAs encoding
a microsomal 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase that is
expressed predominantly in the liver. The predicted product showed 34%
sequence identity with the C19 and C21 3-beta-HSD enzymes, which
participate in steroid hormone metabolism. Schwarz et al. (2000)
observed that, when transfected into cultured cells, the enzyme encoded
by the C27 3-beta-HSD cDNA was active against four 7-alpha-hydroxylated
sterols, indicating that a single C27 3-beta-HSD enzyme can participate
in all pathways of bile acid synthesis known to that time. The expressed
enzyme did not metabolize several different C19/21 steroids as
substrates. The levels of hepatic C27 3-beta-HSD mRNA in the mouse were
not sexually dimorphic and did not change in response to dietary
cholesterol or to changes in bile acid pool size. The human C27
3-beta-HSD gene encodes a protein of 369 amino acids that is about 86%
identical to the mouse protein.
MAPPING
Schwarz et al. (2000) mapped the human HSD3B7 gene to chromosome
16p12-p11.2 by analysis of radiation hybrid panels.
GENE STRUCTURE
Schwarz et al. (2000) determined that the HSD3B7 gene contains 6 exons
and spans 3 kb of DNA.
GENE FUNCTION
Schwarz et al. (2000) observed that the C27 3-beta-HSD enzymes are
active only against 7-alpha hydroxylated sterol substrates. Human C27
3-beta-HSD enzymes were active against the 7-alpha hydroxylated forms of
24-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol
and showed no preference for any of those compounds. Northern blot
analysis identified a single 2.4-kb species present at high levels in
liver, pancreas, and kidney, and at lower levels in heart, skeletal
muscle, and placenta.
MOLECULAR GENETICS
Schwarz et al. (2000) identified a 2-bp deletion in the C27 3-beta-HSD
gene (607764.0001) in a patient with a congenital defect in bile acid
synthesis (CBAS1; 607765) and neonatal cholestasis.
Cheng et al. (2003) performed a molecular analysis of 15 additional
patients from 13 kindreds with C27 3-beta-HSD deficiency deficiency and
identified 12 different mutations in the HSD3B7 gene (see, e.g.,
607764.0001-607764.0005). They studied 10 mutations in detail; these
were shown to cause complete loss of enzyme activity and, in 2 cases,
alterations in the size or amount of the transcribed RNA. Mutations were
homozygous in 13 patients from 10 families and heterozygous in 4
patients from 3 families. Cheng et al. (2003) concluded that a diverse
spectrum of HSD3B7 mutations underlies this rare form of neonatal
cholestasis.
VKORC1
| dbSNP name | rs7294(C,T); rs7200749(G,A); rs2359612(A,G); rs8050894(C,G); rs9934438(G,A); rs17708472(G,A); rs2884737(A,C); rs61742245(C,A) |
| ccdsGene name | CCDS10704.1 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 79001 |
| snpEff Gene Name | RP11-196G11.1 |
| EntrezGene Description | vitamin K epoxide reductase complex, subunit 1 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=79001&%3Brs=61742245|http://www.ncbi.nlm.nih.gov/omim/122700,608547|http://omim.org/entry/608547#0007 |
| Annovar Function | VKORC1:NM_024006:exon1:c.G106T:p.D36Y,VKORC1:NM_206824:exon1:c.G106T:p.D36Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9504 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=79001&%3Brs=61742245|http://www.ncbi.nlm.nih.gov/omim/122700,608547|http://omim.org/entry/608547#0007 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000699 |
| ESP Eur/Amr MAF | 0.001056 |
| ExAC AF | 0.001689 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Macrocephaly;
Brachycephaly;
[Face];
Flat face;
Prominent forehead;
Large anterior fontanel;
[Ears];
Low-set ears;
Conductive hearing loss;
Recurrent episodes of otitis media;
[Eyes];
Hypertelorism;
[Nose];
Absent nasal bridge;
[Mouth];
Cleft palate;
[Teeth];
Malocclusion
SKELETAL:
Joint laxity (hip, knee, shoulder, wrist, fingers);
Joint dislocations;
Delayed bone age;
[Spine];
Kyphoscoliosis;
[Hands];
Cylindrical fingers;
Clinodactyly (4th and 5th fingers);
[Feet];
Clubfoot;
Double calcaneal ossification center
NEUROLOGIC:
Hypotonia;
[Central nervous system];
Developmental delay
LABORATORY ABNORMALITIES:
Abnormal karyotype in 3 patients involving distal 6p
OMIM Title
*608547 VITAMIN K EPOXIDE REDUCTASE COMPLEX, SUBUNIT 1; VKORC1
;;VKOR;;
FLJ00289
OMIM Description
DESCRIPTION
The VKORC1 gene encodes vitamin K epoxide reductase complex subunit-1, a
small transmembrane protein of the endoplasmic reticulum, which plays a
major role in the vitamin K pathway and is the target protein of
warfarin (summary by Ross et al., 2010).
CLONING
Li et al. (2004) used short interfering RNA (siRNA) pools against
individual genes to test their ability to inhibit vitamin K epoxide
reductase (VKOR) activity in human cells. Thus, Li et al. (2004)
identified the VKOR gene as MGC11276. The authors expressed MGC11276 in
insect cells and observed VKOR activity. The 163-amino acid VKORC1
protein contains 1 to 3 transmembrane domains and 7 cysteine residues, 5
of which are conserved among human, mouse, rat, zebrafish, Xenopus, and
Anopheles.
Rost et al. (2004) cloned the VKORC1 gene, which encodes a protein of
163 amino acids with a calculated relative molecular mass of 18 kD.
Northern blot analysis of fetal and adult human tissues detected a
single 1.0-kb transcript, providing no evidence for alternative
splicing. Highest expression was seen in fetal and adult liver, followed
by fetal heart, kidney, and lung, adult heart, and pancreas.
Immunofluorescence experiments demonstrated VKORC1 expression in the
endoplasmic reticulum.
GENE FUNCTION
Rost et al. (2004) showed that overexpression of wildtype VKORC1
resulted in a marked stimulation of VKOR activity: production of vitamin
K quinone was increased 14- to 21-fold as compared with untreated or
mock-transfected cells.
Chu et al. (2006) purified recombinant human VKORC1 from
baculovirus-infected insect cells and found that it could convert
vitamin K epoxide to vitamin K and vitamin K to reduced vitamin K in the
absence of other protein components. Chu et al. (2006) concluded that a
single VKORC1 peptide is responsible for both activities and that VKOR
is not a multisubunit enzyme.
GENE STRUCTURE
The VKORC1 gene contains 3 exons and spans approximately 5 kb (Li et
al., 2004, Rost et al., 2004).
MAPPING
Rost et al. (2004) noted that a linkage group of genes on chromosome
16p11 is orthologous to genes around the warfarin resistance loci R2 in
rats and War in mice, and thus narrowed the critical interval on
16p12-q21 for warfarin resistance, mapped by Fregin et al. (2002), to a
4.0-Mb region on 16p. Rost et al. (2004) and Li et al. (2004) identified
the human VKORC1 gene at chromosome 16p11.2.
MOLECULAR GENETICS
Rost et al. (2004) found 4 different heterozygous mutations in the
VKORC1 gene in individuals with warfarin resistance (122700). Two
unrelated index patients with combined deficiency of vitamin K-dependent
clotting factors type-2 (VKCFD2; 607473) and their affected sibs carried
the same homozygous point mutation in exon 3 (608547.0001).
Rieder et al. (2005) investigated the genetic basis of the wide
variation among patients in response to warfarin therapy. They
determined VKORC1 haplotype frequencies in African American, European
American, and Asian American populations and VKORC1 mRNA expression in
human liver samples. They identified 10 common noncoding VKORC1
single-nucleotide polymorphisms (SNPs) and inferred 5 major haplotypes.
They identified a low-dose haplotype group (A) and a high-dose haplotype
group (B). The mean maintenance dose of warfarin differed significantly
among the 3 haplotype group combinations, at approximately 2.7 mg per
day for A/A, 4.9 mg per day for A/B, and 6.2 mg per day for B/B (p less
than 0.001). VKORC1 haplotype groups A and B explained approximately 25%
of the variance in dose. Asian Americans had a higher proportion of
group A haplotypes and African Americans a higher proportion of group B
haplotypes. VKORC1 mRNA levels varied according to the haplotype
combination. Thus the molecular mechanism of this warfarin dose response
appears to be regulated at the transcriptional level.
Wadelius et al. (2005) phenotyped 201 warfarin-treated patients for
common polymorphisms in the VKORC1 and GGCX (137167) genes. All 5 VKORC1
SNPs covaried significantly with warfarin dose, and explained 29 to 30%
of variance in dose. VKORC1 had a larger impact than cytochrome P450 2C9
(CYP2C9; 601130), which explained 12% of variance in dose. One GGCX SNP
showed a small but significant effect on warfarin dose. Wadelius et al.
(2005) pointed out that incorrect dosage, especially during the initial
phase of treatment, carries a high risk of either severe bleeding or
failure to prevent thromboembolism. Genotype-based dose predictions
might enable personalized drug treatment from the start of warfarin
therapy.
Li et al. (2006) tested for association between single-nucleotide
polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin
dose required to maintain patients at their desired anticoagulation
target. Three of 6 VKORC1 SNPs were found to be very strongly associated
with the average warfarin dose required to achieve the target
international normalized ratio (INR; p less than 0.0001). The mean
weekly dose by genotype ranged from approximately 27 to 47 mg. There was
no evidence for an association between either of the 2 CYP2C9
polymorphisms studied, CYP2C9*2 and CYP2C9*3.
In an editorial, Shurin and Nabel (2007) noted that evidence from
various clinical and population studies suggested that patients of
Asian, European, and African ancestry require, on average, lower,
intermediate, and higher doses of warfarin, respectively. They suggested
that additional studies involving larger numbers of patients of African
and Asian descent were needed to confirm these associations (Takahashi
et al., 2006).
Two polymorphisms of CYP2C9 occur frequently in patients who are
warfarin-sensitive and require lower doses: CYP2C9*2 (R144C;
601130.0002) and CYP2C9*3 (I359L; 601130.0001). Furthermore, the VKORC1
promoter polymorphism -1639G-A (608547.0006) occurs frequently in
patients who are warfarin-sensitive and require lower doses, whereas
patients with VKORC1 missense mutations are warfarin-resistant and
require higher doses. To compare the CYP2C9 and VKORC1 allele and
genotype frequencies among 260 Ashkenazi Jewish and 80 Sephardi Jewish
individuals, Scott et al. (2008) genotyped 6 CYP2C9 and 8 VKORC1
alleles. The sensitive CYP2C9*2 and *3 alleles had significantly higher
frequencies in Sephardi than in Ashkenazi individuals, 0.194 and 0.144
versus 0.127 and 0.081, respectively (p less than 0.001). In contrast,
the VKORC1 D36Y mutation (608547.0007), which predicts warfarin
resistance, had a significantly higher frequency in Ashkenazi than in
Sephardi individuals, 0.043 versus 0.006, respectively. Of note, 11.3%
of Ashkenazi individuals predicted to be CYP2C9 extensive metabolizers
and 8.7% of those predicted to be intermediate and poor metabolizers
were VKORC1 D36Y carriers who required markedly higher warfarin doses.
Thus, approximately 10% of all Ashkenazi individuals would be
misclassified when only genotyping CYP2C9*2, *3, and VKORC1 -1639G-A,
underscoring the importance of screening for D36Y prior to initiating
warfarin anticoagulation in Ashkenazi Jewish individuals. Taken
together, the findings of Scott et al. (2008) showed that about 85% of
Ashkenazi and 90% of Sephardi individuals had at least one sensitive or
resistant allele, indicating that each group has different warfarin
pharmacogenetics and would benefit from genotype-based dose predictions.
In 297 patients starting warfarin therapy, Schwarz et al. (2008)
assessed CYP2C9 genotypes CYP2C9*1, *2, and *3, VKORC1 haplotypes,
designated A and non-A, clinical characteristics, response to therapy as
determined by the international normalized ratio (INR), and bleeding
events. They found that initial variability in the INR response to
warfarin was more strongly associated with genetic variability in the
pharmacologic target of warfarin VKORC1 than with CYP2C9.
The International Warfarin Pharmacogenetics Consortium (2009) found that
a pharmacogenetic dose algorithm for warfarin based on the genotype at
VKORC1 and CYP2C9 accurately identified larger proportions of patients
who required 21 mg of warfarin or less per week and those who required
49 mg or more per week to achieve the targeted international normalized
ratio than did a clinical algorithm alone (49.4% vs 33.3%, p less than
0.001, among patients requiring 21 mg or less per week; and 24.8% vs
7.2%, p less than 0.001, among those requiring 49 mg or more per week).
The authors concluded that the use of a pharmacogenetic algorithm for
estimating the appropriate initial dose of warfarin produces
recommendations that are significantly closer to the required stable
therapeutic dose than those derived from a clinical algorithm or a
fixed-dose approach. The greatest benefits were observed in the 46.2% of
the population that required 21 mg or less of warfarin per week or 49 mg
or more per week for therapeutic anticoagulation.
Among 273 African Americans and 302 European Americans undergoing
warfarin therapy, Limdi et al. (2008) found that variation in the VKORC1
gene could explain 5% and 18% variability, respectively, in warfarin
dosage. An additive effect was observed when also accounting for
polymorphisms in the CYP2C9 gene (8% and 30%, in African Americans and
European Americans, respectively). Four common VKORC1 haplotypes were
identified in European Americans, and 12 in African Americans,
consistent with higher genomic sequence diversity in populations of
African descent. African Americans had a lower frequency of the low-dose
haplotype (10.6%) compared with European Americans (35%, p less than
0.0001). The variability in dose explained by VKORC1 haplotype or
haplotype groups was similar to that of a single informative
polymorphism. Two SNPs in the VKORC1 gene, dbSNP rs9934438 (608547.0008)
and dbSNP rs9923231 (608547.0006), were the best predictors of warfarin
dose among both groups.
PYCARD
| dbSNP name | rs115908198(C,G) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 29108 |
| EntrezGene Description | PYD and CARD domain containing |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0202 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Normal bone age;
[Hands];
Radially deviated phalanges;
Progressive brachydactyly of middle and distal phalanges;
Progressive arthropathy of the interphalangeal and metacarpophalangeal
joints;
[Feet];
Progressive brachydactyly of middle and distal phalanges;
Progressive arthropathy of the interphalangeal and metatarsophalangeal
joints
MISCELLANEOUS:
Onset in first decade of life;
Changes more marked in hands than feet
OMIM Title
*606838 PYD AND CARD DOMAIN-CONTAINING PROTEIN; PYCARD
;;APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN CONTAINING A CARD; ASC;;
TARGET OF METHYLATION-INDUCED SILENCING 1; TMS
OMIM Description
DESCRIPTION
Caspase-associated recruitment domains (CARDs) mediate the interaction
between adaptor proteins such as APAF1 (602233) and the proform of
caspases (e.g., CASP9; 602234) participating in apoptosis. ASC is a
member of the CARD-containing adaptor protein family.
CLONING
By immunoscreening a promyelocytic cell line, Masumoto et al. (1999)
isolated a cDNA encoding ASC. The deduced 195-amino acid protein
contains an N-terminal pyrin (608107)-like domain (PYD) and an
87-residue C-terminal CARD. estern blot analysis showed expression of a
22-kD protein. Fluorescence microscopy demonstrated a ring-like
expression in some transfected cells. Northern and Western blot analyses
showed expression of a 0.8-kb transcript in some leukemia cell lines and
in a melanoma cell line.
Using representational difference analysis to isolate genes
downregulated in cells overexpressing DNMT1 (126375) relative to their
original fibroblast source, Conway et al. (2000) cloned and
characterized ASC, which they termed TMS1.
Martinon et al. (2001) determined that ASC, which they termed PYCARD,
shares the N-terminal PYD with NALP1 (606636) and NALP2 (609364).
GENE FUNCTION
Western blot analysis by Masumoto et al. (1999) indicated that ASC may
have proapoptotic activity by increasing the susceptibility of leukemia
cell lines to apoptotic stimuli by anticancer drugs.
Methylation-sensitive restriction PCR and methylation-specific PCR (MSP)
analyses by Conway et al. (2000) indicated that silencing of TMS1
correlates with hypermethylation of the CpG island surrounding exon 1
and that overexpression of DNMT1 promotes hypermethylation and silencing
of TMS1. Breast cancer cell lines, but not normal breast tissue,
exhibited complete methylation of TMS1 and expressed no TMS1 message.
Expression of TMS1 in breast cancer cell lines inhibited growth and
reduced the number of surviving colonies. Conway et al. (2000) concluded
that TMS1 functions in the promotion of caspase-dependent apoptosis and
that overexpression of TMS1 inhibits the growth of breast cancer cells.
Using bisulfite genomic sequencing, DNase I-hypersensitive site mapping,
and chromatin immunoprecipitation, Stimson and Vertino (2002) showed
that in normal fibroblasts, the TMS1 CpG island is composed of an
unmethylated domain with distinct 5-prime and 3-prime boundaries. De
novo methylation of the CpG island in cells overexpressing DNMT1 was
accompanied by a loss of CpG island-specific hypersensitive site
formation, localized hypoacetylation of histone H3 (see 602810) and H4
(see 602822), and gene silencing. Stimson and Vertino (2002) proposed
the existence of protein-binding sites that demarcate the boundaries of
TMS1 CpG islands in normal cells and that the boundaries are overcome by
aberrant methylation, resulting in gene silencing.
McConnell and Vertino (2000) showed that inducible expression of TMS1
inhibits cellular proliferation and induces DNA fragmentation that can
be blocked by a caspase inhibitor or by dominant-negative CASP9, but not
by CASP8 (601763). TMS1, unlike many CARD-containing proteins, does not
activate nuclear factor kappa-B (NFKB; 164011). Immunofluorescence
microscopy demonstrated that induction of apoptosis causes a
CARD-dependent shift from diffuse cytoplasmic expression to punctate or
spherical perinuclear aggregates.
Ohtsuka et al. (2004) found that, when ectopically expressed, ASC
interacted directly with BAX (600040), colocalized with BAX to the
mitochondria, induced cytochrome c release with a significant reduction
of mitochondrial membrane potential, and resulted in the activation of
CASP9, CASP2 (600639), and CASP3 (600636). The rapid induction of
apoptosis by ASC was not observed in BAX-deficient cells. Induction of
ASC after exposure to genotoxic stress was also dependent on p53
(191170). Blocking of endogenous ASC expression by small interfering RNA
reduced the apoptotic response to p53 or genotoxic insult and inhibited
translocation of BAX to mitochondria, suggesting that ASC is required to
translocate BAX to the mitochondria.
Using gene targeting to generate mice deficient in Asc or Ipaf (CARD12;
606831), Mariathasan et al. (2004) found an absence of the p20 and p10
of Casp1 in homozygous mutant but not wildtype or heterozygote
macrophages after stimulation with lipopolysaccharide (LPS). After
priming by LPS and stimulation with Salmonella typhimurium, secretion of
Il1b (147720) was significantly reduced in Asc -/- and Ipaf -/-, but not
Ripk2 (603455)-deficient, macrophages. Immunoprecipitation analysis
showed that Asc associates with Casp1, indicating that components of the
inflammasome, a multiple adaptor complex in activated monocytes and
macrophages, are released from cells secreting mature Il1b. Asc -/- and
Ipaf -/- macrophages also failed to process Casp1 after priming with Tlr
(e.g., TLR4, 603030) agonists in response to ATP, leading to impaired
release of Il1b, Il1a (147760), and Il18 (600953). Challenge of
Asc-deficient mice with a normally lethal dose of LPS resulted in only
30% mortality in 48 hours and full recovery in the remainder by day 7.
There were also some survivors among the heterozygotes. Analysis of
responses to LPS and Tnf (191160) showed no role for Asc in Erk (e.g.,
MAPK3, 601795) or Nfkb signaling. Infection of Asc- or Ipaf-deficient
macrophages with wildtype but not SipB-toxin-deficient S. typhimurium
does not result in cell death as is seen in wildtype macrophages.
Mariathasan et al. (2004) concluded that ASC is essential for CASP1
activation within the inflammasome and that CARD12 is required for CASP1
activation in response to at least 1 intracellular pathogen.
Agostini et al. (2004) noted that NALP1, unlike other short NALP
proteins, contains a C-terminal CARD domain that interacts with and
activates CASP5 (602665). CASP1 and CASP5 are activated when they
assemble with NALP1 and ASC to form the inflammasome, which is
responsible for processing the inactive IL1B precursor (proIL1B) to
release active IL1B cytokine. Using immunoprecipitation analysis,
Agostini et al. (2004) found that CARD8 (609051), which contains
C-terminal FIIND (function to find) and CARD domains, associated with
constructs of NALP2 and NALP3 (CIAS1; 606416) lacking the N-terminal
pyrin domain and/or the C-terminal leucine-rich repeat domain. They
determined that the interaction was mediated by the FIIND domain of
CARD8 and the centrally located NACHT domain of NALP2 and NALP3. The
pyrin domain of NALP2 and NALP3, like that of NALP1, interacted with the
pyrin domain of ASC, which recruits CASP1. Transfection experiments
showed that an inflammasome could be assembled containing ASC, CARD8,
CASP1, and a short NALP, resulting in activation of CASP1, but not
CASP5, and strong processing of proIL1B.
Muruve et al. (2008) demonstrated that internalized adenoviral DNA
induces maturation of pro-IL1B in macrophages, which is dependent on
NALP3 (606416) and ASC, components of the innate cytosolic molecular
complex termed the inflammasome. Correspondingly, Nalp3- and
Asc-deficient mice displayed reduced innate inflammatory responses to
adenovirus particles. Inflammasome activation also occurred as a result
of transfected cytosolic bacterial, viral, and mammalian (host) DNA, but
sensing was dependent on Asc and not Nalp3. The DNA-sensing
proinflammatory pathway functions independently of TLRs and interferon
regulatory factors. Thus, Muruve et al. (2008) concluded that, in
addition to viral and bacterial components or danger signals in general,
inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening
their central role in innate immunity.
Fernandes-Alnemri et al. (2009) demonstrated that AIM2 (604578), an
interferon-inducible HIN200 family member, senses cytoplasmic DNA by
means of its C-terminal oligonucleotide/oligosaccharide-binding domain
and interacts with ASC through its N-terminal pyrin domain to activate
caspase-1 (CASP1; 147678). The interaction of AIM2 with ASC also leads
to the formation of ASC pyroptosome, which induces pyroptotic cell death
in cells containing caspase-1. Knockdown of AIM2 by short interfering
RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in
human and mouse macrophages, whereas stable expression of AIM2 in the
nonresponsive human embryonic kidney 293T cell line conferred
responsiveness to cytoplasmic DNA. Fernandes-Alnemri et al. (2009)
concluded that their results showed that cytoplasmic DNA triggers
formation of the AIM2 inflammasome by inducing AIM2 oligomerization.
Using mouse and human cells, Hornung et al. (2009) identified the PYHIN
(pyrin and HIN domain-containing protein) family member AIM2 as a
receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain
of AIM2 binds to DNA, whereas the pyrin domain (but not that of the
other PYHIN family members) associates with the adaptor molecule ASC to
activate both NF-kappa-B (see 164011) and caspase-1. Knockdown of Aim2
abrogates caspase-1 activation in response to cytoplasmic
double-stranded DNA and the double-stranded DNA vaccinia virus. Hornung
et al. (2009) concluded that collectively, their observations identify
AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome
with the ligand and ASC to activate caspase-1.
GENE STRUCTURE
By genomic sequence analysis, Conway et al. (2000) determined that the
TMS1 gene contains 3 exons spanning 1.4 kb, with a CpG island
surrounding exon 1.
MAPPING
Using FISH and radiation hybrid analysis, Masumoto et al. (1999) and
Conway et al. (2000) mapped the ASC gene to chromosome 16p12-p11.2.
ANIMAL MODEL
Using mice lacking Asc or mice with a deficiency of Nlrp6 (609650) in
colonic epithelial cells, Elinav et al. (2011) observed a decline in
Il18 levels and altered fetal microbiota with expansion of the
Bacterioidetes phyla. The mutant mice were characterized by spontaneous
intestinal hyperplasia, inflammatory cell recruitment, and exacerbation
of chemical colitis induced by dextran sodium sulfate (DSS). The
colitogenic activity of the altered microbiota was transferable to adult
or neonatal wildtype mice when cohoused with the mutant mice. The
exacerbation of DSS colitis was induced by Ccl5 (187011). Antibacterial,
but not antiviral, antifungal, or antihelminthic, treatment reduced the
severity of DSS colitis in Asc -/- and Nlrp6 -/- mice to wildtype levels
and lowered the transferability and severity of colitis to wildtype
mice. Elinav et al. (2011) proposed that perturbations in this
inflammasome pathway may constitute a predisposing or initiating event
in some forms of inflammatory bowel disease (see 266600).
The propensity of helminths, such as schistosomes (see 181460), to
immunomodulate the host's immune system is an essential aspect of their
survival. Ritter et al. (2010) stimulated mouse bone marrow-derived
dendritic cells (BMDCs) with soluble schistosomal egg antigens (SEAs)
after prestimulation with different TLR ligands and observed suppressed
secretion of Tnf and Il6 (147620) and increased Nlrp3-dependent Il1b
production. Induction of Il1b was phagocytosis-independent, but it
required production of reactive oxygen species, potassium efflux, and
functional Syk (600085) signaling, suggesting inflammasome activation.
SEA stimulation of BMDCs lacking Fcrg (see 146740) or dectin-2 (CLEC6A;
613579) resulted in significantly reduced Il1b production compared with
wildtype BMDCs, suggesting that SEA triggers dectin-2, which couples
with Fcrg to activate the Syk kinase signaling pathway that controls
Nlrp3 inflammasome activation and Il1b release. Infection of mice
lacking Nlrp3 or Asc with S. mansoni resulted in no difference in
parasite burden, but decreased liver pathology and downregulated Th1,
Th2, and Th17 adaptive immune responses. Ritter et al. (2010) concluded
that SEA components induce IL1B production and that NLRP3 plays a
crucial role during S. mansoni infection.
Wlodarska et al. (2014) found that mice deficient in Nlrp6, as well as
mice deficient in Asc or Casp1, which are key components of the Nlrp6
inflammasome signaling pathway, were unable to clear Citrobacter
rodentium, the attaching/effacing pathogen, from colon. Mice lacking
Asc, Casp1, or Nlrp6 lacked a thick continuous overlaying inner mucus
layer and exhibited marked goblet cell hyperplasia. Bacteria were also
more invasive in mutant mice, penetrating deep into crypts, and were
more frequently associated with goblet cells. The goblet cell defect in
Nlrp6 inflammasome-deficient mice was independent of Il1 and Il18
mechanisms. Immunoblot analysis, immunofluorescence analysis, and
electron microscopy demonstrated that the Nlrp6 inflammasome was
critical for autophagy in intestinal epithelial cells. Wlodarska et al.
(2014) concluded that the NLRP6 inflammasome is critical for mucus
granule exocytosis, initiation of autophagy, and maintaining goblet cell
function.
SLC5A2
| dbSNP name | rs9924771(A,G); rs11646054(G,C); rs202200611(C,T); rs3813008(G,A); rs3116150(G,A); rs74015546(T,C); rs61741237(A,G) |
| ccdsGene name | CCDS10714.1 |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 6524 |
| EntrezGene Description | solute carrier family 5 (sodium/glucose cotransporter), member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC5A2:NM_003041:exon4:c.C415T:p.R139C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8366 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P31639 |
| dbNSFP Uniprot ID | SC5A2_HUMAN |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Isolated cases
HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Midface hypoplasia;
Broad face;
[Ears];
Hearing loss (conductive and/or sensorineural);
[Nose];
Broad nasal bridge
CARDIOVASCULAR:
[Heart];
Congenital heart defect
GENITOURINARY:
[Kidneys];
Structural renal anomalies
SKELETAL:
[Spine];
Scoliosis;
[Hands];
Brachydactyly
NEUROLOGIC:
[Central nervous system];
Speech delay;
Mental retardation (IQ 20-78);
Sleep disturbance;
Structural brain abnormalities;
[Peripheral nervous system];
Peripheral neuropathy;
Decreased pain sensitivity;
Normal nerve conduction velocities;
Decrease/absent deep tendon reflexes;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Polyembolokoilamania (insertion of foreign bodies into body orifices);
Behavioral problems;
Self-destructive behavior;
Onychotillomania (pulling out nails);
Wrist-biting;
Head-banging
VOICE:
Hoarse voice
LABORATORY ABNORMALITIES:
Interstitial deletion of 17p11.2 (most common is 3.7Mb)
MISCELLANEOUS:
Most cases result from de novo mutation or deletion of RAI1 (607642)
MOLECULAR BASIS:
Caused by mutation in the retinoic acid-induced gene 1 (RAI1, 607642.0004);
Contiguous gene deletion syndrome caused by deletion (650kb-3.7Mb)
of 17p11.2
OMIM Title
*182381 SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 2;
SLC5A2
;;SODIUM-GLUCOSE TRANSPORTER 2; SGLT2;;
SODIUM-GLUCOSE COTRANSPORTER, RENAL;;
SODIUM-GLUCOSE COTRANSPORTER, KIDNEY LOW AFFINITY
OMIM Description
DESCRIPTION
The SLC5A2 gene encodes a low affinity, high capacity Na(+)/glucose
cotransporter, which is located in the early proximal convoluted tubule
segment S1 and has a Na(+)-to-glucose coupling ratio of 1:1. It is the
major reabsorptive mechanism for D-glucose in the kidney (summary by
Wells et al., 1992).
CLONING
Wells et al. (1992) isolated a human kidney cDNA encoding a 672-amino
acid protein with 59% amino acid similarity to intestinal Na+/glucose
cotransporter (SGLT1, SLC5A1; 182380) and with significant similarity to
other members of the Na+/cotransporter family.
GENE STRUCTURE
The SLC5A2 gene contains 14 exons (Kanai et al., 1994).
MAPPING
By Southern blot analysis of genomic DNA from 16 somatic cell hybrids,
Wells et al. (1993) localized the SLC5A2 gene to chromosome 16. Analysis
of 3 additional hybrids that selectively retained all or part of human
chromosome 16 demonstrated localization of the gene to chromosome
16p11.2.
GENE FUNCTION
Kanai et al. (1994) characterized further the human kidney SGLT2 cDNA
cloned by Wells et al. (1992). Using expression studies with Xenopus
laevis oocytes, they demonstrated that SGLT2 mediates saturable
Na(+)-dependent and phlorizin-sensitive transport with K(m) values
consistent with low affinity Na(+)/glucose cotransport. In contrast to
SGLT1, SGLT2 does not transport D-galactose. Using combined in situ
hybridization and immunocytochemistry with tubule segment specific
marker antibodies, Kanai et al. (1994) demonstrated an extremely high
level of SGLT2 message in proximal tubule S1 segments. This level of
expression was also evident on Northern blots and likely confers the
high capacity of this glucose transport system. Kanai et al. (1994)
suggested that the defect in renal glycosuria (233100) may reside in the
SGLT2 gene.
MOLECULAR GENETICS
In a Turkish patient with congenital isolated renal glucosuria (233100),
van den Heuvel et al. (2002) analyzed each of the 14 exons of the SLC5A2
gene by PCR and sequence analysis of amplification products. DNA
sequence analysis revealed a homozygous nonsense mutation in exon 11
(182381.0001) leading to the formation of a truncated cotransporter.
Both parents and a younger brother, all 3 without renal glucosuria, were
heterozygous for the mutation. Van den Heuvel et al. (2002) stated that
this was the first direct evidence of an etiologic role for SGLT2 in the
pathogenesis of renal glucosuria.
Yu et al. (2011) identified 5 novel mutations in the SLC5A2 gene (see,
e.g., 182381.0004-182381.0006) in Chinese patients with renal
glucosuria. Affected individuals in 2 families were compound
heterozygous for 2 mutations, whereas affected individuals in 2
additional families with a milder phenotype were heterozygous for a
mutation. All mutant proteins were expressed in HEK293 cells and showed
variable decreased glucose transport activity, ranging from 26 to 71% of
normal.
YBX3P1
| dbSNP name | rs141188579(G,T) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 440359 |
| EntrezGene Description | Y box binding protein 3 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
LINC00273
| dbSNP name | rs8062721(C,G) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 649159 |
| snpEff Gene Name | AC136932.2 |
| EntrezGene Description | long intergenic non-protein coding RNA 273 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0352564102564 |
| dbNSFP KGp1 Afr AF | 0.128048780488 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.03535 |
| ExAC AF | 0.012 |
UBE2MP1
| dbSNP name | rs2170422(C,T); rs138816454(C,G) |
| cytoBand name | 16p11.2 |
| EntrezGene GeneID | 606551 |
| EntrezGene Description | ubiquitin-conjugating enzyme E2M pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05601 |
ADCY7
| dbSNP name | rs4785207(G,A); rs375445104(G,A); rs10852608(A,G); rs1872689(G,A); rs35335464(A,G); rs1976115(A,C); rs11076530(G,A); rs62028325(C,A); rs12934796(T,G); rs13338390(A,G); rs4238816(A,C); rs4238817(T,C); rs77150043(C,T); rs67496626(C,T); rs1540619(T,C); rs4785208(T,C); rs9934026(C,T); rs75914111(T,G); rs4573929(G,T); rs7193434(G,T); rs4785398(T,C); rs16948353(G,T); rs4785399(G,A); rs17215978(C,T); rs9938655(A,G); rs191273981(A,C); rs4785400(G,A); rs192800860(G,A); rs9939082(C,T); rs8061808(C,T); rs17216076(T,C); rs4785401(A,G); rs9926720(C,A); rs141611775(A,G); rs62028328(C,A); rs144111007(G,C); rs9940842(A,G); rs4277338(C,A); rs1872688(T,C); rs1078151(C,A); rs368992879(C,T); rs751127(G,T); rs3826171(A,T); rs3826170(T,C); rs3760014(G,C); rs3760013(A,T); rs3760012(T,C); rs3892156(A,G); rs34009001(C,T); rs8053067(T,A); rs12598249(C,T); rs149478082(G,A); rs11644926(C,T); rs9927261(T,G); rs13332825(T,C); rs113878275(C,T); rs202086732(C,T); rs4785402(T,C); rs7202127(G,C); rs9936021(T,G); rs8051594(A,G); rs2302712(A,G); rs2302713(C,T); rs2302714(G,A); rs2302715(T,C); rs9939322(A,G); rs1540624(G,A); rs11648839(A,G); rs2302716(T,C); rs8061123(G,C); rs2302717(C,T); rs35003370(T,C); rs11859417(A,G); rs75623060(G,A); rs4082435(G,A); rs8049122(C,T); rs8052384(G,C); rs7191958(A,G); rs113977162(C,T); rs728962(C,T); rs729229(C,A); rs8045659(T,C); rs8060642(G,C); rs111981224(C,T); rs7186882(G,A); rs7193875(C,T); rs12445243(A,G); rs61731915(C,T); rs9937781(T,C); rs57410111(T,C); rs12444679(C,T); rs11861332(G,A); rs56135636(G,A); rs56342387(G,A); rs4785210(C,T); rs2302680(A,T); rs4785211(A,G); rs72782139(C,T); rs17289102(C,T); rs2302681(C,G); rs11649621(G,A); rs78051832(C,T); rs3826173(G,T); rs62029962(A,G); rs114595661(C,A); rs2302679(T,C); rs77617432(C,T); rs11649380(A,G); rs77463170(A,G); rs28403987(C,T); rs3743774(A,C); rs9926131(A,T); rs3813755(T,C); rs112146345(G,A); rs1872691(G,A); rs56018511(G,A); rs1064448(T,G); rs55881379(A,G); rs4785407(T,C) |
| ccdsGene name | CCDS10741.1 |
| cytoBand name | 16q12.1 |
| EntrezGene GeneID | 113 |
| EntrezGene Description | adenylate cyclase 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ADCY7:NM_001286057:exon11:c.C1439T:p.A480V,ADCY7:NM_001114:exon10:c.C1439T:p.A480V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5043 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P51828 |
| dbNSFP Uniprot ID | ADCY7_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000455 |
| ESP All MAF | 0.003925 |
| ESP Eur/Amr MAF | 0.005699 |
| ExAC AF | 0.005248 |
OMIM Clinical Significance
INHERITANCE:
?Autosomal dominant;
?Autosomal recessive
GROWTH:
[Height];
Short stature (reported in 2 families)
HEAD AND NECK:
[Head];
Microcephaly
SKELETAL:
[Spine];
Kyphoscoliosis (1 patient);
[Hands];
Partial distal aphalangia;
[Feet];
Duplication of metacarpal IV;
Absent/hypoplastic toes;
Cutaneous syndactyly;
Normal great toes
SKIN, NAILS, HAIR:
[Nails];
Hypoplastic nails of affected digits
NEUROLOGIC:
[Central nervous system];
Cognitive deficits
MISCELLANEOUS:
Three families have been reported (last curated November 2010);
The mode of inheritance is unclear
OMIM Title
*600385 ADENYLATE CYCLASE 7; ADCY7
;;ADENYLYL CYCLASE 7
OMIM Description
DESCRIPTION
ADCY7 belongs to the adenylate cyclase (EC 4.6.1.1) family of enzymes
responsible for the synthesis of cAMP (Ludwig and Seuwen, 2002).
CLONING
Hellevuo et al. (1993) identified adenylate cyclase-7 (ADCY7) in the
human erythroleukemia cell line HEL. The deduced protein contains 12
membrane-spanning domains, a characteristic of the adenylyl cyclase
enzyme family. RNase protection assays indicated that ADCY7 is the major
form of adenylyl cyclase in human platelets. Northern blot analysis
detected a 6.7-kb transcript that was abundant in liver. Of brain areas
studied, the transcript was most abundant in the caudate and cerebellum
and present at a slightly lower level in hippocampus.
By semiquantitative RT-PCR, Ludwig and Seuwen (2002) found high
expression of ADCY7 in peripheral blood leukocytes, spleen, thymus,
lung, and heart, moderate expression in several other tissues, including
placenta, ovary, and colon, and little to no expression in brain,
kidney, liver, and skeletal muscle.
GENE STRUCTURE
Ludwig and Seuwen (2002) determined that the ADCY7 gene contains 26
exons and spans over 38.6 kb.
MAPPING
Hellevuo et al. (1995) used PCR techniques in the study of human/rodent
somatic hybrid panels and a YAC library to demonstrate that the ADCY7
gene is located on chromosome 16q12-q13. Hellevuo et al. (1995) noted
that this region of the genome is known to contain other genes encoding
proteins characterized by 12 membrane-spanning domains: norepinephrine
transporter protein-1 (NET1; 163970), located at 16q12.2, and renal
sodium-glucose transporter-2 (SGLT2; 182381), located at 16p11.2.
LINC00919
| dbSNP name | rs183744(G,A); rs13332583(T,C); rs372574463(T,C); rs114038167(G,T); rs111329002(C,T) |
| cytoBand name | 16q12.1 |
| EntrezGene GeneID | 100505619 |
| EntrezGene Description | long intergenic non-protein coding RNA 919 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05923 |
LOC643802
| dbSNP name | rs11860669(T,C); rs10775327(C,A); rs114162112(G,A); rs13333142(T,A) |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 643802 |
| EntrezGene Description | u3 small nucleolar ribonucleoprotein protein MPP10-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07897 |
| ExAC AF | 0.042 |
RBL2
| dbSNP name | rs4146344(C,T); rs1074182(T,G); rs13330182(G,A); rs147721861(G,A); rs9927982(C,T); rs58317601(T,C); rs16952242(G,A); rs72801817(C,T); rs62048518(C,T); rs9921587(A,G); rs72801818(C,T); rs17800577(G,A); rs115512455(A,G); rs9927720(G,A); rs1362429(G,C); rs72801821(G,A); rs4784311(C,T); rs16952246(C,T); rs17800727(A,G); rs72801825(A,G); rs9938788(G,C); rs7204758(G,A); rs9921627(G,A); rs16952251(A,G); rs4783811(A,G); rs111232287(G,T); rs16952252(C,A); rs7202621(G,A); rs9941254(C,T); rs13329946(C,T); rs7194730(A,T); rs13332406(G,A); rs9929873(C,T); rs62048520(C,A); rs2024449(T,C); rs115933924(C,T); rs17801093(C,A); rs139402025(T,G); rs7204496(G,A); rs11859538(A,G); rs11864278(G,T); rs7189726(C,T); rs4784312(T,C); rs8054299(C,G); rs76818213(G,C); rs1072910(A,G); rs1072911(T,C); rs114529727(A,G); rs4281707(G,A); rs8056799(A,T); rs116257079(C,T); rs1131220(G,A); rs11540358(C,G); rs10748(T,C); rs62048523(T,C); rs180852646(C,T); rs143284044(C,T); rs60472240(T,C); rs8061073(C,T); rs73608329(G,A); rs72801843(T,A); rs7184800(G,A); rs117422907(C,T); rs8045674(G,A); rs11642335(A,G); rs56126229(G,A); rs55891028(T,C); rs62048526(G,A); rs8062535(G,A); rs8043918(C,T); rs8049033(T,C); rs17801498(C,G); rs113335556(C,T); rs28666548(C,A); rs8044205(T,C); rs8058684(G,A); rs3803657(T,C); rs9302647(G,C); rs8056370(C,T); rs72801853(A,G); rs7199401(A,T); rs72801854(G,A); rs17193176(T,C); rs4783813(C,G); rs8046307(G,T); rs13337544(T,C); rs13332335(G,A); rs142595191(C,T); rs8057808(G,A); rs60420081(A,G); rs8044091(T,C); rs28399019(T,C); rs76936609(A,G); rs8055279(T,C); rs3929(G,C) |
| ccdsGene name | CCDS10748.1 |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 5934 |
| EntrezGene Description | retinoblastoma-like 2 (p130) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RBL2:NM_005611:exon13:c.G1723C:p.E575Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7927 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0100732600733 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0250659630607 |
| dbSNP GMAF | 0.0101 |
| ESP Afr MAF | 0.004781 |
| ESP All MAF | 0.015625 |
| ESP Eur/Amr MAF | 0.021163 |
| ExAC AF | 0.016 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Somatic mutation
HEAD AND NECK:
[Eyes];
Retinoblastoma (25% bilateral, 15% unilateral);
Retinomas (translucent, grayish retinal mass protruding into the vitreous);
Retinal calcification;
Retinal pigment epithelial migration and proliferation;
Leukocoria;
Vitreous hemorrhage (rare);
Vitritis (rare);
[Mouth];
Cleft palate (rare)
NEOPLASIA:
Osteogenic sarcoma;
Pinealoma (trilateral retinoblastoma);
Leukemia;
Lymphoma;
Ewing sarcoma
MISCELLANEOUS:
Incidence 1 in 15,000-28,000 births;
Approximately 40% of cases are inherited or new germline mutations;
Approximately 60% of cases are due to somatic mutations and are unilateral
MOLECULAR BASIS:
Caused by mutation in the RB1 gene (RB1, 614041.0001)
OMIM Title
*180203 RETINOBLASTOMA-LIKE 2; RBL2
;;RETINOBLASTOMA-RELATED GENE RB2; RB2;;
p130
OMIM Description
CLONING
Mayol et al. (1993) cloned a retinoblastoma-related human gene, referred
to as RB2, on the basis of sequence homology of the E1A-binding domain
of the RB1 gene (614041). Structural homology with RB1 suggested a
possible function of RB2 as a tumor suppressor gene. RBL2 has a
molecular mass of about 120 kD.
GENE FUNCTION
Kong et al. (2006) found that RBL2 and RINT1 (610089) were essential for
telomere length control in human fibroblasts, with loss of either
protein leading to longer telomeres. They proposed that RBL2 forms a
complex with RAD50 (604040) through RINT1 to block
telomerase-independent telomere lengthening.
Williams et al. (2006) found that mouse fibroblasts lacking Rb were less
susceptible to an oncogenic HRAS (190020) allele than wildtype cells. In
contrast, p107 (RBL1; 116957) -/- and p130 -/- fibroblasts were more
susceptible to HRAS-mediated transformation than wildtype cells.
Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs
(miRNAs), proliferate slowly, and accumulate in G1 phase of the cell
cycle. By screening mouse miRNAs for those that could rescue the growth
defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a
group of related ES cell-specific miRNAs, including several members of
the miR290 cluster. Target sites for these miRNAs were identified in the
3-prime UTRs of several inhibitors of the cyclin E (see CCNE1;
123837)-CDK2 (116953) pathway, including Cdkn1a (116899), Rb1, Rbl1,
Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased
expression of these genes in Dgcr8-knockout mouse ES cells.
GENE STRUCTURE
Baldi et al. (1996) characterized the organization and 5-prime flanking
region of the Rb2, or p130, gene. They determined that the gene contains
22 exons and spans over 50 kb.
MAPPING
Yeung et al. (1993) mapped the RBL2 gene to human chromosome 16q12.2 and
rat chromosome 19, using fluorescence in situ hybridization and somatic
hybrid cell analysis, respectively. Based on known syntenic
relationships among human, rat and mouse, the data suggested that the
mouse homolog resides on chromosome 8. Deletions of chromosome 16q have
been found in several human neoplasms, including breast, ovarian,
hepatic, and prostate cancers, which supports the involvement of RB2 in
human cancer as a tumor suppressor gene.
ANIMAL MODEL
Haigis et al. (2006) found that Rb was expressed in all epithelial cells
of mouse colon, whereas p107 was expressed predominantly in the lower
half of the crypt, and p130 was expressed in the upper portion of the
crypt and in the epithelium lining the lumen. Similarly,
undifferentiated cells in the mouse small intestinal crypt expressed Rb
and p107, whereas differentiated cells in the villi expressed Rb and
p130. Conditional deletion of Rb or p130 increased p107 levels, and
Rb/p130 double mutants had even higher levels of p107. Although mutating
any of these 3 genes singly had little or no effect, loss of Rb and p107
or p130 together produced chronic hyperplasia and dysplasia of the small
intestinal and colonic epithelium. In Rb/p130 double mutants, this
hyperplasia was associated with defects in terminal differentiation of
specific cell types and was dependent on the increased proliferation
seen in the epithelium of mutant animals.
FTO-IT1
| dbSNP name | rs856981(C,T); rs856982(C,T); rs856983(A,G); rs3764307(A,G) |
| ccdsGene name | CCDS32448.1 |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 100505692 |
| snpEff Gene Name | FTO |
| EntrezGene Description | FTO intronic transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4715 |
IRX3
| dbSNP name | rs151314016(C,T); rs61744547(G,A); rs1126960(C,A) |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 79191 |
| EntrezGene Description | iroquois homeobox 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001377 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Shorter daily total sleep times compared to age-matched controls;
Earlier sleep-offset time (earlier awakening);
Normal sleep-onset time (normal time of falling asleep);
Increased activity period;
Individuals require less sleep in a 24-hour period compared to age-matched
controls
MISCELLANEOUS:
One family has been reported
MOLECULAR BASIS:
Caused by mutation in the basic helix-loop-helix domain-containing
protein class B, 3 gene (BHLHB3, 606200.0001)
OMIM Title
*612985 IROQUOIS HOMEOBOX PROTEIN 3; IRX3
;;IRXB1
OMIM Description
DESCRIPTION
IRX3 is a member of the Iroquois homeobox gene family (see IRX1; 606197)
and plays a role in an early step of neural development (Bellefroid et
al., 1998). Members of this family appear to play multiple roles during
pattern formation of vertebrate embryos (Lewis et al., 1999).
CLONING
Bellefroid et al. (1998) cloned Xiro3, which is the Xenopus homolog of
IRX3, and identified human and mouse IRX3 sequences. The deduced Xiro3
protein shares 81% identity with mouse Irx3 and shares similarity with a
partial human IRX3 sequence identified by Lewis et al. (1999). Both the
deduced mouse and Xenopus proteins contain a homeodomain with a 3-prime
acidic region, 2 potential MAPK phosphorylation sites, and a conserved
C-terminal region. In situ hybridization of mouse embryos, detected Irx3
expression starting at the end of gastrulation, embryonic (E) day 7.5.
By E8.0, expression was specific to the thickening neural ectoderm and
continued to be specific to neural progenitor cells during embryogenesis
through closure of the neural tube at E9.5.
Lewis et al. (1999) cloned a full-length cDNA corresponding to a human
Iroquois homeobox gene (IRX5; 606195) as well as fragments of
transcripts derived from 4 additional IRX genes, including IRX3 (which
they called IRX1). They determined that the human IRX homeodomains are
about 90% identical to the homeodomains of the Drosophila Iroquois
complex proteins caupolican, araucan, and mirror, and about 93%
identical to each other. Each of the IRX proteins contains a
hexapeptide-like motif.
GENE FUNCTION
Bellefroid et al. (1998) showed that Xiro3 overexpression in Xenopus
embryos induced ectopic neural tissue, suppressed the differentiation of
primary neurons, and increased the spatial distribution of expression
for proneural gene Xash3 (ASCL2; 601886). In addition, Xiro3
overexpression in Xenopus animal caps activated early neural gene
expression. Bellefroid et al. (1998) determined that Xiro3 expression is
induced by noggin (NOG; 602991) and bFGF (FGF2; 134920).
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the IRX3
gene to chromosome 16 (TMAP SHGC-61146).
LPCAT2
| dbSNP name | rs2241148(G,A); rs12930259(T,C); rs8054459(G,A); rs2192853(A,G); rs12446205(G,A); rs12443559(A,G); rs1362399(C,T); rs1595304(T,G); rs1583587(G,C); rs8047179(G,T); rs8053806(C,A); rs8059301(T,C); rs8059302(T,C); rs12708952(G,C); rs8053466(G,T); rs1583586(A,G); rs62027890(G,A); rs1583585(G,A); rs1583588(C,G); rs80152851(A,G); rs1304269(G,A); rs1988531(A,G); rs1304268(G,A); rs35882847(A,G); rs1595306(G,A); rs9921594(C,T); rs11076104(C,T); rs1120208(G,C); rs1120207(G,A); rs2397721(G,A); rs9922328(A,G); rs11646335(G,A); rs11646382(G,T); rs9937093(G,A); rs1558664(C,A); rs1558665(C,T); rs74021210(A,C); rs1558666(G,A); rs1558667(C,T); rs1370292(G,T); rs148244607(A,G); rs13336192(A,G); rs13337274(T,C); rs1898414(A,G); rs837549(G,A); rs61739979(G,A); rs837550(G,A); rs9928922(G,A); rs9932429(C,A); rs837551(G,A); rs4402561(C,T); rs9937957(C,A); rs9930245(T,G); rs16955343(C,T); rs13339550(T,G); rs9928032(G,T); rs9941326(A,G); rs2192855(G,A); rs1420224(A,G); rs3785165(T,C); rs8182127(A,G); rs1420225(G,T); rs140381501(T,C); rs13337402(G,A); rs10521321(G,A); rs1362400(A,G); rs9934598(T,C); rs9921438(G,A); rs9921443(G,A); rs4238780(G,A); rs1894882(C,T); rs141947472(A,G); rs9923296(T,C); rs9930421(G,A); rs10521320(A,C); rs8059882(C,A); rs11644194(C,T); rs8059138(G,A); rs62028768(T,C); rs16955381(A,G); rs10521319(A,C); rs9932991(G,A); rs2397722(G,A); rs7193120(A,G); rs12597687(A,G); rs62028769(C,T); rs12931248(G,A); rs4369660(A,G); rs9934904(A,T); rs2287072(G,A); rs8047714(G,T); rs8049147(C,G); rs1501994(A,G); rs55800295(G,T); rs1420226(C,T); rs55754646(T,G); rs194173(G,A); rs1393257(C,T); rs73551719(T,C); rs194172(G,A); rs73551723(G,A); rs194171(T,C); rs194170(G,A); rs28876218(G,A); rs1501996(C,G); rs1501997(G,A); rs194169(C,T); rs28649571(G,A); rs79575505(C,A); rs194168(G,A); rs13335416(C,T); rs7189685(C,A); rs7190736(A,T); rs16955422(T,C); rs187583(A,G); rs2216058(T,C); rs74021218(C,T); rs1501998(A,G); rs1501999(T,C); rs58109914(G,T); rs1587629(T,A); rs1587630(A,G); rs1587631(C,T); rs2192856(G,A); rs1502000(A,C); rs1502001(G,A); rs1502002(T,C); rs8049098(T,G); rs8049240(T,C); rs1502004(C,T); rs194178(T,C); rs3785163(A,G); rs3785162(C,T); rs168822(C,T); rs6499766(A,T); rs7186546(G,A); rs7186553(G,A); rs11647464(C,T); rs4783896(A,G); rs1354181(A,T); rs194177(A,G); rs79868283(C,A); rs1393258(G,C); rs13334083(G,A); rs183154(G,A); rs7186721(A,G); rs7186227(C,T); rs9925659(T,G); rs194176(A,C); rs1502006(A,G); rs768259(G,T); rs7205660(T,C); rs883180(G,A); rs4784549(T,A); rs1502007(A,G); rs11076105(G,A); rs11076106(A,G); rs76354127(G,T); rs59075118(A,C); rs9940227(T,C); rs8044653(T,C); rs12934747(C,T); rs12933746(G,T); rs1393261(A,G); rs16955475(C,T); rs116006556(G,A); rs12445818(C,T); rs12448764(A,C); rs1044775(C,T); rs12445670(G,C); rs80239261(A,G) |
| ccdsGene name | CCDS10753.1 |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 54947 |
| EntrezGene Description | lysophosphatidylcholine acyltransferase 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LPCAT2:NM_017839:exon3:c.G382A:p.V128I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7121 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7L5N7 |
| dbNSFP Uniprot ID | PCAT2_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.002275 |
| ESP All MAF | 0.007849 |
| ESP Eur/Amr MAF | 0.010698 |
| ExAC AF | 0.007637 |
CAPNS2
| dbSNP name | rs1502003(A,G) |
| ccdsGene name | CCDS54010.1 |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 84290 |
| EntrezGene Description | calpain, small subunit 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CAPNS2:NM_032330:exon1:c.A720G:p.E240E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4224 |
| ESP Afr MAF | 0.402091 |
| ESP All MAF | 0.444181 |
| ESP Eur/Amr MAF | 0.463994 |
| ExAC AF | 0.446 |
DKFZP434H168
| dbSNP name | rs59779556(T,G); rs1190761(A,G) |
| ccdsGene name | CCDS10756.1 |
| cytoBand name | 16q12.2 |
| EntrezGene GeneID | 26077 |
| snpEff Gene Name | GNAO1 |
| EntrezGene Description | uncharacterized LOC26077 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4674 |
| ExAC AF | 0.364 |
MIR6863
| dbSNP name | rs12708966(G,A) |
| ccdsGene name | CCDS10770.1 |
| cytoBand name | 16q13 |
| EntrezGene GeneID | 6559 |
| EntrezGene Symbol | SLC12A3 |
| snpEff Gene Name | SLC12A3 |
| EntrezGene Description | solute carrier family 12 (sodium/chloride transporter), member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03627 |
| ESP Afr MAF | 0.070809 |
| ESP All MAF | 0.03548 |
| ESP Eur/Amr MAF | 0.020113 |
| ExAC AF | 0.031 |
CNGB1
| dbSNP name | rs9934916(T,G); rs9932826(A,G); rs113814133(T,C); rs1477405(C,T); rs78514298(G,T); rs165999(G,A); rs57309302(A,G); rs116564376(A,G); rs11866902(T,C); rs11643127(C,T); rs113810608(A,G); rs580912(C,T); rs3784891(A,C); rs2033250(A,G); rs691656(G,A); rs2033249(G,A); rs77795260(T,C); rs11076207(A,G); rs376919007(C,T); rs138442890(G,A); rs247037(C,T); rs60286951(T,C); rs74019714(C,G); rs115957517(A,G); rs16959471(C,A); rs16959472(T,C); rs55789570(T,C); rs77014482(G,A); rs8049548(T,C); rs138862260(G,C); rs6499921(A,T); rs8044277(G,A); rs8046202(A,G); rs78779042(A,G); rs34861637(C,A); rs35176541(C,G); rs140623556(C,G); rs16959476(G,A); rs9928234(T,G); rs58979009(C,T); rs16959477(C,A); rs7203532(T,C); rs9938276(G,A); rs4784017(G,A); rs7204867(A,G); rs189283665(A,G); rs73562955(A,G); rs8057528(G,A); rs78155143(C,G); rs369503135(G,A); rs13331889(A,G); rs542230(A,T); rs28454865(G,A); rs113103606(G,A); rs189893243(G,A); rs74659209(A,C); rs190319(T,C); rs199906467(G,A); rs79889567(C,T); rs78161913(T,G); rs562728(G,T); rs692055(C,T); rs149365616(G,A); rs144678942(G,A); rs115571521(C,A); rs147320524(G,C); rs74399205(G,A); rs185458615(C,T); rs79836518(C,T); rs74019718(T,C); rs56033685(G,A); rs413562(G,C); rs437920(G,A); rs11491148(C,T); rs419828(T,C); rs72782251(G,A); rs114162461(C,T); rs3784893(C,T); rs417989(C,G); rs8045584(A,G); rs8044990(C,T); rs77064286(G,A); rs450837(G,A); rs411657(T,C); rs3784895(C,T); rs7198229(C,A); rs117600154(C,T); rs433573(T,C); rs381327(C,T); rs115620432(G,A); rs373497(G,A); rs437947(C,A); rs393392(T,C); rs377684104(G,A); rs392569(T,C); rs449565(A,G); rs438712(C,T); rs367933427(T,C); rs148118493(A,G); rs439430(T,A); rs442619(C,T); rs370307(G,A); rs180846084(T,C); rs438722(C,T); rs418138(C,T); rs382533(A,C); rs365313(A,G); rs374375(C,T); rs377195(T,G); rs12927475(C,T); rs76589469(T,A); rs75610225(A,G); rs434962(A,G); rs690746(G,C); rs56097461(C,T); rs435179(A,G); rs416683(A,G); rs422311(T,C); rs411277(T,C); rs115013212(G,A); rs145542262(A,C); rs149177625(G,A); rs67957317(G,A); rs146531923(A,G); rs141522827(C,T); rs8044629(A,T); rs434961(A,G); rs148170769(C,T); rs8049463(T,C); rs9972814(T,A); rs9972816(T,G); rs9972793(A,T); rs516183(T,C); rs515370(G,A); rs515155(A,G); rs112779754(G,A); rs8054728(C,T); rs4555144(G,T); rs838581(G,A); rs10459809(G,T); rs483053(G,A); rs478566(A,G); rs376270(G,A); rs440565(G,C); rs4784871(C,T); rs11076209(C,T); rs3991716(G,A); rs3991715(T,G); rs691490(G,A); rs72782258(A,G); rs186863811(G,A); rs145250301(G,T); rs489106(A,G); rs35424571(C,G); rs691483(T,C); rs2303784(G,A); rs114036962(C,A); rs7195562(A,T); rs7193726(G,T); rs1366530(T,C); rs8052897(G,C); rs146884151(C,T); rs166000(A,G); rs2161703(A,G); rs17241022(G,A); rs2161702(A,G); rs16959513(C,A); rs8059135(G,A); rs68192852(C,T); rs9922949(A,G); rs9932825(C,G); rs3784900(A,G); rs11645218(G,A); rs247064(C,G); rs7184838(G,A); rs28420662(C,T); rs8050968(A,G); rs8051647(A,T); rs71387201(C,T); rs247065(G,C); rs12927214(A,G); rs78292723(G,A); rs3784901(C,T); rs247066(T,C); rs28720913(T,C); rs58914278(A,G); rs57940640(G,A); rs691664(C,A); rs7200641(C,T); rs7199303(G,T); rs691897(C,T); rs13330209(A,G); rs13331301(T,C); rs151287899(C,A); rs12924235(C,A); rs4558407(C,T); rs375728(C,T); rs145735040(C,T); rs385883(T,G); rs7195436(G,A); rs366359(A,G); rs247051(T,A); rs4784872(G,C); rs141488378(T,A); rs7186432(A,G); rs55745717(G,A); rs1108645(T,C); rs247052(T,C); rs113705777(T,A); rs13335409(A,C); rs145479019(T,C); rs6499924(A,G); rs37916(A,G); rs16959567(C,T); rs75999538(T,C); rs17821436(T,C); rs2303778(G,A); rs8052097(G,A); rs6499927(C,A); rs6499928(G,A); rs116615053(T,C); rs77546485(C,T); rs140476710(A,G); rs138287440(A,G); rs8048518(G,A); rs112357433(T,C); rs189756740(C,T); rs113200118(A,G); rs8063092(C,T); rs16959572(C,T); rs148966989(A,G); rs13338118(A,C); rs141552031(C,T); rs59584192(T,C); rs3848260(G,A); rs4436767(A,G); rs152141(T,G); rs152142(C,T); rs9888790(A,G); rs152143(G,A); rs28567529(T,C); rs16959580(A,G); rs152144(C,G); rs8056583(G,A); rs185591760(A,C); rs11858999(G,T); rs144213857(C,T); rs73545172(C,A); rs74019735(A,G); rs152139(C,T); rs113898511(G,A); rs16959596(A,G); rs165998(A,G); rs74019736(A,G); rs112939871(G,A); rs152140(A,C); rs16959598(A,G); rs503686(C,T); rs115710369(G,A); rs399634(T,A); rs414650(A,G); rs9925353(G,T); rs138961420(A,G); rs838578(C,A); rs192628905(T,A); rs144747964(C,G); rs16959602(G,A); rs17821448(G,A); rs13336595(C,T); rs150447118(G,A); rs9302694(G,T); rs9927844(A,C); rs79537249(C,T); rs115569700(A,G); rs3859043(C,T); rs74338843(G,A); rs7185852(T,C); rs3859044(A,G); rs11645665(G,T); rs11645750(G,A); rs2405130(G,A); rs11643697(T,C); rs11647364(G,A); rs8059027(T,C); rs11645062(T,C); rs12933912(A,G); rs79916533(C,T); rs76919526(C,T); rs3848262(G,A); rs114321921(T,C); rs28542085(A,G) |
| ccdsGene name | CCDS42169.1 |
| cytoBand name | 16q21 |
| EntrezGene GeneID | 1258 |
| EntrezGene Description | cyclic nucleotide gated channel beta 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CNGB1:NM_001286130:exon28:c.G2836A:p.V946M,CNGB1:NM_001297:exon28:c.G2854A:p.V952M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5219 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14028-2 |
| dbNSFP KGp1 AF | 0.0173992673993 |
| dbNSFP KGp1 Afr AF | 0.0650406504065 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.01745 |
| ESP Afr MAF | 0.04786 |
| ESP All MAF | 0.021511 |
| ESP Eur/Amr MAF | 0.008531 |
| ExAC AF | 0.012 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Prominent forehead;
Micrognathia
CARDIOVASCULAR:
[Heart];
Cardiomyopathy (severe form);
Aortic insufficiency
RESPIRATORY:
Inspiratory stridor (severe form);
Apnea (severe form)
ABDOMEN:
[Gastrointestinal];
Episodic vomiting (severe form)
MUSCLE, SOFT TISSUE:
Muscle weakness
NEUROLOGIC:
[Central nervous system];
Neonatal/early-infantile onset encephalopathy;
Developmental delay, severe;
Mental retardation;
Hypotonia;
Seizures;
Subependymal cysts;
Delayed gyration;
Delayed myelination;
Enlarged lateral ventricles (occipital>frontal);
Multifocal cerebral white matter abnormalities
LABORATORY ABNORMALITIES:
D-2-hydroxyglutaric aciduria;
Elevated D-2-hydroxyglutaric acid (urine, plasma, CSF);
Elevated L-2-hydroxyglutaric acid (urine);
Elevated 2-ketoglutarate (urine)
MISCELLANEOUS:
Two different phenotypes exist - severe phenotype (early infantile
onset, epileptic encephalopathy and often cardiomyopathy) and mild
phenotype (more variable clinical presentation);
Severe phenotype onset - neonate;
Mild phenotype onset - 11-18 months
MOLECULAR BASIS:
Caused by mutation in the D-2-hydroxyglutarate dehydrogenase gene
(D2HGD, 609186.0001)
OMIM Title
*600724 CYCLIC NUCLEOTIDE-GATED CHANNEL, BETA-1; CNGB1
;;CYCLIC NUCLEOTIDE-GATED CHANNEL, PHOTORECEPTOR, cGMP-GATED, 2; CNCG2;;
CYCLIC NUCLEOTIDE-GATED CHANNEL, PHOTORECEPTOR, cGMP-GATED, 3-LIKE;
CNCG3L;;
GLUTAMIC ACID-RICH PROTEIN 1; GAR1; GARP;;
RETINAL ROD cGMP-GATED CHANNEL, BETA SUBUNIT;;
RETINAL ROD cGMP-GATED CHANNEL, GAMMA SUBUNIT
OMIM Description
The CNGB1 and CNGA1 (123825) gene products form the heterotetrameric rod
photoreceptor cyclic nucleotide-gated (CNG) channel, which conducts a
cation current in response to changes in intracellular levels of cGMP
and mediates the electrical response to light (summary by Kondo et al.,
2004).
CLONING
The human and bovine rod photoreceptor cGMP-gated cation channel
consists of 2 subunits: alpha (63 kD, CNGA1) and beta (240 kD). Ardell
et al. (1996) provided evidence that the human GAR1 protein is encoded
by the N-terminal region of the gene encoding the beta subunit of the
cGMP-gated photoreceptor channel.
Sugimoto et al. (1991) identified a unique glutamic acid-rich protein in
bovine rod photoreceptors. Chen et al. (1994) suggested that this
protein is a third subunit (gamma) of the rod cGMP-gated cation channel.
Ardell et al. (1995) characterized the CNCG3L gene (also referred to by
them as GAR1) that encodes a human homolog of the bovine gamma subunit.
Sequence analysis of cDNA clones encoding human CNCG3L revealed an open
reading frame predicting a protein of 299 amino acids (approximately 32
kD), half the size of the bovine gamma subunit. Within the first 31
amino acids, they found 90% identity between the human and bovine
sequences, and only 60% homology was found throughout the remainder of
the protein sequence. As in bovine gamma, the predicted isoelectric
point of the human protein is very acidic despite the absence of the
bovine C-terminal glutamic acid-rich domain.
Ardell et al. (1996) presented the complete sequence of the human beta
subunit and stated that the GAR1 gene previously reported by Ardell et
al. (1995) encodes the beta subunit N-terminal region. Using PCR, RNA
blot, and genomic DNA analysis, Ardell et al. (1996) provided evidence
that the beta subunit is produced from a locus on chromosome 16
consisting of 2 nonoverlapping transcription units that is capable of
generating independent transcripts corresponding to GAR1 and the
C-terminal two-thirds of the beta subunit. They showed that the
CNCG-beta subunit mRNA encodes the first 291 amino acids of human GAR1,
337 amino acids present only in the beta subunit, and the entire 623
amino acids predicted from the 2a cDNA sequence reported by Chen et al.
(1993).
GENE STRUCTURE
Ardell et al. (1995) demonstrated that the protein coding region of the
human CNGB1 gene consists of 12 exons spanning approximately 11 kb with
sequence identical to that of the cDNA clones.
GENE FUNCTION
Korschen et al. (1999) identified glutamic acid-rich proteins (GARPs) as
multivalent proteins that interact with the key players of cGMP
signaling, phosphodiesterase (see 602676) and guanylate cyclase (see
600179), and with the retina-specific ATP-binding cassette transporter
(ABCR; 601691), through 4 short repetitive sequences. In electron
micrographs, GARPs are restricted to the rim region and incisures of
discs in close proximity to the guanylate cyclase and ABCR, whereas the
phosphodiesterase is randomly distributed. GARP2 associates more
strongly with light-activated than with inactive phosphodiesterase, and
GARP2 potently inhibits phosphodiesterase activity. Korschen et al.
(1999) concluded that the GARPs organize a dynamic protein complex near
the disc rim that may control cGMP turnover and possibly other
light-dependent processes.
Kizhatil et al. (2009) found that targeting of cyclic nucleotide-gated
(CNG) channels to the rod outer segment required their interaction with
ankyrin-G (600465). Ankyrin-G localized exclusively to rod outer
segments, coimmunoprecipitated with the CNG channel, and bound to the
C-terminal domain of the channel beta-1 subunit. Ankyrin-G depletion in
neonatal mouse retinas markedly reduced CNG channel expression.
Transgenic expression of CNG channel beta-subunit mutants in Xenopus
rods showed that ankyrin-G binding was necessary and sufficient for
targeting of the beta-1 subunit to outer segments. Thus, Kizhatil et al.
(2009) concluded that ankyrin-G is required for transport of CNG
channels to the plasma membrane of rod outer segments.
BIOCHEMICAL FEATURES
Zhong et al. (2002) reported the identification of a leucine zipper
homology domain named CLZ (carboxy-terminal leucine zipper) that is
present in the distal C terminus of CNG channel A subunits but is absent
from B subunits and mediates an inter-subunit interaction. With
crosslinking, nondenaturing gel electrophoresis, and analytical
centrifugation, this CLZ domain was found to mediate a trimeric
interaction. In addition, a mutant cone CNG channel A subunit with its
CLZ domain replaced by a generic trimeric leucine zipper produced
channels that behaved much like the wildtype, but less so if replaced by
a dimeric or tetrameric leucine zipper. This A-subunit-only, trimeric
interaction suggested that heteromeric CNG channels actually adopt a
3A:1B stoichiometry. Biochemical analysis of the purified bovine rod CNG
channel confirmed this conclusion. Zhong et al. (2002) concluded that
this revised stoichiometry provides a new foundation for understanding
the structure and function of the CNG channel family.
In Xenopus oocytes, Trudeau and Zagotta (2002) showed that CNGA1-RP, a
mutant form of the CNGA1 subunit which lacks the final 37 amino acids in
the C-terminal region (123825.0004), formed normally-expressed
functional homomeric channels similar to wildtype. In contrast,
coexpression of CNGA1-RP and wildtype CNGB1 resulted in heteromeric
channels that did not convey current and were not detectable at the
membrane surface, despite the presence of these subunit proteins within
the cell interior. Studies revealed a protein-protein interaction
between the C-terminal region of CGNA1, which is deleted in CNGA1-RP,
and an N-terminal region of CNGB1. In the absence of this interaction,
an exposed short N-terminal region in CNGB1 prevented membrane
expression of the heteromeric channel.
Zheng and Zagotta (2004) found that when cRNA for 3 rat olfactory CNG
channel subunits, Cnga2 (300338), Cnga4 (609472), and Cngb1b, a splice
variant of Cngb1, were coinjected into Xenopus oocytes, functional
channels in the surface membrane contained a fixed ratio of
Cnga2:Cnga4:Cngb1b of 2:1:1. When expressed individually with Cnga2, the
Cnga4 and Cngb1b subunits were present as single copies, and when
expressed alone, they did not self-assemble.
MAPPING
Ardell et al. (1995) demonstrated localization of the CNCG3L gene to
chromosome 16 by PCR of somatic cell hybrid DNA with primer pairs that
amplified a portion of the gene. The location of the gene was further
delimited by fluorescence in situ hybridization, which placed the gene
at 16q13. Ardell et al. (1996) localized the CNCG2 gene to chromosome
16q13 by somatic hybrid cell DNA analysis.
MOLECULAR GENETICS
Bareil et al. (2001) studied a consanguineous French family with
autosomal recessive retinitis pigmentosa (RP45; 613767). Bareil et al.
(2001) excluded linkage to known loci involved in RP and by homozygosity
mapping localized the disease gene in this family to 16q13-q21. They
noted 2 candidate genes, KIFC3 (604535) and CNGB1. Mutation analysis
demonstrated that CNGB1 was mutated in this family.
ZNF319
| dbSNP name | rs9083(G,A); rs148995600(G,A); rs3743554(A,C); rs3743555(T,C); rs3743556(C,T) |
| cytoBand name | 16q21 |
| EntrezGene GeneID | 57567 |
| EntrezGene Description | zinc finger protein 319 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4219 |
APOOP5
| dbSNP name | rs2289826(A,G); rs74020085(T,G); rs75599398(G,A) |
| cytoBand name | 16q21 |
| EntrezGene GeneID | 644649 |
| EntrezGene Description | apolipoprotein O pseudogene 5 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07897 |
LOC729159
| dbSNP name | rs113921609(G,A); rs114596708(G,A); rs2407146(T,A); rs73564853(G,A) |
| cytoBand name | 16q21 |
| EntrezGene GeneID | 729159 |
| EntrezGene Description | UPF0607 protein ENSP00000381418-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LOC729159:NM_001282301:exon1:c.C964T:p.R322C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07346 |
B3GNT9
| dbSNP name | rs75897856(A,G) |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 84752 |
| EntrezGene Description | UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04867 |
AGRP
| dbSNP name | rs139948841(G,A); rs5030980(C,T); rs34123523(C,T) |
| ccdsGene name | CCDS10839.1 |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 101927837 |
| EntrezGene Symbol | LOC101927837 |
| EntrezGene Description | uncharacterized LOC101927837 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | AGRP:NM_001138:exon4:c.C357T:p.C119C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.005914 |
| ESP All MAF | 0.002078 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0006993 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Optic atrophy;
Nystagmus
RESPIRATORY:
[Lung];
Pneumonia, recurrent
CHEST:
[External features];
Small chest;
[Ribs, sternum, clavicles, and scapulae];
Anterior cupping of ribs;
Widened anterior ribs
SKELETAL:
Spondylometaphyseal dysplasia;
[Spine];
Mild platyspondyly;
[Pelvis];
Lacy iliac wings;
Narrow sacrosciatic notch;
Irregular proximal femoral metaphyses;
Short femoral necks;
Coxa vara
OMIM Title
*602311 AGOUTI-RELATED PROTEIN, MOUSE, HOMOLOG OF; AGRP
;;AGOUTI-RELATED TRANSCRIPT, MOUSE, HOMOLOG OF; AGRT; ART
OMIM Description
DESCRIPTION
The hypothalamic agouti-related protein (AGRP) regulates body weight via
central melanocortin receptors (see 155555).
CLONING
The agouti gene in mice (see 600201) encodes a cell-signaling protein
that acts as an antagonist at the melanocortin-1 receptor (MC1R;
155555). Shutter et al. (1997) cloned a gene, which they designated ART
for 'agouti-related transcript,' whose sequence predicted a 132-amino
acid protein with 25% identity to human agouti. Northern blot analysis
of human tissues showed that ART is expressed most abundantly in the
adrenal gland, hypothalamus, and subthalamic nucleus, with weaker
expression in the testis, lung, and kidney. The ART gene is
alternatively spliced; Northern blot analysis revealed a 0.7-kb mRNA
with a noncoding 5-prime exon in brain and a 0.5-kb mRNA in peripheral
tissues.
GENE FUNCTION
Because Shutter et al. (1997) observed hypothalamic ART expression to be
elevated 10-fold in the mouse models of obesity ob/ob (164160) and db/db
(601007), they suggested that ART is a participant in the hypothalamic
control of feeding.
From an expressed sequence tag database, Ollmann et al. (1997) isolated
a protein that they named Agrp for 'Agouti-related protein' and showed
that Agrp expression is reduced 5-fold in the hypothalamus of agouti
mutant mice. Ollmann et al. (1997) demonstrated that, in vitro, AGRP was
a potent, selective antagonist of MC3R (155540) and MC4R (155541).
Ubiquitous expression of human AGRP in transgenic mice led to obesity,
but had no effect on pigmentation. Therefore, Ollmann et al. (1997)
concluded that AGRP normally regulates body weight via central
melanocortin receptors, analogous to the relation between agouti and
MC1R for regulation of pigmentation.
Graham et al. (1997) found that overexpression of Agrt recapitulated
many unique features of obese yellow and MC4R-deficient mice, including
obesity, increased body length, hyperinsulinemia, late-onset
hyperglycemia, pancreatic islet hyperplasia, and lack of elevated
corticosterone. The fact that Agrt is expressed in the arcuate nucleus,
is regulated by leptin (164160), and is a potent antagonist of MC3R and
MC4R, suggested that Agrt is an endogenous regulator of
melanocortinergic neurons in the brain. Graham et al. (1997) stated that
the ectopic expression of agouti produces obesity by mimicking the
normal action of Agrt in the hypothalamus.
To investigate the relationship between peripheral blood levels of AGRP
and various parameters of obesity, Katsuki et al. (2001) measured the
plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its
relationship with body mass index (BMI); body fat weight; visceral,
subcutaneous, and total fat areas; fasting insulin (176730) levels;
glucose infusion rate; serum leptin; and plasma alpha-MSH (see 176830).
Obese men had significantly higher plasma concentrations of AGRP than
nonobese men. Univariate analysis showed that plasma levels of AGRP are
proportionally correlated with BMI, body fat weight, and subcutaneous
fat area in obese men. In all men, the plasma levels of AGRP were
significantly correlated with the visceral fat area, total fat area,
fasting insulin level, glucose infusion rate, serum level of leptin, and
the plasma level of alpha-MSH. The authors concluded that the
circulating levels of AGRP are increased in obese men and that they are
correlated with various parameters of obesity.
To determine whether neurons that express neuropeptide Y (NPY; 162640)
and Agrp are essential in mice, Luquet et al. (2005) targeted the human
diphtheria toxin receptor (126150) to the Agrp locus, which allows
temporally controlled ablation of Npy/Agrp neurons to occur after an
injection of diphtheria toxin. Neonatal ablation of Npy/Agrp neurons had
minimal effects on feeding, whereas their ablation in adults caused
rapid starvation. Luquet et al. (2005) concluded that network-based
compensatory mechanisms can develop after the ablation of Npy/Agrp
neurons in neonates but do not readily occur when these neurons become
essential in adults.
Kitamura et al. (2006) delivered adenovirus encoding a constitutively
nuclear mutant Foxo1a (136533) to the hypothalamic arcuate nucleus of
rodents and observed a loss of the ability of leptin to curtail food
intake or to suppress expression of Agrp. Conversely, a
transactivation-deficient Foxo1a mutant prevented induction of Agrp by
fasting. Using reporter gene, gel shift, and immunoprecipitation assays,
Kitamura et al. (2006) demonstrated that Foxo1a and Stat3 (102582)
exerted opposing actions on the expression of Agrp and Pomc (176830)
through transcriptional interference. Foxo1a promoted opposite patterns
of coactivator-corepressor exchange at the Pomc and Agrp promoters,
resulting in activation of Agrp and inhibition of Pomc. Kitamura et al.
(2006) concluded that Foxo1a mediates the Agrp-dependent effects of
leptin on food intake.
Andrews et al. (2008) showed that ghrelin (605353) initiates robust
changes in hypothalamic mitochondrial respiration in mice that are
dependent on uncoupling protein-2 (UCP2; 601693). Activation of this
mitochondrial mechanism is critical for ghrelin-induced mitochondrial
proliferation and electric activation of NPY/AgRP neurons, for
ghrelin-triggered synaptic plasticity of POMC-expressing neurons, and
for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on
NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation
pathway involving AMPK (see 602739), CPT1 (600528), and free radicals
that are scavenged by UCP2. Andrews et al. (2008) concluded that their
results revealed a signaling modality connecting mitochondria-mediated
effects of G protein-coupled receptors on neuronal function and
associated behavior.
Atasoy et al. (2012) mapped synaptic interactions of AGRP neurons with
multiple cell populations in mice and probed the contribution of these
distinct circuits to feeding behavior using optogenetic and
pharmacogenetic techniques. An inhibitory circuit with paraventricular
hypothalamus (PVH) neurons substantially accounted for acute AGRP
neuron-evoked eating, whereas 2 other prominent circuits (the
hypothalamic arcuate nucleus and the parabrachial nucleus) were
insufficient. Within the PVH, Atasoy et al. (2012) found that AGRP
neurons target and inhibit oxytocin neurons, a small population that is
selectively lost in Prader-Willi syndrome (176270), a condition
involving insatiable hunger. By developing strategies for evaluating
molecularly defined circuits, Atasoy et al. (2012) showed that AGRP
neuron suppression of oxytocin neurons is critical for evoked feeding.
Using Cre-recombinase-enabled cell-specific neuron mapping techniques in
mice, Krashes et al. (2014) discovered strong excitatory drive that,
unexpectedly, emanates from the hypothalamic paraventricular nucleus,
specifically from subsets of neurons expressing thyrotropin-releasing
hormone (TRH; 613879) and pituitary adenylate cyclase-activating
polypeptide (PACAP; 102980). Chemogenetic stimulation of these afferent
neurons in sated mice markedly activated Agrp neurons and induced
intense feeding. Conversely, acute inhibition in mice with caloric
deficiency-induced hunger decreased feeding. Krashes et al. (2014)
concluded that discovery of these afferent neurons capable of triggering
hunger advances understanding of how this intense motivational state is
regulated.
GENE STRUCTURE
Brown et al. (2001) determined that the AGRP gene contains 4 exons and
spans 1.2 kb. Exon 1 is noncoding and contains a canonical TATA box and
2 CACCC boxes. In the region upstream of exon 1, they identified a
noncanonical TATA box, a CCAAT box, a CACCC box, a portion of a putative
insulin response element, and STAT (see STAT1; 600555)-recognition
sites.
MAPPING
Shutter et al. (1997) mapped the AGRP gene to chromosome 16q22 by
fluorescence in situ hybridization.
PARD6A
| dbSNP name | rs115108685(C,T); rs35356834(G,A) |
| ccdsGene name | CCDS10843.1 |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 50855 |
| EntrezGene Description | par-6 family cell polarity regulator alpha |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PARD6A:NM_016948:exon3:c.C837T:p.D279D,PARD6A:NM_001037281:exon3:c.C834T:p.D278D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01515 |
| ESP Afr MAF | 0.03162 |
| ESP All MAF | 0.012158 |
| ESP Eur/Amr MAF | 0.002209 |
| ExAC AF | 0.005904 |
C16orf86
| dbSNP name | rs115388552(G,A) |
| ccdsGene name | CCDS32468.2 |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 388284 |
| EntrezGene Description | chromosome 16 open reading frame 86 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C16orf86:NM_001012984:exon2:c.G129A:p.L43L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | low |
| dbSNP GMAF | 0.01515 |
| ESP Afr MAF | 0.02997 |
| ESP All MAF | 0.011131 |
| ESP Eur/Amr MAF | 0.002047 |
| ExAC AF | 0.005568 |
DDX28
| dbSNP name | rs13816(G,C); rs77242604(G,A) |
| ccdsGene name | CCDS10858.1 |
| CosmicCodingMuts gene | DDX28 |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 55794 |
| EntrezGene Description | DEAD (Asp-Glu-Ala-Asp) box polypeptide 28 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DDX28:NM_018380:exon1:c.C1611G:p.P537P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1818 |
| ESP Afr MAF | 0.285942 |
| ESP All MAF | 0.190597 |
| ESP Eur/Amr MAF | 0.14186 |
| ExAC AF | 0.167,3.253e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature (less common)
HEAD AND NECK:
[Eyes];
Cherry-red maculae (less common)
RESPIRATORY:
[Lung];
Dyspnea;
Frequent respiratory infections;
Decreased pulmonary diffusion secondary to alveolar infiltration;
Diffuse reticular or finely nodular infiltrations
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
NEUROLOGIC:
[Central nervous system];
Absence of neurologic manifestations
HEMATOLOGY:
Large vacuolated foam cells ('NP cells') on bone marrow biopsy;
'Sea blue' histiocytes;
Decreased platelets
LABORATORY ABNORMALITIES:
Decreased acid sphingomyelinase activity;
Multiple visceral organs (lung, liver, spleen, kidney) contain foamy
resident cells and histiocytes;
Electron microscopy of foam cells shows lamellar inclusions;
Increased LDL cholesterol;
Increased triglycerides;
Decreased HDL cholesterol
MISCELLANEOUS:
Onset in infancy or childhood;
Variable phenotype;
More common in Ashkenazi Jews;
Allelic disorder to Niemann-Pick disease type A (257200)
MOLECULAR BASIS:
Caused by mutations in the acid lysosomal sphingomyelin phosphodiesterase-1
gene (SMPD1, 607608.0002)
OMIM Title
*607618 DEAD/H BOX 28; DDX28
;;MITOCHONDRIAL DEAD BOX POLYPEPTIDE 28; MDDX28
OMIM Description
DESCRIPTION
DDX28 is an RNA helicase, which unwind double-stranded RNA using
nucleoside triphosphates as an energy source. RNA helicases participate
in essentially all cellular processes that involve RNA.
CLONING
By CpG island subcloning from chromosome 16q22.1 and by screening a
testis cDNA library, Valgardsdottir et al. (2001) cloned DDX28. The
deduced 540-amino acid protein has a calculated molecular mass of 59 kD.
DDX28 contains an N-terminal mitochondrial targeting signal, a putative
leucine-rich nuclear export signal, a nuclear localization signal, and
all of the well conserved DEAD box helicase motifs. It also has several
potential serine and threonine phosphorylation sites, but no tyrosine
phosphorylation sites. DDX28 shares only limited similarity with other
RNA helicases in a region of 300 to 400 amino acids containing all the
conserved DEAD box motifs. Northern blot analysis detected a 2-kb
transcript expressed in all tissues examined. Immunolocalization of
endogenous or transfected DDX28 showed mitochondrial and nuclear
subcellular distributions, with stronger staining in mitochondria.
GENE FUNCTION
By in vitro assay of recombinant protein, Valgardsdottir et al. (2001)
determined that DDX28 hydrolyzed ATP, and this activity was dependent
upon the presence of RNA and magnesium. DDX28 did not hydrolyze GTP.
GENE STRUCTURE
Valgardsdottir et al. (2001) determined that DDX28 is an intronless
gene. The 5-prime end of the MDDX28 gene lies within a CpG island.
MAPPING
Valgardsdottir et al. (2001) identified the DDX28 gene within a PAC
clone mapping to chromosome 16q22.1.
MIR1972-2
| dbSNP name | rs57629257(C,T) |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 100422922 |
| snpEff Gene Name | RP11-419C5.2 |
| EntrezGene Description | microRNA 1972-2 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1901 |
| ExAC AF | 0.049 |
SMG1P7
| dbSNP name | rs115130525(T,C) |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 100506060 |
| EntrezGene Symbol | LOC100506060 |
| EntrezGene Description | SMG1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0629 |
AARS
| dbSNP name | rs11537663(T,A); rs4081753(A,G); rs190043661(C,T); rs9931779(C,T); rs7186104(T,C); rs77790607(T,C); rs141522446(C,T); rs184010145(C,T); rs73575193(C,T); rs117857165(G,A); rs62049419(G,T); rs7193598(C,T); rs2070203(G,A); rs141840552(G,A); rs12149660(G,A); rs8057463(T,A); rs114103198(C,G); rs148493777(G,C); rs775208(T,C); rs138048029(C,A); rs141045868(G,A); rs8062865(G,A); rs141006014(C,A); rs34087264(C,T); rs111461416(C,T) |
| ccdsGene name | CCDS32474.1 |
| cytoBand name | 16q22.1 |
| EntrezGene GeneID | 16 |
| EntrezGene Description | alanyl-tRNA synthetase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AARS:NM_001605:exon6:c.C700T:p.P234S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7545 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E7ETK8 |
| dbNSFP KGp1 AF | 0.00228937728938 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002296 |
| ESP Afr MAF | 0.000682 |
| ESP All MAF | 0.001231 |
| ESP Eur/Amr MAF | 0.001512 |
| ExAC AF | 0.001773 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Diplopia
NEUROLOGIC:
[Central nervous system];
Ataxia, episodic;
Spasticity;
Dysarthria;
Dystonia;
Involuntary movements;
Dyskinesias;
Choreoathetosis;
Spastic paraplegia;
Hyperreflexia;
Pyramidal signs;
Tonic-clonic seizures (less common);
Migraine;
Headache;
Cognitive impairment;
[Peripheral nervous system];
Paresthesias
MISCELLANEOUS:
Onset at 2 to 15 years;
Symptoms precipitated by stress, exertion, fatigue, alcohol;
Variable features;
Some patients respond to acetazolamide
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 2 (facilitated glucose
transporter), member 1 gene (SLC2A1, 138140.0018)
OMIM Title
*601065 ALANYL-tRNA SYNTHETASE; AARS
;;ALARS
OMIM Description
DESCRIPTION
The AARS gene encodes alanyl-tRNA synthetase. Each of the amino acid
synthetases catalyzes the attachment of their respective amino acids to
the appropriate tRNA. The class II Escherichia coli and human
alanyl-tRNA synthetases cross-acylate their respective tRNAs and
require, for aminoacylation, an acceptor helix G3:U70 basepair that is
conserved in evolution (Shiba et al., 1995).
Some of the amino acid synthetases are targets for autoantibodies in the
autoimmune disease polymyositis/dermatomyositis (Nichols et al., 1995)
including histidyl-RS (142810), threonyl-RS (187790), isoleucyl-RS
(600709), glycyl-RS (600287) and alanyl-RS.
CLONING
Shiba et al. (1995) reported the primary structure and expression of an
active human alanyl-tRNA synthetase. The N-terminal 498 amino acids of
the 968-residue polypeptide showed 41% identity with the E. coli
protein. The human protein contains the class-defining domain of the E.
coli enzyme, which includes the part needed for recognition of the
acceptor helix G3:U70 basepair as an RNA signal for alanine. The authors
concluded that mutagenesis, modeling, domain organization, and
biochemical characterization of the E. coli protein are valid as a
template for the human protein.
Lo et al. (2014) reported the discovery of a large number of natural
catalytic nulls for each human aminoacyl tRNA synthetase. Splicing
events retain noncatalytic domains while ablating the catalytic domain
to create catalytic nulls with diverse functions. Each synthetase is
converted into several new signaling proteins with biologic activities
'orthogonal' to that of the catalytic parent. The recombinant aminoacyl
tRNA synthetase variants had specific biologic activities across a
spectrum of cell-based assays: about 46% across all species affect
transcriptional regulation, 22% cell differentiation, 10%
immunomodulation, 10% cytoprotection, and 4% each for proliferation,
adipogenesis/cholesterol transport, and inflammatory response. Lo et al.
(2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA
synthetases. They identified 2 catalytic-null splice variants for AlaRS.
MAPPING
Nichols et al. (1995) mapped the alanyl-RS gene by fluorescence in situ
hybridization to chromosome 16q22. By radiation hybrid panel analysis,
Maas et al. (2001) mapped the AARS gene centromeric to the KARS gene
(601421) and the ADAT1 gene (604230) in region 16q22.2-q22.3.
GENE FUNCTION
The folding of mRNA influences a diverse range of biologic events such
as mRNA splicing and processing, and translational control and
regulation. Because the structure of mRNA is determined by its
nucleotide sequence and its environment, Shen et al. (1999) examined
whether the folding of mRNA could be influenced by the presence of
single-nucleotide polymorphisms (SNPs). They reported marked differences
in mRNA secondary structure associated with SNPs in the coding region of
2 human mRNAs: alanyl-tRNA synthetase and replication protein A, 70-kD
subunit (RPA70; 179835). Enzymatic probing of SNP-containing fragments
of the mRNAs revealed pronounced allelic differences in cleavage pattern
at sites 14 or 18 nucleotides away from the SNP, suggesting that a
single-nucleotide variation can give rise to different mRNA folds. By
using oligodeoxyribonucleotides complementary to the region of different
allelic structures in the RPA70 mRNA, but not extending to the SNP
itself, they found that the SNP exerted an allele-specific effect on the
accessibility of its flanking site in the endogenous human RPA70 mRNA.
The results demonstrated the contribution of common genetic variation
through structural diversity of mRNA and suggested a broader role than
previously thought for the effects of SNPs on mRNA structure and,
ultimately, biologic function.
MOLECULAR GENETICS
In affected members of a large French family with axonal
Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al.
(2010) identified a heterozygous mutation in the AARS gene (R329H;
601065.0001). Affected members of an unrelated affected French family
were found to carry the same mutation. Haplotype analysis excluded a
founder effect in these families.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011)
identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
McLaughlin et al. (2012) identified a heterozygous R329H mutation in an
Australian family with CMT2N.
EVOLUTION
Chihade et al. (2000) presented data on AARS from an early eukaryote and
other sources that were consistent with the notion that mitochondrial
genesis did not significantly precede nucleus formation.
Guo et al. (2009) demonstrated that the C-Ala domain is universally
tethered to the editing domain both in alanyl-tRNA synthetase and in
many homologous free-standing editing proteins. Crystal structure and
functional analyses showed that C-Ala forms an ancient single-stranded
nucleic acid binding motif that promotes cooperative binding of both
aminoacylation and editing domains to tRNA(Ala). In addition, C-Ala may
have played an essential role in the evolution of alanyl-tRNA
synthetases by coupling aminoacylation to editing to prevent
mistranslation.
Mistranslation arising from confusion of serine for alanine by
alanyl-tRNA synthetases (AlaRSs) has profound functional consequences.
Throughout evolution, 2 editing checkpoints prevent disease-causing
mistranslation from confusing glycine or serine for alanine at the
active site of AlaRS. In both bacteria and mice, serine poses a bigger
challenge than glycine. One checkpoint is the AlaRS editing center, and
the other is from widely distributed AlaXps, free-standing,
genome-encoded editing proteins that clear Ser-tRNA(Ala) (AARSD1;
613212). The paradox of misincorporating both a smaller (glycine) and a
larger (serine) amino acid suggests a deep conflict for nature-designed
AlaRS. Guo et al. (2009) showed the chemical basis for this conflict.
Nine crystal structures, together with kinetic and mutational analysis,
provided snapshots of adenylate formation for each amino acid. An
inherent dilemma is posed by constraints of a structural design that
pins down the alpha-amino group of the bound amino acid by using an
acidic residue. This design, dating back more than 3 billion years,
creates a serendipitous interaction with the serine hydroxide that is
difficult to avoid. Apparently because no better architecture for the
recognition of alanine could be found, the serine misactivation problem
was solved through free-standing AlaXps, which appeared
contemporaneously with early AlaRSs.
ANIMAL MODEL
Lee et al. (2006) demonstrated that low levels of mischarged transfer
RNAs can lead to an intracellular accumulation of misfolded proteins in
neurons. These accumulations are accompanied by upregulation of
cytoplasmic protein chaperones and by induction of the unfolded protein
response. Lee et al. (2006) reported that the mouse 'sticky' (sti)
mutation, which causes cerebellar Purkinje cell loss and ataxia, is a
missense mutation in the editing domain of the alanyl-tRNA synthetase
gene that compromises the proofreading activity of this enzyme during
aminoacylation of tRNAs. Lee et al. (2006) concluded that their findings
demonstrated that disruption of translational fidelity in terminally
differentiated neurons leads to the accumulation of misfolded proteins
and cell death, and provided a novel mechanism underlying
neurodegeneration.
DHODH
| dbSNP name | rs3213422(A,C); rs4788597(C,T); rs12149380(G,C); rs2052579(A,G); rs4788598(G,C); rs2335386(G,T); rs2878404(T,C); rs8057016(G,T); rs1465457(C,G); rs8058214(T,G); rs8061140(A,G); rs752434(T,C); rs4788456(G,A); rs8046916(C,G); rs139233323(C,G); rs4788600(G,T); rs3764310(T,C); rs8062895(A,G); rs3812988(T,C); rs8048262(A,T); rs11864453(C,T); rs73586368(C,T); rs11075914(G,C); rs2278027(A,G); rs11647889(C,G); rs75329497(A,G); rs10048144(C,G); rs111993259(C,T); rs10048111(T,C); rs1862752(G,T); rs56387295(C,A); rs2081223(A,C); rs2081222(A,G); rs74803415(G,A); rs12446480(A,G); rs2288002(A,G); rs61733129(C,T); rs113365769(G,A); rs2288001(G,T); rs2288000(A,G); rs2287999(A,G); rs143339631(G,T); rs2287998(T,C) |
| ccdsGene name | CCDS42192.1 |
| cytoBand name | 16q22.2 |
| EntrezGene GeneID | 1723 |
| EntrezGene Description | dihydroorotate dehydrogenase (quinone) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DHODH:NM_001361:exon8:c.C1022T:p.A341V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6565 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q02127 |
| dbNSFP Uniprot ID | PYRD_HUMAN |
| dbNSFP KGp1 AF | 0.0224358974359 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0110497237569 |
| dbNSFP KGp1 Asn AF | 0.0472027972028 |
| dbNSFP KGp1 Eur AF | 0.0224274406332 |
| dbSNP GMAF | 0.0225 |
| ESP Afr MAF | 0.006329 |
| ESP All MAF | 0.020103 |
| ESP Eur/Amr MAF | 0.026856 |
| ExAC AF | 0.027 |
OMIM Clinical Significance
Limbs:
Flexion deformity of fingers;
Rocker-bottom feet;
Ulnar deviation of fingers;
Thumb adduction contraction
Growth:
Variable moderate short stature
Radiology:
Vertical talus
Inheritance:
Autosomal dominant
OMIM Title
*126064 DIHYDROOROTATE DEHYDROGENASE; DHODH
;;DHOdehase;;
URA1, YEAST, HUMAN COMPLEMENT OF
OMIM Description
CLONING
Dihydroorotate dehydrogenase (EC 1.3.3.1) catalyzes the fourth enzymatic
step in de novo pyrimidine biosynthesis. Minet et al. (1992) isolated a
truncated human cDNA encoding this enzyme from a HeLa cell cDNA library
by functional complementation of a corresponding deletion mutant from
the Saccharomyces cerevisiae. The gene in yeast is symbolized ura1. DHO
dehydrogenase is a monofunctional protein which, in most eukaryotic
organisms, is located on the outer surface of the inner mitochondrial
membrane. In yeast, however, it has a cytosolic location.
GENE STRUCTURE
Ng et al. (2010) determined that the DHODH gene contains 9 exons.
GENE FUNCTION
White et al. (2011) used zebrafish embryos to identify the initiating
transcriptional events that occur on activation of human BRAF(V600E)
(164757.0001) in the neural crest lineage. Zebrafish embryos that are
transgenic for mitfa:BRAF(V600E) and lack p53 (191170) have a gene
signature that is enriched for markers of multipotent neural crest
cells, and neural crest progenitors from these embryos fail to
terminally differentiate. To determine whether these early
transcriptional events are important for melanoma pathogenesis, White et
al. (2011) performed a chemical genetic screen to identify
small-molecule suppressors of the neural crest lineage, which were then
tested for their effects on melanoma. One class of compound, inhibitors
of dihydroorotate dehydrogenase (DHODH), e.g., leflunomide, led to an
almost complete abrogation of neural crest development in zebrafish and
to a reduction in the self-renewal of mammalian neural crest stem cells.
Leflunomide exerts these effects by inhibiting the transcriptional
elongation of genes that are required for neural crest development and
melanoma growth. When used alone or in combination with a specific
inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked
decrease in melanoma growth both in vitro and in mouse xenograft
studies. White et al. (2011) concluded that their studies, taken
together, highlight developmental pathways in neural crest cells that
have a direct bearing on melanoma formation.
MAPPING
Barnes et al. (1993) mapped the DHODH gene to 16q22 by fluorescence in
situ hybridization.
MOLECULAR GENETICS
Mutations in the DHODH gene cause Miller syndrome (263750), an autosomal
recessive disorder also known as postaxial acrofacial dysostosis. Ng et
al. (2010) found 10 different missense mutations and 1 frameshift
mutation in the DHODH gene underlying Miller syndrome. All patients were
found to be compound heterozygotes, and each parent a carrier. These
findings were supported by whole-genome sequencing by Roach et al.
(2010).
HPR
| dbSNP name | rs150367531(G,A); rs3794695(C,T); rs56129242(C,G); rs7189115(C,T); rs7188962(A,G); rs7189591(G,T); rs7190994(T,A); rs72787056(C,T); rs145521657(C,G); rs7201643(C,A); rs7203821(T,C); rs34042070(C,G); rs74794641(G,A); rs7185840(A,G); rs56030533(G,A); rs370407396(T,C); rs6499558(G,C); rs3890860(A,G); rs79469260(G,A); rs146760422(C,T); rs113392620(T,C); rs72787058(C,T); rs142822369(T,C); rs184091626(G,A); rs72787060(T,C); rs152838(C,T); rs72787062(G,A); rs8047930(C,T); rs11075919(T,C); rs117689220(G,A); rs201646102(C,T); rs11646364(A,T); rs2021171(G,A); rs470710(C,T) |
| ccdsGene name | CCDS42193.1 |
| cytoBand name | 16q22.2 |
| EntrezGene GeneID | 3250 |
| snpEff Gene Name | HP |
| EntrezGene Description | haptoglobin-related protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.6118 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000233 |
| ESP All MAF | 7.8e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002608 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[External genitalia, male];
Hypospadias;
Short penis;
Chordee;
Bifid scrotum;
[Internal genitalia, female];
Longitudinal vaginal septum;
Double uterus;
Double cervix;
[Kidneys];
Chronic pyelonephritis;
Renal insufficiency;
Renal transplant;
[Ureters];
Vesicoureteral reflux;
Ureteropelvic junction obstruction
SKELETAL:
[Hands];
Short thumbs;
Proximally placed thumbs;
Hypoplastic thenar eminences;
Second finger ulnar deviation;
Fifth finger clinodactyly;
Fifth finger brachydactyly;
Carpal delayed ossification;
Short first metacarpal;
Hypoplastic middle phalanges;
Pseudoepiphyses;
[Feet];
Absent halluces;
Short halluces;
Medially deviated halluces;
Brachydactyly (2nd-5th toes);
Tarsal delayed ossification;
Short first metatarsal;
Hypoplastic distal and middle phalanges;
Fused cuneiforms
MOLECULAR BASIS:
Caused by mutation in the homeobox A13 gene (HOXA13, 142959.0001)
OMIM Title
*140210 HAPTOGLOBIN-RELATED PROTEIN GENE; HPR
OMIM Description
DESCRIPTION
The HPR gene is the product of a segmental duplication of the HP gene
(140100) on chromosome 16. Like HP, HPR binds hemoglobin (Hb) with high
affinity. Together with apolipoprotein L1 (APOL1; 603743), HPR-Hb forms
a protein complex called trypanosome lytic factor-1 (TLF1), which plays
an important role in protection against Trypanosoma brucei, the pathogen
that causes trypanosomiasis, or sleeping sickness (summary by Hardwick
et al., 2014).
CLONING
Bensi et al. (1985) and Maeda (1985) isolated the human HPR gene. Its
predicted amino acid sequence differs by about 8% from that of the
electrophoretically fast-migrating HP variant (HP1F; 140100.0001). The
differences appeared to be located on the surface of the protein
molecule, and the regions and specific residues considered to be
important for binding hemoglobin are identical in the HP and HPR
proteins.
Smithies and Powers (1986) found evidence of gene conversion (see
142200) between the closely linked HP and HPR loci.
GENE STRUCTURE
Maeda and Kim (1990) demonstrated that the 2 genes in the human
haptoglobin cluster, HP and HPR, contain 2 retrovirus-like elements. One
(RTVL-Ia) is in the first intron of the HPR gene, and the second
(RTVL-Ic) is at the 3-prime-end of the gene cluster. In the chimpanzee
3-gene cluster (HP-HPR-HPP), there is an additional retrovirus-like
element (RTVL-Ib) in the intergenic region between the chimpanzee HPR
and HPP loci. RTVL-Ia and RTVL-Ib are essentially full size and have the
general structure 5-prime-LTR--gag--pol-env--3-prime-LTR, while RTVL-Ic
lacks about one-third of its 5-prime portion. Although none of the
elements had retained long open reading frames, Maeda and Kim (1990)
detected stretches with amino acids identical to various parts of
proteins of the Moloney murine leukemia virus (Mo-MuLV). They concluded
that the RTVL-I elements were derived from a virus similar in structure
to Mo-MuLV. The DNA sequences surrounding the insertion points of the 3
RTVL-I elements were dissimilar, implying that they integrated into the
haptoglobin gene cluster independently at some time after the initial
formation of the triplicated gene cluster in primates. Comparison of the
nucleotide sequences of the 3 elements suggested that foreign DNA
introduced into the genome can accumulate mutations more rapidly than
the genomic sequences surrounding them. At least 5 other families of
retrovirus-like sequences have been found in the human genome; for a
review, see Cohen and Larsson (1988). In RTVL-I, the tRNA used for the
primer binding site is ile-tRNA. (RTVL-I = retrovirus-like
sequence--isoleucine.)
MAPPING
The HPR gene maps to chromosome 16q22.1 (Bensi et al., 1985; Maeda,
1985).
Maeda et al. (1986) found that the HPR gene(s) lie on the downstream
side of the HP gene (140100).
GENE FUNCTION
Using immobilized hemoglobin for affinity chromatography, Nielsen et al.
(2006) showed that HPR could bind hemoglobin as efficiently as HP, and
SDS-PAGE showed that HPR migrated as a 45-kD monomer and a 90-kD dimer.
In contrast to HP, HPR did not promote high-affinity binding to CD163
(605545). Western blot analysis of 18 persons with normal HP levels and
13 patients with low HP levels resulting from sickle cell anemia and
extensive intravascular hemolysis indicated that the plasma
concentration of HPR was unaffected by hemolysis, suggesting that
depletion of HP but not HPR in these patients may be a consequence of
the difference in CD163 binding between HP-hemoglobin and HPR-hemoglobin
complexes. Binding of hemoglobin to circulating native HPR incorporated
in the high density lipoprotein (HDL) fraction was indicated by
hemoglobin-affinity precipitation of plasma HPR together with APOL1.
Nielsen et al. (2006) suggested that hemoglobin reported to be present
in TLF represents HPR-bound hemoglobin, which may contribute to the
biologic activity of circulating TLF.
The protozoan parasite Trypanosoma brucei is lysed by APOL1, a component
of HDL particles that are also characterized by the presence of HPR.
Vanhollebeke et al. (2008) reported that this process is mediated by a
parasite glycoprotein receptor, which binds the haptoglobin-hemoglobin
complex with high affinity for the uptake and incorporation of heme into
intracellular hemoproteins. In mice, this receptor was required for
optimal parasite growth and the resistance of parasites to the oxidative
burst by host macrophages. In humans, the trypanosome receptor also
recognized the complex between hemoglobin and HPR, which explains its
ability to capture trypanolytic HDLs. Vanhollebeke et al. (2008)
concluded that, in humans, the presence of HPR has diverted the function
of the trypanosome haptoglobin-hemoglobin receptor to elicit innate host
immunity against the parasite.
BIOCHEMICAL FEATURES
During pregnancy, HPR circulates in plasma; furthermore, Kuhajda et al.
(1989) demonstrated that HPR or HPR-like epitopes are expressed in human
breast carcinoma. This led Kuhajda et al. (1989) to examine the
possibility that anti-HPR immunoreactivity of biopsy specimens from
women with primary breast carcinoma might be related to the clinical
behavior of the tumor. They examined the association between the
expression of HPR and the recurrence of cancer in a retrospective study
of 70 patients with early breast cancer treated by mastectomy from
1977-1985 at the Johns Hopkins Hospital. Expression of HPR epitopes was
associated with earlier recurrence, and multivariate analysis showed
that HPR-epitope expression was an independent prognostic factor. The
authors concluded that it is a clinically important predictor of
recurrence, especially in combination with progesterone-receptor status.
EVOLUTION
McEvoy and Maeda (1988) analyzed the evolutionary history of the
haptoglobin gene family by characterizing the haptoglobin genes in
primates. Whereas the HPR gene in the human is 2.2 kb downstream of the
HP gene, chimpanzees, gorillas, orangutans, and Old World monkeys have a
third gene, which McEvoy and Maeda (1988) named HPP for haptoglobin
primate, located 16 kb downstream of HPR. New World monkeys have only 1
haptoglobin gene. McEvoy and Maeda (1988) interpreted these observations
as suggesting triplication of the haptoglobin locus after divergence of
the New World monkeys, followed by deletion of 1 locus in humans. They
stated that, although in vivo transfection experiments indicated that
the HPR promoter is active and cell-specific, no hemoglobin-binding
protein of the expected structure had been detected.
MOLECULAR GENETICS
Maeda et al. (1986) showed that tandemly arranged HPR genes are linked
to the HP2 allele (140100.0002).
Maeda et al. (1986) found polymorphisms for the number of tandemly
arranged HPR genes in the haptoglobin gene cluster in blacks. Such was
not found in 26 whites and 1 Asian; all had a single HPR gene. In 1
black subject, 6 tandemly arranged HPR genes were demonstrated in 1
chromosome 16 by pulsed field gel electrophoresis; his other chromosome
16 had 1 HPR gene.
African trypanosomes cause disease in humans and animals. Trypanosoma
brucei brucei affects cattle but not humans because of its sensitivity
to a subclass of human high density lipoproteins called trypanosome
lytic factor (TLF). TLF contains 2 apolipoproteins that are sufficient
to cause lysis of T. b. brucei in vitro. Smith et al. (1995) identified
these proteins as the human haptoglobin-related protein (HPR) and
paraoxonase-arylesterase (PON; 168820). They found that an antibody to
haptoglobin inhibited TLF activity. TLF was shown to exhibit peroxidase
activity and to be inhibited by catalase. These results suggested that
TLF kills trypanosomes by oxidative damage initiated by its peroxidase
activity. As noted earlier, Maeda et al. (1986) found polymorphism for
the number of tandemly arranged HPR genes in the haptoglobin gene
cluster in blacks, whereas only a single HPR gene was found in other
races. The work of Smith et al. (1995) raised the possibility that the
development of the polymorphism was related to parasite exposure.
Using fiber-FISH, the paralog ratio test, and array-CGH data, Hardwick
et al. (2014) confirmed that the HPR gene is copy number variable, with
duplication of HPR occurring at polymorphic frequencies in west and
central Africa, up to an allele frequency of 15%. High levels of HPR
duplication overlapped the geographic region where chronic human African
trypanosomiasis is endemic. Although the HPR duplication was somewhat
undertransmitted to children affected by trypanosomiasis from unaffected
parents in the Democratic Republic of Congo, the undertransmission
became statistically significant when assessed together with alleles of
APOL1 in these children.
HCCAT5
| dbSNP name | rs59590642(C,T); rs72795164(G,A); rs7189194(T,G) |
| cytoBand name | 16q22.3 |
| EntrezGene GeneID | 283902 |
| EntrezGene Description | hepatocellular carcinoma associated transcript 5 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07668 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Pelvis];
Hip pain;
Disruption of Shenton line seen on x-ray;
Center-edge angle less than 20 degrees seen on x-ray;
Tonnis angle greater than 10 degrees seen on x-ray;
Extrusion distance between the edge of the femoral head and ilioischial
line greater than 10 mm seen on x-ray;
Femoral neck angle greater than 135 degrees (coxa valga) or less than
127 degrees (coxa vara) seen on x-ray
MISCELLANEOUS:
One family reported (last curated January 2014)
OMIM Title
*615613 HEPATOCELLULAR CARCINOMA-ASSOCIATED TRANSCRIPT 5; HCCAT5
;;HEPATOMA-ASSOCIATED GENE; HTA
OMIM Description
CLONING
Using a bioinformatic screen to identify genes upregulated in
hepatocellular carcinoma (HCC; 114550), followed by 3-prime and 5-prime
RACE of HepG2 cells, Liu et al. (2013) cloned HCCAT5, which they called
HTA. The deduced 92-amino acid protein has a calculated molecular mass
of 10.2 kD. Northern blot analysis detected transcripts of 1.4 and 1.7
kb in HCC cell lines, but not in L-02 normal hepatic cells or in normal
human umbilical vein endothelial cells. RT-PCR and sequencing showed
that the longer transcript retains intron 2.
GENE FUNCTION
Liu et al. (2013) found that overexpression of HTA in the QSG-7701
hepatic cell line promoted proliferation and colony-forming ability.
GENE STRUCTURE
Liu et al. (2013) determined that the HCCAT5 gene has 3 exons.
MAPPING
Hartz (2014) mapped the HCCAT5 gene to chromosome 16q22.3 based on an
alignment of the HCCAT5 sequence (GenBank GENBANK BC019009) with the
genomic sequence (GRCh37).
WWOX
| dbSNP name | rs11545028(C,T); rs4887935(T,C); rs72801001(C,A); rs4887936(C,T); rs79416778(G,T); rs34554575(G,T); rs35251003(G,A); rs34677909(G,A); rs12598564(T,G); rs10871346(T,C); rs80280043(C,A); rs12921245(G,C); rs7192129(C,T); rs187775849(A,G); rs7197900(T,C); rs7191778(G,T); rs11642151(C,T); rs34180005(G,A); rs73562741(T,G); rs7204080(T,C); rs36098342(C,G); rs58249547(G,A); rs12931172(G,C); rs12918750(T,C); rs73562747(G,T); rs57694655(C,T); rs58997179(T,C); rs138377266(C,G); rs113349210(G,A); rs73562757(G,A); rs113385350(T,A); rs73562762(C,T); rs11649069(C,T); rs73562768(G,C); rs35608090(T,G); rs57206085(G,A); rs77002264(C,T); rs8045088(A,G); rs8049744(T,A); rs8045450(A,C); rs8064221(G,A); rs8049912(A,G); rs77270263(C,T); rs61377917(G,A); rs144124717(G,A); rs4887937(T,C); rs79294211(A,G); rs77200969(A,G); rs2287973(T,G); rs2287972(C,T); rs80006768(T,C); rs74348798(A,G); rs60384461(G,A); rs11150042(C,T); rs75392771(C,T); rs68149250(A,G); rs61228651(T,C); rs114699709(A,G); rs117761820(G,T); rs58256360(A,G); rs58334941(T,G); rs113508147(C,G); rs7206182(G,A); rs7200257(G,A); rs1469117(T,G); rs12934051(C,T); rs144601717(C,T); rs12934985(A,C); rs7203387(A,C); rs184223355(A,G); rs4887938(G,A); rs3850107(C,G); rs16947125(A,C); rs16947127(T,C); rs16947129(T,C); rs12917833(C,G); rs11645921(T,C); rs11649531(G,C); rs11645973(T,C); rs67486703(G,A); rs11645006(A,G); rs76796549(A,C); rs7187936(G,A); rs4888744(T,C); rs4888745(G,C); rs141971379(C,T); rs150667883(G,C); rs8060519(A,C); rs8060679(A,G); rs13339407(A,G); rs10431978(T,C); rs3751777(T,A); rs3751776(C,T); rs74384309(C,T); rs2042356(T,C); rs1079569(G,A); rs111930819(G,A); rs12920698(G,C); rs9933874(A,T); rs1076514(G,A); rs16947165(A,G); rs72802975(A,G); rs8056930(T,C); rs148409717(C,T); rs8057015(C,A); rs9319518(C,G); rs12931246(G,C); rs76009490(G,T); rs36017005(T,G); rs184020180(A,G); rs9319519(A,G); rs9929919(T,G); rs34547395(T,C); rs9928004(A,C); rs142580945(G,C); rs11644207(T,G); rs13334300(A,C); rs7203218(A,G); rs7201309(G,A); rs12934734(C,T); rs12921337(T,C); rs72802982(G,A); rs9933217(A,C); rs36041365(A,G); rs35327952(G,A); rs35506392(G,A); rs35302304(T,A); rs12716848(G,A); rs12716849(G,A); rs57508390(G,C); rs13338697(A,G); rs13333314(G,A); rs12918746(T,G); rs56129600(A,C); rs67933378(G,A); rs28607706(C,T); rs12927803(A,G); rs12926275(G,T); rs12928563(A,T); rs9929762(A,G); rs1074963(C,G); rs1074964(C,T); rs9922536(C,T); rs9933156(A,G); rs9937449(T,C); rs16947173(A,G); rs9935941(A,G); rs4888746(A,G); rs12930275(A,G); rs4888747(T,C); rs4888748(A,G); rs4888749(T,C); rs11644071(G,C); rs58304634(C,T); rs8062483(A,G); rs72803000(T,A); rs9925791(T,A); rs12922846(A,G); rs112329887(G,T); rs72803001(T,G); rs114703914(C,T); rs114226110(T,A); rs11150043(A,G); rs71396154(G,C); rs4888750(G,C); rs80167942(C,T); rs3850108(T,C); rs3850109(T,C); rs3850110(G,A); rs3850111(G,A); rs10153091(T,C); rs3850112(C,G); rs79950054(C,G); rs35811275(G,A); rs34521361(G,T); rs3764299(T,C); rs3764298(G,A); rs3764295(T,G); rs34163562(C,T); rs12930571(C,A); rs185340112(A,G); rs11648121(G,A); rs11648242(G,C); rs11644853(A,G); rs78946760(A,G); rs35575945(C,A); rs17650116(G,A); rs8047454(C,A); rs8048266(A,C); rs8052567(C,G); rs8053075(C,T); rs79158905(A,G); rs9745781(G,A); rs76144510(G,T); rs7194147(G,A); rs34285084(C,G); rs7194191(G,T); rs150492218(A,C); rs7359490(T,C); rs1469115(C,T); rs114190598(C,T); rs36025095(G,A); rs76730723(G,T); rs59441926(A,G); rs16947188(A,G); rs57452295(T,A); rs72804922(A,G); rs1079573(A,G); rs1079572(G,A); rs1541690(T,A); rs185687872(C,T); rs16947192(T,C); rs377635261(C,T); rs11860867(A,T); rs1079571(G,A); rs12716850(A,G); rs371709999(C,T); rs68080610(C,T); rs8058162(A,G); rs8056446(G,A); rs12716851(T,G); rs12716852(G,A); rs12716853(A,G); rs77533819(T,C); rs35695084(C,T); rs8059793(A,C); rs8047917(T,A); rs376376085(G,T); rs192171463(C,T); rs72804941(G,A); rs7190335(T,C); rs7206273(G,A); rs76632974(C,T); rs9927362(T,G); rs10871347(C,A); rs79448771(G,C); rs1862696(A,G); rs1922618(T,G); rs79617670(T,A); rs367778206(C,T); rs112635744(T,C); rs4888752(T,A); rs7185712(T,C); rs7185728(T,C); rs4888753(T,C); rs112848799(A,G); rs72804952(G,A); rs113368990(G,A); rs74740095(C,G); rs34512533(G,A); rs79198030(T,C); rs7193947(A,G); rs114553375(G,A); rs13338598(T,G); rs113760151(G,A); rs56407156(G,T); rs56062747(T,C); rs1922619(G,C); rs114505271(T,G); rs12932880(A,G); rs117641681(G,A); rs113108145(G,T); rs11649032(A,G); rs11639881(T,G); rs66812823(A,G); rs74251672(T,A); rs77687699(C,T); rs80061648(C,G); rs719743(C,A); rs113485663(C,T); rs12923935(C,A); rs78771683(G,A); rs77399019(A,G); rs75967182(G,T); rs4359451(T,C); rs2303191(T,C); rs76347249(C,T); rs12325408(T,C); rs2113163(G,A); rs2113162(A,G); rs2113161(C,A); rs76150242(T,C); rs74905026(G,A); rs78777402(G,C); rs79810142(G,A); rs77754442(G,C); rs113265374(A,G); rs116265469(G,T); rs76348177(T,C); rs59137451(C,A); rs12926108(C,G); rs137939350(G,C); rs12445540(C,T); rs184376591(T,G); rs8055883(C,T); rs36106424(C,A); rs77117995(A,T); rs77290228(A,G); rs75575294(A,G); rs116360215(G,A); rs11150044(C,A); rs113107998(G,A); rs11150045(C,G); rs11150047(C,A); rs2113160(G,A); rs12921252(G,T); rs111834449(G,A); rs17572124(G,C); rs77164546(A,G); rs12923504(C,G); rs8048466(A,G); rs16947208(G,A); rs17650788(C,T); rs188329329(A,G); rs11150048(G,C); rs16947213(C,G); rs9927200(A,C); rs7206823(T,A); rs66677309(G,T); rs35503340(G,A); rs11859448(C,A); rs1010080(G,T); rs11859624(C,G); rs17572451(A,G); rs16947220(A,G); rs16947223(G,A); rs12931073(C,G); rs73566386(C,T); rs145758697(T,C); rs8050339(G,T); rs59907647(T,A); rs2345440(A,T); rs12600238(G,A); rs2345441(A,G); rs189509163(C,T); rs180770239(G,A); rs10521025(G,A); rs113591018(G,T); rs71396158(G,C); rs17651294(T,C); rs1076515(C,G); rs885734(C,T); rs76159824(C,A); rs16947239(A,G); rs116096223(A,G); rs11862871(C,G); rs2042353(A,G); rs56301732(G,T); rs2042352(G,C); rs77885266(G,A); rs8044362(G,T); rs12599158(C,T); rs78908275(C,G); rs7198280(T,C); rs7193455(A,T); rs8057046(A,G); rs142994735(G,A); rs117252482(T,G); rs138407978(G,A); rs149242183(C,A); rs4888758(G,C); rs17573298(T,C); rs4888759(T,G); rs76851869(A,G); rs55929707(A,G); rs76822416(G,A); rs6564511(G,A); rs8062547(G,A); rs75974775(C,G); rs6564512(C,A); rs6564513(C,T); rs58924661(G,A); rs117540413(G,A); rs147250635(C,T); rs59485483(T,A); rs61291069(C,A); rs35990854(G,A); rs35777566(A,G); rs10492873(G,C); rs4888760(T,C); rs75226165(C,T); rs9932883(T,C); rs4888761(G,A); rs6564514(C,T); rs16947257(G,A); rs77961350(T,A); rs74745508(C,A); rs73568313(C,G); rs35072073(T,G); rs34846007(A,G); rs1862695(A,G); rs889422(G,A); rs77139225(C,T); rs735164(A,G); rs1862694(A,C); rs1862693(G,C); rs150672775(G,T); rs79755783(C,T); rs143172037(C,T); rs741595(T,A); rs9936991(A,G); rs6564515(G,A); rs79931732(C,T); rs6564516(C,A); rs2345443(A,G); rs35258046(A,G); rs60196064(C,T); rs150406782(T,C); rs80289915(C,G); rs146349520(A,T); rs181406661(T,G); rs2042351(G,A); rs7205631(C,G); rs11150049(G,A); rs7204985(G,A); rs28562472(G,A); rs8048598(T,A); rs7190699(T,A); rs12446984(A,C); rs71396163(T,C); rs188885737(G,A); rs116013134(A,G); rs72806816(C,A); rs71396164(A,G); rs76497356(C,G); rs12929952(C,T); rs80303448(C,T); rs76316351(A,G); rs75166809(G,A); rs182086003(G,A); rs11862120(C,G); rs55751884(T,C); rs9921397(A,T); rs889419(G,C); rs35314035(G,A); rs141317734(T,C); rs741593(T,G); rs76430317(G,A); rs190318638(C,T); rs77061049(T,A); rs2003605(A,G); rs7192037(G,A); rs112046036(G,A); rs7184764(A,G); rs7190387(T,G); rs12148995(C,T); rs12924899(T,C); rs9935597(A,G); rs74597435(G,A); rs11865911(A,C); rs11861568(G,A); rs77356531(C,T); rs16947271(G,C); rs73570404(A,T); rs139026136(T,C); rs72806821(T,C); rs74704311(C,T); rs80270624(C,G); rs76034523(A,G); rs9938637(G,A); rs17652195(G,C); rs372705020(G,A); rs16947272(C,G); rs12443554(G,A); rs28713295(T,A); rs12447896(T,A); rs35620346(T,A); rs72806823(T,G); rs4888763(A,T); rs7500549(C,T); rs7203227(A,T); rs142251374(C,T); rs72806824(C,G); rs182163002(C,G); rs72806825(G,A); rs80046441(G,A); rs8050912(A,T); rs8055997(T,C); rs80235848(G,T); rs2194292(A,G); rs72806827(G,A); rs11867021(G,A); rs9941303(G,A); rs72806828(C,T); rs80138634(G,A); rs9939323(A,T); rs72806832(G,A); rs11639934(A,G); rs140220872(G,A); rs8063888(C,T); rs8048477(T,G); rs977686(C,G); rs190541911(C,T); rs9922503(A,C); rs141539873(A,T); rs13336080(G,T); rs76381892(T,G); rs112763377(G,T); rs9934402(G,C); rs9934479(G,A); rs12051355(C,G); rs13331978(A,G); rs17652533(A,G); rs76929650(C,G); rs34454460(T,C); rs17574299(A,G); rs74027941(C,T); rs12449031(G,A); rs9933348(A,G); rs7186466(C,T); rs74472435(C,T); rs4888764(G,T); rs2067714(G,A); rs3764293(C,T); rs74027943(G,A); rs3751775(A,C); rs56135228(C,T); rs62034012(A,G); rs13333436(G,A); rs56733316(G,T); rs8061900(G,A); rs11646240(C,T); rs55646612(C,T); rs7188086(G,A); rs9927189(T,C); rs60668349(C,A); rs148677594(G,A); rs2059238(A,C); rs4888765(C,T); rs4887945(G,C); rs7189438(G,A); rs7190964(C,G); rs9938036(T,C); rs4887946(C,T); rs4887947(G,A); rs4887948(C,G); rs74027948(T,C); rs74027949(A,G); rs78817933(G,A); rs12935149(C,T); rs12596319(T,C); rs186801058(C,T); rs62034015(G,A); rs35459318(G,A); rs12921948(C,T); rs35578026(A,G); rs7188214(A,G); rs7187715(C,T); rs28413069(C,T); rs7192985(G,A); rs6564517(A,G); rs34707065(G,T); rs71396166(G,T); rs12918471(T,C); rs71396167(A,G); rs74027950(T,G); rs10221047(A,G); rs12931696(G,A); rs12933454(A,C); rs34626702(A,G); rs12918190(G,A); rs59385940(A,T); rs12923828(T,A); rs35530243(A,G); rs36060834(A,G); rs9319520(T,G); rs9935037(T,A); rs9922034(G,A); rs2161635(G,C); rs28658131(T,C); rs2042355(T,C); rs56291110(G,A); rs9935796(A,G); rs9925365(C,T); rs9927005(G,T); rs147978271(C,T); rs9927111(G,A); rs11648208(A,C); rs9940886(T,C); rs55917160(A,T); rs9928203(C,A); rs9941029(T,A); rs9938856(A,G); rs9927818(T,C); rs9935543(C,T); rs9935005(G,C); rs73570469(A,G); rs9935831(C,G); rs1035530(G,A); rs28379571(G,C); rs2113164(A,G); rs28447117(C,T); rs4888766(G,T); rs16947307(C,T); rs7204887(A,C); rs9931632(A,T); rs35958061(G,A); rs141634713(C,T); rs77213325(C,A); rs11639653(C,G); rs28651749(G,A); rs8063113(C,T); rs11639501(G,A); rs11640613(G,A); rs4888767(T,C); rs3751773(C,T); rs11150050(C,G); rs62034046(C,T); rs150999989(C,T); rs12928313(C,T); rs11150051(A,G); rs11642674(C,T); rs67871127(C,T); rs56184195(C,G); rs79437435(C,T); rs11649150(T,C); rs56015326(G,A); rs13335340(C,T); rs11641579(T,C); rs76010112(C,A); rs11863747(G,A); rs117399047(G,A); rs4888768(C,T); rs72790027(A,G); rs116367801(T,G); rs146745950(C,T); rs7187665(T,C); rs76200495(G,A); rs114158627(G,C); rs111894205(G,A); rs77945293(A,C); rs8048681(T,C); rs75739379(T,C); rs4888769(T,C); rs8047321(G,A); rs147788217(C,G); rs8050111(A,G); rs7195355(G,A); rs7197393(A,C); rs116029960(C,G); rs184520454(G,A); rs7197099(C,T); rs7202722(A,C); rs148694170(G,A); rs62034048(A,G); rs34351028(G,A); rs1079192(G,A); rs1079191(A,G); rs114498494(G,A); rs147440715(A,T); rs4334310(C,T); rs142379252(A,G); rs35391857(G,T); rs4377167(C,T); rs4888770(A,G); rs57395847(T,C); rs74027959(G,A); rs9934792(C,T); rs77484073(C,T); rs112348004(C,T); rs7200781(G,A); rs11644333(C,G); rs7203837(C,T); rs74027961(C,T); rs7186914(A,T); rs2278075(A,T); rs7193919(A,G); rs188452680(G,A); rs9938892(C,A); rs59103324(C,T); rs34845496(T,G); rs7198650(G,A); rs12932788(C,A); rs8047483(T,G); rs7206379(C,G); rs11150052(G,A); rs56351211(G,C); rs7189041(G,C); rs7196681(A,C); rs8054537(C,G); rs7195428(G,C); rs7202580(T,C); rs7195585(G,T); rs4544256(C,T); rs181979317(C,T); rs72790045(C,A); rs114138394(A,G); rs142953050(C,T); rs12598688(C,T); rs12935647(A,G); rs12103355(G,C); rs12934082(G,A); rs145457502(G,A); rs72790046(T,C); rs73572410(C,T); rs9933749(T,G); rs12922400(C,T); rs7189213(A,G); rs12598901(A,G); rs7194052(A,G); rs113194467(A,C); rs12923794(T,C); rs116586951(G,A); rs4508428(T,C); rs7191180(A,G); rs12444769(A,G); rs12929792(T,G); rs116506508(G,A); rs76935401(G,A); rs12929555(C,G); rs147804933(C,T); rs186971008(C,T); rs191457907(G,A); rs12928847(G,T); rs114470237(C,T); rs56364915(T,C); rs4888772(T,C); rs115114833(C,G); rs11865828(G,A); rs78507369(A,G); rs116530282(T,C); rs115861359(G,T); rs4519340(G,A); rs4527029(G,A); rs76380999(T,A); rs72790052(G,A); rs150350355(C,T); rs72790054(T,C); rs7202803(G,C); rs12934697(G,A); rs6564520(A,G); rs116029089(G,A); rs4531741(G,A); rs4477719(A,G); rs28583037(A,G); rs4641752(A,G); rs9926888(T,C); rs57552529(G,C); rs1124584(T,C); rs28578031(A,G); rs73572428(G,A); rs79421672(C,T); rs28588861(C,G); rs4594264(A,T); rs4644871(A,G); rs76052796(C,T); rs4536491(T,C); rs4270188(C,A); rs75312318(A,G); rs4380066(C,A); rs75900344(G,C); rs4462603(G,T); rs4243147(G,A); rs4243148(T,C); rs4243149(A,G); rs4243150(G,A); rs4243151(G,A); rs8050128(C,A); rs77067228(A,G); rs76484313(G,A); rs12449245(T,G); rs4334311(G,A); rs77462018(C,T); rs12443641(A,T); rs12444281(T,G); rs12446496(C,T); rs13334637(G,T); rs13330120(A,C); rs12443752(A,G); rs13334974(C,T); rs12935780(G,A); rs12446398(G,A); rs9926171(T,C); rs12598622(G,A); rs12598759(C,T); rs9924232(A,G); rs57012796(C,T); rs9926526(T,C); rs10438625(A,T); rs9319521(A,G); rs9924425(A,G); rs10438626(G,A); rs10438627(T,A); rs12596645(A,G); rs11150053(A,G); rs9936242(G,A); rs12926941(G,A); rs12928587(A,G); rs12928596(A,C); rs12926966(G,A); rs9937017(C,G); rs12928347(C,T); rs4887949(A,T); rs12927416(G,C); rs4888773(C,T); rs55857801(G,A); rs8044017(T,C); rs56179313(C,G); rs12933289(T,C); rs12933480(T,A); rs9927590(C,T); rs8055658(A,T); rs4888774(C,T); rs4887950(A,G); rs12446017(G,A); rs80075585(A,G); rs28722104(G,A); rs72790071(C,G); rs61357459(T,C); rs56075728(A,T); rs28572350(A,G); rs28635592(A,T); rs28566703(G,A); rs28576943(G,A); rs4427816(T,C); rs4581713(G,C); rs62035677(A,G); rs149723070(G,A); rs13331073(A,G); rs13336959(C,G); rs67003685(T,A); rs9938194(G,A); rs9928997(A,C); rs11643583(A,G); rs28545316(C,T); rs13333906(A,T); rs188165814(C,G); rs9941255(G,A); rs9932306(A,G); rs9934482(T,A); rs9921980(C,T); rs75261600(G,A); rs9937030(T,C); rs4888775(G,A); rs4888776(G,A); rs114003092(C,A); rs1005923(A,G); rs74736624(C,G); rs1005924(T,C); rs4267317(G,A); rs11150054(C,G); rs11150055(T,A); rs186382220(A,T); rs145105274(C,T); rs11641628(T,C); rs13335579(C,T); rs4528585(A,C); rs9933406(T,C); rs12922006(T,G); rs9933589(T,G); rs111950467(C,A); rs7203354(G,A); rs113794714(C,T); rs72790089(C,T); rs73574526(A,G); rs72790091(T,C); rs57386345(G,A); rs4569296(A,G); rs73574528(A,G); rs74029870(C,G); rs7199997(C,T); rs7200759(C,G); rs12596093(T,G); rs9922494(A,C); rs6564522(A,T); rs7184669(C,G); rs8049354(T,G); rs62035711(C,G); rs62035712(C,T); rs8053710(T,C); rs7188370(G,C); rs72790101(C,T); rs13333016(T,C); rs28703128(C,T); rs56789501(G,A); rs12597477(A,G); rs12597480(A,G); rs28394853(C,G); rs191448094(A,C); rs113656879(G,C); rs76006696(C,G); rs4888777(G,C); rs28483287(C,G); rs142809218(G,A); rs7203015(G,C); rs144764452(T,G); rs736918(T,G); rs79440112(A,G); rs13337611(A,G); rs13336101(C,T); rs75729871(G,C); rs2077576(T,C); rs1078591(C,T); rs752310(C,T); rs61408858(T,G); rs62035715(C,T); rs79464922(A,G); rs11647486(C,T); rs67080937(C,G); rs181964280(G,A); rs7200663(C,G); rs7199306(G,A); rs4296268(G,A); rs13339028(C,G); rs4313817(A,C); rs7201891(C,A); rs11645368(T,C); rs11640087(G,C); rs150700340(C,T); rs56092548(G,A); rs56168155(C,T); rs56377920(G,A); rs56102854(C,T); rs56313991(T,C); rs56281028(T,C); rs7190022(G,A); rs12596766(G,C); rs181337011(C,T); rs58313156(G,A); rs55664465(T,C); rs34747130(G,C); rs35130461(G,T); rs56061917(C,G); rs34407101(A,G); rs35595703(C,T); rs61400593(G,A); rs61586571(T,C); rs9927661(G,A); rs12930845(C,T); rs6564523(G,T); rs7204400(T,G); rs4447442(T,C); rs72792336(C,T); rs142549510(C,T); rs72792337(G,A); rs4074541(A,C); rs7188259(A,T); rs4073181(A,T); rs11646025(C,T); rs72792340(C,T); rs72792343(T,G); rs4076024(C,T); rs12922419(G,C); rs13332536(T,G); rs182578739(A,G); rs11861359(T,C); rs7192602(G,A); rs28504991(C,T); rs28483621(G,C); rs146279897(C,A); rs13337194(G,A); rs7193395(G,A); rs148635582(A,T); rs4887952(G,A); rs147924125(A,G); rs140909806(G,T); rs7199623(G,A); rs138749269(C,T); rs75466180(A,C); rs12600002(G,C); rs7195347(C,G); rs4887953(G,C); rs4888778(A,G); rs142477168(A,G); rs72792346(C,G); rs144165133(C,G); rs145176853(C,T); rs145874753(T,G); rs144204276(T,G); rs9936264(C,A); rs9635572(A,G); rs11866209(C,T); rs139756752(G,C); rs77581409(T,C); rs9921686(C,T); rs13331203(G,A); rs56000130(G,A); rs9926434(G,C); rs62034372(C,G); rs12932345(G,A); rs9940424(A,C); rs62034373(C,G); rs9930037(C,G); rs78247754(G,A); rs9922483(T,G); rs61704146(C,T); rs182544732(C,T); rs111286740(T,A); rs60332746(C,T); rs11644268(C,A); rs62034375(C,G); rs4992886(C,T); rs12919434(G,C); rs12919559(G,C); rs72792352(T,G); rs78751438(C,T); rs73576428(A,C); rs57912849(G,C); rs28480016(T,C); rs79706995(A,G); rs61539374(C,T); rs57639192(A,G); rs181689983(G,A); rs72792353(G,A); rs11150059(G,T); rs10871348(G,A); rs12444775(G,A); rs72792356(C,G); rs148985574(A,G); rs62034379(G,T); rs10871349(A,G); rs80027738(T,C); rs72792363(C,A); rs62034380(G,C); rs13333779(C,A); rs111603315(G,A); rs62034381(T,C); rs59285947(A,G); rs11863537(C,T); rs60814858(C,G); rs11863566(C,T); rs7189650(T,G); rs62034383(C,A); rs8048594(C,T); rs8048762(C,T); rs11861590(T,C); rs74749728(C,T); rs59477284(A,G); rs4430758(A,G); rs8059699(T,C); rs12933949(T,A); rs72792379(G,C); rs142559979(A,G); rs4888779(T,C); rs56858262(T,A); rs3924959(C,T); rs79614776(T,G); rs9940624(C,T); rs11150060(T,C); rs185600931(T,G); rs9931046(A,G); rs12051298(T,C); rs11863231(A,C); rs7192402(T,A); rs7186903(C,T); rs7187467(C,A); rs9934335(A,C); rs6564525(G,C); rs11647326(A,C); rs8052110(C,T); rs7193880(C,G); rs76615910(G,C); rs113836425(T,C); rs62034403(A,C); rs71386270(A,G); rs72792386(C,G); rs67787349(G,C); rs13336262(C,G); rs12922516(G,A); rs13335972(G,A); rs9933929(G,C); rs11646272(C,T); rs13331558(A,G); rs13336051(G,C); rs113282899(T,C); rs115845795(C,G); rs9936952(C,T); rs9937072(C,A); rs13337264(G,C); rs11647277(G,C); rs188441043(C,T); rs13337639(C,T); rs7499671(C,T); rs13337392(G,A); rs13337700(C,T); rs13337702(C,T); rs13337436(G,A); rs111571722(A,G); rs111458870(T,C); rs113645671(G,T); rs72792389(T,G); rs9939808(C,G); rs13338934(C,G); rs9932259(T,C); rs7201132(C,G); rs1815215(G,A); rs9939517(G,T); rs9939598(G,A); rs4493047(G,A); rs370328726(T,C); rs35991877(C,T); rs34624886(A,T); rs8060138(C,T); rs4036024(A,G); rs4036025(G,T); rs12596183(C,G); rs9922004(G,C); rs9933025(A,G); rs72792392(C,T); rs9922782(C,T); rs9933225(A,G); rs9935452(T,A); rs74558424(T,C); rs4887954(A,G); rs4887955(G,C); rs9937768(T,A); rs4888781(A,G); rs4243152(A,T); rs13336875(A,G); rs13338036(T,C); rs9924784(G,A); rs12596835(C,T); rs72792401(A,G); rs9925676(C,A); rs9938375(T,A); rs8055812(T,A); rs4888782(T,A); rs4888783(G,T); rs57349345(C,A); rs4888784(A,G); rs186279004(C,T); rs28738927(T,G); rs9940910(T,G); rs28496260(G,A); rs79112083(C,G); rs28725364(C,A); rs72794006(G,A); rs28680974(T,G); rs111809530(A,G); rs72794010(A,T); rs72794011(C,G); rs76496209(A,C); rs11150061(C,G); rs112167445(A,C); rs113110872(A,G); rs72794013(A,G); rs112703823(A,G); rs113497265(A,G); rs78234316(C,T); rs72794014(C,G); rs72794016(G,A); rs72794017(T,C); rs72794018(T,C); rs13330980(T,G); rs13329904(A,G); rs13334465(G,C); rs8062830(A,C); rs13334509(G,C); rs377479749(C,T); rs4075210(T,G); rs4075211(C,A); rs371227120(C,T); rs4243153(A,G); rs4075212(C,T); rs76052396(C,T); rs4392084(C,G); rs35290624(A,G); rs35330244(A,G); rs34644513(A,G); rs72794024(G,C); rs72794025(C,G); rs72794026(A,G); rs9926696(T,C); rs77264347(T,C); rs75522647(C,T); rs7193966(C,G); rs12597164(A,G); rs12599225(G,T); rs12597203(A,C); rs12597204(A,G); rs9927290(A,G); rs12599450(C,T); rs9929592(T,C); rs12932415(C,T); rs9931769(T,G); rs9938955(G,T); rs9939767(C,T); rs13338872(C,G); rs72794033(A,C); rs13338906(C,A); rs13334118(A,G); rs13338972(C,T); rs13338641(G,T); rs62034410(C,T); rs13334206(A,G); rs13339050(C,A); rs13339052(C,G); rs13335341(T,C); rs4561477(C,T); rs61236352(T,C); rs72794037(A,G); rs9937805(A,G); rs76535848(G,C); rs72794038(G,A); rs9940114(T,C); rs9926915(G,A); rs9940286(T,A); rs62034411(G,A); rs72794042(T,A); rs9927068(G,A); rs74880189(A,G); rs12929851(C,G); rs75395305(A,G); rs111390771(C,T); rs112969743(T,A); rs12600187(A,T); rs12597788(G,A); rs12600227(A,T); rs4887958(A,G); rs4887959(T,G); rs57557867(T,C); rs57599899(G,A); rs11862932(C,G); rs11859786(T,G); rs9932246(G,A); rs9923073(A,G); rs4375669(T,C); rs4402580(T,A); rs4375670(G,C); rs4569297(C,T); rs11641764(T,A); rs8050647(T,G); rs4328453(C,G); rs4421994(G,A); rs9925970(T,C); rs28592611(G,T); rs11643038(T,C); rs67175168(A,G); rs11646767(G,C); rs11150062(G,A); rs11865137(C,T); rs35551315(C,T); rs34230267(A,G); rs9926641(A,G); rs73565381(A,T); rs4427817(G,A); rs9930964(T,C); rs62033388(G,A); rs9931244(T,C); rs35976157(G,A); rs72794051(G,A); rs8058059(A,G); rs8062569(T,G); rs8062583(T,A); rs8058247(A,C); rs28475389(G,A); rs12932053(C,T); rs8062759(T,A); rs8057779(C,G); rs8057821(C,T); rs8057971(C,G); rs79473166(G,C); rs35798037(G,C); rs34836001(C,T); rs12935254(G,A); rs34424307(T,G); rs12935416(G,A); rs9646316(A,T); rs71396173(T,C); rs9646317(C,T); rs9646318(C,G); rs11649644(G,A); rs9921673(C,T); rs9921677(C,G); rs34221797(C,T); rs9921309(G,A); rs9924096(C,T); rs9924108(C,T); rs57761121(A,G); rs35592895(C,T); rs9934671(A,G); rs9934747(A,T); rs35187273(T,G); rs61485839(A,G); rs114451287(T,G); rs6564527(A,G); rs6564528(C,T); rs71396174(G,T); rs9646319(G,C); rs6564529(A,G); rs6564530(G,T); rs4306520(C,T); rs6564531(T,C); rs111868860(C,T); rs11647872(A,G); rs11642433(G,C); rs11642474(G,A); rs11649146(T,C); rs67646326(C,G); rs4624193(C,T); rs7500418(G,T); rs9929267(G,C); rs9929326(G,A); rs9940527(A,C); rs12446110(C,T); rs62033391(C,T); rs12449092(A,T); rs4630560(C,T); rs4448955(A,G); rs9922850(T,C); rs9941074(A,T); rs9929970(G,C); rs9930559(C,T); rs56032802(A,G); rs74027845(A,G); rs138119622(C,T); rs4530154(C,A); rs4527030(C,G); rs4305032(T,A); rs55822922(T,G); rs4419071(G,T); rs74027846(G,A); rs4563049(C,T); rs4587988(A,G); rs12445154(C,T); rs113781931(G,A); rs11861356(C,T); rs35465376(G,A); rs35870646(G,C); rs147730462(G,A); rs35192490(G,A); rs11866512(T,C); rs71386272(C,T); rs11861230(G,A); rs11861508(C,T); rs36054930(G,C); rs7200961(A,G); rs12931609(G,A); rs7205915(T,C); rs35270593(C,T); rs7199350(G,C); rs7200862(C,A); rs7200865(C,T); rs7206533(T,G); rs114432613(A,G); rs115076043(T,A); rs9745996(G,A); rs114752722(C,G); rs8064138(C,T); rs62033395(G,T); rs8063314(G,A); rs145065819(G,A); rs8048929(T,G); rs11150063(G,C); rs8044888(C,T); rs8048156(G,C); rs8054349(T,C); rs62033396(C,T); rs4522432(A,G); rs12930050(T,A); rs12930065(T,C); rs75342618(G,C); rs12926391(A,G); rs55765039(C,T); rs12925935(C,T); rs12925942(C,T); rs114167928(C,T); rs11647674(G,T); rs8060293(T,A); rs71386273(G,A); rs11648130(C,T); rs8060676(T,C); rs13334450(T,C); rs13338259(C,T); rs12716854(G,T); rs75404949(C,T); rs11643294(A,G); rs11644423(T,C); rs11648339(C,T); rs13333575(A,C); rs62033451(T,C); rs4888785(T,C); rs182859636(G,C); rs8061955(C,G); rs55674426(A,T); rs4888786(A,G); rs76166041(C,T); rs56120232(G,C); rs11150064(G,A); rs11150065(G,A); rs11150066(T,C); rs116127705(C,T); rs11150067(G,A); rs12444202(G,A); rs79114218(C,T); rs56303514(T,A); rs56293135(T,C); rs62033455(A,G); rs62033456(T,C); rs8052210(C,T); rs8057282(T,C); rs62033457(C,T); rs8052976(A,C); rs11642404(C,G); rs9926218(G,T); rs79313051(G,C); rs9926984(C,T); rs9928454(G,A); rs8058104(C,T); rs4598920(G,A); rs8058491(C,T); rs4432273(A,G); rs75182427(C,T); rs4243154(C,T); rs115145458(C,T); rs4887960(T,C); rs116926409(T,C); rs4243155(C,T); rs4076154(A,T); rs114444629(C,G); rs8062581(G,A); rs4362401(G,C); rs62035761(T,C); rs4319781(T,C); rs4076620(A,T); rs4075558(G,C); rs9932337(C,G); rs4077864(C,G); rs4074874(G,A); rs4074873(C,T); rs9930135(A,G); rs9939675(G,T); rs74775056(G,C); rs57426415(T,C); rs4888787(T,G); rs11866898(C,T); rs4888788(C,T); rs7201630(G,A); rs11863022(A,T); rs11859449(G,T); rs4888789(C,A); rs11863982(A,G); rs4888790(T,G); rs4888791(T,G); rs62035778(C,G); rs4131558(A,C); rs4888793(A,C); rs368154249(C,G); rs4888794(G,C); rs4888795(T,G); rs11150068(A,G); rs12926724(C,A); rs28520492(C,T); rs11649509(T,C); rs114647095(C,T); rs62035780(A,C); rs12917864(T,G); rs7199969(A,G); rs12935392(G,A); rs9923918(T,C); rs12918436(C,T); rs4258629(T,C); rs12446391(G,A); rs80068501(A,G); rs74879504(A,T); rs76658097(A,G); rs9933609(G,A); rs77695497(T,G); rs62035781(T,C); rs12922482(G,A); rs9934682(C,G); rs9934762(C,A); rs12597681(T,C); rs12932569(T,C); rs9936564(G,C); rs4412982(A,T); rs12446072(T,C); rs150207755(G,A); rs11649021(G,C); rs11639904(G,A); rs113527777(T,G); rs111316838(C,A); rs11150069(A,C); rs78865443(A,G); rs13337989(T,C); rs13338044(T,C); rs113597076(T,C); rs11150070(A,T); rs11645719(C,T); rs11645844(C,T); rs375926012(A,C); rs62035783(C,T); rs4888796(G,C); rs4888797(A,G); rs62035784(C,G); rs78555058(T,G); rs75436498(C,T); rs4888798(C,T); rs62035785(G,C); rs111785256(G,A); rs112512261(C,G); rs4887961(T,C); rs62035786(A,G); rs76251114(T,C); rs9934452(T,C); rs7189441(T,C); rs7205327(G,A); rs7189636(A,G); rs35396328(C,A); rs4887962(C,T); rs4888800(C,T); rs11860534(C,A); rs369202058(C,G); rs115945600(G,A); rs116235068(G,C); rs4243156(G,A); rs4243157(A,T); rs376051500(C,T); rs8058540(G,C); rs13339305(A,G); rs28618372(G,C); rs28642324(A,G); rs4888801(T,C); rs12446075(G,A); rs11150071(C,T); rs74784426(G,C); rs7186569(A,G); rs7184686(G,A); rs62035788(C,A); rs7198580(T,C); rs9930967(T,C); rs9928827(A,C); rs12448513(C,G); rs76492856(T,A); rs75464051(C,A); rs8055871(G,A); rs8062393(T,G); rs60137776(C,G); rs80069196(T,C); rs9939390(T,C); rs12448113(A,C); rs62034087(G,A); rs113475043(C,G); rs75357183(A,G); rs11643643(C,G); rs11150072(G,A); rs9928955(G,C); rs11643855(C,T); rs9922221(T,C); rs9932296(C,G); rs11545029(G,A); rs61054844(G,A); rs75657283(G,A); rs9925545(A,G); rs9927858(T,C); rs144885767(C,G); rs9937914(C,G); rs7203071(T,C); rs7197571(C,T); rs75686631(C,T); rs75362687(G,C); rs12930880(C,G); rs9933134(T,C); rs77318436(G,A); rs12598627(T,A); rs9940656(G,A); rs13380625(A,C); rs146815449(C,T); rs12922097(C,T); rs76919408(A,G); rs4502225(T,C); rs9923470(G,T); rs79973570(A,G); rs77136886(G,A); rs7192435(G,A); rs7199370(T,G); rs75311365(T,G); rs79578393(A,T); rs9926074(G,A); rs7193029(G,C); rs7200331(T,C); rs4357949(C,G); rs112033704(C,A); rs375552778(C,T); rs4542678(C,G); rs77044644(G,C); rs6564537(T,C); rs62034089(C,A); rs75486699(A,G); rs11150073(A,G); rs11150074(G,A); rs7190067(T,C); rs7184665(C,G); rs74028163(C,T); rs8060137(A,G); rs76071719(C,T); rs75219666(A,G); rs11862908(A,T); rs144248454(C,T); rs76463797(C,T); rs3897139(A,G); rs7185632(C,T); rs11640261(G,A); rs7191058(C,A); rs75315209(G,T); rs4083383(C,T); rs6564538(C,T); rs4609864(G,A); rs3893417(A,G); rs7192844(C,T); rs116083899(C,T); rs7198400(T,G); rs7197711(C,T); rs377665488(C,T); rs7199086(C,G); rs114751200(C,T); rs28591434(C,G); rs11150075(C,T); rs112128351(A,G); rs7187988(T,C); rs13334962(C,G); rs13335035(C,A); rs76903619(G,C); rs73571014(C,G); rs13332398(T,C); rs13331309(A,C); rs73571016(C,A); rs73571018(A,C); rs73571019(C,G); rs57774868(G,T); rs72628241(G,A); rs59216310(G,C); rs58231906(T,G); rs58807329(T,G); rs58746031(T,A); rs59081463(A,G); rs57879216(G,A); rs57459665(C,A); rs28703737(G,T); rs60570512(C,T); rs9674169(C,T); rs114551908(A,C); rs9673699(T,A); rs9319522(C,G); rs73571032(T,G); rs75376533(G,C); rs7201777(C,A); rs73571034(T,G); rs7200912(G,C); rs74028184(C,G); rs7184628(C,T); rs75476629(A,T); rs12102946(A,G); rs12102951(A,G); rs192619993(G,A); rs9937796(T,C); rs9924469(G,A); rs12102499(C,G); rs115523393(G,A); rs113712609(A,G); rs142338970(G,C); rs28432312(C,G); rs28647201(T,G); rs28578322(C,A); rs75099711(G,C); rs8045885(C,T); rs73571042(A,G); rs9923888(A,G); rs3926280(C,G); rs9933797(C,T); rs3926281(C,G); rs8051395(C,T); rs13337144(C,G); rs9936338(C,G); rs77517449(G,T); rs28446324(T,G); rs138007615(C,G); rs76549013(C,T); rs13335170(A,G); rs74028187(C,T); rs8048059(C,G); rs11150076(A,G); rs11860127(G,A); rs11860425(C,T); rs115032334(G,C); rs11860457(C,T); rs72796100(A,G); rs28590161(C,T); rs78588726(T,A); rs190633852(A,G); rs74028188(C,A); rs77801657(A,G); rs8052799(G,A); rs78746370(A,G); rs116465599(C,T); rs28814418(G,C); rs59649684(C,T); rs58479152(C,T); rs61385990(G,C); rs8044154(G,C); rs34642532(C,T); rs79508321(C,T); rs4516239(A,G); rs28707667(G,C); rs73571070(G,T); rs76106079(C,T); rs111307096(G,C); rs76770603(G,A); rs80271093(C,T); rs3206585(C,A); rs75232857(T,C); rs74514506(G,A); rs73571071(G,A); rs73571072(A,C); rs192996704(A,T); rs113525876(A,G); rs9926269(C,G); rs9936826(A,G); rs79673675(T,C); rs7199755(C,G); rs56022724(C,G); rs77139686(A,G); rs116173845(T,G); rs13333868(C,G); rs76795622(C,G); rs10438628(T,C); rs11862579(C,G); rs8058017(G,A); rs28620932(A,G); rs146835201(G,A); rs76138931(A,G); rs58063855(G,C); rs76476458(C,T); rs9931934(G,A); rs72628250(C,T); rs9925091(T,C); rs7188869(G,A); rs73571079(G,T); rs112413810(C,T); rs12051129(T,C); rs12051126(A,T); rs28428622(C,G); rs28694190(G,C); rs117454585(C,T); rs147689779(A,C); rs8060852(T,C); rs8054751(G,A); rs73571085(T,C); rs61668003(C,G); rs28842797(A,G); rs9940773(C,G); rs28798477(C,G); rs8062045(A,C); rs57774709(C,T); rs73571089(G,A); rs6564541(G,A); rs55983288(C,G); rs56027007(A,C); rs56275232(G,A); rs149801691(A,G); rs28634873(A,G); rs6564542(A,G); rs28450552(C,T); rs58135246(T,C); rs8046289(C,T); rs7185819(G,A); rs57226645(T,G); rs9936308(T,C); rs9934210(A,G); rs6564543(A,G); rs6564544(C,T); rs75837605(C,T); rs6564545(T,C); rs6564546(A,C); rs6564547(T,C); rs6564548(A,G); rs6564549(T,C); rs6564550(C,T); rs6564551(A,G); rs77593328(T,C); rs9936956(A,C); rs7193791(C,T); rs77776606(A,G); rs74028191(A,G); rs9937084(A,G); rs73572806(C,T); rs73572807(T,C); rs73572808(G,T); rs73572811(G,C); rs114974235(G,T); rs76389311(T,G); rs73572812(G,C); rs73572813(T,G); rs73572814(C,A); rs73572815(G,A); rs9928734(G,A); rs7201782(A,T); rs7206690(T,A); rs6564552(C,T); rs8064012(A,G); rs9931457(G,A); rs9922365(A,C); rs9932167(C,T); rs4513111(C,T); rs4575544(C,G); rs58579880(C,T); rs4616293(A,G); rs56221217(T,C); rs55762614(T,C); rs8064007(T,C); rs4130513(G,A); rs142806268(A,G); rs4129722(G,C); rs78891306(T,A); rs4129721(A,C); rs9921967(G,A); rs145059474(A,G); rs9922829(C,T); rs182037444(G,T); rs56149108(T,C); rs4073159(G,C); rs4073160(C,T); rs4073161(G,A); rs4073162(T,C); rs8055718(T,C); rs8050734(C,A); rs3935135(C,T); rs4073036(C,T); rs4073035(G,C); rs4073034(C,G); rs8055647(C,T); rs8060920(T,C); rs76224825(C,A); rs111837279(C,T); rs8055263(G,A); rs4597339(A,G); rs9939279(A,G); rs9939288(A,G); rs6564554(A,C); rs7186603(T,C); rs7203908(C,T); rs7202482(G,C); rs6564555(A,G); rs6564556(G,A); rs6564557(C,T); rs6564558(A,G); rs6564559(G,T); rs74970416(A,T); rs7193617(T,G); rs9924307(A,G); rs8046675(G,A); rs7498813(C,G); rs8048744(A,G); rs8048772(A,G); rs118121021(T,G); rs8047039(G,A); rs112166923(C,T); rs7195100(C,G); rs74740608(A,G); rs7201039(T,C); rs28492890(G,T); rs3764340(C,G); rs3764342(A,C); rs180687752(C,G); rs11150079(T,C); rs78723052(C,T); rs28609420(T,G); rs28405739(G,C); rs60507543(G,A); rs62034096(A,G); rs6564560(G,A); rs114419634(G,A); rs8051477(T,C); rs11646795(G,C); rs77547945(A,G); rs1977023(G,T); rs1977024(T,C); rs8057640(A,G); rs138533673(G,C); rs150321990(A,G); rs75503490(A,G); rs76145350(C,G); rs28673949(G,A); rs7204919(C,T); rs13329848(C,T); rs13329990(C,T); rs13336228(T,C); rs189433628(C,A); rs7189855(A,G); rs80240771(C,T); rs72797992(T,C); rs72797994(A,G); rs7200731(T,C); rs7193816(G,A); rs6564561(A,G); rs72797996(C,T); rs72797998(C,T); rs78245757(A,G); rs4036026(A,G); rs9927016(G,T); rs4036027(A,G); rs8060177(T,G); rs4297688(C,G); rs9940393(A,G); rs9929319(G,C); rs28714256(C,G); rs4335784(C,A); rs114852115(G,C); rs117716307(C,G); rs147530821(C,T); rs115557638(C,T); rs11862866(C,T); rs11859740(T,G); rs11862893(C,G); rs115701883(T,A); rs11862902(C,A); rs11862667(G,T); rs11863807(C,T); rs144246459(C,T); rs11863844(C,T); rs7185902(C,G); rs148731759(G,A); rs28386852(G,A); rs13335528(G,C); rs13335564(G,A); rs13336842(C,T); rs74030255(C,G); rs13333164(T,A); rs9926474(A,T); rs74030256(A,G); rs7199023(A,G); rs74030257(C,G); rs74030258(T,G); rs7192132(G,A); rs148469267(C,T); rs151020795(C,T); rs7194084(C,A); rs79453811(C,A); rs7193100(G,A); rs4338816(G,A); rs4268758(G,A); rs4566181(G,C); rs5010833(T,C); rs74030262(G,A); rs75645260(G,C); rs74030264(C,G); rs74030265(A,G); rs4445912(T,A); rs4530150(G,A); rs4587989(G,A); rs4374181(C,A); rs72799915(T,C); rs147772693(T,A); rs7189823(G,T); rs74030266(T,C); rs74872698(C,T); rs4609862(T,C); rs4309410(G,A); rs12448381(C,G); rs74030270(T,A); rs74030271(T,A); rs7202594(G,C); rs7204203(C,A); rs74030272(A,C); rs62034097(A,C); rs74030274(G,A); rs58566873(G,A); rs55826134(T,C); rs56274800(C,T); rs11860831(G,A); rs55878257(C,T); rs56003306(T,C); rs56825787(C,T); rs11866221(T,C); rs74030276(T,G); rs11861181(C,G); rs74030277(T,C); rs74030278(G,A); rs74030279(T,A); rs11150080(T,A); rs12051475(T,G); rs12051479(T,C); rs59404910(C,T); rs59890449(G,C); rs56227916(G,A); rs56183433(T,C); rs56953982(G,C); rs57674068(T,C); rs56384948(T,C); rs59619041(C,T); rs371356827(G,A); rs12051258(C,T); rs12050938(A,G); rs12051228(G,A); rs12051240(G,T); rs12050949(A,C); rs12051039(T,G); rs12051377(A,T); rs12051059(C,G); rs12051453(T,C); rs74028003(A,G); rs74028004(A,C); rs74028005(G,A); rs72799924(C,G); rs74028006(G,T); rs11860794(G,C); rs11865280(A,C); rs74028008(C,T); rs11866184(T,C); rs11866188(T,C); rs11867048(T,C); rs146124057(C,T); rs7197248(G,C); rs74335576(G,T); rs8056598(G,A); rs8062189(C,T); rs79756176(G,C); rs79201199(A,G); rs17719479(C,G); rs16947560(G,A); rs113230133(C,T); rs59634655(G,T); rs113650772(G,T); rs56047770(C,T); rs73572894(C,A); rs2738641(T,C); rs9673695(T,C); rs2738642(G,C); rs2667606(C,A); rs2667607(T,G); rs2738643(A,G); rs7195517(C,G); rs2738644(A,T); rs2738645(G,A); rs145199050(C,T); rs2738646(C,G); rs2738647(G,A); rs4435264(C,G); rs114273202(C,G); rs2738648(G,A); rs2738649(A,T); rs2738650(A,G); rs2738652(T,A); rs59631093(C,T); rs60783744(C,G); rs7206779(G,A); rs1397931(T,C); rs11864020(A,G); rs2738653(C,T); rs2738654(T,C); rs2667629(G,A); rs2244985(A,G); rs16947590(T,G); rs58851480(C,G); rs7197926(C,T); rs7204008(T,C); rs2738656(T,C); rs9673617(C,G); rs2667657(C,T); rs9673583(G,A); rs9673643(C,G); rs2738657(G,A); rs80312799(T,C); rs2738658(T,C); rs2738659(C,A); rs2738660(A,C); rs2667512(G,T); rs2738661(G,T); rs62034123(G,A); rs2345997(A,G); rs2941934(G,A); rs1397930(G,A); rs1397929(A,G); rs2667517(G,A); rs62034124(A,C); rs2738663(C,T); rs2738664(A,G); rs112551601(C,T); rs2738665(T,G); rs74649493(G,A); rs2738666(A,T); rs7205805(G,T); rs7189913(T,C); rs7185271(A,G); rs73574939(T,C); rs117343964(C,G); rs2738667(T,C); rs112902803(T,C); rs113836426(C,A); rs72799936(G,A); rs79066708(T,C); rs76787879(A,C); rs56320405(G,A); rs78918040(G,A); rs16947609(T,G); rs111460769(A,T); rs2738673(A,G); rs17776445(A,G); rs16947610(T,A); rs7196402(C,T); rs2667543(T,C); rs57397584(G,A); rs77921144(A,G); rs74028468(A,C); rs74028470(G,A); rs16947611(T,G); rs2667545(T,C); rs2667546(C,G); rs2667547(G,A); rs2738674(C,T); rs2667548(G,A); rs2738675(G,A); rs2738676(G,C); rs9933282(C,T); rs3115955(A,G); rs7186413(C,G); rs2247099(G,A); rs4624194(C,T); rs2247102(G,A); rs74029631(C,G); rs2738677(C,G); rs17638504(C,G); rs57944343(A,G); rs2667549(C,G); rs62034126(G,A); rs62034127(G,A); rs2667551(G,C); rs2738679(T,C); rs16947616(A,G); rs17705783(A,G); rs2738680(A,G); rs2738681(A,G); rs16947617(A,G); rs17638536(A,G); rs2667552(C,T); rs76196609(T,A); rs16947620(C,T); rs16947623(G,C); rs16947624(G,T); rs73574998(A,G); rs16947626(C,T); rs58682445(C,A); rs16947629(C,G); rs16947630(T,G); rs9931931(A,G); rs9921568(C,A); rs59390574(T,C); rs2941933(A,T); rs16947631(C,G); rs72799950(G,T); rs73576805(T,G); rs62034130(G,C); rs77382368(T,G); rs115554688(T,A); rs7498931(T,A); rs2738682(C,G); rs138557325(A,G); rs73576808(G,C); rs78216103(G,A); rs180943019(C,T); rs16947633(A,G); rs7195680(T,G); rs74029639(C,G); rs9937755(T,C); rs62034131(C,A); rs62034132(T,C); rs9931884(G,C); rs16947641(T,C); rs13336293(G,T); rs74815359(T,G); rs2137090(T,C); rs2137091(G,T); rs2175472(G,A); rs13336411(G,A); rs139846680(C,G); rs1965588(G,C); rs62034157(C,T); rs1125305(T,C); rs16947649(A,T); rs62034158(G,A); rs2667554(A,G); rs2667555(G,T); rs16947653(C,T); rs9931636(A,C); rs8051225(T,C); rs59824084(C,A); rs9934078(A,C); rs9936255(T,G); rs2667556(C,G); rs16947657(G,C); rs80232728(G,T); rs79212444(A,C); rs2667557(C,T); rs4888804(C,G); rs2667558(A,G); rs62036360(T,C); rs2738685(C,G); rs2667560(G,A); rs190292087(C,T); rs2667561(G,A); rs57544481(C,G); rs16947662(T,G); rs2667562(A,G); rs2738686(G,C); rs2667563(A,G); rs62036362(G,A); rs62036363(T,C); rs2738688(C,A); rs2667565(A,G); rs2667566(G,A); rs60586213(A,T); rs2738689(G,C); rs11864507(G,C); rs16947677(A,T); rs2738690(G,T); rs12597367(T,C); rs2667567(C,G); rs2667568(T,G); rs2667569(A,G); rs2738691(C,A); rs2738692(T,A); rs2667570(T,G); rs2667571(A,T); rs2667572(G,T); rs2738693(T,C); rs2667573(A,G); rs74028844(C,A); rs16947696(G,C); rs28374221(C,T); rs2738694(G,A); rs2667574(C,A); rs2738695(T,C); rs2738696(G,A); rs16947701(G,A); rs114711152(A,T); rs74030525(G,C); rs55962522(G,A); rs59916764(C,T); rs56147505(G,A); rs72799963(C,T); rs2667576(A,G); rs2345998(C,T); rs1540757(C,T); rs2667577(G,A); rs145841069(T,G); rs2738697(A,G); rs2254558(A,G); rs2254564(T,C); rs2738699(G,C); rs2667579(C,T); rs2738700(A,G); rs2667580(A,G); rs148246390(A,C); rs2738701(G,A); rs150793963(C,T); rs2738702(T,C); rs2738703(G,C); rs2667581(G,A); rs2738704(G,A); rs59572057(G,C); rs72801921(C,T); rs2738705(G,A); rs2738706(T,C); rs114476113(G,A); rs10871351(G,A); rs2738707(G,A); rs2738708(C,T); rs12933259(C,A); rs4888805(A,T); rs2175473(A,T); rs2738709(C,T); rs2738710(G,A); rs16947728(G,A); rs2738711(C,T); rs2137096(C,T); rs12444091(C,T); rs2667582(G,C); rs2738712(C,G); rs2667583(C,T); rs2667584(G,T); rs2738713(C,T); rs12716855(A,G); rs7192666(A,G); rs2738714(G,A); rs7193201(A,G); rs2859634(C,G); rs2978626(G,A); rs2978627(C,G); rs73578907(G,C); rs8055841(C,T); rs72801928(T,A); rs8054906(G,A); rs62036391(A,G); rs2738716(T,C); rs3115956(A,C); rs2738717(C,G); rs2738718(T,A); rs2738719(C,A); rs7204790(T,C); rs7204795(T,A); rs7203932(C,G); rs4888807(A,G); rs4888808(C,A); rs4888809(C,T); rs4888810(A,G); rs62036393(C,A); rs4888811(T,C); rs4888812(T,C); rs4888813(A,C); rs9930797(G,A); rs2978628(G,C); rs2978629(C,G); rs2859636(G,C); rs2667585(T,C); rs2738720(T,C); rs2738721(C,T); rs2738722(C,T); rs2738723(T,G); rs5019443(C,T); rs5019442(C,T); rs5019441(G,A); rs7200796(A,G); rs117998459(C,T); rs12446611(T,C); rs9939714(C,G); rs9931978(A,G); rs34036911(C,T); rs7205999(C,T); rs7206227(C,G); rs7204870(G,A); rs7184116(A,C); rs7206439(C,T); rs2738724(C,T); rs2738725(C,A); rs2738726(A,G); rs2667586(A,C); rs2667587(G,C); rs2667588(T,A); rs8053698(T,A); rs2738727(A,G); rs2738728(C,A); rs2667589(A,C); rs2667590(G,C); rs2667592(T,C); rs2738730(T,G); rs57164796(T,G); rs4243158(G,A); rs3115957(T,C); rs3419(G,T); rs9938201(A,C); rs2738731(T,C); rs2667593(C,T); rs3115958(T,C); rs115270489(A,G); rs117856896(C,T); rs9930228(C,T); rs9922577(T,G); rs56032971(C,A); rs141027725(A,G); rs12935142(C,T); rs2245006(G,C); rs17639042(A,C); rs2738734(C,A); rs2738735(A,G); rs9923737(A,C); rs1877275(T,C); rs2738736(C,A); rs12931826(T,A); rs1877276(A,G); rs2245201(G,C); rs2245206(A,G); rs2245208(C,T); rs11648573(C,G); rs62036409(A,T); rs2738738(T,C); rs112349049(C,G); rs8062956(C,G); rs11150082(T,C); rs2245412(C,T); rs12446763(A,G); rs12443611(G,A); rs16919(G,A); rs61359464(A,T); rs2667597(T,A); rs12928065(T,G); rs2667598(G,A); rs186240236(A,G); rs1397927(A,G); rs1877277(C,G); rs11863365(G,A); rs75460556(A,T); rs1397926(T,G); rs1397925(G,A); rs1877278(A,G); rs1877279(A,G); rs8064066(G,C); rs1877280(T,C); rs7190170(C,T); rs7190317(C,A); rs1877281(A,G); rs145638874(G,A); rs1877282(C,G); rs1111681(T,A); rs141751604(G,C); rs1111682(T,C); rs142671951(G,A); rs74033004(C,T); rs62036410(C,T); rs62036411(C,G); rs8054925(C,T); rs2667601(T,C); rs62036412(A,G); rs62036413(C,T); rs2667602(A,G); rs1877283(A,G); rs60111001(G,A); rs1882957(T,A); rs1882958(T,G); rs59003277(C,T); rs17706509(C,A); rs62036417(C,T); rs147023064(A,G); rs62036418(C,A); rs62036419(T,C); rs62036420(G,A); rs2738739(C,G); rs7188990(A,G); rs6564564(C,T); rs58366789(G,A); rs34406170(C,T); rs2738740(G,T); rs4257220(A,G); rs148520386(G,A); rs11643490(G,A); rs11643787(C,T); rs193223549(G,A); rs1465099(A,G); rs148833060(T,A); rs1540763(G,A); rs1540762(G,A); rs1111683(C,T); rs35450198(A,C); rs11150083(G,C); rs142908128(G,A); rs1540761(A,C); rs16947866(T,C); rs2458031(T,G); rs9935520(C,G); rs1107102(T,A); rs2459109(G,C); rs1877284(G,C); rs7195479(G,A); rs140062849(G,A); rs1877285(C,G); rs184267247(A,G); rs2175474(A,G); rs2667608(G,A); rs2738741(G,A); rs17706655(C,G); rs2667609(G,T); rs2738742(T,A); rs9319524(T,C); rs11860993(C,A); rs11648637(A,G); rs62033973(C,G); rs74942559(C,T); rs17706673(A,G); rs57991969(G,A); rs140829683(G,T); rs150457466(C,T); rs144088492(A,G); rs72801969(C,A); rs17777341(C,T); rs2667611(T,G); rs189752517(T,A); rs183074439(T,G); rs183360858(T,G); rs11641340(A,G); rs16947895(C,T); rs16947902(C,G); rs2137097(A,G); rs34461109(G,T); rs8058087(T,C); rs191890287(A,G); rs2738743(G,C); rs4319778(A,G); rs72801975(A,G); rs17720666(C,A); rs79707396(T,C); rs16947913(C,A); rs60557070(G,A); rs16947915(T,C); rs371353355(A,G); rs62033975(A,G); rs10468362(G,C); rs80079561(G,C); rs72801987(A,G); rs144641965(C,T); rs148393367(G,A); rs2941954(A,G); rs9928512(C,T); rs9928787(C,G); rs74029523(C,T); rs9930467(G,A); rs9923611(T,G); rs16947931(T,G); rs28578673(T,C); rs2738744(A,G); rs56156753(G,A); rs9931036(G,A); rs62033976(A,G); rs2941953(A,G); rs2667613(C,A); rs9938829(G,A); rs148551431(A,G); rs2978630(G,C); rs11648922(C,T); rs2941952(G,A); rs2941951(G,A); rs16947953(G,A); rs369782643(A,G); rs78481124(C,T); rs2978631(G,T); rs2941948(C,G); rs2978632(T,C); rs9934584(T,A); rs3106330(G,A); rs3115959(T,C); rs3106331(A,G); rs2667614(A,G); rs72802000(A,T); rs16947985(A,G); rs72802001(C,A); rs9923830(G,C); rs2738745(G,A); rs9924476(C,T); rs2738746(G,T); rs12444523(C,T); rs12444416(G,A); rs77579966(A,C); rs55649235(C,T); rs72803904(G,A); rs58715429(C,T); rs2667617(G,A); rs2738747(G,C); rs144989247(T,C); rs2738748(G,C); rs74029528(A,G); rs2667618(T,C); rs4496157(A,G); rs3916129(C,G); rs11150084(C,G); rs56163755(C,T); rs9927678(C,T); rs3929506(C,T); rs9927908(C,T); rs72803908(A,T); rs141431962(T,C); rs76178331(A,G); rs72803909(C,T); rs2859639(C,A); rs28440108(A,G); rs72803911(C,T); rs2738487(C,T); rs118147448(C,T); rs28633096(C,T); rs144708156(G,A); rs12446961(C,G); rs182204817(G,C); rs140655287(C,G); rs11645676(C,T); rs2859640(A,T); rs72803915(C,T); rs28459582(C,T); rs28523447(T,C); rs8046278(C,G); rs2859641(C,T); rs2738488(G,A); rs28419317(A,G); rs28562150(G,A); rs8051498(A,G); rs10438609(G,A); rs2257074(A,G); rs72803918(T,C); rs12447688(G,A); rs142244193(A,G); rs74029535(T,C); rs2738489(T,G); rs2738490(A,T); rs77361516(C,T); rs149430543(A,G); rs374652013(T,G); rs80066418(C,G); rs2738491(G,A); rs72803919(G,C); rs2667622(G,A); rs2859642(T,C); rs72803920(G,A); rs11150085(G,A); rs6564567(T,C); rs4366715(G,T); rs2738494(T,C); rs2667623(C,G); rs76819794(C,G); rs141750962(A,G); rs2860236(G,C); rs12325413(A,G); rs12325414(A,G); rs2738497(T,C); rs2738498(T,C); rs2738499(A,G); rs2667627(C,T); rs2738500(C,T); rs78668939(C,T); rs2667628(A,C); rs2738501(T,C); rs2738502(G,C); rs2246452(T,C); rs2667630(G,C); rs141257845(A,C); rs2667631(A,C); rs77332763(G,T); rs2859644(G,A); rs1574279(C,T); rs78622546(C,A); rs76038525(C,T); rs1106217(C,T); rs1317575(G,C); rs9635580(C,T); rs9635573(C,G); rs1105314(A,G); rs80289862(C,T); rs1105313(A,G); rs2859645(C,G); rs17777700(G,A); rs11640955(C,A); rs2667632(A,G); rs17777718(T,A); rs2667634(C,G); rs11648629(T,G); rs2941947(A,C); rs2941946(C,T); rs11648633(T,C); rs76281671(A,G); rs16948039(C,T); rs11642350(C,A); rs1877286(T,C); rs72803932(C,G); rs183515877(G,A); rs9989362(T,C); rs12445965(C,G); rs12598440(C,T); rs144750191(G,C); rs74029539(C,T); rs74029542(A,G); rs144473404(C,T); rs150300781(C,G); rs115008176(G,A); rs56882555(T,C); rs56742829(C,T); rs140760643(A,G); rs2667646(C,T); rs17721176(C,A); rs17639886(C,A); rs2941940(A,G); rs56124910(T,A); rs11643254(A,T); rs12930620(C,A); rs2978621(C,T); rs72803940(G,T); rs11641817(C,T); rs11641880(C,G); rs183283207(G,T); rs55747120(T,A); rs2667647(T,C); rs2667648(T,C); rs2667649(C,T); rs2667650(G,A); rs111418698(A,G); rs72803944(T,C); rs185144897(T,C); rs76449596(A,G); rs2738510(G,A); rs7206168(G,T); rs79284131(G,T); rs74029544(A,C); rs16948068(A,G); rs74029547(C,T); rs16948069(C,T); rs1877273(T,C); rs77632621(A,G); rs61042468(G,C); rs146583571(A,G); rs2345445(G,A); rs74586785(G,C); rs2667505(C,G); rs2673789(C,T); rs62033997(G,A); rs78674499(A,T); rs74029553(A,G); rs2458028(C,T); rs2458029(G,A); rs8047751(G,A); rs8048265(G,A); rs74029555(G,A); rs8054987(T,C); rs59588435(A,C); rs13339219(T,C); rs16948083(A,G); rs28687257(G,A); rs147832224(G,C); rs147020917(G,C); rs75026856(C,G); rs2738514(C,G); rs34483455(C,A); rs2667507(G,T); rs34879622(C,G); rs35467706(C,A); rs189467140(A,C); rs7203676(C,T); rs17777958(C,G); rs9930942(C,A); rs79414472(A,T); rs9931122(C,T); rs9923592(A,G); rs147822403(C,T); rs75799494(C,G); rs28689502(G,C); rs9933688(C,G); rs74029558(C,A); rs2459108(G,C); rs6564568(G,A); rs2253016(A,G); rs2253019(C,T); rs3915620(T,C); rs1976638(A,G); rs1970869(G,A); rs188169462(T,C); rs1540758(C,T); rs74029567(C,T); rs9925067(C,G); rs16948088(C,T); rs139085514(C,T); rs2859627(C,T); rs80101857(C,G); rs12930179(C,A); rs16948096(T,C); rs2738521(A,G); rs35853810(T,C); rs2673779(C,T); rs12446234(C,T); rs62034001(C,T); rs57549783(G,A); rs7197266(C,G); rs7203310(T,C); rs12930745(C,T); rs9928690(A,G); rs10438629(C,G); rs2345444(G,C); rs11864127(T,A); rs76131976(T,C); rs147962689(A,C); rs74029568(C,T); rs76981451(C,T); rs137975551(C,A); rs36040827(G,T); rs141033348(G,C); rs9923777(G,T); rs9934805(A,T); rs111745280(C,T); rs7205879(T,C); rs56230826(C,G); rs12449050(A,G); rs79221862(C,A); rs142951417(C,G); rs11645103(C,T); rs11640217(A,G); rs11644885(G,C); rs146958384(G,T); rs77087284(G,C); rs3853362(T,G); rs3853363(T,G); rs77386989(A,G); rs139127290(G,T); rs115549789(T,C); rs116210402(A,T); rs57996870(C,T); rs142374999(T,G); rs2346007(A,G); rs2346008(T,G); rs4606728(A,G); rs114628387(T,G); rs71396197(G,A); rs58980559(A,G); rs2175471(T,C); rs144745301(T,G); rs150921112(C,T); rs149215559(T,C); rs71396198(C,G); rs11861719(A,G); rs147403165(A,G); rs77765652(G,A); rs148602356(C,T); rs35701963(G,T); rs2943768(A,C); rs2943767(T,C); rs187358229(C,G); rs11641830(C,A); rs2941935(C,G); rs148257217(C,T); rs9938843(A,G); rs7197903(C,T); rs9927747(G,C); rs142337419(T,C); rs191499926(G,A); rs9921093(T,G); rs9939269(A,G); rs9928840(C,T); rs16948114(G,A); rs9923563(T,C); rs150751789(G,A); rs75112454(C,G); rs145534704(G,A); rs2247294(C,G); rs12599381(C,G); rs4578663(C,A); rs141073049(C,T); rs8048608(C,T); rs149249900(C,G); rs144461635(C,T); rs143571822(G,A); rs13339093(T,C); rs7196526(C,G); rs114942854(C,T); rs11150090(A,G); rs78505173(T,C); rs145588545(C,G); rs114738106(T,G); rs2943766(T,C); rs16948137(A,G); rs75608741(C,T); rs62034036(T,C); rs11862167(T,C); rs75259821(T,C); rs145833607(T,A); rs2859630(C,G); rs11648397(G,C); rs7200682(A,C); rs373627692(C,T); rs16948156(T,C); rs11859483(C,A); rs72803980(T,G); rs11860155(G,C); rs2941931(G,T); rs7190741(A,G); rs72803981(T,G); rs1912803(C,A); rs192672639(T,G); rs1912804(C,G); rs2738540(T,A); rs144940176(G,T); rs2738541(A,G); rs7184757(T,C); rs2459106(A,T); rs7185001(T,C); rs7203119(A,G); rs7203604(C,T); rs11862028(A,G); rs17707772(T,C); rs3021398(T,G); rs2738544(C,T); rs2738545(G,A); rs1110136(A,G); rs1110137(A,T); rs17640520(T,C); rs77752107(C,T); rs7187195(G,C); rs2859631(G,A); rs78282905(T,G); rs9929662(C,G); rs377280036(C,T); rs116232486(T,A); rs76614455(G,A); rs9922893(A,C); rs9932697(C,G); rs116784045(C,T); rs59895849(A,G); rs60754016(A,G); rs115123455(G,A); rs1828518(C,T); rs1828517(T,A); rs73581098(T,A); rs2667542(G,A); rs57450504(T,A); rs2550629(C,A); rs201215614(T,G); rs11865708(G,A); rs76813396(A,C); rs112511149(T,G); rs147656099(G,T); rs78238031(T,A); rs3106329(C,G); rs2113286(A,G); rs73581102(T,C); rs73582804(T,C); rs3135432(G,T); rs2550601(G,C); rs2859498(C,T); rs2550605(C,A); rs149453341(G,T); rs116401113(G,C); rs2738549(G,T); rs55798515(C,T); rs8046002(G,A); rs192996381(A,G); rs191199623(A,G); rs117479948(C,G); rs2287951(C,G); rs78136943(A,G); rs1106507(G,T); rs1126185(G,A); rs74029589(A,T); rs2550649(C,G); rs76690356(C,G); rs2548879(C,A); rs74029590(C,G); rs8050198(C,T); rs74029591(C,G); rs2548877(T,C); rs74029592(C,T); rs72805009(A,G); rs2550667(G,A); rs62037151(A,G); rs62037152(T,C); rs13333606(C,G); rs2550668(C,T); rs2738552(C,G); rs74029593(A,G); rs74029594(T,G); rs2738553(G,A); rs2738554(C,G); rs147550235(G,A); rs74029595(A,G); rs2550580(C,T); rs2738555(A,G); rs9931204(G,A); rs2550581(C,A); rs2548883(G,A); rs116287842(C,T); rs114787786(C,T); rs141377758(T,C); rs111259713(C,T); rs2550582(C,G); rs189797245(A,C); rs115127699(T,A); rs116600813(C,T); rs75251828(G,C); rs142059186(G,A); rs80115237(T,C); rs2550583(A,G); rs139070402(A,G); rs11862592(T,C); rs185358543(G,A); rs11861706(A,G); rs116102730(C,T); rs72805012(A,G); rs192798212(C,T); rs72805014(C,T); rs1125677(G,T); rs79715477(T,C); rs1962835(C,G); rs79176860(C,G); rs3866637(A,C); rs182499922(C,T); rs142351280(C,G); rs72805015(A,G); rs79814385(C,T); rs2548838(A,C); rs79023866(G,A); rs2548837(C,A); rs115389366(T,A); rs75383483(C,G); rs2550586(C,G); rs2550587(G,C); rs189029180(G,C); rs184073692(G,A); rs74932754(T,C); rs77283896(G,A); rs74029596(T,C); rs2548848(C,G); rs77527248(C,G); rs13337079(C,T); rs11150091(G,A); rs2738560(T,C); rs34803204(C,G); rs72805018(A,C); rs149609112(T,G); rs2738561(G,C); rs140981003(G,C); rs2738562(C,G); rs114477706(G,C); rs2550599(C,G); rs2548876(C,T); rs2548875(G,T); rs2738563(G,A); rs12927981(T,G); rs2738565(G,C); rs147286524(T,C); rs113050154(C,A); rs2738566(A,C); rs2673775(A,G); rs72805024(A,G); rs2550602(T,A); rs117551757(G,A); rs2738568(T,C); rs61408223(T,C); rs113017743(A,G); rs79939445(T,A); rs2738569(G,A); rs2550604(C,T); rs2738570(G,T); rs2738571(G,A); rs12596233(T,G); rs2738572(A,C); rs2548861(T,G); rs72805028(T,G); rs74029597(G,A); rs72805029(A,G); rs2548862(A,T); rs2550606(C,G); rs72805034(T,A); rs2738573(T,C); rs2550607(A,G); rs2738574(T,C); rs2472193(G,A); rs62039373(A,C); rs12596464(C,T); rs11860178(C,T); rs2738576(A,C); rs7191880(G,A); rs2738577(G,A); rs2550608(C,G); rs116430887(G,A); rs184601389(A,C); rs4888819(T,A); rs7200698(C,T); rs2432240(A,T); rs2548866(G,A); rs4888820(C,T); rs72792787(T,C); rs2550609(C,G); rs140692830(G,C); rs12598987(C,G); rs4622523(G,C); rs149693742(A,C); rs2548867(A,C); rs77776794(C,G); rs186235280(A,G); rs10514439(T,A); rs2550613(T,G); rs57682625(C,T); rs35940748(C,G); rs74809555(A,G); rs1981881(C,A); rs4888821(C,G); rs143847386(C,T); rs2004942(T,C); rs1079323(C,T); rs1110519(G,A); rs145690412(C,T); rs12716856(C,T); rs76402652(A,T); rs2550615(G,C); rs57817377(C,T); rs2550616(A,T); rs112501737(T,C); rs74029600(A,G); rs182359843(G,A); rs148270279(A,C); rs77941476(C,T); rs7193983(G,C); rs7196183(A,G); rs1981882(A,G); rs7196215(A,G); rs2161720(G,C); rs148576138(G,A); rs2738582(G,C); rs3854985(T,G); rs2550619(C,G); rs2550620(A,C); rs6564571(G,C); rs2042430(C,G); rs2042431(T,C); rs76580427(A,C); rs144683343(G,C); rs116656789(G,T); rs2432241(C,T); rs76358809(G,A); rs2550621(C,T); rs117840246(G,A); rs9923771(T,A); rs185824491(G,T); rs76732315(C,T); rs1107454(C,A); rs75536810(A,G); rs17708094(A,G); rs1107455(A,G); rs67195249(T,A); rs113682924(C,G); rs80324634(C,G); rs2548874(G,A); rs2550626(C,T); rs2548873(T,G); rs190150850(T,C); rs2738586(G,A); rs7189040(G,T); rs7190546(C,T); rs148860587(A,G); rs2881375(T,C); rs2738587(A,C); rs60624620(C,G); rs57818167(C,G); rs7197623(A,G); rs9927291(G,A); rs74616795(G,A); rs73565242(C,G); rs114875261(C,A); rs2548841(C,T); rs2738588(G,A); rs2738589(A,G); rs150721630(C,A); rs2161620(G,A); rs116199179(G,C); rs10514440(C,T); rs1124434(C,T); rs114102983(G,A); rs80147627(C,G); rs1124433(C,T); rs2738591(C,T); rs8046010(C,T); rs2548843(C,A); rs9935953(G,A); rs9936057(G,C); rs9931114(T,G); rs73565252(T,C); rs1559432(T,G); rs1107984(A,G); rs142857200(C,G); rs77373201(A,G); rs10083821(G,T); rs8048335(T,C); rs1424162(C,T); rs8064010(C,T); rs9888816(C,T); rs4035816(T,G); rs4035818(A,G); rs2161721(G,C); rs6564572(T,C); rs2738600(C,T); rs6564573(A,G); rs2859499(C,T); rs7197349(A,G); rs11865943(A,C); rs57417567(A,G); rs79188461(G,C); rs2738603(C,G); rs145288436(A,G); rs80217800(C,G); rs2113120(T,C); rs4888822(A,G); rs57075060(C,G); rs57697380(C,G); rs1559433(G,C); rs79798128(G,T); rs12716857(G,A); rs12325505(A,G); rs143208300(C,G); rs181789895(T,G); rs115283117(G,A); rs1125675(C,G); rs1125676(G,A); rs8059227(A,C); rs8057865(G,C); rs1125668(A,G); rs1125670(T,C); rs1125671(G,A); rs115017357(T,G); rs141241537(G,A); rs2738606(A,C); rs116122833(G,A); rs2738607(A,G); rs59689196(A,C); rs12599543(G,C); rs41362151(T,C); rs2550634(G,A); rs12929711(G,C); rs72794733(C,G); rs12929743(G,C); rs2548846(G,A); rs1559292(A,T); rs1318823(T,C); rs142377943(G,A); rs1109876(C,T); rs80145063(A,T); rs11862140(G,A); rs11150093(C,G); rs16948270(C,G); rs371799337(T,C); rs4887971(C,G); rs148923976(C,G); rs1364295(C,T); rs9925041(G,A); rs1820254(A,G); rs16948273(G,T); rs2548836(A,G); rs28521654(C,T); rs1077963(T,C); rs28524499(A,G); rs16948286(G,A); rs28664623(C,T); rs1077964(A,T); rs115758191(A,G); rs4505339(A,T); rs4284654(G,C); rs2081174(A,G); rs4421995(C,G); rs34261419(C,T); rs115728466(C,G); rs17722185(T,C); rs28410404(C,T); rs7194800(C,T); rs141114722(C,T); rs8054120(C,T); rs138534601(C,G); rs16948291(T,A); rs9937226(G,C); rs16948295(G,A); rs9940252(C,T); rs2194340(T,C); rs115176097(C,T); rs77323446(T,C); rs60003613(C,A); rs8045757(C,T); rs8051011(T,G); rs2251009(T,C); rs182241245(G,A); rs17722251(T,C); rs6564575(T,C); rs8055993(G,C); rs11862360(A,C); rs8062753(T,C); rs13338652(C,G); rs1559291(A,G); rs1125852(G,A); rs2738621(T,C); rs28671261(G,T); rs2550655(G,A); rs28661840(C,A); rs116868438(A,G); rs28710445(T,C); rs9925023(C,G); rs147439318(G,A); rs2550656(G,A); rs8052846(G,C); rs11150094(T,G); rs9927215(G,T); rs7197165(C,G); rs9940697(A,G); rs16948302(T,A); rs17722281(A,C); rs2738622(T,G); rs9929802(G,A); rs2738623(G,C); rs2738624(G,A); rs2548882(A,C); rs28533957(C,G); rs2738625(G,A); rs9923705(A,T); rs9936058(C,T); rs2738626(C,G); rs7193282(A,G); rs7198497(T,G); rs2738627(G,A); rs7193360(C,A); rs2738628(G,A); rs2738629(G,A); rs12926298(G,A); rs9926764(A,C); rs16948307(A,C); rs13380686(A,G); rs13380485(G,A); rs2738630(G,C); rs16948310(A,G); rs3751881(T,C); rs74032724(A,G); rs62036105(G,A); rs3751882(A,G); rs3743682(C,T); rs60665673(G,T); rs56993450(A,G); rs62036109(C,T); rs2738631(G,A); rs2738632(C,G); rs2550659(C,G); rs2738633(C,T); rs2738634(C,G); rs141498376(A,T); rs7185340(A,G); rs7188949(G,C); rs7195845(T,C); rs7190499(C,G); rs28464559(C,T); rs28437814(T,C); rs28438729(C,T); rs12185163(T,G); rs12185154(A,G); rs9927906(T,C); rs9925866(A,G); rs8049301(G,C); rs8049306(G,A); rs9935897(C,T); rs9935899(C,G); rs146527242(A,G); rs79624446(G,T); rs11647935(G,A); rs72796643(C,A); rs72796644(C,G); rs4888823(C,G); rs4888824(T,C); rs12935036(C,T); rs4887973(G,T); rs6564576(A,G); rs6564577(G,A); rs149010829(G,A); rs74032742(A,G); rs35184599(T,C); rs9923515(C,A); rs9936330(T,A); rs7188341(A,G); rs148400386(G,T); rs113031189(A,G); rs113749585(A,G); rs7359361(C,T); rs1424163(C,T); rs7195153(A,G); rs145529731(G,A); rs6564578(C,A); rs7359487(T,A); rs2550666(A,G); rs183073450(G,A); rs13333672(G,C); rs2548832(A,G); rs4888826(T,G); rs75178768(G,C); rs36098204(C,T); rs112549550(C,A); rs78271279(C,T); rs13339404(C,T); rs7203842(A,G); rs7203120(C,G); rs116764346(C,T); rs150545822(G,C); rs7186568(C,T); rs7192304(T,C); rs7190036(G,A); rs4887974(C,A); rs9926201(C,A); rs62806261(G,T); rs62036135(G,A); rs12917793(T,A); rs28625248(C,T); rs28502487(C,T); rs1110557(T,C); rs116316245(G,A); rs74428578(A,G); rs1110556(G,A); rs1110555(G,A); rs112744502(G,C); rs12447115(G,A); rs74918247(G,C); rs8053093(C,T); rs7199674(G,T); rs9921976(G,T); rs1424159(G,A); rs144925188(T,C); rs8062505(A,G); rs8044327(G,A); rs2042432(A,T); rs1862824(A,G); rs1862825(A,C); rs11648234(G,C); rs145524504(A,T); rs7205623(C,A); rs7206203(C,T); rs138006108(G,A); rs56365933(T,C); rs1105243(A,G); rs1105242(C,A); rs149499686(T,A); rs76964277(C,G); rs8060202(C,T); rs11643946(G,C); rs4888828(C,G); rs9932805(G,T); rs11645755(C,T); rs1111228(G,A); rs1111227(G,A); rs1469133(A,G); rs56215379(G,A); rs55643279(C,T); rs116367522(G,T); rs7198725(T,G); rs188502296(C,T); rs1469132(T,A); rs6564579(G,T); rs114149580(C,T); rs66966706(A,C); rs7192902(T,C); rs7188265(A,G); rs115322842(A,G); rs7193483(T,C); rs7188117(C,G); rs112982058(C,A); rs79047643(A,G); rs77827108(C,G); rs77185255(C,T); rs116024539(G,A); rs4888829(G,A); rs79462693(G,A); rs4888830(G,A); rs189460608(A,G); rs77102088(C,T); rs78441813(A,G); rs72799083(T,C); rs72799085(T,C); rs116462147(A,G); rs77281473(C,T); rs73579409(T,G); rs74804357(G,A); rs57861636(G,C); rs56054405(A,G); rs56104417(C,G); rs13330253(T,C); rs76259476(C,T); rs8059714(C,A); rs79394233(G,A); rs11645225(C,T); rs72799088(C,G); rs142619824(G,T); rs56019235(G,C); rs7189367(G,T); rs7189717(G,A); rs7191047(C,T); rs2042433(G,A); rs76972627(T,C); rs115441314(C,T); rs8061477(T,G); rs11645548(T,C); rs77802034(C,T); rs4888831(T,C); rs114112461(A,G); rs79640158(A,G); rs76960625(T,C); rs74376471(A,G); rs138659521(C,G); rs7187364(A,C); rs11640758(C,G); rs11647269(T,C); rs9923426(G,C); rs11860176(C,T); rs9934490(A,G); rs9925569(G,A); rs76494689(C,G); rs78013791(G,A); rs74723994(T,C); rs75815614(A,T); rs28711881(C,G); rs11150097(G,A); rs77274111(T,G); rs13332365(G,A); rs12597711(C,T); rs9939915(A,G); rs114654612(A,G); rs1991015(A,C); rs113292305(A,G); rs9319525(C,A); rs72799094(C,G); rs113134276(T,G); rs4888832(C,A); rs4888833(G,T); rs11647491(G,C); rs11643918(T,C); rs114087623(T,G); rs9937065(G,C); rs147019795(T,C); rs55638337(T,A); rs12933172(G,C); rs12446962(A,G); rs7191486(T,C); rs1968270(T,G); rs1477415(C,T); rs1477416(G,A); rs1477417(A,G); rs79039799(C,G); rs4299170(C,G); rs4340337(T,A); rs4508429(A,G); rs72799100(G,C); rs7198292(T,G); rs6564581(C,T); rs7193634(A,G); rs7196255(G,A); rs2113285(C,G); rs1110560(G,T); rs11643137(G,C); rs7205036(A,G); rs57150307(G,C); rs8047442(T,C); rs12598149(G,C); rs80008088(C,T); rs7188664(A,C); rs7188004(C,T); rs59715569(G,T); rs7188881(A,C); rs143098907(A,G); rs8059324(A,C); rs144165471(A,G); rs73571660(C,G); rs189011258(A,G); rs117763604(C,G); rs9933169(A,G); rs114828392(G,T); rs16948387(A,C); rs183284492(G,T); rs189815497(A,G); rs9925796(T,C); rs8051867(A,G); rs6564583(C,G); rs6564584(A,G); rs192883144(T,G); rs8057617(C,G); rs1364291(G,A); rs1364292(A,G); rs16948413(A,G); rs28591367(A,G); rs8048347(C,G); rs138962654(A,G); rs73571688(T,C); rs11867110(A,G); rs117367463(T,G); rs73571689(C,T); rs7197944(T,A); rs56126557(C,T); rs7187342(G,C); rs186568467(T,C); rs149701260(T,C); rs142689738(C,G); rs117821445(T,C); rs145704669(A,G); rs4887976(C,G); rs137905213(C,T); rs8052158(C,G); rs12599398(A,G); rs191066891(G,A); rs61249444(G,A); rs112713311(C,T); rs4888840(G,C); rs4887980(T,C); rs1424161(T,A); rs1108735(A,C); rs72799974(C,T); rs58495040(C,G); rs60462427(C,T); rs61306490(G,T); rs1107903(A,T); rs57140921(G,A); rs115007840(C,G); rs113976285(C,A); rs73573715(G,A); rs73573716(T,C); rs73573718(C,A); rs112702644(T,G); rs73573719(C,T); rs57138895(G,A); rs60026659(G,A); rs7198697(C,A); rs7199110(C,T); rs73573726(G,C); rs55911111(C,T); rs9924212(T,G); rs3743683(A,G); rs140890469(G,C); rs3743684(A,G); rs185664543(C,T); rs75794784(G,C); rs74033559(T,A); rs9935043(C,G); rs73573729(T,C); rs143752092(C,T); rs11150098(C,G); rs1126186(G,C); rs73573733(A,G); rs76657239(T,A); rs80169631(C,T); rs12596114(G,C); rs1862642(G,C); rs1862643(A,C); rs8182114(A,C); rs7185360(G,A); rs4888842(C,G); rs4888843(G,A); rs13337171(A,G); rs4888844(G,A); rs143933396(C,T); rs1110554(T,C); rs7198672(A,G); rs1110553(C,G); rs8182221(T,C); rs11643459(C,T); rs186839935(G,T); rs7198511(T,C); rs7194114(A,C); rs7199337(T,C); rs7193767(C,G); rs7199518(T,G); rs116536080(A,C); rs113412419(C,G); rs11150099(T,C); rs7199640(G,A); rs12716858(G,C); rs12716859(T,A); rs1469134(G,A); rs56967941(T,G); rs58536301(T,C); rs4887981(T,C); rs117044632(A,T); rs4887982(A,C); rs9938250(A,G); rs9930178(G,C); rs9930346(G,T); rs12716860(G,C); rs4888845(C,G); rs13335618(G,A); rs4887983(G,C); rs4887984(T,C); rs2161719(T,C); rs1125678(A,C); rs148288716(A,T); rs4888846(A,T); rs35587783(C,T); rs35171841(T,G); rs34071876(C,G); rs13337401(C,A); rs10871352(T,C); rs7198930(G,C); rs7199334(G,A); rs7206356(T,G); rs7205435(C,T); rs17709200(A,G); rs16944118(G,A); rs9928973(G,A); rs28445289(T,C); rs74876321(C,T); rs12445943(G,A); rs17642004(G,A); rs36095292(A,G); rs117355856(G,C); rs8045376(A,G); rs62038598(G,T); rs9934620(G,C); rs4887985(G,A); rs9925933(A,G); rs6564587(C,T); rs11150100(T,C); rs10871353(T,C); rs35265902(T,G); rs17709285(G,C); rs10514444(C,G); rs9931387(A,T); rs9940973(G,C); rs1477409(A,G); rs1477410(A,G); rs1477411(A,G); rs149162536(G,T); rs1477412(G,C); rs1477413(C,T); rs1477414(C,T); rs4035780(A,G); rs4887986(G,T); rs4887987(G,A); rs7194007(C,T); rs4888847(G,A); rs1072898(C,G); rs9937734(A,G); rs186220670(C,T); rs11150101(A,G); rs9931539(G,A); rs8043875(A,C); rs9922434(A,G); rs9931648(G,C); rs12920155(C,G); rs59231529(A,G); rs9932263(G,T); rs9932331(G,A); rs12924714(C,T); rs74031428(A,G); rs7191931(C,T); rs7190803(T,C); rs12926134(T,C); rs16948473(C,T); rs144566507(A,T); rs12921046(G,T); rs74031429(G,A); rs77725626(A,G); rs12925315(G,T); rs12926542(C,T); rs8056325(T,C); rs9926161(C,A); rs1119250(C,A); rs4888848(C,G); rs4887988(G,C); rs56227404(C,T); rs56408141(A,G); rs2550590(C,A); rs2550591(C,G); rs2550592(C,T); rs12598809(C,T); rs2550593(G,T); rs4888850(C,G); rs2737306(C,T); rs60091668(G,A); rs12599271(G,A); rs2737305(T,C); rs75414850(G,C); rs7195449(C,T); rs2737304(C,T); rs1119562(C,G); rs62038601(C,G); rs72801910(G,C); rs17723058(A,G); rs2550594(C,G); rs2550595(G,A); rs67880293(G,T); rs62038602(C,G); rs2550596(G,A); rs2550597(G,A); rs7185984(C,A); rs7184611(G,C); rs2550598(G,T); rs7185036(G,A); rs7186551(C,G); rs2737303(A,G); rs2737302(G,C); rs7198122(T,C); rs9936541(A,C); rs7196279(G,A); rs7197824(C,G); rs12448575(A,C); rs1110559(A,G); rs117810819(G,A); rs1110435(A,C); rs1110558(C,T); rs9936415(C,T); rs2737301(C,T); rs2737300(G,T); rs78125873(C,A); rs2737298(G,C); rs139258614(C,T); rs2737297(C,T); rs144089902(A,C); rs2737296(C,G); rs9932188(A,G); rs79837236(C,G); rs7184456(C,G); rs2737295(C,T); rs6564588(G,T); rs7404119(G,C); rs7404120(G,A); rs182747946(C,G); rs2737294(G,T); rs2737293(A,G); rs58560942(G,A); rs59643612(C,T); rs55878153(A,T); rs1118736(C,T); rs4888852(A,T); rs1118735(G,A); rs1118734(A,T); rs2216730(G,T); rs35994022(T,A); rs11860793(T,G); rs12447141(C,G); rs67397147(C,G); rs8050074(G,C); rs141888282(C,T); rs186243014(C,T); rs2550600(T,A); rs7405312(T,C); rs7404901(C,G); rs9931801(T,G); rs6564589(G,A); rs6564590(G,C); rs6564591(T,A); rs2293902(C,T); rs2293901(A,C); rs2293900(T,G); rs2293899(C,G); rs72801039(C,T); rs2293897(G,C); rs8059278(C,G); rs8043588(T,C); rs6564592(A,G); rs6564593(T,C); rs1124808(G,C); rs1123882(A,C); rs1554978(T,G); rs1554977(G,C); rs1554976(T,A); rs6564594(G,A); rs4145519(C,A); rs1554974(C,T); rs7499973(G,C); rs7501059(T,A); rs6564595(T,C); rs1124595(T,C); rs2293896(T,G); rs1124596(T,C); rs2293894(C,G); rs9923322(G,A); rs9936644(T,G); rs3946180(G,A); rs1124597(A,G); rs8052915(C,T); rs8058070(T,C); rs12927430(G,A); rs11643767(C,G); rs72801050(A,G); rs9673415(T,C); rs1997589(A,C); rs1997588(A,G); rs1997587(C,T); rs12925461(C,G); rs1530(G,T); rs56213589(G,A); rs55692572(C,A); rs6564596(C,A); rs111610125(C,T); rs112645897(C,A); rs74031953(G,A); rs7404312(C,T); rs58999333(A,G); rs28489196(C,G); rs72801060(T,G); rs74031956(C,T); rs74031957(C,G); rs7205028(C,G); rs6564597(G,C); rs74031958(T,C); rs6564598(C,G); rs12447302(C,A); rs12445110(T,C); rs74031959(G,T); rs1126343(A,G); rs12448854(C,G); rs7201888(A,G); rs76934740(G,C); rs12448723(G,C); rs7199947(G,A); rs12446194(A,G); rs9940043(G,C); rs12443743(G,A); rs1126341(G,A); rs55666705(C,G); rs76758593(T,C); rs6420407(C,A); rs77984730(G,A); rs7197765(T,A); rs2037961(C,T); rs56209917(G,A); rs2037960(A,G); rs7192635(C,T); rs55861709(A,G); rs9936256(C,T); rs7193003(C,A); rs1072247(A,G); rs2223108(C,T); rs1073923(C,T); rs60474605(C,T); rs9936829(C,A); rs9929243(T,C); rs55694057(T,A); rs56087110(A,C); rs12325279(T,G); rs12930924(G,A); rs12918472(T,C); rs7198624(G,A); rs7201344(A,T); rs139028162(A,T); rs79068750(A,G); rs7206468(A,T); rs7204559(G,C); rs7184196(A,C); rs6564600(C,T); rs7206542(C,T); rs7189479(T,A); rs7184580(A,C); rs78229656(C,A); rs7184760(A,C); rs7189824(T,G); rs8043939(C,A); rs8048851(A,C); rs188096029(C,G); rs6564601(C,G); rs6564602(T,C); rs8048957(C,T); rs79327822(C,G); rs7499843(T,A); rs6564603(G,A); rs11150104(C,T); rs111431473(A,C); rs11150105(C,T); rs372077432(G,C); rs1079635(T,C); rs6564604(A,G); rs57438221(T,G); rs9941131(A,G); rs61185547(T,C); rs6420409(T,C); rs7186325(C,A); rs7192067(T,C); rs141102157(A,C); rs75689059(G,C); rs68020681(T,G); rs62036184(A,C); rs35296080(A,G); rs8051656(C,T); rs6564605(T,C); rs62036185(G,C); rs7404730(G,C); rs74789475(C,T); rs8056057(G,C); rs13338670(C,G); rs11643754(A,C); rs13338444(G,A); rs145364374(C,G); rs73577472(A,T); rs1554983(T,C); rs7501417(A,C); rs1554982(G,C); rs1554981(C,T); rs1126340(G,A); rs147680199(A,C); rs28587933(A,G); rs6564606(C,A); rs12932650(G,C); rs4888854(C,A); rs4888855(C,T); rs1554980(T,C); rs1554979(C,T); rs7185014(C,T); rs1124807(C,T); rs11859802(A,G); rs12920972(C,T); rs12923682(G,C); rs60139965(T,A); rs56062530(A,C); rs12716861(A,G); rs8050944(A,G); rs13332126(A,G); rs78290845(A,G); rs8060300(T,C); rs6564607(C,G); rs6420410(C,T); rs7404007(T,A); rs11649397(G,A); rs78839659(A,G); rs57235061(A,G); rs61464612(T,C); rs73577494(G,C); rs7194133(T,C); rs7499264(G,C); rs12599878(T,G); rs11150106(T,C); rs7194700(A,G); rs1546838(C,G); rs1546837(A,C); rs2205383(G,T); rs2223107(C,T); rs113608380(C,T); rs4888858(T,G); rs4888859(T,C); rs4888860(A,G); rs7405423(T,C); rs4888861(C,G); rs4887989(C,T); rs4888862(C,T); rs11640201(A,T); rs4888863(C,T); rs9922613(A,T); rs12446590(G,T); rs78410737(C,T); rs4888864(A,G); rs77125643(T,G); rs4888865(C,A); rs6420411(A,C); rs79974905(C,T); rs8063932(G,A); rs1543296(A,G); rs6564608(C,G); rs7498176(G,C); rs76362068(T,A); rs11640525(C,T); rs35310715(G,A); rs142583394(C,T); rs116831971(T,C); rs112045810(T,C); rs35384961(G,A); rs8056921(C,G); rs80051429(A,G); rs56128142(T,G); rs78788905(C,G); rs7501409(A,G); rs13335801(G,C); rs13335885(G,C); rs112166443(G,A); rs12447303(C,G); rs148897690(T,G); rs75244456(A,G); rs7190122(A,G); rs7200092(T,C); rs79676606(G,T); rs112941541(G,C); rs11643930(T,C); rs4145518(G,A); rs8058429(G,A); rs8060856(A,C); rs12149540(A,C); rs11150107(G,T); rs112168623(A,T); rs141920395(A,G); rs150679213(T,C); rs11640465(C,G); rs74035122(C,T); rs11645747(A,G); rs12448376(T,A); rs12444620(G,A); rs11150108(G,A); rs1125814(A,C); rs6564609(C,T); rs6564610(A,G); rs4888866(C,T); rs78882345(C,G); rs6564611(T,C); rs74576447(A,G); rs73579334(A,G); rs7404138(G,A); rs59561728(C,T); rs11865833(T,A); rs7197143(T,C); rs2346807(C,T); rs1106695(C,T); rs1076598(A,T); rs12935055(T,C); rs12935224(T,C); rs1106694(G,C); rs4888867(T,G); rs4888868(A,C); rs4888869(G,A); rs12917882(C,A); rs60123013(G,T); rs8051984(T,C); rs11642489(A,G); rs34584497(C,G); rs6564612(C,G); rs79695127(C,G); rs12149493(T,A); rs139341490(A,G); rs9934393(T,C); rs112936325(C,G); rs112746092(G,A); rs8063104(G,A); rs62036229(A,G); rs2656638(C,G); rs62036230(T,C); rs8047591(G,C); rs2737291(A,G); rs2656637(C,T); rs77125046(A,G); rs8054190(C,T); rs8054201(C,T); rs2737290(C,A); rs2737289(T,C); rs78346572(C,G); rs7197238(A,G); rs12930335(A,G); rs7195996(G,C); rs2656636(G,A); rs11643100(T,G); rs34865078(G,A); rs7342716(G,A); rs11643146(T,C); rs12448371(C,T); rs12445635(A,G); rs12448253(G,T); rs2656635(A,G); rs2656634(G,A); rs11648427(C,T); rs113045219(A,G); rs2075832(A,C); rs2075831(A,G); rs2075830(A,T); rs2075829(G,A); rs6420412(C,A); rs147467441(G,A); rs61000495(A,T); rs2142334(G,C); rs2737288(T,C); rs2178952(A,G); rs76918190(A,G); rs6564613(G,A); rs139338868(T,C); rs7194588(A,G); rs28628147(G,A); rs148078815(A,G); rs9926713(C,T); rs8051859(G,A); rs16948653(A,C); rs2737286(G,A); rs1504886(G,C); rs1504885(T,C); rs146732046(C,T); rs2737285(T,C); rs2737284(G,C); rs16948659(C,T); rs78594904(A,C); rs80194026(C,T); rs7200349(G,C); rs148322937(C,T); rs2737283(G,A); rs2737282(A,G); rs2737281(T,C); rs7185504(A,G); rs2737280(G,A); rs2737279(T,C); rs180761508(T,G); rs2737278(C,T); rs6564614(A,G); rs6564615(G,C); rs2134995(A,G); rs6420413(T,C); rs2174404(G,A); rs17633044(A,G); rs2252435(T,A); rs1394573(G,T); rs114509940(T,C); rs144569453(A,C); rs72804703(T,C); rs140469030(G,C); rs17633136(T,G); rs960862(A,G); rs3752910(T,C); rs56341534(T,C); rs1079638(A,G); rs1079637(C,T); rs1110888(A,G); rs1079636(G,C); rs1106616(T,C); rs1076600(C,T); rs10492911(T,C); rs1079634(G,T); rs187454717(C,T); rs1076599(C,A); rs2656630(C,T); rs1394572(T,C); rs2656629(A,T); rs117585302(C,T); rs11865743(C,G); rs13337942(C,G); rs2656628(C,A); rs2656627(A,G); rs2656626(C,G); rs2656625(A,G); rs11862750(T,C); rs78057897(G,T); rs2656624(G,A); rs191148237(G,C); rs2656623(A,G); rs16948711(A,C); rs2656622(C,G); rs2656621(G,A); rs2656620(C,A); rs2656619(G,A); rs2656618(G,T); rs6564616(G,A); rs117401299(C,T); rs9923225(C,A); rs1912422(A,C); rs16948720(T,A); rs76850998(A,G); rs2656616(A,T); rs5019006(G,A); rs5019007(C,A); rs145089825(G,C); rs4888871(C,T); rs2656615(A,G); rs7203648(T,C); rs7404729(G,A); rs117050063(G,A); rs7404742(G,A); rs137936457(G,C); rs12932449(A,G); rs16948735(C,A); rs4435265(A,G); rs76268968(C,G); rs113742182(C,A); rs56011281(G,T); rs149438892(A,G); rs8061768(G,A); rs112156244(G,A); rs35977799(C,T); rs34267720(A,T); rs145633994(G,C); rs4243162(A,G); rs138542615(C,G); rs12917998(G,C); rs143832180(A,C); rs12918302(G,C); rs12918342(G,A); rs905779(A,G); rs117368029(A,G); rs17706982(C,G); rs4887990(A,G); rs4356490(C,G); rs4887991(A,G); rs10492910(A,G); rs79775315(A,G); rs10451157(C,T); rs72804719(G,T); rs142063201(G,C); rs958361(G,A); rs4888872(C,G); rs117747181(A,T); rs57648136(C,G); rs10492909(A,G); rs11641087(A,T); rs11861122(A,G); rs55851063(C,G); rs10451158(C,G); rs146098796(C,T); rs10451159(T,C); rs10451160(G,A); rs12926355(G,T); rs35263951(A,G); rs35465866(T,G); rs192441349(T,C); rs35784565(G,T); rs72804723(C,G); rs142489125(C,T); rs144871672(C,G); rs150396517(A,T); rs188393042(C,G); rs77904589(A,G); rs11639940(C,T); rs11639743(G,T); rs117343824(A,G); rs11647676(T,A); rs11646646(A,G); rs8049189(C,T); rs8048092(G,C); rs147165616(C,G); rs8050494(A,G); rs62036257(T,A); rs62036258(A,G); rs9935765(C,G); rs1124356(A,C); rs2174403(T,C); rs372576050(A,G); rs2292124(G,C); rs138188873(C,T); rs59441349(T,A); rs56358084(A,G); rs58423913(T,C); rs58796896(T,C); rs56215585(G,T); rs72804739(C,T); rs12449222(G,A); rs72804741(G,C); rs12716862(A,G); rs11150110(C,T); rs8047431(C,A); rs6564617(G,A); rs6564618(G,T); rs7192392(G,A); rs9939235(T,C); rs9926631(C,G); rs9937233(A,G); rs9939686(T,C); rs62038062(A,G); rs8052368(G,C); rs140091943(C,G); rs2062894(C,T); rs2062895(A,G); rs2062896(G,T); rs11150111(G,A); rs13331535(T,G); rs149788760(T,G); rs8064038(G,A); rs8050115(T,C); rs8048020(G,C); rs117815759(C,T); rs11864605(G,A); rs7191942(A,C); rs2047925(G,C); rs67382945(C,G); rs16948787(G,T); rs149632464(C,A); rs72804751(G,A); rs72804753(A,G); rs1876974(G,C); rs13334368(T,C); rs34327236(C,G); rs9938373(C,G); rs149949107(G,A); rs6564619(T,G); rs4888873(T,C); rs11150112(G,A); rs56186839(C,T); rs62038064(C,G); rs1542933(C,T); rs7203004(G,C); rs1542934(G,A); rs7205288(A,G); rs113760949(C,T); rs78561937(G,A); rs8061943(T,A); rs12597575(C,T); rs72806719(C,T); rs55760002(C,G); rs6564620(A,G); rs8062305(T,C); rs6564621(A,T); rs6564622(A,G); rs7200156(A,G); rs149505519(G,T); rs11150113(G,A); rs369896372(A,C); rs16948799(A,G); rs4888874(A,G); rs10431970(T,C); rs4888875(G,C); rs139044157(A,G); rs16948801(C,G); rs75133459(G,C); rs16948804(G,C); rs60554456(G,T); rs11861377(T,C); rs8053244(T,G); rs61305399(C,A); rs147104307(G,A); rs60581926(C,T); rs139451162(C,G); rs3898101(C,G); rs954811(G,A); rs7194627(G,C); rs116915619(C,T); rs4573936(A,C); rs1847590(C,G); rs1604952(A,G); rs1604953(G,A); rs112014749(G,A); rs55855050(T,G); rs1847591(A,G); rs146253783(G,A); rs12443967(C,T); rs7184151(G,A); rs7184180(G,A); rs11864001(A,G); rs7186391(A,G); rs116889096(C,G); rs148773962(A,G); rs142434245(C,T); rs1033049(G,C); rs7192748(C,T); rs1014101(T,C); rs1553821(A,G); rs180913510(G,T); rs12931310(C,G); rs117670448(A,C); rs1472753(T,C); rs8060900(G,A); rs117150769(G,A); rs16948856(C,T); rs113932570(C,A); rs113777247(C,G); rs139370318(A,G); rs111324197(T,C); rs16948861(G,C); rs56371929(T,C); rs55653553(T,A); rs112166008(G,A); rs117270810(G,A); rs151186161(C,T); rs141340308(A,G); rs6564623(A,G); rs142960148(A,G); rs114668635(G,A); rs4888876(T,G); rs4888877(T,A); rs141327927(T,C); rs7206452(C,G); rs79488959(T,A); rs7206881(C,G); rs7205490(G,A); rs7184227(C,G); rs7206265(G,A); rs35217962(C,T); rs7189505(C,G); rs34026040(A,G); rs7188703(G,A); rs8047995(G,C); rs8049613(C,T); rs12923991(G,T); rs8048717(G,C); rs146449977(C,T); rs16948912(G,A); rs1394567(C,T); rs1394568(C,T); rs8055573(C,T); rs2221434(G,A); rs56223955(T,G); rs1394570(C,G); rs1394571(C,T); rs1125630(C,G); rs2007178(G,T); rs75775102(A,G); rs9923451(A,G); rs9925595(T,A); rs11150114(C,T); rs10871356(G,C); rs34984226(T,C); rs74711652(A,C); rs35740183(G,T); rs7192071(G,A); rs7192452(G,T); rs72806748(C,T); rs2346815(G,A); rs1510216(T,C); rs2881483(A,G); rs8059300(A,C); rs1018159(G,T); rs9934829(T,C); rs7498636(G,A); rs12444287(G,A); rs7190125(A,C); rs12716863(A,G); rs12716864(C,G); rs13336781(A,G); rs76916674(G,A); rs4888879(T,C); rs4888880(G,T); rs2346817(A,G); rs117941881(G,A); rs111251366(G,T); rs79551727(C,T); rs11641771(A,T); rs74032437(T,A); rs12925863(A,C); rs56003201(G,A); rs59283096(A,G); rs4887992(C,A); rs12448546(C,T); rs11645638(T,C); rs982383(T,G); rs12918324(C,G); rs2134993(C,T); rs117978248(A,G); rs2134992(G,A); rs189595607(A,C); rs186773649(G,T); rs8052474(T,C); rs115792598(A,G); rs4243163(A,T); rs12448710(T,A); rs12932804(T,C); rs140710099(T,G); rs8053583(C,T); rs58504900(A,G); rs8052534(G,C); rs982783(A,T); rs982784(C,A); rs55797578(C,G); rs28750193(A,G); rs12918989(G,C); rs11859772(A,G); rs11860644(A,G); rs74370548(A,G); rs62038103(G,T); rs12930134(T,C); rs12924818(G,A); rs34416902(C,T); rs12928676(G,C); rs8055230(C,T); rs35213849(T,G); rs116332774(C,G); rs62035963(A,G); rs377758521(G,A); rs4888881(A,G); rs72806764(G,C); rs4887994(C,T); rs7198756(A,G); rs11866965(C,T); rs12934215(G,A); rs60209796(A,G); rs114438282(C,A); rs34328652(G,A); rs8060810(G,C); rs28361930(T,C); rs73583254(T,C); rs7199757(A,G); rs146910241(A,G); rs62035964(G,A); rs8047671(T,C); rs7206663(A,G); rs148438502(C,A); rs17505656(T,C); rs140924594(T,C); rs1349(G,C); rs1347(C,T); rs1345(C,T); rs1342(G,A); rs77695820(A,C); rs62035965(T,G); rs7190041(A,G); rs16948943(A,G); rs28526561(C,T); rs28540864(C,G); rs2062897(A,T); rs62035966(T,A); rs7202207(A,G); rs7200501(G,A); rs7200657(G,C); rs7185057(T,C); rs7203016(A,C); rs12598030(A,G); rs7203568(A,G); rs7203590(A,G); rs12925128(T,C); rs12921094(C,G); rs12596126(G,A); rs12596284(C,G); rs12599133(T,A); rs12596836(C,T); rs12596852(C,T); rs13332148(C,T); rs13337252(A,G); rs13332931(G,A); rs118167568(T,C); rs13333056(G,T); rs10083726(T,C); rs13333229(G,T); rs13333234(G,A); rs61190086(T,C); rs9930476(G,A); rs13334706(C,G); rs75440579(T,G); rs9921744(A,T); rs9930944(G,C); rs114365637(T,G); rs73584234(T,A); rs6564624(G,C); rs6564625(C,G); rs13331318(A,G); rs10083788(C,G); rs6564626(A,G); rs75729981(A,T); rs115172362(C,T); rs7189340(C,G); rs8049143(A,T); rs7195069(T,C); rs7205481(G,A); rs73584239(A,G); rs4888884(G,T); rs9935088(A,G); rs11646571(A,G); rs4888885(G,A); rs1827681(C,T); rs2011480(G,A); rs1986594(T,C); rs7499860(A,G); rs67051757(T,A); rs1995869(G,C); rs2062898(C,G); rs79781201(C,T); rs11643794(G,A); rs74032448(G,A); rs8061217(A,G); rs8061399(A,T); rs62035969(A,G); rs4888886(G,A); rs8062102(A,G); rs4887995(G,A); rs61287756(C,G); rs7184656(G,A); rs73584245(G,A); rs7185273(G,A); rs35159584(A,G); rs7185469(G,A); rs62035971(T,C); rs116199227(G,C); rs11642227(A,T); rs10871357(G,C); rs11647189(C,T); rs11150117(T,C); rs4888887(G,T); rs12927476(C,G); rs1995549(C,T); rs1995548(A,G); rs34312843(G,A); rs1995547(C,G); rs7197702(G,C); rs78695874(A,G); rs7198076(G,T); rs8056512(G,A); rs8063186(T,C); rs11648482(G,A); rs8063389(A,G); rs8062986(C,T); rs75314908(A,T); rs77914851(T,C); rs7206333(A,G); rs57934395(C,T); rs12918434(G,T); rs8044258(A,G); rs11150118(G,A); rs9935435(A,T); rs75726262(T,C); rs72808737(T,C); rs13332886(C,A); rs905773(G,C); rs76989298(G,C); rs112170290(G,A); rs7205145(C,T); rs1110890(T,C); rs13339612(G,A); rs7205567(C,G); rs11639533(G,C); rs140063097(C,T); rs17709129(C,G); rs12444278(G,T); rs77527189(G,A); rs75621947(C,G); rs79914828(A,C); rs17635971(G,T); rs11150119(G,A); rs9319530(C,G); rs80330320(C,G); rs9319531(G,C); rs13334115(C,G); rs75438824(C,A); rs79548483(G,A); rs74032452(C,T); rs74032453(G,T); rs12446617(G,T); rs11641434(T,C); rs10871358(A,G); rs12446679(G,T); rs12596756(T,A); rs77893638(A,G); rs79713614(A,G); rs76961065(A,C); rs76251075(A,G); rs74032454(A,G); rs12925319(C,G); rs184301378(G,T); rs79337373(C,G); rs59881766(C,T); rs115689521(A,G); rs113588565(C,G); rs8055881(C,T); rs8056828(A,C); rs16949036(A,G); rs8057599(A,G); rs9933395(T,C); rs12447067(T,C); rs9941223(C,T); rs12449098(G,C); rs116548828(C,A); rs11645925(T,C); rs79730335(C,G); rs114070828(A,G); rs9923762(C,T); rs7189021(A,G); rs7189419(A,G); rs28402951(C,T); rs17636170(C,G); rs8052880(C,T); rs12448124(A,G); rs4600477(G,A); rs4587992(G,C); rs9926476(G,C); rs114460399(C,T); rs7196198(A,C); rs7196204(A,T); rs141558724(C,T); rs4888888(T,C); rs62036003(A,G); rs113339362(C,G); rs4888889(C,G); rs4888890(G,T); rs4888891(T,C); rs79105232(G,A); rs9927534(T,G); rs9927540(T,C); rs9935248(C,T); rs8052893(G,A); rs377129900(T,G); rs7201806(C,T); rs192145054(T,A); rs11150120(G,C); rs74464049(C,G); rs13339083(G,A); rs4888892(C,G); rs4888893(A,G); rs4243164(A,G); rs200311067(G,T); rs4587990(G,T); rs1566882(C,T); rs77999142(G,C); rs79001380(G,T); rs13330742(C,A); rs75551198(G,T); rs111934347(G,T); rs16944152(T,C); rs2047927(A,G); rs116207651(T,C); rs35368632(G,A); rs116666442(C,G); rs5024396(G,A); rs78322683(A,G); rs12444623(G,A); rs17636262(G,C); rs78073198(T,C); rs2062899(T,C); rs16949045(A,T); rs2062900(G,A); rs2062901(C,T); rs2062902(T,C); rs2055845(C,G); rs8057659(A,G); rs6564628(G,A); rs6564629(G,T); rs11150121(C,T); rs28728058(C,G); rs28666503(C,T); rs12716865(T,C); rs7205680(T,C); rs7198655(G,C); rs7200078(C,G); rs1467067(A,C); rs11860206(T,C); rs1105706(A,G); rs77379988(C,T); rs74634498(T,C); rs141553492(G,A); rs146405142(G,A); rs2004675(G,C); rs1110891(A,G); rs1110892(T,C); rs1110893(G,A); rs1110894(T,C); rs8048317(C,T); rs35853246(T,G); rs4888894(G,A); rs4888895(A,G); rs4887996(A,T); rs4888896(C,A); rs4888897(C,T); rs4887997(T,G); rs10492908(G,A); rs11150122(C,A); rs16949065(C,G); rs28757856(C,G); rs4888898(A,T); rs35073078(A,G); rs4887998(G,A); rs4887999(G,A); rs11866789(C,G); rs77313634(C,G); rs79294982(A,G); rs139735909(G,A); rs11150123(G,A); rs11150124(T,C); rs11866773(T,G); rs9927800(C,T); rs8055295(C,G); rs8060634(T,G); rs143924485(C,T); rs7197569(C,G); rs150601135(A,C); rs77779059(T,C); rs72808764(A,C); rs12921056(T,G); rs111677065(T,G); rs12935510(A,G); rs12921519(T,A); rs9930281(G,A); rs12051206(C,G); rs9930939(C,T); rs12918211(A,T); rs1875940(T,G); rs4888899(A,G); rs1875939(G,C); rs7186745(G,A); rs12447264(C,A); rs11150125(C,G); rs4888000(A,G); rs13332405(A,G); rs28403123(A,G); rs9928956(T,C); rs1566884(T,C); rs11647122(G,C); rs11150126(C,G); rs4888900(T,C); rs4888001(C,T); rs8063569(C,G); rs924870(T,C); rs8062872(G,C); rs12919788(C,G); rs9922292(C,A); rs12444526(C,T); rs16949121(A,T); rs2014980(C,G); rs13331853(C,T); rs144027265(G,T); rs59357646(C,T); rs3751835(T,A); rs16949136(A,G); rs6564630(C,T); rs3751834(A,G); rs965384(G,A); rs72628254(T,C); rs28483771(G,A); rs115767773(C,T); rs12447117(C,T); rs12444900(T,C); rs78971368(C,T); rs62036036(A,C); rs113727692(C,A); rs8046676(C,T); rs4620969(C,T); rs1546360(G,C); rs8062195(C,G); rs17637309(T,C); rs16949152(A,G); rs12444286(C,T); rs76843903(C,G); rs11150127(T,A); rs4888901(T,G); rs9926344(G,A); rs8052309(G,T); rs12933151(C,T); rs12934073(C,A); rs12449126(A,T); rs9931916(G,C); rs955199(A,G); rs4146510(G,C); rs16949163(A,T); rs11641680(T,G); rs11645258(G,A); rs4888902(G,A); rs4362402(A,G); rs12925802(C,G); rs78687686(A,G); rs62036057(C,T); rs1983093(A,G); rs1983094(C,T); rs1983096(C,G); rs11644520(T,C); rs79022547(G,C); rs4888903(T,C); rs4888904(T,C); rs10492907(C,T); rs4888905(A,G); rs4888906(G,C); rs4888907(G,C); rs11645918(T,C); rs11644811(A,C); rs11645929(T,C); rs2036808(G,A); rs4316768(G,A); rs115459251(T,C); rs4273049(A,G); rs4580173(T,C); rs114870693(T,A); rs4888908(G,C); rs11864328(A,G); rs4888002(T,C); rs4888003(C,G); rs4888004(G,A); rs4888909(T,C); rs4888005(G,A); rs4888006(G,A); rs4888910(G,A); rs11150128(A,C); rs75097474(C,T); rs11150129(G,C); rs12599933(T,G); rs12596965(G,A); rs11150130(T,C); rs2047929(G,A); rs2047930(T,C); rs4888911(A,C); rs4888912(C,G); rs17637675(A,G); rs12448309(C,A); rs80205998(C,A); rs2347079(G,C); rs2136668(C,A); rs8060242(C,T); rs8060781(C,G); rs2062903(T,A); rs4888913(G,C); rs56067029(A,T); rs112428386(C,T); rs1566885(G,C); rs2134999(G,T); rs2134998(G,C); rs181799669(C,T); rs56242500(T,C); rs17643319(C,T); rs12596848(G,A); rs56355302(G,A); rs145607865(A,T); rs137870925(A,G); rs9941213(T,C); rs12931421(C,A); rs12932228(A,G); rs72791505(A,G); rs2347080(C,G); rs871571(T,C); rs55995798(C,G); rs874077(C,T); rs874078(A,T); rs871572(A,C); rs79569775(A,G); rs35300355(C,G); rs36046662(G,A); rs905778(G,C); rs12598330(C,T); rs10492906(A,C); rs77832299(G,C); rs905777(T,C); rs905776(T,C); rs112266411(G,A); rs10492905(G,A); rs7189595(C,T); rs34261173(A,G); rs11865458(C,T); rs13337599(C,T); rs67558905(T,C); rs34205151(G,A); rs13337633(C,G); rs55731711(C,T); rs12929415(A,C); rs55837346(G,A); rs68154713(T,G); rs115274667(C,G); rs4888914(A,G); rs74032476(C,T); rs1109934(C,T); rs1110896(T,C); rs905775(G,C); rs11866798(C,T); rs2006902(G,T); rs77992911(G,C); rs184381331(C,T); rs144560079(A,G); rs13338273(A,G); rs13332888(G,C); rs56892093(G,A); rs13332891(G,A); rs57254180(C,A); rs77209664(T,C); rs2134997(A,C); rs4888008(A,G); rs2347082(T,C); rs76353187(G,A); rs2347083(A,G); rs9652678(C,G); rs11644322(C,T); rs57521144(A,G); rs74032479(C,T); rs9652679(T,G); rs28634857(A,T); rs112033175(G,A); rs28457088(T,C); rs58373874(G,A); rs113496184(G,T); rs74032480(C,G); rs185000004(C,T); rs113428657(T,C); rs7185743(G,A); rs76923134(G,C); rs34982954(T,C); rs12598700(C,T); rs80241752(C,G); rs9935794(G,A); rs17711186(C,G); rs115462384(C,G); rs4888915(G,T); rs4888916(G,A); rs12928261(A,T); rs28445852(A,G); rs12932061(T,C); rs2550732(T,C); rs56276219(C,T); rs8057993(A,C); rs8056452(G,A); rs8056763(G,T); rs889745(G,T); rs34310485(A,G); rs12103272(G,A); rs74032482(T,G); rs13338622(G,A); rs2113307(T,C); rs1862842(A,G); rs1469136(C,G); rs1469135(G,C); rs74032483(A,C); rs7184417(C,T); rs115159431(G,A); rs7185147(A,G); rs79270349(C,G); rs74032493(C,T); rs2550731(G,T); rs2550730(C,T); rs2550728(C,T); rs35574096(A,G); rs150302596(G,T); rs12598091(C,G); rs2656659(G,A); rs2550726(G,C); rs185610721(G,T); rs11645605(C,T); rs2656658(C,A); rs12598471(G,T); rs2550725(T,C); rs62040096(A,G); rs115764361(C,A); rs1862841(A,T); rs74032497(A,C); rs77421955(T,G); rs16949214(C,T); rs2656656(A,G); rs2656655(T,A); rs2550724(G,T); rs9921664(C,A); rs12447246(A,C); rs7187460(C,G); rs2550723(G,C); rs2656654(A,G); rs374203961(C,G); rs16949222(C,T); rs2550722(A,G); rs74603829(C,A); rs28655843(A,G); rs148462454(C,T); rs146969749(C,T); rs12932339(G,A); rs2113305(T,G); rs2550721(G,A); rs9931739(G,C); rs9932373(C,G); rs7185820(A,G); rs8064141(G,A); rs35859178(A,C); rs115988242(G,C); rs2550720(A,C); rs2550719(C,T); rs12925579(A,G); rs72793697(G,A); rs7196173(T,G); rs16949238(G,A); rs16949240(G,A); rs2656653(T,C); rs16949243(A,G); rs2550718(A,C); rs2550717(G,A); rs60586777(T,G); rs56033560(G,C); rs11647712(G,C); rs73569136(T,C); rs2550716(A,G); rs28367265(G,A); rs182396818(C,G); rs16949251(A,G); rs7205005(A,C); rs28439645(A,G); rs8047597(A,G); rs2550711(G,A); rs2550710(A,C); rs16949257(G,T); rs7199119(T,A); rs16949262(A,G); rs147686532(A,T); rs79763768(T,A); rs2550708(T,C); rs112606321(C,G); rs2550707(T,C); rs1808447(T,C); rs905781(C,G); rs35963664(A,C); rs58721019(A,G); rs2656650(A,C); rs57683261(C,T); rs151206850(G,A); rs2550704(G,C); rs62040099(C,G); rs8044395(T,C); rs116654161(C,T); rs2550703(G,A); rs6564634(A,C); rs112078691(A,G); rs2550702(C,A); rs2550701(C,G); rs2656649(A,G); rs11645630(A,C); rs16949276(G,A); rs146509607(T,C); rs111823946(C,T); rs7187331(A,G); rs8055577(T,C); rs58309994(T,C); rs2656647(A,G); rs144073560(C,G); rs16949286(A,C); rs2656646(T,C); rs1862840(G,C); rs1862839(G,C); rs1876977(C,T); rs1876976(C,G); rs57248849(T,G); rs139293183(T,A); rs2656645(T,C); rs2550697(T,A); rs115877737(C,A); rs11863336(C,G); rs11641140(T,G); rs1862838(A,G); rs9285361(T,C); rs2656642(A,G); rs2656641(C,T); rs2102280(A,C); rs1862837(C,T); rs74036007(G,A); rs62040103(G,C); rs190415285(T,C); rs62040104(G,A); rs1120114(T,C); rs62040105(G,A); rs1120115(A,C); rs62040106(C,T); rs2550694(G,C); rs8055815(A,G); rs114540319(T,A); rs4888009(A,C); rs2550692(G,A); rs2550691(T,A); rs141656671(C,T); rs1559443(C,G); rs77134256(G,A); rs2656639(C,G); rs2550690(G,C); rs67991121(G,A); rs116823548(G,A); rs16949333(C,G); rs62040107(G,A); rs2656633(C,T); rs79442008(G,A); rs988373(G,C); rs137948523(A,G); rs2656617(A,G); rs1828349(A,G); rs190408034(T,C); rs2550689(G,T); rs1397158(T,C); rs115707351(G,A); rs2656614(A,C); rs889743(C,G); rs889742(C,G); rs905780(C,T); rs12325019(G,C); rs2247465(G,A); rs16949366(C,A); rs2656613(C,G); rs142177640(A,G); rs145232047(A,G); rs9930250(C,A); rs2656612(A,G); rs9940793(A,T); rs2202423(A,G); rs144143462(T,C); rs2194344(G,A); rs2202422(A,G); rs1110898(A,G); rs2656611(C,A); rs2250443(A,G); rs8046508(C,T); rs2656610(C,T); rs8061345(C,A); rs1110565(G,C); rs1110897(T,C); rs73570812(A,G); rs17646636(A,G); rs114997638(T,C); rs2656667(G,A); rs2550687(A,C); rs2656665(G,A); rs2656664(G,A); rs148689039(T,A); rs192673921(A,C); rs80215791(T,C); rs142074029(T,C); rs56105124(T,G); rs2656663(G,C); rs13335371(C,G); rs13335415(C,G); rs60349708(G,A); rs16949409(G,C); rs28564132(C,G); rs16949412(A,G); rs183472652(C,G); rs2656662(G,T); rs11648133(C,T); rs11647906(G,C); rs146794602(C,T); rs62040125(C,T); rs2550685(A,C); rs2550683(T,G); rs2656661(G,T); rs2911434(C,G); rs9806790(C,G); rs13335971(A,G); rs13330637(G,A); rs2550681(A,G); rs2550680(T,C); rs114547002(G,A); rs2656652(C,T); rs2550679(A,G); rs5021354(C,A); rs1966515(A,T); rs2550678(A,G); rs8047303(C,G); rs2550677(G,A); rs80219526(G,T); rs8052586(C,T); rs2247561(T,C); rs28439411(C,A); rs28407142(G,T); rs28669118(T,C); rs59229739(A,G); rs9319532(C,T); rs75050686(C,G); rs9319533(A,G); rs76655049(A,G); rs11645695(T,A); rs28392618(T,C); rs1319738(G,A); rs1121404(T,C); rs9922793(G,C); rs13337209(A,G); rs4888918(T,C); rs72795632(A,C); rs9319534(T,G); rs9319535(T,G); rs9939158(A,G); rs9921050(T,C); rs9921059(T,G); rs74034328(T,C); rs9928080(G,A); rs2161726(G,T); rs2161725(A,C); rs11643445(C,T); rs74034331(G,A); rs11648833(A,G); rs2113304(C,T); rs2113303(G,C); rs10492903(C,A); rs9921688(T,G); rs9929289(C,T); rs2881550(G,A); rs74034332(A,G); rs2347085(T,A); rs2347086(G,T); rs2347087(G,A); rs9319536(A,G); rs2347088(G,A); rs79930120(G,C); rs9972758(C,T); rs9972759(C,G); rs9972661(T,A); rs9972633(A,C); rs9972753(G,T); rs12102460(A,G); rs12103013(C,G); rs10492902(G,C); rs12103000(G,A); rs13336209(G,A); rs11860637(A,G); rs11646307(G,C); rs12103168(C,T); rs55660615(C,G); rs9972822(C,G); rs8059832(T,G); rs9972825(C,T); rs377194204(G,A); rs9972704(A,C); rs8053789(G,A); rs80052005(C,T); rs9940608(C,T); rs77906742(C,T); rs13330275(G,C); rs9922235(G,C); rs16944165(C,A); rs9923032(C,T); rs12596258(G,C); rs28545210(C,G); rs7193437(C,T); rs74794325(G,C); rs73570888(G,T); rs73570890(C,T); rs12325126(A,C); rs76970573(G,C); rs17647978(T,C); rs76714322(C,T); rs59591935(C,G); rs58235561(T,G); rs28697115(A,G); rs77854716(C,A); rs9929635(A,T); rs7201655(A,G); rs11150132(T,A); rs7189207(T,G); rs10871359(C,G); rs12324967(C,T); rs7206235(G,C); rs150506328(C,T); rs17726834(C,T); rs7190868(A,C); rs28627309(C,T); rs9925128(C,T); rs188039371(T,C); rs12930934(A,T); rs72795658(A,C); rs16949485(T,G); rs28391611(C,T); rs9930132(G,A); rs1110563(G,C); rs1110562(A,G); rs7204158(C,T); rs56116462(G,T); rs113848118(G,C); rs72795663(T,C); rs1116432(G,A); rs12445885(A,G); rs12446495(T,C); rs7206237(T,C); rs62040131(A,C); rs6564638(G,A); rs34233224(A,T); rs77318199(T,C); rs116562377(A,G); rs115984925(T,A); rs78996966(C,A); rs11648721(G,C); rs28609070(T,G); rs16949501(T,G); rs4888919(T,A); rs56122904(G,C); rs75490164(T,C); rs9937803(A,G); rs75946815(C,T); rs149442420(T,C); rs77640346(C,T); rs75009965(A,T); rs12600154(A,C); rs11150133(C,T); rs59301717(G,C); rs11150134(C,T); rs12149527(C,T); rs34026410(A,G); rs142507906(T,G); rs73572915(C,G); rs77673233(C,T); rs58510262(T,C); rs12925972(T,C); rs8049292(G,C); rs9925869(A,C); rs11861850(T,C); rs12926028(C,T); rs12924981(G,C); rs12926047(C,T); rs12716866(C,G); rs12925253(G,C); rs9928254(T,C); rs68187430(T,G); rs34176441(A,C); rs112406746(G,A); rs17648647(A,C); rs73572928(T,C); rs6564639(G,A); rs73572932(G,C); rs6564640(T,G); rs58489137(A,G); rs6564641(C,G); rs73572938(G,C); rs73572943(T,A); rs73572945(T,A); rs73572947(C,T); rs73572950(T,C); rs8055998(G,C); rs6564642(G,A); rs144574470(A,G); rs12102852(A,G); rs7205541(A,G); rs151165376(A,T); rs12935535(G,C); rs7205886(A,G); rs77279002(G,C); rs140224649(C,A); rs12918601(C,T); rs6564643(A,C); rs1080511(A,C); rs116674260(C,G); rs2014633(G,A); rs1114709(G,A); rs139990038(C,G); rs76846953(G,A); rs150958081(C,T); rs4888920(A,G); rs17727546(A,C); rs16949517(C,T); rs11861546(C,T); rs17727594(G,C); rs6564644(G,C); rs74886033(G,C); rs7199945(G,A); rs12920082(C,T); rs76431033(G,C); rs12598395(G,A); rs58663315(A,G); rs67246679(C,A); rs34549159(T,A); rs13339155(G,A); rs9635581(C,G); rs28680554(C,T); rs34210462(G,C); rs114722338(A,T); rs140518710(T,A); rs78423168(G,T); rs138341665(A,G); rs57739271(G,A); rs75818939(G,A); rs67789620(G,C); rs78512002(A,G); rs57225484(C,G); rs4888923(A,G); rs60427429(C,G); rs62038831(A,G); rs28515528(C,G); rs76287276(C,G); rs35074985(C,T); rs35685499(G,A); rs139777297(C,T); rs115006231(C,T); rs144189820(C,T); rs35740112(C,G); rs151048467(T,G); rs145773884(T,G); rs147970590(C,T); rs367762031(G,C); rs11866696(G,A); rs183302103(C,G); rs12920897(C,G); rs4888924(A,G); rs4888925(G,A); rs144406416(C,T); rs11864213(A,G); rs189244440(A,T); rs138378675(G,C); rs76194926(G,T); rs142981429(T,C); rs60668068(A,T); rs57584823(C,G); rs61086787(T,G); rs11865164(A,T); rs145408296(T,C); rs139633486(A,T); rs142624647(C,T); rs11865264(A,G); rs151005833(C,T); rs11863868(G,C); rs143357844(A,T); rs148376650(C,T); rs143858305(G,A); rs144087264(G,T); rs9933420(G,C); rs148687449(T,C); rs146756537(G,A); rs72795696(G,A); rs8052725(A,C); rs28496920(C,T); rs9931714(T,C); rs112368077(A,C); rs9939718(C,T); rs151175445(A,G); rs140533568(C,T); rs6564645(A,G); rs74519365(T,A); rs8062496(G,A); rs142667490(G,C); rs8062989(G,A); rs8063006(G,A); rs8048767(T,C); rs8048899(T,C); rs181693849(C,T); rs146031461(C,A); rs139448451(T,C); rs8049291(A,C); rs8049461(A,G); rs8049467(A,T); rs58570674(C,G); rs74034950(A,C); rs113934017(C,G); rs12925895(A,G); rs190994790(C,T); rs73575166(T,G); rs73575168(T,G); rs181884080(C,A); rs75153316(G,A); rs191817454(A,T); rs142403373(T,G); rs4888926(C,T); rs9926990(C,G); rs4888927(G,C); rs5009398(T,C); rs5009397(A,T); rs2347089(G,C); rs11150135(T,G); rs1981875(C,T); rs9925697(A,C); rs12716868(C,A); rs73576943(C,A); rs73576946(G,A); rs76663638(C,T); rs73576952(C,G); rs1424104(C,T); rs4888928(C,T); rs7206890(C,T); rs193273191(T,C); rs7185485(T,C); rs73576955(C,T); rs7191506(T,C); rs62038838(T,G); rs116985496(G,A); rs73576961(A,G); rs12931629(A,G); rs7198404(C,A); rs4888011(C,G); rs12928653(T,C); rs138631855(T,C); rs11649247(C,T); rs9940536(C,T); rs2005036(C,T); rs73576984(A,C); rs140447079(C,G); rs16949559(A,G); rs1107650(A,G); rs2002640(G,T); rs8044667(G,A); rs186421643(G,A); rs1424103(A,G); rs1424102(A,G); rs16949592(T,C); rs11647295(A,G); rs10492901(T,C); rs11150136(A,G); rs12447103(C,G); rs10492900(A,G); rs8045079(G,A); rs8047289(A,G); rs142685102(T,A); rs7191918(G,A); rs11647397(C,A); rs7205565(T,G); rs117979204(G,A); rs17728372(C,G); rs62038852(A,G); rs11150137(A,C); rs7498200(A,G); rs1424109(C,G); rs12923469(G,T); rs8054312(T,C); rs8048674(G,A); rs62038853(C,G); rs8048682(G,C); rs7197121(A,T); rs11648193(A,C); rs12599773(A,G); rs11862546(G,A); rs11866970(A,G); rs9646321(A,G); rs9646322(G,A); rs9646323(C,G); rs13331974(T,G); rs16949655(A,G); rs34394761(C,G); rs62038854(A,G); rs9646324(G,A); rs9646325(G,A); rs2042437(G,T); rs182324037(C,G); rs12716869(T,G); rs192914715(T,C); rs11866026(G,A); rs11866029(G,C); rs11862384(A,G); rs1424110(A,G); rs72797409(A,G); rs8053118(C,A); rs9937633(A,G); rs4611476(A,G); rs2042413(T,C); rs2042414(A,G); rs12597702(G,T); rs2347090(A,G); rs2347091(G,A); rs141562211(G,A); rs9932499(C,G); rs9932512(C,T); rs146036235(C,T); rs1111231(T,C); rs115367284(A,T); rs1111230(A,G); rs78476680(A,T); rs7196461(T,A); rs1424112(A,G); rs1424113(A,G); rs76937835(A,T); rs11647803(G,C); rs9930659(T,C); rs11647886(G,T); rs9938556(C,G); rs72797415(A,G); rs7203720(C,T); rs1981883(C,T); rs28689934(G,A); rs7193539(C,A); rs62038855(G,A); rs2113271(C,T); rs7192765(G,A); rs7200634(A,C); rs7200334(C,T); rs12449061(A,C); rs9925100(T,C); rs7200529(G,T); rs7202835(A,T); rs7184952(T,C); rs11863848(T,A); rs7202713(C,T); rs7203436(A,C); rs8045284(A,G); rs142179488(C,T); rs8044764(C,G); rs8050239(T,C); rs11859942(C,G); rs59715840(T,C); rs7190436(G,C); rs56928727(G,A); rs7191404(G,C); rs7191617(G,A); rs7193157(C,G); rs8056647(G,A); rs12050992(T,C); rs13334837(C,G); rs9921694(A,G); rs7204022(G,C); rs7205572(C,T); rs12050933(A,G); rs7188904(T,A); rs7184152(A,G); rs7204962(G,C); rs9924268(A,G); rs8046140(G,A); rs12928188(T,A); rs6564648(T,G); rs6564649(G,T); rs6564650(C,G); rs7190400(A,C); rs7190432(A,T); rs117535561(A,G); rs7194608(C,G); rs8053895(A,G); rs8052122(G,A); rs4309411(C,G); rs4309412(C,T); rs4309413(C,T); rs4381615(T,C); rs4459555(T,C); rs4622524(T,C); rs4315347(C,T); rs7201082(C,T); rs7201292(C,T); rs7199872(G,A); rs12446803(T,A); rs13339141(C,G); rs12934227(C,G); rs12934230(C,T); rs1117007(T,C); rs5009591(A,C); rs8050187(T,C); rs9922411(G,C); rs62040668(C,T); rs1126183(G,C); rs5029635(G,A); rs2003877(G,T); rs13332065(C,G); rs9938707(T,G); rs140562949(C,G); rs8050423(G,A); rs8058094(C,G); rs9939576(C,T); rs9931844(T,A); rs8059106(A,C); rs28654283(A,T); rs28694895(A,C); rs114645781(A,C); rs11859414(C,G); rs11859454(C,T); rs11864641(T,C); rs13335506(A,G); rs11859281(G,A); rs9932990(A,G); rs9933164(A,G); rs77882212(G,T); rs59557179(A,G); rs8048787(G,C); rs11861871(C,A); rs10153125(C,G); rs10153236(T,G); rs13334444(G,T); rs62040670(T,C); rs71398136(C,A); rs8046352(G,C); rs8050958(G,C); rs34999162(A,T); rs28637516(T,C); rs4888929(C,G); rs79595746(G,A); rs114504742(T,C); rs4888930(A,G); rs77961339(G,C); rs13329828(G,A); rs12443833(C,T); rs8045067(A,C); rs28578081(A,G); rs58865296(C,G); rs74038917(C,T); rs4888931(A,G); rs1110543(T,C); rs1110542(A,T); rs9972791(G,C); rs73582752(C,T); rs112801371(T,G); rs113940861(G,C); rs111273775(G,A); rs9972794(G,A); rs16949748(C,G); rs12051388(C,T); rs11150140(G,A); rs11150141(A,G); rs182663409(G,A); rs1946279(G,A); rs17656178(A,G); rs28480113(A,G); rs7203399(G,A); rs7205445(A,G); rs8047649(T,C); rs8046276(G,C); rs1116525(T,C); rs112426496(A,C); rs113799607(C,G); rs9940050(A,T); rs59826930(A,G); rs4888932(G,C); rs77131863(A,G); rs12920362(T,A); rs6564652(C,G); rs78822383(C,T); rs111744193(A,T); rs114674926(G,T); rs28707691(C,G); rs28441246(C,T); rs28568544(G,C); rs112399581(T,C); rs12373089(G,A); rs9935023(G,T); rs35506727(A,G); rs8055765(T,C); rs8049536(G,C); rs6564653(G,C); rs8056120(T,C); rs11150142(C,A); rs1111415(C,G); rs1812063(T,A); rs1111414(G,A); rs2011394(G,C); rs1110546(G,C); rs1110545(A,G); rs2347568(C,A); rs2011200(G,C); rs1963839(T,C); rs2011189(A,G); rs2011188(A,T); rs2011184(A,G); rs12444578(A,G); rs143534052(A,G); rs9924917(A,C); rs9924918(A,T); rs8049330(A,C); rs77483330(A,G); rs8049501(A,G); rs8053844(T,C); rs4888934(C,G); rs4888935(T,C); rs4888936(G,A); rs4888937(G,C); rs4243165(C,A); rs13333215(A,C); rs28690342(A,T); rs12716871(C,G); rs12934392(A,T); rs35603254(C,T); rs12935684(A,G); rs3751832(A,G); rs3751831(G,T); rs1834037(C,T); rs192812289(C,T); rs72797436(G,T); rs11860626(G,A); rs9925793(C,G); rs138415415(G,A); rs8052087(C,G); rs4888014(G,A); rs59161288(C,T); rs28421139(T,A); rs1424106(G,A); rs72797440(G,A); rs1424107(G,C); rs73584706(G,A); rs73584708(G,C); rs13330002(A,G); rs13334956(C,G); rs13330144(A,T); rs116451104(C,G); rs28515196(T,C); rs146597544(C,G); rs61007640(C,G); rs58313572(A,G); rs184705109(C,T); rs77437035(G,A); rs16949819(A,G); rs17730134(G,A); rs147216800(G,C); rs114603089(G,A); rs28524560(C,T); rs6564654(G,T); rs74753262(G,T); rs2017466(C,G); rs1110567(G,C); rs1108663(G,A); rs446684(G,A); rs1110910(C,G); rs2017010(G,C); rs16949846(A,G); rs494736(A,G); rs7186096(G,C); rs7186097(G,A); rs428420(C,G); rs55986698(G,A); rs428899(G,A); rs371086(G,A); rs438574(A,G); rs434342(C,A); rs28451668(A,G); rs118011534(T,G); rs181251290(G,A); rs374752(A,G); rs28707448(G,T); rs441574(G,C); rs444443(T,C); rs440233(T,C); rs436387(T,C); rs377651(C,T); rs144912448(T,C); rs72628257(A,C); rs386497(T,C); rs399238(C,G); rs367064(G,T); rs375992(G,A); rs34762624(G,A); rs73584747(G,C); rs184013848(A,G); rs415738(A,G); rs7189876(C,T); rs378819(G,A); rs434395(C,T); rs441083(C,T); rs2010020(T,G); rs414723(C,T); rs1559406(G,C); rs1559407(T,C); rs12445467(T,C); rs117144701(G,A); rs388512(G,C); rs382888(A,C); rs385160(G,C); rs73584755(G,C); rs412099(A,C); rs187900812(A,T); rs71398137(A,G); rs562773(C,G); rs383673(A,C); rs448302(T,A); rs145894878(G,A); rs424074(G,A); rs12445829(G,C); rs410233(T,C); rs59344(A,C); rs398255(A,G); rs454120(A,G); rs450553(T,A); rs445862(C,G); rs400497(A,C); rs441004(A,G); rs369487(T,G); rs1813526(C,T); rs870(G,A); rs1553723(G,C); rs2016545(C,T); rs12935369(T,C); rs74465625(T,C); rs77610657(A,T); rs7197664(T,C); rs80342186(C,G); rs72818822(G,A); rs59879442(G,A); rs11861007(C,T); rs62040701(T,G); rs12927043(C,A); rs442608(T,C); rs11861125(C,T); rs60052137(C,G); rs419512(T,C); rs417711(A,G); rs58306472(T,C); rs183551708(C,G); rs449842(T,C); rs17642520(C,T); rs17796342(T,C); rs409150(G,A); rs384228(C,A); rs420196(C,G); rs58406349(T,C); rs4888015(A,G); rs79734883(A,C); rs115577721(T,A); rs116326902(T,C); rs403632(G,T); rs143107772(T,C); rs421405(T,A); rs407083(T,C); rs368920(C,G); rs450829(A,G); rs72628258(C,T); rs76302700(G,T); rs79495055(C,G); rs77979794(C,G); rs140357431(G,C); rs413263(G,T); rs12449081(C,T); rs78710990(T,G); rs12446313(A,G); rs11150144(T,A); rs386776(G,C); rs12448954(G,A); rs438254(C,T); rs8045652(A,G); rs427883(G,C); rs79737342(T,A); rs418017(T,C); rs74488365(T,C); rs76455842(T,C); rs384216(T,C); rs383362(G,T); rs2288035(G,C); rs2288034(C,G); rs2288033(T,C); rs117863142(G,A); rs2288032(G,A); rs12828(G,A); rs145901191(C,G); rs391870(T,C) |
| ccdsGene name | CCDS42196.1 |
| cytoBand name | 16q23.1 |
| EntrezGene GeneID | 51741 |
| EntrezGene Description | WW domain containing oxidoreductase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | WWOX:NM_001291997:exon6:c.A374G:p.Y125C,WWOX:NM_016373:exon7:c.A713G:p.Y238C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6067 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000754 |
| ESP All MAF | 0.000243 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0001225 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature (of varying degrees);
[Other];
Poor growth in infancy;
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
[Ears];
Low-set ears;
Dysmorphic ears;
[Eyes];
Hypertelorism;
Strabismus;
Epicanthal folds;
Narrow palpebral fissures;
Downslanting palpebral fissures;
Thick eyebrows;
Synophrys;
Long eyelashes (in some patients);
[Nose];
Broad nose;
[Mouth];
Thin upper lip;
High-arched palate;
Cupid's bow, exaggerated (in some patients)
ABDOMEN:
[Gastrointestinal];
Constipation (in some patients)
SKELETAL:
Delayed bone age (in some patients);
[Hands];
Short fingers;
Fifth finger clinodactyly;
Short middle phalanges;
Tapering fingers (in some patients);
[Feet];
Short toes
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple (in some patients);
[Hair];
Thick eyebrows;
Hairy elbows;
Hypertrichosis, patchy (in some patients);
Hypertrichosis, generalized (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia;
Slim, muscular build (in some patients);
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures (1 patient);
Wide-based gait;
Speech delay;
[Behavioral/psychiatric manifestations];
Aggressive behavior;
Autistic features
MISCELLANEOUS:
Hairy elbows become apparent in infancy and regress during adolescence;
Facial appearance becomes more apparent with age
MOLECULAR BASIS:
Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia
gene (MLL, 159555.0001)
OMIM Title
*605131 WW DOMAIN-CONTAINING OXIDOREDUCTASE; WWOX
;;FRAGILE SITE FRA16D OXIDOREDUCTASE; FOR;;
WOX1
FRAGILE SITE 16q23.2, INCLUDED; FRA16D, INCLUDED
OMIM Description
CLONING
By use of shotgun genomic sequencing and isolation and analysis of
transcripts mapping to a region of chromosome 16 commonly affected by
allelic loss in breast cancer, Bednarek et al. (2000) identified and
cloned a novel gene, the genomic structure of which spanned the entire
region. They designated the gene WWOX because it encodes a 414-amino
acid protein containing 2 WW domains coupled to a region with high
homology to the short-chain dehydrogenase/reductase (SRD) family of
enzymes. Northern blot analysis detected overexpression of a 2.2-kb WWOX
transcript in breast cancer cell lines when compared to normal tissues.
The highest normal expression was detected in hormonally regulated
tissues such as testis, ovary, and prostate. This expression pattern and
the presence of an SRD domain and specific amino acid features suggested
a role for WWOX in steroid metabolism. The presence of WW domains
indicated a role in protein-protein interactions.
Ried et al. (2000) independently identified this alternatively spliced
gene, which they named FOR (fragile site FRA16D oxidoreductase).
Alternatively spliced FOR transcripts (FOR I, FOR II, and FOR III)
encode proteins which share N-terminal WW domains and differ at their C
termini, with FOR III having a truncated oxidoreductase domain.
Using Western blot analysis and immunocytochemical staining, Aqeilan et
al. (2007) found that mouse Wwox was expressed predominantly as a
cytoplasmic protein in all tissues examined, with highest levels in
prostate, bone, lung, endocrine tissues, and brain.
GENE FUNCTION
Chang et al. (2001) showed that the mouse Wox1 protein is an essential
mediator of tumor necrosis factor-alpha-induced apoptosis. Furthermore,
mouse Wox1 protein binds directly to p53 (191170), and blocking Wox1 by
expression of antisense mRNA abolishes p53-mediated apoptosis in NIH 3T3
cells. The high conservation of WWOX protein between Homo sapiens and
Mus musculus (93% identity) supported a similar, important role in
apoptosis for human WWOX.
Bednarek et al. (2001) presented data indicating that WWOX behaves as a
potent suppressor of tumor growth and suggesting that abnormalities
affecting this gene at the genomic and transcriptional level may be
relevant in carcinogenesis.
Chang et al. (2003) found that Jnk1 (MAPK8; 601158) inhibited
Wox1-mediated apoptosis in mouse and human cell cultures. Jnk1
phosphorylated Wox1 and interacted directly with phosphorylated Wox1 in
coimmunoprecipitation assays.
GENE STRUCTURE
Bednarek et al. (2000) determined that the WWOX gene contains 9 exons.
MAPPING
By genomic sequence analysis, Bednarek et al. (2000) mapped the WWOX
gene to chromosome 16q23.3-q24.1
Two of the most frequently observed fragile sites in humans, FRA3B (see
601153) and FRA16D, show a high frequency of breakage and colocalize
with genes crossing large regions of breakage. At FRA3B, the fragile
histidine triad gene (FHIT; 601153) spans more than 1 Mb, and at FRA16D
the WWOX gene spans more than 750 kb. In the mouse, the common fragile
site Fra14A2 and the Fhit gene are conserved in the homologous region of
the genome. Krummel et al. (2002) positioned the mouse homolog of WWOX
(Wox1) at band 8E1 of the mouse genome, colocalizing with Fra8E1. The
sequence from this region, including introns, is highly conserved over
at least a 100-kb region. This evolutionary conservation suggests that
the 2 most active common fragile sites share many features and that they
and their associated genes may be necessary for cell survival.
MOLECULAR GENETICS
Bednarek et al. (2000) performed a mutation screen of WWOX exons in a
panel of breast cancer lines, most of which were hemizygous for the 16q
genomic region associated with allelic loss in breast cancer. They found
no evidence of mutations, indicating that WWOX is probably not a tumor
suppressor gene. However, they observed that 1 case of homozygous
deletion and 2 previously described translocation breakpoints map to
intronic regions of this gene. They speculated that the WWOX gene may
span the region of the common fragile site FRA16D.
Ried et al. (2000) determined that FRA16D-associated deletions
selectively affect the FOR gene transcripts, and 3 of 5 previously
mapped translocation breakpoints in multiple myeloma are also located
within the FOR gene. The authors hypothesized that FOR is therefore the
principal genetic target for DNA instability at 16q23.2 and that
perturbation of FOR function is likely to contribute to the biologic
consequences of DNA instability at FRA16D in cancer cells.
In a mutation screen of WWOX in human cancer, Paige et al. (2001)
demonstrated homozygous deletion of WWOX exons from ovarian cancer cells
and 3 different tumor cell lines. They also identified an internally
deleted WWOX transcript from a further primary ovarian tumor. In 3 of
these samples the deletions resulted in frameshifts, and in each case
the resulting WWOX transcripts lacked part, or all, of the short-chain
dehydrogenase domain and the putative mitochondrial localization signal.
Sequencing demonstrated several missense polymorphisms in tumor cell
lines and identified a high level of single nucleotide polymorphism
within the WWOX gene. The authors stated that the evidence strengthened
the case for WWOX as a tumor suppressor gene in ovarian cancer and other
tumor types.
Finnis et al. (2005) screened 53 cancer cell lines for deletions in the
WWOX gene and detected deletions in the Co115, KM12C, and KM12SM cell
lines. Homozygous deletions in these and 2 previously identified tumor
cell lines were intragenic on both alleles, suggesting a distinct
mutation mechanism from that causing LOH. Identical FRA16D deletions in
2 cell lines demonstrated that FRA16D DNA instability can be an early,
transient event. Sequence analysis of 1 deletion implicated AT-rich
repeats in FRA16D DNA instability. Another deletion was associated with
de novo repetition of a 9-bp AT-rich sequence at 1 of the deletion
endpoints. FRA16D-deleted cells retained cytogenetic fragile site
expression, indicating that the deletions were susceptible sites for
breakage rather than regions that confer fragility. Most cell lines with
FRA16D homozygous deletions also had FRA3B deletions. Finnis et al.
(2005) concluded that common fragile sites represent highly susceptible
genomewide targets for a distinct form of mutation.
Jiang et al. (2009) analyzed chromatin modification patterns within the
6 human common fragile sites (CFSs) with the highest levels of breakage,
including FRA3B and FRA16D (see 605131), and their surrounding
non-fragile regions. Chromatin at most of the CFSs analyzed had
significantly less histone acetylation than that of their surrounding
non-fragile regions. Trichostatin A and/or 5-azadeoxycytidine treatment
reduced chromosome breakage at CFSs. Chromatin at the most commonly
expressed CFS, FRA3B, was more resistant to micrococcal nuclease than
that of the flanking non-fragile sequences. The authors concluded that
histone hypoacetylation is a characteristic epigenetic pattern of CFSs,
and chromatin within CFSs may be relatively more compact than that of
the NCFSs, indicating a role for chromatin conformation in genomic
instability at CFSs. Jiang et al. (2009) hypothesized that lack of
histone acetylation at CFSs may contribute to the defective response to
replication stress characteristic of CFSs, leading to the genetic
instability characteristic of these regions.
- Autosomal Recessive Spinocerebellar Ataxia 12
In affected members of 2 consanguineous families of Saudi Arabian and
Israeli Palestinian descent, respectively, with autosomal recessive
spinocerebellar ataxia-12 (SCAR12; 614322), Mallaret et al. (2014)
identified 2 different homozygous missense mutations in the WWOX gene
(P47T, 605131.0002 and G372R, 605131.0003). The mutations, which were
found by whole-exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder in the families. The patients had onset of
generalized seizures in infancy, delayed psychomotor development with
mental retardation, and cerebellar ataxia. The 2 Israeli Palestinian
patients also showed spasticity. Western blot analysis of patient
fibroblasts showed normal amounts of the mutant P47T protein, but in
vitro functional studies showed that the mutant protein was unable to
bind a PPPY-containing oligopeptide, suggesting that the mutation causes
a conformational change that alters its ability to interact with normal
protein motifs. None of the patients or heterozygous carriers developed
cancer. No WWOX mutations were found in 189 additional unrelated ataxic
patients.
In an Egyptian girl, born of consanguineous parents, with a severe
lethal neurologic phenotype resulting in death at age 16 months,
Abdel-Salam et al. (2014) identified a homozygous nonsense mutation in
the WWOX gene (R54X; 605131.0004). The mutation, which was found by
whole-exome sequencing and confirmed by Sanger sequencing, segregated
with the disorder in the family. The patient had microcephaly, optic
atrophy, refractory seizures, and lack of psychomotor development.
Abdel-Salam et al. (2014) noted that the phenotype was similar to that
of the Wwox-null mouse, 'lethal dwarfism and epilepsy' (lde) (Suzuki et
al., 2009). The findings suggested a role for WWOX in neurodevelopment.
ANIMAL MODEL
Aqeilan et al. (2007) found that Wwox-null mouse pups were obtained at
the expected frequency; however, 4 of 13 Wwox-null mice developed focal
lesions that appeared to be chondroid osteosarcomas along the diaphysis
between age 3 days and 2.5 weeks, and all died by 4 weeks of age. Wwox
+/- mice were indistinguishable from wildtype littermates, but they
developed spontaneous lung papillary carcinomas as adults. These mice
also developed more ethyl nitrosourea-induced lung tumors and lymphomas
in comparison to wildtype littermates. Wwox +/- tumors expressed Wwox
protein, suggesting that haploinsufficiency of Wwox is cancer
predisposing.
Suzuki et al. (2009) described a spontaneous rat mutant, 'lethal
dwarfism with epilepsy' (lde/lde), characterized by dwarfism, postnatal
lethality, male hypogonadism, and a high incidence of epilepsy.
Neuropathology showed extracellular vacuoles in the hippocampus and
amygdala, and testes analysis showed retarded differentiation of Leydig
cells and increased apoptosis of spermatocytes. Sound stimulation
induced epileptic seizures in 95% of lde/lde rats, which started as wild
running and sometimes progressed to tonic-clonic seizures. The locus was
mapped to rat chromosome 19, and a homozygous 13-bp deletion in exon 9
was found in the Wwox gene. Western blot analysis detected Wwox proteins
of 47 and 42 kD in normal testes and hippocampi, whereas both products
were undetectable in the testes and hippocampi of homozygous mutant
rats, indicating a functionally null mutation.
Mallaret et al. (2014) observed that Wwox-null mice developed
spontaneous seizures and noise-induced seizures at around 2 weeks of
age. Knockout mice also developed balance disturbances. The progression
of these symptoms suggested a neurodegenerative process. These mice died
from failure to thrive before age 4 weeks.
MAF
| dbSNP name | rs30411(T,C); rs30412(C,G); rs2287974(T,C); rs30413(A,G); rs76707698(A,T); rs3743597(A,G); rs78971625(A,G); rs3826106(A,G); rs1055708(A,G); rs73587068(G,C); rs73587069(G,A); rs30414(C,T); rs117707161(G,A); rs77685317(A,G); rs1046729(G,C); rs1046958(G,A) |
| cytoBand name | 16q23.2 |
| EntrezGene GeneID | 4094 |
| EntrezGene Description | v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1033 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Venous thrombosis;
Portal hypertension
ABDOMEN:
[Liver];
Hepatic venous thrombosis;
Portal vein thrombosis;
Portal hypertension;
Hepatomegaly;
[Spleen];
Splenomegaly
NEUROLOGIC:
[Central nervous system];
Seizures, absence;
Seizures, atonic
HEMATOLOGY:
No hemolysis;
No bone marrow abnormalities
LABORATORY ABNORMALITIES:
Decreased expression of glycosylphosphatidylinositol-linked proteins
(e.g., CD59 107271 and CD24 600274) on hematopoietic cells
MISCELLANEOUS:
Two unrelated families have been reported (last curated May 2014);
Onset of thrombosis by age 2 years
MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol glycan, class M gene
(PIGM, 610273.0001)
OMIM Title
*610303 V-MAF AVIAN MUSCULOAPONEUROTIC FIBROSARCOMA ONCOGENE HOMOLOG A; MAFA
;;RIPE3B1
OMIM Description
DESCRIPTION
MAFA is a transcription factor that binds RIPE3b, a conserved enhancer
element that regulates pancreatic beta cell-specific expression of the
insulin gene (INS; 176730) (Olbrot et al., 2002).
CLONING
By searching a genomic database for sequences similar to hamster Mafa,
followed by PCR of genomic DNA, Olbrot et al. (2002) cloned human MAFA.
The deduced 352-amino acid protein contains an N-terminal activation
domain rich in serine, proline, and threonine, followed by 2
glycine-rich regions separated by a histidine-rich region, and a
C-terminal DNA-binding and dimerization domain containing a basic
leucine zipper. Northern blot analysis detected Mafa in mouse and
hamster insulinoma cells, in mouse thymus, and in mouse embryos at
embryonic day 14, and there was evidence of alternative splicing. No
expression was detected in other mouse tissues examined or in a
glucagon-producing cell line.
GENE FUNCTION
Using EMSA, Olbrot et al. (2002) found that full-length and N-terminally
truncated MAFA bound a RIPE3b probe, and it appeared to bind as a
homodimer. Following transfection in HeLa cells, only the full-length
protein activated insulin gene expression from the RIPE3b element,
although the N-terminally truncated form localized to the nucleus.
Expression of MAFA, as well as PDX1 (600733) and BETA2 (NEUROD1;
601724), 2 other transcription factors that bind enhancer elements in
the insulin gene, is enriched in beta cells. Following their
transfection into non-beta cell lines, Zhao et al. (2005) found that
rodent Pdx1 and Beta2 showed little or no activation of a reporter
construct driven by the insulin promoter in the absence of Mafa. Mafa
together with Pdx1 or Beta2 produced synergistic activation, and insulin
promoter activity was even higher when all 3 proteins were present.
Stimulation was attenuated upon compromising either Mafa transactivation
or DNA-binding activity. Coimmunoprecipitation and in vitro pull-down
assays showed that Mafa directly bound endogenous rodent Pdx1 and Beta2.
Dominant-negative and small interfering RNAs of Mafa profoundly reduced
insulin promoter activity in rodent beta cell lines. Mafa was induced in
parallel with insulin mRNA in glucose-stimulated rat islets, and insulin
mRNA levels were elevated in rat islets by adenovirus-mediated Mafa
expression. Zhao et al. (2005) concluded that MAFA plays a key role in
coordinating and controlling the level of insulin gene expression in
islet beta cells.
GENE STRUCTURE
Olbrot et al. (2002) determined that the coding region of the MAFA gene
is intronless.
MAPPING
By genomic sequence analysis, Olbrot et al. (2002) mapped the MAFA gene
to chromosome 8q24.
ANIMAL MODEL
Zhang et al. (2005) found that Mafa-null mice were born at the expected
frequency and survived until adulthood. Mafa-null mice displayed
intolerance to glucose and developed diabetes mellitus. Glucose-,
arginine-, or KCl-stimulated insulin secretion from pancreatic beta
cells was severely impaired, although insulin content per se was not
significantly affected. Mafa-null mice also showed age-dependent
pancreatic islet abnormalities. Molecular analysis revealed that Ins1,
Ins2, Pdx1, Beta2, and Glut2 (SLC2A2; 138160) transcripts were
diminished in Mafa-deficient mice.
Zhou et al. (2008) used a strategy of reexpressing key developmental
regulators in vivo to identify a specific combination of 3 transcription
factors, Neurog3 (604882), Pdx1 (600733), and Mafa, that reprogrammed
differentiated pancreatic exocrine cells in adult mice into cells that
closely resembled beta cells. Induced beta cells were indistinguishable
from endogenous islet beta cells in size, shape, and ultrastructure.
They expressed genes essential for beta cell function and could
ameliorate hyperglycemia by remodeling local vasculature and secreting
insulin. Zhou et al. (2008) concluded that their study provided an
example of cellular reprogramming using defined factors in an adult
organ and suggested a general paradigm for directing cell reprogramming
without reversion to a pluripotent stem cell state.
MIR7854
| dbSNP name | rs2925980(A,G) |
| ccdsGene name | CCDS54045.1 |
| cytoBand name | 16q23.2 |
| EntrezGene GeneID | 80790 |
| EntrezGene Symbol | CMIP |
| snpEff Gene Name | CMIP |
| EntrezGene Description | c-Maf inducing protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3641 |
| ExAC AF | 0.142 |
MIR6504
| dbSNP name | rs74469188(T,C) |
| ccdsGene name | CCDS54045.1 |
| cytoBand name | 16q23.2 |
| EntrezGene GeneID | 80790 |
| EntrezGene Symbol | CMIP |
| snpEff Gene Name | CMIP |
| EntrezGene Description | c-Maf inducing protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.129 |
| ExAC AF | 0.029 |
LOC100129617
| dbSNP name | rs3935338(T,C); rs4889359(G,C); rs144167711(C,T); rs57165671(C,G); rs4889360(C,T); rs4539589(C,T); rs138471902(G,A); rs112066886(G,A) |
| ccdsGene name | CCDS54045.1 |
| cytoBand name | 16q23.2 |
| EntrezGene GeneID | 100129617 |
| snpEff Gene Name | CMIP |
| EntrezGene Description | uncharacterized LOC100129617 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3416 |
MIR8058
| dbSNP name | rs16958290(G,C) |
| ccdsGene name | CCDS56009.1 |
| cytoBand name | 16q23.3 |
| EntrezGene GeneID | 1012 |
| EntrezGene Symbol | CDH13 |
| snpEff Gene Name | CDH13 |
| EntrezGene Description | cadherin 13 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09734 |
| ExAC AF | 0.007496 |
FLJ30679
| dbSNP name | rs3751796(T,C); rs918727(A,G); rs7189970(G,T); rs67417095(C,T); rs7197427(A,T) |
| cytoBand name | 16q24.1 |
| EntrezGene GeneID | 146512 |
| snpEff Gene Name | MTHFSD |
| EntrezGene Description | uncharacterized protein FLJ30679 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2287 |
| ExAC AF | 0.186 |
FOXL1
| dbSNP name | rs7184856(G,C); rs7186936(A,C); rs2288016(C,T); rs7185593(G,A); rs4843173(C,T) |
| cytoBand name | 16q24.1 |
| EntrezGene GeneID | 2300 |
| EntrezGene Description | forkhead box L1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.174 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)
ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism
LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration
MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)
MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)
OMIM Title
*603252 FORKHEAD BOX L1; FOXL1
;;FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 11; FKHL11;;
FORKHEAD-RELATED ACTIVATOR 7; FREAC7;;
FKH6
OMIM Description
CLONING
The forkhead domain is a 100-amino acid monomeric DNA-binding motif
originally identified as a region of homology between the Drosophila
forkhead protein and rat Hnf3. Pierrou et al. (1994) identified 7 human
genes encoding proteins with forkhead domains, including FOXL1, which
they designated FREAC7. Northern blot analysis of several human tissues
using a genomic FREAC7 fragment failed to detect FREAC7 expression.
GENE STRUCTURE
Madison et al. (2009) found that the upstream region of the FOXL1 gene
contains 5 conserved GLI (see 165220)-binding sites, as well as homeobox
and forkhead consensus sites.
MAPPING
Hartz (2009) mapped the FOXL1 gene to chromosome 16q24.1 based on an
alignment of the FOXL1 sequence (GenBank GENBANK BC117226) with the
genomic sequence (build 36.1).
Madison et al. (2009) stated that mouse Foxl1 maps to a region of
chromosome 8 containing several genes encoding forkhead transcription
factors.
GENE FUNCTION
Pierrou et al. (1994) determined the DNA binding specificity of FREAC7
through selection of high-affinity binding sites from random sequence
oligonucleotides.
Madison et al. (2009) found that expression of Foxf1 (601089) and Foxl1
in developing mouse stomach and intestine was dependent on Gli2 (165230)
and Gli3 (165240) and was induced by an N-terminal fragment of Shh
(600725). Several highly conserved Gli-binding sites appeared crucial
for Gli-mediated binding and transcriptional activation of Foxf1 and
Foxl1.
MOLECULAR GENETICS
In 10 patients with alveolar capillary dysplasia with misalignment of
pulmonary veins (ACDMPV; 265380) associated with multiple congenital
anomalies, Stankiewicz et al. (2009) identified 6 overlapping
microdeletions encompassing the FOX transcription factor gene cluster,
all but 1 of which included the FOXF1 gene; they also identified
heterozygosity for point mutations in 4 unrelated ACDMPV patients
(601089.0001-601089.0004, respectively). Stankiewicz et al. (2009) noted
that in contrast to the association of point mutations in FOXF1 with
bowel malrotation, microdeletions of FOXF1 were associated with
hypoplastic left heart syndrome and gastrointestinal atresias, which
they suggested was due to haploinsufficiency for the neighboring FOXC2
(602402) and FOXL1 genes.
ANIMAL MODEL
Kaestner et al. (1997) found that Fkh6-null mice showed postnatal growth
retardation secondary to severe structural abnormalities of the stomach,
duodenum, and jejunum. Dysregulation of epithelial cell proliferation in
these organs resulted in an approximately 4-fold increase in the number
of dividing intestinal epithelial cells and marked expansion of the
proliferative zone. As a consequence, the tissue architecture of the
stomach and small intestine was distorted, with abnormal crypt
structure, formation of mucin-filled cysts, and lengthening of villi.
Changes in the cellular phenotype and composition of the gastric and
intestinal epithelia also suggested that epithelial cell lineage
allocation or differentiation was affected by loss of Fkh6. Expression
of Bmp2 (112261) and Bmp4 (112262) was reduced in the gastrointestinal
tract of Fkh6-null mice, suggesting that FKH6 mediates communication
between the mesenchyme and endoderm of the gut to regulate cell
proliferation.
Fukamachi et al. (2001) generated Fkh6 -/- mice by targeted disruption.
In mice, Fkh6 is expressed only in gastrointestinal mesenchyme. Fkh6 -/-
mice had gastric mucosa hyperplasia with disordered glandular
structures. Both basal and stimulated acid secretion were severely
suppressed in the Fkh6 -/- stomachs, while immunohistochemical studies
showed that comparable numbers of parietal cells were differentiated in
both wildtype and mutant animals. Ultrastructurally, Fkh6 -/- parietal
cells were furnished with developed intracellular canaliculi and many
mitochondria, but their canaliculi were not enlarged or fully connected
to the luminal surface even when animals were treated with histamine,
suggesting that Fkh6 -/- parietal cells are far less responsive to acid
secretion-inducing stimulations than wildtype cells. Fukamachi et al.
(2001) concluded that FKH6 plays an essential role in the development
and differentiation of parietal cells via epithelial-mesenchymal
interactions.
Fukuda et al. (2003) found delayed formation of Peyer patches in the
small intestines of Foxl1-deficient mice. Peyer patch defects were
concordant with significantly decreased expression of lymphotoxin
B-receptor (LTBR; 600979) in the caudal region of the fetal intestine.
Katz et al. (2004) found that Foxl1 -/- mice had reduced uptake of
D-glucose in small intestine and decreased levels of the intestinal
D-glucose transporter Sglt1 (SLC5A1; 182380).
Takano-Maruyama et al. (2006) found that the small intestines of
Foxl1-deficient mice showed aberrant crypt structure, including abnormal
distribution of Paneth cells, that was associated with ectopic and
increased expression of Ephb2 (600997) and Ephb3 (601839), which are key
regulators of epithelial cell positioning. Real-time PCR showed that a
subset of Wnt family genes (see WNT1; 164820) was highly expressed in
the gut mesenchyme of Foxl1-deficient mice compared with that of
wildtype mice.
ZNF469
| dbSNP name | rs11648572(T,C); rs11640794(A,C); rs74032864(C,A); rs4782300(C,T); rs12445417(T,G); rs74032865(C,T); rs111916311(T,G); rs9931465(C,G); rs273585622(G,A); rs3812955(G,A); rs3812953(C,T); rs138771545(G,A); rs1983014(A,G); rs202129382(G,A); rs141042464(C,A); rs4782301(A,G); rs4782362(C,T); rs148260049(G,T); rs3894713(G,A); rs3848234(A,G) |
| ccdsGene name | CCDS45544.1 |
| cytoBand name | 16q24.2 |
| EntrezGene GeneID | 84627 |
| EntrezGene Description | zinc finger protein 469 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF469:NM_001127464:exon1:c.T1069C:p.S357P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96JG9 |
| dbNSFP Uniprot ID | ZN469_HUMAN |
| dbNSFP KGp1 AF | 0.983058608059 |
| dbNSFP KGp1 Afr AF | 0.993902439024 |
| dbNSFP KGp1 Amr AF | 0.986187845304 |
| dbNSFP KGp1 Asn AF | 0.998251748252 |
| dbNSFP KGp1 Eur AF | 0.963060686016 |
| dbSNP GMAF | 0.01699 |
| ExAC AF | 0.972 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive;
Cachexia;
Weight loss
HEAD AND NECK:
[Eyes];
Poor visual contact;
External ophthalmoplegia
ABDOMEN:
[Gastrointestinal];
Feeding difficulties;
Intestinal dysmotility (1 patient)
GENITOURINARY:
[Kidneys];
Proximal renal tubulopathy
MUSCLE, SOFT TISSUE:
Hypotonia;
Mitochondrial DNA depletion, severe;
Abnormal mitochondrial proliferation;
Cytochrome c oxidase deficiency;
Ragged red fibers
NEUROLOGIC:
[Central nervous system];
Neurologic deterioration;
Mental retardation;
Seizures;
Ataxic gait
METABOLIC FEATURES:
Lactic acidosis
LABORATORY ABNORMALITIES:
Aminoaciduria
MISCELLANEOUS:
Onset usually in infancy;
Death can occur in infancy;
Progressive disorder;
Some patients have later onset and more variable phenotype (MNGIE)
MOLECULAR BASIS:
Caused by mutation in the ribonucleotide reductase, M2 B gene (RRM2B,
604712.0001)
OMIM Title
*612078 ZINC FINGER PROTEIN 469; ZNF469
;;KIAA1858
OMIM Description
CLONING
By sequencing clones with the potential to encode large proteins
expressed in brain, Nagase et al. (2001) identified ZNF469, which they
designated KIAA1858. The deduced protein contains 772 amino acids.
RT-PCR ELISA detected moderate ZNF469 expression in most adult and fetal
tissues and specific adult brain regions examined. Expression was lower
only in adult pancreas.
MAPPING
By radiation hybrid analysis, Nagase et al. (2001) mapped the ZNF469
gene to chromosome 16. Abu et al. (2008) noted that an autosomal
dominant form of keratoconus had been mapped to chromosome 16q22.3-q23.1
(see KTCN2, 608932) and suggested that some patients with isolated
keratoconus might harbor mutations in ZNF469.
MOLECULAR GENETICS
Abu et al. (2008) analyzed the candidate gene ZNF469 in 4 Tunisian
Jewish families, including the family originally reported by Ticho et
al. (1980), and 1 Palestinian family with brittle cornea syndrome-1
(BCS1; 229200) and identified homozygosity for 2 different 1-bp
deletions (612078.0001 and 612078.0002, respectively).
In a Norwegian brother and sister with brittle cornea syndrome who were
originally described by Bertelsen (1968), Christensen et al. (2010)
identified homozygosity for a missense mutation in the ZNF469 gene that
affected the fourth of 5 zinc finger domains (612078.0003).
In affected sibs from a consanguineous Syrian family with brittle cornea
syndrome (BCS1), Khan et al. (2010) identified homozygosity for a
nonsense mutation in the ZNF469 gene (612078.0004).
Burkitt Wright et al. (2011) noted that the phenotypic spectrum in BCS
patients with mutations in either the ZNF469 or PRDM5 (614161) genes is
extremely similar if not identical (see BCS2, 614170), suggesting that
the 2 genes act within the same developmental pathway. Quantitative PCR
of mutant fibroblasts from BCS1 and BCS2 patients showed that mutation
in either ZNF469 or PRDM5 causes significant downregulation of genes
encoding molecules involved in extracellular matrix development and
maintenance, including fibrillar collagens, e.g., COL4A1 (120130) and
COL11A1 (120280), connective tissue components, e.g., HAPLN1 (115435),
and molecules regulating cell migration and adhesion, e.g., EDIL3
(606018) and TGFB2 (190220), compared to controls.
LOC400558
| dbSNP name | rs192347617(C,T) |
| cytoBand name | 16q24.3 |
| EntrezGene GeneID | 400558 |
| snpEff Gene Name | CDH15 |
| EntrezGene Description | uncharacterized LOC400558 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
MC1R
| dbSNP name | rs3212354(T,C); rs3212357(T,C); rs3212358(A,G); rs3212359(C,T); rs3212361(G,A); rs3212363(A,T); rs2228478(A,G); rs3212369(A,G); rs3212371(A,G) |
| cytoBand name | 16q24.3 |
| EntrezGene GeneID | 4157 |
| snpEff Gene Name | RP11-566K11.2 |
| EntrezGene Description | melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3131 |
OMIM Clinical Significance
Limbs:
One or 2 grotesquely enlarged fingers
Inheritance:
No report of familial occurrence
OMIM Title
*155555 MELANOCORTIN 1 RECEPTOR; MC1R
;;MELANOCYTE-STIMULATING HORMONE RECEPTOR; MSHR;;
MELANOTROPIN RECEPTOR
OMIM Description
CLONING
Melanocyte-stimulating hormone (MSH; melanotropin) and
adrenocorticotropic hormone (ACTH) regulate pigmentation and
adrenocortical function, respectively. They are products of the same
gene, the proopiomelanocortin (POMC; 176830) gene. MSH and ACTH bind to
receptors that couple to heterotrimeric guanine nucleotide-binding
proteins (G proteins) that activate adenylyl cyclase. Chhajlani and
Wikberg (1992) isolated from human melanoma cells a cDNA for the
melanocyte-stimulating hormone receptor. The cloned cDNA encoded a
317-amino acid protein with transmembrane topography characteristic of a
G protein-coupled receptor. Mountjoy et al. (1992) cloned the murine and
human MSH receptors and a human ACTH receptor (202200). These receptors
were said to define a subfamily of receptors coupled to G proteins that
may include the cannabinoid receptor (114610). The human MSH receptor
was 76% identical to the amino acid sequence of the murine receptor,
whereas the human ACTH receptor was approximately 39% identical with the
human MSH receptor. MSHR mRNA was expressed in melanocytes, and ACTHR
mRNA was expressed in adrenal tissue. Human MSHR was encoded
predominantly by a 3-kb species. Using PCR with primers based on
conserved areas of other members of 7-transmembrane G protein-linked
receptors, Gantz et al. (1993) isolated several genes encoding an
'orphan' subfamily of receptors specific for melanocortins. One was
identified as an alpha-MSH receptor, otherwise known as the
melanocortin-1 (MC1) receptor (Mountjoy et al., 1992; Chhajlani and
Wikberg, 1992).
GENE FUNCTION
Because of the potential immunogenicity of the MC1R gene, Lopez et al.
(2007) evaluated its expression in uveal melanoma. Their results
demonstrated that MC1R was expressed by uveal melanoma to a
significantly greater extent than other melanoma markers. MC1R was found
in 95% of melanoma tissues tested, including 1 liver metastasis. Even
though MC1R was mainly located intracellularly, its cell surface
expression could be promoted by cytokines, such as interferon-gamma
(147570) and tumor necrosis factor-alpha (191160). The data supported
MC1R as a new marker for the diagnosis of uveal melanoma and as a
putative therapeutic target.
MAPPING
By fluorescence in situ hybridization (FISH), Gantz et al. (1994) mapped
the MC1R gene to 16q24.3. Magenis et al. (1994) confirmed the assignment
of MSHR to 16q24 by FISH; by study of an intersubspecific backcross
mapping panel, they assigned the gene to mouse chromosome 8.
MOLECULAR GENETICS
- Hair and Skin Pigmentation
In mice, mutations in either the Mc1r gene or the agouti gene (AGTI;
600201) affect the pattern of melanogenesis, resulting in changes in
coat color (Jackson, 1993). Valverde et al. (1995) found MC1R gene
sequence variants in over 80% of individuals with red hair and/or fair
skin that tan poorly (see 266300) but in fewer than 20% of individuals
with brown or black hair, and in less than 4% of those who showed a good
tanning response. They interpreted the findings as indicating that MC1R
is a control point in the regulation of pigmentation phenotype and that
variations in this protein are associated with a poor tanning response.
In this study, they amplified by PCR and directly sequenced the entire
MC1R gene from 30 unrelated British or Irish individuals with different
shades of red hair and a poor tanning response and in 30 control
subjects of the same ethnicity with brown or black hair and good tanning
response. In all, 9 different changes were identified; 8 of them
clustered in a region of 42 amino acids, between the first cytoplasmic
loop and the first extracellular loop, spanning the second transmembrane
domain. The ninth change, asp294 to his (D294H; 155555.0001), was in the
seventh transmembrane domain and was the most common, occurring in 16 of
the individuals. Only 1 change in the coding region was found in 13
individuals, whereas 8 had 2 or more changes. They could establish that
7 of the 8 were compound heterozygotes for the changes. Although all
these changes may not represent functionally significant variants,
Valverde et al. (1995) noted that the most commonly observed variant,
D294H, replaces an acidic residue with a basic one. The other frequent
substitution, val92 to met (V92M; 155555.0002), together with the
changes at codons 84 and 95, might be expected to alter the alpha-helix
structure of the second transmembrane domain. The A64S substitution in
the first cytoplasmic loop of the MC1R could affect the ability to
stimulate adenylyl cyclase. The second transmembrane domain and the
first extracellular loop represent a key region of the receptor. All 3
dominant gain-of-function mutations in the mouse found by Robbins et al.
(1993) involved missense mutations in this region. The fairly common
occurrence of multiple variants in the same allele was considered
unusual, although not unprecedented (Savov et al., 1995).
Spritz (1995) pointed out puzzling features: one might expect mutations
associated with red hair to be recessive; most of the red-head and
fair-skinned individuals in their study were either heterozygous or had
no identifiable mutations. In other species, amino acid substitutions
within or adjacent to the second transmembrane domain of the MSHR
polypeptide constitutively activate the corresponding receptors,
resulting in dominant alleles. Alternatively, alleles that are
associated with red coat color in Norwegian red cattle (Klungland et
al., 1995) and in the red guinea pig are recessive and contain null
mutations.
Smith et al. (1998) studied a general Irish population in which there
was a preponderance of individuals with fair skin type; 75% carried a
variant in the MC1R gene, with 30% carrying 2 variants. The R151C
(155555.0004), R160W (155555.0005), and D294H variants were
significantly associated with red hair. Importantly, all individuals
harboring 2 of these 3 variants had red hair, although some red-haired
individuals showed only 1 alteration. The D294H variant was similarly
associated with red hair in a Dutch population, but was infrequent in
red-haired subjects from Sweden. The D294H variant was also
significantly associated with nonmelanoma skin cancer in a U.K.
population.
To determine the functional significance of the MC1R mutations
associated with red hair, Schioth et al. (1999) carried out transfection
and binding studies. Expression in COS-1 cells of the D294H, R151C, and
R160W mutations, as well as 2 other missense mutations, showed that
these receptors were unable to stimulate cAMP production as strongly as
the wildtype receptor in response to alpha-MSH stimulation. None of the
mutant receptors displayed complete loss of alpha-MSH binding.
Flanagan et al. (2000) studied MC1R variation in 174 individuals from 11
large kindreds with a preponderance of red hair (266300) and an
additional 99 unrelated redheads. They concluded that red hair is
usually inherited as a recessive characteristic with the R151C, R160W,
D294H, R142H, 86insA, and 537insC alleles at this locus. The V60L
(155555.0006) variant, which is common in the Caucasian population, may
act as a partially penetrant recessive allele. These individuals plus
167 randomly ascertained Caucasians demonstrated that heterozygotes for
2 alleles, R151C and 537insC, have a significantly elevated risk of red
hair. The shade of red hair frequently differs in heterozygotes from
that in homozygotes or compound heterozygotes. The authors also
presented evidence for a heterozygote effect on beard hair color, skin
type, and freckling.
Akey et al. (2001) studied the contribution of the MC1R and P (OCA2;
611409) genes to interindividual variation in skin pigmentation in a
Tibetan population. They genotyped 3 single-nucleotide polymorphisms
(SNPs) in the MC1R gene and 2 SNPs in the P gene in 184 randomly
ascertained Tibetan subjects, whose skin color was measured as a
quantitative trait by reflective spectroscopy. Single-locus analyses
failed to demonstrate an association between any of the 5 SNPs and skin
pigmentation. However, when an epistatic model was applied to the data,
a significant gene-gene interaction was identified between val92 to met
in the MC1R gene and IVS13-15T-C in the P gene.
Healy et al. (2000) examined variants in the MC1R gene in individuals
from Ireland and the U.K. Individuals with one variant allele were
intermediate with regard to skin type and the ability to tan after
repeated sun exposure between those with 2 variant alleles and those
with none of the variants. Analysis for trend from 0 to 2 variants was
highly significant, with little evidence of any nonlinear trend. Healy
et al. (2000) suggested that the MC1R gene status therefore determines
sun sensitivity in people without red hair.
Ephelides and solar lentigines are different types of pigmented skin
lesions. Ephelides (freckles) appear early in childhood and are
associated with fair skin type and red hair. Solar lentigines appear
with increasing age and are a sign of photodamage. Both lesions are
strong risk indicators for melanoma and nonmelanoma skin cancer. In a
large case-control study, Bastiaens et al. (2001) studied patients with
melanoma and nonmelanoma skin cancer and subjects without a history of
skin cancer. Carriers of 1 or 2 MC1R gene variants had a 3- and 11-fold
increased risk of developing ephelides, respectively (both P less than
0.0001), whereas the risk of developing severe solar lentigines was
increased 1.5- and 2-fold (P = 0.035 and P less than 0.0001),
respectively. These associations were independent of skin type and hair
color, and were comparable in patients with and without a history of
skin cancer. The population attributable risk for ephelides to MC1R gene
variants was 60%, and a dosage effect was found between the degree of
ephelides and the number of MC1R gene variants. As nearly all
individuals with ephelides were carriers of at least 1 MC1R gene
variant, the authors proposed that MC1R gene variants may be necessary
to develop ephelides, and may play a less important role in the
development of solar lentigines.
John and Ramsay (2002) reported 4 novel variants in MC1R in red-haired
South African individuals of European descent.
In Jamaica there are persons who self-identify as black who have
auburn/reddish hair, freckles, and a 'rust-colored' complexion
(sometimes called 'red Ibos'). McKenzie et al. (2003) examined MC1R
sequence and hair melanins in 4 Jamaican 'redheads.' Sequencing of the
MC1R gene revealed that all of the redheads were compound heterozygotes
for variants that were either known to or predicted to disrupt MC1R
function. The melanin values were within the range seen in white UK
individuals of equivalent MC1R status, suggesting that even on a
different genetic background MC1R variants exert a significant
phenotypic effect. McKenzie et al. (2003) concluded that red hair in
this group (with West African ancestry) can be accounted for in terms of
mutation of MC1R.
Rees (2004) stated that more than 65 human MC1R alleles with
nonsynonymous changes had been identified, and that the evidence at hand
suggested that many of them vary in their physiologic activity, such
that a graded series of responses can be achieved on the basis of (i)
dosage effects (of 1 or 2 alleles) and (ii) individual differences in
the pharmacologic profile in response to ligand. Thus, a single locus,
identified within a mendelian framework, can contribute significantly to
human pigmentary variation. Despite a large number of murine coat-color
mutations, only this 1 gene in humans was known to account for
substantial variation in skin and hair color and in skin cancer
incidence.
In 22 redheaded individuals with 2 or more MC1R variant alleles (R151C,
R160W, and D294H) known to abolish receptor function, Mogil et al.
(2005) found increased baseline pain tolerance and increased analgesic
response after administration of the mu-opioid selective morphine
metabolite, morphine-6-glucuronide (M6G), compared to controls.
Experiments in Mc1r-null mice yielded similar results; in both humans
and mice, the M6G/MC1R interaction was sex-independent.
Using immunofluorescence and ligand-binding studies, Beaumont et al.
(2005) found that melanocytic cells exogenously or endogenously
expressing MC1R showed strong surface localization of wildtype and D294H
receptors, but markedly reduced cell surface expression of R151C, R160W,
D84E (15555.0003), and I155T receptors. Variants weakly associated with
red hair color, such as V60L, V92M, and R163Q, were expressed with
normal or intermediate cell surface receptor levels. Beaumont et al.
(2005) suggested that receptor localization, in addition to reduced
receptor coupling activity, may also contribute to the genetic
association between the MC1R variants and the red hair color phenotype.
Gerstenblith et al. (2007) reviewed 52 published studies that examined
the allele frequency of MC1R polymorphisms in various human populations.
There were large differences in the distribution of variants across
populations, with a prominent difference between lightly and darkly
pigmented individuals. Among Caucasian groups, there were 7 variants
with significantly different allele frequencies.
Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide
association scan for variants associated with hair and eye pigmentation,
skin sensitivity to sun, and freckling. The most closely associated SNPs
from 6 regions were then tested for replication in a second sample of
2,718 Icelanders and a sample of 1,214 Dutch. Sulem et al. (2007)
detected a 1-Mb region of strong linkage spanning 38 SNPs and containing
the MC1R gene that was associated with red hair, skin sensitivity to
sun, and freckles. SNPs within the region also showed a trend towards
association with blond hair. The association signal was due to the
previously reported SNPs dbSNP rs1805007 (R151C; 155555.0004) and dbSNP
rs1805008 (R160W; 155555.0005). Analysis of allele frequencies suggested
that both mutated alleles may have been at least weakly affected by
recent positive selection.
- Melanoma
Valverde et al. (1996) reported that certain variants of the MC1R gene
are more common in individuals with melanoma (CMM5; 613099) than in
control subjects and that this association is greater than the
association between melanoma and skin type. MC1R variants in the second
and seventh transmembrane domains were more common in melanoma cases
than controls (chi square = 6.75, 1 d.f.; p = 0.0094) with a relative
risk to carriers of variant alleles compared with normal homozygotes of
3.91. The D84E variant was only present in melanoma cases.
Palmer et al. (2000) studied the relationship between risk of melanoma
and MC1R polymorphisms. They reported the occurrence of 5 common MC1R
variants in an Australian population-based sample of 460 individuals
with familial and sporadic CMM and 399 control individuals, as well as
the relationship of these polymorphisms to such other risk factors as
skin, hair, and eye color, freckling, and nevus count. There was a
strong relationship between MC1R variants and hair color and skin type.
Moreover, MC1R variants were found in 72% of persons with CMM, whereas
only 56% of the control individuals carried at least 1 variant (P less
than 0.01), a finding independent of strength of family history of
melanoma. Three 'active' alleles previously associated with red hair
(R151C, R160W, and D294H) doubled CMM risk for each additional allele
carried. No such independent association could be demonstrated with the
V60L and D84E variants. Among pale-skinned individuals alone, this
association between CMM and MC1R variants was absent, but it persisted
among those reporting a medium or olive/dark complexion. Palmer et al.
(2000) concluded that the effect that MC1R variant alleles have on CMM
is partly mediated via determination of pigmentation phenotype, and that
these alleles may have also negated the protection normally afforded by
darker skin coloring in some members of this white population.
Mutations in the CDKN2A gene (600160) are melanoma predisposition
alleles with high penetrance, although they have low population
frequencies. In contrast, variants of MC1R confer much lower melanoma
risk but are common in European populations. To test for possible
modifier effects on melanoma risk, Box et al. (2001) assessed 15
Australian CDKN2A mutation-carrying melanoma pedigrees for MC1R
genotype. A CDKN2A mutation in the presence of a homozygous consensus
MC1R genotype had a raw penetrance of 50%, with a mean age at onset of
58.1 years. When an MC1R variant allele was also present, the raw
penetrance of the CDKN2A mutation increased to 84%, with a mean age at
onset of 37.8 years (P = 0.01). The presence of a CDKN2A mutation gave a
hazard ratio of 13.35, and a hazard ratio of 3.72 for MC1R variant
alleles was also significant. The impact of MC1R variants on risk of
melanoma was mediated largely through the action of the 3 common
alleles, R151C, R160W, and D294H, associated with red hair, fair skin,
and skin sensitivity to ultraviolet light.
Van der Velden et al. (2001) found that the MC1R variant R151C modified
melanoma risk in Dutch families with melanoma. They concluded that the
R151C variant is overrepresented in patients with melanoma from families
with the p16-Leiden mutation (600160.0003). They suggested that the
R151C variant may be involved in melanoma tumorigenesis in a dual
manner, both as a determinant of fair skin and as a component in an
independent additional pathway, because the variant contributed to
increased melanoma risk even after statistical correction for its effect
on skin type.
Bastiaens et al. (2001) presented findings indicating that MC1R gene
variants are important independent risk factors for nonmelanoma skin
cancer. A strong association between MC1R gene variants and fair skin
and red hair was established, but when subjects were stratified by skin
type and hair color, analyses showed that these factors did not
materially change the relative risk of nonmelanoma skin cancer.
Landi et al. (2006) showed that MC1R variants are strongly associated
with BRAF (164757) mutations in nonchronic sun-induced damage melanomas.
In this tumor subtype, the risk for melanoma associated with MC1R is due
to an increase in risk of developing melanomas with BRAF mutations.
Landi et al. (2006) found that BRAF mutations were more frequent in
nonchronic sun-induced damage melanoma cases with germline MC1R variants
than in those with 2 wildtype MC1R alleles. When the authors categorized
patients into 2 groups, homozygous MC1R wildtype versus all others, they
found that BRAF mutations were 6 to 13 times as frequent in those with
at least 1 MC1R variant allele compared to those with no MC1R variants.
Four more tests for interaction between age and MC1R were not
significant. Comparison of nonchronic sun-damaged Italian cases with 171
healthy Italian controls showed that the overall melanoma risk was
higher by a factor of 3.3 (95% CI 1.5-6.9) in individuals with any MC1R
variant allele compared to individuals with no variant alleles and that
the risk increased with the number of variant MC1R alleles.
Perez Oliva et al. (2009) performed functional characterization of 6
MC1R missense mutations found in Spanish melanoma patients, 1 of which
was found to be a functionally silent polymorphism. The 5 other
mutations were associated with varying degrees of loss of function,
ranging from moderate decreases in coupling to the cAMP pathway to
nearly complete absence of functional coupling. Two of the variants were
trafficked to the cell surface but were unable to bind agonists
efficiently, whereas the other 3 variants had reduced cell surface
expression due to retention in the endoplasmic reticulum.
- Susceptibility to UV-Induced Sun Damage
Nakayama et al. (2006) identified 3 rare novel variants of the MC1R gene
(155555.0007-155555.0009) among 995 individuals from 30 Asian and
Oceanian populations. The variants were found only in East Asian
populations that were geographically localized in relatively high
latitudes, suggesting that the adaptation to ambient UV light intensity
may play a role in shaping the geographic distribution of MC1R alleles
in Asia and Oceania. Frequency of the V92M (155555.0002) variant was
particularly high in Southeast Asia (0.43), which the authors postulated
was due to demographic effects and migration.
- Kappa-Opioid Analgesia
Mogil et al. (2003) noted that sex specificity of neural mechanisms
modulating nociceptive information has been demonstrated in rodents, and
these qualitative sex differences appear to be relevant to analgesia
from kappa-opioid receptor (165196) agonists, a drug class reported to
be clinically effective only in women. By QTL mapping followed by a
candidate gene strategy using both mutant mice and pharmacologic tools,
Mogil et al. (2003) demonstrated that the Mc1r gene mediates
kappa-opioid analgesia (613098) in female mice only. This finding
suggested that individuals with variants of the human MC1R gene
associated with red hair and fair skin might also display altered
kappa-opioid analgesia. Of 9 males and 5 females with 2 variant MC1R
alleles (i.e., either homozygotes or compound heterozygotes), 3 were
homozygous for R151C (155555.0004), 1 was homozygous for D294H
(155555.0001), 6 were compound heterozygous for R151C and R160W
(155555.0005), 2 were compound heterozygous for R151C/D294H, and 1 was
compound heterozygous for R160W/V92M (155555.0002). Mogil et al. (2003)
found that women with 2 variant MC1R alleles (see 155555.0004 and
155555.0005) displayed significantly greater analgesia from the
kappa-opioid pentazocine than all other groups. They observed that skin
type appeared to be a better proxy for MC1R genotype than hair color, as
these effects reached significance for ischemic pain when light- versus
dark-skinned women were compared, but did not do so when red-haired
women were compared with women without red hair. This study demonstrated
an unexpected role for the MC1R gene, verified that pain modulation in
the 2 sexes involves neurochemically distinct substrates, and
represented an example of a direct translation of a pharmacogenetic
finding from mouse to human.
- Modification of Oculocutaneous Albinism
King et al. (2003) pointed out that oculocutaneous albinism (OCA) can be
produced by mutations at least 11 loci. They provided the first
demonstration of a gene modifying the OCA phenotype in humans. Most
individuals with OCA develop some cutaneous melanin; this is
predominantly seen as yellow/blond hair, whereas fewer have brown hair.
The OCA phenotype is dependent on the constitutional pigmentation
background of the family, with more OCA pigmentation found in families
with darker constitutional pigmentation, which indicates that other
genes may modify the OCA phenotype. In the average population, sequence
variation in the MC1R gene is associated with red hair, but red hair is
unusual in OCA. King et al. (2003) identified 8 probands with OCA2
(203200) who had red hair at birth. Mutations in the P gene were
responsible for the classic phenotype of OCA2 in all 8, and mutations in
the MC1R gene were responsible for the red (rather than yellow/blond)
hair in the 6 of the 8 who continued to have red hair after birth. They
illustrated one of their patients, an 18-year-old female of northern
European ancestry with red hair. She carried a trp679-to-cys mutation in
the P gene (W679C; 611409.0009) from her mother and an asn489-to-asp
mutation (N489D; 611409.0010) in the P gene from her father. At the MC1R
locus she was a compound heterozygote for arg151 to cys (R151C;
155555.0004) and arg160 to trp (R160W; 155555.0005).
EVOLUTION
Rompler et al. (2006) identified coat-color polymorphisms in the mammoth
(Mammuthus primigenius) Mc1r gene. One of these, arg67 to cys, is
carried at the homologous sequence position by light-colored populations
of the beach mouse (Peromyscus polionotus leucocephalus). Functional
tests and crossing experiments revealed both a reduction in basal and
induced activity highly similar to that observed for the mammoth MC1R
protein and a strong association between this amino acid polymorphism
and adaptive coat color phenotype (Hoekstra et al., 2006).
The MC1R gene regulates pigmentation in human and other vertebrates.
Variants of MC1R with reduced function are associated with pale skin
color and red hair in humans of primarily European origin. Lalueza-Fox
et al. (2007) amplified and sequenced a fragment of the MC1R gene (mc1r)
from 2 Neanderthal remains. Both specimens had a mutation (arg307 to
gly) that was not found in approximately 3,700 modern humans analyzed.
Functional analyses showed that this variant reduces MC1R activity to a
level that alters hair and/or skin pigmentation in humans. The impaired
activity of this variant suggested that Neanderthals varied in
pigmentation levels, potentially on the scale observed in modern humans.
Lalueza-Fox et al. (2007) concluded that inactive MC1R variants evolved
independently in both modern humans and Neanderthals.
The brown mutation in blind Mexican cave fish results in reduced
pigmentation of the eye and reduced number and size of melanophores of
the skin. Gross et al. (2009) identified 2 independent genetic changes
in the coding sequence of the Mc1r gene in 2 geographically separated
populations of Mexican cave fish with the brown mutant phenotype.
ANIMAL MODEL
In the mouse, the coat color extension locus has been identified with
the MSH receptor gene. A truncated MSH receptor leads to light coat
color, while activating mutations of the receptor lead to dark coat
color (Robbins et al., 1993).
Joerg et al. (1996) demonstrated that red coat color in Holstein cattle
is associated with a deletion in the MSHR gene. Chestnut (red) coat
color in horses was shown by Johansson et al. (1994) to cosegregate with
polymorphism at the MSHR locus. Marklund et al. (1996) demonstrated that
polymorphism consists of a single missense mutation, ser83phe, in the
MC1R allele associated with the chestnut color. The substitution occurs
in the second transmembrane region, which apparently plays a key role in
the molecule since substitutions associated with coat color variance in
mice and cattle as well as red hair and fair skin in humans are found in
this part of the molecule.
Loss of MC1R function in nonhuman mammals results in red or yellow hair
pigmentation. Healy et al. (2001) demonstrated that a mouse bacterial
artificial chromosome (BAC) containing Mc1r rescued loss of Mc1r in
transgenic mice, and overexpression of the receptor suppressed the
effect of the endogenous antagonist, agouti protein (ASIP; 600201). The
human receptor also efficiently rescued Mc1r deficiency and, in
addition, appeared to be completely resistant to the effects of agouti,
suggesting agouti protein may not play a role in human pigmentary
variation. Three human variant alleles (D294H, 155555.0001; R151C,
155555.0004; and R160W, 155555.0005) were engineered into the BAC, and
each had reduced, but not completely absent, function in transgenic
mice. Comparison of the phenotypes of alpha-MSH-deficient mice and
humans in conjunction with these data suggested to the authors that red
hair may not be the null phenotype of MC1R.
Eizirik et al. (2003) studied the molecular genetics and evolution of
melanism in the cat family. Melanistic coat coloration occurs as a
common polymorphism in 11 of 37 felid species and reaches high
population frequency in some cases but never achieves complete fixation.
Eizirik et al. (2003) mapped, cloned, and sequenced the cat homologs of
2 putative candidate genes for melanism, ASIP and MC1R, and identified 3
independent deletions associated with dark coloration in 3 different
felid species. Association and transmission analyses revealed that a
2-bp deletion in the ASIP gene specifies black coloration in domestic
cats, and 2 different in-frame deletions in the MC1R gene are implicated
in melanism in jaguars and jaguarundis. Melanistic individuals from 5
other felid species did not carry any of these mutations, implying that
there are at least 4 independent genetic origins for melanism in the cat
family. The inferred multiple origins and independent historical
elevation in population frequency of felid melanistic mutations
suggested the occurrence of adaptive evolution of this visible phenotype
in a group of related free-ranging species.
An MC1R arg306-to-ter (R306X) mutation was shown to cause a completely
red or yellow coat color in certain dog breeds such as Irish setters,
yellow Labrador retrievers, and golden retrievers (Newton et al., 2000;
Everts et al., 2000). Black mask is a characteristic pattern in which
red, yellow, tan, fawn, or brindle dogs exhibit a melanistic muzzle
which may extend up onto the ears. Melanistic mask is inherited in
several dog breeds as an autosomal dominant trait, and appears to be a
fixed trait in a few breeds. Schmutz et al. (2003) examined the amino
acid sequence of the MC1R gene in 17 dogs with melanistic masks from 7
breeds, 19 dogs without melanistic masks, and 7 dogs in which their coat
color made the mask difficult to distinguish. All dogs with a melanistic
mask had at least one copy of a valine substitution for methionine at
amino acid 264 (M264V) and none was homozygous for the R306X mutation.
Nachman et al. (2003) described the molecular changes underlying
adaptive coat color variation in a natural population of rock pocket
mice. These mice are generally light-colored and live on light-colored
rocks. However, populations of dark (melanic) mice are found on dark
lava, and this concealing coloration provides protection from avian and
mammalian predators. Nachman et al. (2003) conducted association studies
by using markers in candidate pigmentation genes and discovered 4
mutations in the Mc1r gene that seem to be responsible for adaptive
melanism in one population of lava-dwelling pocket mice. However,
another melanic population of these mice on a different lava flow showed
no association with Mc1r mutations, indicating that adaptive dark color
had evolved independently in this species through changes at different
genes.
'Tawny' is an autosomal recessive coat color found in a wild population
of Japanese mice and maintained in an inbred laboratory strain. Tawny
mice show light yellowish brown coloration on the dorsal region, with a
white belly and black eyes. Wada et al. (2005) identified 6 nucleotide
changes in the Mc1r gene in tawny mice, leading to 3 amino acid
substitutions. They determined that one of the substitutions, trp252 to
cys, is unique to tawny mice and is therefore responsible for the tawny
coat color.
Natural populations of beach mice exhibit a characteristic color
pattern, relative to their mainland conspecifics, driven by natural
selection for crypsis. Hoekstra et al. (2006) identified a derived,
charge-changing amino acid mutation in the melanocortin-1 receptor
(R65C) in beach mice that decreases receptor function. In genetic
crosses, allelic variation at Mc1r explains 9.8% to 36.4% of the
variation in 7 pigmentation traits determining color pattern. The
derived Mc1r allele is present in Florida's Gulf Coast beach mice but
not in Atlantic coast mice with similar light coloration, suggesting
that different molecular mechanisms are responsible for convergent
phenotypic evolution. Hoekstra et al. (2006) concluded that they were
able to link a single mutation in the coding region of a pigmentation
gene to adaptive quantitative variation in the wild.
D'Orazio et al. (2006) showed that ultraviolet light potently induced
expression of melanocyte-stimulating hormone (MSH; 176830) in
keratinocytes, but failed to stimulate pigmentation in the absence of
functional MC1R in red/blonde-haired mice possessing an inactivating
mutation of the MSH receptor (Mclr(e/e) mice, formerly known as
extension). However, pigmentation could be rescued by topical
application of the cyclic AMP agonist forskolin, without the need for
ultraviolet light, demonstrating that the pigmentation machinery is
available despite the absence of functional MC1R. This chemically
induced pigmentation was protective against ultraviolet light-induced
cutaneous DNA damage and tumorigenesis when tested in the cancer-prone,
xeroderma pigmentosum complementation group C (278720)-deficient genetic
background. D'Orazio et al. (2006) concluded that these data emphasize
the essential role of intercellular MSH signaling in the tanning
response, and suggest a clinical strategy for topical small-molecule
manipulation of pigmentation.
Jackson et al. (2007) found that the pigmentation pattern of wildtype
mice and transgenic mice expressing human MC1R appeared identical.
However, human MC1R was more sensitive to the exogenous ligand alpha-MSH
than was mouse Mc1r. Mouse Mc1r, but not human MC1R, elicited eumelanin
synthesis in the absence of ligand. Mouse Asp blocked activation of
human MC1R, but it did not exaggerate the inhibition of MC1R toward
reverse signaling as it did with mouse Mc1r. Both human and mouse MC1R
showed ligand-independent signaling in transfected cells.
Melanism in the gray wolf, Canis lupus, is caused by mutation in the K
locus, which encodes a beta-defensin protein (DEFB103A; 606611) that
acts as an alternative ligand for Mc1r. Anderson et al. (2009) showed
that the melanistic K locus mutation in North American wolves derives
from past hybridization with domestic dogs, has risen to high frequency
in forested habitats, and exhibits a molecular signature of positive
selection. The same mutation also causes melanism in the coyote, Canis
latrans, and in Italian gray wolves. Anderson et al. (2009) concluded
that their results demonstrated how traits selected in domesticated
species can influence the morphologic diversity of their wild relatives.
Mitra et al. (2012) introduced a conditional, melanocyte-targeted allele
of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying
an inactivating mutation in the Mc1r gene, Mc1r(e/e), which results in a
phenotype analogous to red hair/fair skin humans. The authors observed a
high incidence of invasive melanomas without providing additional gene
aberrations or ultraviolet radiation exposure. To investigate the
mechanism of ultraviolet radiation-independent carcinogenesis, Mitra et
al. (2012) introduced an albino allele, which ablates all pigment
production on the Mc1r(e/e) background. Selective absence of pheomelanin
synthesis was protective against melanoma development. In addition,
normal Mc1r(e/e) mouse skin was found to have significantly greater
oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. Mitra
et al. (2012) concluded that these data suggested that the pheomelanin
pigment pathway produces ultraviolet radiation-independent carcinogenic
contributions to melanogenesis by a mechanism of oxidative damage. The
authors further concluded that although protection from ultraviolet
radiation remains important, additional strategies may be required for
optimal melanoma prevention.
CENPBD1
| dbSNP name | rs13336336(G,A); rs4785755(G,A); rs4424910(C,A) |
| cytoBand name | 16q24.3 |
| EntrezGene GeneID | 92806 |
| snpEff Gene Name | DEF8 |
| EntrezGene Description | CENPB DNA-binding domains containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05188 |
C16orf3
| dbSNP name | rs3785183(C,T); rs74424322(G,T); rs12926012(C,G); rs12925087(G,A) |
| ccdsGene name | CCDS32518.1 |
| CosmicCodingMuts gene | C16orf3 |
| cytoBand name | 16q24.3 |
| EntrezGene GeneID | 2622 |
| EntrezGene Symbol | GAS8 |
| EntrezGene Description | growth arrest-specific 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C16orf3:NM_001214:exon1:c.G190A:p.V64I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O95177 |
| dbNSFP Uniprot ID | CP003_HUMAN |
| dbNSFP KGp1 AF | 0.292124542125 |
| dbNSFP KGp1 Afr AF | 0.39837398374 |
| dbNSFP KGp1 Amr AF | 0.292817679558 |
| dbNSFP KGp1 Asn AF | 0.18006993007 |
| dbNSFP KGp1 Eur AF | 0.307387862797 |
| dbSNP GMAF | 0.292 |
| ExAC AF | 0.24 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature (of varying degrees);
[Other];
Poor growth in infancy;
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
[Ears];
Low-set ears;
Dysmorphic ears;
[Eyes];
Hypertelorism;
Strabismus;
Epicanthal folds;
Narrow palpebral fissures;
Downslanting palpebral fissures;
Thick eyebrows;
Synophrys;
Long eyelashes (in some patients);
[Nose];
Broad nose;
[Mouth];
Thin upper lip;
High-arched palate;
Cupid's bow, exaggerated (in some patients)
ABDOMEN:
[Gastrointestinal];
Constipation (in some patients)
SKELETAL:
Delayed bone age (in some patients);
[Hands];
Short fingers;
Fifth finger clinodactyly;
Short middle phalanges;
Tapering fingers (in some patients);
[Feet];
Short toes
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple (in some patients);
[Hair];
Thick eyebrows;
Hairy elbows;
Hypertrichosis, patchy (in some patients);
Hypertrichosis, generalized (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia;
Slim, muscular build (in some patients);
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures (1 patient);
Wide-based gait;
Speech delay;
[Behavioral/psychiatric manifestations];
Aggressive behavior;
Autistic features
MISCELLANEOUS:
Hairy elbows become apparent in infancy and regress during adolescence;
Facial appearance becomes more apparent with age
MOLECULAR BASIS:
Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia
gene (MLL, 159555.0001)
OMIM Title
*605179 CHROMOSOME 16 OPEN READING FRAME 3; C16ORF3
OMIM Description
CLONING
Loss of heterozygosity involving chromosome 16q24.3 is common in breast
and prostate cancer and suggests the presence of a tumor suppressor
gene. Whitmore et al. (1998) characterized a transcript located in the
smallest region of deletion (GAS11; 605178). Within the second intron of
the GAS11 gene, they discovered a second gene, C16ORF3 (chromosome 16
open reading frame 3), that is intronless, transcribed in the opposite
orientation, and expressed at low levels. They performed mutational
analysis by SSCA and could find no nucleotide base changes in either
gene between 17 primary tumors and their corresponding matched normal
DNA.
DBIL5P
| dbSNP name | rs2251689(G,A); rs11654315(T,C); rs73975100(C,T); rs73975101(G,C); rs3087833(G,A); rs3813431(G,A) |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 100131454 |
| snpEff Gene Name | GEMIN4 |
| EntrezGene Description | diazepam binding inhibitor-like 5, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4183 |
OR1D2
| dbSNP name | rs4300683(G,A); rs769424(T,C); rs769423(C,T) |
| ccdsGene name | CCDS11019.1 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 4991 |
| EntrezGene Description | olfactory receptor, family 1, subfamily D, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1D2:NM_002548:exon1:c.C719T:p.T240I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P34982 |
| dbNSFP Uniprot ID | OR1D2_HUMAN |
| dbNSFP KGp1 AF | 0.157051282051 |
| dbNSFP KGp1 Afr AF | 0.443089430894 |
| dbNSFP KGp1 Amr AF | 0.17679558011 |
| dbNSFP KGp1 Asn AF | 0.0227272727273 |
| dbNSFP KGp1 Eur AF | 0.0633245382586 |
| dbSNP GMAF | 0.1561 |
| ESP Afr MAF | 0.309805 |
| ESP All MAF | 0.147547 |
| ESP Eur/Amr MAF | 0.064419 |
| ExAC AF | 0.102 |
OMIM Clinical Significance
Mouth:
Odontoma
GI:
Dysphagia
Lab:
Esophageal smooth muscle hypertrophy
Inheritance:
Autosomal dominant
OMIM Title
*164342 OLFACTORY RECEPTOR, FAMILY 1, SUBFAMILY D, MEMBER 2; OR1D2
;;OLFACTORY RECEPTOR 1; OLFR1;;
TESTICULAR ODORANT RECEPTOR OR17-4; OR17-4
OMIM Description
DESCRIPTION
The olfactory system is able to distinguish a very large number of
odorant molecules. Olfactory receptors are encoded by an extremely large
subfamily of G protein-coupled receptors. These receptors share a
7-transmembrane domain structure with many neurotransmitter and hormone
receptors. They are responsible for the recognition and G
protein-mediated transduction of odorant signals. The genes encoding
these receptors are devoid of introns within their coding regions, but
have a long intron splicing the 5-prime untranslated region (summary by
Schurmans et al., 1993).
OR1D2 is believed to function in human sperm chemotaxis and may be a
critical component of the fertilization process (Spehr et al., 2003).
CLONING
Schurmans et al. (1993) cloned a member of the olfactory receptor family
of genes, OLFR1, from a genomic library by cross-hybridization with a
gene fragment obtained by PCR.
Spehr et al. (2003) identified OR17-4, the human testicular olfactory
receptor. With the use of ratiofluorometric imaging, calcium signals
were induced by a small subset of applied chemical stimuli, establishing
the molecular receptive fields for the recombinantly expressed receptor
in HEK293 cells and the native receptor in human spermatozoa. Bourgeonal
was a powerful agonist for both recombinant and native receptor types,
as well as a strong chemoattractant in subsequent behavioral bioassays.
In contrast, undecanal was a potent olfactory receptor antagonist to
bourgeonal and related compounds. Spehr et al. (2003) concluded that
human OR17-4 functions in human sperm chemotaxis and may be a critical
component of the fertilization process.
GENE FUNCTION
Nekrasova et al. (1996) overexpressed human (OR17-4) and rat (olp4)
olfactory receptor genes in insect cells, purified them, and
characterized them biochemically. They identified monomeric, dimeric,
and trimeric forms of the proteins corresponding to molecular weights of
32, 69, and 94 kD by electrophoresis. The oligomers were resistant to
reduction and alkylation and were therefore thought to be held together
by SDS-resistant hydrophobic interactions, consistent with observations
of other G protein-coupled receptors.
MAPPING
By isotopic in situ hybridization, Schurmans et al. (1993) mapped the
OLFR1 gene to 17p13-p12 with a peak at band 17p13. A minor peak was
detected on chromosome 3, with a maximum in the region 3q13-q21. After
MspI digestion, a RFLP was demonstrated. Using this in a study of 3 CEPH
pedigrees, they demonstrated linkage with D17S126 at 17pter-p12; maximum
lod = 3.6 at theta = 0.0. Used as a probe on Southern blots under
moderately stringent conditions, the cDNA hybridized to at least 3
closely related genes.
GENE FAMILY
Buck and Axel (1991) discovered this large family of genes encoding
putative odorant receptor genes. The isolation of OR genes from the rat
by Buck and Axel (1991) was based on 3 assumptions. First, ORs are
likely G protein-coupled receptors, which characteristically are
7-transmembrane proteins. Second, ORs are likely members of a multigene
family of considerable size, because an immense number of chemicals with
vastly different structures can be detected and discriminated by the
vertebrate olfactory system. Third, ORs are likely expressed selectively
in olfactory sensory neurons.
Issel-Tarver and Rine (1997) performed a comparative study of 4
subfamilies of olfactory receptor genes first identified in the dog to
assess changes in the gene family during mammalian evolution, and to
begin linking the dog genetic map to that of humans. These 4 families
were designated by them OLF1, OLF2, OLF3, and OLF4 in the canine genome.
The subfamilies represented by these 4 genes range in size from 2 to 20
genes. They are all expressed in canine olfactory epithelium but were
not detectably expressed in canine lung, liver, ovary, spleen, testis,
or tongue. The OLF1 and OLF2 subfamilies are tightly linked in the dog
genome and also in the human genome. The smallest family is represented
by the canine OLF1 gene. Using dog gene probes individually to hybridize
to Southern blots of genomic DNA from 24 somatic cell hybrid lines,
Issel-Tarver and Rine (1997) showed that the human homologous OLF1
subfamily maps to human chromosome 11. The human gene with the strongest
similarity to the canine OLF2 gene also mapped to chromosome 11. Both
members of the human subfamily that hybridized to canine OLF3 were
located on chromosome 7. It was difficult to determine to which
chromosome or chromosomes the human genes that hybridized to the canine
OLF4 probe mapped. This subfamily is large in mouse and hamster as well
as human, so the rodent background largely obscured the human
cross-hybridizing bands. It was possible, however, to discern some
human-specific bands in blots corresponding to human chromosome 19.
Issel-Tarver and Rine (1997) refined the mapping of the human OLF1
homolog by hybridization to YACs that map to 11q11. In dogs, the OLF1
and OLF2 subfamilies are within 45 kb of one another (Issel-Tarver and
Rine (1996)). Issel-Tarver and Rine (1997) demonstrated that in the
human OLF1 and OLF2 homologs are likewise closely linked. By studying
YACs, Issel-Tarver and Rine (1997) found that the human OLF3 homolog
maps to 7q35. A chromosome 19-specific cosmid library was screened by
hybridization with the canine OLF4 gene probe, and clones that
hybridized strongly to the probe even at high stringency were localized
to 19p13.1 and 19p13.2. These clones accounted, however, for a small
fraction of the homologous human bands.
Rouquier et al. (1998) demonstrated that members of the olfactory
receptor gene family are distributed on all but a few human chromosomes.
Through fluorescence in situ hybridization analysis, they showed that OR
sequences reside at more than 25 locations in the human genome. Their
distribution was biased for terminal bands of chromosome arms.
Flow-sorted chromosomes were used to isolate 87 OR sequences derived
from 16 chromosomes. Their sequence relationships indicated the inter-
and intrachromosomal duplications responsible for OR family expansion.
Rouquier et al. (1998) determined that the human genome has accumulated
a striking number of dysfunctional copies: 72% of these sequences were
found to be pseudogenes. ORF-containing sequences predominate on
chromosomes 7, 16, and 17.
Zhao et al. (1998) provided functional proof that one OR gene encodes a
receptor for odorants.
Mombaerts (1999) reviewed the molecular biology of the odorant receptor
genes in vertebrates. According to Mombaerts (1999), the sequences of
more than 150 human OR clones had been reported. The human OR genes
differ markedly from their counterparts in other species by their high
frequency of pseudogenes, except the testicular OR genes. Research
showed that individual olfactory sensory neurons express a small subset
of the OR repertoire. In rat and mouse, axons of neurons expressing the
same OR converge onto defined glomeruli in the olfactory bulb.
Fuchs et al. (2001), who referred to the repertoire of olfactory
receptor genes as the olfactory subgenome, analyzed 224 such genes
derived by a literature survey, data mining at 14 genomic clusters, and
an OR-targeted experimental sequencing strategy. This set of genes
contained at least 53% pseudogenes and was minimally divided into 11
gene families. One family has undergone a particularly extensive
expansion in primates.
The online database of human olfactory receptor genes designated HORDE
(Human Olfactory Receptor Data Exploratorium) stated in 2002 that 906
human olfactory receptor genes had been identified and that more than
60% appeared to be pseudogenes. Only chromosomes 20 and Y appeared to be
devoid of olfactory receptor genes. Chromosome 11 contained the largest
number of OR genes, clustered on the short arm near the centromere and
telomere.
- Olfactory Receptor Gene Cluster on 17p
Ben-Arie et al. (1994) cloned 16 human OLFR genes, all from 17p13.3. The
intronless coding regions are mapped to a 350-kb contiguous cluster,
with an average intergenic separation of 15 kb. The OLFR genes in the
cluster belong to 4 different gene subfamilies, displaying as much
sequence variability as any randomly selected group of OLFRs. This
suggested that the cluster may be one of several copies of an ancestral
OLFR gene repertoire whose existence may have predated the divergence of
mammals. Localization to 17p13.3 was performed by fluorescence in situ
hybridization as well as by somatic cell hybrid mapping.
Glusman et al. (1996) described the results of complete sequencing of an
OR-rich cosmid spanning the center of the OR gene cluster on 17p13.3.
The resulting 40-kb sequence revealed 3 known OR coding regions, 2 OR
genes which may have originated from a tandem duplication event, and a
new OR pseudogene fused to another OR gene.
Olfactory receptor genes are organized in the mammalian genome in many
clusters. The cluster on 17p13.3, fully sequenced by Glusman et al.
(2000), includes 17 OR genes out of the expected several hundred in the
human olfactory subgenome. The OR genes in this cluster belong to
various families and subfamilies. Conversely, genes from the same family
have been found in different clusters and on different chromosomes
(Sullivan et al., 1996; Rouquier et al., 1998), suggesting a complex
history of gene and cluster duplications. By 'data mining,' Glusman et
al. (2000) identified 831 OR coding regions (including pseudogenes) in
24 vertebrate species. A nomenclature system for the OR gene superfamily
was proposed, based on a divergence evolutionary model.
- Gene Function
The ability to distinguish different odors depends on a large number of
different odorant receptors (ORs). Sullivan et al. (1996) noted that ORs
are expressed by nasal olfactory sensory neurons; each neuron expresses
only 1 allele of a single OR gene. In the nose, different sets of ORs
are expressed in distinct spatial zones. Neurons that express the same
OR gene are located in the same zone; however, in that zone they are
randomly interspersed with neurons expressing other ORs. This
distribution suggested to the authors that, when the cell chooses an OR
gene for expression, it may be restricted to a specific zonal gene set,
but it may select from that set by a stochastic mechanism. Proposed
models of OR gene choice fall into 2 classes: locus-dependent and
locus-independent. Locus-dependent models posit that OR genes are
clustered in the genome, perhaps with members of different zonal gene
sets clustered at distinct loci. In contrast, locus-independent models
do not require that OR genes be clustered. To assess the feasibility of
these models, Sullivan et al. (1996) determined the expression zones,
sequences, and chromosomal locations of a number of mouse OR genes. They
mapped OR genes to 11 different regions on 7 chromosomes. These loci lie
within paralogous chromosomal regions that appear to have arisen by
duplications of large chromosomal domains followed by extensive gene
duplication and divergence. These studies showed that OR genes expressed
in the same zone map to numerous loci; moreover, a single locus can
contain genes expressed in different zones. These findings raised the
possibility that OR gene choice is locus-independent or involved
consecutive stochastic choices.
Mammals are able to detect a wide diversity of scents; even the
relatively olfactorily impaired human species is capable of detecting
approximately 10,000 distinct scents (Buck and Axel, 1991). To achieve
such diversity, mammals have approximately 1,000 olfactory genes, which
account for approximately 3% of their entire genome (Mombaerts, 1999).
The ORs are believed to be 7-helix transmembrane proteins, with an
odorant-binding site on the periplasmic domain and a G protein-binding
site on the cytoplasmic domain. Odorants first bind to an OR, which then
undergoes a structural change that triggers the G protein activation and
the following cascade of events leading to nerve cell activity. Wang et
al. (2003) hypothesized that metal ions play an important role in
odorant recognition. They analyzed the predicted structure and consensus
sequence of the ORs and proposed a metal-binding site in the loop
between the fourth and fifth helices (4-5 loop). They synthesized a
pentapeptide that contains this putative binding site and found that it
not only has high affinity for binding Cu(II) and Zn(II) ions, but also
undergoes a dramatic transition to an alpha-helical structure upon metal
ion binding. Based on these observations, they proposed a 'shuttlecock'
mechanism for the possible structural change in ORs upon odorant
binding. This mechanism involves membrane penetration of the 4-5 loop
after residue charge neutralization by metal ion binding.
The report of Zou and Buck (2006), which concluded that binary odorant
mixes stimulate cortical neurons that are not stimulated by their
individual component odorants, was retracted by Buck, who was not able
to reproduce the results. Zou declined to sign the retraction.
In mammals, odorant receptors direct the axons of olfactory sensory
neurons (OSNs) toward targets in the olfactory bulb. Imai et al. (2006)
showed that cyclic adenosine monophosphatase (cAMP) signals that
regulate the expression of axon guidance molecules are essential for the
odorant receptor-instructed axonal projection. Genetic manipulations of
odorant receptors, stimulatory G protein (GNAS; 139320), cAMP-dependent
protein kinase (PKA; see 176911), and cAMP response element-binding
protein (CREB; 123810) shifted the axonal projection sites along the
anterior-posterior axis in the olfactory bulb. Thus, it is the odorant
receptor-derived cAMP signals, rather than the direct action of OR
molecules, that determine the target destination of olfactory sensory
neurons.
- Evolution
Trask et al. (1998) characterized a subtelomeric DNA duplication that
provided insight into the variability, complexity, and evolutionary
history of that unusual region of the human genome, the telomere. Using
a DNA segment cloned from chromosome 19, they demonstrated that the
blocks of DNA sequence shared by different chromosomes can be very large
and highly similar. Three chromosomes appeared to have contained the
sequence before humans migrated around the world. In contrast to its
multicopy distribution in humans, this subtelomeric block maps
predominantly to a single locus in chimpanzee and gorilla, that site
being nonorthologous to any of the locations in the human genome. Three
new members of the olfactory receptor (OR) gene family were found to be
duplicated within this large segment of DNA, which was found to be
present at 3q, 15q, and 19p in each of 45 unrelated humans sampled from
various populations. From its sequence, one of the OR genes in this
duplicated block appeared to be potentially functional. The findings
raised the possibility that functional diversity in the OR family is
generated in part through duplications and interchromosomal
rearrangements of the DNA near human telomeres.
Gilad et al. (2000) reported the population sequence diversity of
genomic segments within a 450-kb cluster of olfactory receptor genes on
chromosome 17. They found a dichotomy in the pattern of nucleotide
diversity between OR pseudogenes and introns on the one hand and the
closely interspersed intact genes on the other. They suggested that weak
positive selection is responsible for the observed patterns of genetic
variation. This was inferred from a lower ratio of polymorphism to
divergence in genes compared with pseudogenes or introns, high
nonsynonymous substitution rates in OR genes, and a small but
significant overall reduction in variability in the entire OR gene
cluster compared with other genomic regions. The dichotomy among
functionally distinct segments within a short genomic distance requires
high recombination rates within this OR cluster.
Young and Trask (2002) reviewed the evolution and physiology of the
olfactory receptor gene superfamily.
Gilad et al. (2003) stated that approximately 40% of the more than 1,000
OR genes in the human have an intact coding region and are therefore
putatively functional. In contrast, the fraction of intact OR genes in
the genomes of the great apes is significantly greater (68 to 72%),
suggesting that selective pressures on the OR repertoire vary among
these species. Gilad et al. (2003) examined the evolutionary forces that
shaped the OR gene family in humans and chimpanzees by resequencing 20
OR genes in 16 humans, 16 chimpanzees, and 1 orangutan. They compared
the variation at the OR genes with that at intergenic regions. In both
humans and chimpanzees, OR pseudogenes seemed to evolve neutrally. In
chimpanzees, patterns of variability were consistent with purifying
selection acting on intact OR genes, whereas, in humans, there was
suggestive evidence for positive selection acting on intact OR genes.
These observations were considered to be due to differences in
lifestyle, between humans and great apes, that led to distinct sensory
needs.
- Other Features
Young et al. (2008) undertook a detailed study of copy number variation
of olfactory receptors to elucidate the selective and mechanistic forces
acting on this gene family and the true impact of copy number variation
on human olfactory receptor repertoires. They argued that the properties
of copy number variants (CNVs) and other sets of large genomic regions
violate the assumptions of statistical methods that are commonly used in
the assessment of gene enrichment. Using more appropriate methods, Young
et al. (2008) provided evidence that OR enrichment in CNVs is not due to
positive selection but is because of OR preponderance in segmentally
duplicated regions, which are known to be frequently copy
number-variable, and because purifying selection against CNVs is lower
in OR-containing regions than in regions containing essential genes.
Young et al. (2008) also combined multiplex ligation-dependent probe
amplification (MLPA) and PCR to assay the copy numbers of 37 candidate
CNV ORs in a panel of approximately 50 individuals. The authors
confirmed copy number variation of 18 ORs but found no variation in this
human diversity panel for 16 others, highlighting the caveat that
reported intervals often overrepresent true CNVs. Young et al. (2008)
concluded that the copy number variation they describe is likely to
underpin significant variation in olfactory abilities among human
individuals and showed that both homology-based and homology-independent
processes have played a recent role in remodeling the OR family.
ANIMAL MODEL
Issel-Tarver and Rine (1996) characterized 4 members of the canine
olfactory receptor gene family. The 4 subfamilies comprised genes
expressed exclusively in olfactory epithelium. Analysis of large DNA
fragments using Southern blots of pulsed field gels indicated that
subfamily members were clustered together, and that 2 of the subfamilies
were closely linked in the dog genome. Analysis of the 4 olfactory
receptor gene subfamilies in 26 breeds of dog provided evidence that the
number of genes per subfamily was stable in spite of differential
selection on the basis of olfactory acuity in scent hounds, sight
hounds, and toy breeds.
OR1G1
| dbSNP name | rs144637093(C,T); rs61736115(G,A); rs9892491(C,G) |
| ccdsGene name | CCDS11020.1 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 8390 |
| EntrezGene Description | olfactory receptor, family 1, subfamily G, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1G1:NM_003555:exon1:c.G433A:p.V145M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.2162 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P47890 |
| dbNSFP Uniprot ID | OR1G1_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.001816 |
| ESP All MAF | 0.000615 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 3.171e-04,8.132e-06 |
OR1A2
| dbSNP name | rs2241093(T,C); rs2241092(G,C); rs2241091(G,T); rs2469791(C,T); rs12150427(G,T) |
| ccdsGene name | CCDS11021.1 |
| CosmicCodingMuts gene | OR1A2 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 26189 |
| EntrezGene Description | olfactory receptor, family 1, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1A2:NM_012352:exon1:c.T15C:p.N5N, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3347 |
| ESP Afr MAF | 0.116432 |
| ESP All MAF | 0.284253 |
| ESP Eur/Amr MAF | 0.370233 |
| ExAC AF | 0.344 |
OR1A1
| dbSNP name | rs4325604(T,C); rs4374201(C,T); rs4375699(G,A); rs769425(G,T); rs17762735(G,A); rs62090945(C,T); rs61737301(C,T); rs769427(C,T) |
| ccdsGene name | CCDS11022.1 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 8383 |
| EntrezGene Description | olfactory receptor, family 1, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1A1:NM_014565:exon1:c.T94C:p.L32L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1804 |
| ESP Afr MAF | 0.16296 |
| ESP All MAF | 0.102414 |
| ESP Eur/Amr MAF | 0.071395 |
| ExAC AF | 0.866 |
OR3A2
| dbSNP name | rs769434(C,T) |
| ccdsGene name | CCDS42233.1 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 4995 |
| EntrezGene Description | olfactory receptor, family 3, subfamily A, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR3A2:NM_002551:exon1:c.G846A:p.G282G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1772 |
| ESP Afr MAF | 0.038855 |
| ESP All MAF | 0.107671 |
| ESP Eur/Amr MAF | 0.142239 |
| ExAC AF | 0.193 |
OR3A1
| dbSNP name | rs703903(C,T) |
| ccdsGene name | CCDS11023.1 |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 4994 |
| EntrezGene Description | olfactory receptor, family 3, subfamily A, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR3A1:NM_002550:exon1:c.G374A:p.R125Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P47881 |
| dbNSFP Uniprot ID | OR3A1_HUMAN |
| dbNSFP KGp1 AF | 0.589285714286 |
| dbNSFP KGp1 Afr AF | 0.25406504065 |
| dbNSFP KGp1 Amr AF | 0.57182320442 |
| dbNSFP KGp1 Asn AF | 0.958041958042 |
| dbNSFP KGp1 Eur AF | 0.536939313984 |
| dbSNP GMAF | 0.4105 |
| ESP Afr MAF | 0.307989 |
| ESP All MAF | 0.459557 |
| ESP Eur/Amr MAF | 0.462791 |
| ExAC AF | 0.561,1.082e-03 |
OR3A4P
| dbSNP name | rs8071097(G,C); rs61734050(T,C); rs9905684(A,G); rs9905086(C,G); rs9906179(A,G); rs9911226(C,A); rs9912090(A,G); rs231678(T,G); rs8076130(G,A) |
| cytoBand name | 17p13.3 |
| EntrezGene GeneID | 390756 |
| snpEff Gene Name | OR3A4 |
| EntrezGene Description | olfactory receptor, family 3, subfamily A, member 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1809 |
OR1E1
| dbSNP name | rs769422(A,T); rs11078448(G,T) |
| ccdsGene name | CCDS11024.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 8387 |
| EntrezGene Description | olfactory receptor, family 1, subfamily E, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1E1:NM_003553:exon1:c.T771A:p.G257G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1552 |
| ESP Afr MAF | 0.070813 |
| ESP All MAF | 0.06597 |
| ESP Eur/Amr MAF | 0.063488 |
| ExAC AF | 0.1 |
OR3A3
| dbSNP name | rs12939997(A,G); rs227787(A,G) |
| ccdsGene name | CCDS11025.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 8392 |
| EntrezGene Description | olfactory receptor, family 3, subfamily A, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR3A3:NM_012373:exon1:c.A859G:p.M287V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P47888 |
| dbNSFP Uniprot ID | OR3A3_HUMAN |
| dbNSFP KGp1 AF | 0.0338827838828 |
| dbNSFP KGp1 Afr AF | 0.115853658537 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0145118733509 |
| dbSNP GMAF | 0.03398 |
| ESP Afr MAF | 0.110985 |
| ESP All MAF | 0.047286 |
| ESP Eur/Amr MAF | 0.014651 |
| ExAC AF | 0.02 |
OR1E2
| dbSNP name | rs61739591(A,G) |
| ccdsGene name | CCDS11026.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 8388 |
| EntrezGene Description | olfactory receptor, family 1, subfamily E, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1E2:NM_003554:exon1:c.T876C:p.P292P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1919 |
| ESP Afr MAF | 0.138675 |
| ESP All MAF | 0.367676 |
| ESP Eur/Amr MAF | 0.485 |
| ExAC AF | 0.34 |
GSG2
| dbSNP name | rs1185511(C,T); rs3809806(T,C); rs170208(A,G); rs9896869(A,G); rs72825407(C,T) |
| ccdsGene name | CCDS11036.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 83903 |
| EntrezGene Description | germ cell associated 2 (haspin) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GSG2:NM_031965:exon1:c.C390T:p.C130C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1318 |
| ESP Afr MAF | 0.425502 |
| ESP All MAF | 0.146355 |
| ESP Eur/Amr MAF | 0.002998 |
| ExAC AF | 0.041 |
CYB5D2
| dbSNP name | rs12453863(C,T); rs8079619(C,T); rs8080327(A,G); rs8066337(T,C); rs2054040(G,A); rs35050090(C,G); rs62072179(C,T); rs2054041(A,G); rs141633859(T,C); rs4790173(C,T); rs7208820(G,T); rs192748288(G,A); rs11078483(G,A); rs62072180(G,T); rs146117260(G,T); rs11657169(A,G); rs62072181(C,T); rs4567758(T,A); rs4553662(G,A); rs7219437(C,T); rs7219793(C,T); rs7224699(T,G); rs7220107(C,G); rs9891135(T,C); rs62072182(A,C); rs146946310(G,A); rs9891440(T,C); rs62072183(C,T); rs116192899(C,G); rs12939130(A,G); rs34014959(C,A); rs4790174(T,C); rs897027(A,G); rs146379193(G,C); rs4790573(T,G); rs8076592(C,G); rs7218900(G,A); rs4790576(G,T); rs9896297(G,A); rs78800959(C,G); rs12935850(G,A); rs74789530(T,C); rs140668956(C,T); rs17176322(G,A); rs9905631(C,A); rs80261572(G,A); rs1992159(A,G); rs78150716(G,A); rs1992158(G,C); rs8078296(C,T); rs144989131(C,T); rs4790175(G,A); rs139135688(C,G); rs4790176(A,G); rs79555385(C,T); rs150592769(C,T); rs76481447(G,A); rs1049523(G,T) |
| ccdsGene name | CCDS58501.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 124936 |
| EntrezGene Description | cytochrome b5 domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CYB5D2:NM_001254756:exon3:c.C182T:p.P61L,CYB5D2:NM_001254755:exon3:c.C182T:p.P61L,CYB5D2:NM_144611:exon3:c.C518T:p.P173L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8223 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WUJ1 |
| dbNSFP Uniprot ID | NEUFC_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002114 |
CHRNE
| dbSNP name | rs3514(C,G); rs12936083(A,G); rs12940036(G,A); rs2229200(A,G); rs2229199(C,T); rs34563587(G,A); rs77481135(C,T) |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 1145 |
| snpEff Gene Name | MINK1 |
| EntrezGene Description | cholinergic receptor, nicotinic, epsilon (muscle) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1878 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases;
Multifactorial
NEUROLOGIC:
[Central nervous system];
Normal, timely language development;
[Behavioral/psychiatric manifestations];
Impaired social interactions;
Impaired use of nonverbal behaviors, such as eye-to-eye gaze, facial
expression, body posture, and gestures;
Impaired ability to form peer relationships;
Lack of spontaneous play;
Restrictive behavior, interests, and activities;
Stereotyped, repetitive behavior;
Inflexible adherence to routines or rituals;
Relatively higher cognitive abilities than classic autism
MISCELLANEOUS:
Onset in early childhood;
Genetic heterogeneity (see 608638)
OMIM Title
%608631 ASPERGER SYNDROME, SUSCEPTIBILITY TO, 2; ASPG2
OMIM Description
DESCRIPTION
Asperger syndrome is considered to be a form of childhood autism (see,
e.g., 209850). The DSM-IV (American Psychiatric Association, 1994)
specifies several diagnostic criteria for Asperger syndrome, which has
many of the same features as autism. In general, patients with Asperger
syndrome and autism exhibit qualitative impairment in social
interaction, as manifest by impairment in the use of nonverbal behaviors
such as eye-to-eye gaze, facial expression, body postures, and gestures,
failure to develop appropriate peer relationships, and lack of social
sharing or reciprocity. Patients also exhibit restricted, repetitive and
stereotyped patterns of behavior, interests, and activities, including
abnormal preoccupation with certain activities and inflexible adherence
to routines or rituals. Asperger syndrome is primarily distinguished
from autism by the higher cognitive abilities and a more normal and
timely development of language and communicative phrases. Gillberg et
al. (2001) described the development of the Asperger syndrome (and
high-functioning autism) Diagnostic Interview (ASDI), which they claimed
has a strong validity in the diagnosis of the disorder.
For a discussion of genetic heterogeneity of Asperger syndrome, see
ASPG1 (608638).
CLINICAL FEATURES
Anneren et al. (1995) reported a 10-year-old boy with Asperger syndrome.
Development was normal until 3 years of age when he became anxious and
withdrawn; he later developed depression and school phobic symptoms.
Gross motor movements were clumsy, and his speech was stereotyped and
monotonous. He lacked social interactions and had no close friends. The
boy also had an apparently balanced de novo translocation
t(17;19)(p13.3;p11). Tentler et al. (2002) reported follow-up on the
patient reported by Anneren et al. (1995). The authors noted that he met
criteria for ASPG, but not for childhood autism.
Tentler et al. (2002) reported a second, unrelated male with ASPG who
also met criteria for childhood autism. He had an apparently de novo
balanced translocation t(13;17)(q14;p13). Although no other family
members had the translocation, the patient's mother had a history of
anorexia nervosa (606788) and obsessive personality traits, 1 half
sister had attention deficit-hyperactivity disorder (ADHD; 143465), and
another half sister had autism.
MAPPING
By Southern blot analysis of the chromosome 17p13 breakpoints in 2
patients with Asperger syndrome, Tentler et al. (2002) determined that
the breakpoint is positioned within a 0.7-kb region located between the
CHRNE (100725) and GP1BA (606672) genes, 0.8 kb from the 5-prime end of
the CHRNE gene.
C17orf107
| dbSNP name | rs35400274(G,A); rs12942540(G,C); rs72835061(C,A) |
| ccdsGene name | CCDS45591.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 100130311 |
| EntrezGene Description | chromosome 17 open reading frame 107 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C17orf107:NM_001145536:exon3:c.G456A:p.W152X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.20695970696 |
| dbNSFP KGp1 Afr AF | 0.44512195122 |
| dbNSFP KGp1 Amr AF | 0.232044198895 |
| dbNSFP KGp1 Asn AF | 0.0856643356643 |
| dbNSFP KGp1 Eur AF | 0.131926121372 |
| dbSNP GMAF | 0.2071 |
| ESP Afr MAF | 0.356936 |
| ESP All MAF | 0.205431 |
| ESP Eur/Amr MAF | 0.139535 |
| ExAC AF | 0.143 |
GP1BA
| dbSNP name | rs6065(C,T) |
| ccdsGene name | CCDS54068.1 |
| cytoBand name | 17p13.2 |
| EntrezGene GeneID | 2811 |
| EntrezGene Description | glycoprotein Ib (platelet), alpha polypeptide |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/pubmed?term=22139419 |
| Annovar Function | GP1BA:NM_000173:exon2:c.C482T:p.T161M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A5CKE2 |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/pubmed?term=22139419 |
| dbNSFP KGp1 AF | 0.129120879121 |
| dbNSFP KGp1 Afr AF | 0.264227642276 |
| dbNSFP KGp1 Amr AF | 0.140883977901 |
| dbNSFP KGp1 Asn AF | 0.0699300699301 |
| dbNSFP KGp1 Eur AF | 0.0804749340369 |
| dbSNP GMAF | 0.1295 |
| ESP Afr MAF | 0.213573 |
| ESP All MAF | 0.123156 |
| ESP Eur/Amr MAF | 0.07963 |
| ExAC AF | 0.098 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
ABDOMEN:
[Liver];
Hepatomegaly
LABORATORY ABNORMALITIES:
Hypermethioninemia;
Elevated transaminases
MOLECULAR BASIS:
Caused by mutations in the glycine N-methyltransferase gene (GNMT,
606628.0001)
OMIM Title
*606672 GLYCOPROTEIN Ib, PLATELET, ALPHA POLYPEPTIDE; GP1BA
;;GP Ib, ALPHA SUBUNIT;;
PLATELET GLYCOPROTEIN Ib, ALPHA POLYPEPTIDE;;
CD42B
GLYCOCALICIN, INCLUDED
OMIM Description
DESCRIPTION
Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein that
functions as a receptor for von Willebrand factor (VWF; 613160). The
main portion of the receptor is a heterodimer composed of 2 polypeptide
chains, an alpha chain and a beta chain (GP1BB; 138720), that are linked
by disulfide bonds. The GP1BA gene encodes the alpha subunit. The
complete receptor complex includes noncovalent association of the alpha
and beta subunits with platelet glycoprotein IX (GP9; 173515) and
platelet glycoprotein V (GP5; 173511) (review by Lopez et al., 1998).
CLONING
The alpha subunit of GP Ib is susceptible to cleavage by trypsin or by
the calcium-dependent protease calpain, giving rise to a soluble heavily
glycosylated N-terminal fragment known as 'glycocalicin.' By screening a
human cDNA library with an antibody to glycocalicin, Lopez et al. (1987)
isolated a potential alpha subunit cDNA encoding a 610-amino acid
protein with a molecular mass of approximately 145 kD. The predicted
protein has an extracytoplasmic leucine-rich domain composed of a
24-amino acid motif that contains 7 conserved leucine positions. The
extracytoplasmic domain is followed by a 29-amino acid transmembrane
domain and a 100-amino acid intracellular domain at the carboxyl end of
the molecule. The GP1B beta subunit, GP9, and GP5 have similar
leucine-rich domains.
MAPPING
By in situ hybridization using a genomic clone, Wenger et al. (1989)
demonstrated that the GP1BA gene is located on chromosome 17pter-p12.
GENE FUNCTION
The binding of platelet GP Ib to von Willebrand factor facilitates
initial platelet adhesion to vascular subendothelium after vascular
injury. The binding of VWF to the GP Ib complex also initiates signaling
events within the platelet that lead to enhanced platelet activation,
thrombosis, and hemostasis (Lopez et al., 1998). Michelson et al. (1986)
presented evidence that a portion of the oligosaccharide chains on
glycocalicin contributes to the VWF binding activity of GP Ib. Harmon
and Jamieson (1986) found that GP Ib was a receptor for thrombin
(176930), and that glycocalicin was the site of thrombin binding.
Michelson et al. (1988) showed that there is a large intraplatelet pool
of GP Ib.
Andrews and Fox (1992) noted that the GP Ib complex is a major site of
attachment of the platelet membrane skeleton to the plasma membrane,
mediated by the interaction of actin-binding protein with the receptor
complex. They showed that a region between thr536 and phe568 of the
cytoplasmic domain of the alpha subunit participates in the interaction.
Steinberg et al. (1987) measured plasma concentration of glycocalicin,
as an aid to classification of thrombocytopenia; values were low in
situations of bone marrow suppression and normal or elevated when there
was accelerated platelet turnover. Beer et al. (1994) also suggested
that glycocalicin is a useful platelet marker in certain diseases.
BIOCHEMICAL FEATURES
- Crystal Structure
Huizinga et al. (2002) presented the crystal structure of the GP1BA
amino-terminal domain and its complex with the VWF (613160) domain A1.
In the complex, GP1BA wraps around one side of A1, providing 2 contact
areas bridged by an area of solvated charge interaction. The structures
explain the effects of gain-of-function mutations related to bleeding
disorders and provide a model for shear-induced activation.
Celikel et al. (2003) determined that the structure of platelet GP1BA
bound to thrombin at 2.3 angstrom resolution and defined 2 sites that
bind to exosite II and exosite I of 2 distinct alpha-thrombin molecules,
respectively. GP1BA occupancy may be sequential, as the site binding to
alpha-thrombin exosite I appears to be cryptic in the unoccupied
receptor but exposed when a first thrombin molecule is bound through
exosite II. Celikel et al. (2003) suggested that these interactions may
modulate alpha-thrombin function by mediating GP1BA clustering and
cleavage of protease-activator receptors, which promote platelet
activation, while limiting fibrinogen clotting through blockade of
exosite I.
Dumas et al. (2003) independently determined the crystal structure of
the GP1BA-thrombin complex at 2.6 angstrom resolution. They found that
in the crystal lattice, the periodic arrangement of GP1BA-thrombin
complexes mirrors a scaffold that could serve as a driving force for
tight platelet adhesion.
MOLECULAR GENETICS
- Polymorphisms
By SDS-PAGE, Moroi et al. (1984) studied GP Ib from 131 Japanese
subjects and identified 4 slightly different species of GP Ib
corresponding to different molecular masses (see also 606672.0002). On
the assumption of a 4-allele system, the gene frequencies calculated
were: A, 0.073; B, 0.011; C, 0.561; and D, 0.355. Platelets of different
GP Ib phenotypes showed the same functional properties. Furthermore, no
individual had more than 2 types; the relative amounts of the 2 bands on
SDS-PAGE were about equal in each person; the phenotype was constant on
multiple testings and the phenotypes of children were consistent with
those of their parents: e.g., the parents of a person with the rare
phenotype BC were CC and BD.
Polymorphisms described in the GP1BA gene include the Kozak T/C
polymorphism at position -5, the variable number of tandem repeats
(VNTR; 606672.0002), and the thr145-to-met polymorphism.
The platelet-specific alloantigen Sib(a), located within the GP Ib alpha
subunit, is involved in the pathogenesis of platelet transfusion
refractoriness. Murata et al. (1992) identified a threonine/methionine
dimorphism at position 145 of the GP Ib-alpha sequence and determined
that the Sib(a) antigen corresponds to the molecule containing
methionine-145. The diallelic codons were detected by restriction enzyme
analysis of amplified genomic DNA fragments from the GP1BA gene. Among
61 healthy blood donors, the allele frequencies were 89% and 11% for the
threonine-145 and methionine-145 codons, respectively. A positive
correlation existed between platelet reactivity with the anti-Sib(a)
antibody and the presence of a methionine-145 encoding allele. The
findings provide methods useful in transfusion medicine to match donor
and recipient platelets. Baker et al. (2001) referred to the thr145
polymorphism as human platelet antigen-2a (HPA-2a) and met145 as HPA-2b.
T/C polymorphism at the -5 position from the initiator ATG codon of the
GP1BA gene was first reported by Kaski et al. (1996) and is located
within the 'Kozak' consensus nucleotide sequence. The presence of a
cytosine (C) at this position significantly increases the surface
expression of the GP Ib/V/IX complex (Afshar-Kharghan et al., 1999).
This result prompted Ishida et al. (2000) to examine the presence of
Kozak sequence polymorphism of GP1BA in Asian populations and to
determine whether this polymorphism has a role in coronary artery
disease. The frequency of cytosine was 0.283 and 0.219 in Japanese and
Korean populations, respectively. The C allele is linked with human
platelet antigen-2a and smaller types of variable number of tandem
repeats (VNTR). No association was observed between these alleles and
coronary artery disease in a case-control study.
Baker et al. (2001) noted that platelets are pivotal to the process of
arterial thrombosis resulting in ischemic stroke and that thrombosis is
initiated by the interaction of VWF and GP Ib. They studied whether
GP1BA polymorphisms are candidate genes for first-ever ischemic stroke.
The frequency (22.8%) of T/C heterozygotes in the Caucasian Australian
population studied was similar to that in other populations. The
heterozygous genotype was elevated in the stroke group (32.2%) and the
increased relative risk was still apparent after adjusting for
conventional cardiovascular risk factors such as hypertension, diabetes,
hyperlipidemia, smoking, and previous vascular events. CC homozygotes
were uncommon and the study was not powered to examine the role of the
CC genotype alone. The authors hypothesized that the Kozak polymorphism
influences the pathogenesis of ischemic stroke because the C allele
increases the level of platelet glycoprotein GP Ib-alpha on the platelet
surface.
- Disease-causing Mutations
In a patient with autosomal recessive Bernard-Soulier syndrome (BSSA1;
231200), Ware et al. (1990) identified a homozygous nonsense mutation in
the GP1BA gene (606672.0001).
In a Caucasian family in which 5 members over 2 generations were
affected with an autosomal dominant form of Bernard-Soulier syndrome
(BSSA2; 153670), Miller et al. (1992) identified a heterozygous mutation
in the GP1BA gene (606672.0004).
Platelet-type von Willebrand disease (177820), also known as pseudo-von
Willebrand disease, is an autosomal dominant bleeding disorder
characterized by abnormally enhanced binding of von Willebrand factor by
patients' platelets. In 7 affected members of a family with pseudo-VWD,
Miller et al. (1991) identified a heterozygous mutation in the GP1BA
gene (606672.0003).
ANIMAL MODEL
Bergmeier et al. (2006) generated mice expressing Gp1ba in which the
extracellular domain was replaced by that of the human IL4 receptor
(IL4R; 147781). Platelet adhesion to ferric chloride-treated mesenteric
arteries was virtually absent in transgenic mice compared to avid
adhesion in wildtype mice, and resulted in complete inhibition of
arterial thrombus formation. When infused into wildtype mice, transgenic
IL4R/Gp1ba platelets or wildtype platelets lacking the 45-kD N-terminal
domain of Gp1ba failed to incorporate into growing arterial thrombi,
even if the platelets were activated before infusion. Bergmeier et al.
(2006) concluded that GP1BA is required for recruitment of platelets to
both exposed subendothelium and thrombi under arterial flow conditions
and that it contributes to arterial thrombosis by adhesion mechanisms
independent of binding to VWF.
C17orf100
| dbSNP name | rs7226265(A,G); rs4796532(G,A); rs4796533(G,C); rs4796343(A,T) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 388327 |
| snpEff Gene Name | MED31 |
| EntrezGene Description | chromosome 17 open reading frame 100 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3434 |
MIR4520A
| dbSNP name | rs8078913(C,T) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 100616466 |
| EntrezGene Symbol | MIR4520B |
| snpEff Gene Name | C17orf100 |
| EntrezGene Description | microRNA 4520b |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4307 |
| ExAC AF | 0.299 |
C17orf49
| dbSNP name | rs14309(T,C) |
| ccdsGene name | CCDS32542.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 100529209 |
| EntrezGene Symbol | RNASEK-C17orf49 |
| snpEff Gene Name | AC040977.1 |
| EntrezGene Description | RNASEK-C17orf49 readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | C17orf49:NM_174893:exon3:c.T117C:p.G39G,C17orf49:NM_001142798:exon3:c.T117C:p.G39G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbNSFP KGp1 AF | 0.753663003663 |
| dbNSFP KGp1 Afr AF | 0.589430894309 |
| dbNSFP KGp1 Amr AF | 0.627071823204 |
| dbNSFP KGp1 Asn AF | 0.844405594406 |
| dbNSFP KGp1 Eur AF | 0.852242744063 |
| dbSNP GMAF | 0.2456 |
| ESP Afr MAF | 0.387426 |
| ESP All MAF | 0.227741 |
| ESP Eur/Amr MAF | 0.14593 |
| ExAC AF | 0.813 |
ACADVL
| dbSNP name | rs140566084(A,G); rs9646410(T,C); rs76547988(C,T); rs77763289(T,A); rs148584617(G,A) |
| ccdsGene name | CCDS11090.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 37 |
| EntrezGene Description | acyl-CoA dehydrogenase, very long chain |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACADVL:NM_001033859:exon4:c.A242G:p.K81R,ACADVL:NM_001270447:exon6:c.A377G:p.K126R,ACADVL:NM_000018:exon5:c.A308G:p.K103R,ACADVL:NM_001270448:exon4:c.A80G:p.K27R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6009 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G3V1M7 |
| dbNSFP KGp1 AF | 0.00641025641026 |
| dbNSFP KGp1 Afr AF | 0.0264227642276 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.006428 |
| ESP Afr MAF | 0.012029 |
| ESP All MAF | 0.004306 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.001683 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Skull];
Symmetrical, oval parietal bone defects;
Cranium bifidum
SKIN, NAILS, HAIR:
[Skin];
Scalp defect
MISCELLANEOUS:
Genetic heterogeneity (see PFM1, 168500)
OMIM Title
*609575 ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN; ACADVL
;;VLCAD
OMIM Description
DESCRIPTION
The ACADVL gene encodes very long-chain acyl-CoA dehydrogenase (VLCAD)
(EC 1.3.99.13). VLCAD is unique among the acyl-CoA dehydrogenases in its
size, structure, and intramitochondrial distribution (Aoyama et al.,
1995).
CLONING
Izai et al. (1992) identified and purified a novel acyl-CoA
dehydrogenase, Acadvl, from rat liver mitochondria.
Aoyama et al. (1995) cloned and sequenced 2 overlapping cDNA clones
corresponding to human mitochondrial VLCAD. The cDNA encodes a 655-amino
acid protein with a 40-amino acid leader peptide, yielding a mature
615-residue protein.
Whereas the other acyl-CoA dehydrogenases are homotetramers of a 43- to
45-kD subunit, VLCAD purified from human liver was shown by Aoyama et
al. (1995) to be a 154-kD homodimer of a 70-kD subunit. VLCAD was
loosely bound to the mitochondrial inner membrane and required detergent
for stabilization. In contrast, the other 3 acyl-CoA dehydrogenases
others were readily extractable into the soluble fraction without
detergent, indicating that they are located in the mitochondrial matrix.
Andresen et al. (1996) isolated cDNA clones for human VLCAD by using rat
Vlcad cDNA sequences to identify an EST from human fetal brain in the
GenBank database, followed by 5-prime and 3-prime rapid amplification of
cDNA ends (RACE) to identify overlapping clones. Sequence analysis of
the coding region and the 5-prime noncoding region of the VLCAD cDNA
showed no differences with the sequence published by Aoyama et al.
(1995). Andresen et al. (1996) found 26 to 33% homology between VLCAD
and other human acyl-CoA dehydrogenases. Northern blot analysis detected
a 2.4-kb mRNA transcript in a variety of human tissues.
By real-time RT-PCR, Zhou and Blumberg (2003) detected VLCAD expression
in all tissues examined, with highest expression in heart and skeletal
muscle, followed by placenta and pancreas.
GENE FUNCTION
Izai et al. (1992) found that the properties of Acadvl purified from rat
liver mitochondria differed from those of the short (ACADS; 606885)-,
medium (ACADM; 607008)-, and long (ACADL; 609576)-chain acyl-CoA
dehydrogenases. Acadvl was active toward very long-chain fatty acids.
Aoyama et al. (1995) found that human VLCAD had 10 times higher specific
activity toward palmitoyl-CoA than did LCAD. The enzyme was found to
catalyze the major part of mitochondrial palmitoyl-CoA dehydrogenation
in liver, heart, skeletal muscle, and skin fibroblasts.
GENE STRUCTURE
Strauss et al. (1995) determined that the ACADVL gene contains 20 exons.
The ACADVL gene is about 5.4 kb long (Zhou and Blumberg, 2003).
Zhang et al. (2003) noted that the VLCAD and the DLG4 (602887) genes are
located in a head-to-head orientation on chromosome 17p. The transcribed
regions of the 2 genes overlap by about 220 bp. Using serial promoter
partial deletion constructs in a reporter gene assay, they found that
the essential promoter activity of DLG4 is carried within a region of
about 400 bp and covers the entire VLCAD minimal promoter, which spans
about 270 bp. The results from di-(2-ethylhexyl) phthalate
(DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter can
upregulate VLCAD expression in response to DEHP treatment. Site-directed
mutagenesis experiments showed that a mutated AP2 (107580)-binding site
markedly reduced the transcriptional activity of both the VLCAD and DLG4
promoters and abolished the minimal VLCAD promoter's response to DEHP
treatment.
Independently, Zhou and Blumberg (2003) determined that the VLCAD and
DLG4 genes overlap. The 2 genes share 245 nucleotides at their 5-prime
ends, and the transcription start site for DLG4 extends into the coding
region of VLCAD exon 1. The upstream regions of the VLCAD and DLG4
genes, including the overlapping region, contain 2 potential TATA-less
promoters with potential binding sites for several common transcription
factors. RT-PCR detected unique patterns of expression for VLCAD and
DLG4, indicating that, although they share common regulatory elements,
VLCAD and DLG4 also have distinct tissue-specific elements. The mouse
Dlg4 and Vlcad genes are oriented in a head-to-head manner, but they do
not overlap and are separated by almost 3.5 kb.
MAPPING
Andresen et al. (1996) mapped the ACADVL gene to human chromosome
17p13.1-p11.2 by analysis of rodent-human hybrids.
By fluorescence in situ hybridization, Orii et al. (1997) mapped the
murine Acadvl gene to chromosome 11 in a region of synteny to human
17p13.
MOLECULAR GENETICS
In cultured fibroblasts of 2 patients with VLCAD deficiency (201475),
Aoyama et al. (1995) identified a 105-bp deletion in the ACADVL gene
(609575.0001).
Andresen et al. (1996) identified 9 different mutations in the ACADVL
gene in 4 unrelated patients with VLCAD deficiency. Two patients carried
3 different mutations. Different mutations were observed in each of the
patients. Western blot analysis on fibroblasts from 3 of the patients
revealed severe quantitative reduction in VLCAD protein.
Mathur et al. (1999) identified 21 different mutations in the ACADVL
gene in 18 of 37 children with cardiomyopathy, nonketotic hypoglycemia
and hepatic dysfunction, skeletal myopathy, or sudden death in infancy
with hepatic steatosis. Sixty-seven percent of children had severe
dilated or hypertrophic cardiomyopathy at presentation. In 7 patients,
only 1 mutation was found despite direct sequencing of all exons.
Missense, frameshift, and splice consensus sequence mutations were seen,
as well as in-frame deletions. Eighty percent of these mutations were
associated with cardiomyopathy. The authors concluded that infantile
cardiomyopathy is the most common clinical phenotype for VLCAD
deficiency and highlighted the marked allelic heterogeneity in this
disorder.
Since VLCAD-deficient patients frequently harbor missense mutations with
unpredictable effects on enzyme activity, Gobin-Limballe et al. (2007)
investigated the response to bezafibrate as a function of genotype in 33
VLCAD-deficient fibroblast cell lines representing 45 different
mutations. Treatment with bezafibrate (400 microM for 48 hours) resulted
in a marked increase in FAO capacities, often leading to restoration of
normal values, for 21 genotypes that mainly corresponded to patients
with the myopathic phenotype. In contrast, bezafibrate induced no
changes in FAO for 11 genotypes corresponding to severe neonatal or
infantile phenotypes. This pattern of response was not due to
differential inductions of VLCAD mRNA, as shown by quantitative
real-time PCR, but reflected variable increases in measured VLCAD
residual enzyme activity in response to bezafibrate. Genotype
cross-analysis allowed the identification of alleles carrying missense
mutations, which could account for these different pharmacologic
profiles and, on this basis, led to the characterization of 9 mild and
11 severe missense mutations. The responses to bezafibrate reflected the
severity of the metabolic blockage in various genotypes, which appeared
to be correlated with the phenotype. This study emphasized the potential
of bezafibrate, a widely prescribed hypolipidemic drug, for the
correction of VLCAD deficiency and exemplified the integration of
molecular information in a therapeutic strategy.
ANIMAL MODEL
Cox et al. (2001) generated mice with VLCAD deficiency (Vlcad -/-) and
compared their pathologic and biochemical phenotypes to mice with Lcad
deficiency (Lcad -/-) and wildtype mice. Vlcad -/- mice had milder fatty
acid change in liver and heart. Dehydrogenation of various acyl-CoA
substrates by liver, heart, and skeletal muscle mitochondria differed
among the 3 genotypes. The results for liver were most informative as
Vlcad -/- mice had a reduction in activity toward palmitoyl-CoA and
oleoyl-CoA (58% and 64% of wildtype, respectively), whereas Lcad -/-
mice showed a more profoundly reduced activity toward these substrates
(35% and 32% of wildtype, respectively), with a significant reduction of
activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA.
C16 and C18 acylcarnitines were elevated in bile, blood, and serum of
fasted Vlcad -/- mice, whereas abnormally elevated C12 and C14
acylcarnitines were prominent in Lcad -/- mice. Progeny with the
combined Lcad +/+//Vlcad +/- genotype were overrepresented in offspring
from sires and dams heterozygous for both Lcad and Vlcad mutations. In
contrast, no live mice with a compound Lcad -/-/Vlcad -/- genotype were
detected, suggesting that this genotype may be lethal in utero or in the
periparturient period.
To define the onset and molecular mechanism of myocardial disease, Exil
et al. (2003) generated Vlcad-deficient mice by homologous
recombination. They found that Vlcad-deficient hearts had microvesicular
lipid accumulation and marked mitochondrial proliferation, and
demonstrated facilitated induction of polymorphic ventricular
tachycardia, without antecedent stress. The expression of acyl-CoA
synthetase-1 (ACS1; 152425), adipophilin, Ap2, cytochrome c, and the
peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1;
604517) were increased immediately after birth, preceding overt
histologic lipidosis, whereas Acs1 expression was markedly downregulated
in the adult heart. Exil et al. (2003) concluded that mice with Vlcad
deficiency have altered expression of a variety of genes in the fatty
acid metabolic pathway from birth, reflecting metabolic feedback
circuits, with progression to ultrastructural and physiologic correlates
of the associated human disease in the absence of stress.
KCTD11
| dbSNP name | rs3809830(C,T); rs17732672(G,T) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 147040 |
| snpEff Gene Name | ACAP1 |
| EntrezGene Description | potassium channel tetramerization domain containing 11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1621 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, severe to profound
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the TRIO- and F-actin-binding protein (TRIOBP,
609761.0001)
OMIM Title
*609848 POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 11; KCTD11
;;GENE INDUCED BY RETINOIC ACID, EGF, AND NGF; REN
OMIM Description
CLONING
Gallo et al. (2002) cloned mouse Kctd11, which they called Ren. The
deduced 232-amino acid protein has an apparent molecular mass of 26 kD
and contains an N-terminal BTB/POZ domain and several sites for
N-myristoylation and phosphorylation. Northern blot analysis detected
Ren expression in adult lung and day-7 mouse embryos. RT-PCR detected
peak Ren expression at embryonic day 8.5, with decreasing levels
thereafter. In situ hybridization showed that Ren was expressed in the
neural fold epithelium of the mouse embryo during gastrulation, and
subsequently throughout the ventral neural tube, the outer layer of the
ventricular encephalic neuroepithelium, and in neural crest derivatives,
including dorsal root ganglia.
By searching databases for sequences similar to mouse Ren, followed by
RT-PCR and RACE of cerebellum, medulloblastoma, and keratinocyte cell
lines, Di Marcotullio et al. (2004) cloned human REN. The deduced
232-amino acid protein has an N-terminal BTB/POZ domain and shares 91%
amino acid identity with mouse Ren. Northern blot analysis detected a
2.9-kb REN transcript in whole brain and cerebellum and in a human
medulloblastoma cell line.
GENE FUNCTION
Gallo et al. (2002) found that Ren was upregulated by neurogenic
signals, such as retinoic acid, EGF (131530), and NGF (NGFB; 162030), in
pluripotent mouse embryonic stem cells and in rat neural progenitor cell
lines in association with neuronal differentiation. Ren overexpression
induced neuronal differentiation, growth arrest, and p27(KIP1) (CDKN1B;
600778) expression in central and peripheral neural progenitor cell
lines. Inhibition of Ren impaired retinoic acid induction of
neurogenin-1 (NEUROG1; 601726) and NeuroD (NEUROD1; 601724) expression.
Because REN maps to a region of chromosome 17 frequently deleted in
medulloblastomas, Di Marcotullio et al. (2004) analyzed primary
medulloblastomas and medulloblastoma cell lines for REN ploidy. One REN
allele was deleted in 7 of 18 primary tumor samples and in 4 of 6 cell
lines examined. REN transcript levels were 5-fold lower in hemizygous
medulloblastoma cell lines and primary tumors than in normal cerebellar
tissue. There was a 50% decrease in REN mRNA in REN +/+ tumors and cell
lines, indicating that REN expression is downregulated in
medulloblastomas by mechanisms other than allelic loss. Di Marcotullio
et al. (2004) found that REN inhibited medulloblastoma cell
proliferation and colony formation in vitro and suppressed xenograft
tumor growth in athymic nude mice. REN antagonized Gli1 (GLI;
165220)-mediated transactivation of hedgehog (see SHH; 600725) target
genes by affecting Gli1 nuclear transfer, and the growth inhibitory
activity of REN was impaired by Gli1 inactivation, suggesting that REN
inhibits medulloblastoma growth by negatively regulating the hedgehog
pathway. Di Marcotullio et al. (2004) concluded that REN is a suppressor
of hedgehog signaling and that its inactivation leads to deregulation of
the tumor-promoting hedgehog pathway in medulloblastomas.
GENE STRUCTURE
Di Marcotullio et al. (2004) determined that the KCTD11 gene is
intronless.
MAPPING
By genomic sequence analysis, Di Marcotullio et al. (2004) mapped the
KCTD11 gene to chromosome 17p13.2. They mapped the mouse Kctd11 gene to
a region of chromosome 11 that shares homology of synteny with human
chromosome 17p13.2.
C17orf74
| dbSNP name | rs13290(T,G) |
| ccdsGene name | CCDS42255.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 201243 |
| EntrezGene Description | chromosome 17 open reading frame 74 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C17orf74:NM_175734:exon3:c.T322G:p.S108A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q0P670 |
| dbNSFP Uniprot ID | CQ074_HUMAN |
| dbNSFP KGp1 AF | 0.357142857143 |
| dbNSFP KGp1 Afr AF | 0.306910569106 |
| dbNSFP KGp1 Amr AF | 0.419889502762 |
| dbNSFP KGp1 Asn AF | 0.0332167832168 |
| dbNSFP KGp1 Eur AF | 0.604221635884 |
| dbSNP GMAF | 0.3558 |
| ESP Afr MAF | 0.354946 |
| ESP All MAF | 0.454991 |
| ESP Eur/Amr MAF | 0.359801 |
| ExAC AF | 0.504,1.305e-04,8.158e-06 |
TMEM102
| dbSNP name | rs12950374(G,A) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 284114 |
| snpEff Gene Name | FGF11 |
| EntrezGene Description | transmembrane protein 102 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1373 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor growth
MUSCLE, SOFT TISSUE:
Hypotonia;
Myopathy
NEUROLOGIC:
[Central nervous system];
Severe brain damage
LABORATORY ABNORMALITIES:
Urinary excretion of 2-ethyl-3-keto-hexanoic acid;
Urinary excretion of 2-ethyl-3-hydroxy-hexanoic acid;
Urinary excretion of 2-ethyl-hexanedioic acid;
Decreased acetyl-CoA carboxylase activity
MISCELLANEOUS:
Onset in the perinatal period;
One patient has been reported (as of April 2011)
OMIM Title
*613936 TRANSMEMBRANE PROTEIN 102; TMEM102
;;COMMON BETA CHAIN-ASSOCIATED PROTEIN; CBAP
OMIM Description
CLONING
The ligand-binding alpha subunits of the GMCSF receptor (CSF2RA;
306250), the IL3 receptor (IL3RA; 308385), and the IL5 receptor (IL5RA;
147851) all interact with a signal-transducing common beta chain, or
beta-c (CSF2RB; 138981). Using the box-2 motif of beta-c as bait in a
yeast 2-hybrid screen of a human lymphocyte cDNA library, Kao et al.
(2008) cloned TMEM102, which they called CBAP. The deduced 508-amino
acid protein has a central transmembrane domain. Confocal microscopy
showed that CBAP localized predominantly to intracellular compartments
of TF1 erythroleukemia cells, with some localization at the cell
surface. Database analysis revealed close orthologs of CBAP in several
mammalian species.
GENE FUNCTION
Kao et al. (2008) found that removal of GMCSF (CSF2; 138960) increased
the amount of beta-c and CBAP that immunoprecipitated from TF1 cells and
that colocalized in intracellular compartments. Overexpression of CBAP
in IL3 (147740)-dependent Ba/F3 pro-B cells increased the percentage of
cells showing mitochondrial changes characteristic of apoptosis and
enhanced the apoptotic effect of GMCSF deprivation. Conversely,
knockdown of CBAP in TF1 cells reduced cell sensitivity to GMCSF
deprivation, but not to other proapoptotic stimuli. Mutation analysis of
CBAP revealed an N-terminal apoptotic domain (AD1) and a C-terminal
apoptotic domain (AD2), which included the transmembrane region. AD2,
but not AD1, also bound beta-c. The isolated hinge region of CBAP did
not induce apoptosis or bind beta-c, but it enhanced binding of AD2 to
beta-c. Kao et al. (2008) concluded that CBAP binds the isolated beta-c
molecule and has a role in GMCSF deprivation-induced apoptosis.
MAPPING
Hartz (2011) mapped the TMEM102 gene to chromosome 17p13.1 based on an
alignment of the TMEM102 sequence (GenBank GENBANK AK094197) with the
genomic sequence (GRCh37).
NAA38
| dbSNP name | rs4724(G,A); rs8522(A,G) |
| ccdsGene name | CCDS11122.1 |
| CosmicCodingMuts gene | LSMD1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 84316 |
| EntrezGene Symbol | LSMD1 |
| snpEff Gene Name | LSMD1 |
| EntrezGene Description | LSM domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NAA38:NM_032356:exon1:c.C345T:p.F115F, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1841 |
| ESP Afr MAF | 0.292102 |
| ESP All MAF | 0.172459 |
| ESP Eur/Amr MAF | 0.111163 |
| ExAC AF | 0.172 |
CYB5D1
| dbSNP name | rs12453250(C,A); rs74578237(G,T); rs8080692(A,G) |
| ccdsGene name | CCDS11123.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 124637 |
| EntrezGene Description | cytochrome b5 domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CYB5D1:NM_144607:exon1:c.C60A:p.F20L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6P9G0-2 |
| dbNSFP KGp1 AF | 0.186355311355 |
| dbNSFP KGp1 Afr AF | 0.264227642276 |
| dbNSFP KGp1 Amr AF | 0.234806629834 |
| dbNSFP KGp1 Asn AF | 0.230769230769 |
| dbNSFP KGp1 Eur AF | 0.0791556728232 |
| dbSNP GMAF | 0.186 |
| ESP Afr MAF | 0.302315 |
| ESP All MAF | 0.176073 |
| ESP Eur/Amr MAF | 0.111395 |
| ExAC AF | 0.173 |
VAMP2
| dbSNP name | rs1150(A,G); rs1061032(T,G) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 6844 |
| EntrezGene Description | vesicle-associated membrane protein 2 (synaptobrevin 2) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3765 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Conductive hearing loss;
Stapes ankylosis
SKELETAL:
[Limbs];
[Hands];
Carpal bone fusion;
Proximal interphalangeal (PIP) joint synostoses;
Distal interphalangeal (DIP) joint synostoses (occasional);
Short 5th metacarpal;
[Feet];
Tarsal bone fusion
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Allelic to multiple synostoses syndrome 1 (186500), tarsal-carpal
coalition syndrome (186570), and stapes ankylosis syndrome without
symphalangism (184460)
MOLECULAR BASIS:
Caused by mutation in the homolog of the mouse Noggin gene (NOG, 602991.0001)
OMIM Title
*185881 VESICLE-ASSOCIATED MEMBRANE PROTEIN 2; VAMP2
;;SYNAPTOBREVIN 2; SYB2
OMIM Description
DESCRIPTION
Intracellular vesicles travel among cellular compartments and deliver
their specific cargo to target membranes by membrane fusion. The
specificity of cargo delivery and membrane fusion is controlled, in
part, by the pairing of vesicle v-SNAREs (soluble
N-ethylmaleimide-sensitive factor attachment protein receptors), such as
VAMP2, with target membrane t-SNAREs (summary by McNew et al., 2000).
CLONING
Archer et al. (1990) isolated and characterized cosmid clones containing
the human genes encoding synaptobrevins 1 and 2. Their coding regions
are highly homologous, being interrupted at identical positions by
introns of different size and sequence. The deduced synaptobrevin-2
protein contains 116 amino acids.
GENE FUNCTION
Christodoulou et al. (1997) mapped a gene for familial infantile
myasthenia (605809) to the telomeric region of 17p and pointed to SYB2
as a likely candidate gene because of its map location and because it
encodes a synaptic vesicle protein of the sort that has been implicated
in the pathogenesis of familial infantile myasthenia. Synaptobrevin
probably participates in neurotransmitter release at a step between
docking and fusion (Hunt et al., 1994). The protein forms a stable
complex with syntaxin (see syntaxin 1A, 186590), synaptosomal-associated
protein, 25-kD (SNAP25; 600322), and synaptotagmin (185605). It also
forms a distinct complex with synaptophysin (313475).
McNew et al. (2000) tested all of the potential v-SNAREs encoded in the
yeast genome for their capacity to trigger fusion by partnering with
t-SNAREs that mark the Golgi, the vacuole, and the plasma membrane.
McNew et al. (2000) found that, to a marked degree, the pattern of
membrane flow in the cell is encoded and recapitulated by its isolated
SNARE proteins, as predicted by the SNARE hypothesis. The heterodimer of
syntaxin Sso1, which is homologous to syntaxin-1A, and Sec9, which is
homologous to SNAP25, is a t-SNARE of the yeast plasma membrane, with
Snc2, which is homologous to VAMP2, as its cognate v-SNARE. Thus, the
yeast plasma membrane t-SNARE complex closely resembles its neuronal
counterpart (Weber et al., 1998).
SNARE proteins normally face the cytoplasm, within which their helical
domains can pair to link membranes for fusion. To ascertain whether
SNAREs can fuse cells, Hu et al. (2003) flipped their orientation and
engineered cognate cells to express either the v- or t-SNAREs. Hu et al.
(2003) found that cells expressing the interacting domains of v- (VAMP2)
and t-SNAREs (syntaxin 1A and SNAP25) on the cell surface fused
spontaneously, demonstrating that SNAREs are sufficient to fuse
biological membranes.
To investigate the role of astrocytes in regulating synaptic
transmission, Pascual et al. (2005) generated inducible transgenic mice
that expressed a dominant-negative SNARE domain selectively in
astrocytes to block the release of transmitters from these glial cells.
By releasing ATP, which accumulates as adenosine, astrocytes tonically
suppressed synaptic transmission, thereby enhancing the dynamic range
for long-term potentiation and mediated activity-dependent,
heterosynaptic depression. Pascual et al. (2005) concluded that their
results indicated that astrocytes are intricately linked in the
regulation of synaptic strength and plasticity and provide a pathway for
synaptic crosstalk.
Burre et al. (2010) showed that maintenance of continuous presynaptic
SNARE complex assembly requires a nonclassical chaperone activity
mediated by synucleins. Specifically, alpha-synuclein (163890) directly
bound to the SNARE protein SYB2/VAMP2 and promoted SNARE complex
assembly. Moreover, triple-knockout mice lacking synucleins developed
age-dependent neurologic impairments, exhibited decreased SNARE complex
assembly, and died prematurely. Thus, Burre et al. (2010) concluded that
synucleins may function to sustain normal SNARE complex assembly in a
presynaptic terminal during aging.
Shi et al. (2012) used in vitro membrane fusion and exocytosis assays
that paired liposomes containing a t-SNARE complex of rat syntaxin-1A
and mouse Snap25 with flat nanodisc proteolipid particles containing the
mouse v-SNARE Vamp2. They found that a single Vamp2 protein could
mediate efficient SNARE complex formation, vesicle fusion, and lipid
mixing between the liposome and nanodisc, but not pore formation or
release of liposome cargo. Cargo release was highly sensitive to the
number of SNARE complexes formed between the liposome and nanodisc, and
maximum efflux required 3 or 4 Vamp2 proteins per nanodisc. Use of
chimeric proteins revealed that the membrane-spanning transmembrane
domain of VAMP2 mediated efficient release of vesicle contents by
stabilizing the nascent fusion pore formed between VAMP2 and the
t-SNAREs. Shi et al. (2012) concluded that membrane fusion requires only
a single SNARE complex between membranes, but pore formation, widening,
and stabilization, as well as efficient cargo efflux, requires several
SNARE complexes.
BIOCHEMICAL FEATURES
- Crystal Structure
Stein et al. (2009) reported the x-ray structure of the neuronal SNARE
complex, consisting of the SNARE motifs of rat syntaxin-1A, Snap25, and
synaptobrevin-2 (VAMP2), with the C-terminal linkers and transmembrane
regions of both syntaxin-1A and synaptobrevin-2 at 3.4-angstrom
resolution. The structure showed that assembly proceeds beyond the known
core SNARE complex, resulting in a continuous helical bundle that is
further stabilized by side-chain interactions in the linker region. The
results suggested that the final phase of SNARE assembly is directly
coupled to membrane merger.
- Physical Chemistry
Gao et al. (2012) used optical tweezers to observe in a cell-free
reconstitution experiment in real time a long-sought SNARE assembly
intermediate in which only the membrane-distal amino-terminal half of
the bundle is assembled. Their findings supported the zippering
hypothesis, but suggested that zippering proceeds through 3 sequential
binary switches, not continuously, in the amino- and carboxyl-terminal
halves of the bundle and the linker domain. The half-zippered
intermediate was stabilized by externally applied force that mimicked
the repulsion between apposed membranes being forced to fuse. This
intermediate then rapidly and forcefully zippered, delivering free
energy of 36 k(B)T (where k(B) is the Boltzmann constant and T is
temperature) to mediate fusion.
GENE STRUCTURE
Archer et al. (1990) determined that the SYB2 gene contains 5 exons
spanning approximately 3 kb.
MAPPING
By Southern analysis of rodent-human somatic cell hybrids, Archer et al.
(1990) mapped the SYB2 gene to human chromosome 17. By study of various
deleted chromosomes 17 in somatic cell hybrids, they showed that the
gene is located in region 17pter-p12. Archer et al. (1990) identified a
PstI RFLP at the SYB2 locus. By fluorescence in situ hybridization,
Zoraqi et al. (2000) localized the SYB2 gene to 17p12. By analysis of
somatic cell hybrids between mouse cells and those of Chinese hamster or
rat, Archer et al. (1990) assigned the Syb2 gene in the mouse to
chromosome 11.
ANIMAL MODEL
Schoch et al. (2001) generated mice deficient in Vamp2 and used
electrophysiologic methods to measure fusion. In the absence of
synaptobrevin-2, spontaneous synaptic vesicle fusion and fusion induced
by hypertonic sucrose were decreased approximately 10-fold, but fast
calcium-triggered fusion was decreased more than 100-fold. Thus, Schoch
et al. (2001) concluded that synaptobrevin-2 may function in catalyzing
fusion reactions and stabilizing fusion intermediates but is not
absolutely required for synaptic fusion.
Deak et al. (2004) found a defect in the endocytosis of synaptic
vesicles in Vamp2 -/- mouse neurons. They concluded that Vamp2 is
essential for 2 fast synapse-specific membrane trafficking reactions:
fast exocytosis for neurotransmitter release, and fast endocytosis for
the rapid reuse of synaptic vesicles.
C17orf59
| dbSNP name | rs8531(T,G) |
| ccdsGene name | CCDS11133.2 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 54785 |
| EntrezGene Description | chromosome 17 open reading frame 59 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C17orf59:NM_017622:exon1:c.A765C:p.P255P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4082 |
| ESP Afr MAF | 0.334244 |
| ESP All MAF | 0.23135 |
| ESP Eur/Amr MAF | 0.178705 |
| ExAC AF | 0.714 |
RANGRF
| dbSNP name | rs869773(C,T) |
| ccdsGene name | CCDS11137.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 399512 |
| EntrezGene Symbol | SLC25A35 |
| EntrezGene Description | solute carrier family 25, member 35 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1579 |
| ESP Afr MAF | 0.098048 |
| ESP All MAF | 0.061818 |
| ESP Eur/Amr MAF | 0.043256 |
| ExAC AF | 0.097 |
KRBA2
| dbSNP name | rs186387036(C,T); rs373085(T,C); rs370752(G,A); rs143766177(A,G); rs2430949(G,A); rs74532943(G,A) |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 124751 |
| EntrezGene Description | KRAB-A domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
MFSD6L
| dbSNP name | rs78093130(C,T); rs2242373(C,T); rs2242374(G,A); rs34184531(A,G); rs16957601(A,G); rs17854013(G,T); rs150313646(T,G) |
| ccdsGene name | CCDS11146.1 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 162387 |
| EntrezGene Description | major facilitator superfamily domain containing 6-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MFSD6L:NM_152599:exon1:c.G1720A:p.D574N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.2967 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IWD5 |
| dbNSFP Uniprot ID | MFS6L_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.00813008130081 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.014299 |
| ESP All MAF | 0.007919 |
| ESP Eur/Amr MAF | 0.004651 |
| ExAC AF | 5.392e-03,1.627e-05 |
WDR16
| dbSNP name | rs11656540(A,G); rs35309856(A,G); rs76883105(C,T); rs8064915(C,G); rs12453336(A,G); rs368907834(C,T); rs12453912(T,G); rs12453913(T,A); rs188709331(A,G); rs2872833(A,G); rs7503761(A,G); rs192457104(C,T); rs8076248(T,C); rs148827882(G,A); rs4791854(C,A); rs7224675(T,C); rs34662285(G,A); rs55862252(C,A); rs182735297(G,A); rs187903909(C,A); rs28555611(C,T); rs187603624(A,C); rs7207303(C,T); rs1968765(A,G); rs185352302(C,T); rs61407923(C,A); rs6503232(C,G); rs113471796(C,T); rs11657876(C,A); rs11654310(T,C); rs11657922(C,T); rs150190874(G,A); rs188627526(G,A); rs12602714(T,C); rs9916826(G,C); rs9898166(A,G); rs1807022(C,G); rs79165165(A,T); rs145032534(C,T); rs56408235(C,T); rs755307(T,C); rs34162768(C,T); rs7214348(G,A); rs73253847(A,T); rs9907091(T,C); rs35397077(A,G); rs34653219(G,A); rs1979287(A,G); rs1979288(A,T); rs7222448(G,T); rs66835682(G,A); rs8080667(T,C); rs149894242(G,T); rs7220517(A,G); rs115922623(G,A); rs6503233(G,T); rs12051784(G,A); rs8080111(G,A); rs73253863(T,G); rs147656194(T,G); rs2016355(T,C); rs922016(G,A); rs79792561(T,G); rs4791353(G,A); rs9902732(A,G); rs2054229(T,C); rs9889814(T,C); rs9911158(C,T); rs9889489(C,T); rs11656135(T,G); rs11078808(G,A); rs56237272(A,G); rs11078809(A,G); rs7225814(G,A); rs11653066(C,T); rs6503234(C,T); rs12602008(C,T); rs77686457(G,A); rs2034948(T,C); rs111592407(G,A); rs12103586(A,G); rs184005755(G,C); rs56238892(C,A); rs6503235(G,A); rs6503236(A,G); rs113440291(A,G); rs79224292(C,A); rs8068403(C,T); rs8067557(G,T); rs34654539(C,A); rs73253893(C,G); rs113220597(A,G); rs114250092(T,C); rs2654718(T,C); rs149896840(G,A); rs113633622(T,A); rs184560330(C,A); rs75671790(C,T); rs112431705(T,A); rs151185341(G,A); rs73253896(G,T); rs73253897(A,G); rs113651658(C,T); rs57323725(T,A); rs418706(G,T); rs7224680(C,T); rs2654722(C,T); rs389995(G,A); rs113544023(C,T); rs73253902(G,C); rs56371689(G,A); rs192777467(G,A); rs79811592(T,C); rs368266408(C,T); rs200770987(T,A); rs11656567(G,A); rs79276762(T,C); rs274899(G,A) |
| ccdsGene name | CCDS11149.2 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 146845 |
| EntrezGene Description | WD repeat domain 16 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | WDR16:NM_145054:exon4:c.G509A:p.R170Q,WDR16:NM_001080556:exon3:c.G305A:p.R102Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5328 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N1V2-2 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 3.253e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Seizures, generalized, associated with fever;
Generalized tonic-clonic seizures;
Seizures usually last less than 15 minutes;
Seizures usually occur less than 3 times;
Some patients may develop afebrile seizures later in life;
Patients show normal psychomotor development
MISCELLANEOUS:
Onset 6 months to 2.5 years;
Genetic heterogeneity (see GEFS+, 604233);
See also febrile seizures (FEB1, 121210)
OMIM Title
*609804 WD REPEAT-CONTAINING PROTEIN 16; WDR16
;;WD40 REPEAT-CONTAINING PROTEIN UPREGULATED IN HEPATOCELLULAR CARCINOMA;
WDRPUH
OMIM Description
DESCRIPTION
WD repeat-containing proteins, such as WDR16, play crucial roles in a
wide range of physiologic functions, including signal transduction, RNA
processing, remodeling the cytoskeleton, regulation of vesicular
traffic, and cell division (Silva et al., 2005).
CLONING
Using cDNA microarray analysis to identify genes upregulated in
hepatocellular carcinomas (HCCs), followed by 5-prime RACE of testis
mRNA, Silva et al. (2005) cloned WDR16, which they designated WDRPUH.
WDR16 contains 11 WD40 repeat domains and shares 84 to 89% amino acid
identity with the mouse, rat, and monkey Wdr16 proteins. Northern blot
analysis of 16 human tissues detected a 2.2-kb WDR16 transcript only in
testis. Immunofluorescence localization detected WDR16 in the cytoplasm
of transfected human cell lines.
GENE FUNCTION
By microarray analysis, Silva et al. (2005) found that WDR16 was
overexpressed in 11 of 12 HCCs. RT-PCR showed that WDR16 was
overexpressed in 8 of 10 additional HCC tissues. Small interfering RNA
directed to WDR16 significantly reduced WDR16 expression in HCC cells
and resulted in growth suppression. By mass spectrometry of
immunoprecipitated proteins, Silva et al. (2005) found that WDR16
interacted directly with HSP70 (see 140550), BRCA2 (600185), and
CCT1-delta (CCT4; 605142).
GENE STRUCTURE
Silva et al. (2005) determined that the WDR16 gene contains 14 exons and
spans about 60 kb.
MAPPING
By genomic sequence analysis, Silva et al. (2005) mapped the WDR16 gene
to chromosome 17p13.1.
MYH13
| dbSNP name | rs62060457(C,G); rs2008528(C,T); rs117943063(C,T); rs9908029(A,G); rs9906544(T,C); rs36041546(C,A); rs9907053(T,C); rs116935297(G,A); rs10491094(G,A); rs9895678(T,C); rs75268069(C,T); rs12603986(G,T); rs6503304(T,C); rs4791974(A,G); rs61503459(C,T); rs11868948(G,A); rs10852921(A,G); rs2074867(C,T); rs16943279(C,G); rs4239113(C,A); rs4791401(G,A); rs4451985(G,A); rs143928002(T,A); rs62061560(C,A); rs62061561(A,G); rs17690195(C,T); rs2240577(C,T); rs2240578(A,T); rs4791975(G,A); rs12602120(C,A); rs77764876(G,T); rs16943288(G,A); rs11869661(C,A); rs62061562(G,A); rs73283687(G,C); rs8079253(G,A); rs2074868(G,A); rs2074869(C,T); rs2074870(A,G); rs2074871(A,G); rs2074873(A,G); rs112462085(G,A); rs113178316(G,C); rs111895847(C,T); rs28574885(C,T); rs16943303(A,G); rs2074874(C,T); rs11658229(G,A); rs2074875(A,G); rs2074876(G,T); rs2074877(T,C); rs1990226(T,C); rs2074878(A,C); rs202221384(C,T); rs62058070(T,G); rs16943327(G,A); rs7221884(C,G); rs145163247(G,A); rs111381824(C,T); rs12940814(G,A); rs116959643(G,A); rs28661121(G,A); rs12944070(C,T); rs4791977(A,T); rs3826442(C,T); rs12945894(A,G); rs1859999(A,G); rs7342842(T,C); rs7342843(T,G); rs12939466(C,T); rs9890494(G,C); rs12946984(C,T); rs12938606(T,C); rs8067928(A,G); rs2320791(A,G); rs2277644(C,T); rs2277645(A,C); rs73285903(C,T); rs8068005(C,T); rs8067532(G,A); rs74432441(A,G); rs66539869(G,A); rs72814754(C,T); rs60279728(G,A); rs2270054(G,C); rs4791403(T,C); rs4791404(C,T); rs17208457(C,T); rs9903582(C,T); rs73281982(C,T); rs72814757(C,T); rs8064714(G,C); rs73281983(C,A); rs73281985(C,T); rs9909522(G,A); rs11654733(A,C); rs2240579(G,A); rs10083847(C,T); rs11078841(T,A); rs73281987(C,G); rs55652827(T,C); rs55752747(C,G); rs10083868(G,T); rs10083849(C,T); rs77693151(T,C); rs72814768(C,T); rs4791978(A,G); rs12939209(G,A); rs9908371(C,T); rs9906701(G,C); rs11078842(G,A); rs9915630(T,C); rs9907202(G,A); rs12943737(C,G); rs12952386(T,C); rs12943772(C,A); rs112870238(A,C); rs8070079(A,G); rs8069814(C,T); rs8070527(A,G); rs8070674(A,G); rs12951088(G,C); rs9889881(A,C); rs12943663(C,T); rs9902422(T,G); rs1548646(T,C); rs1548647(T,C); rs9895816(G,A); rs4445936(C,A); rs3760423(G,A); rs3760424(T,C); rs3760425(C,T); rs2874357(A,G); rs2320792(G,T); rs2320793(T,G); rs2320794(T,C); rs2320795(T,C); rs9303254(A,G); rs9303255(G,A); rs8071436(C,T); rs8076045(T,G); rs8071613(C,T); rs6503306(T,C); rs8073085(A,G); rs11869897(C,T); rs8073355(A,G); rs4791979(G,A); rs9897482(G,A); rs9897941(G,C); rs9900439(A,C); rs9898203(G,A); rs9906479(T,C); rs71369641(G,T); rs9901113(A,G); rs9303256(T,C); rs12938209(G,A); rs12938754(G,A); rs140369774(G,A); rs6503307(T,G); rs1812043(G,A); rs933366(T,C); rs12602139(G,T); rs11078843(T,G); rs11655438(G,C); rs11652249(T,C); rs11651414(A,G); rs2320796(C,T); rs8080154(G,A); rs116710897(C,G); rs2108568(A,G); rs141621010(C,T); rs9893067(C,T); rs73977144(C,T); rs11078844(G,C); rs56338029(C,T); rs187361971(C,T); rs139147254(C,A); rs77711493(T,C); rs11654213(C,T); rs8068826(G,A); rs140995098(G,A); rs145083427(G,A); rs8071196(A,T); rs11655678(G,C); rs4791980(T,C); rs144500423(G,C); rs28469270(C,T); rs117173938(C,T); rs191585178(C,T); rs149156841(G,T); rs17810975(T,C); rs72814785(T,C); rs180957069(A,G); rs9807084(G,A); rs147175542(A,T); rs2190730(A,T); rs147406920(T,C); rs2277647(T,C); rs2024074(A,G); rs6503309(A,G); rs2024075(A,G); rs9807016(C,T); rs2072265(G,A); rs12948227(C,T); rs74564389(G,A); rs12948936(T,C); rs9303257(G,A); rs7226048(C,T); rs12950258(C,T); rs11658869(A,G); rs12948082(G,A); rs12950630(C,A); rs4791981(C,T); rs12951002(T,G); rs12936065(C,T); rs12951469(G,T); rs9915882(G,A); rs11650841(G,A); rs11651182(C,G); rs12936019(G,C); rs12936552(G,A); rs7215096(T,C); rs11658620(A,G); rs11653603(G,A); rs12165041(G,A); rs732426(A,G); rs113925312(C,A); rs60712920(C,T) |
| ccdsGene name | CCDS45613.1 |
| CosmicCodingMuts gene | MYH13_ENST00000252172 |
| cytoBand name | 17p13.1 |
| EntrezGene GeneID | 8735 |
| EntrezGene Description | myosin, heavy chain 13, skeletal muscle |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYH13:NM_003802:exon37:c.C5464T:p.R1822W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6294 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UKX3 |
| dbNSFP Uniprot ID | MYH13_HUMAN |
| dbNSFP KGp1 AF | 0.0114468864469 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0197889182058 |
| dbSNP GMAF | 0.01148 |
| ESP Afr MAF | 0.002043 |
| ESP All MAF | 0.01261 |
| ESP Eur/Amr MAF | 0.018023 |
| ExAC AF | 0.011 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
ABDOMEN:
[Liver];
Nonalcoholic fatty liver disease;
Hepatic steatosis;
Fibrosis;
Hepatocyte ballooning;
[Pancreas];
Pancreatitis
NEUROLOGIC:
[Central nervous system];
Sudden onset of neuropsychiatric symptoms;
Disorientation;
Confusion;
Disturbance of consciousness;
Coma;
Brain edema
NEOPLASIA:
Hepatocellular carcinoma
LABORATORY ABNORMALITIES:
Hyperammonemia;
Citrullinemia;
Abnormal liver enzymes;
Low serum albumin;
Increased serum triglycerides;
Increased serum pancreatic secretory trypsin inhibitor (PSTI);
Secondary decreased activity of argininosuccinate synthetase (ASS1)
MISCELLANEOUS:
Mean age of diagnosis is 40 years (range 11 to 79 years);
Some patients may be asymptomatic;
Natural aversion to carbohydrates;
Favoring of fat and protein;
Increased frequency in individuals of Asian descent;
1 in 19,000 in Japan;
1 in 50,000 in Korea;
1 in 17,000 in China
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 25 (mitochondrial
carrier, citrin), member 13 (SLC25A13, 603859.0001)
OMIM Title
*603487 MYOSIN, SKELETAL MUSCLE, HEAVY CHAIN 13; MYH13
;;MYOSIN, HEAVY CHAIN, EXTRAOCULAR MUSCLE;;
EO MYOSIN;;
MYHC-EO
OMIM Description
For background information on the myosin heavy chain genes, see MYH1
(160730).
CLONING
Wieczorek et al. (1985) isolated a rat gene encoding a myosin heavy
chain (MHC) expressed specifically in the extraocular (EO) musculature
fibers of the adult rat. Winters et al. (1998) isolated homologous
partial human, mouse and hamster genomic clones.
Weiss et al. (1999) used RT-PCR of RNA isolated from human skeletal
muscle samples to obtain the full-length coding sequence for the MYH13
gene, which they called MYHC-EO. MYHC-EO expression had been detected in
laryngeal muscles (Lucas et al., 1995) but was restricted primarily to
the extrinsic eye muscles, which are specialized for function in eye
movement.
MAPPING
By analysis of a radiation hybrid panel and by inclusion within mapped
clones, Winters et al. (1998) mapped the MYH13 gene to human chromosome
17p13.1-p12. Using an interspecific backcross, they determined that the
mouse EO myosin gene maps to chromosome 11. In both mouse and human, the
MYH13 gene is located in a region containing several other MHC genes.
Weiss et al. (1999) determined that the linear order of the MYHC genes
on human 17p13.1 and mouse chromosome 11 is MYHC-embryonic (MYH3;
160720)--MYHC2A (MYH2; 160740)--MYHC2X/D (MYH1)--MYHC2B (MYH4;
160742)--MYHC-perinatal (MYH8; 160741)--MYHC-extraocular. They found
that the order, transcriptional orientation, and relative intergenic
distances of these genes are remarkably conserved between human and
mouse. Unlike many cluster gene families, this order did not reflect the
known temporal expression patterns of these genes. However, the
conservation of gene organization since the estimated divergence of
these species, approximately 75 to 110 million years ago, suggested that
the physical organization of these genes may be significant for their
regulation and function.
CDRT15P1
| dbSNP name | rs11649821(G,A) |
| cytoBand name | 17p12 |
| EntrezGene GeneID | 94158 |
| snpEff Gene Name | COX10-AS1 |
| EntrezGene Description | CMT1A duplicated region transcript 15 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1354 |
MEIS3P1
| dbSNP name | rs143985665(C,G); rs534861(T,C); rs533242(G,C) |
| cytoBand name | 17p12 |
| EntrezGene GeneID | 4213 |
| snpEff Gene Name | 5S_rRNA |
| EntrezGene Description | Meis homeobox 3 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | rRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02893 |
| ExAC AF | 0.009059 |
RASD1
| dbSNP name | rs711352(G,C); rs1671822(T,C); rs11545787(G,A) |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 51655 |
| snpEff Gene Name | MED9 |
| EntrezGene Description | RAS, dexamethasone-induced 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4513 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Initial loss of central visual acuity and color vision;
Photophobia and epiphora in day light;
Eventual loss of peripheral vision and night blindness;
Marked macular degeneration;
Mild retinal arteriolar constriction;
Mild temporal optic nerve pallor;
Mild peripheral retinal pigmentary changes
LABORATORY ABNORMALITIES:
Electroretinogram is abnormal--rod responses are mildly abnormal and
cone responses are markedly diminished
OMIM Title
*605550 RAS PROTEIN, DEXAMETHASONE-INDUCED, 1; RASD1
;;DEXAMETHASONE-INDUCED RAS PROTEIN 1; DEXRAS1
OMIM Description
CLONING
Using differential display, Kemppainen and Behrend (1998) identified
Dexras1, a novel RAS superfamily gene induced by dexamethasone in AtT-20
cells (mouse-derived corticotroph tumor cells). The deduced 280-amino
acid mouse protein shares highest homology (36% identity) with human
RAP2B (179541). Northern blot analysis of mouse tissues detected
expression of Dexras1 in brain, heart, kidney, and liver.
By yeast 2-hybrid screening of a lung cDNA library with the third SH3
domain of NCK2 (604930) as bait, Tu and Wu (1999) isolated a cDNA
encoding RASD1, which they called DEXRAS1. The deduced 281-amino acid
protein, which is 98% identical to the mouse protein, contains a P loop,
guanine base-binding loops, and a C-terminal farnesylation site.
SDS-PAGE analysis detected a 33-kD protein, close to the predicted size.
Northern blot analysis revealed ubiquitous expression of a 5.0-kb RASD1
transcript, with highest levels in heart. Dexamethasone exposure
upregulated RASD1 expression.
Fang et al. (2000) isolated cDNAs encoding rat Dexras1 following a yeast
2-hybrid screen using the phosphotyrosine-binding domain of the neuronal
nitric oxide synthase (nNOS; 163731) adaptor protein CAPON (NOS1AP;
605551) as bait. Northern blot analysis in rat showed prominent
expression of Dexras1 mRNA in brain, with somewhat lesser levels in
testis and still lower levels in lung. Dexras1 contains a CAAX box,
suggesting that it may be prenylated. Fang et al. (2000) found that
Dexras1 was principally soluble, though a small fraction was detectable
in membrane fractions.
GENE FUNCTION
Fang et al. (2000) identified a selective interaction between CAPON and
DEXRAS1, a brain-enriched membrane of the RAS family of small monomeric
G proteins. Dexras1 was found to be S-nitrosylated by NO donors. Fang et
al. (2000) determined that Dexras1 is activated by NO donors as well as
by NMDA receptor-stimulated NOS in cortical neurons. The importance of
Dexras1 as a physiologic target of nNOS was established by the selective
decrease of Dexras1 activation, but not of Hras (190020) or 4 other RAS
family members, in the brains of mice harboring a targeted genomic
deletion of nNOS. Fang et al. (2000) showed that nNOS, CAPON, and
Dexras1 form a ternary complex that enhances the ability of nNOS to
activate Dexras1. They concluded that their findings identify DEXRAS1 as
a novel physiologic NO effector and suggest that anchoring of nNOS to
specific targets is a mechanism by which NO signaling is enhanced.
MAPPING
The International Radiation Hybrid Consortium mapped the RASD1 gene to
chromosome 17 (TMAP RH78076).
ANIMAL MODEL
Cheng et al. (2004) found that Rasd1-null mice were born at expected
mendelian frequency, were fertile, and appeared healthy. Histologic
analysis revealed no overt structural or morphologic defects in adult
Rasd1 -/- animals, and Rasd1 -/- mice were indistinguishable from
wildtype controls in most tests of behavior. However, Rasd1 deletion
altered circadian rhythms. Loss of Rads1 reduced photic entrainment by
eliminating pertussis-sensitive circadian response to
N-methyl-D-aspartate. In addition, the mutation potentiated nonphotic
responses to neuropeptide Y (NPY; 162640) and unmasked a nonphotic
response to arousal.
SMCR5
| dbSNP name | rs941446(C,T); rs941445(T,G); rs143620566(A,G); rs77657059(G,A); rs1006656(G,A) |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 140771 |
| snpEff Gene Name | RAI1 |
| EntrezGene Description | Smith-Magenis syndrome chromosome region, candidate 5 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3053 |
MYO15A
| dbSNP name | rs854766(G,A); rs9902983(A,T); rs9904030(G,A); rs2955361(G,A); rs76528177(A,G); rs2955362(G,C); rs9914362(T,C); rs9891617(G,A); rs2955363(T,C); rs2925141(A,G); rs117746839(C,G); rs2955364(C,G); rs113511281(C,T); rs2925142(A,G); rs2925143(A,G); rs1101727(T,C); rs147815223(C,T); rs138086218(A,G); rs2975000(G,C); rs9907044(A,T); rs854767(C,A); rs2975001(T,C); rs854768(T,C); rs854769(G,A); rs854770(A,G); rs28426379(T,G); rs854815(C,G); rs741782(T,C); rs9899595(T,C); rs712267(G,A); rs854817(T,C); rs712268(C,G); rs854789(C,T); rs2975002(A,G); rs1008136(C,G); rs1008135(A,G); rs148669276(G,A); rs854790(C,G); rs854791(C,T); rs854792(T,C); rs854793(G,A); rs115463904(C,T); rs712269(A,G); rs8078991(A,G); rs112198349(C,T); rs854787(G,A); rs73980805(C,T); rs16960927(G,A); rs854786(A,G); rs114328138(C,T); rs854785(A,T); rs854784(C,T); rs2280777(C,T); rs2075658(A,C); rs854783(A,G); rs854782(C,A); rs860567(G,A); rs854781(A,C); rs143418025(C,T); rs2072652(C,T); rs854779(T,C); rs2075659(C,T); rs11658477(G,A); rs2072653(G,A); rs12449609(G,A); rs80114135(C,G); rs854778(A,C); rs139347804(G,A); rs8065026(T,C); rs854777(T,C); rs2272571(G,A); rs854776(T,C); rs77683151(G,A); rs147131723(A,G); rs854775(C,T); rs854774(T,C); rs4303606(A,G); rs2955379(T,C); rs2056841(G,A); rs854773(G,T); rs865923(T,C); rs854772(G,A); rs62073602(A,G); rs712272(C,T); rs2242595(G,A); rs861278(C,T); rs854771(G,A); rs854807(G,A); rs712273(T,C); rs854806(G,T); rs712274(T,C); rs62073603(C,T); rs114195423(A,G); rs8077577(C,T); rs854805(G,A); rs7207276(G,C); rs62073604(T,C); rs62073605(C,T); rs147458358(A,G); rs854804(A,G); rs62073606(G,A); rs72827432(G,T); rs854795(A,G); rs75220059(A,G); rs111822257(C,G); rs854796(G,A); rs854797(C,T); rs62073607(A,G); rs62073608(T,C); rs62073609(T,C); rs62073611(C,G); rs146684075(A,G); rs34474249(T,C); rs854799(G,A); rs11654146(A,C); rs75762289(C,T); rs200456053(G,A); rs854800(T,C); rs11871039(C,G); rs860568(C,T); rs62073615(T,A); rs62073649(T,C); rs57186648(T,C); rs62073650(G,A); rs854801(C,T); rs10048161(C,G); rs854802(G,A) |
| ccdsGene name | CCDS42271.1 |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 51168 |
| EntrezGene Description | myosin XVA |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO15A:NM_016239:exon64:c.G10403A:p.R3468Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5607 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.000255 |
| ESP All MAF | 0.000328 |
| ESP Eur/Amr MAF | 0.000362 |
| ExAC AF | 5.390e-04,8.167e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Cranial dystonia;
[Face];
Facial dystonia;
Jaw dystonia;
[Neck];
Torticollis;
[Mouth];
Tongue dystonia
RESPIRATORY:
[Larynx];
Laryngeal dystonia
SKELETAL:
[Limbs];
Dystonia, upper and lower limbs
NEUROLOGIC:
[Central nervous system];
Torsion dystonia;
Dystonia, trunk and limbs (upper and lower);
Writer's cramp;
Dysarthria;
Dysphonia;
Myoclonus (less common)
MISCELLANEOUS:
Variable distribution, may be focal, segmental, multifocal, or generalized;
Average age at onset 19 years (range 5 to 38);
Often presents with cranial or cervical involvement;
Reduced penetrance (about 60%)
MOLECULAR BASIS:
Caused by mutation in the THAP domain-containing protein 1 gene (THAP1,
609520.0001)
OMIM Title
*602666 MYOSIN XVA; MYO15A
;;MYOSIN XV; MYO15
OMIM Description
CLONING
Wang et al. (1998) isolated a partial MYO15A cDNA from a human
chromosome 17-specific human cDNA library. The deduced 1,585-amino acid
partial protein shares 99% amino acid identity with a mouse partial
protein isolated by Probst et al. (1998). MYO15A contains an N-terminal
motor domain, 2 light-chain binding IQ motifs, and a tail region
containing a MyTH4 and a talin (186745)-like domain. The extent of
sequence divergence of the MYO15A motor domain from other reported
myosins qualified MYO15A as a new branch of the myosin superfamily.
Northern blot analysis detected MYO15A expression in human fetal and
adult brain, and RT-PCR analysis detected expression in human fetal
cochlea. RNA dot-blot analysis showed expression in ovary, testis,
kidney, and pituitary gland.
Probst et al. (1998) isolated a partial mouse Myo15a clone. Northern
blot analysis detected Myo15a in adult mouse brain and kidney.
Liang et al. (1999) characterized the complete MYO15A sequence. The
3,530-residue protein has a calculated molecular mass of 395 kD. The
corresponding mouse protein contains 3,511 residues and shares 82%
overall identity. A full-length 11.9-kb mRNA, not including the poly(A)
tail, was detected. The MYO15A protein sequence was found to be unusual
for myosins in that it contains a 1,200-residue N-terminal extension,
encoded by exon 2, that precedes the conserved motor domain. Several
alternatively spliced transcripts were identified in both species,
including 1 transcript that skipped exon 2. There was high expression in
the adult pituitary gland.
Belyantseva et al. (2005) noted that the C terminus of MYO15A contains 2
repeats each composed of a MyTH4 and a FERM domain, separated by an SH3
domain, with a PDZ ligand at the C-terminal tip.
GENE FUNCTION
Belyantseva et al. (2005) determined that the C-terminal PDZ ligand of
mouse Myo15a interacted with the third PDZ domain of whirlin (WHRN;
607928), and this interaction was required for the targeting of whirlin
to the tips of stereocilia. Reintroduction of Myo15a into hair cells of
Myo15a-deficient mice restored the recruitment of endogenous whirlin to
the tips of stereocilia. Belyantseva et al. (2005) concluded that the
interaction of MYO15A with whirlin is a key event in hair bundle
morphogenesis.
Delprat et al. (2005) showed that whirlin, like myosin XVa, is present
at the very tip of rat stereocilium in the developing and mature hair
bundles of the cochlear and vestibular system. The myosin XVa SH3-MyTH4
region bound to the short isoform of whirlin (PR-PDZ3), whereas the
C-terminal MyTH4-FERM region of myosin XVa bound to the PDZ1 and PDZ2
domains of the long whirlin isoform. Delprat et al. (2005) concluded
that a direct myosin XVa/whirlin interaction at the stereocilia tip is
likely to control the elongation of stereocilia.
Manor et al. (2011) determined that Myo15a and whirlin interacted with
Eps8 (600206) at the tips of stereocilia in mouse inner and outer
cochlear and vestibular hair cells. Knockout of Eps8, like knockout of
Myo15a and whirlin, caused shortening of stereocilia and profound
deafness. Knockdown studies showed that Eps8 was dependent upon Myo15a
for its stereocilia localization. Knockdown of whirlin reduced
expression of both Myo15a and Eps8 at stereocilia tips. Overexpression
of Eps8 with Myo15a resulted in stereocilia elongation. In transfected
COS-7 cells, Myo15a and Eps8 expression cooperatively elongated actin
protrusions. Protein pull-down experiments with truncated proteins
revealed that the second MyTh4-FERM domain of the Myo15a tail interacted
predominantly with the C terminus of Eps8. The N terminus of Eps8
interacted with whirlin.
GENE STRUCTURE
Liang et al. (1999) determined that the MYO15A gene contains 66 exons
and spans about 71 kb.
MOLECULAR GENETICS
In affected individuals from 3 unrelated families with autosomal
recessive congenital deafness (DFNB3; 600316), Wang et al. (1998)
identified homozygous mutations in the MYO15A gene
(602666.0001-602666.0003).
In 3 consanguineous families from Pakistan and India with DFNB3, Liburd
et al. (2001) identified homozygous mutations in the MYO15A gene
(602666.0004-602666.0006). In addition, a hemizygous missense mutation
(602666.0007) was found in a patient with Smith-Magenis syndrome
(182290) due to a deletion in chromosome 17p11.2. The patient had
moderately severe hearing loss. The unaffected mother was heterozygous
for the mutation.
Nal et al. (2007) identified 16 novel MYO15A mutations that cosegregated
with DFNB3 hearing loss in 20 families from Turkey, India, and Pakistan.
Two mutations (E1105X; 602666.0008 and 3334delG; 602666.0009) were
located in the alternatively-spliced exon 2 that encodes the large
N-terminal extension of the MYO15A protein. The findings indicated that
the long isoform of MYO15A is necessary for normal auditory function.
In a large multigenerational consanguineous Brazilian pedigree with
prelingual severe to profound sensorineural deafness, negative for
mutations in the deafness-associated GJB2 (121011) and GJB6 (604418)
genes and for the A1555G mitochondrial mutation in the MTRNR1 gene
(561000.0001), Lezirovitz et al. (2008) identified unexpected genetic
heterogeneity: 15 affected individuals from 'branch 2' of the family
were homozygous for a 1-bp deletion (10573delA; 602666.0012) in the
MYO15A gene, whereas 4 affected sibs from 'branch 1' and 1 individual
from 'branch 2' were compound heterozygous for 10573delA and a 4-bp
deletion (602666.0013) in MYO15A. In 1 patient, only the 10573delA
mutation could be identified. No mutations in MYO15A were identified in
5 patients from 2 additional branches of the family.
ANIMAL MODEL
Shaker-2 (sh2) is a recessive mouse mutation on chromosome 11 that arose
in the progeny of an x-ray irradiated mouse. Affected mice lack a normal
startle response to sound and show no auditory brainstem responses to
sound pressure levels up to high levels, indicating profound deafness.
Associated vestibular defects cause head-tossing and circling behavior.
The stereociliary bundles on both the inner and outer hair cells of
1-month-old shaker-2 mice are short and dysmorphic, but are arrayed in a
nearly normal pattern. Complete 1-Mb yeast artificial chromosome (YAC)
and bacterial artificial chromosome (BAC) contigs that spanned the
shaker-2 critical region were generated. Probst et al. (1998) used a BAC
transgene from the shaker-2 critical region to correct the vestibular
defects, deafness, and inner ear morphology of shaker-2 mice. Using this
approach, the authors identified an unconventional myosin gene,
designated Myo15. Shaker-2 mice were found to have an amino acid
substitution at a highly conserved position within the motor domain of
this myosin. Auditory hair cells of shaker-2 mice have very short
stereocilia and a long actin-containing protrusion extending from the
basal end. This histopathology suggested that Myo15 is necessary for
actin organization in the hair cells of the cochlea.
Anderson et al. (2000) described the shaker-2(J) lesion, which is a
14.7-kb deletion that removes the last 6 exons from the 3-prime terminus
of the Myo15 transcript. These exons encode a FERM (F, ezrin, radixin,
and moesin) domain that may interact with integral membrane proteins.
Despite the deletion of 6 exons, in situ hybridization revealed that
Myo15 mRNA transcripts and protein were present in the postnatal day 1
shaker-2J inner ear, suggesting that the FERM domain is critical for the
development of normal hearing and balance. Myo15 transcripts were first
detectable at embryonic day 13.5 in wildtype mice. Myo15 transcripts in
the mouse inner ear were restricted to the sensory epithelium of the
developing cristae ampularis, macula utriculi, and macula sacculi of the
vestibular system, as well as to the developing organ of Corti. Similar
to shaker-2, shaker-2J alleles result in abnormally short hair cell
stereocilia in the cochlear and vestibular systems. The authors
suggested that Myo15 may be important for both the structure and
function of these sensory epithelia.
The MYO15, MYO6 (600970), and MYO7A (276903) genes are essential for
hearing in both humans and mice. Despite widespread expression,
homozygosity for mutations in these genes only results in auditory or
ocular dysfunction. The pirouette (pi) mouse exhibits deafness and inner
ear pathology resembling that of Myo15 mutant mice. Karolyi et al.
(2003) crossed shaker-2 mice to Myo6, Myo7a, and pi mutant mouse
strains. Viable double-mutant homozygotes were obtained from each cross,
and hearing in doubly heterozygous mice was similar to singly
heterozygous mice. All critical cell types of the cochlear sensory
epithelium were present in double-mutant mice, and cochlear stereocilia
exhibited a superimposition of single-mutant phenotypes. Karolyi et al.
(2003) suggested that the function of Myo15 is distinct from that of
Myo6, Myo7a, or pi in development and/or maintenance of stereocilia.
MAPK7
| dbSNP name | rs2233072(T,G) |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 5598 |
| snpEff Gene Name | MFAP4 |
| EntrezGene Description | mitogen-activated protein kinase 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3779 |
OMIM Clinical Significance
INHERITANCE:
Somatic mutation
GROWTH:
[Height];
Increased birth length;
[Weight];
Increased birth weight;
[Other];
Somatic overgrowth, asymmetric;
Hemihyperplasia
HEAD AND NECK:
[Head];
Megalencephaly;
Macrocephaly, progressive in infancy;
[Face];
Broad forehead;
Smooth philtrum;
[Ears];
Fleshy earlobes;
[Eyes];
Epicanthus;
Hypertelorism;
Downslanting palpebral fissures;
Unilateral microphthalmia;
[Nose];
Flattened nasal bridge;
[Mouth];
Narrow arched palate
CARDIOVASCULAR:
[Heart];
Ventricular septal defect
SKELETAL:
Joint laxity;
[Hands];
Syndactyly;
Polydactyly;
[Feet];
Syndactyly;
Polydactyly
SKIN, NAILS, HAIR:
[Skin];
Thick, loose, doughy skin;
Cutaneous vascular malformations;
Patchy, reticular stains;
Cutis marmorata
MUSCLE, SOFT TISSUE:
Thickened subcutaneous tissue
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation;
Hypotonia;
Seizures;
MRI shows brain asymmetry;
Ventriculomegaly;
Hydrocephalus;
Large cerebellum, progressive;
Cerebellar tonsil herniation;
Crowding of the posterior fossa;
Cavum septum pellucidum;
Cavum vergae;
Polymicrogyria;
Cortical dysgenesis;
Thickened corpus callosum;
Thickened optic nerve sheath;
Dilated venous sinuses;
White matter signal abnormalities in the deep white matter and periventricular
regions
NEOPLASIA:
Increased risk of meningioma;
Increased risk of Wilms tumor;
Increased risk of leukemia
MOLECULAR BASIS:
Caused by somatic mutation in the phosphatidylinositol 3-kinase, catalytic,
alpha polypeptide gene (PIK3CA, 171834.0003)
OMIM Title
*602521 MITOGEN-ACTIVATED PROTEIN KINASE 7; MAPK7
;;PROTEIN KINASE, MITOGEN-ACTIVATED, 7; PRKM7;;
EXTRACELLULAR SIGNAL-REGULATED KINASE 5; ERK5
OMIM Description
CLONING
Mitogen-activated protein kinases (MAPKs, or PRKMs) are activated by an
upstream cascade of kinases in response to a wide variety of
extracellular stimuli. Specific PRKM kinases (MAPKKs, or PRKMKs) have
been shown to phosphorylate and activate specific PRKMs in a given
signaling pathway. Using the yeast 2-hybrid system with mutant forms of
PRKMK5 (602520) as baits, Zhou et al. (1995) identified a cDNA encoding
MAPK7, called ERK5 by them. They demonstrated that MAPK7 interacts
specifically with PRKMK5, but not with PRKMK1 (176872) or PRKMK2
(601263), suggesting that the PRKMK5/MAPK7 protein cascade is a novel
signaling pathway. The 815-amino acid MAPK7 contains the conserved
thr-glu-tyr activation motif of ERK-type MAPKs. MAPK7 has an
uncharacteristic 400-amino acid C-terminal domain with sequences
indicating that it may be targeted to the cytoskeleton. Zhou et al.
(1995) found that full-length MAPK7 has no detectable kinase activity in
vitro, whereas removal of the C terminus results in autophosphorylation,
suggesting that the C terminus may play a role in regulating MAPK7.
Northern blot analysis detected a 3.1-kb transcript in a number of human
tissues, with the highest levels in heart and skeletal muscle.
By degenerate PCR, Lee et al. (1995) isolated a cDNA encoding a PRKM
which they named BMK1. BMK1 shows 98% amino acid identity to ERK5; they
differ in a short span of residues at the N terminus. Lee et al. (1995)
speculated that these kinases are derived from the same gene, possibly
via differential mRNA splicing.
MAPPING
By PCR analysis of a somatic cell hybrid panel, Purandare et al. (1998)
mapped the MAPK7 gene to human chromosome 17p11.2.
GENE FUNCTION
Thymocyte emigration after positive selection requires KLF2 (602016)
expression. Although KLF2 expression by endothelial cells requires ERK5,
which is phosphorylated in response to IL7 (146660), Weinreich et al.
(2011) found that Erk5-deficient mouse T cells underwent normal
development and had no Klf2 deficiency. They concluded that IL7 and ERK5
do not control KLF2 or the semimature to mature single-positive
thymocyte transition.
ANIMAL MODEL
To assess the biologic role of MAPK7 (called ERK5 by them), Regan et al.
(2002) deleted the gene in mice. Inactivation of the gene resulted in
defective blood vessel and cardiac development leading to embryonic
lethality around embryonic day 9.5 to 10.5. Cardiac development was
retarded, and the heart failed to undergo normal looping. Endothelial
cells that line the developing myocardium of erk5 -/- embryos displayed
a disorganized, rounded morphology. Vasculogenesis occurred, but
extraembryonic and embryonic blood vessels were disorganized and failed
to mature. Furthermore, the investment of embryonic blood vessels with
smooth muscle cells was attenuated.
Hayashi et al. (2004) found that targeted ablation of MAPK7 using the
Mx1-Cre transgene in adult mice led to lethality within 2 to 4 weeks
after the induction of Cre recombinase. Physiologic analysis showed that
blood vessels became abnormally leaky after deletion of the MAPK7 gene;
histologically, the endothelial cells lining the leaky blood vessels
were round, irregularly aligned, and ultimately apoptotic. In vitro
removal of MAPK7 also led to the death of endothelial cells, partially
due to the downregulation of transcriptional factor MEF2C (600662),
which is a direct substrate of MAPK7. In addition, endothelial-specific
Mapk7 knockout led to cardiovascular defects identical to that of global
Mapk7 -/- mice, but mice lacking Mapk7 only in cardiomyocytes developed
to term with no apparent defects. Hayashi et al. (2004) concluded that
the MAPK7 pathway is critical for endothelial function and maintenance
of blood vessel integrity.
MFAP4
| dbSNP name | rs1054206(G,C); rs6587082(T,G) |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 4239 |
| snpEff Gene Name | MAPK7 |
| EntrezGene Description | microfibrillar-associated protein 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0831 |
OMIM Clinical Significance
Head:
Craniosynostosis
Skel:
Coned epiphyses of hands and feet;
Distal and middle phalangeal hypoplasia;
Carpal bone malsegmentation;
Hallux valgus;
Phalangeal, tarsonavicular and calcaneonavicular foot fusions
Inheritance:
? Autosomal dominant (4p16)
OMIM Title
*600596 MICROFIBRILLAR-ASSOCIATED PROTEIN 4; MFAP4
OMIM Description
CLONING
Zhao et al. (1995) cloned a human cDNA, designated
microfibrillar-associated protein-4 (MFAP4), encoding a deduced
225-amino acid protein with a fibrinogen-like domain. The N-terminus of
the protein contains an RGD sequence that serves as the ligand motif for
cell surface receptor integrin (see 192975). MFAP4 shares a high level
of sequence identity with the partial sequence of a bovine 36-kD
microfibril-associated glycoprotein identified by Kobayashi et al.
(1994) and thought to be a Ca(2+)-dependent adhesive protein associated
with elastin (ELN; 130160) microfibrils in the extracellular matrix.
Northern blot analysis of human tissues revealed wide expression of
MFAP4, with highest expression in heart, lung, ovary, and small
intestine and lowest expression in peripheral blood leukocytes, liver,
thymus, and brain.
GENE FUNCTION
Zhao et al. (1995) suggested that MFAP4 is an extracellular matrix
protein involved in cell adhesion or intercellular interactions.
MAPPING
Zhao et al. (1995) identified the MFAP4 gene within the region of
chromosome 17p11.2 that is deleted in Smith-Magenis syndrome (SMS;
182290).
MOLECULAR GENETICS
Zhao et al. (1995) demonstrated deletion of the MFAP4 gene in 30 of 31
SMS patients using either fluorescence in situ hybridization or PCR and
Southern blot analysis of somatic cell hybrids retaining the
del(17)(p11.2) chromosome typical of SMS.
MTRNR2L1
| dbSNP name | rs62051410(G,A); rs56270535(C,A); rs17052204(C,A); rs73982945(G,C); rs62051411(T,C) |
| cytoBand name | 17p11.2 |
| EntrezGene GeneID | 100462977 |
| EntrezGene Description | MT-RNR2-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4871 |
SEBOX
| dbSNP name | rs9910163(A,G); rs2277667(T,C) |
| ccdsGene name | CCDS45634.1 |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 645832 |
| snpEff Gene Name | VTN |
| EntrezGene Description | SEBOX homeobox |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SEBOX:NM_001080837:exon3:c.T542C:p.L181S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HB31 |
| dbNSFP Uniprot ID | SEBOX_HUMAN |
| dbNSFP KGp1 AF | 0.869963369963 |
| dbNSFP KGp1 Afr AF | 0.981707317073 |
| dbNSFP KGp1 Amr AF | 0.78729281768 |
| dbNSFP KGp1 Asn AF | 0.994755244755 |
| dbNSFP KGp1 Eur AF | 0.742744063325 |
| dbSNP GMAF | 0.1304 |
| ESP Afr MAF | 0.04123 |
| ESP All MAF | 0.162925 |
| ESP Eur/Amr MAF | 0.223326 |
| ExAC AF | 0.796 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature (childhood);
Birth length normal;
[Weight];
Birth weight normal
HEAD AND NECK:
[Eyes];
White to faintly blue sclera;
[Teeth];
Dentinogenesis imperfecta (in one family)
SKELETAL:
Moderate to severe bone fragility;
Moderately deforming osteogenesis imperfecta;
Joint laxity;
Decreased bone mineral density Z score;
Osteopenia;
[Skull];
No wormian bones;
[Spine];
Wedge-shaped vertebrae;
Biconcave vertebrae;
Vertebral compression fractures (8/8 patients);
Scoliosis (5/8 patients);
[Pelvis];
Unilateral/bilateral coxa vara (5/8 patients);
Protrusio acetabuli (4/8 patients);
'Fish-scale' pattern of lamellae;
Increased osteoid volume;
Hyperosteoidosis;
[Limbs];
Bulbous metaphyses (2/8 patients);
Bowed extremities;
Long bone deformity
SKIN, NAILS, HAIR:
[Skin];
Normal skin;
No easy bruisability
LABORATORY ABNORMALITIES:
Elevated serum alkaline phosphatase
MISCELLANEOUS:
Onset of fractures 4-18 months of life;
Severe ambulatory restriction;
May be autosomal dominant with parental mosaicism
OMIM Title
*610975 SKIN-, EMBRYO-, BRAIN-, AND OOCYTE-SPECIFIC HOMEOBOX
;;SEBOX;;
OG9
OMIM Description
DESCRIPTION
Homeodomain proteins, such as SEBOX, play a key role in coordinating
gene expression during development (Cinquanta et al., 2000).
CLONING
Rovescalli et al. (1996) cloned a partial cDNA encoding the mouse
homeodomain protein Og9. Northern blot analysis detected expression in
mouse embryos from day 7 to 17. In adult mouse tissues, expression was
detected in skeletal muscle, with trace expression in brain.
By searching databases for homologs of mouse Sebox, Cinquanta et al.
(2000) identified human SEBOX. The predicted 221-amino acid human
protein contains a central homeodomain and shares 63% amino acid
identity with mouse Sebox. Compared with mouse Sebox, the human protein
has substitutions at the normally invariant residues asn51 and arg53,
suggesting it may be nonfunctional. Northern blot analysis detected
Sebox expression in adult mouse brain, skin, ovary, and liver.
Expression was low in 12-day mouse embryos and higher in 18- and 19-day
embryos. In situ hybridization revealed Sebox expression in maturing
mouse oocytes, eggs, zygotes, and 2-cell embryos, but not 4-cell
embryos.
GENE STRUCTURE
Cinquanta et al. (2000) determined that the SEBOX gene contains 3 exons.
MAPPING
By genomic sequence analysis, Cinquanta et al. (2000) mapped the SEBOX
gene to chromosome 17. They mapped the mouse gene to a region of
chromosome 11 that shows homology of synteny to human chromosome 17.
FOXN1
| dbSNP name | rs79946739(G,A); rs614434(G,A); rs76766579(C,A); rs598858(A,G); rs76777321(A,G); rs570499(C,T); rs4795450(T,C); rs147849562(G,A); rs57293524(G,A); rs634065(T,G); rs634061(G,A); rs2002887(G,A); rs35240903(T,C); rs548973(A,G); rs143070091(C,T); rs78473546(C,A); rs59361667(C,T); rs12451259(C,T); rs12449554(T,C); rs113368140(G,T); rs62066768(G,A); rs113679772(A,T); rs76337427(G,A); rs683289(T,C); rs667486(C,G); rs667049(T,C); rs667026(G,C); rs2286521(C,T); rs9889455(A,G); rs113097916(C,A); rs113760759(G,T); rs637931(T,C); rs624196(C,T); rs532648(G,C); rs3744635(G,A) |
| ccdsGene name | CCDS11232.1 |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 8456 |
| EntrezGene Description | forkhead box N1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FOXN1:NM_003593:exon7:c.C1315A:p.L439M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5243 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O15353 |
| dbNSFP Uniprot ID | FOXN1_HUMAN |
OMIM Clinical Significance
GU:
Nocturnal enuresis
Inheritance:
Autosomal dominant (12q13-q21);
heterogeneity
OMIM Title
*600838 FORKHEAD BOX N1; FOXN1
;;WINGED HELIX NUDE; WHN
OMIM Description
CLONING
Mutations at the 'nude' locus of mice and rats disrupt normal hair
growth and thymus development, causing nude mice and rats to be
immune-deficient. Nehls et al. (1994) showed that a gene designated whn,
located in the region of mouse chromosome 11 known to contain the nude
locus, encodes a new member of the winged-helix domain family of
transcription factors. The predicted protein is 648 amino acids long.
The whn gene was disrupted on the mouse and rat nude alleles. Mutant
transcripts did not encode the characteristic DNA-binding domain,
strongly suggesting that the whn gene is the nude gene. Mutations in
winged-helix domain genes cause homeotic transformations in Drosophila
and distort cell-fate decisions during vulval development in C. elegans.
The whn gene was thus the first member of this class of genes to be
implicated in a specific developmental defect in vertebrates.
Segre et al. (1995) confirmed that mutations in whn produce the nude
phenotype in mice and determined the sequence of the rat cDNA, a
mutation of which produces both hairlessness and athymia.
Using cross-hybridization, Schorpp et al. (1997) isolated the human
ortholog of the mouse whn gene. The predicted human protein also
contains 648 amino acids, 85% of which are identical to the mouse
protein.
Frank et al. (1999) noted that, in mammals, Whn expression occurs in
epithelial cells of the thymus, as well as in specific cells of the hair
follicle. In human, they detected WHN mRNA expression in the
differentiating cells of the hair follicle precortex and the innermost
cell layer of the outer root sheath. Expression in thymus was not
determined.
GENE STRUCTURE
Schorpp et al. (1997) characterized the mouse and human FOXN1 genes.
Both comprise 8 coding exons and contain 2 alternative first exons.
MAPPING
By radiation hybrid analysis, Schorpp et al. (1997) assigned the FOXN1
gene to chromosome 17q11-q12.
GENE FUNCTION
Using RT-PCR, Balciunaite et al. (2002) detected Wnt1 (164820)
expression in nude (i.e., Foxn1-deficient) fetal thymus and both Wnt1
and Wnt3 (165330) expression in adult wildtype thymus, where their
expression in thymic epithelial cells (TECs) was independent of the
presence of thymocytes. Nude fetal and adult wildtype thymus also
expressed Wnt4 (603490), Wnt5b (606361), and Wnt10b (601906), whereas
wildtype fetal thymus at embryonic day 13 only expressed Wnt4 and a
trace amount of Wnt5b. Luciferase reporter analysis showed that Wnt1 and
Wnt4 can signal to TECs. However, overexpression of Wnt4, but not of
Wnt1, induced an increase in Foxn1 mRNA and protein. Expression of Foxn1
in TECs was regulated by Wnt4 and Wnt5b bound to Fzd7 (603410) and Fzd8
(606146). Balciunaite et al. (2002) concluded that Wnt signaling in
thymic stromal cells regulates a genetic program critical for the
control of thymic epithelial development and consequent T-cell
lymphopoiesis.
Using in vivo cell lineage analysis in mice, Bleul et al. (2006)
demonstrated the presence of a common progenitor of cortical and
medullary TECs after birth. To probe the function of postnatal
progenitors, a conditional mutant allele of Foxn1 was reverted to
wildtype function in single epithelial cells in vivo. This led to the
formation of small thymic lobules containing both cortical and medullary
areas that supported normal thymopoiesis. Thus, Bleul et al. (2006)
concluded that single epithelial progenitor cells can give rise to a
complete and functional thymic microenvironment, suggesting that
cell-based therapies could be developed for thymus disorders.
External coloration in mammals requires pigment donors and pigment
recipients. Pigment donors are melanocytes, which synthesize melanin in
distinct organelles called melanosomes. Pigment recipients are
epithelial cells, which acquire and hold most cutaneous melanin. By
immunofluorescence analysis of mouse hair follicles, Weiner et al.
(2007) detected Foxn1 primarily in differentiating precursors of the
hair cortex, which receive pigment from melanocytes. Gain- and
loss-of-function experiments in mice showed that Foxn1 activated the
pigment-recipient phenotype and that Fgf2 (134920) was released by
recipient cells. Weiner et al. (2007) noted that human FOXN1 is also
expressed in precursors of the hair cortex. By immunofluorescence
analysis of human skin, they detected FOXN1 in numerous suprabasal
keratinocytes, including all first layer suprabasal keratinocytes. FOXN1
was also found in a subset of basal keratinocytes. Weiner et al. (2007)
concluded that, in both mice and humans, FOXN1 is associated with
pigment-recipient cell populations.
MOLECULAR GENETICS
In 2 sisters with T-cell immunodeficiency, congenital alopecia, and nail
dystrophy (601705), Frank et al. (1999) identified a homozygous nonsense
mutation in the WHN gene (600838.0001).
ANIMAL MODEL
Su et al. (2003) generated a Foxn1 allele, termed Foxn1-delta, that
encoded a transcript lacking exon 3, resulting in a 154-amino acid
deletion from the 285-residue N terminus of the protein. Mice homozygous
for this allele showed abnormal thymic architecture, lacking cortical
and medullary domains. In contrast to thymi from nude mice lacking
Foxn1, thymi from mice homozygous for Foxn1-delta promoted T-cell
development but with specific defects at both the double-negative and
double-positive stages. Su et al. (2003) concluded that initiation and
progression of TEC differentiation are genetically separable functions
of FOXN1 and that the N-terminal domain is required for
cross-talk-dependent TEC differentiation.
Amorosi et al. (2008) found expression of the mouse Foxn1 gene in
epithelial cells of the developing choroid plexus, a structure filling
the lateral, third, and fourth ventricles of the embryonic brain. The
findings suggested that FOXN1 may be involved in brain and neural tube
development and function.
SGK494
| dbSNP name | rs16963468(C,T); rs117417742(T,C) |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 100506436 |
| EntrezGene Symbol | SPAG5-AS1 |
| snpEff Gene Name | AC005726.6 |
| EntrezGene Description | SPAG5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09826 |
TLCD1
| dbSNP name | rs2288595(C,T) |
| ccdsGene name | CCDS11242.1 |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 116238 |
| EntrezGene Description | TLC domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TLCD1:NM_138463:exon3:c.G324A:p.T108T,TLCD1:NM_001160407:exon3:c.G183A:p.T61T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09871 |
| ESP Afr MAF | 0.128915 |
| ESP All MAF | 0.102722 |
| ESP Eur/Amr MAF | 0.089302 |
| ExAC AF | 0.101 |
PHF12
| dbSNP name | rs140797913(C,T); rs2277665(G,A); rs4795475(G,C); rs73266406(G,A); rs79940167(C,T); rs142689891(G,A); rs34554118(C,T); rs79107626(C,T); rs8066347(G,A); rs2320589(T,C); rs183612298(C,T); rs8076554(A,C); rs111368248(C,T); rs11652544(C,T); rs34120713(C,T); rs12948391(T,C); rs75705131(A,T); rs66701171(G,T) |
| ccdsGene name | CCDS11247.1 |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 57649 |
| EntrezGene Description | PHD finger protein 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PHF12:NM_001290131:exon8:c.C1186T:p.P396S,PHF12:NM_001033561:exon8:c.C1186T:p.P396S,PHF12:NM_020889:exon8:c.C1186T:p.P396S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.775 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DFE2 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.004993 |
| ESP All MAF | 0.001692 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0005286 |
CDK5R1
| dbSNP name | rs118075579(C,T) |
| cytoBand name | 17q11.2 |
| EntrezGene GeneID | 8851 |
| snpEff Gene Name | MYO1D |
| EntrezGene Description | cyclin-dependent kinase 5, regulatory subunit 1 (p35) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01423 |
C17orf102
| dbSNP name | rs9916859(G,A); rs9898175(T,C); rs9898832(T,G); rs1014250(A,G); rs114630191(G,A); rs72817876(G,A); rs77137264(T,C); rs4795007(C,T); rs9891306(G,A); rs4795936(A,G); rs887231(G,A); rs887230(C,T); rs58529418(C,G) |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 400591 |
| EntrezGene Description | chromosome 17 open reading frame 102 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2608 |
ZNF830
| dbSNP name | rs931196(T,G); rs8249(A,T) |
| ccdsGene name | CCDS32618.1 |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 91603 |
| EntrezGene Description | zinc finger protein 830 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF830:NM_052857:exon1:c.T297G:p.H99Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96NB3 |
| dbNSFP Uniprot ID | ZN830_HUMAN |
| dbNSFP KGp1 AF | 0.899267399267 |
| dbNSFP KGp1 Afr AF | 0.69918699187 |
| dbNSFP KGp1 Amr AF | 0.961325966851 |
| dbNSFP KGp1 Asn AF | 0.93006993007 |
| dbNSFP KGp1 Eur AF | 0.976253298153 |
| dbSNP GMAF | 0.101 |
| ESP Afr MAF | 0.291421 |
| ESP All MAF | 0.112025 |
| ESP Eur/Amr MAF | 0.020116 |
| ExAC AF | 0.943 |
SLC35G3
| dbSNP name | rs73989559(C,G); rs1299732(C,G); rs71381421(C,T); rs8182314(C,T); rs17547201(C,T); rs7208407(T,C) |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 146861 |
| snpEff Gene Name | UNC45B |
| EntrezGene Description | solute carrier family 35, member G3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07346 |
SNORD7
| dbSNP name | rs114393730(A,G) |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 692076 |
| snpEff Gene Name | PEX12 |
| EntrezGene Description | small nucleolar RNA, C/D box 7 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.049658 |
| ESP All MAF | 0.015521 |
| ESP Eur/Amr MAF | 0.000502 |
| ExAC AF | 0.004658 |
LINC00672
| dbSNP name | rs677843(T,G); rs573556(A,C); rs649997(G,A); rs512003(A,G); rs115343914(G,C) |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 100505576 |
| snpEff Gene Name | LASP1 |
| EntrezGene Description | long intergenic non-protein coding RNA 672 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4151 |
TCAP
| dbSNP name | rs1053651(A,C) |
| ccdsGene name | CCDS11342.1 |
| CosmicCodingMuts gene | TCAP |
| cytoBand name | 17q12 |
| EntrezGene GeneID | 8557 |
| EntrezGene Description | titin-cap |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCAP:NM_003673:exon2:c.A453C:p.A151A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4252 |
| ESP Afr MAF | 0.434941 |
| ESP All MAF | 0.38166 |
| ESP Eur/Amr MAF | 0.287826 |
| ExAC AF | 0.669 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle weakness and atrophy, proximal;
Muscle weakness and atrophy, distal;
Painful muscle cramps;
Fasciculations;
Neurogenic changes seen on EMG and biopsy;
Fatty replacement in hip muscles and proximal muscles of the lower
limb seen on MRI
NEUROLOGIC:
[Central nervous system];
Gait disturbance;
Bulbar symptoms may occur (less common);
Hand tremor (in some patients);
Loss of anterior horn cells;
Loss of dorsal root ganglion cells;
Loss of myelinated fibers in spinal cord roots;
Gliosis;
TFG- and TDP43-positive intraneuronal inclusions in some sensory and
motor spinal cord neurons;
[Peripheral nervous system];
Axonal motor and sensory neuropathy;
Distal sensory loss;
Hypo- or areflexia;
Mild loss of touch and temperature;
More severe loss of position and vibration;
Tetraplegia in advanced disease;
Loss of peripheral nerve axons;
Loss of myelinated fibers;
Axonal degeneration seen on nerve conduction studies
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase;
Hyperlipidemia
MISCELLANEOUS:
Adult onset (27 to 48 years);
Slow progression;
Some patients may become bedridden 10 to 20 years after onset;
Prevalent among individuals of East Asian descent
MOLECULAR BASIS:
Caused by mutation in the TRK-fused gene (TFG, 602498.0001)
OMIM Title
*604488 TITIN-CAP; TCAP
;;TELETHONIN
OMIM Description
DESCRIPTION
TCAP is a sarcomeric protein found exclusively in striated and cardiac
muscle, where it localizes to the periphery of Z discs that define the
border of the sarcomere and serve as both a structural anchor and a
signaling center. TCAP glues 2 parallel titin (TTN; 188840) within the
same sarcomere by directly binding to the N-terminal Z1Z2 domain of
titin in a palindromic arrangement, which dramatically increases the
mechanical resistance ability of titin (summary by Zhang et al., 2009).
CLONING
By PCR of a human skeletal muscle cDNA library, Valle et al. (1997)
cloned TCAP, which they called telethonin. The deduced 197-amino acid
protein has a calculated molecular mass of 19 kD. Northern blot analysis
of human tissues detected expression in skeletal and heart muscle only,
which was confirmed by RT-PCR analysis. Immunofluorescence analysis of
human skeletal muscle showed a banded pattern for TCAP that overlapped
with myosin (see 160730) and alternated with actin (see 102610).
GENE STRUCTURE
The TCAP gene contains 2 exons (Moreira et al., 2000).
MAPPING
Valle et al. (1997) mapped the TCAP gene to chromosome 17q12, adjacent
to the phenylethanolamine N-methyltransferase gene (PNMT; 171190).
BIOCHEMICAL FEATURES
Using x-ray crystallography, Zou et al. (2006) showed how the amino
terminus of the longest filament component in the Z disc of muscle, the
giant muscle protein titin, is assembled into an antiparallel (2:1)
sandwich complex by the Z disc ligand telethonin. The pseudosymmetric
structure of telethonin mediates a unique palindromic arrangement of 2
titin filaments, a type of molecular assembly previously found only in
protein-DNA complexes. Zou et al. (2006) confirmed its unique
architecture in vivo by protein complementation assays, and in vitro by
experiments using fluorescence resonance energy transfer. Zou et al.
(2006) proposed a model that provides a molecular paradigm of how major
sarcomeric filaments are crosslinked, anchored, and aligned within
complex cytoskeletal networks.
MOLECULAR GENETICS
Moreira et al. (2000) found that mutations in the telethonin gene cause
limb-girdle muscular dystrophy type 2G (LGMD2G; 601954), an autosomal
recessive disorder.
In a patient with CMD1N (607487), Knoll et al. (2002) identified an
arg87-to-gln mutation (R87Q; 604488.0003) in the TCAP gene.
ANIMAL MODEL
Zhang et al. (2009) cloned tcap in zebrafish and showed that it is
functionally conserved. The Tcap protein appeared in the sarcomeric Z
disc, and reduction of Tcap resulted in muscular dystrophy-like
phenotypes including deformed muscle structure and impaired swimming
ability. A defective interaction between the sarcomere and plasma
membrane was detected, which was further underscored by the disrupted
development of the T-tubule system. Zebrafish tcap exhibited a variable
expression pattern during somitogenesis. The variable expression was
inducible by stretch force, and the expression level of Tcap was
negatively regulated by integrin-link kinase (ILK; 602366), a protein
kinase that is involved in stretch sensing signaling. The authors
suggested that the pathogenesis in LGMD2G may be due to a disruption of
sarcomere-tubular interaction, but not of sarcomere assembly per se.
Zhang et al. (2009) hypothesized that the transcription level of TCAP
may be regulated by the stretch force to ensure proper
sarcomere-membrane interaction in striated muscle.
Markert et al. (2010) generated knockout mice carrying a null mutation
in the Tcap gene and described skeletal muscle function in 4- and
12-month-old affected mice. Muscle histology of Tcap-null mice revealed
abnormal myofiber size variation with central nucleation, similar to
findings in the muscles of LGMD2G patients. An analysis of a Tcap
binding protein, myostatin (MSTN; 601788), showed that deletion of Tcap
was accompanied by increased protein levels of myostatin. The Tcap-null
mice exhibited a decline in the ability to maintain balance on a
rotating rod, relative to wildtype controls. No differences were
detected in force or fatigue assays of isolated extensor digitorum
longus or soleus muscles.
Ibrahim et al. (2013) found that, at 3 months of age, T-tubule density
appeared normal in isolated Tcap -/- mouse cardiomyocytes, but that
there were isolated T-tubule defects and minor changes in calcium
handling. By 8 months of age, Tcap -/- cardiomyocytes showed progressive
loss of T-tubules, remodeling of the cell surface, and prolonged and
dysynchronous calcium transients. Tcap -/- mice were more sensitive than
wildtype to chronic mechanical overload due to thoracic aortic
constriction, with increased calcium spark frequency, significantly
greater loss of T-tubules, and greater deterioration in T-tubule
regularity. Ibrahim et al. (2013) concluded that TCAP is a
load-dependent regulator of T-tubule structure and function in the
heart.
GJD3
| dbSNP name | rs35530628(T,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 125111 |
| EntrezGene Description | gap junction protein, delta 3, 31.9kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1524 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild (IQ range from 50 to 70);
Mildly delayed developmental milestones;
No autistic features
MISCELLANEOUS:
Males may be more affected than females
MOLECULAR BASIS:
Caused by mutation in the cereblon gene (CRBN, 609262.0001)
OMIM Title
*607425 GAP JUNCTION PROTEIN, DELTA-3; GJD3
;;GAP JUNCTION PROTEIN, ALPHA-11; GJA11;;
GAP JUNCTION PROTEIN, 31.9-KD;;
CONNEXIN 31.9; CX31.9;;
GAP JUNCTION PROTEIN, CHI-1, FORMERLY; GJC1, FORMERLY
OMIM Description
DESCRIPTION
CX31.9 is a member of the large family of connexins that are required
for the formation of gap junctions, which allow the transfer of low
molecular mass substances between cells. Six connexin monomers form a
hemichannel, or connexon, on the cell surface. This connexon can
interact with a connexon from a neighboring cell, thus forming a channel
linking the cytoplasm of the 2 cells (summary by Nielsen et al., 2002).
CLONING
Nielsen et al. (2002) identified an EST containing CX31.9, which they
also referred to as gap junction protein alpha-11 (GJA11), by homology
with other connexin sequences. They cloned the full-length cDNA by
5-prime and 3-prime RACE of a testis cDNA library. The deduced 294-amino
acid protein contains 4 transmembrane domains and shows conserved
spacing of cysteine residues in the 2 extracellular domains. The
C-terminal region contains 4 potential protein kinase C (see 176960)
phosphorylation sites and a casein kinase II (see 115440)
phosphorylation site. The amino acid identity between CX31.9 and other
connexins ranges from 32 to 41%. Connexins most similar to CX31.9 are
members of the alpha group of connexins. Northern blot analysis revealed
a 4.4-kb transcript in all tissues examined, although with varying
intensities. The intensities of minor transcripts of 1, 0.5, and 0.4 kb
correlated with the intensity of the 4.4-kb transcript. Western blot
analysis revealed a protein of 30 to 33 kD in heart, colon, and artery,
but not in brain and skeletal muscle. Immunohistologic analysis of
tissue sections revealed immunoreactivity localized to vascular smooth
muscle cells of testis, brain, and tonsil. Fluorescence-tagged CX31.9
expressed in HEK cells localized to gap junction-like structures and to
intracellular puncta that partly colocalized with ZO1 (TJP1; 601009).
GENE FUNCTION
By immunoprecipitation of transfected HEK cells and by in vitro
pull-down assays, Nielsen et al. (2002) determined that CX31.9 directly
interacts with ZO1. Mutation analysis and stearic hindrance from the
addition of a large fluorescent tag suggested that the C-terminal
residues of CX31.9 interact with the second PDZ domain of ZO1. Nielsen
et al. (2002) determined that CX31.9 channels expressed in paired
Xenopus oocytes conferred significant cell-to-cell conductances that
increased with the concentration of injected CX31.9 cRNA. The gap
junctions showed very little voltage sensitivity.
White et al. (2002) confirmed the lack of voltage gating by CX31.9
expressed in paired Xenopus oocytes and in transfected mouse
neuroblastoma cells. They found that, like other connexins, CX31.9
junctions are gated by cytoplasmic acidification or exposure to
halothane.
Bukauskas et al. (2006) found that CX31.9 and its mouse ortholog,
Cx30.2, formed functional channels that were permeable to cationic dyes
up to about 400 kD. Cells expressing CX31.9 or Cx30.2 exhibited much
faster dye uptake than cells expressing other connexins, and the rate of
uptake increased at low exterior calcium concentration and was decreased
by hemichannel blockers. Mouse Cx30.2 hemichannels also showed weak
voltage sensitivity. Unitary conductance of fully open mouse Cx30.2
hemichannels was about 20 pS, approximately double that of cell-cell
channels.
MAPPING
By genomic sequence analysis, Nielsen et al. (2002) mapped the GJC1 gene
to chromosome 17q21.1.
ANIMAL MODEL
Kreuzberg et al. (2006) generated mice that were conditionally null for
Cx30.2, the mouse homolog of human CX31.9. The mice exhibited a PQ
interval that was about 25% shorter than that of wildtype littermates,
due to significantly accelerated conduction above the His bundle. Atrial
stimulation revealed an elevated AV-nodal conduction capacity and faster
ventricular response rates during induced episodes of atrial
fibrillation in mutant mice. Kreuzberg et al. (2006) concluded that
Cx30.2 contributes to the slowdown of impulse propagation in the AV node
and additionally limits the maximum number of beats conducted from atria
to ventricles.
KRT10
| dbSNP name | rs1132367(T,C); rs12231(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 3858 |
| EntrezGene Description | keratin 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1171 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (less than tenth percentile)
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Round face early in life;
Triangular face later in life;
Long philtrum;
[Ears];
Large, prominent ears;
[Eyes];
Hypertelorism;
Telecanthus;
Long palpebral fissures;
Broad bushy eyebrows;
[Nose];
Anteverted nares;
Hypoplastic alae nasi;
[Teeth];
Macrodontia;
Wide upper central incisors;
Ridged teeth;
Fused incisors;
Oligodontia
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Cervical rib fusion;
Accessory cervical ribs
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Delayed bone maturation;
[Spine];
Vertebral body fusion;
Vertebral arch abnormalities;
Thoracic kyphosis;
[Hands];
Clinodactyly;
Decreased hand length;
Syndactyly
SKIN, NAILS, HAIR:
[Skin];
Simian crease;
[Hair];
Broad, bushy eyebrows;
Low anterior hairline;
Low posterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation
MISCELLANEOUS:
Male to female ratio 21:8
OMIM Title
*148080 KERATIN 10; KRT10
;;K10
OMIM Description
CLONING
Keratin-10 is an intermediate filament (IF) chain which belongs to the
acidic type I family and is expressed in terminally differentiated
epidermal cells. Epithelial cells almost always coexpress pairs of type
I and type II keratins, and the pairs that are coexpressed are highly
characteristic of a given epithelial tissue. For example, in human
epidermis, 3 different pairs of keratins are expressed: keratins 5 (type
II) and 14 (type I), characteristic of basal or proliferative cells;
keratins 1 (type II) and 10 (type I), characteristic of suprabasal
terminally differentiating cells; and keratins 6 (type II) and 16 (type
I) (and keratin 17 [type I]), characteristic of cells induced to
hyperproliferate by disease or injury, and epithelial cells grown in
cell culture. Darmon et al. (1987) presented the nucleotide sequence of
a 1,700 bp cDNA encoding human epidermal keratin-10 (56.5 kD). Zhou et
al. (1988) presented the complete amino acid sequence of human
keratin-10. Korge et al. (1992) described extensive polymorphism of the
KRT10 gene, restricted to insertions and deletions of the glycine-rich
quasipeptide repeats that form the glycine-loop motif in the C-terminal
domain.
Langbein et al. (2005) examined the expression of several keratins in
eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT10
was expressed throughout the duct region but not in the deeper secretory
portion of the gland. In plantar epidermis, KRT10 was expressed in the
stratum corneum through to the lower suprabasal layer, but not in the
basal layer.
MAPPING
By use of specific cDNA clones in conjunction with somatic cell hybrid
analysis and in situ hybridization, Lessin et al. (1988) mapped the
KRT10 gene to 17q12-q21 in a region proximal to the breakpoint at 17q21
that is involved in a t(17;21)(q21;q22) translocation associated with a
form of acute leukemia. KRT10 appeared to be telomeric to 3 other loci
that map in the same region: CSF3 (138970), ERBA1 (190120), and HER2
(164870). NGFR (162010) and HOX2 (142960) are distal to K9. Romano et
al. (1991) demonstrated that the KRT10, KRT13, and KRT15 genes are
located in the same large pulsed field gel electrophoresis fragment. A
correlation of assignments of the 3 genes makes 17q21-q22 the likely
location of the cluster.
MOLECULAR GENETICS
- Epidermolytic Hyperkeratosis
Heterozygous mutations in the KRT10 gene (148080.0001-148080.0009) as
the cause of epidermolytic hyperkeratosis (EHK; 113800) were described
by Rothnagel et al. (1992), Cheng et al. (1992), and Chipev et al.
(1994). Heterozygous mutations in the KRT1 gene (139350) also cause EHK,
a finding consistent with the fact that this keratin pair forms
heterodimers and comprises the keratin intermediate filaments in the
suprabasal epidermal cells.
In a consanguineous family segregating autosomal recessive EHK, Muller
et al. (2006) identified homozygosity for a nonsense mutation in the
KRT10 gene (148080.0019) in 2 affected sibs. The clinically unaffected
parents and 5 other unaffected relatives were heterozygous for the
mutation, which was not found in 50 controls. Semiquantitative RT-PCR
and Western blot analysis demonstrated degradation of the KRT10
transcript, resulting in complete absence of keratin-10 protein in the
epidermis and cultured keratinocytes of the homozygous individuals.
Muller et al. (2006) noted strong induction of the wound-healing
keratins KRT6 (see 148041), KRT16 (148067), and KRT17 (148069) in the
suprabasal dermis, which was unable to compensate for lack of KRT10.
In a 3-year-old Turkish girl with mild EHK, born of first-cousin
parents, Tsubota et al. (2008) identified homozygosity for a nonsense
mutation in the KRT10 gene (148080.0020). Immunohistochemical labeling
of suprabasal epidermal layers by antibodies to KRT5 (148040), KRT6, and
KRT14 (148066) suggested compensatory expression of 1 or more of these
keratins by suprabasal keratinocytes.
In a girl with severe EHK from a consanguineous family of Sudanese
descent, Terheyden et al. (2009) identified homozygosity for a 1-bp
insertion in the KRT10 gene (148080.0021). KRT6, KRT16, and KRT17 were
upregulated in the proband, with maximal expression at the sites of
cytolysis. Terheyden et al. (2009) noted that the 3 mutations reported
to that time in recessive EHK were all located in exon 6 of the KRT10
gene, near the end of the 2B domain and just upstream of the highly
conserved helix termination peptide.
In an infant with severe epidermolytic ichthyosis who was born of
consanguineous North African parents and died at 3 days of age, Covaciu
et al. (2010) identified homozygosity for a splice site mutation in the
KRT10 gene (148080.0022). Immunohistology of the patient's skin showed
loss of keratin-10 expression in the suprabasal epidermis, with
induction of KRT5, KRT14, KRT16, and KRT17. The authors stated that
their study confirmed that in humans, the compensatory upregulation of
other cytokeratins in the suprabasal layers elicited by complete absence
of KRT10 is not sufficient for phenotypic rescue.
- Ichthyosis with Confetti
In 7 kindreds with ichthyosis with confetti (IWC; 609165), also known as
congenital reticular ichthyosiform erythroderma (CRIE), Choate et al.
(2010) identified heterozygous mutations (see, e.g.,
148080.0016-148080.0018) resulting in frameshifts that create an
arginine-rich C terminus that redirects keratin-10 from the cytokeratin
filament network to the nucleolus. None of the mutations was found in
control chromosomes or in the revertant spots (clones of normal skin
that arise from loss of heterozygosity on chromosome 17q via mitotic
recombination) that comprise the 'confetti' for which the disorder is
named.
- Nonepidermolytic Keratosis Palmaris et Plantaris
In a 5-generation Uzbek family with nonepidermolytic keratosis palmaris
et plantaris (NEPPK; 600962), Rogaev et al. (1993) found tight linkage
to an insertion-deletion polymorphism in the C-terminal coding region of
the KRT10 gene (maximum lod score = 8.36 at theta = 0.00). It is
noteworthy that it was a rare, high molecular weight allele of the KRT10
polymorphism that segregated with the disorder. The allele was observed
once in 96 independent chromosomes from unaffected Caucasians. The KRT10
polymorphism arose from the insertion/deletion of imperfect (CCG)n
repeats within the coding region and gave rise to a variable glycine
loop motif in the C-terminal tail of the keratin-10 protein. It is
possible that there was a pathogenic role for the expansion of the
imperfect trinucleotide repeat.
ANIMAL MODEL
Fuchs et al. (1992) discovered that transgenic mice expressing a mutant
keratin-10 gene have the phenotype of epidermolytic hyperkeratosis (EHK;
113800), thus suggesting that a genetic basis for the human disorder
resides in mutations in genes encoding suprabasal keratins KRT1 (139350)
or KRT10. They also showed that stimulation of basal cell proliferation
can result from a defect in suprabasal cells and that distortion of
nuclear shape or aberrations in cytokinesis can occur when an
intermediate filament network is perturbed.
KRTAP3-3
| dbSNP name | rs11652331(T,C); rs8072775(T,C); rs146288467(G,A); rs12452295(G,A); rs1989365(A,G) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85293 |
| EntrezGene Description | keratin associated protein 3-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.073 |
KRTAP3-2
| dbSNP name | rs9911772(A,G); rs17843004(A,G); rs3813047(G,A); rs3829598(G,A); rs9897046(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 83897 |
| EntrezGene Description | keratin associated protein 3-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3324 |
KRTAP3-1
| dbSNP name | rs142754182(G,A); rs10491133(T,G); rs111531901(C,T); rs112432710(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 83896 |
| EntrezGene Description | keratin associated protein 3-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07713 |
KRTAP1-5
| dbSNP name | rs148755068(T,C); rs12937940(A,T); rs9916638(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 83895 |
| snpEff Gene Name | KRTAP1-4 |
| EntrezGene Description | keratin associated protein 1-5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009642 |
KRTAP1-4
| dbSNP name | rs8074117(C,T); rs150955506(G,A); rs8074887(A,C) |
| ccdsGene name | CCDS58548.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 728255 |
| EntrezGene Description | keratin associated protein 1-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP1-4:NM_001257305:exon1:c.G300A:p.P100P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2975 |
| ExAC AF | 0.294 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, hypertrophic
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
MUSCLE, SOFT TISSUE:
Distal muscle weakness, occurs initially;
Proximal muscle weakness occurs later;
Limb-girdle muscle weakness;
Foot drop;
Hyporeflexia at ankle joints;
EMG shows myopathic changes;
Neck muscle weakness;
Trunk muscle weakness;
Velopharyngeal muscle weakness;
Muscle biopsy shows dystrophic changes;
Fiber size variation;
Fiber splitting;
Accumulation of intrasarcoplasmic granulofilamentous aggregates that
are immunoreactive to desmin and alpha-beta-crystallin;
Autophagic vacuoles;
Z-disks with abnormal homogeneous material
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset;
Slowly progressive;
Clinical variability;
Two patients without cardiomyopathy or cataracts have been reported
MOLECULAR BASIS:
Caused by mutation in the alpha-B-crystallin gene (CRYAB, 123590.0001)
OMIM Title
*608821 KERATIN-ASSOCIATED PROTEIN 1-4; KRTAP1-4
;;KAP1.4
OMIM Description
DESCRIPTION
The main structural proteins of mammalian hair fiber are the hair
keratins (see 601077) and the keratin-associated proteins (KAPs), which
form a rigid and resistant hair shaft through extensive disulfide bond
crosslinking with the abundant cysteines of hair keratins (Shimomura et
al., 2002).
CLONING
By screening a human PAC library and an arrayed human scalp cDNA
library, Rogers et al. (2001) cloned KAP1.4. The deduced 121-amino acid
protein has a calculated molecular mass of 12.3 kD. KAP1.4 is classified
as a high sulfur protein owing to a cysteine content of 24.8 mol %. It
contains 2 unique motifs conserved among KAP1 family members, several
characteristic pentapeptide repeats, and a 20-amino acid subdomain that
was conserved among KAP1 family members in all species examined. KAP1.4
lacks an amino-terminal motif common to other members of the KAP1
family.
Shimomura et al. (2002) analyzed the KAP1.4 gene in unrelated Japanese
and Caucasian individuals. By in situ hybridization, Shimomura et al.
(2002) demonstrated KAP1.4 expression in the middle to upper cortex
region of the human hair follicle. While Shimomura et al. (2002) found
polymorphism in the KAP1.1 (608819) and KAP1.3 (608820) genes in
Japanese and Caucasian individuals, they found none in the KAP1.4 gene.
GENE STRUCTURE
Rogers et al. (2001) stated that the KRTAP1-4 gene is about 1.0 kb long
and consists of a single exon.
MAPPING
By genomic sequence analysis, Rogers et al. (2001) mapped the KRTAP1-4
gene to a region of chromosome 17q12-q21 that contains 8 other
identified KAP genes or pseudogenes.
KRTAP1-3
| dbSNP name | rs137921045(A,G); rs17843050(T,C); rs17843049(G,A); rs12936959(A,T) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 81850 |
| snpEff Gene Name | KRTAP1-4 |
| EntrezGene Description | keratin associated protein 1-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, hypertrophic
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
MUSCLE, SOFT TISSUE:
Distal muscle weakness, occurs initially;
Proximal muscle weakness occurs later;
Limb-girdle muscle weakness;
Foot drop;
Hyporeflexia at ankle joints;
EMG shows myopathic changes;
Neck muscle weakness;
Trunk muscle weakness;
Velopharyngeal muscle weakness;
Muscle biopsy shows dystrophic changes;
Fiber size variation;
Fiber splitting;
Accumulation of intrasarcoplasmic granulofilamentous aggregates that
are immunoreactive to desmin and alpha-beta-crystallin;
Autophagic vacuoles;
Z-disks with abnormal homogeneous material
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset;
Slowly progressive;
Clinical variability;
Two patients without cardiomyopathy or cataracts have been reported
MOLECULAR BASIS:
Caused by mutation in the alpha-B-crystallin gene (CRYAB, 123590.0001)
OMIM Title
*608820 KERATIN-ASSOCIATED PROTEIN 1-3; KRTAP1-3
;;KAP1.3
KAP1.2, INCLUDED;;
KAP18.A, INCLUDED;;
KAP18.B, INCLUDED;;
KAP1.9, INCLUDED;;
B2B, INCLUDED
OMIM Description
DESCRIPTION
The main structural proteins of mammalian hair fiber are the hair
keratins (see 601077) and the keratin-associated proteins (KAPs), which
form a rigid and resistant hair shaft through extensive disulfide bond
crosslinking with the abundant cysteines of hair keratins (Shimomura et
al., 2002).
CLONING
By screening a human PAC library and an arrayed human scalp cDNA
library, Rogers et al. (2001) cloned KAP1.3. The deduced 167-amino acid
protein has a calculated molecular mass of 17.1 kD. KAP1.3 is classified
as a high sulfur protein owing to a cysteine content of 25.7 mol %. It
contains 2 unique motifs conserved among KAP1 family members, several
characteristic pentapeptide repeats, and a 20-amino acid subdomain that
was conserved among KAP1 family members in all species examined.
Shimomura et al. (2002) analyzed the KAP1.3 gene in unrelated Japanese
and Caucasian individuals and identified several polymorphisms,
designated KAP1.8A, KAP1.8B, and KAP1.9. They also showed that the
KAP1.2 protein identified by Rogers et al. (2001) represents a rare
polymorphism of the KAP1.3 gene. The 175-amino acid KAP1.2 protein lacks
a C-terminal domain relative to other members of the KAP1 family and has
a calculated molecular mass of 18.2 kD, with a cysteine content of 26.3
mol % (Rogers et al., 2001). RT-PCR and 3-prime RACE confirmed the
expression of variants 1.8A and 1.8B in total RNA from freshly plucked
hair follicles of 2 Japanese individuals.
GENE STRUCTURE
Rogers et al. (2001) stated that the KRTAP1-3 gene is about 1.0 kb long
and consists of a single exon.
MAPPING
By genomic sequence analysis, Rogers et al. (2001) mapped the KRTAP1-3
gene to a region of chromosome 17q12-q21 that contains 8 other
identified KAP genes or pseudogenes.
KRTAP2-1
| dbSNP name | rs6503577(T,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 81872 |
| EntrezGene Description | keratin associated protein 2-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3343 |
KRTAP2-2
| dbSNP name | rs417882(G,C); rs443838(G,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 728279 |
| EntrezGene Description | keratin associated protein 2-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1226 |
KRTAP2-3
| dbSNP name | rs400041(C,T); rs12936757(G,A); rs2646023(A,G) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 730755 |
| snpEff Gene Name | KRTAP2-2 |
| EntrezGene Description | keratin associated protein 2-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1139 |
KRTAP4-7
| dbSNP name | rs2320192(T,C); rs4544293(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 100132476 |
| snpEff Gene Name | KRTAP4-9 |
| EntrezGene Description | keratin associated protein 4-7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4215 |
KRTAP4-8
| dbSNP name | rs6416912(A,G); rs7212517(A,C); rs72625994(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 728224 |
| snpEff Gene Name | AC100808.7 |
| EntrezGene Description | keratin associated protein 4-8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4197 |
KRTAP4-9
| dbSNP name | rs6503596(C,T); rs6503597(G,A); rs141432143(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 100132386 |
| EntrezGene Description | keratin associated protein 4-9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1079 |
KRTAP4-11
| dbSNP name | rs150832040(G,T); rs113975046(T,G); rs11654403(G,A); rs9897031(C,T) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 653240 |
| EntrezGene Description | keratin associated protein 4-11 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08035 |
KRTAP4-12
| dbSNP name | rs143188679(A,T); rs142711760(G,A); rs146939021(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 83755 |
| snpEff Gene Name | KRTAP4-11 |
| EntrezGene Description | keratin associated protein 4-12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006428 |
KRTAP4-6
| dbSNP name | rs4890158(A,T); rs73983171(T,C); rs937403(A,C); rs73983173(C,G) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 81871 |
| EntrezGene Description | keratin associated protein 4-6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3572 |
KRTAP4-5
| dbSNP name | rs1497383(G,A) |
| ccdsGene name | CCDS32650.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85289 |
| EntrezGene Description | keratin associated protein 4-5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP4-5:NM_033188:exon1:c.C64T:p.R22C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BYR2 |
| dbNSFP Uniprot ID | KRA45_HUMAN |
| dbNSFP KGp1 AF | 0.436813186813 |
| dbNSFP KGp1 Afr AF | 0.378048780488 |
| dbNSFP KGp1 Amr AF | 0.516574585635 |
| dbNSFP KGp1 Asn AF | 0.377622377622 |
| dbNSFP KGp1 Eur AF | 0.481530343008 |
| dbSNP GMAF | 0.4357 |
| ESP Afr MAF | 0.376476 |
| ESP All MAF | 0.446112 |
| ESP Eur/Amr MAF | 0.481831 |
| ExAC AF | 0.476,8.139e-06 |
KRTAP4-4
| dbSNP name | rs447974(G,A); rs447972(G,T) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 84616 |
| EntrezGene Description | keratin associated protein 4-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08678 |
KRTAP4-3
| dbSNP name | rs375705(A,G); rs440681(G,T); rs424617(T,A); rs413638(G,C); rs428371(G,A); rs440374(A,G) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85290 |
| EntrezGene Description | keratin associated protein 4-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08586 |
KRTAP4-2
| dbSNP name | rs7220116(T,C); rs377518(T,C); rs389784(T,C); rs493514(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85291 |
| EntrezGene Description | keratin associated protein 4-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4477 |
KRTAP4-1
| dbSNP name | rs453545(A,G); rs452216(G,A); rs398825(C,T); rs2320231(T,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85285 |
| snpEff Gene Name | KRTAP4-2 |
| EntrezGene Description | keratin associated protein 4-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04775 |
KRTAP9-1
| dbSNP name | rs61743546(A,G); rs238824(T,C) |
| ccdsGene name | CCDS56029.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 728318 |
| EntrezGene Description | keratin associated protein 9-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP9-1:NM_001190460:exon1:c.A1G:p.M1V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | start_lost |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.130036630037 |
| dbNSFP KGp1 Afr AF | 0.0284552845528 |
| dbNSFP KGp1 Amr AF | 0.17679558011 |
| dbNSFP KGp1 Asn AF | 0.0804195804196 |
| dbNSFP KGp1 Eur AF | 0.211081794195 |
| dbSNP GMAF | 0.1295 |
| ExAC AF | 0.2 |
KRTAP9-4
| dbSNP name | rs2191379(C,A); rs3967754(A,G); rs2270178(T,G) |
| ccdsGene name | CCDS11386.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 85280 |
| EntrezGene Description | keratin associated protein 9-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP9-4:NM_033191:exon1:c.C437A:p.S146Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BYQ2 |
| dbNSFP Uniprot ID | KRA94_HUMAN |
| dbNSFP KGp1 AF | 0.668498168498 |
| dbNSFP KGp1 Afr AF | 0.522357723577 |
| dbNSFP KGp1 Amr AF | 0.779005524862 |
| dbNSFP KGp1 Asn AF | 0.643356643357 |
| dbNSFP KGp1 Eur AF | 0.729551451187 |
| dbSNP GMAF | 0.3324 |
| ESP Afr MAF | 0.4798 |
| ESP All MAF | 0.344918 |
| ESP Eur/Amr MAF | 0.275814 |
| ExAC AF | 0.737 |
KRTAP9-9
| dbSNP name | rs2007206(G,C) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 81870 |
| EntrezGene Description | keratin associated protein 9-9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3333 |
KRTAP29-1
| dbSNP name | rs1001191(A,T); rs1005197(A,G); rs758741(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 100533177 |
| EntrezGene Description | keratin associated protein 29-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP29-1:NM_001257309:exon1:c.T628A:p.C210S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.226648351648 |
| dbNSFP KGp1 Afr AF | 0.252032520325 |
| dbNSFP KGp1 Amr AF | 0.157458563536 |
| dbNSFP KGp1 Asn AF | 0.305944055944 |
| dbNSFP KGp1 Eur AF | 0.183377308707 |
| dbSNP GMAF | 0.2273 |
| ExAC AF | 0.151 |
KRTAP16-1
| dbSNP name | rs2074286(G,C); rs2074285(G,C); rs2074284(C,G); rs12453338(C,T) |
| ccdsGene name | CCDS56032.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 100505753 |
| EntrezGene Description | keratin associated protein 16-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP16-1:NM_001146182:exon1:c.C1460G:p.A487G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.328296703297 |
| dbNSFP KGp1 Afr AF | 0.465447154472 |
| dbNSFP KGp1 Amr AF | 0.218232044199 |
| dbNSFP KGp1 Asn AF | 0.36013986014 |
| dbNSFP KGp1 Eur AF | 0.267810026385 |
| dbSNP GMAF | 0.3292 |
| ExAC AF | 0.219 |
KRTAP17-1
| dbSNP name | rs80235743(T,A); rs12449671(G,A) |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 83902 |
| EntrezGene Description | keratin associated protein 17-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1772 |
KRT33B
| dbSNP name | rs73983408(C,T); rs35142024(C,T); rs16966738(T,C); rs71373411(A,C); rs61741663(T,C); rs113515081(G,A); rs111628830(C,T); rs76516720(C,T); rs12450621(C,T) |
| ccdsGene name | CCDS11389.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 3884 |
| EntrezGene Description | keratin 33B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT33B:NM_002279:exon1:c.G253A:p.E85K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5045 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14525 |
| dbNSFP Uniprot ID | KT33B_HUMAN |
| dbNSFP KGp1 AF | 0.0265567765568 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0331491712707 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0580474934037 |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.011348 |
| ESP All MAF | 0.045231 |
| ESP Eur/Amr MAF | 0.062602 |
| ExAC AF | 0.049 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
OMIM Title
*602762 KERATIN 33B; KRT33B
;;KERATIN, HAIR, ACIDIC, 3B; KRTHA3B;;
KERATIN, HARD, TYPE I, 3II; HA3II
OMIM Description
DESCRIPTION
See KRTHA1 (601077) for general information on hair keratins.
CLONING
By screening a human scalp cDNA library with a mouse Ha2 (see 602760)
cDNA, Rogers et al. (1994) cloned a partial cDNA encoding KRTHA3B, which
they named HA3II. The cDNA has an open reading frame that encodes 362
amino acids, including a predicted 37-amino acid C-terminal domain; the
authors estimated that the cDNA lacks the coding sequence for 43
N-terminal residues. The partial HA3II isoform differs from the HA3I
isoform (KRTHA3A; 602761) by 24 amino acids, 8 of which are in the
center of the C-terminal domain. Using PCR, sequence, and Southern blot
analyses, Rogers et al. (1994) demonstrated that HA3I and HA3II are
distinct, single-copy genes.
Rogers et al. (1998) reported that the deduced KRTHA3B protein has 405
amino acids and shares 93.3% amino acid sequence identity with KRTHA3A.
By RT-PCR, Rogers et al. (1998) showed that KRTHA3B is expressed in the
human hair follicle. See Langbein et al. (1999) for further details on
the expression pattern of the KRTHA3B gene in the hair follicle.
GENE STRUCTURE
Rogers et al. (1998) reported that the KRTHA3B gene contains 7 exons.
MAPPING
Rogers et al. (1998) isolated and characterized 2 overlapping human PAC
clones that cover 190 kb on 17q12-q21 and contain 9 type I hair keratin
genes, 1 transcribed hair keratin pseudogene, and 1 orphan exon. The
order of the genes is 5-prime--KRTHA6 (604540)--KRTHA5 (602764)--KRTHA2
(602760)--orphan exon--KRTHA8 (604542)--KRTHA7
(604541)--pseudogene--KRTHA1--KRTHA4
(602763)--KRTHA3B--KRTHA3A--3-prime. The hair keratin genes range in
size from 4.2 to 7.5 kb, and the genes are separated from each other by
5.5 to 18.4 kb; all are located within about 140 kb. Each gene is
transcribed from the 5-prime to 3-prime direction. Based on sequence
homologies, the genes can be grouped into 3 subclusters of tandemly
arranged genes. One subcluster, group A, consists of KRTHA1, KRTHA3A,
KRTHA3B, and KRTHA4, which share 89% overall amino acid identity. A
second subcluster, group B, contains KRTHA7 and KRTHA8, as well as the
hair keratin pseudogene, which the authors called HAA. The functional
hair keratins and hypothetical HAA hair keratin share approximately 81%
overall amino acid identity. The third subcluster, group C, consists of
the structurally less related hair keratins KRTHA2, KRTHA5, and KRTHA6,
which share about 70% amino acid identity.
KRT19
| dbSNP name | rs1869719(A,C); rs1869720(T,A); rs4796780(A,G); rs201146086(T,C); rs4601(A,G); rs61320338(G,A); rs7209408(T,G); rs8065433(G,T); rs3786142(G,A); rs4602(G,C) |
| ccdsGene name | CCDS11399.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 3880 |
| EntrezGene Description | keratin 19 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT19:NM_002276:exon3:c.A551G:p.N184S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.693 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DE59 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Glomerulonephritis
SKIN, NAILS, HAIR:
[Skin];
Photosensitive skin rashes
IMMUNOLOGY:
Systemic lupus erythematosus;
Dermatomyositis;
Anaphylactoid purpura;
Vasculitis
LABORATORY ABNORMALITIES:
Absent CH50 activity in complete C4 deficiency
MISCELLANEOUS:
Two loci control synthesis of C4, C4A (120810) and C4B (120820);
Patients with total C4 deficiency are homozygous for double null C4
haplotype;
Prevalence of homozygous c4A deficiency in SLE 10-15x higher than
general population
MOLECULAR BASIS:
Caused by mutation in the complement component 4A gene (C4A, 120810.0001)
OMIM Title
*614384 MICRO RNA 492; MIR492
;;miRNA492
OMIM Description
DESCRIPTION
Micro RNAs (miRNAs), such as MIR492, are small noncoding RNAs that
repress gene expression predominantly by binding to complementary
sequences in the 3-prime UTRs of target mRNAs (Wu et al., 2011).
CLONING
By searching for miRNAs expressed in humans but not rodents, Devor
(2006) identified MIR492. Database analysis revealed orthologs of the
MIR492 precursor only in African and Asian apes and African and Asian
Old World monkeys.
GENE FUNCTION
Wu et al. (2011) identified BSG (109480) as an MIR492 target gene.
MAPPING
Devor (2006) mapped the MIR492 gene within a processed pseudogene of
KRT19 (148020) on chromosome 12q22.
Von Frowein et al. (2011) presented evidence suggesting that mature
MIR492 can also be processed from the coding sequence of the KRT19 gene
on chromosome 17. The MIR492 precursor sequence within KRT19 is 93%
identical to that on chromosome 17 and yields an identical mature
sequence.
KRT14
| dbSNP name | rs2001185(T,C); rs936100(T,A); rs113794908(G,A); rs897428(A,G); rs2070671(G,C); rs2320456(T,C); rs71373427(G,A); rs75795684(T,C); rs188343094(G,A); rs71373428(G,A); rs71373429(A,G); rs147037354(G,C); rs35849957(A,G); rs1809200(G,A); rs9915113(G,C); rs146346549(G,A); rs11551759(G,A) |
| ccdsGene name | CCDS11400.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 3861 |
| EntrezGene Description | keratin 14 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRT14:NM_000526:exon1:c.C463T:p.R155W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7249 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P02533 |
| dbNSFP Uniprot ID | K1C14_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.000122 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (less than tenth percentile)
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Round face early in life;
Triangular face later in life;
Long philtrum;
[Ears];
Large, prominent ears;
[Eyes];
Hypertelorism;
Telecanthus;
Long palpebral fissures;
Broad bushy eyebrows;
[Nose];
Anteverted nares;
Hypoplastic alae nasi;
[Teeth];
Macrodontia;
Wide upper central incisors;
Ridged teeth;
Fused incisors;
Oligodontia
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Cervical rib fusion;
Accessory cervical ribs
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Delayed bone maturation;
[Spine];
Vertebral body fusion;
Vertebral arch abnormalities;
Thoracic kyphosis;
[Hands];
Clinodactyly;
Decreased hand length;
Syndactyly
SKIN, NAILS, HAIR:
[Skin];
Simian crease;
[Hair];
Broad, bushy eyebrows;
Low anterior hairline;
Low posterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation
MISCELLANEOUS:
Male to female ratio 21:8
OMIM Title
*148066 KERATIN 14; KRT14
;;K14
OMIM Description
DESCRIPTION
KRT14 belongs to a large group of acidic type I keratins that interact
with basic type II keratins to form the 8-nm cytoskeletal filaments of
epithelial cells. Both type I and type II keratins have a central
alpha-helical domain of over 300 amino acids that mediates keratin
interaction. KRT14 is expressed in the basal layer of stratified
squamous epithelia, including epidermis (summary by Albers and Fuchs
(1987) and Rosenberg et al. (1988)).
CLONING
Albers and Fuchs (1987) constructed a complete human K14 cDNA using a
partial cDNA isolated by Hanukoglu and Fuchs (1982) and a genomic clone
described by Marchuk et al. (1984, 1985). The deduced 472-amino acid
protein has an N-terminal domain, 4 helical domains, and a short
C-terminal tail. Helical domain-4 has a highly conserved sequence
(TYRRLLEGE) found in nearly all intermediate filament proteins.
MAPPING
Rosenberg et al. (1988) mapped the keratin-14 gene to chromosome 17.
Rosenberg et al. (1991) stated that the KRT14 and KRT16 (148067) genes,
as well as a yet-unidentified keratin gene, had been localized to
chromosome 17q12-q21. Another cluster of genes located at chromosome
17p12-p11 contained a nonfunctional gene for KRT16 and 2 genes for
KRT14, at least 1 of which was found to be a pseudogene.
Milisavljevic et al. (1996) analyzed P1 clones containing multiple
acidic keratin genes using restriction analysis and Southern blot
hybridization with PCR-amplified probes specific for functional human
keratin genes 15 (148030), 17 (148069), and 19 (148020). Their results
showed that there are 2 clusters of acidic keratin loci on chromosome
17q12-q21, very closely linked to each other within a 55-kb region. The
genes were organized 5-prime to 3-prime in the following order:
K19--K15--K17--K16--K14. Between K15 and K17 at least 1 additional,
unidentified keratin gene was present.
GENE FUNCTION
PtK2 potoroo kidney epithelial cells express only the type I keratin K18
(148070) and the type II keratin K8 (148060). Albers and Fuchs (1987)
showed that epitope-tagged human K14 was incorporated into endogenous
keratin filaments along with K18 and K8 in PtK2 cells. Truncation of K14
after helical domain-4 had no effect on incorporation of K14 into
filaments. However, progressive truncation of K14 within helix-4
resulted in a correspondingly progressive disruption of filament
structure and accumulation of the truncated protein into cytoplasmic
aggregates. The integrity of all other cytoskeletal structures remained
intact. Albers and Fuchs (1987) concluded that the mutant protein both
interfered with the formation of new keratin filaments and disrupted the
existing keratin cytoskeleton.
Langbein et al. (2005) examined the expression of several keratins in
eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT14
was expressed in lower portions of the duct and in the deeper secretory
region of the gland, but not in the superficial region. In plantar
epidermis, KRT14 was expressed only in the basal layer and in part of
the lower suprabasal layer.
In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside
in the proximal nail matrix and are defined by high expression of
keratin-14, keratin-17, and KI67 (MKI67; 176741). The mechanisms
governing NSC differentiation are coupled directly to their ability to
orchestrate digit regeneration. Early nail progenitors undergo Wnt (see
164820)-dependent differentiation into the nail. After amputation, this
Wnt activation is required for nail regeneration and also for attracting
nerves that promote mesenchymal blastema growth, leading to the
regeneration of the digit. Amputations proximal to the Wnt-active nail
progenitors result in failure to regenerate the nail or digit.
Nevertheless, beta-catenin (116806) stabilization in the NSC region
induced their regeneration. Takeo et al. (2013) concluded that their
results established a link between nail stem cell differentiation and
digit regeneration, and suggested that NSCs may have the potential to
contribute to the development of novel treatments for amputees.
MOLECULAR GENETICS
Missense mutations in the KRT14 gene act in a dominant-negative fashion
because the mutant protein combines with the wildtype proteins in the
keratin heterodimers to perturb intermediate filament (IF) assembly
(Fuchs and Coulombe, 1992).
- Epidermolysis Bullosa Simplex
In a family with at least 16 affected individuals in 5 generations with
localized epidermolysis bullosa simplex (131800), Chen et al. (1993)
identified a heterozygous mutation in the KRT14 gene (148066.0005).
Although all previous mutations identified in the KRT14 and KRT5 genes
behaved as dominant negatives with an autosomal dominant pattern of the
clinical disorder, Hovnanian et al. (1993) described a French family in
which 2 children with unaffected first-cousin parents had EB simplex and
homozygosity for a glu144-to-ala mutation (148066.0004) which was
present in heterozygous state in both parents.
Chan et al. (1994) analyzed a very rare case of severe recessive
epidermolysis bullosa simplex (EBSB1; 601001) in which the patient
lacked a discernible keratin filament network in basal epidermal cells.
Genetic analyses demonstrated homozygosity for a point mutation in the
KRT14 gene (Y204X; 148066.0006) that yielded a premature termination
codon in the major basal type I keratin gene and caused complete
ablation of KRT14. The consanguineous parents were clinically normal,
each harboring 1 copy of the null KRT14 mutation. Analysis of cultured
keratinocytes revealed that the loss of KRT14 was not compensated for by
the upregulation of other type I keratins. Thus, the cell fragility
resulted from lack of an extensive basal keratin network.
Chen et al. (1995) systematically screened genomic sequences of KRT14
for mutations in patients of 49 apparently independent EBS kindreds
using SSCP analysis. Most affected individuals were identified through
assistance of the National EB Registry or through DEBRA of America, a
genetic support group. KRT14 mutations were found in 10 of the families.
The 10 mutations were clustered at 3 sites--the ends of the helices and
the L12 linker region, where previous, more limited studies had
identified mutations. Early onset of blistering in these 10 families was
correlated with more widespread distribution of cutaneous mutations.
Those with early onset of blisters (e.g., by age 1 week) had generalized
disease; those with the later onset (e.g., after several months to 2
years) had blisters predominantly at acral sites. As in other families,
patients with substitution of arg125 (148066.0002, 148066.0003) all had
generalized blistering (131760). Chen et al. (1995) reported a family
with an arg125-to-ser mutation in which the proband had onset at 2 days
of age. Generalized blistering was also present in a kindred with a
gln120-to-arg mutation, giving onset in the first week of life. Chen et
al. (1995) stated that they were aware of formal publication of
mutations in either KRT5 or KRT14 in 22 apparently independent kindreds
(7 in KRT5 and 15 in KRT14). They discussed the reason that mutation was
identified in only 10 of the 49 kindreds.
Humphries et al. (1996) concluded that the M272R mutation (148066.0007)
in KRT14 accounts for many cases of generalized dominant epidermolysis
bullosa simplex (131900) in Ireland.
- Other Disorders
Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) and
dermatopathia pigmentosa reticularis (DPR; 125595) are 2 closely related
autosomal dominant ectodermal dysplasia syndromes that clinically share
complete absence of dermatoglyphics (fingerprint lines), a reticulate
pattern of skin hyperpigmentation, thickening of the palms and soles
(palmoplantar keratoderma), abnormal sweating, and other subtle
developmental anomalies of the teeth, hair, and skin. Lugassy et al.
(2006) studied one family with DPR and 4 families with NFJS. Both
disorders map to 17q11.2-q21 (Whittock et al., 2000; Sprecher et al.,
2002), which supported the suggestion that the disorders are allelic.
Lugassy et al. (2006) refined the mapping of NFJS/DPR, finding a maximum
lod score of 8.3 at marker D17S800 at a recombination fraction of 0.0.
The disease interval was found to harbor 230 genes, including a large
cluster of keratin genes. Heterozygous nonsense or frameshift mutations
in KRT14 were found to segregate with the disease traits in all 5
families.
GENOTYPE/PHENOTYPE CORRELATIONS
In contrast with mutations affecting the central alpha-helical rod
domain of keratin-14, which are found in association with epidermolysis
bullosa simplex in its various clinical forms, NFJS/DPR-associated
mutations were found in a region of the gene encoding the nonhelical
head (E1/V1) domain and were found to result in very early termination
of translation (Lugassy et al., 2006). The data suggested that KRT14
plays an important role during ontogenesis of dermatoglyphics and sweat
glands. Among other functions, the N-terminal part of keratin molecules
confers protection against proapoptotic signals. Ultrastructural
examination of patient skin biopsy specimens provided evidence for
increased apoptotic activity in the basal cell layer where KRT14 is
expressed, suggesting that apoptosis is an important mechanism in the
pathogenesis of NFJS/DPR.
HISTORY
In mapping studies, McAlpine (1990) used the symbols KRT14L1, KRT14L2,
and KRT14L3 because of the uncertainty as to which of the hybridizing
bands represent active gene(s).
ANIMAL MODEL
In transgenic mice, Vassar et al. (1991) showed that a mutant KRT14
gene, which was driven by the normal human KRT14 enhancer/promoter at
the 5-prime end and encoded a truncated keratin molecule lacking 135
amino acids from its carboxyl terminus, resulted in abnormalities
resembling the group of genetic disorders known as epidermolysis bullosa
simplex (e.g., 131950, 131900).
HSPB9
| dbSNP name | rs1122326(A,C); rs61746680(G,C) |
| ccdsGene name | CCDS11418.1 |
| cytoBand name | 17q21.2 |
| EntrezGene GeneID | 94086 |
| EntrezGene Description | heat shock protein, alpha-crystallin-related, B9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HSPB9:NM_033194:exon1:c.A5C:p.Q2P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BQS6 |
| dbNSFP Uniprot ID | HSPB9_HUMAN |
| dbNSFP KGp1 AF | 0.304029304029 |
| dbNSFP KGp1 Afr AF | 0.684959349593 |
| dbNSFP KGp1 Amr AF | 0.209944751381 |
| dbNSFP KGp1 Asn AF | 0.134615384615 |
| dbNSFP KGp1 Eur AF | 0.229551451187 |
| dbSNP GMAF | 0.3044 |
| ESP Afr MAF | 0.401044 |
| ESP All MAF | 0.350454 |
| ESP Eur/Amr MAF | 0.22314 |
| ExAC AF | 0.25 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Spine];
Scoliosis;
[Hands];
Claw hand deformity;
[Feet];
Pes cavus;
Talipes equinovarus
NEUROLOGIC:
Normal early motor milestones;
[Peripheral nervous system];
Lower and upper limb muscle weakness due to peripheral neuropathy;
Lower and upper limb muscle atrophy due to peripheral neuropathy;
Clumsy gait;
'Steppage' gait;
Foot drop;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
Neuropathic changes seen on EMG;
Normal to decreased nerve conduction velocities (NCV);
Loss of large myelinated fibers seen on nerve biopsy;
Regenerating axons;
Demyelination;
Thin myelination;
Occasional early 'onion' bulb formations
MISCELLANEOUS:
Onset in early childhood (2-4 years);
Severe course;
Clinical and pathologic features of both demyelinating and axonal
CMT;
Allelic to several forms of autosomal recessive CMT (see 214400)
MOLECULAR BASIS:
Caused by mutation in the ganglioside-induced differentiation-associated
protein-1 gene (GDAP1, 606598.0006)
OMIM Title
*608344 HEAT-SHOCK 27-KD PROTEIN 9
;;HSPB9
OMIM Description
CLONING
By searching an EST database for sequences containing the
alpha-crystallin domain characteristic of small heat-shock proteins,
followed by PCR of genomic DNA, Kappe et al. (2001) cloned HSPB9. The
deduced protein contains 159 amino acids. Northern blot analysis of
several human tissues detected a 0.8-kb transcript only in testis. In
situ hybridization of adult mouse testis showed expression of Hspb9 in
spermatogenic cells from late pachytene spermatocyte stage until the
elongate spermatid stage.
GENE STRUCTURE
Kappe et al. (2001) determined that the HSPB9 gene is intronless.
MAPPING
By genomic sequence analysis, Kappe et al. (2001) mapped the HSPB9 gene
to chromosome 17.
COA3
| dbSNP name | rs61757401(C,G) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 28958 |
| snpEff Gene Name | WNK4 |
| EntrezGene Description | cytochrome c oxidase assembly factor 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03994 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Large forehead (in 1 family);
[Face];
Long face;
Pointed chin;
Long philtrum;
[Ears];
Short ears (in 1 family);
[Eyes];
Strabismus (in some patients);
Palpebral edema (in 1 family);
[Nose];
Wide flat nose;
Bulbous nose;
Anteverted nostrils;
[Mouth];
Thick lower lip;
Small mouth (in 1 family);
[Teeth];
Abnormally implanted teeth (in 1 family)
MUSCLE, SOFT TISSUE:
Hypotonia, neonatal
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, mild;
Intellectual disability;
Speech delay;
Unsteady gait;
Ataxia;
Dysmetria, mild;
Dysarthria;
Cerebellar hypoplasia (in some patients);
Hippocampal atrophy (in 2 siblings);
Cortical atrophy (in 2 siblings);
[Behavioral/psychiatric manifestations];
Behavioral difficulties (in some patients)
MISCELLANEOUS:
Dysmorphic facial features are variable;
Ataxia is nonprogressive
MOLECULAR BASIS:
Caused by disruption of the calmodulin-binding transcription activator
1 gene (CAMTA1, 611501.0001)
OMIM Title
*614775 CYTOCHROME C OXIDASE ASSEMBLY FACTOR 3; COA3
;;COILED-COIL DOMAIN-CONTAINING PROTEIN 56; CCDC56;;
MITOCHONDRIAL TRANSLATION REGULATION ASSEMBLY INTERMEDIATE OF CYTOCHROME
c OXIDASE 12; MITRAC12
OMIM Description
CLONING
By searching a human database for sequences similar to Drosophila
Ccdc56, Peralta et al. (2012) identified COA3, which they called CCDC56.
The deduced 106-amino acid protein contains a central single pass
transmembrane domain and a C-terminal coiled-coil domain. Human CCDC56
shares 42% identity with the Drosophila protein. Database analysis
revealed conservation of CCDC56 in metazoans, but not in yeast or
plants.
Using database analysis and protein profiling to identify human
orthologs of yeast cytochrome c oxidase (COX) assembly proteins,
Szklarczyk et al. (2012) independently identified COA3.
Mick et al. (2012) found that disruption of mitochondrial outer
membranes in HEK293 cells led to exposure of the MITRAC12 C terminus,
suggesting that MITRAC12 is an inner mitochondrial membrane protein with
its C terminus exposed to the intermembrane space.
MAPPING
By genomic sequence analysis, Peralta et al. (2012) mapped the COA3 gene
to chromosome 17q21.31.
GENE FUNCTION
By immunoprecipitation analysis of HEK293 cells, Mick et al. (2012)
found that MITRAC12 associated with the cytochrome c oxidase assembly
protein SURF1 (185620) and with COX1 (MTCO1; 516030), a subunit of
respiratory complex IV. Depletion of MITRAC12 in HEK293 cells via small
interfering RNA resulted in a growth defect, reduced content of newly
synthesized complex IV, and reduced cytochrome c oxidase activity.
Quantitative affinity purification and mass spectrometry showed that
MITRAC12 interacted with central complex IV subunits and with several
complex IV assembly factors.
ANIMAL MODEL
Peralta et al. (2012) found that homozygous Ccdc56 knockout in
Drosophila resulted in developmental delay, followed by arrest at the
third larval stage and death before pupariation. The main biochemical
phenotype was severe isolated COX complex IV deficiency.
AOC4P
| dbSNP name | rs138960281(C,T) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 90586 |
| EntrezGene Description | amine oxidase, copper containing 4, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005969 |
BRCA1
| dbSNP name | rs12516(G,A); rs8176318(C,A); rs8176314(A,G); rs8176312(T,C); rs8068463(G,A); rs8176310(T,C); rs4793190(T,C); rs4792972(T,C); rs3092988(C,T); rs8070179(G,A); rs8176297(T,A); rs8176296(T,C); rs4793191(A,G); rs4793192(T,C); rs143681310(G,A); rs6503725(G,A); rs8176290(G,A); rs7212284(A,G); rs8176289(T,C); rs8176287(T,C); rs8176282(T,C); rs8066171(C,A); rs8176279(A,C); rs8176278(T,C); rs11652377(C,T); rs4793193(A,C); rs35330014(C,T); rs111581719(G,A); rs8077486(C,T); rs2187603(C,T); rs8176265(C,T); rs3092994(C,T); rs8176257(G,T); rs8176255(G,A); rs8176250(G,T); rs8176245(A,G); rs8176242(C,T); rs4793194(G,A); rs4793195(T,C); rs8176236(A,G); rs8176231(A,G); rs8176228(C,A); rs8176220(A,G); rs3092987(T,C); rs1799966(T,C); rs111499627(G,C); rs8176214(T,C); rs8176212(G,C); rs2236762(A,T); rs12940378(T,C); rs4239148(G,A); rs4318274(T,A); rs117089582(G,A); rs8176202(G,A); rs8176201(A,G); rs8176200(A,G); rs8176199(T,G); rs8176198(A,T); rs8176194(A,C); rs8176193(C,T); rs8176192(G,C); rs4793197(G,A); rs6416927(G,C); rs8176190(C,T); rs186198860(T,C); rs1060915(A,G); rs8067269(G,A); rs3950989(G,A); rs8176166(T,C); rs8176161(C,A); rs8176160(T,C); rs2070834(T,G); rs799916(T,G); rs16942(T,C); rs16941(T,C); rs799917(G,A); rs16940(A,G); rs1799949(G,A); rs55906931(A,G); rs7503154(A,C); rs8176147(C,T); rs8176145(A,G); rs8176141(C,G); rs8176140(T,A); rs799923(G,A); rs10445303(C,T); rs10445321(T,G); rs67060599(A,G); rs35908185(A,T); rs799912(T,C); rs8176133(A,C); rs8176130(C,T); rs55974475(A,G); rs799913(T,C); rs8176120(C,T); rs8065872(A,T); rs12936316(A,G); rs8176117(T,C); rs8176116(A,C); rs187294938(G,A); rs8176114(A,G); rs8176109(A,G); rs2671874(G,A); rs8176103(G,A); rs8176098(A,C); rs370677799(G,A); rs8176092(T,G); rs8176091(C,T); rs8176090(G,C); rs8176088(G,A); rs8176087(C,A); rs36086436(A,C); rs8176086(G,A); rs3765640(A,G); rs8176077(T,C); rs375003483(T,G) |
| ccdsGene name | CCDS11455.2 |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 672 |
| EntrezGene Description | breast cancer 1, early onset |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=672&%3Brs=55906931 |
| Annovar Function | BRCA1:NM_007294:exon10:c.T1456C:p.F486L,BRCA1:NM_007300:exon10:c.T1456C:p.F486L,BRCA1:NM_007297:exon9:c.T1315C:p.F439L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.581 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=672&%3Brs=55906931 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0002928 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Somatic mutation
GENITOURINARY:
[Kidneys];
Nephroblastoma (Wilms tumor)
NEOPLASIA:
Nephroblastoma (Wilms tumor)
MISCELLANEOUS:
Tumor suppressor gene;
Most cases are sporadic
MOLECULAR BASIS:
Linked to a locus at 7p15-p11.2.
OMIM Title
*601593 BRCA1-ASSOCIATED RING DOMAIN 1; BARD1
OMIM Description
CLONING
In an effort to understand the function of BRCA1 (113705), Wu et al.
(1996) used a yeast 2-hybrid system to identify proteins that associate
with BRCA1 in vivo. This analysis led to the identification of a novel
protein that interacts with the N-terminal region of BRCA1. Wu et al.
(1996) designated this protein BARD1 (BRCA1-associated RING domain-1).
In addition to its ability to bind BRCA1 in vivo and in vitro, BARD1
shares homology with the 2 most conserved regions of BRCA1: the
N-terminal RING motif and the C-terminal BRCT domain. The RING motif is
a cysteine-rich sequence found in a variety of proteins that regulate
cell growth, including the products of tumor suppressor genes and
dominant protooncogenes. The BARD1 protein also contains 3 tandem
ankyrin repeats. Wu et al. (1996) demonstrated that the BARD1/BRCA1
interaction is disrupted by tumorigenic amino acid substitutions in
BRCA1, implying that the formation of a stable complex between these
proteins may be an essential aspect of BRCA1 tumor suppression. They
proposed that BARD1 itself may be the target of oncogenic mutations in
breast or ovarian cancer.
GENE FUNCTION
By Western and immunofluorescence analyses in synchronized T24 bladder
cancer cells, Jin et al. (1997) studied the expression patterns of the
BARD1 and BRCA1 proteins. They found that the steady state levels of
BARD1, unlike those of BRCA1, remain relatively constant during cell
cycle progression. However, immunostaining revealed that BARD1 resides
within BRCA1 nuclear dots during S phase of the cell cycle, but not
during the G1 phase. Nevertheless, BARD1 polypeptides are found
exclusively in the nuclear fractions of both G1- and S-phase cells.
Therefore, progression to S phase is accompanied by the aggregation of
nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell
cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for
BARD1 in BRCA1-mediated tumor suppression.
Kleiman and Manley (1999) demonstrated that the 50-kD subunit of
cleavage stimulation factor (CSTF1; 600369) interacts in vitro and in
intact cells with BARD1. The BARD1-CSTF1 interaction inhibited
polyadenylation in vitro. BARD1, like CSTF1, interacts with RNA
polymerase-2. BARD1, BRCA1, and CSTF1 were shown to associate in vivo.
Kleiman and Manley (1999) demonstrated that BARD1 inhibits pre-mRNA
3-prime cleavage in vitro and that the same region of BARD1 required for
binding of CSTF1 is necessary for inhibiting 3-prime pre-mRNA cleavage.
Kleiman and Manley (1999) concluded that their results suggested a model
in which BARD1, as part of the RNA polymerase-2 holoenzyme, senses sites
of DNA damage and repair, and the inhibitory interaction with CSTF1
ensures that nascent RNAs are not erroneously polyadenylated at such
sites.
Irminger-Finger et al. (2001) suggested that BARD1 is a mediator of
apoptosis because (1) cell death in vivo (ischemic stroke) and in vitro
was accompanied by increased levels of BARD1 protein and mRNA; (2)
overexpression of BARD1 induced cell death with all features of
apoptosis; and (3) BARD1-repressed cells were defective for the
apoptotic response to genotoxic stress. The proapoptotic activity of
BARD1 involved binding to and elevation of p53 (191170). BRCA1 was not
required for induction of apoptosis by BARD1 but partially counteracted
it. A tumor-associated mutation of BARD1 (glu564 to his) was defective
in apoptosis induction, suggesting a role for BARD1 in tumor suppression
by mediating the signaling from proapoptotic stress toward induction of
apoptosis.
Dong et al. (2003) isolated a holoenzyme complex containing BRCA1, BRCA2
(600185), BARD1, and RAD51 (179617), which they called the BRCA1- and
BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1;
602961)-dependent ubiquitin E3 ligase activity. Inclusion of BRE
(610497) and BRCC3 (300617) enhanced ubiquitination by the complex, and
cancer-associated truncations in BRCA1 reduced the association of BRE
and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa
cells increased cell sensitivity to ionizing radiation and resulted in a
defect in G2/M checkpoint arrest. Dong et al. (2003) concluded that the
BRCC is a ubiquitin E3 ligase that enhances cellular survival following
DNA damage.
Joukov et al. (2006) found that the heterodimeric tumor suppressor
complex BRCA1/BARD1 was required for mitotic spindle-pole assembly and
for accumulation of TPX2 (605917), a major spindle organizer, on spindle
poles in both HeLa cells and Xenopus egg extracts. This BRCA1/BARD1
function was centrosome independent, operated downstream of Ran GTPase
(601179), and depended upon BRCA1/BARD1 E3 ubiquitin ligase activity.
Joukov et al. (2006) concluded that BRCA1/BARD1 function in mitotic
spindle assembly likely contributes to its role in chromosome stability
control and tumor suppression.
MAPPING
By PCR analysis of human monochromosomal hybrid cell line DNA, Wu et al.
(1996) mapped the BARD1 gene to chromosome 2q. By FISH, Thai et al.
(1998) regionalized the gene to 2q34-q35.
MOLECULAR GENETICS
To investigate whether aberrations in the BARD1 gene predispose to
hereditary breast and/or ovarian cancer, Karppinen et al. (2004)
analyzed the index cases of 126 Finnish cancer families. A cys557-to-ser
substitution (C557S; 601593.0001) was seen at elevated frequency in the
cancer family patients compared to healthy controls (5.6% vs 1.4%, p =
0.005). The highest prevalence of C557S was found among a subgroup of 94
patients with breast cancer (114480) whose family history did not
include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al.
(2004) concluded that C557S may be a commonly occurring and mainly
breast cancer-predisposing allele.
In transient colony and apoptosis assays, Sauer and Andrulis (2005)
demonstrated a correlation between loss of growth suppression and loss
of apoptosis, respectively, with several putative disease-causing
variants of BARD1 including C557S (601593.0001). There was no loss of
function with the putative benign polymorphisms P24S, E153K, R658C, and
I738V.
For a discussion of a possible association between variation in the
BARD1 gene and aggressive high-risk neuroblastoma, see 256700.
ANIMAL MODEL
McCarthy et al. (2003) determined that Bard1-null mouse embryos died
between embryonic day 7.5 and embryonic day 8.5 due to severely impaired
cell proliferation and not to increased apoptosis. In Bard1 -/-; p53 -/-
double mutant embryos, the developmental defects were partly
ameliorated, and lethality was delayed until embryonic day 9.5. Mitotic
spreads of cells from double mutant embryos showed increased chromosomal
aneuploidy over that shown by p53-null cells alone, suggesting a role
for Bard1 in maintaining genomic stability. McCarthy et al. (2003) also
developed Bard1 -/-; Brca1 -/- double mutant embryos. Embryos that
carried at least 1 wildtype allele of both Bard1 and Brca1 were normal
and had 20 to 25 somites, while each embryo that was null for either
Bard1 or Brca1 exhibited the characteristic phenotype of severe growth
retardation and degeneration. Embryos with double mutant Bard1 -/-;
Brca1 -/- genotype were phenotypically indistinguishable from either
single Bard1 or single Brca1 homozygous mutants. The similarity of
phenotypes indicated to McCarthy et al. (2003) that the developmental
functions of Brca1 and Bard1 are mediated by the Brca1/Bard1
heterodimer.
Shakya et al. (2008) found that conditional inactivation of Bard1 in
mouse mammary epithelial cells induced basal-like mammary carcinomas
with a frequency, latency, and histopathology indistinguishable from
those developed in conditional Brca1-mutant mice and in double
conditional Bard1/Brca1-mutant mice. Reminiscent of human breast
carcinomas due to BRCA1 mutation, the mouse tumors were triple negative
for estrogen receptor (see 133430) and progesterone receptor (PGR;
607311) expression and Her2/neu (ERBB2; 164870) amplification. They also
expressed basal cytokeratins Ck5 (KRT5; 148040) and Ck14 (KRT14;
148066), had elevated frequency of p53 lesions, and displayed high
levels of chromosomal instability. Shakya et al. (2008) concluded that
the tumor suppressor activities of both BARD1 and BRCA1 are mediated
through the BRCA1/BARD1 heterodimer.
MIR2117
| dbSNP name | rs7207008(T,A) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 100313779 |
| EntrezGene Description | microRNA 2117 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4293 |
| ESP Afr MAF | 0.491329 |
| ESP All MAF | 0.48883 |
| ESP Eur/Amr MAF | 0.480201 |
| ExAC AF | 0.405 |
SOST
| dbSNP name | rs75335214(G,C); rs17886183(C,T); rs75901553(G,A) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 50964 |
| EntrezGene Description | sclerostin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07025 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Nose];
Epistaxis
ABDOMEN:
[Gastrointestinal];
Gastrointestinal bleeding
GENITOURINARY:
[Internal genitalia, female];
Menorrhagia
SKELETAL:
[Limbs];
Hemarthroses
SKIN, NAILS, HAIR:
[Skin];
Easy bruising
HEMATOLOGY:
Increased bleeding (menorrhagia, gastrointestinal bleeding, hemarthroses);
Post-surgical bleeding;
Platelet aggregation defect;
Prostaglandin-endoperoxide synthase 1 (PTGS1, 176805) deficiency
in platelets;
Platelets cannot synthesize thromboxane A2 from arachidonic acid
MISCELLANEOUS:
Congenital onset
OMIM Title
*605740 SCLEROSTIN; SOST
OMIM Description
DESCRIPTION
Sclerostin and noggin (NOG; 602991) are bone morphogenic protein (BMP)
antagonists that modulate mitogenic activity through sequestering BMPs
(Winkler et al., 2004).
CLONING
Through homozygosity mapping followed by positional cloning in Afrikaner
families with sclerosteosis (269500), Brunkow et al. (2001) found 2
independent mutations in a novel gene, which they termed SOST. The SOST
gene encodes a deduced 213-amino acid protein, sclerostin, that shares
89% and 88% sequence identity with the rat and mouse homologs. The
protein contains a putative secretion signal and 2 N-glycosylation
sites. It also contains a cystine knot motif (residues 80-167) with high
similarity to the dan family of secreted glycoproteins, including dan
(600613), cerberus (603777), gremlin (603054), and caronte (604172),
which have been shown to act as antagonists of members of the
transforming growth factor-beta superfamily (see 190180). Quantitative
RT-PCR showed relatively low overall expression of SOST, but significant
expression in whole long bone, cartilage, kidney, and liver and lower
expression in placenta and fetal skin.
Balemans et al. (2001) independently isolated the SOST gene.
Quantitative RT-PCR experiments revealed highest tissue expression in
human kidney, followed by bone marrow and osteoblasts.
Using in situ hybridization, Kusu et al. (2003) found that Sost was
intensely expressed in developing bones of developing mouse embryos.
Punctate expression of Sost was localized on the surface of both
intramembranously forming skull bones and endochondrally forming long
bones. Sost colocalized with Mmp9 (120361), an osteoclast marker.
Recombinant Sost expressed in insect cells was secreted as a monomer.
By RT-PCR, Winkler et al. (2003) found human sclerostin expressed in
primary human osteoblasts, mesenchymal cells differentiated in culture
to osteoblasts, and hypertrophic chondrocytes in cartilage tissue. It
was not expressed in adipocytes or adipose tissue. Immunohistochemical
analysis of human bone detected expression in osteocytes and osteocytic
canaliculi and/or cell processes in both cortical and trabecular bone.
Staining was also observed in chondrocytes and weakly in other
osteoblastic cells.
GENE STRUCTURE
The SOST gene contains 2 exons (Brunkow et al., 2001).
MAPPING
The SOST gene maps to chromosome 17q12-q21 (Brunkow et al., 2001).
Gross (2014) mapped the SOST gene to chromosome 17q21.31 based on an
alignment of the SOST sequence (GenBank GENBANK AF326736) with the
genomic sequence (GRCh37).
GENE FUNCTION
Kusu et al. (2003) coexpressed mouse Sost with several human BMP cDNAs
in a mouse preosteoblastic cell line and found that Sost inhibited
differentiation stimulated by BMP6 (112266) and BMP7 (112267), but not
BMP2 (112261) and BMP4 (112262). Sost bound BMP6 and BMP7 with high
affinity and BMP2 and BMP4 with lower affinity. Kusu et al. (2003)
concluded that SOST is a secreted osteoclast-derived BMP antagonist that
represses BMP-induced osteoblast differentiation and/or function.
Winkler et al. (2003) found that recombinant human sclerostin bound
BMP2, BMP4, BMP5 (112265), BMP6, and BMP7 in vitro with similar binding
kinetics and affinities. Competition studies indicated that the BMP
proteins competed for the same site on sclerostin. Sclerostin binding to
BMP6 competed with BMP6 binding to type I and type II BMP receptors (see
601299 and 600799, respectively) and with the BMP antagonist DAN.
Preincubation of sclerostin with human BMP6 partially blocked
phosphorylation of SMADs (see SMAD1; 601595) by BMP6 in mouse
mesenchymal cells. Sclerostin reduced expression of genes associated
with osteoblast differentiation and reduced proliferation of, and
mineral deposition by, differentiated human mesenchymal cells and
primary human osteoblasts in a dose-dependent manner. Overexpression of
human SOST in transgenic mice resulted in a marked decrease in
osteoblast activity and decreased bone formation.
Winkler et al. (2004) found that human sclerostin interacted directly
with noggin in vitro. The sclerostin-noggin interaction neutralized the
ability of either protein to bind and inhibit BMP6, permitting BMP6
mitogenic activity in a mouse osteosarcoma cell line.
Immunoprecipitation of sclerostin from a rat osteosarcoma cell line
indicated that endogenous rat sclerostin forms a complex with Bmp2,
Bmp5, and noggin.
Semenov et al. (2005) found that human SOST antagonized Wnt (see 606359)
signaling in Xenopus embryos and mammalian cells by binding to the
extracellular domains of the Wnt coreceptors Lrp5 (603506) and Lrp6
(603507) and disrupting Wnt-induced frizzled (see 603408)-Lrp complex
formation.
Using tandem affinity purification and mass spectrometry of proteins
isolated from HEK293 and rat UMR-106 osteoblastic cells, Leupin et al.
(2011) found that sclerostin interacted with LRP4 (604270), LRP5, and
LRP6. ELISA experiments confirmed a dose-dependent interaction between
recombinant LRP4 and sclerostin. Mutation analysis revealed that
membrane localization mediated by the beta-propeller domain of LRP4 was
required for the interaction. Overexpression of LRP4 in HEK293 cells or
C28a2 human chondrocytes enhanced sclerostin-mediated inhibition of WNT1
(164820) signaling, whereas knockdown of LRP4 mRNA in HEK293 cells via
RNA interference reduced sclerostin- but not DKK1 (605189)-mediated
inhibition of WNT signaling. Knockdown of Lrp4 significantly blocked
sclerostin inhibition of bone mineralization in mouse bone marrow
stromal cells.
MOLECULAR GENETICS
- Sclerosteosis 1
In Afrikaners with sclerosteosis (SOST1; 269500), Brunkow et al. (2001)
found homozygosity for a nonsense mutation in the N terminus of
sclerostin (605740.0001). In an unrelated affected person of Senegalese
origin reported by Tacconi et al. (1998), they found homozygosity for a
splice mutation within the single intron of the SOST gene (605740.0002).
Balemans et al. (2001) described 2 families with sclerosteosis harboring
homozygous mutations in the SOST gene.
- Van Buchem Disease
Brunkow et al. (2001) analyzed the SOST gene in 7 Dutch patients with
van Buchem disease (239100) and detected no mutations in the coding
region.
In affected members from a large consanguineous Dutch family with van
Buchem disease studied by Van Hul et al. (1998), Balemans et al. (2002)
identified a homozygous 52-kb deletion approximately 35 kb downstream of
the SOST gene. Three additional Dutch patients with van Buchem disease
also had the deletion. The parents of affected individuals were
heterozygous for the deletion. Analysis of the sequences flanking the
deletion breakpoints showed the presence of Alu repeats on either side,
suggesting an Alu-mediated, unequal homologous recombination event as
the mechanism causing the deletion. As no coding sequences could be
identified within the deleted region, Balemans et al. (2002) suggested
that the deletion may alter transcription of the SOST gene in patients
with van Buchem disease.
Using transgenic mice, Loots et al. (2005) characterized expression of
human SOST from the wildtype allele and an allele carrying the van
Buchem disease-associated 52-kb noncoding deletion downstream of SOST
(VB allele). Transgenic mice with the wildtype allele expressed human
SOST by embryonic day 9.5, predominantly in mesenchymal tissue of the
developing limb bud, and adult transgenic mice expressed SOST in bone,
kidney, and heart. These mice grew to skeletal maturity with normal body
size and weight, but they displayed decreased bone mineral density. In
contrast, transgenic mice expressing the VB allele did not express SOST
in adult bone, and their bone parameters were indistinguishable from
nontransgenic littermates. The numbers of osteocytes and osteoclasts
were not significantly affected by transgenic expression, but elevated
levels of SOST in transgenic mice with either allele resulted in a wide
range of fused and missing digits in forelimbs and hindlimbs. Loots et
al. (2005) identified 7 evolutionarily conserved regions (ECRs) within
the van Buchem disease-associated deletion. They examined skeletal
structures of transgenic mouse embryos expressing each of these human
ECRs and found that the 250-bp ECR5 enhanced SOST expression in
cartilage of ribs, vertebrae, and skull plates. ECR5 was also capable of
activating the human SOST promoter in osteoblast-like cell lines. Loots
et al. (2005) concluded that van Buchem disease is caused by deletion of
a SOST-specific regulatory element and is allelic to sclerosteosis.
- Autosomal Dominant Craniodiaphyseal Dysplasia
In a Korean girl with autosomal dominant craniodiaphyseal dysplasia
(CDD; 122860), Kim et al. (2011) identified a de novo heterozygous
mutation in the SOST gene (V21M; 605740.0005). Genetic analysis of an
affected patient reported by Bieganski et al. (2007) identified a second
heterozygous SOST mutation affecting the same residue (V21L;
605740.0006). DNA from the possibly affected mother of the second
patient was not available. Both mutations affected the secretion signal
peptide of the protein, and in vitro functional expression studies
showed that the mutations resulted in significantly decreased SOST
secretion, although the proteins were produced in the cells. Kim et al.
(2011) noted the phenotypic differences from other disorders due to SOST
mutations, which are less severe and transmitted in an autosomal
recessive pattern, and postulated a dominant-negative mechanism in CDD.
- SOST Polymorphisms Associated with Bone Mineral Density
Uitterlinden et al. (2004) studied whether the SOST gene is an
osteoporosis risk gene by examining its association with bone mineral
density (BMD). They used a set of 8 polymorphisms from the SOST region
to genotype 1,939 elderly men and women from a large population-based
prospective cohort study of Dutch whites. They found that a 3-bp
insertion in the presumed SOST promoter region, with a gene frequency of
0.38, was associated with decreased BMD in women at the femoral neck and
lumbar spine, with evidence of an allele dosage effect in the oldest age
group. Similarly, a G variant in the van Buchem deletion region (gene
frequency = 0.40) was associated with increased BMD in men at the
femoral neck and lumbar spine. In both cases, differences between
extreme genotypes reached 0.2 standard deviations. No genotype effects
on fracture risk were observed for the 234 osteoporotic fractures
validated during 8.2 years of follow-up and for the 146 vertebral
prevalent fractures analyzed. Uitterlinden et al. (2004) found evidence
of additive effects of the insertion polymorphism with the Sp1-binding
site polymorphism of the COL1A1 gene (120150.0051). They suggested that
the moderate SOST genotype effects involved differences in regulation of
SOST gene expression.
FAM215A
| dbSNP name | rs61455159(G,A); rs61231498(T,C); rs231458(C,T); rs16940368(T,G); rs58692840(T,C); rs55825296(C,A); rs16940374(C,G) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 23591 |
| EntrezGene Description | family with sequence similarity 215, member A (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07897 |
| ExAC AF | 0.05 |
UBTF
| dbSNP name | rs9910055(C,T); rs369557079(C,G); rs376731901(C,T); rs113823176(A,G); rs9895423(T,C); rs374807973(G,A); rs2071167(C,T); rs191434359(C,A); rs199568031(G,A); rs2228196(G,A); rs113172365(G,A); rs735490(C,G); rs138211556(C,T); rs737303(G,A); rs143723766(G,A); rs115183012(C,T); rs76052008(G,C); rs2269908(G,C); rs2269907(G,A); rs2269906(A,C); rs2269905(A,G); rs150749143(A,C); rs77766018(C,G); rs8072954(G,A) |
| ccdsGene name | CCDS11480.1 |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 101926967 |
| EntrezGene Symbol | LOC101926967 |
| EntrezGene Description | uncharacterized LOC101926967 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | UBTF:NM_014233:exon20:c.T2040C:p.D680D,UBTF:NM_001076683:exon19:c.T1929C:p.D643D,UBTF:NM_001076684:exon19:c.T1929C:p.D643D, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5561 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0508130081301 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01194 |
| ESP Afr MAF | 0.023831 |
| ESP All MAF | 0.008073 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 2.797e-03,8.132e-06 |
OMIM Clinical Significance
Immunology:
Severe recurrent varicella
Inheritance:
? Autosomal recessive
OMIM Title
*600673 UPSTREAM BINDING TRANSCRIPTION FACTOR (RNA POLYMERASE I); UBTF
;;UPSTREAM BINDING FACTOR; UBF
OMIM Description
DESCRIPTION
Upstream binding factor (UBF) is a transcription factor required for
expression of the 18S, 5.8S, and 28S ribosomal RNAs, along with SL1 (a
complex of TBP (600075) and multiple TBP-associated factors or 'TAFs').
Two UBF polypeptides, of 94 and 97 kD, exist in the human (Bell et al.,
1988). UBF is a nucleolar phosphoprotein with both DNA binding and
transactivation domains. Sequence-specific DNA binding to the core and
upstream control elements of the human rRNA promoter is mediated through
several HMG boxes (Jantzen et al., 1990).
CLONING
The mouse Ubf cDNA and gene were cloned by Hisatake et al. (1991).
Alternative use of exon 8 produces cDNAs encoding either a 765- or
728-amino acid protein. O'Mahony and Rothblum (1991) identified 2 forms
of the Ubtf mRNA in the rat.
Jantzen et al. (1990) cloned human UBF by screening a HeLa cell cDNA
library with DNA probes based on tryptic peptides of the protein. They
found an open reading frame encoding the 764-amino acid UBF. The authors
also characterized DNA binding characteristics of UBF. Chan et al.
(1991) cloned the human cDNA by screening an expression library with a
specific autoantibody that recognizes nucleolar organizing regions.
Matera et al. (1997) reported that the 2 observed isoforms of UBTF,
which differ by 37 amino acids, are generated by alternative splicing.
GENE FUNCTION
Cell size is strongly dependent on ribosome biogenesis, which is
controlled by RNA polymerase I (see 602000). The activity of this
polymerase is modulated by a complex of proteins, including UBTF. From
experiments with mouse embryonic fibroblasts, Drakas et al. (2004)
presented evidence that a nuclear complex forms between IRS1 (147545),
UBTF, and PI3K (see 171834), leading to the serine phosphorylation of
UBF1 and regulation of rRNA synthesis.
By immunoprecipitation analysis, Shimono et al. (2005) found that MCRS1
(609504) interacted with MI2-beta (CHD4; 603277), RFP (TRIM27; 602165),
and UBF. Confocal microscopy demonstrated colocalization of MCRS1,
MI2-beta, RFP, and UBF in nucleoli. Chromatin immunoprecipitation assays
showed that MCRS1, MI2-beta, and RFP associated with rDNA and were
involved in transactivation of ribosomal gene transcription, which could
be downregulated by small interfering RNA-mediated downregulation of
MCRS1, MI2-beta, and RFP.
GENE STRUCTURE
Hisatake et al. (1991) showed that the mouse Ubf gene contains 13 exons
and spans more than 13 kb.
MAPPING
Jones et al. (1995) mapped the UBTF gene to the BRCA1 region of 17q21 by
analyzing genomic clones from that region. They found the gene order to
be cen--PPY(167780)--UBTF--EPB3(109270)--GP2B(607759)--tel. Using
fluorescence in situ hybridization and radiation hybrid mapping, Matera
et al. (1997) mapped the UBTF gene to 17q21.3.
FZD2
| dbSNP name | rs3803869(G,T); rs4792948(C,T); rs4793121(T,C) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 2535 |
| EntrezGene Description | frizzled family receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3471 |
OMIM Clinical Significance
GU:
Adult polycystic kidney disease, type III
Inheritance:
Autosomal dominant form not linked to either 16p or 4q
OMIM Title
*600667 FRIZZLED, DROSOPHILA, HOMOLOG OF, 2; FZD2
OMIM Description
CLONING
Following up on the identification of trinucleotide repeat expansions as
the basis of many inherited human disorders, Zhao et al. (1995) isolated
and characterized cDNAs containing trinucleotide repeats. In the course
of these studies, they discovered a human homolog of the Drosophila
polarity gene 'frizzled' (fz). The fz locus in Drosophila is required
for the transmission of polarity signals across the plasma membrane in
epidermal cells. The Drosophila fz gene encodes a protein with 7
putative transmembrane domains that is thought to function as a G
protein-coupled receptor. Zhao et al. (1995) isolated a human homolog,
symbolized FZD2, from a human ovarian cDNA library. The full-length cDNA
of FZD2 encodes a protein of 565 amino acids that shares 56% sequence
identity with Drosophila fz protein. Zhao et al. (1995) found that the
expression of the FZD2 gene appears to be developmentally regulated,
with high levels of expression in fetal kidney and lung and in adult
colon and ovary. The structure of FZD2 suggests that it has a role in
transmembrane signal transmission, although its precise physiologic
function and associated pathways have yet to be determined. Wang et al.
(1996) showed that a large family of frizzled homologs exists in
mammals. These authors also isolated another human homolog, 'frizzled
5,' (601723).
GENE FUNCTION
The rat frizzled-2 receptor binds Wnt proteins and can signal by
activating calcium release from intracellular stores. Ahumada et al.
(2002) demonstrated that the wildtype Fzd2 and a chimeric receptor
consisting of the extracellular and transmembrane portions of the
beta-2-adrenergic receptor with cytoplasmic domains of Fzd2 also
signaled through modulation of cGMP. Activation of either receptor led
to a decline in the intracellular concentration of cGMP, a process that
was inhibited in cells treated with pertussis toxin, reduced by
suppression of the expression of the G protein transducin (GNAT2;
139340), and suppressed through inhibition of cGMP-specific
phosphodiesterase (PDE) activity. Moreover, Ahumada et al. (2002) showed
that PDE inhibitors blocked Fzd2-induced calcium transients in zebrafish
embryos. Thus, Ahumada et al. (2002) concluded that FZD2 appears to
couple to PDEs and calcium transients through G proteins.
MAPPING
Zhao et al. (1995) mapped the human FZD2 gene to 17q21.1 by fluorescence
in situ hybridization. Wang et al. (1996) mapped the FZD2 gene to mouse
chromosome 11, syntenic to human chromosome 17q, by interspecific
backcross analysis.
HEXIM1
| dbSNP name | rs3809745(G,C); rs1801920(A,C); rs1801921(G,C); rs901753(C,T); rs8070447(A,C) |
| cytoBand name | 17q21.31 |
| EntrezGene GeneID | 10614 |
| snpEff Gene Name | ACBD4 |
| EntrezGene Description | hexamethylene bis-acetamide inducible 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2126 |
RPRML
| dbSNP name | rs113736567(A,C) |
| cytoBand name | 17q21.32 |
| EntrezGene GeneID | 388394 |
| snpEff Gene Name | GOSR2 |
| EntrezGene Description | reprimo-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
HOXB1
| dbSNP name | rs7226137(T,C); rs7207109(C,T); rs12939811(T,A); rs12946855(G,A) |
| ccdsGene name | CCDS32675.1 |
| cytoBand name | 17q21.32 |
| EntrezGene GeneID | 3211 |
| EntrezGene Description | homeobox B1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HOXB1:NM_002144:exon2:c.A794G:p.E265G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P14653 |
| dbNSFP Uniprot ID | HXB1_HUMAN |
| dbNSFP KGp1 AF | 0.986721611722 |
| dbNSFP KGp1 Afr AF | 0.94512195122 |
| dbNSFP KGp1 Amr AF | 0.994475138122 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 1.0 |
| dbSNP GMAF | 0.01286 |
| ESP Afr MAF | 0.047208 |
| ESP All MAF | 0.015993 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.995,2.440e-05 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142968 HOMEOBOX B1; HOXB1
;;HOMEOBOX 2I; HOX2I;;
Hox-2.9, MOUSE, HOMOLOG OF
OMIM Description
DESCRIPTION
HOXB1 is a member of the highly conserved homeobox (HOX) gene family,
which encodes homeodomain-containing transcription factors that confer
specificity of spatial-temporal patterning in vertebrates, Drosophila
and C. elegans (summary by Webb et al., 2012).
CLONING
Webb et al. (2012) noted that the HOXB1 protein is composed of 301 amino
acids with the 60-amino acid homeodomain located from amino acid 203 to
262. The homeodomain comprises a flexible N-terminal arm followed by 3
alpha helices.
GENE FUNCTION
Iimura and Pourquie (2006) demonstrated that in the paraxial mesoderm of
the chick embryo, Hoxb genes are first activated in a temporal colinear
fashion in precursors located in the epiblast lateral to the primitive
streak. Their data suggested that colinear activation of Hoxb genes
regulates the flux of cells from the epiblast to the streak and thus
directly controls the establishment of the genes' characteristic nested
expression domains in the somites. Iimura and Pourquie (2006) concluded
that establishment of the spatial colinearity in the embryo is directly
controlled by the Hox genes themselves.
MAPPING
By fluorescence in situ hybridization, Apiou et al. (1996) mapped the
HOXB gene cluster, which includes the HOXB1 gene, to chromosome 17q21.3.
MOLECULAR GENETICS
In 2 unrelated families of conservative German American background with
hereditary congenital facial palsy (HCFP3; 614744), Webb et al. (2012)
identified homozygosity for a missense mutation in the HOXB1 gene
(R207C; 142968.0001) that segregated with disease in each family.
ANIMAL MODEL
Expression of Hoxb1 is prominent in rhombomere 4 during mouse embryonic
development. Studer et al. (1996) found that Hoxb1 -/- mice were
indistinguishable from wildtype at birth; however, about 98% died within
24 hours. Early patterning of rhombomere 4 initiated properly, but was
not maintained, and facial branchiomotor, vestibuloacoustic efferent,
and visceromotor neurons were missing from their normal locations and
showed abnormal axonal trajectories. Studer et al. (1996) concluded that
Hoxb1 is involved in regulating neuronal migration in the hindbrain.
Goddard et al. (1996) generated mice homozygous for 2 different
mutations in the Hoxb1 gene: a deletion of exon 2, which encodes the
homeodomain, or deletion of both exons 1 and 2. They found that mice
homozygous for either mutation failed to form the somatic motor
component of the VIIth (facial) nerve and showed facial paralysis. Mice
homozygous for deletion of both exons 1 and 2, but not those lacking
only exon 2, exhibited a high degree of lethality, which was likely due
to impaired feeding behavior. The structure of rhombomere 4, neural
crest cell production, and neural crest cell migration appeared to be
normal in all mutant mice.
HOXB2
| dbSNP name | rs1042822(G,T); rs1042818(T,C); rs1042815(G,A) |
| cytoBand name | 17q21.32 |
| EntrezGene GeneID | 3212 |
| EntrezGene Description | homeobox B2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1185 |
OMIM Clinical Significance
Neuro:
Semilobar holoprosencephaly
Facies:
Flat nasal bridge;
Flattened nasal tip;
Absent nasal septum
Eyes:
Hypotelorism;
Ptosis
Mouth:
Wide midline cleft lip/palate
Inheritance:
Autosomal dominant (14q11.1-q13)
OMIM Title
*142967 HOMEOBOX B2; HOXB2
;;HOMEOBOX 2H; HOX2H;;
Hox-2.8, MOUSE, HOMOLOG OF
OMIM Description
DESCRIPTION
The HOX genes, distributed into 4 gene clusters, encode homeodomain-type
transcription factors that work in concert to regionalize the developing
embryo along its major axes. Expression of HOX genes within each cluster
is controlled temporally and spatially so that the 3-prime gene is
activated prior to and in a more anterior region of the embryo than its
5-prime neighbor (summary by Barrow and Capecchi, 1996).
CLONING
The mammalian HOX gene family contains 38 homeobox gene members located
in 4 independent complexes named HOXA, HOXB, HOXC, and HOXD (or, in
keeping with the nomenclature of the Human Gene Mapping Workshops, HOX1,
HOX2, HOX3, and HOX4, respectively). These 4 clusters of genes are
located on chromosomes 7, 17, 12, and 2, respectively. These genes are
expressed during embryonic development, at which time they have a
determinant role in the body plan organization. They have also been
implicated in the regulation of hematopoietic cell growth and
differentiation. Genes of the HOXB (or HOX2) complex are expressed
specifically in erythromegakaryocytic cell lines, and some of them are
expressed only in hematopoietic progenitors. Vieille-Grosjean and Huber
(1995) isolated the 5-prime flanking sequence of the HOXB2 (HOX2H) gene
and characterized a promoter fragment extending 323 bp upstream from the
transcriptional start site. In transfection experiments, this promoter
region was sufficient to direct the tissue-specific expression of HOXB2
in an erythroid cell line. Through analysis of point mutations,
Vieille-Grosjean and Huber (1995) identified a potential GATA-binding
site in the promoter that is essential for its transcriptional activity.
They suggested the existence of a regulatory hierarchy in which GATA1
(305371) is upstream of the HOXB2 gene in erythroid cells.
GENE FUNCTION
To investigate the functions of paralogous HOX genes, Pollock et al.
(1995) compared the phenotypic consequences of altering the embryonic
patterns of expression of Hoxb8 and Hoxc8 in transgenic mice. Altering
expression of the 2 paralogs in the axial skeletons of newborns resulted
in an array of common transformations as well as morphologic changes
unique to each gene. Divergence of function of the 2 paralogs was
clearly evident in costal derivatives, where increased expression of the
2 genes affected opposite ends of the ribs. Many of the morphologic
consequences of expanding the mesodermal domain and magnitude of
expression of either gene were atavistic, inducing the transformation of
axial skeleton structures from a modern to an earlier evolutionary form.
Pollock et al. (1995) proposed that regional specialization of the
vertebral column has been driven by regionalization of HOX gene function
and that a major aspect of this evolutionary progression may have been
restriction of HOX gene expression.
Zhai et al. (2005) reported that HOXB2 interacted with the G93A
(147450.0008)-mutant SOD1 (147450) in a yeast 2-hybrid screen. HOXB2
coprecipitated and colocalized with mutant SOD1 in neuronal cell lines,
as well as in brain and spinal cord of G93A-mutant SOD1 transgenic mice.
In motor neuron-like NSC-34 cells, overexpression of HOXB2 or its
homeodomain decreased the insolubility of mutant SOD1 and inhibited G93A
or G86R (see 147450.0006)-mutant SOD1-induced neuronal cell death. In
human and mouse tissues, expression of HOXB2 persisted in adult spinal
cord and was primarily localized in nuclei of motor neurons. In G93A
transgenic mice, HOXB2 colocalized with mutant SOD1 and was
redistributed to perikarya and proximal neurites of motor neurons. There
was progressive accumulation of HOXB2 and mutant SOD1 as punctate
inclusions in the neuropil surrounding motor neurons. Zhai et al. (2005)
concluded that HOXB2 interacts with mutant SOD1 in motor neurons of
G93A-mutant SOD1 transgenic mice, and suggested that this interaction
may modulate the neurotoxicity of mutant SOD1.
ANIMAL MODEL
To investigate the functions of group 2 homeobox genes in early
neurogenesis, Davenne et al. (1999) analyzed single and double Hoxa2
(604685) and Hoxb2 mutants. Morphologic analysis showed that the normal
number of segments form in the mutants, but that the boundaries between
rhombomere segments are incorrectly generated. Math3 expression is
reduced in rhombomere (r) 4 in Hoxb2 mutants. Whereas Hoxa2 appears to
control the distribution of subsets of neuronal precursors in r2 and r3,
Hoxb2 appears to function mainly in r4. In addition, Hoxa2 controls
development in alar and 'dorsal' basal plates of r2 and r3, whereas
Hoxb2 is essential for motor neuron development in the 'ventral' basal
plate of r4. In situ hybridization studies identified this pattern of
changes in molecular marker expression with probes for Mash1 (100790),
ngn2 (606624), and Phox2b (603851).
Barrow and Capecchi (1996) generated mice with a disruption in Hoxb2 by
gene targeting. They obtained Hoxb2 -/- mice at a mendelian ratio, but
the majority died prior to week 3, likely due to severe malformation of
the sternum. All animals that survived showed a less severe sternal
phenotype, but were characterized by marked facial narrowing and
paralysis resulting from a failure to form the somatic motor component
of the VIIth (facial) nerve. Some Hoxb2 +/- and Hoxb2 -/- animals showed
anterior transformations of the axis (C2) such that it more closely
resembled the atlas (C1) or a change in the orientation of the anterior
arch of the atlas compared with wildtype. Second branchial arch
structures were unaffected in Hoxb2 -/- mice and expression of hindbrain
markers appeared normal. Expression of Hoxb1 (142968) and Hoxb4
(142965), but not Hoxb3 (142966), were also altered in Hoxb2 -/- mice
and appeared to contribute to the phenotype.
PRAC1
| dbSNP name | rs1054072(A,G) |
| cytoBand name | 17q21.32 |
| EntrezGene GeneID | 84366 |
| snpEff Gene Name | HOXB13 |
| EntrezGene Description | prostate cancer susceptibility candidate 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4596 |
| ESP Afr MAF | 0.393786 |
| ESP All MAF | 0.483793 |
| ESP Eur/Amr MAF | 0.430547 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
GENITOURINARY:
[Kidneys];
Progressive renal failure;
Membranoproliferative glomerulonephritis type II;
Thickening of the glomerular basement membrane on renal biopsy;
Deposition of complement component C3 in glomerular basement membrane;
Hematuria
IMMUNOLOGY:
Continuous activation of the alternative complement pathway;
Hypocomplementemia;
Depletion of components of the alternative complement pathway;
Increased susceptibility to certain bacterial infections, especially
Neisseria meningitidis
LABORATORY ABNORMALITIES:
Decreased serum complement factor H;
Normal levels of complement factor H, but impaired function;
Hypocomplementemia
MISCELLANEOUS:
Onset in infancy or childhood;
Variable phenotype;
Some patients may be asymptomatic
MOLECULAR BASIS:
Caused by mutation in the complement factor H gene (CFH, 134370.0002)
OMIM Title
*609819 PROSTATE, RECTUM, AND COLON GENE 1; PRAC1
;;SMALL NUCLEAR PROTEIN PRAC
OMIM Description
CLONING
By in silico analysis, Liu et al. (2001) identified a cluster of
sequence-homologous ESTs derived only from human prostate cDNA
libraries. Using these EST sequences and 5-prime RACE, they assembled a
full-length cDNA, which they designated PRAC (prostate, rectum, and
colon), from LNCaP mRNA and prostate tumor total RNA. PRAC encodes a
deduced 57-amino acid protein with several potential phosphorylation
sites and a molecular mass of about 6 kD. RNA dot-blot analysis detected
high expression of PRAC in prostate, rectum, and distal colon, and weak
expression in bladder. No difference in expression was found between
normal prostate and prostate tumor samples. Northern blot analysis
revealed a 450-bp PRAC transcript in prostate and colon as well as in
the prostate adenocarcinoma cell lines LNCaP and PC-3. RT-PCR detected
low expression in the prostate cell line DU145. Western blot analysis
localized PRAC to the nucleus.
MAPPING
By sequence analysis, Liu et al. (2001) mapped the PRAC1 gene to
chromosome 17q21.3 about 4 kb downstream from the HOXB13 gene (604607).
PRAC2
| dbSNP name | rs3110599(T,G); rs56290537(G,C); rs2271891(C,G) |
| cytoBand name | 17q21.32 |
| EntrezGene GeneID | 360205 |
| snpEff Gene Name | HOXB13 |
| EntrezGene Description | prostate cancer susceptibility candidate 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PRAC2:NM_001282276:exon2:c.T102G:p.C34W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1795 |
| ExAC AF | 0.053,9.634e-04,1.606e-03 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Normal birth length;
[Weight];
Normal birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Normal birth head circumference;
Microcephaly, acquired;
[Eyes];
Sparse eyebrows;
Sparse eyelashes
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy
SKIN, NAILS, HAIR:
[Skin];
Ichthyosis;
[Hair];
Sparse eyebrows;
Sparse eyelashes;
Minimal hair growth
NEUROLOGIC:
[Central nervous system];
Hypotonia, profound muscular (in some patients);
Seizures (in some patients);
Hypsarrhythmia (in some patients)
METABOLIC FEATURES:
Hypoketotic hypoglycemia (in some patients)
LABORATORY ABNORMALITIES:
Abnormal transferrin isoelectric focusing (IEF);
Increased disialo- and asialotransferrin;
Decreased lipid-linked oligosaccharides (LLO)
MISCELLANEOUS:
Death in early infancy (in some patients);
Some patients present with apparent nonsyndromic dilated cardiomyopathy
in early childhood
MOLECULAR BASIS:
Caused by mutation in the transmembrane protein 15 gene (TMEM15, 610746.0001)
OMIM Title
*610787 HOXB CLUSTER ANTISENSE RNA 5; HOXBAS5
;;PROSTATE, RECTUM, AND COLON GENE 2; PRAC2
OMIM Description
CLONING
By database analysis of the genomic region surrounding the PRAC gene
(609819), Olsson et al. (2003) identified a cluster of
sequence-homologous ESTs derived solely from human prostate cDNA
libraries. Using these EST sequences and 5-prime RACE, they assembled a
full-length cDNA, which they designated PRAC2. Using constructs
expressing each of 3 possible open reading frames expressed in human
embryonic kidney 293T cells followed by Western analysis, Olsson et al.
(2003) determined that PRAC2 encodes a 14-kD protein, which corresponds
to use of the second ORF, with a deduced 90-amino acid sequence and a
predicted molecular mass of 10.5 kD. Northern blot analysis detected a
500- to 600-bp transcript in prostate. PCR analysis of 24 tissues
detected highest PRAC2 expression in prostate followed by testis; lower
expression was detected in placenta, muscle, colon, peripheral blood
lymphocytes, and skin. Weak expression was also detected in 2 prostate
cancer cell lines. RNA dot-blot analysis of 61 adult and fetal tissues
confirmed expression in prostate, some regions of large bowel, and
testis. Olsson et al. (2003) concluded that, like PRAC, PRAC2 displays
restricted tissue expression with predominant expression in prostate,
rectum, and testis. Immunofluorescence and cell fractionation studies
localized PRAC2 primarily to the nucleus in NIH3T3 cells with a granular
pattern within the cytoplasm as well.
GENE STRUCTURE
Olsson et al. (2003) determined that the PRAC2 gene contains 2 exons and
is transcribed in the opposite orientation to the adjacent PRAC gene.
MAPPING
By genomic sequence analysis, Olsson et al. (2003) mapped the PRAC2 gene
(HOXBAS5) to chromosome 17q21 between the HOXB13 (604607) and PRAC
genes.
DLX4
| dbSNP name | rs58769681(G,A); rs1811329(C,T); rs750522(C,G); rs1075885(T,A); rs150024578(C,T); rs1058562(T,C); rs1058564(C,T); rs4793623(C,A); rs8066341(A,G) |
| ccdsGene name | CCDS45728.1 |
| cytoBand name | 17q21.33 |
| EntrezGene GeneID | 1748 |
| EntrezGene Description | distal-less homeobox 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DLX4:NM_001934:exon2:c.C380T:p.P127L,DLX4:NM_138281:exon3:c.C596T:p.P199L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7585 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q92988-2 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 5.692e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Hypertension due to renal disease
GENITOURINARY:
[Kidneys];
Proteinuria;
Microscopic hematuria;
Nephrotic syndrome;
Renal failure;
End-stage renal disease;
Enlarged glomeruli;
Mesangial and subendothelial granular or fibrillar deposits which
show immunoreactivity to fibronectin
MISCELLANEOUS:
Onset of proteinuria in the second to fourth decades;
Onset of end-stage renal disease 15 to 20 years after onset;
Slow progression
MOLECULAR BASIS:
Caused by mutation in the fibronectin 1 gene (FN1, 135600.0001)
OMIM Title
*601911 DISTAL-LESS HOMEOBOX 4; DLX4
DISTAL-LESS HOMEOBOX 7; DLX7, INCLUDED;;
BETA PROTEIN 1, INCLUDED; BP1, INCLUDED
OMIM Description
CLONING
Using degenerate PCR, Nakamura et al. (1996) cloned the DLX4 gene, which
they called DLX7, from human and mouse. They isolated a human DLX7 cDNA
predicting a 167-amino acid protein. The homeodomains of human and mouse
DLX7 are highly similar to those of all other vertebrate DLX genes, but
there is divergence upstream of the homeodomain between human and mouse
DLX7 and between DLX7 and other DLX genes. Nakamura et al. (1996)
presented evidence that the mouse Dlx7 gene is alternatively spliced
upstream of the homeodomain and suggested that this may explain some of
the divergence. By Northern blot analysis, Nakamura et al. (1996) found
that DLX7 was expressed as a 2.3-kb transcript in several human cell
lines.
Quinn et al. (1997) undertook a DNA binding site screen of a 32-week
human placenta cDNA library using a consensus homeodomain binding site
as a probe. They claimed that this study represented the first library
screen carried out to isolate homeobox genes from the human placenta.
Quinn et al. (1997) found that 3 homeobox genes known to be expressed in
embryo, HB24 (142995), GAX (600535), and MSX2 (123101), are also
expressed in the placenta. They also identified the DLX4 gene, which
shows 85% sequence identity with the homeodomain encoded by the
Drosophila 'distal-less' gene.
BP1 represses beta-globin (141900) expression by binding to 2 silencer
regions upstream of the beta-globin gene. By screening an
erythroleukemia cell line cDNA expression library with an
oligonucleotide probe containing beta-globin silencer II sequence,
followed by 5-prime and 3-prime RACE, Chase et al. (2002) cloned
full-length BP1. The deduced 240-amino acid protein has a calculated
molecular mass of 26 kD and contains the 3 predicted alpha helices found
in homeodomains. Chase et al. (2002) determined that BP1, DLX4 (Quinn et
al., 1997), and DLX7 (Nakamura et al., 1996) are splice variants of the
DLX4 gene. All 3 isoforms are identical within the homeodomain, but the
region upstream of the homeodomain is significantly divergent. Chase et
al. (2002) noted that the mouse Dlx7 cDNA cloned by Nakamura et al.
(1996) shares 88% DNA homology with BP1 and only 46% identity with DLX7,
suggesting that it corresponds to BP1. Northern blot analysis detected a
2.1-kb BP1 transcript in the erythroleukemia cell line. RNA dot blot
analysis of 50 human tissues detected BP1 expression only in placenta
and kidney. RT-PCR detected BP1 in two 20-week human fetal liver
samples. Western blot analysis detected BP1 in erythroleukemia cells at
an apparent molecular mass of about 32 kD, indicating that the protein
may undergo posttranslational modification.
GENE FUNCTION
By electrophoretic mobility shift assay, Chase et al. (2002) confirmed
that BP1 bound silencer I and silencer II of the beta-globin gene. It
also bound Indian haplotype beta-globin sequences with high affinity.
Analysis of the effect of transient BP1 transfection on reporter gene
activity indicated that BP1 has repressor function toward the
beta-globin promoter, acting through the 2 silencer elements.
Furthermore, induction of erythroid differentiation in an erythroid
progenitor cell line by erythropoietin (133170) was associated with
increased expression of beta-globin and decreased expression of BP1.
MAPPING
By FISH, Nakamura et al. (1996) mapped the DLX4 gene to chromosome
17q21.3-q22. They stated that the human DLX4 and DLX3 (600525) genes are
10 kb apart and are arranged in a tail-to-tail tandem orientation,
similarly to that found in mouse. Using dual-color FISH, Nakamura et al.
(1996) determined that human DLX4 and HOX9B (142964) lie within 2 Mb of
one another.
Using FISH, Quinn et al. (1997) assigned the DLX4 gene to chromosome
17q21-q22, within the same region as DLX3 and the HOXB homeobox gene
cluster. DLX1 (600029) and DLX2 (126255) are closely linked on
chromosome 2, and DLX5 (600028) and DLX6 (600030) are closely linked on
chromosome 7. Thus, Quinn et al. (1997) predicted that DLX3 and DLX4 are
closely linked and that they arose through gene duplication and
divergence from a common ancestral precursor.
Using FISH, Morasso et al. (1997) localized the DLX4 gene, which they
designated DLX8, to 17q21.3-q22.
HILS1
| dbSNP name | rs1046329(C,G); rs151305009(C,T); rs36107109(C,T); rs2696293(C,G) |
| ccdsGene name | CCDS32679.1 |
| cytoBand name | 17q21.33 |
| EntrezGene GeneID | 373861 |
| snpEff Gene Name | SGCA |
| EntrezGene Description | histone linker H1 domain, spermatid-specific 1, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1391 |
| ExAC AF | 0.134 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Cardiomyopathy (rare)
SKELETAL:
Contractures;
[Spine];
Scoliosis may occur
MUSCLE, SOFT TISSUE:
Limb-girdle muscle weakness;
Limb-girdle muscle atrophy;
Unsteady gait;
Calf muscle hypertrophy;
Necrosis and degeneration seen on muscle biopsy;
Adhalin deficiency seen on muscle biopsy;
Decreased immunostaining for alpha-sarcoglycan;
Myopathic changes seen on EMG
NEUROLOGIC:
[Central nervous system];
Loss of reflexes due to myopathy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset in childhood (3 to 10 years);
Loss of independent walking by teenage years (in some);
Progressive disorder;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the alpha-sarcoglycan gene (SGCA, 600119.0001)
OMIM Title
*608101 SPERMATID-SPECIFIC LINKER HISTONE H1-LIKE PROTEIN
;;HILS1
OMIM Description
DESCRIPTION
In mouse, Hils1 displays characteristics of a linker histone and is
expressed in nuclei of late maturing spermatids (Yan et al., 2003).
CLONING
Yan et al. (2003) cloned mouse Hils1, which encodes a deduced 170-amino
acid protein. By searching databases using mouse Hils1, followed by
5-prime and 3-prime RACE, they cloned human HILS1. The deduced 231-amino
acid protein shares 50% identity with mouse Hils1, which has a shorter N
terminus. Mouse and human HILS1 each have an N-terminal domain, a
globular domain, and a C-terminal domain, and both contain 2 conserved
phosphorylation sites. The authors predicted that the globular domain of
HILS1 forms a winged-helix structure similar to histone H1 (see 142709).
Northern blot analysis of mouse tissues detected a 1.0-kb transcript
only in testis. RT-PCR confirmed that HILS1 is expressed exclusively in
testis in mouse and human. By in situ hybridization and immunostaining
of mouse testis, Yan et al. (2003) found that expression of Hils1 mRNA
initiated at step 4 of spermatid development and peaked during steps 6
to 8, while protein expression initiated at step 9 and peaked during
steps 10 to 13, during elongation. Hils1 localized to step-12 spermatid
nuclei in a pattern that was similar but not identical to that displayed
by Tnp1 (190231).
GENE FUNCTION
Yan et al. (2003) found that mouse Hils1 displayed several biochemical
properties similar to those of linker histones, including the abilities
to bind reconstituted mononucleosomes, to produce a chromatosome stop
during micrococcal nuclease digestion, and to aggregate chromatin.
Because Hils1 was expressed in late spermatids that did not contain core
histones, Yan et al. (2003) proposed that Hils1 may participate in
spermatid nuclear condensation through a mechanism distinct from that of
linker histones. They also suggested, based on the structure of Hils1,
that it may regulate gene transcription, DNA repair, or other chromosome
processes during spermiogenesis.
GENE STRUCTURE
Yan et al. (2003) determined that the human HILS1 gene contains 2 exons,
while the mouse gene is intronless.
MAPPING
By genomic sequence analysis, Yan et al. (2003) mapped the HILS1 gene to
chromosome 17q21.33. They mapped the mouse Hils1 gene to a region of
chromosome 11 that shows homology of synteny to human chromosome
17q21.33. The mouse and human HILS1 genes are contained within intron 8
of the SGCA gene (600119) and are transcribed in the opposite
orientation of SGCA.
ABCC3
| dbSNP name | rs12604031(G,A); rs9890046(C,G); rs8070592(C,T); rs9303560(A,G); rs10153257(G,A); rs4148405(T,G); rs4148407(C,T); rs114593181(G,A); rs77996580(T,C); rs2412333(A,G); rs60300548(A,C); rs185861995(G,A); rs114401727(G,A); rs1548529(A,G); rs73342287(G,A); rs183904195(C,T); rs73344347(G,C); rs4148409(T,C); rs148454244(T,C); rs739922(T,A); rs60612836(G,A); rs62059744(T,C); rs1541392(T,G); rs374410694(C,T); rs7215354(A,G); rs7218932(G,A); rs12051822(G,A); rs79611829(A,G); rs34858494(A,C); rs34221557(A,C); rs61497295(A,T); rs9893660(T,C); rs140687331(G,T); rs4794173(G,A); rs62059745(A,G); rs4793666(G,C); rs28470592(C,T); rs719717(C,G); rs2107438(C,A); rs4793667(T,C); rs35364174(G,A); rs2023907(C,G); rs4148411(G,C); rs4148412(T,C); rs2301836(G,A); rs733393(G,C); rs55981810(C,G); rs72837547(A,G); rs8076674(A,G); rs9905584(A,G); rs111337922(G,C); rs11568581(G,A); rs7216383(T,C); rs1137449(T,C); rs61479331(T,G); rs201464280(T,A); rs36088946(A,G); rs12944018(G,A); rs886493(G,T); rs879459(C,T); rs150218388(G,A); rs4794176(G,C); rs4794177(A,G); rs12946653(A,G); rs8075406(A,T); rs8079556(T,C); rs115244767(G,A); rs142755562(G,A); rs8079432(A,G); rs16949207(T,C); rs116919241(G,A); rs191753816(G,T); rs72837555(C,T); rs12451302(T,G); rs149220452(T,C); rs11079922(T,C); rs4148415(C,T); rs2072365(C,T); rs2072366(G,A); rs4148416(C,T); rs76521597(G,A); rs113459842(G,T); rs2240802(G,A); rs967935(C,T); rs3785912(C,T); rs1989226(A,T); rs1989283(G,A); rs79484792(G,A); rs2277624(C,T); rs114877000(C,T); rs872793(T,C); rs740786(A,T); rs1558288(G,A); rs2015146(G,A); rs77160978(C,T); rs12946683(G,A); rs61571652(C,T); rs3826434(C,G); rs3785911(A,C); rs77073476(A,G); rs1051640(A,G); rs138342952(G,C) |
| ccdsGene name | CCDS32681.1 |
| cytoBand name | 17q21.33 |
| EntrezGene GeneID | 8714 |
| EntrezGene Description | ATP-binding cassette, sub-family C (CFTR/MRP), member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCC3:NM_003786:exon28:c.C4054T:p.L1352F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6259 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O15438 |
| dbNSFP Uniprot ID | MRP3_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.004539 |
| ESP All MAF | 0.001768 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0004391 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, 4 to 7 SD below the mean
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild to moderate
MOLECULAR BASIS:
Caused by mutation in the cancer susceptibility candidate 5 gene (CASC5,
609173.0001)
OMIM Title
*604323 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 3; ABCC3
;;MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 3; MRP3;;
CANALICULAR MULTISPECIFIC ORGANIC ANION TRANSPORTER 2; CMOAT2
OMIM Description
CLONING
Bile secretion in liver is driven in large part by ATP-binding cassette
(ABC)-type proteins that reside in the canalicular membrane and effect
ATP-dependent transport of bile acids, phospholipids, and non-bile acid
organic anions. Canalicular ABC-type proteins can be classified into 2
subfamilies based on membrane topology and sequence identity: MDR1
(ABCB1; 171050), MDR3 (ABCB4; 171060), and SPGP (ABCB11; 603201)
resemble the MDR1 P-glycoprotein, whereas MRP2 (ABCC2; 601107) is
similar in structure and sequence to the multidrug resistance protein
MRP1 (ABCC1; 158343) and transports similar substrates. By PCR with
degenerate primers for the ABCC group, followed by screening a liver
cDNA library, Uchiumi et al. (1998) isolated a cDNA encoding ABCC3,
which they termed CMOAT2/MRP3. The predicted 1,527-amino acid protein is
56% identical to MRP1 and 45% identical to MRP2. Northern blot analysis
revealed high expression of a 6.5-kb transcript in liver and low
expression in colon, small intestine, prostate, and pancreas.
Independently, Belinsky et al. (1998) and Kiuchi et al. (1998) cloned
ABCC3, which they called MOATD and MRP3, respectively. By Northern blot
analysis, Kiuchi et al. (1998) detected increased expression of ABCC3 in
a liver cell line exposed to phenobarbital.
Ortiz et al. (1999) reported the isolation of the Mrp3 gene from rat
liver and found that it codes for a 1,522-amino acid protein that
exhibits extensive sequence similarity with MRP1 and MRP2. Northern blot
analysis indicated that rat Mrp3 is expressed in lung and intestine of
Sprague-Dawley rats as well as in liver of Eisai hyperbilirubinemic rats
and TR(-) mutant rats, which are deficient in Mrp2 expression. Mrp3
expression is also transiently induced in liver shortly after birth and
during obstructive cholestasis. Antibodies raised against Mrp3 recognize
a polypeptide of 190 to 200 kD, which is reduced in size to 155 to 165
kD after treatment with endoglycosidases. Immunoblot analysis and
immunoconfocal microscopy indicated that Mrp3 in the rat is present in
the canalicular membrane, suggesting that it may play a role in bile
formation.
Fromm et al. (1999) cloned 2 MRP3 splice variants, which they termed
MRP3A and MRP3B, resulting from incomplete removal of intronic sequences
from the full-length gene. The variants are truncated proteins of 1,238
and 510 amino acids, respectively.
Using immunoblot analysis, Konig et al. (1999) detected expression of
190- and 170-kD ABCC3 proteins. After tunicamycin treatment to inhibit
glycosylation, they observed a single 165-kD protein, suggesting the
existence of splice variants in the untreated cells. Immunofluorescence
microscopy demonstrated expression on the basolateral membrane of
hepatocytes, but no expression was found on the canalicular membrane,
where ABCC2 is expressed. Expression of ABCC3 was apparently enhanced in
2 patients with Dubin-Johnson syndrome (237500) in which ABCC2
expression was lacking.
Kool et al. (1999) detected expression of ABCC3 in the lateral side of
cholangiocytes and in the basolateral membranes of hepatocytes, where it
mediates transport of S-glutathione. When expressed in ovarian carcinoma
cells, ABCC3 conferred resistance to the anticancer drugs methotrexate,
etoposide, and teniposide. The authors noted that sequence analysis of
ABCC3 predicts a protein organized in a way similar to ABCC1 and ABCC2.
MAPPING
Using FISH, Uchiumi et al. (1998) mapped the ABCC3 gene to chromosome
17q22.
ANIMAL MODEL
Using vesicular uptake experiments, Zelcer et al. (2005) determined that
vesicles prepared from insect cells overexpressing Mrp3 transported
morphine-3-glucuronide (M3G) and M6G. Mrp3-null mice were unable to
excrete M3G from the liver into the bloodstream, resulting in increased
levels of M3G in liver and bile, a 50-fold reduction in the plasma M3G
level, and a shift in the main disposition route for morphine and M3G,
predominantly via urine in wildtype mice, but via feces in Mrp3-null
mice. The absence of Mrp3 led to decreased antinociceptive potency of
injected M6G.
TOB1
| dbSNP name | rs4626(T,C); rs35220381(C,T) |
| ccdsGene name | CCDS11576.1 |
| cytoBand name | 17q21.33 |
| EntrezGene GeneID | 10140 |
| EntrezGene Description | transducer of ERBB2, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TOB1:NM_005749:exon2:c.A957G:p.K319K,TOB1:NM_001243877:exon3:c.A957G:p.K319K,TOB1:NM_001243885:exon2:c.A540G:p.K180K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3806 |
| ESP Afr MAF | 0.327281 |
| ESP All MAF | 0.295787 |
| ESP Eur/Amr MAF | 0.279651 |
| ExAC AF | 0.677 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
ABDOMEN:
[Liver];
Intrahepatic cholestasis, episodic, recurrent, may be permanent in
some patients later in life;
Jaundice, episodic;
Hepatomegaly;
Cholelithiasis;
Mild fibrosis (some), shown on biopsy;
Progression to end-stage liver disease does not occur
SKIN, NAILS, HAIR:
[Skin];
Jaundice, episodic;
Pruritus, episodic
LABORATORY ABNORMALITIES:
Normal or mildly increased serum gamma-GGT (231950);
Conjugated hyperbilirubinemia;
Increased alkaline phosphatase;
Increased serum bile acids
MISCELLANEOUS:
Onset in first 2 decades;
Disease-free intervals can last weeks to years during which there
is no clinical or biochemical evidence of cholestasis;
Precipitating factors include viral illness and pregnancy;
Allelic disorder to progressive familial intrahepatic cholestasis-2
(PFIC2, 601847)
MOLECULAR BASIS:
Caused by mutation in the ATP-binding cassette, subfamily B, member
11 gene (ABCB11, 603201.0002)
OMIM Title
*605523 TRANSDUCER OF ERBB2, 1; TOB1
;;TOB
OMIM Description
CLONING
Matsuda et al. (1996) cloned a cDNA encoding TOB1, which they called
TOB, a protein that interacts with the ERBB2 (164870) gene product p185.
Sequence analysis revealed that TOB1 is a 45-kD, 345-amino acid protein
whose N-terminal half is homologous to the antiproliferative gene
product BTG1 (109580). The C-terminal half of TOB1 is characterized by
the presence of a proline- and glutamine-rich sequence. Expression of
TOB1 mRNA was observed in various cell types.
GENE FUNCTION
Matsuda et al. (1996) found that, like BTG1, exogenously expressed TOB1
was able to suppress growth of NIH 3T3 cells, but the growth suppression
was hampered by the presence of kinase-active p185. By using GST-TOB1
proteins containing either full-length TOB1 or the N-terminal half of
TOB1, Matsuda et al. (1996) showed that the C-terminal half of TOB1 was
relevant to its interaction with p185. Furthermore, TOB1 could be
coimmunoprecipitated with anti-ERBB2 antibody, and reciprocally, p185
could be coimmunoprecipitated with anti-TOB1 antibodies. These data
suggested that p185 negatively regulates the TOB1-mediated
antiproliferative pathway through its interaction with TOB1, resulting
possibly in growth stimulation by p185. Expression of TOB1 mRNA was not
correlated with expression of ERBB2, suggesting that other receptor-type
protein-tyrosine kinases are also involved in the TOB1-mediated
regulation of cell growth.
Tzachanis et al. (2001) used antigen-specific T-cell clones rendered
anergic by stimulation of T-cell receptor (see 186810) in the absence of
costimulation or interleukin-2 (IL2; 147680) and suppression subtractive
hybridization and differential screening to identify genes selectively
expressed in anergic cells. TOB was constitutively expressed in primary
peripheral blood T lymphocytes and had to be downregulated for T-cell
activation. Immunoprecipitation, immunoblot, and gel-shift analyses
showed that TOB interacts with SMAD4 (MADH4; 600093) and, to a lesser
degree, with SMAD2 (601366) and augments SMAD DNA binding to sites in
the IL2 promoter, leading to an inhibition of IL2 transcription.
Tzachanis et al. (2001) concluded that T-cell quiescence is an actively
maintained phenotype that must be suppressed to allow T-cell activation
to occur, suggesting targets for the manipulation of the immune
response.
Xiong et al. (2006) found that zebrafish Tob1a was required for correct
dorsoventral patterning. Tob1a inhibited beta-catenin (CTNNB1; 116806)
transcriptional activity by physically associating with beta-catenin and
preventing formation of beta-catenin/Lef1 (153245) complexes. Although
Tob1a also inhibited the transcriptional activity of Smad3 (603109), its
role in limiting dorsal development was executed primarily by
antagonizing the beta-catenin signal. By immunoprecipitation analysis,
Xiong et al. (2006) showed that endogenous TOB1 and beta-catenin
interacted in human HEK293T cells. SMAD3 also immunoprecipitated with
TOB1 in human cells.
MAPPING
By FISH, Matsuda et al. (1996) mapped the TOB1 gene to 17q21.
ANIMAL MODEL
Yoshida et al. (2000) showed that murine Tob is a negative regulator of
bone morphogenetic protein (BMP; see 112265)/SMAD signaling in
osteoblasts. Mice carrying a targeted deletion of the Tob gene had a
greater bone mass due to increased numbers of osteoblasts. Orthotopic
bone formation in response to Bmp2 (112261) was elevated in
Tob-deficient mice. Overproduction of Tob repressed Bmp2-induced,
Smad-mediated transcriptional activation. Tob associated with
receptor-regulated Smads, including Smad1 (601595), Smad5 (603110), and
Smad8 (603295), and colocalized with these SMADs in the nuclear bodies
upon BMP2 stimulation. The results indicated that Tob negatively
regulates osteoblast proliferation and differentiation by suppressing
the activity of the receptor-regulated Smad proteins.
Schulze-Topphoff et al. (2013) found that the experimental autoimmune
encephalomyelitis (EAE) model of multiple sclerosis (MS; 126200) in
Tob1-null mice was associated with augmented central nervous system
inflammation, increased Cd4 (186940)-positive and Cd8 (see
186910)-positive T cells, increased myelin-reactive T helper-1 (Th1) and
Th17 (see 603149) cells, and reduced numbers of regulatory T cells.
Reconstitution of T cell-deficient Rag1 (179615)-null mice with
Tob1-null Cd4-positive T cells also resulted in the aggressive EAE
phenotype. Schulze-Topphoff et al. (2013) concluded that Tob1 plays a
critical role in the adaptive T-cell responses that drive development of
demyelinating disease and proposed that TOB1 may be a useful biomarker
for demyelinating disease activity.
TOB1-AS1
| dbSNP name | rs12601477(G,A) |
| cytoBand name | 17q21.33 |
| EntrezGene GeneID | 400604 |
| snpEff Gene Name | TOB1 |
| EntrezGene Description | TOB1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.404 |
KIF2B
| dbSNP name | rs3803824(C,T); rs9912492(G,C); rs59657238(C,T); rs3803825(A,G); rs3803826(C,T); rs73989591(G,C); rs73989592(T,C); rs73989593(G,A); rs4561518(C,T); rs4561519(C,G); rs3826355(C,T) |
| ccdsGene name | CCDS32685.1 |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 84643 |
| EntrezGene Description | kinesin family member 2B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KIF2B:NM_032559:exon1:c.C335T:p.A112V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N4N8 |
| dbNSFP Uniprot ID | KIF2B_HUMAN |
| dbNSFP KGp1 AF | 0.238095238095 |
| dbNSFP KGp1 Afr AF | 0.0325203252033 |
| dbNSFP KGp1 Amr AF | 0.28729281768 |
| dbNSFP KGp1 Asn AF | 0.167832167832 |
| dbNSFP KGp1 Eur AF | 0.401055408971 |
| dbSNP GMAF | 0.2388 |
| ESP Afr MAF | 0.085565 |
| ESP All MAF | 0.300015 |
| ESP Eur/Amr MAF | 0.409884 |
| ExAC AF | 0.329 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Relative macrocephaly;
[Face];
Malar hypoplasia;
Broad forehead
RESPIRATORY:
Recurrent respiratory infections
SKELETAL:
[Limbs];
Bone pain (in some patients);
Bone dysplasia (in some patients);
Lacunar bone lesions (in some patients);
Cortical thickening (in some patients);
Modeling defects at the long bone diaphyses (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Livedo;
Telangiectasia on the cheeks
IMMUNOLOGY:
Immunodeficiency;
Decreased IgM and IgG2;
Lack of acquired antibodies;
Low memory B cells;
Low naive T cells;
Decreased T cell proliferation
MISCELLANEOUS:
Onset at birth;
One French family has been reported (last curated March 2013)
MOLECULAR BASIS:
Caused by mutation in the DNA polymerase, epsilon gene (POLE, 174762.0002)
OMIM Title
*615142 KINESIN FAMILY MEMBER 2B; KIF2B
OMIM Description
DESCRIPTION
KIF2A (602591), KIF2B, and KIF2C (604538) comprise the kinesin-13 family
of microtubule motor proteins, which are characterized by the
localization of the kinesin motor domain in the middle of the
polypeptide. Kinesin-13 proteins are nonmotile and induce microtubule
depolymerization by disassembling tubulin subunits from the polymer end.
KIF2B participates in several key events during mitosis, including
bipolar spindle assembly, cytokinesis, and chromosome movement (Manning
et al., 2007).
CLONING
Using Western blot analysis, Manning et al. (2007) found that KIF2B had
an apparent molecular mass of about 80 kD. KIF2B was highly expressed in
lung, with weaker expression in ovary, heart, kidney, skeletal muscle,
and placenta. Proteins with lower molecular mass were detected in
placenta, skeletal muscle, and spleen. No expression was detected in
brain, liver, or testis. Fluorescence-tagged KIF2B localized to spindle
midzone and midbody in late anaphase and telophase and colocalized with
HEC1 (NDC80; 607272) at kinetochores in prometaphase.
GENE FUNCTION
Using RNA interference in human U2OS and RPE cells, Manning et al.
(2007) found that each of the kinesin-13 family members has a distinct
role during mitosis. MCAK (KIF2C) deficiency resulted in exaggerated
astral microtubule length. KIF2A and KIF2B deficiency resulted in
similar defects, with delayed progression through mitosis, appearance of
monopolar or disorganized spindles, and increased number of binucleated
or dead cells. However, knockdown of KIF2B, but not KIF2A, reduced the
poleward kinetochore force acting on chromosomes. Knockdown of KIF2B did
not disrupt the pole localization of KIF2A or the centromere and spindle
localization of MCAK.
MAPPING
Manning et al. (2007) stated that the KIF2B gene maps to chromosome
17q22.
NOG
| dbSNP name | rs139325910(G,A) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 9241 |
| EntrezGene Description | noggin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002296 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602991 NOGGIN, MOUSE, HOMOLOG OF; NOG
OMIM Description
CLONING
Using Xenopus noggin cDNA, Valenzuela et al. (1995) cloned full-length
human genomic and cDNA NOG clones from a placenta genomic and a temporal
cortex cDNA library. They also cloned a partial rat NOG cDNA from a
brain cDNA library. Human NOG encodes a deduced 232-amino acid protein
that shares 81% sequence identity with the Xenopus protein. In protein
activity assays, human NOG appeared to share the inductive actions of
Xenopus noggin during early embryogenesis. Northern blot analysis of
adult rat tissues revealed predominant expression in most parts of the
central nervous system, with especially high expression in mitral and
tufted cells in the olfactory bulb, and in Purkinje cells in the
cerebellum. Low or undetectable levels were found in peripheral nerve
and nonneural tissues; in the latter tissues, detectable levels were
found in lung, skeletal muscle, and skin.
GENE STRUCTURE
Rudnik-Schoneborn et al. (2010) noted that the NOG gene contains a
single exon.
MAPPING
Using fluorescence in situ hybridization, Valenzuela et al. (1995)
showed that the NOG gene maps to chromosome 17q22. Both proximal
symphalangism (SYM1A; 185800) and the multiple synostoses syndrome
(SYNS1; 186500) were known to map to the same region. Gong et al. (1999)
performed radiation hybrid mapping, placing NOG between genetic markers
D17S790 and D17S794. Thus, NOG was a prime candidate gene for SYM1 and
SYNS1 and prompted a mutation search.
BIOCHEMICAL FEATURES
- Crystal Structure
Groppe et al. (2002) reported the crystal structure of the antagonist
noggin bound to BMP7 (112267), which showed that noggin inhibits BMP
signaling by blocking the molecular interfaces of the binding epitopes
for both type I and type II receptors. The BMP binding affinity of
site-specific variants of noggin was correlated with alterations in bone
formation and apoptosis in chick limb development, showing that noggin
functions by sequestering its ligand in an inactive complex. The
scaffold of noggin contains a cystine (the oxidized form of cysteine)
knot topology similar to that of BMPs. Thus, Groppe et al. (2002)
concluded that ligand and antagonist seem to have evolved from a common
ancestral gene.
GENE FUNCTION
The bones of the developing limb bud are formed by condensations of
chondrocytes followed by endochondral ossification. Postembryonic growth
continues at the growth plates, at the ends of the bones. A series of
inductive events determines the size and shape of individual limb
skeletal elements. Many growth factors of the bone morphogenetic protein
(BMP) family have been implicated in limb growth and patterning. The
joints are formed after the initial cartilage condensation and are first
recognized histologically by an increase in cell density. Cell death and
cavitation follows. Growth/differentiation factor-5 (GDF5; 601146), a
divergent member of the BMP family, is implicated in joint specification
through its expression in prospective joints and its disruption in the
'brachypodism' mouse mutation. GDF5, also known as cartilage-derived
morphogenetic protein-1, is mutant in several chondrodysplasias, such as
the Grebe type of chondrodysplasia (200700) and the Hunter-Thompson type
of acromesomelic dysplasia (201250), as well as in type C brachydactyly
(113100). Brunet et al. (1998) showed that expression of the mouse
noggin gene is essential for proper skeletal development. BMP activities
are modulated not only through gene expression and protein processing,
but also by interaction with antagonists such as noggin and chordin
(603475). Excess BMP activity in noggin-null mice results in excess
cartilage and failure to initiate joint formation. Murine noggin is
expressed in condensing cartilage and immature chondrocytes, as are many
BMPs. The excess BMP activity in the absence of noggin antagonism may
enhance the recruitment of cells into cartilage, resulting in oversized
growth plates. Chondrocytes are also refractory to joint-inducing
positional cues. The noggin gene was first discovered as an important
factor in brain and nerve development. Knockout mice have stubby,
continuous limbs with lack of joints in the paws, along with a fatal
array of other developmental defects. The gene earned its name when, in
connection with studies of its role in the brain and nervous system, it
was found that frog embryos injected with its mRNA grew exceptionally
large heads. In the developing frog, the noggin protein also mimics the
activity of the Spemann organizer, which can make dorsal tissue out of
ventral tissue.
In a series of expression studies in mouse, Tucker et al. (1998)
demonstrated that BMP4 activates the expression of Msx1 (142983),
leading to incisor tooth development. BMP4 inhibited expression of Barx1
(603260), which marks presumptive molar teeth, and limits expression to
the proximal, presumptive molar mesenchyme at embryonic day 10.
Fibroblast growth factor-8 (FGF8; 600483) stimulated Barx1 expression.
When BMP4 signaling in early development was inhibited by application of
exogenous noggin protein, ectopic Barx1 expression resulted in
transformation of tooth identity from incisor to molar.
Gazzerro et al. (1998) examined the expression of noggin and chordin in
cultures of osteoblast-enriched cells from 22-day-old fetal rat
calvaria. BMP2 (112261) caused a time- and dose-dependent increase in
noggin mRNA and polypeptide levels. The effects of BMP2 on noggin
transcripts were dependent on protein synthesis, but independent of DNA
synthesis. BMP2 increased the rates of noggin transcription. BMP4, BMP6
(112266), and TGF-beta-1 (190180) increased noggin mRNA in rat calvaria
cells, but basic fibroblast growth factor-2 (FGF2; 134920),
platelet-derived growth factor-beta (PDGFB; 190040), and insulin-like
growth factor-1 (IGF1; 147440) did not. Noggin decreased the stimulatory
effects of BMPs on DNA and collagen synthesis as well as alkaline
phosphatase activity in rat calvaria cells. The authors concluded that
BMPs induced noggin transcription in osteoblast cells, a probable
mechanism to limit BMP action in osteoblasts.
The morphogenesis of organs as diverse as lungs, teeth, and hair
follicles is initiated by a downgrowth from a layer of epithelial stem
cells. During follicular morphogenesis, stem cells form this bud
structure by changing their polarity and cell-cell contact. Jamora et
al. (2003) showed that this process is achieved through simultaneous
receipt of 2 external signals: a WNT protein (WNT3A; 606359) to
stabilize beta-catenin (116806), and a bone morphogenetic protein
inhibitor (noggin) to produce Lef1 (153245). Beta-catenin binds to and
activates Lef1 transcription complexes that appear to act
uncharacteristically by downregulating the gene encoding E-cadherin
(192090), an important component of polarity and intercellular adhesion.
When either signal is missing, functional Lef1 complexes are not made,
and E-cadherin downregulation and follicle morphogenesis are impaired.
In Drosophila, E-cadherin can influence the plane of cell division and
cytoskeletal dynamics. Consistent with this notion, Jamora et al. (2003)
showed that forced elevation of E-cadherin levels block invagination and
follicle production. Jamora et al. (2003) concluded that their findings
reveal an intricate molecular program that links 2 extracellular
signaling pathways to the formation of a nuclear transcription factor
that acts on target genes to remodel cellular junctions and permit
follicle formation.
Warren et al. (2003) demonstrated that noggin is expressed postnatally
in the suture mesenchyme of patent, but not of fusing, cranial sutures,
and that noggin expression is suppressed by FGF2 (134920) and syndromic
FGFR signaling. Warren et al. (2003) studied the effects of Apert
(S252W; 176943.0010) and Crouzon (see C342Y; 176943.0001) syndrome Fgfr2
gain-of-function mutations on noggin production in dural cell and
osteoblast cultures. Both Apert and Crouzon syndrome Fgfr2 mutants
markedly downregulated noggin protein production in sagittal dura mater.
The Apert and Crouzon Fgfr2 constructs also downregulated Bmp4
(112262)-induced noggin expression in calvarial osteoblasts. Because
both Apert and Crouzon syndrome Fgfr gain-of-function mutations promote
pathologic suture fusion, Warren et al. (2003) concluded that their
findings provide an important link between the murine models and the
gain-of-function Fgfr mutations associated with syndromic Fgfr-mediated
craniosynostoses. Warren et al. (2003) also showed that forced
expression of noggin maintained posterior frontal suture patency in
mice. They suggested that since ectopic noggin expression prevented the
fusion of mouse posterior frontal sutures, it is possible that
therapeutic noggin could be exploited to control postnatal skeletal
development.
Winkler et al. (2004) found that human sclerostin (SOST; 605740)
interacted directly with noggin in vitro. The sclerostin-noggin
interaction neutralized the ability of either protein to bind and
inhibit BMP6, permitting BMP6 mitogenic activity in a mouse osteosarcoma
cell line. Immunoprecipitation of sclerostin from a rat osteosarcoma
cell line indicated that endogenous rat sclerostin forms a complex with
Bmp2, Bmp5 (112265), and noggin.
MOLECULAR GENETICS
- Proximal Symphalangism and Multiple Synostoses Syndrome
1
Gong et al. (1999) identified 5 dominant human NOG mutations in
unrelated families with SYM1 (185800) and a de novo mutation in a
patient with unaffected parents. They also found a dominant NOG mutation
in a family segregating SYNS1; both SYM1 and SYNS1 have multiple joint
fusion as their principal feature. All 7 NOG mutations altered
evolutionarily conserved amino acid residues. The findings confirmed
that NOG is essential for joint formation and suggested that NOG
requirements during skeletogenesis differ between species and between
specific skeletal elements within species. Differences between humans
and mice with respect to phenotypes caused by heterozygous mutations had
been observed previously with GDF5 (601146), which encodes a member of
the TGF-beta superfamily. This prompted Gong et al. (1999) to determine
whether similar differences result from heterozygous mutations in the
TGF-beta family member antagonist NOG.
Marcelino et al. (2001) investigated the effect on the structure and
function of noggin of the W217G mutation (602991.0003), which causes
SYNS, and the P223L mutation (602991.0004) and the G189C (602991.0005)
mutation, each of which causes SYM1. The SYNS1 mutation abolished, and
the SYM1 mutations reduced, the secretion of functional noggin dimers in
transiently transfected COS-7 cells. Coexpression of mutant noggin with
wildtype noggin, to resemble the heterozygous state, did not interfere
with wildtype noggin secretion. These data indicated that the human
disease-causing mutations are hypomorphic alleles that reduce secretion
of functional dimeric noggin. The authors concluded that noggin has both
species-specific and joint-specific dosage-dependent roles during joint
formation.
In a German father and son with multiple synostoses syndrome and
overgrowth, Rudnik-Schoneborn et al. (2010) identified heterozygosity
for a missense mutation (602991.0019) in the NOG gene. Rudnik-Schoneborn
et al. (2010) noted that experimental evidence showed that suppression
of noggin might accelerate osteogenesis (Wan et al., 2007), which could
explain the accelerated growth phenotype in this family.
- Tarsal-Carpal Coalition Syndrome
Dixon et al. (2001) identified 3 different missense mutations in NOG
that resulted in tarsal-carpal coalition syndrome (186570). Two of these
mutations are identical to mutations previously reported to cause
proximal symphalangism.
- Stapes Ankylosis with Broad Thumbs and Toes
Brown et al. (2002) identified truncating mutation in the NOG gene in 2
families with autosomal dominant stapes ankylosis with broad thumbs and
toes, hyperopia, and skeletal anomalies (184460) but without
symphalangism. The first family, of Italian descent, had conductive
hearing loss that was inherited as an autosomal dominant with complete
penetrance. Each affected individual was thought to have had
nonsyndromic otosclerosis but was found on further study to have a
congenital stapes ankylosis syndrome that included hyperopia, a
hemicylindrical nose, broad thumbs and big toes, and other minor
skeletal anomalies. The second family was that reported by Milunsky et
al. (1999).
In a 22-year-old woman of Jewish Ashkenazi origin diagnosed with
Teunissen-Cremers syndrome, Hirshoren et al. (2008) identified a
missense mutation in the NOG gene (602991.0012) previously found in
patients with proximal symphalangism (185800) and type B2 brachydactyly
(611377). Pedigree analysis revealed 7 family members with hearing loss
and skeletal anomalies segregating in an autosomal dominant fashion.
- Brachydactyly Type B2
In most patients with brachydactyly type B (BDB; see 113000), the
characteristic terminal deficiency of fingers and toes is caused by
heterozygous truncating mutations in ROR2 (602337). In a subset of
ROR2-negative patients with BDB clinically defined by the additional
occurrence of proximal symphalangism and carpal synostosis (BDB2;
611377), Lehmann et al. (2007) identified 6 different missense mutations
(e.g., P35A, 602991.0017) in the BMP antagonist NOG. In contrast to
previously described loss-of-function mutations in NOG, which cause a
range of conditions associated with abnormal joint formation but without
BDB, the newly identified BDB mutations did not indicate a major loss of
function, as suggested by calculation of free-binding energy of the
modeled NOG-GDF5 (601146) complex and functional analysis of the
micromass culture system. Rather, they presumably alter the ability of
NOG to bind to BMPs and GDFs in a subtle way, thus disturbing the
intricate balance for BMP signaling. The combined features observed in
this phenotypic subtype of BDB argued for a functional connection
between BMP and ROR2 signaling and supported previous findings of a
modulating effect of ROR2 on the BMP receptor pathway through the
formation of a heteromeric complex of the receptors at the cell surface.
ANIMAL MODEL
The secreted polypeptide noggin (encoded by the Nog gene) binds and
inactivates members of the transforming growth factor-beta superfamily
signaling proteins, such as bone morphogenetic protein-4 (BMP4; 112262).
By diffusing through extracellular matrices more efficiently than
members of the TGF-beta superfamily, noggin may have a principal role in
creating morphogenic gradients. During mouse embryogenesis, Nog is
expressed at multiple sites, including developing bones. Nog -/- mice
die at birth from multiple defects that include bony fusion of the
appendicular skeleton (McMahon et al., 1998; Brunet et al., 1998).
Bachiller et al. (2000) demonstrated that at midgastrula, expression of
noggin overlaps that of chordin. Noggin mutants underwent normal
gastrulation and anterior central nervous system patterning, although at
later stages a number of abnormalities were observed in posterior spinal
cord and somites. Bachiller et al. (2000) set up intercrosses between
mice compound heterozygous for noggin and chordin mutations, but no
double-homozygous mutants were recovered among the neonates. Two
chordin/noggin double-null embryos were found among animals dissected
close to term. Both were undergoing resorption, but clearly had
holoprosencephaly, with a single nasal pit, a cyclopic eye, and
agnathia. These malformations, not observed in either mutant on its own,
represented the weakest phenotypes found in double-mutant mice and
resembled embryos lacking Sonic hedgehog (SHH; 600725). At embryonic day
12.5, double-mutant embryos were recovered with more severe phenotypes
resembling aprosencephaly. In double-mutant embryos dissected at
embryonic day 8.5, forebrain reduction was clearly evident. Bachiller et
al. (2000) concluded that chordin and noggin are not necessary for
establishing the anterior visceral endoderm but are required for
subsequent elaboration of anterior pattern. Mesodermal development was
also affected, indicated by the lack of shh. Bachiller et al. (2000)
suggested that the BMP antagonists chordin and noggin compensate for
each other during early mouse development. When both gene products are
removed, antero-posterior, dorso-ventral, and left-right patterning are
all affected.
Using adult Nog +/- mice with a LacZ transgene inserted at the site of
the Nog deletion, Wu et al. (2003) demonstrated Nog expression in
osteoblast and chondrocyte cell lines as well as bone marrow
macrophages. They found that despite identical BMP levels, osteoblasts
of 20-month-old C57BL/6J and 4-month-old senescence-accelerated (SAM-P6)
mice had noggin expression levels that were approximately 4-fold higher
than those of 4-month-old C57BL/6J and SAM-R1 (control) mice,
respectively. Transgenic mice overexpressing noggin in mature
osteocalcin-positive osteoblasts showed dramatic decreases in bone
mineral density and bone formation rates. These results suggested that
NOG, expressed in mature osteoblasts, inhibits osteoblast
differentiation and bone formation. Wu et al. (2003) concluded that
overproduction of NOG during biologic aging may result in impaired
osteoblast formation and function and thus net bone loss.
Hwang and Wu (2008) found that the conductive hearing loss in Nog +/-
mice is caused by an ectopic bone bridge located between the stapes and
the posterior wall of the tympanum, which affects the normal mobility of
the ossicle and likely interferes with sound conduction. Their studies
suggested that ectopic bone formation is caused by a failure of the
stapes and styloid process to separate completely during development.
This failure of bone separation in Nog +/- mice revealed another
consequence of chondrocyte hyperplasia due to unopposed BMP activities.
Hwang and Wu (2008) suggested that this was the first animal model for
conductive, rather than neurosensory, hearing loss.
HISTORY
Although there have been reports indicating that mutations in the NOG
gene cause fibrodysplasia ossificans progressiva (FOP; 135100), numerous
studies have refuted this association.
Lucotte et al. (1999) reported that a patient with FOP had a 42-bp
heterozygous deletion in the NOG gene. To determine if NOG mutations are
a general finding in FOP, Xu et al. (2000) examined 31 families with one
or more FOP patients, including the patient reported by Lucotte et al.
(1999). No mutations were found. Xu et al. (2000) noted that the
protein-coding region of this single-exon gene is extremely GC-rich
(67%), which suggests that the gene may be highly methylated and/or
susceptible to secondary structure formation, conditions that interfere
with the fidelity of PCR amplification and could plausibly explain the
previously reported and subsequently unverifiable NOG deletion in the
patient with FOP.
In 4 Spanish patients with FOP, Semonin et al. (2001) reported
heterozygosity for 3 different mutations in the NOG gene. Xu et al.
(2002) stated that these reported mutations in the NOG gene are PCR
errors as described in their previous study (Xu et al., 2000). Warman
(2002) suggested that the divergent results might arise from
methodologic issues including possible phenotype error and/or the use of
a nested PCR approach which increases the likelihood of PCR-induced
artifacts; he proposed that photographs and radiographs of the patients
with FOP and NOG mutations be published and that DNA samples from
patients with putative disease-causing FOP mutations be shared with
other laboratories for independent confirmation using a different
methodology. Xu et al. (2002, 2000) had previously reported a patient
with FOP in whom mutation in the NOG gene had been reported but not
verified. Shore et al. (2006) subsequently studied this patient and
identified heterozygosity for an R206H mutation (102576.0001) in the
ACVR1 gene.
Using the disputed DNA sequencing techniques as previously described by
Semonin et al. (2001) involving a nested approach prone to PCR-induced
artifacts (Xu et al., 2000; Warman, 2002), Lucotte et al. (2007)
analyzed the NOG gene in 45 unrelated patients diagnosed with FOP and
reported identification of 6 additional patients with a mutation in NOG.
They also identified heterozygosity for the R206H mutation in the ACRV1
gene in 23 patients, 1 of whom had previously been reported to have a
42-bp deletion in the NOG gene (Lucotte et al., 1999) and another who
had been reported to carry a 'rare polymorphism' in NOG (Fontaine et
al., 2005).
MTVR2
| dbSNP name | rs2525990(A,G); rs17729228(T,C); rs58456651(A,G) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 246754 |
| snpEff Gene Name | TRIM25 |
| EntrezGene Description | mouse mammary tumor virus receptor homolog 2 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4688 |
RNF126P1
| dbSNP name | rs7214370(G,A); rs3213728(C,T) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 376412 |
| EntrezGene Description | ring finger protein 126 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2144 |
CCDC182
| dbSNP name | rs12451748(T,C); rs12451753(T,A); rs145543944(T,G); rs12449409(G,A) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 101927581 |
| EntrezGene Symbol | LOC101927581 |
| snpEff Gene Name | AC007431.1 |
| EntrezGene Description | coiled-coil domain-containing protein ENSP00000299415 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4311 |
| ExAC AF | 0.43 |
LOC101927666
| dbSNP name | rs7224660(A,C); rs7225351(G,A); rs72839937(T,C); rs8065435(G,A); rs8069790(A,C); rs112729956(C,T); rs35308567(A,T); rs9912779(C,T) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 101927666 |
| snpEff Gene Name | AC015813.1 |
| EntrezGene Description | uncharacterized LOC101927666 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1185 |
OR4D1
| dbSNP name | rs12602205(G,A); rs7218964(C,A) |
| ccdsGene name | CCDS42365.1 |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 26689 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D1:NM_012374:exon1:c.G161A:p.R54Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q15615 |
| dbNSFP Uniprot ID | OR4D1_HUMAN |
| dbNSFP KGp1 AF | 0.0544871794872 |
| dbNSFP KGp1 Afr AF | 0.0487804878049 |
| dbNSFP KGp1 Amr AF | 0.0635359116022 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0936675461741 |
| dbSNP GMAF | 0.05418 |
| ExAC AF | 0.083 |
MSX2P1
| dbSNP name | rs8081708(G,A); rs72839961(T,A); rs3863503(C,A); rs1987665(G,A); rs3760172(T,A); rs73993611(C,A); rs60194146(G,A) |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 55545 |
| snpEff Gene Name | OR4D1 |
| EntrezGene Description | msh homeobox 2 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3264 |
OR4D2
| dbSNP name | rs60994383(C,A); rs74730740(C,T) |
| ccdsGene name | CCDS32688.1 |
| cytoBand name | 17q22 |
| EntrezGene GeneID | 124538 |
| EntrezGene Description | olfactory receptor, family 4, subfamily D, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR4D2:NM_001004707:exon1:c.C85A:p.L29I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P58180 |
| dbNSFP Uniprot ID | OR4D2_HUMAN |
| dbNSFP KGp1 AF | 0.228021978022 |
| dbNSFP KGp1 Afr AF | 0.361788617886 |
| dbNSFP KGp1 Amr AF | 0.182320441989 |
| dbNSFP KGp1 Asn AF | 0.157342657343 |
| dbNSFP KGp1 Eur AF | 0.21635883905 |
| dbSNP GMAF | 0.2282 |
| ESP Afr MAF | 0.355651 |
| ESP All MAF | 0.271413 |
| ESP Eur/Amr MAF | 0.228256 |
| ExAC AF | 0.227 |
LOC653653
| dbSNP name | rs8075789(T,C) |
| cytoBand name | 17q23.1 |
| EntrezGene GeneID | 653653 |
| EntrezGene Description | adaptor-related protein complex 1, sigma 2 subunit pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3632 |
| ExAC AF | 0.696 |
SCARNA20
| dbSNP name | rs79851920(C,T); rs7218312(G,A) |
| ccdsGene name | CCDS32697.1 |
| cytoBand name | 17q23.2 |
| EntrezGene GeneID | 677681 |
| snpEff Gene Name | USP32 |
| EntrezGene Description | small Cajal body-specific RNA 20 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01331 |
| ESP Afr MAF | 0.047945 |
| ESP All MAF | 0.014998 |
| ESP Eur/Amr MAF | 0.000502 |
| ExAC AF | 0.003866 |
NACA2
| dbSNP name | rs146671736(G,T); rs17610181(G,A); rs61739273(G,C); rs17531723(C,T) |
| cytoBand name | 17q23.2 |
| EntrezGene GeneID | 342538 |
| EntrezGene Description | nascent polypeptide-associated complex alpha subunit 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.001135 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 8.945e-05 |
EFCAB3
| dbSNP name | rs9900307(T,G); rs7217093(G,C); rs1972605(T,C); rs1972606(T,C); rs7222472(G,A); rs17545743(A,T); rs7222736(A,G); rs72845544(G,A); rs745132(C,A); rs888500(C,A); rs114792407(C,T); rs8071676(G,A); rs9906840(T,C); rs8075814(A,G); rs115634202(G,A); rs9912556(C,T); rs7220269(A,G); rs7220586(A,G); rs8082307(G,A); rs8073135(C,T); rs55937716(T,C); rs72845557(A,C); rs1858422(C,T); rs76572903(G,A); rs116176108(C,T); rs9898709(G,A); rs140977584(A,G); rs144834872(A,G); rs2009866(A,T); rs62074003(A,G); rs28507122(T,C); rs9908956(C,T); rs9909704(C,T); rs1421302(A,G); rs9896974(G,C); rs9900571(T,C); rs8068386(A,G); rs78364651(T,A); rs74566238(T,C); rs11871848(C,T); rs12950962(C,T); rs11872006(G,C); rs74593140(G,A); rs10853040(T,G); rs11079476(C,T); rs1362893(T,C); rs4986766(A,T); rs149427384(G,A); rs187979945(A,G); rs7215493(C,T); rs73329498(A,G); rs4968522(A,T); rs78013533(A,G); rs8071930(G,A); rs202173986(T,A); rs62074033(T,C); rs370949269(G,T); rs8068208(C,T); rs115042128(C,A); rs150418359(A,T); rs8074566(T,C); rs12450901(G,A); rs8074112(A,G); rs4968423(T,C); rs180826686(T,G); rs146603917(A,G); rs57926064(T,A); rs1975642(G,A); rs7209559(C,G); rs3863510(G,A); rs183440662(A,T); rs113424928(G,A); rs78388447(A,G) |
| ccdsGene name | CCDS11632.1 |
| cytoBand name | 17q23.2 |
| EntrezGene GeneID | 146779 |
| EntrezGene Description | EF-hand calcium binding domain 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EFCAB3:NM_173503:exon8:c.C814A:p.P272T,EFCAB3:NM_001144933:exon10:c.C970A:p.P324T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5913 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N7B9 |
| dbNSFP Uniprot ID | EFCB3_HUMAN |
| ExAC AF | 2.521e-04,8.132e-06,2.033e-04 |
KCNH6
| dbSNP name | rs867640(T,C); rs4257270(G,A); rs7212529(A,T); rs12951967(T,A); rs113580918(T,C); rs12941370(A,G); rs150376284(G,A); rs9914151(A,C); rs75323060(G,A); rs117657537(G,A); rs8071201(C,A); rs7221517(T,C); rs11655589(A,G); rs140160386(G,A); rs9898552(T,C); rs113639915(C,T); rs12937836(A,G); rs113727640(A,G); rs145293059(C,T); rs11654105(T,A); rs11654107(T,C); rs11658641(G,T); rs35995591(C,A); rs7225568(T,C); rs112220747(G,A); rs4968592(C,T); rs4968593(A,G); rs7221979(G,A); rs4465659(T,G); rs4968656(A,G); rs113366938(G,A); rs112324547(G,A); rs115644220(C,T); rs113981651(A,G); rs12949197(C,T); rs79634433(G,C); rs76957877(C,T); rs8070334(T,G); rs115343420(G,A); rs148464755(C,A); rs12603614(A,G); rs35819807(C,T); rs9890263(C,T); rs28621034(G,A) |
| ccdsGene name | CCDS11638.1 |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 81033 |
| EntrezGene Description | potassium voltage-gated channel, subfamily H (eag-related), member 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KCNH6:NM_001278920:exon12:c.C2052A:p.D684E,KCNH6:NM_030779:exon13:c.C2529A:p.D843E,KCNH6:NM_173092:exon13:c.C2262A:p.D754E,KCNH6:NM_001278919:exon12:c.C2421A:p.D807E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7326 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DPJ3 |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.009079 |
| ESP All MAF | 0.003076 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0009352 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive;
Isolated cases
HEAD AND NECK:
[Head];
Microcephaly, acquired;
[Face];
Mask-like facies;
Expressionless facial appearance;
Bitemporal narrowing;
Frontal bossing, mild;
Prominent glabella;
Maxillary hypoplasia;
Retrognathia;
Long, smooth philtrum;
[Ears];
Abnormal ear configuration;
Triangular-shaped ears;
Prominent antihelices;
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Short palpebral fissures;
Blepharophimosis;
Hypertelorism;
Sparse eyelashes;
Sparse eyebrows;
[Nose];
Flat, broad nasal bridge;
Short nose;
Large, anteverted nasal tip;
[Mouth];
Small mouth;
Long, everted upper lip;
Thin upper lip;
High-arched palate;
[Teeth];
Abnormal dentition;
Curved incisors;
[Neck];
Short neck;
Broad neck
CHEST:
[External features];
Laterally displaced nipples;
Hypoplastic nipples
GENITOURINARY:
[External genitalia, male];
Small penis;
[Internal genitalia, male];
Cryptorchidism;
[External genitalia, female];
Hypoplastic labia
SKELETAL:
Joint contractures;
[Skull];
Asymmetric skull;
Craniosynostosis;
[Hands];
Camptodactyly;
Clinodactyly;
Tapering fingers
SKIN, NAILS, HAIR:
[Skin];
Tight, glistening facial skin;
[Hair];
Upswept frontal hair pattern;
Low anterior hairline;
Sparse hair;
Unruly hair;
Sparse eyebrows;
High-arched eyebrows;
Misaligned eyebrows;
Sparse eyelashes
NEUROLOGIC:
[Central nervous system];
Developmental delay;
[Behavioral/psychiatric manifestations];
Happy demeanor
OMIM Title
*608168 POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 6; KCNH6
;;ETHER-A-GO-GO-RELATED GENE 2; ERG2; HERG2;;
EAG-RELATED GENE 2;;
KV11.2
OMIM Description
DESCRIPTION
KCNH6 belongs to the ERG subfamily of voltage-gated potassium channels.
ERG channels are characterized by their anomalous gating behavior, with
inactivation kinetics being faster than activation kinetics and with
recovery from inactivation being faster than deactivation.
CLONING
Bauer et al. (2003) stated that the human KCNH6 gene, which they called
HERG2, had been cloned (GenBank GENBANK AF311913). Using RT-PCR, they
detected expression of HERG2 in prolactin-secreting adenomas.
By RT-PCR and in situ hybridization, Papa et al. (2003) found that rat
Erg1 (KCNH2; 152427), Erg2, and Erg3 (KCNH7; 608169) were expressed
throughout the brain, including the olfactory bulb, cerebral cortex,
hippocampus, hypothalamus, and cerebellum.
GENE FUNCTION
Bauer et al. (2003) analyzed the kinetics of rat Erg2 expressed in
Chinese hamster ovary cells. The time constant for deactivation was
voltage dependent and decreased with more negative potentials. The
deactivation kinetics of Erg2 and Erg1 were similar, but were
significantly slower than those of Erg3.
LIMD2
| dbSNP name | rs75786329(C,T) |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 80774 |
| snpEff Gene Name | MAP3K3 |
| EntrezGene Description | LIM domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007805 |
LOC729683
| dbSNP name | rs1376110(A,C) |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 729683 |
| snpEff Gene Name | STRADA |
| EntrezGene Description | uncharacterized LOC729683 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3131 |
GH2
| dbSNP name | rs139959045(G,A); rs143223560(A,G); rs2006123(G,T) |
| ccdsGene name | CCDS11648.1 |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 2689 |
| EntrezGene Description | growth hormone 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GH2:NM_022557:exon4:c.C598T:p.P200S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7404 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B1A4H7 |
| ESP Afr MAF | 0.000454 |
| ESP All MAF | 0.000461 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.0006181 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Obesity (in some);
[Height];
Short stature;
[Other];
Prenatal growth deficiency
HEAD AND NECK:
[Head];
Microcephaly;
Incomplete jaw opening;
[Face];
Maxillary hypoplasia;
Midface hypoplasia;
Prognathism;
Short philtrum;
[Ears];
Small ears;
Anomalous middle ear bones;
Low-set ears;
Deafness, early-onset mixed conductive and sensorineural;
[Eyes];
Blepharophimosis;
Narrow palpebral fissures;
Hypertelorism;
Microphthalmia (rare);
Hyperopia;
Strabismus;
Deep-set eyes;
Bushy eyebrows;
[Nose];
Prominent nasal root;
Broad mid-nose;
Narrow alar root;
[Mouth];
Small mouth;
Thin upper lip;
Cleft lip/palate (less common);
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Congenital heart defect;
Septal defects;
Aortic stenosis;
Patent ductus arteriosus;
Aortic coarctation;
Pericardial effusion;
Pericardial fibrosis, requiring pericardiectomy;
[Vascular];
Hypertension
RESPIRATORY:
[Larynx];
Laryngotracheal stenosis, recurrent;
[Lung];
Respiratory failure (in some patients)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Broad ribs
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
menstrual abnormality
SKELETAL:
Decreased joint mobility;
[Skull];
Thickened calvarium;
[Spine];
Large, flattened vertebrae with large pedicles;
Platyspondyly;
Vertebral fusions;
[Pelvis];
Hypoplastic iliac wings;
[Limbs];
Short long bones;
Cone-shaped epiphyses;
[Hands];
Brachydactyly;
Clinodactyly;
Camptodactyly;
Dupuytren contractures (1 patient);
[Feet];
Brachydactyly;
Toe syndactyly, 2-3;
Overlapping toes
SKIN, NAILS, HAIR:
[Skin];
Thickened skin;
Stiff skin;
[Hair];
Sparse, fine hair;
Bushy eyebrows
MUSCLE, SOFT TISSUE:
Generalized muscle hypertrophy
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures (rare);
Cerebellar ataxia (1 patient);
Cerebellar atrophy, progressive (1 patient);
[Behavioral/psychiatric manifestations];
Autism or autistic-like condition
VOICE:
Abnormal voice
MISCELLANEOUS:
All reported cases have occurred sporadically;
Clinical features may vary;
Associated with advanced paternal age
MOLECULAR BASIS:
Caused by mutation in the Drosophila homolog of the mothers against
decapentaplegic, 4 gene (SMAD4, 600993.0015)
OMIM Title
*139250 GROWTH HORMONE 1; GH1
;;GH;;
GROWTH HORMONE, NORMAL; GHN;;
GROWTH HORMONE, PITUITARY
OMIM Description
DESCRIPTION
Growth hormone (GH) is synthesized by acidophilic or somatotropic cells
of the anterior pituitary gland. Human growth hormone has a molecular
mass of 22,005 and contains 191 amino acid residues with 2 disulfide
bridges (Niall et al., 1971).
CLONING
By 1977, not only had the amino acid sequence of GH been determined, but
the sequence of nucleotides in the structural gene for GH had been
determined as well (Baxter et al., 1977).
By molecular cloning of cDNA, Masuda et al. (1988) demonstrated that the
20-kD variant of human GH is produced by the same gene (GHN or GH1) as
the 22-kD form, and that a process of alternative splicing is involved.
Chen et al. (1989) sequenced the entire 66,500 bp of the GH gene
cluster. The expression of the 5 genes in this cluster was examined by
screening pituitary and placenta cDNA libraries, using gene-specific
oligonucleotides. According to this analysis, the GHN gene is
transcribed exclusively in the pituitary, whereas the other 4 genes
(CSL, 603515; CSA, 150200; GHV, 139240; and CSB, 118820) are expressed
only in placental tissues. The CSL gene carries a G-to-A transition in a
sequence used by the other 4 genes as an intronic 5-prime splice donor
site. The mutation results in a different splicing pattern and, hence,
in a novel sequence of the CSL gene mRNA and the deduced polypeptide.
GH and CSH (CSA) have 191 amino acid residues and show about 85%
homology in amino acid sequence (Owerbach et al., 1980). Their messenger
RNAs have more than 90% homology.
GENE FUNCTION
Human GH binds 2 GHR (600946) molecules and induces signal transduction
through receptor dimerization. Sundstrom et al. (1996) noted that at
high concentrations, GH acts as an antagonist because of a large
difference in affinities at the respective binding sites. This
antagonist action can be enhanced further by reducing binding in the
low-affinity binding site. A possible mechanism by which mutant,
biologically inactive GH may have its effect is to act as an antagonist
to the binding of normal GH to its receptor, GHR.
The regulation of GH synthesis and release is modulated by a family of
genes that include the transcription factors PROP1 (601538) and PIT1
(173110). PROP1 and PIT1 regulate differentiation of pituitary cells
into somatotrophs, which synthesize and release GH. Genes that are
important in the release of GH include the GHRH (139190) and GHRHR
(139191) genes. After GHRH is synthesized and released from the
hypothalamus, it travels to the anterior pituitary where it binds to
GHRHR, resulting in transduction of a signal into the somatotroph which
promotes release of presynthesized GH that is stored in secretory
granules. Other gene products that are important in GH synthesis and
release are GHR and the growth hormone-binding proteins (GHBP). The
GHBPs are derived from the membrane bound receptor (GHR) and they remain
bound to GH in the circulation. Following binding of GH to 2 GHR
molecules, the signal to produce IGF1 (147440) is transduced. The GH
molecules that are bound to membrane-anchored GH receptors can be
released into the circulation by excision of the extracellular portion
of the GHR molecules. At this point, the extracellular portion of the
GHR, which is referred to as the GHBP, serves to stabilize GH in the
circulation. The final genes in the GH synthetic pathway include IGF1
and its receptor (IGF1R; 147370), whose products stimulate growth in
various tissues including bones and muscle (Phillips, 1995; Rimoin and
Phillips, 1997).
Boguszewski et al. (1997) investigated the proportion of circulating
non-22-kD GH1 isoforms in prepubertal children with short stature
(height less than -2 SD score) of different etiologies. The study groups
consisted of 17 girls with Turner syndrome (TS), aged 3 to 13 years; 25
children born small for gestational age (SGA) without postnatal catch-up
growth, aged 3 to 13 years; and 24 children with idiopathic short
stature (ISS), aged 4 to 15 years. The results were compared with those
from 23 prepubertal healthy children of normal stature (height +/- 2 SD
score), aged 4 to 13 years. Serum non-22-kD GH levels, expressed as a
percentage of the total GH concentration, were determined by the 22-kD
GH exclusion assay. The median proportion of non-22-kD GH isoforms was
8.1% in normal children; it was increased in children born SGA (9.8%; P
= 0.05) and in girls with TS (9.9%; P = 0.01), but not in children with
ISS (8.9%). In children born SGA, the proportion of non-22-kD GH
isoforms directly correlated with different estimates of spontaneous GH
secretion and inversely correlated with height SD score. The authors
concluded that the ratio of non-22-kD GH isoforms in the circulation may
have important implications for normal and abnormal growth.
Mendlewicz et al. (1999) studied the contributions of genetic and
environmental factors in the regulation of the 24-hour GH secretion. The
24-hour profile of plasma GH was obtained at 15-minute intervals in 10
pairs of monozygotic and 9 pairs of dizygotic normal male twins, aged 16
to 34 years. A major genetic effect was evidenced on GH secretion during
wakefulness (heritability estimate of 0.74) and, to a lesser extent, on
the 24-hour GH secretion. Significant genetic influences were also
identified for slow-wave sleep and height. These results suggested that
human GH secretion in young adulthood is markedly dependent on genetic
factors.
Hindmarsh et al. (1999) studied GH secretory patterns in the elderly by
constructing 24-hour serum GH profiles in 45 male and 38 female
volunteers, aged 59.4 to 73.0 years, and related patterns to IGF1,
IGFBP3 (146732), and GH-binding protein levels; body mass index; and
waist/hip ratio. There was a highly significant difference in mean
24-hour serum GH concentrations in females compared to males as a result
of significantly higher trough GH levels in females. Peak values were
not significantly different. Serum IGF1 levels were significantly higher
in males. Peak GH values were related to serum IGF1 levels, whereas
trough GH levels were not. GH was secreted with a dominant periodicity
of 200 minutes in males and 280 minutes in females. GH secretion
assessed by ApEn was more disordered in females, and increasing disorder
was associated with lower IGF1 levels. Body mass index was negatively
related to GH in both sexes. In males, trough values were the major
determinant, whereas in females, the peak value was the major
determinant. Trough GH levels were inversely related in both sexes to
waist/hip ratio and to increasing secretory disorder. These data
demonstrated a sexually dimorphic pattern of GH secretion in the
elderly.
De Groof et al. (2002) evaluated the GH/IGF1 axis and the levels of
IGF-binding proteins (IGFBPs), IGFBP3 protease, glucose, insulin
(176730), and cytokines in 27 children with severe septic shock due to
meningococcal sepsis during the first 3 days after admission. The median
age was 22 months. Significant differences were found between
nonsurvivors and survivors for the levels of total IGF1, free IGF1,
IGFBP1 (146730), IGFBP3 protease activity, IL6 (147620), and TNFA
(191160). The pediatric risk of mortality score correlated significantly
with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with
levels of total IGFI and free IGFI. Levels of GH and IGFBP1 were
extremely elevated in nonsurvivors, whereas total and free IGFI levels
were markedly decreased and were accompanied by high levels of the
cytokines IL6 and TNFA.
In rodents and humans there is a sexually dimorphic pattern of GH
secretion that influences the serum concentration of IGF1. Geary et al.
(2003) studied the plasma concentrations of IGF1, IGF2 (147470), IGFBP3,
and GH in cord blood taken from the offspring of 987 singleton Caucasian
pregnancies born at term and related these values to birth weight,
length, and head circumference. Cord plasma concentrations of IGF1,
IGF2, and IGFBP3 were influenced by factors related to birth size:
gestational age at delivery, mode of delivery, maternal height, and
parity of the mother. Plasma GH concentrations were inversely related to
the plasma concentrations of IGF1 and IGFBP3; 10.2% of the variability
in cord plasma IGF1 concentration and 2.7% for IGFBP3 was explained by
sex of the offspring and parity. Birth weight, length, and head
circumference measurements were greater in males than females (P less
than 0.001). Mean cord plasma concentrations of IGF1 and IGFBP3 were
significantly lower in males than females. Cord plasma GH concentrations
were higher in males than females, but no difference was noted between
the sexes for IGF2. After adjustment for gestational age, parity, and
maternal height, cord plasma concentrations of IGF1 and IGFBP3 along
with sex explained 38.0% of the variability in birth weight, 25.0% in
birth length, and 22.7% in head circumference.
Ho et al. (2002) noted that the human GH gene cluster encompasses GHN,
which is expressed primarily in pituitary somatotropes, and 4 genes,
CSA, CSB, CSL, and GHV, which are expressed specifically in
syncytiotrophoblast cells lining the placental villi. A multicomponent
locus control region (LCR) is required for transcriptional activation in
both pituitary and placenta. In addition, 2 genes overlap with the GH
LCR: SCN4A (603967) on the 5-prime end and CD79B (147245) on the 3-prime
end. Ho et al. (2002) studied mice carrying an 87-kb human transgene
encompassing the GH LCR and most of the GH gene cluster. By deleting a
fragment of the transgene, they showed that a single determinant of the
human GH LCR located 14.5 kb 5-prime to the GHN promoter has a critical,
specific, and nonredundant role in facilitating promoter trans factor
binding and activating GHN transcription. Ho et al. (2002) found that
this same determinant plays an essential role in establishing a 32-kb
acetylated domain that encompasses the entire GH LCR and the contiguous
GHN promoter. These data supported a model for long-range gene
activation via LCR-mediated targeting and extensive spreading of core
histone acetylation.
Using mice carrying the 87-kb human GH transgene, Ho et al. (2006) found
that insertion of a Pol II terminator within the GH LCR blocked
transcription of the CD79B gene adjacent to the LCR and repressed GHN
expression. However, the insertion had little effect on acetylation
within the GH locus. Selective elimination of CD79B also repressed GHN
expression. Ho et al. (2006) concluded that Pol II tracking and histone
acetylation are not linked and that transcription, but not translation,
of the CD79B gene is required for GHN expression.
In addition to expression in pituitary and placenta and functions in
growth and reproduction, prolactin (PRL; 176760), GH, and placental
lactogen (CSH1; 150200) are expressed in endothelial cells and have
angiogenic effects. Ge et al. (2007) found that BMP1 (112264) and
BMP1-like proteinases processed PRL and GH in vitro and in vivo to
produce approximately 17-kD N-terminal fragments with antiangiogenic
activity.
GENE STRUCTURE
The GH, PL (CSH1), and PRL genes contain 5 exons separated by 4 introns.
The introns occur at the same sites, supporting evolutionary homology
(Baxter, 1981). All 5 genes in the GH gene cluster are in the same
transcriptional orientation (Ho et al., 2002).
Baxter (1981) found evidence for the existence of at least 3 GH and 3
CSH, also called placental lactogen (PL), genes on chromosome 17.
Whether they are situated GH:GH:GH:PL:PL:PL or arranged
GH:PL:GH:PL:GH:PL was not clear.
BIOCHEMICAL FEATURES
- Crystal Structure
Sundstrom et al. (1996) crystallized a GH antagonist mutant, gly120 to
arg, with its receptor as a 1-to-1 complex and determined the crystal
structure at 2.9-angstrom resolution. The 1-to-1 complex with the
agonist is remarkably similar to the native GHR 1-to-2 complex. A
comparison between the 2 structures revealed only minimal differences in
the conformations of the hormone or its receptor in the 2 complexes.
EVOLUTION
Owerbach et al. (1980) estimated that the GH and CSH genes diverged
about 50 to 60 million years ago, whereas the PRL and GH genes diverged
about 400 million years ago.
Human PL and human GH are more alike than are rat GH and human GH. (PL
has more growth-promoting effects than milk-producing effects.) Baxter
(1981) proposed that in evolution the prolactin gene diverged early from
the gene that was the common progenitor of the GH and PL genes.
(Placental lactogen was the official Endocrine Society designation;
Grumbach (1981) promoted the term chorionic somatomammotropin, which has
functional legitimacy.)
MAPPING
By a combination of restriction mapping and somatic cell hybridization,
Owerbach et al. (1980) assigned genes for growth hormone, chorionic
somatomammotropin (CSH), and a third growth hormone-like gene (GH2;
139240) to the growth hormone gene cluster that is assigned to
chromosome 17.
Lebo (1980) corroborated the assignment of the GH gene to chromosome 17
by the technique of fluorescence-activated chromosome sorting. George et
al. (1981) assigned the genes for GH and CSH to the 17q21-qter region.
Ruddle (1982) found that the GH family of genes is between galactokinase
(604313) and thymidine kinase (TK1; 188300), with galactokinase being
closer to the centromere.
Harper et al. (1982) used in situ hybridization to assign the GH gene
cluster to 17q22-q24. A gene copy number experiment showed that both
genes are present in about 3 copies per haploid genome. The sequence of
genes in the GH gene cluster is thought to be GHN--CSL--CSA--GHV--CSB
(Phillips, 1983). Normal growth hormone (GHN, referred to now as GH1)
encodes GH. CSA and CSB both encode chorionic somatomammotropin. GHV, or
growth hormone variant, is now designated GH2.
Xu et al. (1988) assigned the growth hormone complex to 17q23-q24 by in
situ hybridization.
MOLECULAR GENETICS
Using GH cDNA as a specific DNA probe in Southern blot analyses,
Phillips et al. (1981) found that the GHN (GH1) gene was deleted in 2
families with type IA growth hormone deficiency (Illig type; 262400). On
the other hand, the GH genes of persons with type IB (612781) (in 6
families) had normal restriction patterns. Two affected sibs in 2 of the
6 families were discordant for 2 restriction markers closely linked to
the GH cluster.
Braga et al. (1986) reported the cases of a son and daughter of
first-cousin Italian parents who had isolated growth hormone deficiency
(IGHD) resulting from homozygosity for a 7.6-kb deletion within the GH
gene cluster. Both developed antibodies in response to treatment with
human GH, but in neither was there interference with growth. The
deletion affected not only the structural gene for GH (GH1) but also
sequences adjacent to CSL.
Goossens et al. (1986) described a double deletion in the GH gene
cluster in cases of inherited growth hormone deficiency. A total of
about 40 kb of DNA was absent due to 2 separate deletions flanking the
CSL gene (603515). Two affected sibs were homozygous. The parents were
'Romany of French origin' (i.e., French gypsies) and related as first
cousins once removed. Restriction patterns in them were consistent with
heterozygosity.
Vnencak-Jones et al. (1988) described the molecular basis of deletions
within the human GH gene cluster in 9 unrelated patients. Their results
suggested that the presence of highly repetitive DNA sequences flanking
the GH1 gene predisposed to unequal recombinant events through
chromosomal misalignment.
In a Chinese family, He et al. (1990) found that 2 sibs with GH
deficiency had a deletion of approximately 7.1 kb of DNA. The parents,
who were related as second cousins, were heterozygous but of normal
stature. The affected children had not received exogenous GH, but the
authors suspected that their disorder represented IGHD type IA.
Akinci et al. (1992) described a Turkish family in which 3 children had
IGHD type IA. A homozygous deletion of approximately 45 kb encompassing
the GH1, CSL, CSA, and GH2 genes was found. The end points of the
deletion lay within 2 regions of highly homologous DNA sequence situated
5-prime to the GH1 gene and 5-prime to the CSB gene. The parents, who
were consanguineous, were both heterozygous for the deletion.
Mullis et al. (1992) analyzed GH1 DNA from circulating lymphocytes of 78
subjects with severe IGHD. The subjects analyzed were broadly grouped
into 3 different populations: 32 north European, 22 Mediterranean, and
24 Turkish. Of the 78 patients, 10 showed a GH1 deletion; 8 had a 6.7-kb
deletion, and the remaining 2 had a 7.6-kb GH1 deletion. Five of the 10
subjects developed anti-hGH antibodies to hGH replacement followed by a
stunted growth response. Parental consanguinity was found in all
families, and heterozygosity for the corresponding deletion was present
in each parent. The proportion of deletion cases was about the same in
each of the 3 population groups.
Phillips and Cogan (1994) tabulated mutations found in the GH gene.
Takahashi et al. (1996) reported the case of a boy with short stature
and heterozygosity for a mutant GH gene (139250.0008). In this child,
the GH not only could not activate the GH receptor (GHR; 600946) but
also inhibited the action of wildtype GH because of its greater affinity
for GHR and GH-binding protein (GHBP), which is derived from the
extracellular domain of the GHR. Thus, a dominant-negative effect was
observed. See Kowarski syndrome, 262650.
Splicing of pre-mRNA transcripts is regulated by consensus sequences at
intron boundaries and the branch site. In vitro studies showed that the
small introns of some genes also require intron splice enhancers (ISE)
to modulate splice site selection. An autosomal dominant form of
isolated growth hormone deficiency (IGHD II; 173100) can be caused by
mutations in intron 3 (IVS3) of the GH1 gene that cause exon 3 skipping,
resulting in truncated GH1 gene products that prevent secretion of
normal GH. Some of these GH1 mutations are located 28 to 45 nucleotides
into IVS3 (which is 92 nucleotides long). McCarthy and Phillips (1998)
localized this ISE by quantitating the effects of deletions within IVS3
on skipping of exon 3. The importance of individual nucleotides to ISE
function was determined by analyzing the effects of point mutants and
additional deletions. The results showed that (1) an ISE with a
G(2)X(1-4)G(3) motif resides in IVS3 of the GH1 gene; (2) both runs of
Gs are required for ISE function; (3) a single copy of the ISE regulates
exon 3 skipping; and (4) ISE function can be modified by an adjacent AC
element. The findings revealed a new mechanism by which mutations can
cause inherited human endocrine disorders and suggested that (1) ISEs
may regulate splicing of transcripts of other genes, and (2) mutations
of these ISEs or of the transacting factors that bind them may cause
other genetic disorders.
Hasegawa et al. (2000) studied polymorphisms in the GH1 gene that were
associated with altered GH production. The subjects included 43
prepubertal short children with GHD without gross pituitary
abnormalities, 46 short children with normal GH secretion, and 294
normal adults. A polymorphism in intron 4 (A or T at nucleotide 1663,
designated P1) was identified. Two additional polymorphic sites (T or G
at nucleotide 218, designated P2, and G or T at nucleotide 439,
designated P3) in the promoter region of the GH1 gene were also
identified and matched with the P1 polymorphism (A or T, respectively)
in more than 90% of the subjects. P1, P2, and P3 were considered to be
associated with GH production. For example, the allele frequency of T at
P2 in prepubertal short children with GHD without gross pituitary
abnormalities (58%) was significantly different from that in short
children with normal GH secretion and normal adults (37% and 44%,
respectively). Furthermore, significant differences were observed in
maximal GH peaks in provocative tests, IGF1 (147440) SD scores, and
height SD scores in children with the T/T or G/G genotypes at P2. In the
entire study group, significant differences in IGF1 SD scores and height
SD scores were observed between the T/T and G/G genotypes at P2.
Hasegawa et al. (2000) concluded that GH secretion is partially
determined by polymorphisms in the GH1 gene, explaining some of the
variations in GH secretion and height.
Dennison et al. (2004) examined associations between common SNPs in the
GH1 gene and weight in infancy, adult bone mass and bone loss rates, and
circulating GH profiles. Genomic DNA was examined for 2 SNPs in the GH
gene, 1 in the promoter region and 1 in intron 4. Homozygotes at loci
GH1 A5157G and T6331A displayed low baseline bone density and
accelerated bone loss; there was also a significant (P = 0.04)
interaction among weight at 1 year, GH1 genotype, and bone loss rate.
There was a graded association between alleles and circulating GH
concentration among men. The authors concluded that common diversity in
the GH1 region predisposes to osteoporosis via effects on the level of
GH expression.
The proximal promoter region of the GH1 gene is highly polymorphic,
containing at least 15 SNPs. This variation is manifest in 40 different
haplotypes, the high diversity being explicable in terms of gene
conversion, recurrent mutation, and selection. Horan et al. (2003)
showed by functional analysis that 12 haplotypes were associated with a
significantly reduced level of reporter gene expression, whereas 10
haplotypes were associated with a significantly increased level. The
former tended to be more prevalent in the general population than the
latter (p less than 0.01), possibly as a consequence of selection.
Haplotype partitioning identified 6 SNPs as major determinants of GH1
gene expression, which is influenced by an LCR located between 14.5 and
32 kb upstream of the GH1 gene (Jones et al., 1995). Horan et al. (2003)
used a series of LCR-GH1 proximal promoter constructs to demonstrate
that the LCR enhanced proximal promoter activity by up to 2.8-fold
depending upon proximal promoter haplotype, and that the activity of a
given proximal promoter haplotype was also differentially enhanced by
different LCR haplotypes. The genetic basis of interindividual
differences in GH1 gene expression thus appeared to be extremely
complex.
Millar et al. (2003) sought to identify subtle mutations in the GH1
gene, which had been regarded as a comparatively rare cause of short
stature, in 3 groups: 41 individuals selected for short stature, reduced
height velocity, and bone age delay, 11 individuals with short stature
and IGHD, and 154 controls. Heterozygous mutations were identified in
all 3 groups but disproportionately in the individuals with short
stature, both with and without IGHD. Twenty-four novel GH1 gene lesions
were found. Fifteen novel GH1 gene mutations were considered to be of
probable phenotypic significance. Although most such lesions may be
insufficient on their own to account for the observed clinical
phenotype, they were considered likely to play a contributory role in
the etiology of short stature.
In a screen of the GH1 gene for mutations in a group of 74 children with
familial short stature, Lewis et al. (2004) identified 4 mutations, 2 of
which were novel: an ile179-to-met (I179M) substitution and a
single-basepair substitution in the promoter region. Resistance to
proteolysis and secretion from rat pituitary cells of I179M GH were
consistent with a lack of significant misfolding. Receptor binding
studies were normal, but molecular modeling studies suggested that the
I179M substitution might perturb interactions between GH and the GH
receptor loop containing residue trp169, thereby affecting signal
transduction. In contrast to its ability to activate STAT5 (601511)
normally, activation of ERK (see 176948) by the I179M variant was
reduced to half that observed with wildtype. The subject exhibited
normal GH secretion after pharmacologic stimulation. That the I179M
variant did not cosegregate with the short stature phenotype in the
family strongly suggested to Lewis et al. (2004) that this variant was
on its own insufficient to fully account for the observed clinical
phenotype.
Cogan et al. (1995, 1997) and Moseley et al. (2002) described 3
mutations (139250.0016; 139250.0011; 139250.0012) that are not located
at the 5-prime splice site in intron 3 but still alter splicing of GH1
to cause increased production of a 17.5-kD isoform. All 3 mutations
reside within purine-rich sequences that resemble exonic and intronic
splicing enhancers (ESE and ISE). Since splicing enhancers often
activate specific splice sites to facilitate exon definition, Ryther et
al. (2003) considered that the splicing defects caused by these
mutations could be due to a defect in exon definition, resulting in exon
skipping. They showed that overexpression of the dominant-negative
17.5-kD isoform also destroyed the majority of somatotrophs, leading to
anterior pituitary hypoplasia in transgenic mice. They demonstrated that
dual splicing enhancers are required to ensure exon 3 definition to
produce full-length 22-kD hormone. They also showed that splicing
enhancer mutations that weaken exon 3 recognition produce variable
amounts of the 17.5-kD isoform, a result that could potentially explain
the clinical variability observed in IGHD II. Noncanonical splicing
mutations that disrupt splicing enhancers, such as those represented by
the 3 mutations discussed, demonstrate the importance of enhancer
elements in regulating alternative splicing to prevent human disease.
Mullis et al. (2005) studied a total of 57 subjects with IGHD type II
(173100) belonging to 19 families with different splice site as well as
missense mutations within the GH1 gene. The subjects presenting with a
splice site mutation within the first 2 bp of intervening sequence 3
(5-prime IVS +1/+2 bp; 139250.0009) leading to a skipping of exon 3 were
more likely to present in the follow-up with other pituitary hormone
deficiencies. In addition, although the patients with missense mutations
had been reported to be less affected, a number of patients presenting
with a missense GH form showed some pituitary hormone impairment. The
development of multiple hormonal deficiencies is not age-dependent, and
there is a clear variability in onset, severity, and progression, even
within the same families. Mullis et al. (2005) concluded that the
message of clinical importance from these studies is that the pituitary
endocrine status of all such patients should continue to be monitored
closely over the years because further hormonal deficiencies may evolve
with time.
Shariat et al. (2008) studied a 4-generation family segregating
autosomal dominant growth hormone deficiency and identified a
heterozygous missense mutation in the GH gene (EX3+1G-A; 139250.0025) in
affected individuals. Analysis of the effects of this variant as well as
G-T and G-C changes at the first nucleotide of exon 3 illustrated the
multiple mechanisms by which changes in sequence can cause disease:
splice site mutations, splicing enhancer function, messenger RNA decay,
missense mutations, and nonsense mutations. The authors noted that for
IGHD II, only exon skipping leads to production of the dominant-negative
isoform, with increasing skipping correlating with increasing disease
severity.
Horan et al. (2006) observed an association between 4 core promoter
haplotypes in the GH1 gene and increased risk for hypertension and
stroke in a study of 111 hypertensive patients and 155 stroke patients.
The association was more significant for females than males. Horan et
al. (2006) also observed an association between an isoform of the GHR
gene lacking exon 3 (GHRd3) and hypertension in female stroke patients.
The authors postulated a complex interaction between variants in the GH1
and GHR genes involving height.
Giordano et al. (2008) studied the contribution to IGHD of genetic
variations in the GH1 gene regulatory regions. The T allele of a G-to-T
polymorphism at position -57 (dbSNP rs2005172), within the vitamin
D-responsive element, showed a positive significant association when
comparing patients with normal (P = 0.006) or short stature (P = 0.0011)
controls. The genotype -57TT showed an odds ratio of 2.93 (1.44-5.99)
and 2.99 (1.42-6.31), respectively. Giordano et al. (2008) concluded
that the common -57G-T polymorphism contributes to IGHD susceptibility,
indicating that it may have a multifactorial etiology.
ANIMAL MODEL
By Southern analysis of DNA from mouse-rat somatic cell hybrids, Cooke
et al. (1986) found that the GH gene is on rat chromosome 10 and the PRL
gene (176760) is on rat chromosome 17. Thus, in the rat, as in man,
these genes are on different chromosomes even though they show an
evolutionary relationship.
Morgan et al. (1987) showed that retrovirus-mediated gene transfer can
be used to introduce a recombinant human GH1 gene into cultured human
keratinocytes. The transduced keratinocytes secreted biologically active
GH into the culture medium. When grafted as an epithelial sheet onto
athymic mice, these cultured keratinocytes reconstituted a
normal-appearing epidermis from which, however, human growth hormone
could be extracted. Transduced epidermal cells may be a general vehicle
for the delivery of gene products by means of grafting.
Smith et al. (1997) demonstrated a role of GH in retinal
neovascularization, which is the major cause of untreatable blindness.
They found that retinal neovascularization was inhibited in transgenic
mice expressing a GH antagonist gene and in normal mice given an
inhibitor of GH secretion. In these mice retinal neovascularization was
inhibited in inverse proportion to serum levels of GH and IGF1.
Inhibition was reversed with exogenous IGF1 administration. GH
inhibition did not diminish hypoxia-stimulated retinal vascular
endothelial growth factor (VEGF; 192240) or VEGF receptor (VEGFR;
191306) expression. Smith et al. (1997) suggested that systemic
inhibition of GH or IGF1, or both, may have therapeutic potential in
preventing some forms of retinopathy.
Growth hormones from primates are unique in that they are able to bind
with and activate both primate and nonprimate GHRs, whereas GHs from
nonprimates are ineffective in primates. Behncken et al. (1997)
investigated the basis of primate specificity of binding by the GHR.
They examined the interaction between GHR residues arg43 (primate) or
leu43 (nonprimate) and their complementary hormone residues asp171
(primate) and his170 (nonprimate). They found that the interaction
between arg43 and his170/171 is sufficient to explain virtually all of
the primate species specificity.
In mouse preadipocytes, Wolfrum et al. (2003) found that Foxa2 (600288)
inhibited adipocyte differentiation by activating transcription of
preadipocyte factor-1 (DLK1; 176290), and that expression of both Foxa2
and Dlk1 was enhanced by growth hormone in primary preadipocytes.
Wolfrum et al. (2003) suggested that the antiadipogenic activity of
growth hormone is mediated by Foxa2.
Using GH-deficient Socs2 (605117) -/- mice, Greenhalgh et al. (2005)
demonstrated that the Socs2 -/- phenotype is dependent upon the presence
of endogenous GH. Treatment with exogenous GH induced excessive growth
in terms of overall body weight, body and bone lengths, and the weight
of internal organs and tissues. Microarray analysis on liver RNA
extracts after exogenous GH administration revealed a heightened
response to GH. The conserved C-terminal SOCS-box motif was essential
for all inhibitory function. SOCS2 was found to bind 2 phosphorylated
tyrosines on the GH receptor, and mutation analysis of these amino acids
showed that both were essential for SOCS2 function. Greenhalgh et al.
(2005) concluded that SOCS2 is a negative regulator of GH signaling.
CSHL1
| dbSNP name | rs2006122(A,T); rs201707845(G,A); rs2727307(G,T); rs2246207(G,A); rs141576938(G,C) |
| ccdsGene name | CCDS11652.1 |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 1444 |
| snpEff Gene Name | GH1 |
| EntrezGene Description | chorionic somatomammotropin hormone-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CSHL1:NM_022581:exon2:c.C133G:p.R45G,CSHL1:NM_022579:exon2:c.C133G:p.R45G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7411 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14406 |
| dbNSFP Uniprot ID | CSHL_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000692 |
| ESP Eur/Amr MAF | 0.001047 |
| ExAC AF | 7.481e-04,8.132e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly
SKELETAL:
[Spine];
Scoliosis;
[Limbs];
Contractures
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Spastic diplegia, symmetric;
Spastic quadriplegia;
Hyperreflexia;
Hypertonia;
Extensor plantar responses
MISCELLANEOUS:
Genetic heterogeneity;
Onset in infancy
MOLECULAR BASIS:
Caused by mutation in the glutamate decarboxylase 1 gene (GAD1, 605363.0001)
OMIM Title
*603515 CHORIONIC SOMATOMAMMOTROPIN HORMONE-LIKE 1; CSHL1
;;CHORIONIC SOMATOMAMMOTROPIN-LIKE; CSL
OMIM Description
CLONING
The human growth hormone/human chorionic somatomammotropin (GH/CS) gene
cluster contains 5 genes, including chorionic somatomammotropin-like
(CSL). Chen et al. (1989) isolated CSL cDNAs from a placenta library.
They noted that CSL cDNAs were present at a relatively low level in the
library compared to CSA (150200) and CSB (118820) cDNAs. The CSL gene
has a single nucleotide substitution (relative to the other 4 genes in
the cluster) in a splice donor site that results in a different mRNA
splicing pattern and, hence, in a novel sequence of the predicted CSL
protein. Chen et al. (1989) proposed that the CSL protein may be
evolving into a distinct hormone. Using RT-PCR, MacLeod et al. (1992)
found 2 alternatively spliced CSL transcripts in the placental villi.
However, they found no evidence that either of these transcripts is
translated or functional.
GENE FUNCTION
Misra-Press et al. (1994) found that CSL is actively transcribed in the
placenta and exhibits a complex pattern of alternative splicing. The
majority of the CSL transcripts encode predicted nonfunctional proteins.
However, a subpopulation of mRNAs retain the potential for synthesis of
a functional, secreted, gestational hormone. These authors noted that
Goossens et al. (1986) (see 139250) and Wurzel et al. (1982) (see CSA)
described normally developed infants who lacked the other 3 placentally
expressed genes of the GH/CS cluster but who had an intact CSL gene.
Misra-Press et al. (1994) stated that these studies suggest that CSL
might compensate for absence of the other members of the GH/CS cluster
during human gestation.
MAPPING
By in situ hybridization, Harper et al. (1982) mapped the GH gene
cluster to chromosome 17q22-q24.
SCN4A
| dbSNP name | rs16947276(T,C); rs113385942(C,G); rs2727277(A,T); rs2532111(A,G); rs2532112(C,T); rs2228997(C,T); rs2070720(T,C); rs56342400(G,T); rs2058194(T,C); rs8074752(G,A); rs8074344(A,G); rs35501848(G,T); rs11869827(C,T); rs60444956(C,T); rs2877372(T,C); rs201916531(C,T); rs11657448(C,T); rs75828444(G,A); rs3785569(G,T); rs3785568(T,C); rs13341114(G,T); rs73992418(G,A); rs117201544(G,A); rs190281941(G,A); rs73992419(G,A); rs34684062(G,A); rs12386045(C,T); rs8080613(T,A); rs73992421(G,A); rs4968604(G,A); rs113181958(G,A); rs2109079(T,G); rs183409204(C,T); rs113937879(G,T); rs9894841(T,C); rs149594719(C,T); rs6504191(T,C); rs2331408(G,T); rs917558(A,G); rs2877373(T,C); rs9891362(G,A); rs11079516(A,G); rs2009051(C,G); rs73326367(A,C); rs4968677(T,C); rs4968678(A,G); rs758517(T,C); rs4968679(C,T); rs12952532(T,C); rs11656511(C,T); rs1808274(G,A); rs7405829(T,G); rs4968680(A,G); rs2302236(A,G); rs2302237(C,T); rs9892013(A,G) |
| ccdsGene name | CCDS45761.1 |
| cytoBand name | 17q23.3 |
| EntrezGene GeneID | 6329 |
| EntrezGene Description | sodium channel, voltage-gated, type IV, alpha subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SCN4A:NM_000334:exon19:c.G3604A:p.E1202K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7824 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P35499 |
| dbNSFP Uniprot ID | SCN4A_HUMAN |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.000228 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 5.694e-05 |
OMIM Clinical Significance
Neuro:
Hyperthermia
Muscle:
Myopathy;
Rhabdomyolysis may follow severe exercise in hot conditions, neuroleptic
drugs, alcohol, or infections
Metabolic:
Lactic acidosis
Misc:
Precipitated by general anesthesia;
Hypertonicity of voluntary muscles;
Response to Dantrolene sodium
Lab:
Elevated blood CPK, phosphate and potassium
Inheritance:
Autosomal dominant form (unlinked to 19q13.1-q13.2);
heterogeneous
OMIM Title
%154275 MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 2
;;MHS2
OMIM Description
For a phenotypic description and a discussion of genetic heterogeneity
of malignant hyperthermia, see MHS1 (145600).
MAPPING
In 3 unrelated families, Levitt et al. (1991) excluded linkage of the
MHS phenotype to loci on 19q13.1, thus indicating genetic heterogeneity.
Levitt et al. (1992) extended these studies to 16 MHS families. Four
were found to be linked to chromosome 19; 5 were found to be closely
linked to the anonymous marker NM23 (156490) on 17q11.2-q24 (maximum lod
= 3.26 at theta = 0.0); and 2 families were clearly unlinked to either
of these regions. In 5 additional families, there were insufficient data
to determine their linkage status.
Olckers et al. (1992) provided evidence for linkage of MHS to the SCN4A
gene (603967), which encodes the adult sodium channel alpha subunit, in
3 informative families (cumulative lod score of 2.1 at theta = 0.0). In
a large family with autosomal dominant HYPP (170500) and MHS, Moslehi et
al. (1998) found evidence for linkage of both disorders to the SCN4A
locus on chromosome 17q (maximum lod for HYPP = 6.79 at theta = 0.0; lod
for MHS = 1.76 at theta = 0.0).
In 3 families in which MHS did not show linkage to chromosome 19,
Sudbrak et al. (1993) excluded linkage also to an 84-cM interval on 17q.
At the same time, they excluded linkage to CACNL1A3, which is located on
1q, as well as to CACNLB1 (114207), CACNLG (114209), and SCN4A, which
are located on 17q.
APOH
| dbSNP name | rs190137879(T,A); rs6933(G,A); rs1801690(C,G); rs8178861(A,G); rs1558359(G,A); rs4790914(C,G); rs8178944(C,T); rs4791079(T,G); rs4791078(A,C); rs141772543(C,T); rs1971682(G,C); rs1801689(A,C); rs4581(C,A); rs8178938(G,A); rs8178858(G,A); rs8178857(G,T); rs7210892(G,A); rs4366742(T,C); rs7214731(C,T); rs8078603(T,C); rs8077564(A,G); rs8178855(A,C); rs8178854(A,G); rs8178853(G,A); rs8178852(C,G); rs8178851(A,C); rs8178850(T,G); rs7212060(G,T); rs2215415(G,A); rs8178848(G,A); rs7212477(A,G); rs2215414(A,G); rs8178926(C,T); rs3744317(G,A); rs8178847(C,T); rs52797880(A,G); rs79228460(T,G); rs138152501(A,G); rs75037199(A,G); rs8178923(T,C); rs8178845(C,A); rs8178921(G,A); rs8178844(G,A); rs16958975(A,G); rs8178843(C,A); rs8178842(C,T); rs8178918(A,T); rs3785617(T,C); rs8178841(G,A); rs8178839(T,G); rs8178838(T,C); rs8178837(T,A); rs3815410(G,C); rs8178835(A,G); rs111790351(G,A); rs59934404(C,T); rs8178907(C,A); rs8178906(G,C); rs7222718(T,C); rs59422744(G,A); rs59857699(C,A); rs202180592(T,A); rs8178829(G,C); rs8178828(G,A); rs8178827(C,T); rs16958979(C,T); rs7213041(C,T); rs114248359(C,A); rs8178823(A,C); rs8178901(G,A); rs8178822(G,T) |
| ccdsGene name | CCDS11663.1 |
| cytoBand name | 17q24.2 |
| EntrezGene GeneID | 350 |
| EntrezGene Description | apolipoprotein H (beta-2-glycoprotein I) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | APOH:NM_000042:exon7:c.T973G:p.C325G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9267 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P02749 |
| dbNSFP Uniprot ID | APOH_HUMAN |
| dbNSFP KGp1 AF | 0.0201465201465 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0441988950276 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0369393139842 |
| dbSNP GMAF | 0.0202 |
| ESP Afr MAF | 0.008398 |
| ESP All MAF | 0.026911 |
| ESP Eur/Amr MAF | 0.036395 |
| ExAC AF | 0.024,4.879e-05 |
OMIM Clinical Significance
GU:
Renal colic;
Renal oxalate stones
Lab:
Hyperglycinuria
Inheritance:
Autosomal dominant
OMIM Title
*138700 APOLIPOPROTEIN H; APOH
;;GLYCOPROTEIN I, BETA-2; B2GP1;;
GLYCOPROTEIN 1, BETA-2;;
BG
OMIM Description
DESCRIPTION
The APOH gene encodes beta-2 glycoprotein I, also known as
apolipoprotein H, a single-chain plasma protein of about 50 kD. Beta-2
GPI binds to and neutralizes negatively charged phospholipid
macromolecules, thereby diminishing inappropriate activation of the
intrinsic blood coagulation cascade. Beta-2 GPI has been implicated in a
variety of physiologic pathways, including blood coagulation,
hemostasis, and the production of antiphospholipid antibodies
characteristic of antiphospholipid syndrome (APS; 107320) (summary by
Mehdi et al., 2003).
CLONING
Lozier et al. (1984) determined the full amino acid sequence of
beta-2-glycoprotein (apoH). The deduced 326-amino acid protein contains
5 attached glucosamine-containing oligosaccharides. Computerized
analysis of the sequence revealed 5 consecutive homologous segments in
which cysteine, proline, and tryptophan appeared to be highly conserved.
Mehdi et al. (1991) cloned and sequenced APOH cDNAs from human liver and
from a human hepatoma cell line. Both cDNAs predicted a protein of 345
amino acids, including a 19-amino acid hydrophobic, N-terminal signal
sequence that is not present in the mature protein. The level of APOH
mRNA expressed by the hepatoma cells was downregulated by incubation
with inflammatory mediators, implying that APOH is a negative
acute-phase protein.
By Northern blot analysis, Steinkasserer et al. (1992) established that
APOH is synthesized in the liver where a transcript of approximately 1.5
kb was identified.
Sanghera et al. (2001) found that the chimpanzee APOH gene encodes a
deduced 326-amino acid protein, as in humans. The human and chimpanzee
APOH proteins share 99.4% sequence similarity.
GENE STRUCTURE
Sheng et al. (1997) found that the mouse Apoh gene contains 8 exons and
spans approximately 18 kb.
Sanghera et al. (2001) found that the chimpanzee APOH gene, like the
human gene, contains 8 exons.
MAPPING
Haagerup et al. (1991) demonstrated RFLPs in the APOH gene and used
these in CEPH family studies to locate the gene on 17q. The marker that
showed closest linkage was HOX2 (142960), located at 17q21-q22; lod
score = 8.83 at theta = 0.05. Linkage to COL1A1 (120150) was indicated
by a lod score of 6.18 at theta = 0.12. By hybridizing a cDNA probe for
APOH to a panel of somatic cell hybrids, Steinkasserer et al. (1992)
showed that the structural locus maps to 17q23-qter.
Nonaka et al. (1992) mapped the mouse Apoh gene to chromosome 11. Nonaka
et al. (1992) commented that the mouse Apoh protein is composed of 5
repeating units called short consensus repeats (SCR), which are found
mostly in the regulatory proteins of the complement system.
GENE FUNCTION
Nakaya et al. (1980) demonstrated beta-2-glycoprotein I activation of
lipoprotein lipase and designated this glycoprotein as apolipoprotein H.
Lozier et al. (1984) noted that B2GI is associated with lipoproteins,
binds to platelets, interacts with heparin, and may be involved in blood
coagulation.
McNeil et al. (1990) identified beta-2-glycoprotein I as a cofactor
required for antiphospholipid antibodies (APA) to bind to cardiolipin.
These findings suggested that APA are directed against a complex antigen
that includes B2GPI. In addition, B2GPI bound to anionic phospholipids
in the absence of anticardiolipin antibodies. McNeil et al. (1990)
hypothesized that anticardiolipin APA may interfere with the function of
apoH in vivo, which may explain the association of these antibodies with
thrombotic tendencies.
Sanghera et al. (1997) noted that apoH had been implicated in a variety
of physiologic pathways including lipoprotein metabolism, coagulation,
and the production of antiphospholipid autoantibodies. They cited
reports supporting the conclusion that apoH is a required cofactor for
anionic phospholipid binding by the antiphospholipid autoantibodies
found in sera of many patients with systemic lupus erythematosus (SLE;
152700) and primary antiphospholipid syndrome (107320), but it does not
seem to be required for the reactivity of antiphospholipid
autoantibodies associated with infections. These studies suggested that
the apoH-phospholipid complex forms the antigen to which the
autoantibodies are directed. Sanghera et al. (1997) postulated that
genetically determined structural abnormalities in the lipid-binding
domain(s) of apoH may affect its ability to bind lipid and consequently
the production of the autoantibodies.
Agar et al. (2010) used electron microscopy to demonstrate that B2GPI
exists in at least 2 different conformations: a closed circular plasma
conformation and an activated open conformation. The closed circular
conformation is maintained by interaction between the first (DI) and
fifth (DV) domains. In the activated open conformation, a cryptic
epitope in the first domain becomes exposed that enables antibodies to
bind and form an antibody-B2GPI complex. The open conformation prolonged
the activated partial thromboplastin time (APTT) when added to normal
plasma, and the APTT was further prolonged by addition of anti-B2GPI
antibodies, consistent with an anticoagulant effect. The conformations
could be converted into each other by changing pH and salt
concentrations.
In a review, Giannakopoulos et al. (2011) noted that B2GPI contains
multiple cysteine residues that mediate platelet and endothelial cell
adhesion via thiol exchange reactions. Evidence also suggests that B2GPI
may play a role in apoptosis by binding to blebs on apoptotic cells.
MOLECULAR GENETICS
Richter and Cleve (1988) demonstrated genetic variation of APOH by means
of isoelectric focusing, and data on gene frequencies of allelic
variants were tabulated by Roychoudhury and Nei (1988).
Using thin-layer polyacrylamide isoelectric focusing gels and
immunologic identification, Kamboh et al. (1988) demonstrated
genetically determined polymorphism of apolipoprotein H. Three common
alleles were identified in U.S. whites and blacks. A fourth allele was
observed in individuals of African descent. Family data confirmed
autosomal codominant inheritance of 4 alleles at a single APOH locus.
Sepehrnia et al. (1988) provided data on the distribution of
apolipoprotein polymorphisms in Nigeria, including polymorphism of APOH.
The observations supported the conclusion that the APOH*4 is a marker
allele unique to blacks and one that may be widely distributed among
African populations, whereas the APOH*1 allele may be a unique Caucasian
allele that was introduced into the black population of the U.S. by
admixture.
Eiberg et al. (1989) reported linkage data suggesting that the
structural and quantitative polymorphisms associated with serum
beta-2-glycoprotein I were very tightly linked (maximum lod score = 3.28
at theta = 0.0, male and female data combined). Sepehrnia et al. (1989)
found specific associations between particular APOH alleles and the
level of triglycerides in females.
In a population of black Africans from the Ivory Coast, Cleve et al.
(1992) found that the gene frequencies of APOH*1, APOH*2, APOH*3, and
APOH*4 were 0.012, 0.921, 0.047, and 0.020, respectively. In a tabular
review of reported frequencies in different populations, APOH*4 was
found only in individuals of African descent. The most common allele in
all populations, including African, Caucasian, European, and East Asian
descent, was APOH*2.
Among 661 non-Hispanic whites, Sanghera et al. (1997) found that the
frequency of the APOH*1, APOH*2, and APOH*3 alleles were 0.059, 0.868,
and 0.073, respectively. Sanghera et al. (1997) determined that the
APOH*1 allele is due to a ser88-to-asn (S88N) substitution in exon 3 of
the APOH gene. The frequency of the asn88 allele was 0.011, 0.043, and
0.056 in blacks, Hispanics, and non-Hispanic whites, respectively. Based
upon reactivity with a certain monoclonal apoH antibody, the APOH*3
allele could be subdivided into APOH*3(W) (reactive) and APOH*3(B)
(non-reactive). The APOH*3(W) allele was found to result from a
trp316-to-ser (W316S) substitution in the APOH gene. White had a
significantly higher frequency of APOH*3(W) (0.059) compared to blacks
(0.008).
Sanghera et al. (1997) found that the W316S substitution in the APOH
gene occurs in the fifth domain (domain V) of the protein, which affects
phospholipid binding. Another structural substitution in this domain,
cys306-to-gly (C306G), was also shown to disrupt binding of APOH to
phospholipid. These data indicated that domain V of APOH harbors the
lipid-binding region.
Among 455 non-Hispanic individuals, Mehdi et al. (1999) found that the
APOH*3(W) allele was associated with decreased plasma levels of apoH and
was estimated to account for about 10% of the phenotypic variation in
plasma levels in both men and women. However, Mehdi et al. (2003) found
that the W316S allele was in linkage disequilibrium with a promoter
polymorphism in the APOH gene, which explained the variation in plasma
apoH levels.
Hirose et al. (1999) found that the val247 allele (138700.0001) was
significantly associated with the presence of anti-B2GPI antibodies in
Asian patients with antiphospholipid syndrome (APS; 107320) in a study
of 370 healthy controls from different racial backgrounds and 149
patients with APS. The V allele and the VV genotype occurred most often
among Caucasians, less among African Americans, and least among Asians.
Conversely, the V allele and the VV genotype were found more frequently
among Asian patients with antiphospholipid syndrome than among controls
(p = 0.0028 and p = 0.0023, respectively). There were no significant
differences in allele or genotype frequencies when comparing Caucasian
or African American APS patients with appropriate controls. The
differences in allele and genotype frequencies seen in Asian APS
patients were restricted to those with anti-B2GPI antibodies.
HISTORY
Haupt et al. (1968) described a family in which 2 brothers had complete
absence of what they termed beta-2-glycoprotein I (Bg) in the serum.
Both parents, a sister, and both children of 1 of the brothers had
half-normal levels of the protein. Cleve and Rittner (1969) found 9
families out of 88 in which 1 parent and about half the children had
intermediate concentrations of beta-2-glycoprotein I, presumed to be
heterozygous for a deficiency ('null') gene.
Hoeg et al. (1985) observed the rare occurrence of total lack of
detectable apoH protein in less than 0.3% of clinic patients. A study of
family members of 5 such patients demonstrated autosomal codominant
inheritance pattern for plasma levels. The authors were impressed by the
lack of consistent effects on other plasma lipoproteins, and concluded
that the lack of apolipoprotein H does not result in a significant
perturbation of normal lipoprotein metabolism, suggesting that the
finding may not have clinical relevance.
Bancsi et al. (1992) concluded that deficiency of plasma B2GPI is not a
risk factor for thrombosis. In a comparison of healthy volunteers and 4
different groups of patients with familial thrombophilia, the prevalence
of B2GPI deficiency (plasma levels less than 77%) was found to be very
similar (6.8-12.5%) and not statistically significant between the
groups. One thrombophilic patient was found to be homozygous-deficient
for B2GPI and this transmission of the defect in his family followed
autosomal inheritance. However, 1 of his brothers was also
homozygous-deficient and was free of thromboembolic complications at the
age of 35 years.
ANIMAL MODEL
Using isoelectric focusing and immunoblotting, Sanghera et al. (2001)
screened 155 chimpanzees (128 unrelated captured parents and 27
captive-born offspring) for the apoH protein polymorphism. The most
common IEF pattern in chimpanzees was identical to a previously
described APOH*3 allele in humans. In addition, they identified in
chimpanzees an allele designated APOH*4, resulting from a lys210-to-glu
missense change in exon 6. They found that the prevalence of anti-apoH
antibodies in chimpanzees (64%) was unusually high compared to that in
humans. No association was found between the lys210-to-glu mutation and
the occurrence of anti-apoH antibodies. The authors suggested that the
chimpanzee may serve as a useful animal model for human antiphospholipid
syndrome (107320).
Sheng et al. (2001) found that B2ghi-null mice were born at lower than
expected frequencies, suggesting that B2gpi may play a role in
implantation. However, B2gpi-null mice themselves did not show
reproductive abnormalities: the number of pregnancies, litter size, and
birth weight was similar to that of heterozygotes and controls.
B2gpi-null mice had no detectable organ pathology, and in vivo
coagulation profiles were also similar to controls. However, in vitro
studies of blood derived from the B2gpi-null mice showed less thrombin
generation compared to heterozygotes or controls.
SNORA38B
| dbSNP name | rs9906731(A,G); rs61602831(T,C) |
| ccdsGene name | CCDS11671.1 |
| cytoBand name | 17q24.2 |
| EntrezGene GeneID | 100124536 |
| snpEff Gene Name | NOL11 |
| EntrezGene Description | small nucleolar RNA, H/ACA box 38B |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02388 |
C17orf58
| dbSNP name | rs9891146(T,C); rs28368756(T,C) |
| ccdsGene name | CCDS45765.1 |
| CosmicCodingMuts gene | C17orf58_ENST00000449250 |
| cytoBand name | 17q24.2 |
| EntrezGene GeneID | 284018 |
| EntrezGene Description | chromosome 17 open reading frame 58 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C17orf58:NM_181655:exon3:c.A274G:p.I92V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q2M2W7 |
| dbNSFP Uniprot ID | CQ058_HUMAN |
| dbNSFP KGp1 AF | 0.5086996337 |
| dbNSFP KGp1 Afr AF | 0.321138211382 |
| dbNSFP KGp1 Amr AF | 0.638121546961 |
| dbNSFP KGp1 Asn AF | 0.297202797203 |
| dbNSFP KGp1 Eur AF | 0.728232189974 |
| dbSNP GMAF | 0.4913 |
| ESP Afr MAF | 0.396866 |
| ESP All MAF | 0.377792 |
| ESP Eur/Amr MAF | 0.270517 |
| ExAC AF | 0.638 |
LOC440461
| dbSNP name | rs62085746(T,C) |
| cytoBand name | 17q24.2 |
| EntrezGene GeneID | 440461 |
| EntrezGene Description | Rho GTPase activating protein 27 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1534 |
ABCA5
| dbSNP name | rs7212957(G,A); rs373006078(G,A); rs7213764(G,A); rs183123999(C,A); rs12942867(G,A); rs1990248(G,A); rs1476749(C,T); rs15886(A,T); rs184905056(C,T); rs2067851(T,C); rs151246972(C,T); rs1420904(G,A); rs1420905(C,T); rs201677603(T,C); rs7208451(A,C); rs180701610(T,C); rs188592212(C,T); rs6501313(T,C); rs9909726(T,C); rs139806791(A,G); rs200509187(A,G); rs180924615(A,C); rs143171555(C,T); rs10445224(T,C); rs56389663(G,C); rs9907148(T,C); rs138667562(T,C); rs11869324(G,C); rs186109900(T,A); rs7223895(A,G); rs12941297(G,A); rs12943504(T,C); rs73998220(C,T); rs138252135(T,C); rs16973880(C,T); rs187949751(C,T); rs73378346(T,C); rs12945481(G,T); rs184244790(C,T); rs12945908(T,C); rs9646388(A,G); rs57758461(T,C); rs477847(A,G); rs568164(T,C); rs190091862(C,T); rs142846864(T,A); rs12449649(A,G); rs12450167(T,C); rs34609440(T,C); rs34334829(C,T); rs190892304(C,T); rs9907847(G,A); rs11654323(T,C); rs151334955(G,A); rs140592418(A,T); rs60784573(C,T); rs817126(A,G); rs57949169(A,T); rs16973883(G,T); rs12450522(C,T); rs1992741(C,T); rs557491(T,C); rs477178(G,A); rs520754(T,C); rs191727958(G,A); rs817127(G,A); rs817128(C,T); rs817121(A,G); rs11077445(A,C); rs817122(A,T); rs471193(T,A); rs817123(A,C); rs523505(C,T); rs1345462(G,A); rs12938064(C,T); rs536009(C,A); rs142165698(C,A); rs12452340(C,A); rs149271823(T,C); rs180955343(C,T); rs139111333(A,G); rs188696986(C,T); rs139792801(G,C); rs531586(A,C); rs564426(A,C); rs186899155(T,C); rs190362176(G,A); rs190132541(T,C); rs1550828(T,C); rs191946094(C,T); rs187070861(G,C); rs201603344(C,T); rs4246423(C,A); rs4553686(A,C); rs55773491(C,T); rs374441522(G,A); rs486840(G,A); rs148530456(C,G); rs115819511(G,C); rs12952942(T,C); rs544940(A,G); rs11656389(G,C); rs17759819(T,G); rs511854(T,C); rs12946566(A,G); rs189277360(A,C); rs477045(C,T); rs62080888(T,C); rs73998226(G,A); rs115052249(T,C); rs192991792(A,G); rs139331316(T,A); rs2441358(C,A); rs17686569(T,C); rs189344088(A,C); rs181506386(G,A); rs12450743(T,C); rs180946493(T,G); rs11651815(A,T); rs11651872(A,G); rs533899(C,A); rs481876(G,A); rs191081405(A,G); rs187066409(A,G); rs487382(A,G); rs568536(C,G); rs116762852(C,T); rs12944980(T,C); rs551226(T,C); rs12946776(A,G); rs182952306(T,C); rs476677(C,G); rs183914689(C,T); rs12938097(T,C); rs1011549(A,T); rs534645(G,A); rs4310935(A,G); rs4310936(A,G); rs494946(C,G); rs181537327(C,T); rs186405379(A,T); rs509830(A,G); rs488714(C,T); rs148494265(T,C); rs568354(A,G); rs11649744(T,G); rs140459028(T,C); rs191716399(T,C); rs11652207(T,G); rs4968854(G,A); rs11544715(C,T); rs34985085(T,G); rs11871086(C,T); rs138347797(A,G); rs28592152(A,G); rs180849720(C,T); rs16973904(A,G); rs73998229(T,C); rs112914(C,T); rs184599886(A,G); rs146888179(C,T); rs11650658(T,C); rs62080893(A,G); rs180940234(G,A); rs75295694(A,C); rs9302899(A,G); rs182840680(A,G); rs78578708(C,A); rs544829(G,A); rs143084873(A,G); rs7225147(T,G); rs7225762(T,C); rs527102(C,G); rs551818(C,A); rs180696633(C,G); rs185503270(C,T); rs190557757(C,T); rs12937947(G,A); rs182270889(G,A); rs145120406(G,T); rs707243(G,A); rs143152681(G,C); rs475283(C,G); rs12949267(T,C); rs333937(T,C); rs193237321(G,C); rs67740186(A,G); rs12940364(G,A); rs7213377(A,T); rs11656456(C,G); rs184561277(C,A); rs10512526(G,A); rs188634416(A,C); rs10512527(C,G) |
| ccdsGene name | CCDS11685.1 |
| cytoBand name | 17q24.3 |
| EntrezGene GeneID | 23461 |
| EntrezGene Description | ATP-binding cassette, sub-family A (ABC1), member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ABCA5:NM_018672:exon29:c.G3943A:p.A1315T,ABCA5:NM_172232:exon30:c.G3943A:p.A1315T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8604 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WWZ7 |
| dbNSFP Uniprot ID | ABCA5_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.003195 |
| ESP All MAF | 0.001084 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.00035 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Isolated cases
GROWTH:
[Height];
Normal height
HEAD AND NECK:
[Head];
Macrocephaly (half of cases);
[Face];
Mild dysmorphism;
Frontal bossing;
[Eyes];
Hypertelorism
NEUROLOGIC:
[Central nervous system];
Hypoplasia of corpus callosum and cerebellar vermis;
Mental retardation, mild-moderate (some);
Learning disabilities;
Seizures (rare);
[Behavioral/psychiatric manifestations];
Autism;
Schizophrenia
MISCELLANEOUS:
Incomplete penetrance
MOLECULAR BASIS:
Caused by a 1.35-Mb duplication of chromosome 1q21
OMIM Title
*612503 ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 5; ABCA5
;;KIAA1888
OMIM Description
DESCRIPTION
Members of the ABC family of membrane proteins, such as ABCA5, are
involved in energy-dependent transport of a wide variety of substrates
across membranes (Allikmets et al., 1996).
CLONING
Using the N-terminal ATP-binding domain of PGY1 (ABCB1; 171050) and the
complete sequence of CFTR (602421) to query a human EST database,
Allikmets et al. (1996) identified an ABCA5 clone, which they designated
EST90625, from an infant spleen cDNA library. Northern blot analysis
detected a 7-kb transcript in heart and skeletal muscle and a 2.5-kb
transcript in liver.
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2001) cloned ABCA5, which they designated
KIAA1888. The deduced 737-amino acid protein shares significant
similarity with ABCA2 (600047). RT-PCR ELISA detected moderate ABCA5
expression in all tissues and specific brain regions examined, with
highest levels in skeletal muscle and cerebellum.
By RT-PCR of testis RNA, followed by 5-prime RACE of hepatoma cell line
RNA, Petry et al. (2003) cloned full-length ABCA5. The deduced
1,642-amino acid protein has a calculated molecular mass of 183 kD. It
has up to 16 predicted transmembrane segments in 2 transmembrane
domains, which are followed by their respective nucleotide-binding
folds. Petry et al. (2003) also identified 2 alternatively-spliced ABCA5
transcripts, one of which encodes a 925-amino acid ABC half-transporter
with 9 transmembrane segments and only the first nucleotide-binding fold
of the full-length protein. Northern blot analysis detected a 6.2-kb
transcript in skeletal muscle, with lower levels in kidney, liver, and
placenta.
Using RT-PCR, Ohtsuki et al. (2004) detected expression of ABCA2 and
ABCA5 in cultured human brain capillary endothelial cells, which form
the blood-brain barrier.
Kubo et al. (2005) cloned mouse Abca5. The deduced 1,642-amino acid
protein has 12 membrane-spanning segments and 2 nucleotide-binding
domains, and it shares 77% identity with human ABCA5. Northern blot
analysis detected 3 mouse Abca5 transcripts, with high expression in
brain, testis, and lung, and lower expression in heart, liver, kidney,
skeletal muscle, and placenta. Immunofluorescence microscopy localized
Abca5 in cardiomyocytes of heart, oligodendrocytes and astrocytes of
brain, alveolar type II cells of lung, and in a lysosome-related
compartment of lung epithelial cells, but Abca5 was not observed in
liver. In transfected cells, Abca5 colocalized with marker proteins of
lysosomes and late endosomes. Glycosidase treatment reduced the apparent
molecular mass of Abca5, suggesting that it is a glycoprotein.
Using in situ hybridization on human hair follicles in the growth
(anagen) phase of the hair cycle, DeStefano et al. (2014) observed ABCA5
expression in both the epithelial and mesenchymal compartments, present
within the outer root sheath of the hair follicle as well as the dermal
sheath. Immunohistochemistry performed on paraffin-embedded skin
sections determined that expression was most evident in the dermal
sheath, perifollicular dermis, and outer and inner root sheaths of hair
follicles. RT-PCR demonstrated strong ABCA5 expression in plucked hair
follicles and microdissected outer root sheaths, as well as in the
perifollicular dermis, including the dermal sheath. Using
immunohistochemistry and immunofluorescence staining on adult mouse
testis sections, DeStefano et al. (2014) observed strong localization of
Abca5 to basal cells of seminiferous tubules, to interstitial cells
consisting of Leydig cells, and to the tunica albuginea. In the
epididymis, there was very strong and specific localization of Abca5 to
the connective tissue outlining the cylindrical epithelium in the corpus
and cauda regions, including fibrocytes and smooth muscle cells, as well
as within the basal and tall columnar cells of the corpus cylindrical
epithelium. In mouse anagen hair follicles, there were high levels of
Abca5 localization to the outer and inner hair sheaths, with expression
also observed in the dermal sheath and perifollicular dermis. Noting
that ABCA5 localization in hair follicles and skin appeared to be
conserved between human and mouse, with a broad expression pattern
spanning multiple cell lineages, DeStefano et al. (2014) suggested a
prominent, evolutionarily conserved role for this transporter in
regulating hair growth.
GENE STRUCTURE
Petry et al. (2003) determined that the ABCA5 gene contains 39 exons and
spans about 80 kb. Exon 2 contains the putative translation start site.
MAPPING
Using somatic cell hybrid, radiation hybrid, and YAC analyses, Allikmets
et al. (1996) mapped the ABCA5 gene to chromosome 17q21-q24. By genomic
sequence analysis, Petry et al. (2003) mapped the ABCA5 gene to
chromosome 17q24.3, where it is the first gene in a tandem array of 5
related ABCA genes.
MOLECULAR GENETICS
In an 11-year-old Yemeni girl, born of first-cousin parents, who had
generalized hypertrichosis and severe gingival hyperplasia (HTC3;
135400) as well as epilepsy, DeStefano et al. (2014) performed
whole-exome sequencing and identified homozygosity for a splice site
mutation in the ABCA5 gene (612503.0001). The mutation, which segregated
with disease in the family, was not found in 10 controls or in genome
databases. The authors noted that ABCA5 lies within the minimal common
region determined in 4 familial cases and 1 sporadic case of autosomal
dominant HTC reported by Sun et al. (2009).
ANIMAL MODEL
Kubo et al. (2005) obtained Abca5 -/- mice at a mendelian ratio, and the
mutant mice were fertile. Upon reaching adulthood, they exhibited
subcutaneous edema, exophthalmos, and trembling, and they finally died.
Prior to death, Abca5 -/- cardiomyocytes showed degeneration due to
vacuolation and accumulation of autolysosomes and autophagosomes.
Exophthalmos was accompanied by hypothyroidism due to collapse of
thyroid follicles.
KCNJ2-AS1
| dbSNP name | rs9889883(G,A); rs9897832(G,C) |
| cytoBand name | 17q24.3 |
| EntrezGene GeneID | 400617 |
| snpEff Gene Name | KCNJ2 |
| EntrezGene Description | KCNJ2 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.06015 |
SOX9
| dbSNP name | rs1042667(A,C); rs1042673(A,G); rs74999341(T,C) |
| cytoBand name | 17q24.3 |
| EntrezGene GeneID | 400618 |
| EntrezGene Symbol | SOX9-AS1 |
| EntrezGene Description | SOX9 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3916 |
| ESP Afr MAF | 0.208579 |
| ESP All MAF | 0.364518 |
| ESP Eur/Amr MAF | 0.444483 |
| ExAC AF | 0.396 |
OMIM Clinical Significance
Skin:
Skin photosensitivity;
Early onset skin cancer (basal cell, squamous cell and malignant melanoma);
Early freckle-like lesions in exposed areas;
Poikiloderma;
Increased/decreased skin pigment;
Skin atrophy;
Telangiectasia;
Actinic keratoses;
Angiomas;
Keratoacanthomas
Eyes:
Photophobia;
Conjunctivitis;
Keratitis;
Ectropion;
Entropion
Neuro:
Mental deterioration;
Low intelligence;
Microcephaly;
Sensorineural deafness;
Hyporeflexia;
Spasticity;
Areflexia (common);
Ataxia (often);
Choreoathetosis
Growth:
Dwarfism
GU:
Gonadal hypoplasia
Radiology:
Cerebral and olivopontocerebellar atrophy
Misc:
May occur in any one of the 7 complementation groups, but most often
in those of complementation group D (278730);
Defective DNA repair after ultraviolet radiation damage
Inheritance:
Autosomal recessive
OMIM Title
#278850 46,XX SEX REVERSAL 2; SRXX2
;;CHROMOSOME 17q24 DUPLICATION SYNDROME;;
46,XX SEX REVERSAL, PARTIAL OR COMPLETE, SOX9-RELATED
OMIM Description
A number sign (#) is used with this entry because in some cases familial
46,XX sex reversal can be caused by duplication in a regulatory region
upstream of the SOX9 gene (608160) on chromosome 17q24.
CLINICAL FEATURES
Kuhnle et al. (1993) described a family with a 46,XX male and a 46,XX
true hermaphrodite sib. An offspring of a maternal uncle had 46,XX true
hermaphroditism. The maternal as well as paternal transmission of the
disorder allows the possibility of either autosomal dominant or
X-chromosomal dominant inheritance. Since molecular genetic analysis
showed that both hermaphrodites as well as the 46,XX male were negative
for Y-chromosomal sequences, testicular determination seemed to be due
to varying expression of the same genetic defect, which presumably was
incompletely penetrant. A mutation in an autosomal or X-chromosomal gene
downstream from SRY (480000) could have turned itself or another gene
into a testis-determining factor (TDF)-like gene. In the case of the
mutation of an X-chromosomal gene, a different X inactivation pattern
could explain the different phenotypes: random inactivation in XX true
hermaphrodites and nonrandom in XX males. They pointed out that the
46,XX male could in fact have been a true hermaphrodite with unambiguous
male external genitalia, since no surgical biopsy of both gonads to
exclude the presence of ovarian parts was performed.
Slaney et al. (1998) reported a family in which 4 related 46,XX
individuals with no evidence of Y chromosome DNA sequences underwent
variable degrees of male sexual differentiation. One 46,XX male had
apparently normal male external genitalia, whereas his brother and 2
cousins had various degrees of sexual ambiguity and were found to be
46,XX true hermaphrodites. Slaney et al. (1998) stated that the presence
of male sexual development in genetic females with transmission through
normal male and female parents indicated that the critical genetic
defect was most likely an autosomal dominant mutation, with the
different phentypic effects arising from variable penetrance. They
proposed that there might be an 'activating' mutation in this family,
mimicking the initiating role of the SRY gene in 46,XX individuals.
Cox et al. (2011) identified a family with 46,XX testicular disorder of
sex development in which 3 adult males, 2 brothers and a paternal uncle,
were determined to be female according to karyotype (46,XX) and were
negative for the SRY gene. The secondary sexual characteristics,
behavior, growth and development, and skeletal development in these men
were all those of normal males. Their general health and intelligence
were normal. Affected individuals were infertile with azoospermia. In 2
men the testes had been removed and prostheses placed during their 20s
because of testicular pain secondary to testosterone replacement.
Histologic exams showed the presence of Leydig and Sertoli cells,
severely diminished and atrophied seminiferous tubules, and no
spermatogenesis.
INHERITANCE
Blecher and Erickson (2007) reviewed knowledge of sexual development and
proposed a new paradigm, namely, that sexual dimorphism precedes gonadal
development, in a so-called 'pregonadal stage.' Noting that absence of
testicular hormones does not produce a normal female phenotype, they
stated that contrary to the classic paradigm, female development does
not occur by default. Blecher and Erickson (2007) suggested that
proximate gonad-determining genes are probably on the autosomes, with
indirect and complex interactions between these and the primary factors
on sex chromosomes.
CYTOGENETICS
In a newborn infant with severe penile/scrotal hypospadias, bifid
scrotum, palpable gonads, and no uterus by ultrasound examination, Huang
et al. (1999) performed cytogenetic analysis and demonstrated a de novo
mosaic 46,XX,dup(17)(q23.1q24.3)/46,XX karyotype. Fluorescence in situ
hybridization studies revealed that the SOX9 gene was duplicated on the
rearranged chromosome 17 and ruled out the presence of SRY.
Microsatellite analysis using 13 markers on 17q23-q24 showed that the
duplication was maternal in origin, with boundaries approximately 12 cM
proximal and 4 cM distal to the SOX9 gene. Huang et al. (1999) concluded
that these findings suggested that an extra dose of SOX9 is sufficient
to initiate testis differentiation in the absence of SRY.
MOLECULAR GENETICS
In 2 brothers and their uncle with normal male phenotypes and 46,XX
karyotypes, Cox et al. (2011) found a 178-kb duplication 600 kb upstream
of SOX9 (608160.0014). The brothers' healthy, fertile father also
carried the duplication. Cox et al. (2011) noted that the 1.9-Mb region
of chromosome 17 upstream of SOX9 contains no other genes, is
evolutionarily highly conserved in mammals, and gives rise to a wide
range of phenotypes when mutated. They commented that although SRY is
normally needed for SOX9 activation and the male phenotype, in this
family a small duplication alone seemed to be sufficient to override
this fundamental genetic process. Only the sex-dependent expression of
SOX9 was affected, presumably through specific enhanced promoter
activity.
ANIMAL MODEL
Sex reversal mutations have been observed in the goat (Hamerton et al.,
1969) and in the mouse (Cattanach et al., 1971). The disorder is
recessive in the goat, but dominant in the mouse. In these cases the
autosomal gene apparently causes the indifferent gonad of genetic
females to differentiate partially or completely into a testis. Selden
et al. (1978) studied an instructive family of American cocker spaniels
which suggested that abnormality of sexual development (development of
testes or ovotestes) in animals with an XX karyotype was caused by
anomalous transmission of H-Y genes. The observations suggested a common
basis for the XX male syndrome and for XX true hermaphroditism.
HISTORY
Kasdan et al. (1973) described a family in which a paternally
transmitted, non-Y, male-determining autosomal gene was postulated as
the only plausible explanation for sex reversal. The phenotype resembled
that of the Klinefelter syndrome. Translocation of Y-chromosome material
to an autosome could be excluded as the cause in at least some cases.
With the discovery of the SRY ('sex region on the Y') gene (480000) and
its equating to the TDF (testis-determining factor) gene, it became
possible to demonstrate Y-chromosome material on one X chromosome in XX
males (see 400045).
Like Kasdan et al. (1973) and Berger et al. (1970), Skordis et al.
(1987) described XX true hermaphrodites and XX males in the same family.
In the report of Skordis et al. (1987), the propositus was a paternal
uncle with 46,XX true hermaphroditism. One of his brothers fathered a
46,XX daughter with true hermaphroditism; a second brother fathered two
46,XX males. Both fathers had normal male karyotypes and phenotypes.
Skordis et al. (1987) concluded that XX true hermaphrodites and XX males
represent alternative manifestations of the same genetic defect and that
the abnormality occurs via paternal transmission of an autosomal
testis-determining factor. It was pointed out by de la Chapelle (1987)
that in the several instances of familial XX maleness and XX true
hermaphroditism, most affected persons are true hermaphrodites or XX
males with ambiguous genitalia, whereas XX males without genital
ambiguity are rare in such families. No Y-chromosome DNA has been found
in familial cases. Typical autosomal dominant inheritance of XX
testicular differentiation occurs in informative pedigrees. De la
Chapelle (1987) hypothesized that an autosomal dominant
testis-determining factor, TDFA, exists. They suggested that TDFA shows
somewhat variable expression in XX persons, often causing genital
ambiguity or true hermaphroditism, but has no phenotypic effect in XY
persons.
Pierella et al. (1981) suggested the existence, at least in some cases,
of an autosomal mutation that causes inactivation of a subterminal
portion of Xp which normally escapes inactivation. The suggestion was
based on the demonstration of male levels of steroid sulfatase in 2
affected cousins who could not share the same X chromosome because they
were related through their fathers and their paternal grandfathers. An
autosomal factor influencing sex determination, H-Y antigen (426000)
production, Xg (314700) expression, and steroid sulfatase (300747)
levels can be understood if its effects are mediated via autosomal
control of inactivation of a distal segment of Xp. Autosomal control of
X inactivation may be suggested by the presence of more than one active
X per cell in tetraploids and some triploids. There is probably
pathogenetic heterogeneity in the category of XX males.
C17orf77
| dbSNP name | rs58253413(C,T); rs545652(C,A); rs7208696(C,G); rs12941999(T,C); rs12949223(G,T); rs524536(T,C); rs141832104(G,A); rs180946467(C,T); rs553781(T,C) |
| ccdsGene name | CCDS32721.1 |
| CosmicCodingMuts gene | C17orf77 |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 146723 |
| EntrezGene Description | chromosome 17 open reading frame 77 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C17orf77:NM_152460:exon3:c.C593T:p.T198I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96MU5 |
| dbNSFP Uniprot ID | CQ077_HUMAN |
| dbNSFP KGp1 AF | 0.102564102564 |
| dbNSFP KGp1 Afr AF | 0.115853658537 |
| dbNSFP KGp1 Amr AF | 0.0552486187845 |
| dbNSFP KGp1 Asn AF | 0.195804195804 |
| dbNSFP KGp1 Eur AF | 0.0461741424802 |
| dbSNP GMAF | 0.1024 |
| ESP Afr MAF | 0.089877 |
| ESP All MAF | 0.058435 |
| ESP Eur/Amr MAF | 0.042326 |
| ExAC AF | 0.07 |
LOC100287042
| dbSNP name | rs3809716(G,T); rs3744231(C,T); rs3744230(C,T); rs7198(G,C); rs4789164(C,T) |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 100287042 |
| snpEff Gene Name | SLC25A19 |
| EntrezGene Description | uncharacterized LOC100287042 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.404 |
GALR2
| dbSNP name | rs113884061(C,T); rs76669670(G,A) |
| ccdsGene name | CCDS11739.1 |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 8811 |
| EntrezGene Description | galanin receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GALR2:NM_003857:exon2:c.C876T:p.Y292Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.000461 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.000114 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Brachycephaly;
Cranium bifidum, anterior;
[Eyes];
Hypertelorism;
Telecanthus;
Myopia (in some patients);
Ptosis (in some patients);
Corneal dermoid cyst (rare);
Glaucoma (rare);
Optic nerve hypoplasia, segmental (rare);
Persistent primary vitreous (rare);
[Nose];
Bifid nose;
Nostril notching;
Broad nasal tip;
Separation of nostrils;
[Mouth];
Carp-shaped mouth (in some patients);
Cleft lip;
Cleft palate
RESPIRATORY:
[Airways];
Upper airway obstruction, severe (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism (in some patients)
SKELETAL:
[Skull];
Persistent craniopharyngeal canal (rare);
Vertical clivus (in some patients);
[Limbs];
Patellar hypoplasia or aplasia (in some patients);
Tibial hypoplasia;
[Hands];
Preaxial polydactyly;
Preaxial polysyndactyly;
[Feet];
Preaxial polydactyly;
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Vertical creases of plantar surface between first and second toes;
[Nails];
Clubbed, thickened nails of halluces (1 patient)
NEUROLOGIC:
[Central nervous system];
Encephalocele;
Agenesis of corpus callosum;
Hypoplasia of corpus callosum;
Ventricular dilatation;
Mental retardation;
Periventricular nodular heterotopia;
Choroid plexus cyst;
Septum pellucidum deficient or cavum;
Calcification of the falx;
Interhemispheric lipoma;
Absent olfactory bulbs;
Enlarged sella turcica;
Absence of anterior pituitary;
Fenestrated basilar artery;
Persistent falcine venous sinus;
Retrocerebellar cyst;
Seizures
ENDOCRINE FEATURES:
Hypopituitarism (in some patients)
MISCELLANEOUS:
Brain anomalies variable;
Four unrelated patients with ZSWIM6 mutations have been described
(last curated September 2014)
MOLECULAR BASIS:
Caused by mutation in the zinc finger SWIM domain-containing protein
6 (ZSWIM6, 615951.0001)
OMIM Title
*603691 GALANIN RECEPTOR 2; GALR2
;;GALNR2
OMIM Description
DESCRIPTION
The neuropeptide galanin mediates a diverse spectrum of biologic
activities by interacting with specific G protein-coupled receptors
(GPCRs), such as GALR1 (600377) and GALR2. The activities mediated by
galanin include modulation of the release of several neurotransmitters
and hormones and regulation of gastrointestinal smooth muscle
contractility; galanin has effects as well on cognition, sensory/pain
processing, sexual activity, and appetite.
CLONING
Fathi et al. (1998), Borowsky et al. (1998), and Bloomquist et al.
(1998) each isolated cDNAs encoding the human homolog of the rat galanin
receptor, GalR2. By sequence analysis, Fathi et al. (1998) found that
the predicted 387-amino acid GALR2 protein contains the 7 transmembrane
domain structure typical of GPCRs. GALR2 shares 87% and 40% protein
sequence identity with rat GalR2 and human GALR1, respectively. Using
RT-PCR, Borowsky et al. (1998) determined that GALR2 is expressed
abundantly within the central nervous system in both hypothalamus and
hippocampus. In peripheral tissues, the strongest expression was
observed in heart, kidney, liver, and small intestine.
Kolakowski et al. (1998) isolated cDNAs encoding GALR2 and GALR3
(603692).
GENE FUNCTION
Fathi et al. (1998) found that GALR2 exhibited a pharmacologic profile
similar to, but distinct from, that of GALR1 when expressed in mammalian
cells. Both human receptors interacted with N-terminal residues of the
galanin peptide.
Kolakowski et al. (1998) reported that the primary signaling mechanism
for GALR2 is through the phospholipase C/protein kinase C pathway (via
Gq; see 600998), in contrast to GALR1, which communicates its
intracellular signal by inhibition of adenylyl cyclase through Gi (see
139310). However, Fathi et al. (1998) demonstrated that GALR2 coupled
efficiently to both the Gq and the Gi proteins to simultaneously
activate 2 independent signal transduction pathways.
Xia et al. (2004) determined that rat Galr2 undergoes constitutive
endocytosis and recycling and that both ligand-independent and
ligand-dependent internalization use the clathrin-dependent endocytic
recycling pathway.
GENE STRUCTURE
Fathi et al. (1998) reported that the GALR2 gene contains 2 coding
exons.
MAPPING
By fluorescence in situ hybridization, Fathi et al. (1998) mapped the
GALR2 gene to 17q25.3.
SPHK1
| dbSNP name | rs346803(G,A); rs3744037(T,C); rs346801(G,A) |
| ccdsGene name | CCDS11744.1 |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 8877 |
| EntrezGene Description | sphingosine kinase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SPHK1:NM_182965:exon2:c.G100A:p.A34T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NYA1-2 |
| dbNSFP KGp1 AF | 0.900183150183 |
| dbNSFP KGp1 Afr AF | 0.843495934959 |
| dbNSFP KGp1 Amr AF | 0.903314917127 |
| dbNSFP KGp1 Asn AF | 0.998251748252 |
| dbNSFP KGp1 Eur AF | 0.861477572559 |
| dbSNP GMAF | 0.09917 |
| ESP Afr MAF | 0.11253 |
| ESP All MAF | 0.104139 |
| ESP Eur/Amr MAF | 0.100253 |
| ExAC AF | 0.883 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Microphthalmia, bilateral;
Coloboma of iris;
Coloboma, choreoretinal;
Coloboma, uveoretinal
MISCELLANEOUS:
Reduced penetrance
MOLECULAR BASIS:
Caused by mutation in the sonic hedgehog gene (SHH, 600725.0016)
OMIM Title
*611646 SPHK1-INTERACTING PROTEIN; SPHKAP
;;SPHK1 INTERACTOR, AKAP DOMAIN-CONTAINING;;
SKIP;;
KIAA1678
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated human fetal brain
cDNA library, Nagase et al. (2000) cloned KIAA1678. The deduced protein
contains 1,302 amino acids. RT-PCR ELISA of human tissues detected
strong expression in heart and moderate expression in adult brain, fetal
brain, and ovary. Amygdala, hippocampus, and thalamus showed strong
expression with moderate expression in cerebellum caudate nucleus,
substantia nigra, subthalamic nucleus, and spinal cord.
By yeast 2-hybrid screening of a human brain cDNA library using SPHK1
(603730) as bait, Lacana et al. (2002) cloned SKIP. The deduced
305-amino acid protein shared 99% identity with the C terminus of
KIAA1678. Northern blot analysis of human tissues detected a 7-kb
transcript with highest expression in heart, followed by spleen, ovary,
and brain. SKIP shares 35-40% amino acid identity with the C-terminal
region of AKAP3 (604689) and AKAP11 (604696). Confocal microscopy
localized SKIP to the cytoplasm despite the presence of a putative
nuclear targeting sequence and signal peptide.
GENE FUNCTION
Using GST pull-down and immunoprecipitation studies, Lacana et al.
(2002) showed that SKIP interacted with SPHK1. Overexpression of SKIP in
HEK293 cells significantly reduced SPHK1 activity in both the cytosolic
and particulate fractions. Using BrdU incorporation, they showed that
NIH3T3 cells expressing SPHK1 displayed an increased proportion of cells
in S phase; however, SKIP overexpression reduced BrdU incorporation and
abolished SPHK1-promoted cell proliferation. In addition, SKIP
overexpression enhanced apoptosis of serum-starved cells and induced
cell rounding, and SKIP reduced activation of ERK1 (MAPK3; 601795)/ERK2
(MAPK1; 176948) induced by SPHK1.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the SKIP
gene to chromosome 2 (TMAP RH11952).
SNORD1B
| dbSNP name | rs16969028(A,C) |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 100507246 |
| EntrezGene Symbol | SNHG16 |
| snpEff Gene Name | ST6GALNAC2 |
| EntrezGene Description | small nucleolar RNA host gene 16 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07392 |
| ESP Afr MAF | 0.256279 |
| ESP All MAF | 0.079526 |
| ESP Eur/Amr MAF | 0.001758 |
| ExAC AF | 0.022 |
SRSF2
| dbSNP name | rs237059(T,C) |
| cytoBand name | 17q25.1 |
| EntrezGene GeneID | 6427 |
| snpEff Gene Name | METTL23 |
| EntrezGene Description | serine/arginine-rich splicing factor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08127 |
OMIM Clinical Significance
GU:
Nocturnal enuresis
Inheritance:
Autosomal dominant (12q13-q21);
heterogeneity
OMIM Title
*600813 SPLICING FACTOR, SERINE/ARGININE-RICH, 2; SRSF2
;;SERINE/ARGININE-RICH SPLICING FACTOR 2;;
SPLICING FACTOR SC35; SC35;;
SPLICING FACTOR, ARGININE/SERINE-RICH, 30-KD, B; SRp30b;;
SPLICING FACTOR, ARGININE/SERINE-RICH, 2; SFRS2
OMIM Description
CLONING
Fu and Maniatis (1992) isolated a human cDNA termed pre-mRNA splicing
factor SC35, or SFRS2, that is required for spliceosome assembly. The
predicted protein contains a ribonucleoprotein (RNP)-type RNA-binding
motif and a carboxyl-terminal serine/arginine-rich (SR) domain.
GENE FUNCTION
Wang et al. (2001) reported that Cre-mediated conditional deletion of
the prototypic SR protein Sc35 in mouse thymus caused a defect in T-cell
maturation. Deletion of Sc35 altered alternative splicing of CD45
(151460), a receptor tyrosine phosphatase regulated by differential
splicing during thymocyte development and activation.
Lareau et al. (2007) reported that in every member of the human SR
family of splicing regulators, highly or ultraconserved elements are
alternatively spliced, either as alternative 'poison cassette exons'
containing early in-frame stop codons, or as alternative introns in the
3-prime untranslated region. These alternative splicing events target
the resulting mRNAs for degradation by means of an RNA surveillance
pathway called nonsense-mediated mRNA decay. Mouse orthologs of the
human SR proteins exhibit the same unproductive splicing patterns. Three
SR proteins, SRp20 (603364), SC35, and 9G8 (SFRS7; 600572), had been
previously shown to direct splicing of their own transcripts, and SC35
autoregulates its expression by coupling alternative splicing with
decay. Lareau et al. (2007) concluded that unproductive splicing is
important for regulation of the entire SR family and found that
unproductive splicing associated with conserved regions has arisen
independently in different SR genes, suggesting that splicing factors
may readily acquire this form of regulation.
MAPPING
Bermingham et al. (1995) used recombinant inbred mapping to locate the
mouse homologs of the human SFRS1 (600812) and SFRS2 loci to mouse
chromosome 11 in a region that is homologous to human chromosome 17.
Mapping using F1 hybrid backcross mice confirmed the finding.
Kuhlenbaeumer et al. (1998) placed the SFRS2 gene within the hereditary
neuralgic amyotrophy (162100) locus on 17q25 and excluded it as a
candidate gene.
FLJ45079
| dbSNP name | rs72892232(C,G); rs7223556(T,C); rs60437509(A,T); rs894546(G,A); rs58318876(G,A); rs894545(T,C); rs2077228(C,T); rs374335966(G,A); rs3935192(G,A) |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 400624 |
| snpEff Gene Name | AC015804.1 |
| EntrezGene Description | FLJ45079 protein |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08127 |
TNRC6C-AS1
| dbSNP name | rs2273280(C,T); rs1048591(G,C); rs67686854(C,T); rs16970842(A,G) |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 100131096 |
| snpEff Gene Name | TNRC6C |
| EntrezGene Description | TNRC6C antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09917 |
SOCS3
| dbSNP name | rs4969168(A,G); rs4969169(T,C); rs41522945(C,T) |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 9021 |
| EntrezGene Description | suppressor of cytokine signaling 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3462 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Midface hypoplasia (in some patients);
[Ears];
Otitis media, recurrent;
[Eyes];
Hypertelorism (in some patients);
Eyebrow hypoplasia (in some patients)
RESPIRATORY:
[Lung];
Pulmonary infections, recurrent
ABDOMEN:
[Spleen];
Splenomegaly
SKELETAL:
[Hands];
Hypermobile fingers - 'beak of swan' appearance (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Poikiloderma;
Keratoderma of palms and soles;
[Nails];
Pachyonychia
HEMATOLOGY:
Neutropenia
IMMUNOLOGY:
Recurrent infections at variable sites (sinusitis, otitis media,
facial cellulitis, adenitis, blepharitis, conjunctivitis, gastroenteritis)
LABORATORY ABNORMALITIES:
Neutropenia
MOLECULAR BASIS:
Caused by mutation in the chromosome 16 open reading frame 57 gene
(C16ORF57, 613276.0001)
OMIM Title
*604176 SUPPRESSOR OF CYTOKINE SIGNALING 3; SOCS3
;;STAT-INDUCED STAT INHIBITOR 3; SSI3;;
CYTOKINE-INDUCIBLE SH2 PROTEIN 3; CIS3
OMIM Description
DESCRIPTION
Suppressor of cytokine signaling (SOCS) proteins are key regulators of
immune responses and exert their effects in a classic negative-feedback
loop. SOCS3 is transiently expressed by multiple cell lineages within
the immune system and functions predominantly as a negative regulator of
cytokines that activate the JAK (see 147795)-STAT3 (102582) pathway
(summary by Hill et al., 2010).
CLONING
Minamoto et al. (1997) isolated a human cDNA encoding SSI3 (STAT-induced
STAT inhibitor-3) from a Jurkat cDNA library based on its sequence
similarity and hybridization to a mouse Ssi1 probe. The SSI3 gene
encodes a deduced 225-amino acid protein. Masuhara et al. (1997)
isolated the same gene and referred to it as CIS3 (cytokine-inducible
SH2 protein-3). Starr et al. (1997) referred to the gene as SOCS3
(suppressor of cytokine signaling-3).
GENE FUNCTION
Masuhara et al. (1997) showed that CIS3 bound to the JAK2 (147796)
tyrosine kinase domain.
Using macrophages obtained from Soc3-deficient mice, Yasukawa et al.
(2003) observed that IL10 (124092) or IL6 suppressed Tnf (191160) and
Il12 (see 161561) production after lipopolysaccharide stimulation. These
results suggested that SOCS3 selectively blocks signaling by IL6.
Lang et al. (2003) reported that phosphorylation of Stat3 is prolonged
after IL6, but not IL10, stimulation in Socs3-deficient macrophages.
They concluded that SOCS3 prevents the activation of an IFN-induced
program of gene expression.
He et al. (2003) reported the identification of frequent
hypermethylation in CpG islands of the functional SOCS3 promoter that
correlated with its transcription silencing in cell lines (lung cancer,
breast cancer, and mesothelioma) and primary lung cancer tissue samples.
Restoration of SOCS3 in lung cancer cells where SOCS3 was
methylation-silenced resulted in the downregulation of active STAT3
(102582), induction of apoptosis, and growth suppression. These results
suggested that methylation silencing of SOCS3 is one of the important
mechanisms of constitutive activation of the JAK/STAT pathway in cancer
pathogenesis. The data also suggested that SOCS3 therapy may be useful
in the treatment of cancer.
Spangenburg (2005) found that Socs3 mRNA level and transcriptional
activity increased during differentiation in a mouse myoblast cell line.
Socs3 expression was induced, at least in part, by activation of
insulin-like growth factor-1 receptor (IGF1R; 147730) during
differentiation. Overexpression of Socs3 cDNA increased transcription of
reporter genes activated by skeletal muscle alpha-actin (see 102610) and
serum response factor (SRF; 600589) promoters during myoblast
differentiation, but it did not affect transcription from an Nfat (see
NFAT1; 600489) promoter. Socs3 contributed to myoblast differentiation
in the absence of Igf1 (147440), suggesting that SOCS3 activation is
downstream of IGF1 signaling.
Jo et al. (2005) created cell-penetrating (CP) forms of murine Socs3 by
adding membrane-translocating motifs to either the N- or C-terminal ends
of the Socs3 protein. Both recombinant CP-Socs3 proteins distributed to
multiple organs in mice within 2 hours following intraperitoneal
injection and persisted for at least 8 hours in leukocytes and
lymphocytes. CP-Socs3 protected mice from the lethal effects of
staphylococcal enterotoxin B and lipopolysaccharide by reducing
production of inflammatory cytokines and attenuating liver apoptosis and
hemorrhagic necrosis. CP-Socs3 also reduced concavalin A-induced liver
apoptosis. Jo et al. (2005) concluded that replenishing intracellular
stores of SOCS3 with CP-SOCS3 suppresses the effects of acute
inflammation.
Using microarray analysis and quantitative real-time PCR, Sonkoly et al.
(2007) showed that expression of miR203 (MIRN203; 611899) was
consistently upregulated in psoriatic skin lesions (see 177900) compared
with normal skin. In situ hybridization revealed increased expression of
miR203 in all epidermal layers of psoriatic lesional skin. Sonkoly et
al. (2007) identified an evolutionarily conserved putative 10-nucleotide
miR203-binding site in the 3-prime UTR of SOCS3. Immunohistochemical
analysis showed that expression of SOCS3 protein was complementary to
that of miR203, with higher SOCS3 expression in the basal layer of
keratinocytes in healthy skin and suppression of SOCS3 in the dermis of
psoriatic lesions. Western blot analysis confirmed downregulation of
SOCS3 in psoriasis. Quantitative real-time PCR showed no significant
difference in SOCS3 mRNA expression in psoriatic and healthy skin,
suggesting that downregulation of SOCS3 in psoriasis occurs at the
posttranscriptional level. Since SOCS3 deficiency leads to sustained
activation of STAT3 in response to IL6 (147620), a cytokine present in
psoriatic lesions, Sonkoly et al. (2007) proposed that suppression of
SOCS3 by miR203 in psoriatic lesions leads to constant STAT3 activation.
Ma et al. (2007) stated that Hnf1b (189907) knockout in mouse kidney
results in cyst formation. Using genomewide chromatin
immunoprecipitation and DNA microarray analysis and microarray analysis
of mRNA expression, Ma et al. (2007) identified Socs3 as an Hnf1b target
gene in mouse kidney. Hnf1b bound to the Socs3 promoter and repressed
Socs3 transcription. Expression of Socs3 increased in Hnf1b-knockout
mice and in renal epithelial cells expressing dominant-negative mutant
Hnf1b. Increased levels of Socs3 inhibited Hgf (142409)-induced
tubulogenesis by decreasing phosphorylation of Erk (see MAPK1; 176948)
and Stat3. Conversely, knockdown of Socs3 in renal epithelial cells
expressing dominant-negative mutant Hnf1b rescued the defect in
Hgf-induced tubulogenesis by restoring phosphorylation of Erk and Stat3.
Ma et al. (2007) concluded that HNF1B regulates renal tubulogenesis by
controlling expression of SOC3.
Sabio et al. (2008) explored the mechanism of JNK1 (601158) signaling by
engineering mice in which the Jnk1 gene was ablated selectively in
adipose tissue. JNK1 deficiency in adipose tissues suppressed high-fat
diet-induced insulin resistance in the liver. JNK1-dependent secretion
of the inflammatory cytokine IL6 by adipose tissue caused increased
expression of liver SOCS3, which induces hepatic insulin resistance.
Sabio et al. (2008) concluded that JNK1 activation in adipose tissue can
cause insulin resistance in the liver.
Deletion of either PTEN (601728) or SOCS3 in adult retinal ganglion
cells (RGCs) individually promotes significant optic nerve regeneration,
but regrowth tapers off around 2 weeks after crush injury (Park et al.,
2008; Smith et al., 2009). Sun et al. (2011) showed that, remarkably,
simultaneous deletion of both PTEN and SOCS3 enables robust and
sustained axon regeneration. Sun et al. (2011) further showed that PTEN
and SOCS3 regulate 2 independent pathways that act synergistically to
promote enhanced axon regeneration. Gene expression analyses suggested
that double deletion not only results in the induction of many
growth-related genes, but also allows RGCs to maintain the expression of
a repertoire of genes at the physiologic level after injury. Sun et al.
(2011) concluded that their results revealed concurrent activation of
mTOR (601231) and STAT3 (102582) pathways as key for sustaining
long-distance axon regeneration in adult central nervous system, a
crucial step towards functional recovery.
BIOCHEMICAL FEATURES
Babon et al. (2006) described the solution structure of murine Socs3 in
complex with a phosphotyrosine-containing peptide from the Il6 receptor
signaling subunit gp130 (IL6ST; 600694). The structure of the complex
showed that 7 residues form a predominantly hydrophobic binding motif.
Regions outside the Socs3 SH2 domain were important for ligand binding;
in particular, a 15-residue alpha helix immediately N-terminal to the
SH2 domain made direct contacts with the phosphotyrosine binding loop
and, in part, determined its geometry. The SH2 domain itself contains a
35-residue unstructured PEST motif that increased Socs3 turnover.
MOLECULAR GENETICS
For discussion of a possible association between variation in the SOCS3
gene and atopic dermatitis, see ATOD4 (605805).
ANIMAL MODEL
During embryonic development, SOCS3 is highly expressed in erythroid
lineage cells and is erythropoietin (EPO; 133170) independent. Marine et
al. (1999) found that transgene-mediated expression in mice blocked
fetal erythropoiesis, resulting in embryonic lethality. Homozygous
deletion of the Socs3 gene in mice resulted in embryonic lethality at 12
to 16 days associated with marked erythrocytosis. Moreover, the in vitro
proliferative capacity of progenitors was greatly increased.
Socs3-deficient fetal liver stem cells could reconstitute hematopoiesis
in lethally irradiated adults, indicating that its absence does not
disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages
in Jak3 (600173)-deficient mice also occurred normally. These results
demonstrated that SOCS3 is critical in negatively regulating fetal liver
hematopoiesis.
Roberts et al. (2001) generated mice lacking a functional Socs3 gene.
They showed that the death of Socs3 -/- mice at midgestation is not
related to defects in the embryo but is associated with abnormalities in
specific regions of the placenta. They concluded that lethality in
Socs3-null mice results from placental insufficiency and found no
evidence of defective erythropoiesis.
Takahashi et al. (2003) found that Socs3-deficient placentas had reduced
spongiotrophoblasts and increased trophoblast secondary giant cells.
Overexpression of Socs3 in a trophoblast stem cell line suppressed giant
cell differentiation. Conversely, Socs3-deficient trophoblast stem cells
differentiated more readily to giant cells in culture. Leukemia
inhibitory factor (LIF; 159540) promoted giant cell differentiation in
vitro, and Lif receptor (LIFR; 151443) deficiency resulted in loss of
giant cell differentiation in vivo. Lifr deficiency rescued the
Socs3-deficient placenta defect and embryonic lethality. Takahashi et
al. (2003) concluded that SOCS3 is an essential regulator of LIFR
signaling in trophoblast differentiation.
Croker et al. (2003) used conditional gene targeting to generate mice
lacking Socs3 in liver and macrophages. They found that IL6 (147620)
induced prolonged activation of Stat1 (600555) and Stat3 (102582) in
Soc3 -/- cells, whereas IFNG (147570) induced normal activation.
Conversely, Stat activation was normal in Socs1-deficient cells after
IL6 stimulation but prolonged after IFNG stimulation. Microarray
analysis showed that the gene expression pattern in livers of
Soc3-deficient mice after IL6 injection resembled that of normal mice
injected with IFNG. Croker et al. (2003) concluded that SOCS3 and SOCS1
have reciprocal functions in IL6 and IFNG regulation and that SOCS3 may
have a role in preventing IFNG-like responses in cells stimulated by
IL6.
Members of the suppressor of cytokine signaling (SOCS) family are
involved in the pathogenesis of many inflammatory diseases. SOCS3 is
predominantly expressed in T-helper type 2 cells, and Seki et al. (2003)
investigated its role in TH2-related allergic diseases. They found a
strong correlation between SOCS3 expression and the pathology of asthma
and atopic dermatitis, as well as serum IgE levels in allergic human
patients. Socs3 transgenic mice showed increased TH2 responses and
multiple pathologic features characteristic of asthma in an airway
hypersensitivity model system. In contrast, dominant-negative mutant
Socs3 transgenic mice, as well as mice with a heterozygous deletion of
Socs3, had decreased TH2 development. These data indicated that SOCS3
has an important role in regulating the onset and maintenance of
TH2-mediated allergic immune disease, and suggested that SOCS3 may be a
new therapeutic target for antiallergic drugs.
Chen et al. (2006) used a conditional knockout approach to examine the
effect of Socs3 on T-helper (Th) cell polarization in mice. They found
that Socs3 had little effect on Th1 or Th2 polarization, but it had a
significant role in constraining generation of Th17 cells, the subset of
Th cells that selectively produce Il17 (603149) and are putative
regulators of inflammation. Il23 (see 605580)-induced phosphorylation of
Stat3 was enhanced in Th cells lacking Socs3. Chromatin
immunoprecipitation and PCR analysis showed that Stat3 bound to both the
Il17 and Il17f (606496) promoters and that the binding was enhanced by
stimulation with Il23. RT-PCR, ELISA, and flow cytometric analysis
demonstrated increased Il17 expression in the absence of Socs3.
Stimulation with Tgfb (190180) and Il6 potently induced Il17 secretion,
and this stimulation was enhanced in the absence of Socs3. Chen et al.
(2006) concluded that SOCS3 plays an important role in Th cell
differentiation by limiting development of Th17 cell polarization
through attenuation of phosphorylation of Stat3, which is likely to be a
direct regulator of IL17 transcription.
Wong et al. (2006) found that a mouse model of rheumatoid arthritis (RA;
180300) induced by methylated bovine serum albumin and Il1 (see 147760)
was exacerbated in mice lacking Socs3 in hematopoietic and endothelial
cells. The enhanced inflammatory arthritis in mutant mice was associated
with marked bone destruction and increased osteoclast and neutrophil
infiltration. Neutrophil numbers were also increased in blood, spleen,
and bone marrow. Serum levels of Il6 and Gcsf (CSF3; 138970) were
elevated, and draining lymph nodes were enlarged and contained
hyperproliferative T cells producing Il17. Macrophages from mutant mice
were also hyperresponsive to Il1. Wong et al. (2006) concluded that
SOCS3 is a critical negative regulator of IL1-dependent acute
inflammatory arthritis and osteoclast generation.
Hill et al. (2010) studied the contribution of Socs3 to
graft-versus-host disease (GVHD; see 614395) after allogeneic stem cell
transplantation. They found that grafts from mice lacking Socs3 only in
hematopoietic cells had an augmented capacity to induce acute GVHD.
Transplantation with donors in which Socs3 deficiency was restricted
either to myeloid or T-cell lineages showed that acute GVHD mortality
with gastrointestinal pathology occurred only in grafts from
Socs3-deficient T-cell donors. T cells lacking Socs3 underwent enhanced
alloantigen-dependent proliferation and produced Il10, Il17, and Ifng
after stem cell transplantation, although acute GVHD induction was
dependent only on Ifng. In addition, Socs3-deficient donor T cells
induced severe Tgfb (190180)- and Ifng-dependent sclerodermatous GVHD.
Hill et al. (2010) proposed that delivery of small SOCS3 mimetics may be
useful in the inhibition of both acute and chronic GVHD.
Smith et al. (2009) found that knockout of Socs3 in retinal ganglion
cells promoted neuronal survival and permitted regeneration of the optic
nerve following crush injury. Double knockout of gp130 (IL6ST; 600694)
and Socs3 blocked axon regeneration after injury, suggesting that Socs3
inhibits a gp130-dependent signaling pathway. Ciliary growth factor
(CNTF; 118945) was upregulated following nerve injury, and intravitreous
injection of Cntf further enhanced axon regeneration in Socs3-knockout
mice.
CBX8
| dbSNP name | rs4889891(C,A); rs61758361(T,C) |
| ccdsGene name | CCDS11765.1 |
| CosmicCodingMuts gene | CBX8 |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 57332 |
| EntrezGene Description | chromobox homolog 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CBX8:NM_020649:exon5:c.G950T:p.G317V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HC52 |
| dbNSFP Uniprot ID | CBX8_HUMAN |
| dbNSFP KGp1 AF | 0.552197802198 |
| dbNSFP KGp1 Afr AF | 0.792682926829 |
| dbNSFP KGp1 Amr AF | 0.687845303867 |
| dbNSFP KGp1 Asn AF | 0.356643356643 |
| dbNSFP KGp1 Eur AF | 0.47889182058 |
| dbSNP GMAF | 0.4481 |
| ESP Afr MAF | 0.225 |
| ESP All MAF | 0.403193 |
| ESP Eur/Amr MAF | 0.494207 |
| ExAC AF | 0.535 |
CCDC40
| dbSNP name | rs73437682(C,T); rs8074956(C,A); rs113842196(T,C); rs56136831(G,A); rs111790619(C,T); rs113396249(G,A); rs8068767(A,G); rs6565636(A,G); rs75421299(T,C); rs112431937(G,A); rs144372618(T,C); rs113467013(T,C); rs2289527(G,C); rs9909509(C,G); rs7502655(C,A); rs11654426(C,T); rs9900359(A,G); rs4640227(T,A); rs73434923(T,C); rs8071281(T,C); rs8070467(A,G); rs8070479(A,G); rs12942476(A,G); rs8081980(C,T); rs67154249(C,T); rs9896509(G,A); rs139852551(T,C); rs9902006(A,C); rs370321916(C,T); rs9897499(G,A); rs12943127(A,G); rs58650474(G,T); rs9916688(A,G); rs8073491(G,A); rs34681986(C,T); rs9903512(T,C); rs78037598(T,C); rs11650121(G,T); rs9892044(G,A); rs9904447(T,C); rs12951051(C,G); rs187597809(G,A); rs7207441(A,G); rs7212525(T,C); rs7212643(T,C); rs7223648(C,A); rs7223806(C,T); rs7212117(A,G); rs7212141(A,C); rs3816255(C,T); rs3829610(C,A); rs3829609(T,A); rs3829608(T,C); rs3829605(T,C); rs3829604(G,A); rs8074779(T,C); rs2289529(G,A); rs2289530(C,G); rs28404913(C,G); rs28484809(A,C); rs28645791(A,G); rs28397044(A,G); rs7219552(G,A); rs61998241(G,A); rs9890752(C,A); rs9902461(G,A); rs9914519(T,C); rs28363849(C,T); rs28754675(C,A); rs28726257(C,T); rs28675331(G,A); rs28706288(A,G); rs28406023(A,G); rs8071959(T,C); rs9915428(A,G); rs9905131(C,T); rs72849306(G,A); rs2013841(G,C); rs2044104(G,A); rs56003911(C,T); rs9944435(C,T); rs9944482(G,A); rs9944501(A,T); rs9944502(A,G); rs9906474(G,T); rs9906324(C,T); rs34780571(G,A); rs62074549(T,C); rs9907292(C,T); rs142521007(G,A); rs9891814(A,G); rs12600892(A,T); rs7208049(T,A); rs113698593(C,T); rs58550133(G,A); rs12948591(A,C); rs12952555(C,T); rs11868355(C,G); rs11871372(G,A); rs68137473(T,C); rs9909904(G,A); rs56091937(T,C); rs146646353(G,C); rs62000409(G,A); rs141472003(T,A); rs11654770(C,T); rs7225076(A,G); rs1134515(A,G); rs112872991(A,G); rs6565637(T,A); rs8068206(A,T); rs55808851(C,T); rs7208452(C,G); rs62074551(T,G); rs7217817(G,A); rs9897503(A,G); rs7221635(A,G); rs9904652(T,C); rs9904924(T,C); rs9893288(G,A); rs62074552(G,A); rs73439026(T,C); rs28510950(A,G); rs28585081(G,C); rs28642798(A,G); rs72849330(G,C); rs10083833(A,G); rs10083894(C,T); rs9319622(C,T); rs34865586(T,C); rs9894725(G,A); rs55959152(C,A); rs34629435(C,A); rs56071031(C,T); rs112533809(G,C); rs10083858(G,A); rs56126512(C,T); rs2289534(G,A); rs8082554(C,T); rs11867647(T,C); rs76013152(C,T); rs8076374(T,A); rs8076516(T,C); rs62074555(G,A); rs8072596(G,A); rs8080522(T,C); rs8080669(T,C); rs8073108(G,A); rs144820872(G,A); rs11871701(C,A); rs11867737(A,G); rs11868400(T,A); rs11867810(A,G); rs151038976(C,A); rs28613059(C,T); rs28736720(T,C); rs111584657(G,A); rs12602234(A,C); rs117320584(A,G); rs116186224(G,A); rs62074556(G,A); rs6420485(A,G); rs8079986(G,T); rs141964250(G,C); rs9902389(G,A); rs4889951(A,G); rs55938998(G,A); rs12937566(C,T); rs55710301(G,A); rs57277486(A,T); rs56381973(T,C); rs12602605(T,G); rs8072492(A,C); rs8069815(C,G); rs62074559(G,A); rs62075560(G,A); rs114334756(A,G); rs4889812(T,C); rs71389730(T,C); rs6565639(A,G); rs9907837(T,G); rs9319623(C,G); rs62075561(T,G); rs35578653(T,G); rs9899138(C,T); rs9889677(T,C); rs9910668(A,C); rs9905540(G,C); rs4889814(G,A); rs12451320(G,T); rs715041(G,A); rs2361704(C,T); rs76781594(C,T); rs2017601(A,G); rs60684213(G,A); rs145047968(G,A); rs73436177(G,A); rs73436179(G,A); rs7224338(C,T); rs1561811(T,A); rs1467979(C,T); rs1561812(C,T); rs11150836(T,G); rs149204485(G,T); rs11150838(G,C); rs11150839(A,C); rs11150840(G,A); rs12942049(A,C); rs112484891(G,A); rs7502097(C,A); rs2361702(A,G); rs12150060(G,A); rs4889953(G,C); rs7207166(G,A); rs9905685(G,C); rs72849375(T,G); rs12150151(T,C); rs12150633(C,T); rs4889954(G,A); rs2010193(C,T); rs112498718(G,A); rs2004193(T,C); rs894307(A,G); rs73438103(A,G); rs2361701(G,A); rs4889955(G,A); rs10871501(A,T); rs77605983(T,C); rs1982244(C,T); rs1561810(C,A); rs4514704(C,A); rs12951177(A,G); rs114825720(C,T); rs4889957(A,G); rs4889958(G,A); rs4889959(T,C); rs4889960(A,C); rs55654762(C,A); rs12945883(G,C); rs56379329(A,G); rs58449684(T,C); rs58526201(C,T); rs142198800(C,T); rs72849388(C,T); rs12952612(T,C); rs59252872(A,G); rs56968343(C,A); rs75030468(C,T); rs77778968(A,G); rs56027829(A,G); rs55986047(T,C); rs58502797(T,G); rs60161044(G,A); rs60804615(T,C); rs56120040(T,G); rs55662397(T,C); rs56176300(G,A); rs55990144(G,A); rs56407805(A,G); rs2304854(A,G); rs2304853(T,C); rs2304852(T,C); rs2304851(A,C); rs2289538(A,C) |
| ccdsGene name | CCDS42395.1 |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 55036 |
| EntrezGene Description | coiled-coil domain containing 40 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCDC40:NM_017950:exon8:c.G1303A:p.E435K,CCDC40:NM_001243342:exon8:c.G1303A:p.E435K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6325 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00549450549451 |
| dbNSFP KGp1 Afr AF | 0.0223577235772 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.014618 |
| ESP All MAF | 0.004839 |
| ESP Eur/Amr MAF | 0.00012 |
| ExAC AF | 1.845e-03,1.632e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Hypertelorism;
[Mouth];
Abnormal uvula;
High-arched palate;
Cleft palate (rare);
[Teeth];
Dental malocclusion
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Mitral valve regurgitation;
Aortic insufficiency;
Left ventricular hypertrophy;
Atrial fibrillation;
Pulmonary valve stenosis (rare);
[Vascular];
Aortic aneurysm;
Aortic dissection;
Arterial aneurysm;
Arterial tortuosity;
Persistent ductus arteriosus (rare);
Varices;
Veins, spider
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus deformity
ABDOMEN:
[External features];
Umbilical hernia;
Inguinal hernia;
[Gastrointestinal];
Bowel prolapse
GENITOURINARY:
[Internal genitalia, female];
Uterine prolapse;
[Bladder];
Bladder prolapse
SKELETAL:
Osteoporosis (rare);
[Spine];
Intervertebral disc degeneration;
Facet joint osteoarthritis;
Uncovertebral (C3-C7) joint osteoarthritis;
Dural ectasia;
Scoliosis;
Spondylysis;
Spondylolisthesis;
[Pelvis];
Hip osteoarthritis;
Protrusio acetabuli;
[Limbs];
Long bone overgrowth (dolichostenomelia);
Osteochondritis dissecans;
Knee osteoarthritis;
Meniscal lesions;
Wrist osteoarthritis;
Ankle osteoarthritis;
Joint laxity;
[Hands];
Hand osteoarthritis;
Arachnodactyly;
Camptodactyly;
[Feet];
Foot osteoarthritis;
Pes planus
SKIN, NAILS, HAIR:
[Skin];
Skin velvety;
Striae;
Easy bruisability;
Atrophic scarring
MOLECULAR BASIS:
Caused by mutation in the mothers against decapentaplegic, Drosophila,
homolog of, 3 gene (SMAD3, 603109.0001)
OMIM Title
*613799 COILED-COIL DOMAIN-CONTAINING PROTEIN 40; CCDC40
;;KIAA1640
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned CCDC40, which they designated
KIAA1640. RT-PCR ELISA detected highest CCDC40 expression in ovary,
followed by brain, lung, kidney, testis, fetal brain, and fetal liver.
Lower expression was detected in heart, liver, and pancreas, with little
to no expression in skeletal muscle and spleen. CCDC40 was detected in
all specific adult brain regions examined, with highest expression in
caudate nucleus and subthalamic nucleus.
Becker-Heck et al. (2011) stated that the human CCDC40 protein contains
1,142 amino acids. They cloned mouse Ccdc40, which encodes a deduced
1,192 amino acid protein. Ccdc40 was expressed throughout the cytoplasm
of embryonic mouse node cells. Immunohistochemical analysis revealed
Ccdc40 localization to cilia of respiratory epithelium. In zebrafish,
Ccdc40 was expressed in tissues containing motile cilia, including
Kupffer vesicle, floorplate, pronephric tubule, and otic vesicle.
GENE STRUCTURE
Becker-Heck et al. (2011) determined that the CCDC40 gene contains 20
exons.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the CCDC40
gene to chromosome 17. Hartz (2011) mapped the CCDC40 gene to chromosome
17q25.3 based on an alignment of the CCDC40 sequence (GenBank GENBANK
AK000760) with the genomic sequence (GRCh37).
Becker-Heck et al. (2011) stated that the mouse Ccdc40 gene maps to
chromosome 11.
MOLECULAR GENETICS
In 17 patients with primary ciliary dyskinesia-15 (CILD15; 613808),
Becker-Heck et al. (2011) identified loss-of-function mutations in the
CCDC40 gene (see, e.g., 613799.0001-613799.0004). All patients except 1
were homozygous or compound heterozygous for the mutations; a second
mutant allele could not be found in 1 patient. Affected individuals had
recurrent upper and lower airway infections; in addition, 5 (32%) had
situs solitus (32%) and 11 (68%) showed situs inversus, consistent with
randomization of left-right body asymmetry. Videomicroscopy analyses of
respiratory cilia showed a severely altered beating pattern in all
analyzed samples, with markedly reduced beating amplitudes, and rigid
cilia with fast, flickery movements. Transmission electron microscopy
studies showed defects in several axonemal structures, including
occasional absent or eccentric central pairs, displacement of outer
doublets, reductions in the mean number of inner dynein arms, and
abnormal radial spokes and nexin links. Outer dynein arms appeared
normal. The was also an absence of the inner dynein arm component DNALI1
(610062) from respiratory ciliary axonemes, which accumulated in the
apical cytoplasm, as well as an accumulation of GAS8 (605278) in the
apical cytoplasm. These findings indicated that CCDC40 is necessary for
the correct assembly of at least 2 distinct axonemal complexes
regulating ciliary beat: the inner dynein arms and the dynein regulatory
complex. Further studies showed that CCDC40 deficiency affected axonemal
localization of CCDC39 (613798), which was absent from the cilium and
enriched in the apical cytoplasm at the ciliary base.
Antony et al. (2013) applied Sanger sequencing of the CCDC39 and CCDC40
genes and whole-exome sequencing to identify 12 different mutations in
the CCDC39 gene and 13 different mutations in the CCDC40 gene among
affected members of 37 (69%) of 54 unrelated families with primary
ciliary dyskinesia and a 'radial spoke defect.' These mutations were
absent from large control databases, segregated with the disorder in the
families, and were predicted to result in premature protein termination,
likely associated with nonsense-mediated mRNA and complete loss of
protein function. There was no clustering of the mutations to a
particular region of either gene, suggesting that protein termination at
any point leads to the same deleterious dysfunction. The 248delC
mutation in CCDC40 (613799.0001) was the most common mutation, found in
63% of mutant alleles of Northern European origin worldwide. All
patients had a classic homogeneous PCD phenotype, with respiratory tract
infections, pneumonia, rhinosinusitis, otitis media, and age-dependent
bronchiectasis. About half had situs inversus, and infertility was
documented in several males and females. Transmission electron
microscopy of patient respiratory bronchial epithelial cells showed
disorganization of the peripheral microtubular doublets, absent or
shifted central pairs, and partial or complete loss of inner dynein
arms. Outer dynein arms were intact. Immunohistochemical studies showed
the presence of components of the radial spoke head and stalk,
suggesting that the radial spoke structures are preserved in these
patients. Antony et al. (2013) suggested that the term 'radial spoke
defect' should be replaced with the more accurate term 'inner dynein arm
(IDA) and microtubular disorganization defect.'
ANIMAL MODEL
Using a genetic screen, Becker-Heck et al. (2011) identified homozygous
links (lnks) mutant mouse embryos that showed defects in left-right
patterning, including situs inversus and left isomerism. The majority of
lnks/lnks pups died before weaning. Hydrocephalus was present in 2
lnks/lnks pups that were examined. Becker-Heck et al. (2011) identified
the lnks mutation as a ser792-to-ter (S792X) substitution in the middle
of the coiled-coil domain of Ccdc40. Morpholino-mediated knockout of
Ccdc40 in zebrafish resulted in laterality defects: either reversed
organ patterning or randomized organ patterning. Becker-Heck et al.
(2011) identified a gln778-to-ter (Q778X) mutation in the Ccdc40 gene in
zebrafish with the lok phenotype, which is identical to the phenotype
resulting from Ccdc40 knockdown. Scanning electron microscopy showed
reduced length of cilia in nodal pit cells of lnks/lnks mice and reduced
length of cilia in Kupffer vesicles and pronephric tubules of Ccdc40
morphant zebrafish.
OXLD1
| dbSNP name | rs1128812(C,T) |
| ccdsGene name | CCDS32766.1 |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 339229 |
| snpEff Gene Name | C17orf90 |
| EntrezGene Description | oxidoreductase-like domain containing 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OXLD1:NM_001039842:exon2:c.G312A:p.A104A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1309 |
| ESP Afr MAF | 0.144349 |
| ESP All MAF | 0.081655 |
| ESP Eur/Amr MAF | 0.049535 |
| ExAC AF | 0.07 |
ARHGDIA
| dbSNP name | rs147882325(A,G) |
| cytoBand name | 17q25.3 |
| EntrezGene GeneID | 396 |
| EntrezGene Description | Rho GDP dissociation inhibitor (GDI) alpha |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01331 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Hypertension due to renal disease
GENITOURINARY:
[Kidneys];
Proteinuria;
Microscopic hematuria;
Nephrotic syndrome;
Renal failure;
End-stage renal disease;
Enlarged glomeruli;
Mesangial and subendothelial granular or fibrillar deposits which
show immunoreactivity to fibronectin
MISCELLANEOUS:
Onset of proteinuria in the second to fourth decades;
Onset of end-stage renal disease 15 to 20 years after onset;
Slow progression
MOLECULAR BASIS:
Caused by mutation in the fibronectin 1 gene (FN1, 135600.0001)
OMIM Title
*601925 RHO GDP-DISSOCIATION INHIBITOR ALPHA; ARHGDIA
;;RHOGDI;;
GDP-DISSOCIATION INHIBITOR, APLYSIA RAS-RELATED 1; GDIA1
OMIM Description
DESCRIPTION
The ARHGDIA gene encodes the Rho-GDP dissociation inhibitor-alpha, which
sequesters Rho-GTPases in an inactive state in the cytosol (summary by
Gupta et al., 2013). Aplysia Ras-related homologs (ARHs), also called
Rho genes, belong to the RAS gene superfamily encoding small guanine
nucleotide exchange (GTP/GDP) factors. The ARH proteins may be kept in
the inactive, GDP-bound state by interaction with GDP dissociation
inhibitors, such as ARHGDIA (Leffers et al., 1993).
CLONING
By screening a transformed amnion cell library with an ARHGDIB (602843)
cDNA, Leffers et al. (1993) isolated cDNAs encoding ARHGDIA. They found
that ARHGDIA corresponded to a protein in the keratinocyte
2-dimensional-gel protein database known as IEF (isoelectric focusing)
8118. By 2-dimensional gel electrophoresis, the predicted 204-amino acid
protein had a pI of 4.74 and migrated at 29 kD. The amino acid sequences
of human and bovine ARHGDIA are 97% identical. Northern blot analysis
revealed that ARHGDIA was expressed in all cell lines and tissues
tested.
GENE STRUCTURE
Leffers et al. (1993) found that the ARHGDIA gene contains 6 exons.
MAPPING
Wagner et al. (1997) demonstrated by fluorescence in situ hybridization
that the ARHGDIA gene maps to chromosome 17q25.3. The assignment was
confirmed by the use of a new somatic cell hybrid panel for chromosome
17q.
GENE FUNCTION
Leffers et al. (1993) found that overexpression of ARHGDIB in mammalian
cells caused them to 'round up' and disrupted the actin cytoskeleton,
mimicking the phenotypic changes associated with inactivation of Rho
proteins.
Using immunohistochemistry, Gupta et al. (2013) found that the Arhgdia
protein was highly expressed in the glomerulus of the adult mouse
kidney, where it localized to podocytes. The protein was also detected
in mesangial cells. Mouse podocytes with knockdown of the Arhgdia gene
using shRNA showed higher levels of activated RhoA (165390), Rac1
(602048), and Cdc42 (116952) compared to control cells. These findings
demonstrated that those Rho-GTPases were no longer maintained in their
inactive state in the absence of functional Arhgdia. Further studies
showed that these cells had impaired cell motility, as demonstrated by
impaired wound healing, likely due to altered actin dynamics.
MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome (NPHS8; 615244), Gupta et al. (2013) identified a
homozygous 3-bp in-frame deletion in the ARHGDIA gene (601925.0001). The
mutation was found by whole-exome sequencing and confirmed by Sanger
sequencing. In vitro functional studies and studies of patient
fibroblasts showed that the mutation resulted in the hyperactivation of
3 Rho-GTPases due to loss of ARHGDIA function and impaired cell
motility. Both girls presented in the first weeks of life with severe
nephrotic syndrome, resulting in death in one. Renal biopsy of 1 patient
showed diffuse mesangial sclerosis. The findings suggested that the
mutation caused an imbalance in the active and inactive forms of
Rho-GTPases, leading to derangements in the actin cytoskeleton within
podocytes and subsequent nephrotic syndrome. Gupta et al. (2013) noted
that Arhgdia-null mice also develop proteinuria and progressive renal
failure.
By homozygosity mapping and exome sequencing in 2 sibs of Ashkenazi
Jewish descent with early-onset steroid-resistant nephrotic syndrome
with diffuse mesangial sclerosis, Gee et al. (2013) identified a
homozygous mutation in the ARHGDIA gene (G173V; 601925.0003). Screening
of the ARHGDIA gene in 65 individuals with diffuse mesangial sclerosis
and 350 individuals with steroid-resistant nephrotic syndrome identified
a different homozygous mutation (R120X) in a Moroccan infant with
congenital nephrotic syndrome. Both mutations were confirmed by Sanger
sequencing and segregated with the disorder in the families. Gee et al.
(2013) demonstrated that the mutations abrogated interaction with RHO
GTPases and increased active GTP-bound RAC1 (602048) and CDC42 (116952),
resulting in a migratory phenotypic change of podocytes (foot process
effacement) and proteinuria. Knockdown of arhgdia in zebrafish
recapitulated the nephrotic phenotype, which was partially rescued with
RAC1 inhibitors.
ANIMAL MODEL
Shibata et al. (2008) found that Arhgdia -/- mice developed progressive
renal disease characterized by heavy albuminuria and podocyte damage.
These renal changes were associated with increased Rac1 (602048) and
mineralocorticoid receptor (NR3C2; 600983) signaling in the kidney
without alteration in systemic aldosterone status. Pharmacologic
intervention with a Rac-specific small molecule inhibitor diminished
mineralocorticoid receptor overactivity and renal damage. Furthermore,
mineralocorticoid receptor blockade suppressed albuminuria and
histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded
that RAC1 modulates mineralocorticoid receptor activity, and that
activation of the RAC1-mineralocorticoid receptor pathway has a major
role in the pathogenesis of renal damage.
CETN1
| dbSNP name | rs11875237(A,C); rs568365(T,C); rs114728825(A,T); rs186209031(G,A); rs571200(A,T) |
| cytoBand name | 18p11.32 |
| EntrezGene GeneID | 1068 |
| EntrezGene Description | centrin, EF-hand protein, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03306 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts (anterior- subcapsular);
Conjunctivitis (recurrent);
Orbital darkening;
Keratoconus;
[Nose];
Allergic rhinitis
RESPIRATORY:
[Airways];
Bronchial asthma
SKIN, NAILS, HAIR:
[Skin];
Pruritus (major feature);
Dermatitis (chronic or chronically relapsing, major feature);
Flexural lichenification in adults (major feature);
Facial or extensor involvement in infants and children (major feature);
Eczema (perifollicular accentuation);
Facial pallor;
Facial erythema;
Hand dermatitis (non-allergic, irritant);
Ichthyosis;
Cutaneous infections (Staphylococcus aureus, herpes simplex);
Infraorbital fold (Dennie-Morgan lines);
Keratosis pilaris;
Nipple dermatitis;
Palmar hyperlinearity;
Pityriasis alba;
White dermatographism;
Xerosis
IMMUNOLOGY:
Elevated IgE
LABORATORY ABNORMALITIES:
Immediate (type I) skin test reactivity
MISCELLANEOUS:
Food intolerance;
Diagnosis requires 3 major features (a positive family history is
also considered a major feature) and at least 3 minor features
OMIM Title
*603187 CENTRIN 1; CETN1
;;CEN1
OMIM Description
DESCRIPTION
Centrins play important roles in the determination of centrosome
position and segregation, and in the process of microtubule severing.
See CETN3 (602907).
CLONING
By screening a human testis cDNA expression library with antibodies
against recombinant Chlamydomonas centrin, Errabolu et al. (1994)
isolated CETN1, or CEN1, cDNAs. The predicted 172-amino acid protein
contains 4 putative EF-hand calcium-binding domains. Sequence analysis
revealed that CETN1 is highly conserved; it shares 81% and 68% protein
sequence identity with Xenopus centrin and Chlamydomonas centrin,
respectively. CETN1 isolated from HeLa cell extracts has a molecular
mass of approximately 20 kD and a pI of 4.5 to 4.7. Using
immunofluorescence, Errabolu et al. (1994) localized centrin to the
centrosome of interphase cells. CETN1 redistributes to the region of the
spindle poles during mitosis, reflecting the dynamic behavior of the
centrosome during the cell cycle.
MAPPING
Errabolu et al. (1994) stated that the CETN1 gene was mapped to
chromosome 18 by analysis of a somatic cell hybrid panel.
LINC00526
| dbSNP name | rs13423(C,T); rs10972(G,A); rs9947320(T,G); rs9956056(C,G); rs7244432(A,G); rs35455334(T,C); rs11875052(G,T); rs7242964(G,C); rs3210631(G,A); rs138407399(G,A); rs7244467(C,G); rs1201525(G,A); rs7244505(C,T) |
| cytoBand name | 18p11.31 |
| EntrezGene GeneID | 147525 |
| snpEff Gene Name | AP001496.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 526 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1015 |
EPB41L3
| dbSNP name | rs9953490(T,A); rs4258718(G,T); rs4441367(G,T); rs4441366(G,A); rs79669098(C,T); rs4453598(T,C); rs7229903(G,A); rs73375705(G,A); rs375999728(A,G); rs58817821(C,T); rs149315843(G,A); rs59176398(T,C); rs151294672(C,T); rs8089025(C,T); rs76120239(G,A); rs76292729(T,C); rs55997318(G,A); rs56695386(C,T); rs72866810(C,T); rs8099075(G,A); rs149681400(A,T); rs7236089(T,C); rs7232333(A,G); rs7231743(C,T); rs12959487(G,C); rs72866812(C,A); rs7237045(T,G); rs1880022(C,A); rs7236131(G,T); rs1968180(G,C); rs1974694(G,A); rs2874686(C,T); rs2322093(A,G); rs9965501(T,G); rs12605370(C,A); rs12604181(T,C); rs186006594(G,C); rs7240696(A,C); rs115712113(G,T); rs16948118(A,C); rs16948127(C,T); rs183467148(G,A); rs3794818(C,T); rs2041855(A,G); rs143652233(G,T); rs6506299(G,C); rs6506300(T,C); rs1987744(T,C); rs7242524(G,C); rs4260157(G,A); rs9959505(G,A); rs9960193(C,T); rs77265921(G,C); rs11081191(T,C); rs11081192(T,C); rs17466432(T,C); rs8082898(T,C); rs9966357(C,T); rs6506301(C,A); rs17466502(A,C); rs10502330(T,G); rs4798353(G,A); rs1880021(A,T); rs4797210(C,T); rs16948164(A,G); rs73375734(T,C); rs115934635(G,A); rs74440272(C,T); rs2280568(C,A); rs59564759(T,C); rs58115282(T,C); rs117538203(C,T); rs3752061(A,G); rs17381858(C,T); rs116596083(A,G); rs1963827(T,C); rs56088453(T,A); rs56262724(A,C); rs115140639(C,T); rs4798355(C,G); rs111419513(A,G); rs138253215(C,T); rs17466824(G,A); rs12606598(A,G); rs12607210(A,T); rs184628855(G,T); rs4797212(C,T); rs144544277(A,G); rs74363568(C,T); rs78127447(G,A); rs1987654(C,T); rs1987728(C,T); rs77791276(A,T); rs9951353(A,G); rs191286316(C,A); rs7240261(C,T); rs59463599(C,A); rs11876050(T,A); rs11876144(T,C); rs4798357(G,C); rs4798358(T,C); rs149158629(A,G); rs1963826(G,A); rs3924849(G,A); rs7237323(T,C); rs1610067(T,C); rs1610066(G,A); rs2272130(A,C); rs3931700(C,T); rs16948207(C,T); rs72866876(C,G); rs80266946(A,G); rs146317018(C,T); rs12605180(G,A); rs9963430(A,C); rs117276462(G,A); rs117741304(T,G); rs3862166(C,T); rs185936279(T,G); rs2058732(G,A); rs62080551(G,T); rs75474181(T,C); rs58461379(G,A); rs1963341(T,A); rs6506302(A,G); rs7230691(C,T); rs79604149(C,T); rs113264396(C,T); rs879315(G,A); rs1317901(T,A); rs139407843(C,T); rs17382252(T,C); rs150939373(T,C); rs145519040(C,A); rs28498693(C,T); rs8088404(C,T); rs1965652(A,G); rs10853332(T,G); rs76856473(C,T); rs2322095(G,T); rs79068200(A,G); rs2041856(C,G); rs7233968(G,C); rs79708834(C,T); rs11081195(T,C); rs7230414(T,C); rs1963340(A,G); rs7243789(G,A); rs7226478(A,T); rs3931117(T,A); rs62081963(C,T); rs62081964(A,G); rs79072125(C,A); rs8087912(A,G); rs9964022(A,T); rs2322096(T,C); rs113901007(C,T); rs8088783(G,C); rs73937138(A,G); rs2322097(A,G); rs2322098(C,G); rs75924515(T,C); rs76060919(G,C); rs78931856(G,A); rs6506304(C,T); rs6506305(C,T); rs10775435(A,C); rs11081197(G,A); rs11662796(C,G); rs7244835(G,T); rs28439720(T,C); rs11874161(T,C); rs114023293(G,A); rs114670279(G,A); rs4798360(G,C); rs11875075(T,G); rs114295796(T,C); rs11663092(T,A); rs11665584(C,T); rs11081199(C,T); rs11081200(T,A); rs78967434(A,G); rs11660110(C,G); rs7234759(T,C); rs4798361(A,T); rs4798362(T,A); rs12962743(G,T); rs11081201(T,C); rs4797213(G,C); rs11662027(C,T); rs12954936(C,T); rs11662552(G,A); rs12961691(A,T); rs12455661(T,C); rs117953201(T,C); rs9962118(A,C); rs9964681(T,C); rs9950450(C,T); rs9949881(G,A); rs9952940(C,T); rs11664867(A,G); rs67424787(T,C); rs7237985(G,A); rs11660092(T,C); rs4798363(T,C); rs4798364(A,C); rs4798365(C,G); rs145926576(T,G); rs56193925(C,T); rs11081202(G,T); rs4798366(G,T); rs2874687(G,A); rs4798367(T,C); rs4798368(A,G); rs4797214(C,T); rs7241997(A,T); rs63286760(A,C); rs68175238(T,G); rs2322100(T,C); rs2322101(A,G); rs2322102(C,G); rs4497789(C,T); rs7238186(A,G); rs2874688(C,A); rs2874689(C,G); rs11874131(G,C); rs2247879(C,A); rs2293228(C,G); rs9965051(A,G); rs2293227(C,A); rs77751403(T,C); rs7233813(C,T); rs7238801(T,C); rs7233031(G,A); rs7233189(G,A); rs74980340(C,G); rs75876700(A,G); rs73379566(A,C); rs12967064(G,C); rs79629518(A,G); rs79859149(T,C); rs75072757(C,A); rs1987083(C,G); rs7231031(T,C); rs6506307(T,C); rs75686006(A,G); rs57887281(G,A); rs77071121(C,T); rs9951951(G,A); rs8096929(A,C); rs9955253(C,A); rs76348112(C,A); rs61201798(C,T); rs116426722(G,A); rs9947755(A,G); rs78010838(A,G); rs9950508(T,C); rs9960776(G,A); rs74532769(T,C); rs8093344(G,A); rs78775633(T,A); rs58920109(C,T); rs74473754(T,G); rs9954882(C,A); rs74545188(G,A); rs80211721(A,G); rs75452348(G,A); rs8087591(T,A); rs4798370(T,C); rs9963454(G,A); rs8096852(T,G); rs28470490(G,A); rs7242448(C,A); rs78356886(C,T); rs75659977(C,A); rs34291060(C,A); rs34695178(G,A); rs7242618(C,A); rs113748610(G,A); rs111512571(C,A); rs73379580(C,T); rs78910847(G,A); rs78857068(A,T); rs11081203(G,C); rs140907000(C,T); rs8090036(C,A); rs74361598(C,T); rs8091052(A,G); rs188410035(T,G); rs8095556(A,T); rs6506308(T,C); rs28444421(C,T); rs112558908(G,A); rs28490333(T,G); rs77379719(C,T); rs34089422(G,A); rs34884133(A,C); rs4798371(A,C); rs73379586(C,A); rs4798372(C,T); rs28491200(C,T); rs10221302(C,G); rs8088620(C,T); rs8088796(C,T); rs8091980(G,C); rs79386023(T,G); rs9944608(T,C); rs79737592(A,T); rs73379591(T,C); rs185502189(C,T); rs76817611(C,G); rs78861669(C,T); rs61388309(T,C); rs60979927(A,T); rs9958170(A,G); rs76755164(T,G); rs9955455(G,A); rs1815072(C,T); rs1719945(C,T); rs78423832(C,T); rs1719946(T,C); rs1719947(G,A); rs1719948(T,G); rs1719949(A,G); rs12965156(C,T); rs1785398(T,C); rs1719950(A,G); rs11664740(C,G); rs1719951(G,T); rs56095997(C,T); rs1719952(G,A); rs1719953(C,T); rs73937152(T,C); rs67146836(G,A); rs1627600(G,T); rs1719954(C,T); rs2040193(A,C); rs73383738(C,T); rs1785399(A,G); rs1618055(G,A); rs1719955(A,C); rs1618179(G,A); rs1719956(A,T); rs12607610(G,A); rs1619802(C,G); rs1621335(A,G); rs1719957(A,T); rs8097586(T,C); rs2186913(T,G); rs1941003(G,T); rs7506785(C,A); rs1893195(T,G); rs1893196(G,C); rs1539809(C,T); rs1941004(A,G); rs186325876(T,C); rs948309(C,T); rs1719978(T,C); rs34292654(C,T); rs1785400(A,G); rs72868434(G,A); rs1611793(A,T); rs1719977(T,C); rs76072260(G,A); rs1719976(G,A); rs1719975(A,C); rs1615542(T,C); rs150764692(G,C); rs1557314(T,G); rs68162515(C,T); rs182670214(G,C); rs1785401(G,A); rs1785402(T,C); rs1719972(G,A); rs1544242(A,G); rs78100224(C,A); rs74462314(C,A); rs115333509(C,T); rs1785403(G,C); rs1719971(C,T); rs1785404(C,A); rs188898419(G,A); rs28646123(C,T); rs28727374(G,C); rs186646281(T,C); rs1719969(A,G); rs7229362(C,T); rs1617446(T,G); rs3638(A,G); rs1626709(G,A); rs1719968(C,T); rs12607868(G,T); rs12607998(C,T); rs10853333(C,G); rs12457384(T,C); rs7505578(T,C); rs7231142(C,T); rs1785383(A,G); rs58722840(T,G); rs1719967(G,C); rs1557312(G,A); rs1785384(A,G); rs1719966(T,C); rs1719965(G,C); rs1785385(G,A); rs1785386(C,T); rs1719964(G,A); rs1940996(T,G); rs9950603(A,C); rs1619854(C,T); rs1619724(T,C); rs79595921(C,T); rs11662284(T,C); rs1785387(C,T); rs1785388(A,G); rs1785389(G,A); rs1719963(C,T); rs1719962(G,T); rs1615003(G,C); rs1615855(G,C); rs1616724(G,C); rs1719961(A,G); rs1719960(C,T); rs1719959(C,T); rs1940999(G,A); rs73937160(T,A); rs73385799(G,A); rs73385800(C,T); rs73937163(C,T); rs73385802(G,T); rs8095619(A,G); rs1941000(C,T); rs1941001(T,C); rs12955291(C,T); rs73387911(T,C); rs12954752(G,C); rs112336757(G,C); rs111672548(G,C); rs73387913(T,C); rs1785390(A,G); rs1785391(T,C); rs8091944(G,A); rs73387914(T,G); rs1719958(C,A); rs1941002(G,C); rs1785392(C,T); rs1785393(C,T); rs1719991(C,T); rs1785394(T,C); rs1719990(T,G); rs1785397(A,G); rs78863749(G,A); rs8090286(T,G); rs7235551(C,T); rs7237054(A,G); rs62077750(G,A); rs35924124(T,C); rs12454208(G,T); rs2027687(A,G); rs2027688(A,G); rs75786970(C,T); rs2027689(T,C); rs2298544(T,C); rs73387939(T,C); rs7236818(A,G); rs79596496(A,G); rs12458743(T,C); rs1719987(A,T); rs1941015(C,T); rs1719986(C,G); rs147232211(G,A); rs1785426(C,T); rs940131(T,C); rs1941016(T,C); rs113417159(C,T); rs8085771(T,C); rs11876037(T,C); rs1616117(A,G); rs11664536(T,C); rs192401562(C,T); rs1785427(A,G); rs1719932(A,G); rs1719933(T,C); rs188639104(G,C); rs7234955(C,T); rs1719934(A,G); rs16948465(A,G); rs77523687(T,C); rs77094566(C,T); rs8082900(T,C); rs8095856(C,G); rs8094843(G,T); rs11665404(A,C); rs1719935(A,G); rs76586534(A,C); rs78514215(A,C); rs56030801(T,C); rs1785377(C,T); rs1785378(G,A); rs1719937(A,G); rs1940991(A,G); rs1630813(C,T); rs1617563(A,G); rs1785380(A,C); rs1621880(C,T); rs1785381(C,T); rs16948470(T,C); rs1719938(A,C); rs36055965(G,A); rs34218968(C,T); rs1785382(C,T); rs1940994(A,G); rs77695385(C,A); rs12457330(C,T); rs1719939(T,C); rs35403520(G,A); rs9962915(C,T); rs1719940(A,T); rs12185436(G,A); rs12185437(G,A); rs1785406(A,G); rs1785407(A,G); rs115351108(C,T); rs1785408(A,G); rs80284521(C,A); rs1719943(C,T); rs1785409(T,C); rs16948479(T,C); rs1785410(C,T); rs1785411(A,G); rs116387583(C,A); rs1785412(T,C); rs8087988(T,C); rs116169821(G,C); rs149974999(C,T); rs1539811(C,T); rs113843859(T,C); rs1539812(T,C); rs79378112(C,T); rs79595961(C,T); rs113791520(C,T); rs4798374(G,A); rs112335275(G,A); rs1719944(T,C); rs1719983(C,T); rs1785413(A,G); rs16948484(A,G); rs114465085(A,G); rs115114995(T,A); rs1785414(T,G); rs1719984(A,C); rs77300590(G,A); rs1719985(C,T); rs1785415(G,A); rs1785416(T,C); rs78087433(T,A); rs1785417(T,C); rs139382152(G,A); rs139687783(C,T); rs76040396(G,A); rs9959992(T,C); rs79030656(C,A); rs115027779(G,A); rs1785418(G,A); rs1785419(C,G); rs940130(A,G); rs143387490(G,A); rs1719980(G,A); rs28481760(G,A); rs1785420(C,T); rs149520962(G,A); rs1719979(T,A); rs12605083(T,G); rs148699606(C,T); rs4798376(T,C); rs112455585(G,A); rs11663020(G,A); rs11660759(T,C); rs75423654(G,A); rs180996588(T,A); rs149011574(T,C); rs9965239(C,T); rs9303976(C,T); rs1785422(A,G); rs1719981(G,A); rs1880725(G,C); rs1880724(A,G); rs116425786(A,G); rs1719982(T,C); rs115296007(A,C); rs114244573(C,T); rs8098397(C,T); rs1785423(A,G); rs11659933(G,A); rs8090893(T,C); rs7241283(A,G); rs7240716(C,T); rs7240903(C,T); rs28682887(C,T); rs8083607(T,C); rs8082912(C,T); rs76679366(A,G); rs62079267(G,C); rs4798378(A,C); rs58157717(T,C); rs73937175(T,C); rs140189284(G,T); rs948311(A,G); rs76744448(C,T); rs76123177(C,T); rs4290555(A,G); rs17384555(G,T); rs1893197(C,T); rs2140948(G,A); rs9948202(C,G); rs4798379(C,T); rs16948514(T,C); rs79523759(A,T); rs721565(C,G); rs9952759(A,T); rs17384756(A,T); rs11874896(A,T); rs4798380(G,A); rs4798381(C,T); rs9946758(C,T); rs115499748(A,G); rs11659725(G,C); rs34394097(G,A); rs138958337(T,C); rs80343628(G,C); rs35444489(G,A); rs9962192(A,C); rs80244289(C,T); rs75082622(G,A); rs140401727(G,A); rs9965462(A,G); rs55666109(T,C); rs73937191(A,G); rs28725247(G,A); rs73937192(G,A); rs10853334(G,C); rs73937193(A,G) |
| ccdsGene name | CCDS11838.1 |
| cytoBand name | 18p11.31 |
| EntrezGene GeneID | 23136 |
| EntrezGene Description | erythrocyte membrane protein band 4.1-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | EPB41L3:NM_001281535:exon14:c.G1220A:p.R407Q,EPB41L3:NM_012307:exon12:c.G1493A:p.R498Q,EPB41L3:NM_001281533:exon12:c.G1547A:p.R516Q,EPB41L3:NM_001281534:exon12:c.G1547A:p.R516Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9077 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.001589 |
| ESP All MAF | 0.004229 |
| ESP Eur/Amr MAF | 0.005581 |
| ExAC AF | 0.004253 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Trigonocephaly;
[Face];
Hypoplastic supraorbital ridge;
Thin philtrum;
Glabellar capillary hemangioma;
Nevus flammeus (eyelids);
Micrognathia;
[Ears];
Posteriorly rotated ears;
Low-set ears;
[Eyes];
Hypotelorism;
Proptosis;
Ptosis;
Epicanthal folds;
Short palpebral fissures;
Upward slanting palpebral fissures;
Strabismus;
Myopia;
[Nose];
Prominent nasal bridge;
[Mouth];
High-arched palate;
Microstomia
CARDIOVASCULAR:
[Heart];
Pulmonary stenosis;
Atrial septal defect
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum;
[Breasts];
Inverted nipples
SKELETAL:
[Skull];
Craniosynostosis (coronal and metopic suture)
SKIN, NAILS, HAIR:
[Skin];
Capillary hemangioma (glabellar);
Nevus flammeus (eyelids and nape of neck)
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mild mental retardation
OMIM Title
*605331 ERYTHROCYTE MEMBRANE PROTEIN BAND 4.1-LIKE 3; EPB41L3
;;DIFFERENTIALLY EXPRESSED IN ADENOCARCINOMA OF THE LUNG; DAL1;;
NONERYTHROID PROTEIN 4.1, BRAIN TYPE; 4.1B
OMIM Description
CLONING
Tran et al. (1999) identified a protein-4.1 gene, DAL1 (differentially
expressed in adenocarcinoma of the lung), located on chromosome 18p11.3,
which is lost in approximately 60% of non-small cell lung carcinomas,
and exhibits growth-suppressing properties in lung cancer cell lines.
DAL1 is 73% identical in its N-terminal domain to members of the protein
4.1 family and shares structural similarity to the Drosophila 4.1
homolog 'coracle.' DAL1 is normally expressed at high levels in brain,
with lower levels in kidney, intestine, and testis.
GENE FUNCTION
Using LOH, RT-PCR, western blot, and immunohistochemistry analyses,
Gutmann et al. (2000) demonstrated DAL1 loss in 60% of sporadic
meningiomas. The NF2 tumor suppressor gene (607379), encoding merlin, is
inactivated in 40% of sporadic meningiomas. Gutmann et al. (2000) showed
that, analogous to merlin, DAL1 loss is an early event in meningioma
tumorigenesis, suggesting that these 2 protein-4.1 family members are
critical growth regulators in the pathogenesis of meningiomas. The
authors hypothesized that membrane-associated alterations may be
important in the early stages of neoplastic transformation.
MAPPING
Tran et al. (1999) mapped the EPB41L3 gene to chromosome 18p11.3 by
FISH.
GENE FAMILY
The protein 4.1 (EPB41; 130500) family of membrane-associated proteins,
of which DAL1 is a member, includes merlin (or schwannomin), encoded by
NF2 (607379), ezrin (123900), radixin (179410), and moesin (309845)
(summary by Tran et al., 1999).
EVOLUTION
Tan et al. (2005) found that the EPB41 and EPB41L3 genes from fish,
bird, amphibian, and mammalian genomes exhibit shared features,
including alternative first exons and differential splicing acceptors in
exon 2. In all cases, the most 5-prime exon, exon 1A, splices
exclusively to a weaker internal acceptor site in exon 2, skipping a
fragment designated exon 2-prime. Conversely, alternative first exons 1B
and 1C always splice to the stronger first acceptor site, retaining exon
2-prime. These correlations were independent of cell type or species of
origin. Since exon 2-prime contains a translation initiation site,
splice variants generate protein isoforms with distinct N termini. Tan
et al. (2005) calculated that coupling between upstream promoters and
downstream splicing in EPB41 and EBP41L3 has been conserved for at least
500 million years.
TMEM200C
| dbSNP name | rs28656885(C,A) |
| ccdsGene name | CCDS45825.1 |
| cytoBand name | 18p11.31 |
| EntrezGene GeneID | 645369 |
| EntrezGene Description | transmembrane protein 200C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM200C:NM_001080209:exon1:c.G426T:p.P142P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3535 |
| ESP Afr MAF | 0.42766 |
| ESP All MAF | 0.397094 |
| ESP Eur/Amr MAF | 0.38176 |
| ExAC AF | 0.353,8.158e-06 |
SLC35G4P
| dbSNP name | rs75301503(G,A) |
| cytoBand name | 18p11.21 |
| EntrezGene GeneID | 646000 |
| EntrezGene Symbol | SLC35G4 |
| snpEff Gene Name | SLC35G4 |
| EntrezGene Description | solute carrier family 35, member G4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC35G4P:NM_001282300:exon1:c.G479A:p.C160Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.164377289377 |
| dbNSFP KGp1 Afr AF | 0.0528455284553 |
| dbNSFP KGp1 Amr AF | 0.17679558011 |
| dbNSFP KGp1 Asn AF | 0.335664335664 |
| dbNSFP KGp1 Eur AF | 0.101583113456 |
| dbSNP GMAF | 0.1644 |
| ExAC AF | 0.148 |
MC5R
| dbSNP name | rs1541276(A,C); rs2236699(G,T); rs17848292(C,T); rs2236700(C,G); rs2236701(C,T); rs11080686(A,C) |
| cytoBand name | 18p11.21 |
| EntrezGene GeneID | 4161 |
| EntrezGene Description | melanocortin 5 receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1919 |
| ESP Afr MAF | 0.205629 |
| ESP All MAF | 0.181455 |
| ESP Eur/Amr MAF | 0.16907 |
| ExAC AF | 0.162 |
OMIM Clinical Significance
Skel:
Skeletal dysplasia;
Severely retarded ossification of epiphyses, pelvis, hands, and feet
Limbs:
Abnormal modeling of bones of hands and feet
Neuro:
No mental retardation
Inheritance:
Autosomal recessive
OMIM Title
*600042 MELANOCORTIN 5 RECEPTOR; MC5R
;;MC5 RECEPTOR
OMIM Description
CLONING
Gantz et al. (1994) reported the molecular cloning of a novel gene
encoding a fifth member of the melanocortin receptor family in mouse.
The mouse Mc5r gene encodes a predicted 325-amino acid protein. Northern
blot analysis demonstrated the expression of mouse Mc5r mRNA at high
levels in skeletal muscle and at lower levels in lung, spleen, and
brain.
MAPPING
Chowdhary et al. (1995) mapped the human MC5R gene to chromosome 18p11.2
by fluorescence in situ hybridization.
ANIMAL MODEL
Chen et al. (1997) reported that targeted disruption of the mouse MC5R
gene produced mice with a severe defect in water repulsion and
thermoregulation due to decreased production of sebaceous lipids. High
levels of MC5R were found in multiple exocrine tissues, including
Harderian, preputial, lacrimal, and sebaceous glands, and were required
for production and stress-regulated synthesis of porphyrins by the
Harderian gland and ACTH/MSH-regulated protein secretion by the lacrimal
gland. These data showed a requirement for the MC5R in multiple exocrine
glands for the production of numerous products, indicative of a
coordinated system for regulation of exocrine gland function by
melanocortin peptides.
LOC101927642
| dbSNP name | rs786021(G,A) |
| cytoBand name | 18p11.21 |
| EntrezGene GeneID | 101927642 |
| EntrezGene Description | uncharacterized LOC101927642 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3577 |
MIR133A1HG
| dbSNP name | rs9948906(T,C); rs8089787(T,C); rs6508626(T,C); rs2155975(G,A); rs4591246(G,A); rs78641532(A,G); rs9989532(C,T) |
| ccdsGene name | CCDS11871.1 |
| cytoBand name | 18q11.2 |
| EntrezGene GeneID | 57534 |
| EntrezGene Symbol | MIB1 |
| snpEff Gene Name | MIB1 |
| EntrezGene Description | mindbomb E3 ubiquitin protein ligase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07989 |
GATA6-AS1
| dbSNP name | rs9946505(T,A); rs79335487(A,C) |
| cytoBand name | 18q11.2 |
| EntrezGene GeneID | 100128893 |
| snpEff Gene Name | GATA6 |
| EntrezGene Description | GATA6 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03673 |
CTAGE1
| dbSNP name | rs9965155(T,C); rs45444991(A,T); rs8093101(A,C); rs143471249(T,C); rs3813129(G,A); rs9946136(T,C); rs61747177(T,C); rs9946145(T,C) |
| cytoBand name | 18q11.2 |
| EntrezGene GeneID | 64693 |
| EntrezGene Description | cutaneous T-cell lymphoma-associated antigen 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07254 |
SLC25A52
| dbSNP name | rs113093917(C,G); rs11875226(C,T) |
| ccdsGene name | CCDS32812.2 |
| cytoBand name | 18q12.1 |
| EntrezGene GeneID | 147407 |
| snpEff Gene Name | MCART2 |
| EntrezGene Description | solute carrier family 25, member 52 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC25A52:NM_001034172:exon1:c.G543C:p.E181D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.195 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3SY17 |
| dbNSFP Uniprot ID | MCAR2_HUMAN |
| dbNSFP KGp1 AF | 0.0119047619048 |
| dbNSFP KGp1 Afr AF | 0.0487804878049 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01102 |
| ESP Afr MAF | 0.042669 |
| ESP All MAF | 0.014536 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.003887 |
WBP11P1
| dbSNP name | rs9954414(T,C); rs2015877(A,C); rs2015883(T,C); rs718721(C,T); rs1985293(G,A); rs147923519(C,G); rs11873902(A,C) |
| cytoBand name | 18q12.1 |
| EntrezGene GeneID | 441818 |
| EntrezGene Description | WW domain binding protein 11 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4555 |
MIR4318
| dbSNP name | rs11873400(A,G) |
| cytoBand name | 18q12.2 |
| EntrezGene GeneID | 100422857 |
| EntrezGene Description | microRNA 4318 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04775 |
| ExAC AF | 0.018 |
TCEB3B
| dbSNP name | rs35084651(T,G); rs3744863(C,T); rs892586(C,A); rs2010834(C,A); rs61745190(G,A); rs2571028(C,G); rs140604456(G,T); rs2571026(C,T); rs147815940(C,G) |
| cytoBand name | 18q21.1 |
| EntrezGene GeneID | 83473 |
| EntrezGene Symbol | KATNAL2 |
| snpEff Gene Name | KATNAL2 |
| EntrezGene Description | katanin p60 subunit A-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004132 |
DYM
| dbSNP name | rs895669(C,T); rs895670(C,G); rs12965679(G,T); rs35807361(G,A); rs833522(C,T); rs833523(G,A); rs1662121(C,T); rs1662122(T,C); rs357855(T,C); rs11082727(A,C); rs357854(T,C); rs17189079(T,C); rs112607702(G,T); rs357893(T,C); rs17774887(G,T); rs62102284(C,T); rs76159917(T,C); rs77478443(A,C); rs78549315(G,A); rs116074790(G,C); rs357894(C,T); rs357895(G,A); rs1000055(G,A); rs2044550(C,T); rs357897(C,T); rs357900(T,A); rs357901(A,T); rs1787200(G,A); rs11659241(C,T); rs1662116(T,C); rs142301929(T,C); rs1662129(A,G); rs62102286(T,G); rs79114336(A,G); rs145330340(G,A); rs112788639(T,A); rs1288797(T,G); rs78696305(A,G); rs72921663(C,T); rs1288796(G,A); rs77037767(C,T); rs112422290(C,T); rs72921666(C,T); rs113743659(C,T); rs76017405(T,A); rs1288795(T,A); rs34125642(G,A); rs1290500(T,A); rs10520770(T,C); rs9304371(T,C); rs1288794(C,T); rs71355367(T,A); rs72921672(A,T); rs11664336(A,T); rs2584758(T,A); rs833497(T,C); rs79082509(A,G); rs72921674(A,G); rs72921677(A,T); rs357853(C,T); rs184815775(T,C); rs35718562(T,C); rs33973388(G,T); rs35054365(T,A); rs72921680(G,C); rs357885(T,G); rs141746516(G,A); rs357886(C,T); rs11873029(C,T); rs79814176(T,C); rs111582717(T,C); rs2028966(A,G); rs7239949(T,G); rs7229507(C,T); rs1295494(T,G); rs77085463(C,T); rs28470838(A,G); rs146000214(T,C); rs861300(G,A); rs833503(C,G); rs357872(A,T); rs114962351(G,A); rs9284426(G,A); rs11082728(T,C); rs11082729(C,T); rs357873(T,A); rs357879(G,C); rs181552(C,T); rs35470500(T,C); rs833502(G,T); rs8085780(C,T); rs77468645(G,A); rs35812305(T,G); rs10468999(G,A); rs1103804(A,G); rs833501(G,A); rs78710869(T,G); rs698610(T,C); rs976256(C,T); rs833499(T,C); rs112254916(T,G); rs8097746(C,T); rs9963666(T,G); rs2053516(C,T); rs2053515(A,G); rs71355370(G,T); rs7240784(C,G); rs10502897(T,C); rs62102329(T,C); rs2848878(T,C); rs2848877(C,T); rs2878902(G,T); rs76915972(A,G); rs8083334(T,C); rs973042(A,T); rs7236575(G,A); rs115340392(G,T); rs8096411(C,G); rs11082734(G,A); rs59643060(G,T); rs77798548(T,G); rs374644712(C,T); rs201073920(T,A); rs189085338(G,A); rs78877886(G,A); rs11082735(C,T); rs75228040(G,T); rs34925638(C,T); rs8090871(G,A); rs6507883(C,T); rs1823178(T,C); rs1823179(G,T); rs72923805(T,C); rs6507884(G,A); rs77942889(T,C); rs10775489(G,A); rs80149155(T,C); rs2337210(A,G); rs35226819(C,A); rs190889441(G,A); rs182933942(T,C); rs7236594(G,A); rs10775490(C,A); rs76455424(G,T); rs7242876(C,A); rs79816264(C,G); rs12051980(A,G); rs7236064(C,A); rs62102334(T,C); rs185138281(C,T); rs8087713(A,G); rs76123684(T,C); rs9951691(A,G); rs17196970(A,G); rs9951872(A,G); rs1838963(C,A); rs1838962(A,G); rs60898836(C,G); rs149553773(A,G); rs1965844(T,C); rs1965843(G,A); rs8091000(C,G); rs72923816(G,T); rs2006639(G,A); rs72923818(A,C); rs2166670(A,G); rs1530608(A,T); rs8094480(G,A); rs4435323(G,T); rs10775491(A,G); rs11082736(T,C); rs8086595(C,T); rs6507885(T,C); rs111478078(T,C); rs7231453(G,A); rs76923467(T,G); rs12232591(A,C); rs79748322(A,G); rs8092003(G,C); rs9676075(C,A); rs12455537(T,A); rs191212153(T,C); rs12970381(T,G); rs7233575(A,T); rs151089550(C,G); rs6507886(A,G); rs181804103(G,T); rs1943000(A,G); rs1893528(G,A); rs1893529(T,G); rs115778713(A,G); rs4519395(T,C); rs4559968(T,C); rs4559969(T,C); rs4424966(T,C); rs4493133(A,G); rs4567802(G,A); rs111386941(A,C); rs192886154(G,A); rs10853576(T,A); rs142391324(C,T); rs7241593(C,A); rs948789(G,A); rs11874831(A,G); rs17776402(G,A); rs79845003(T,C); rs16950403(A,T); rs16950406(C,T); rs111377446(G,A); rs10163832(G,T); rs9954569(A,G); rs76864753(G,A); rs79533727(G,A); rs7238371(T,C); rs1893526(G,A); rs1893527(T,A); rs1942998(C,T); rs1942999(T,C); rs8090015(T,G); rs74963026(T,C); rs7235532(T,C); rs4939846(G,A); rs55658710(G,C); rs77353410(A,G); rs7232791(T,C); rs186385991(A,G); rs1943002(G,A); rs11661731(C,T); rs1943001(G,A); rs78852589(T,C); rs77597516(C,T); rs2032252(C,T); rs2032251(T,A); rs78063241(T,C); rs6507887(T,A); rs11872567(C,T); rs10853577(G,A); rs113779376(G,T); rs7235020(G,C); rs139158682(T,C); rs62102349(G,A); rs7235619(C,G); rs8087711(A,T); rs7237062(C,T); rs4939849(A,G); rs72925817(T,C); rs111477892(G,T); rs11665239(A,G); rs4939850(C,G); rs4939851(C,T); rs8092381(T,C); rs74938181(A,G); rs4503868(G,A); rs2156252(A,T); rs2051326(T,C); rs1943010(G,A); rs1943009(A,G); rs12968991(C,A); rs2156251(C,T); rs12961303(C,T); rs12961466(C,T); rs1943008(T,C); rs10469000(C,T); rs4586520(C,T); rs4483916(C,T); rs139338356(T,C); rs4630621(C,T); rs6507890(T,C); rs12968802(G,A); rs12954773(G,A); rs7242217(T,G); rs1943007(A,G); rs1943005(G,T); rs12606493(G,A); rs2156250(A,T); rs191693727(C,A); rs8084753(C,T); rs16950454(C,A); rs4939852(A,G); rs8084170(T,C); rs35415862(A,G); rs76446148(C,A); rs9304373(C,T); rs4491603(G,C); rs28731147(G,A); rs11082741(G,A); rs10775492(G,C); rs76527927(T,C); rs6507891(C,G); rs2032250(A,C); rs16950460(A,G); rs7240529(C,T); rs7240563(C,A); rs76959377(G,A); rs16950465(C,T); rs1977951(C,G); rs4939574(T,C); rs184017156(T,C); rs76816954(G,A); rs4939853(A,G); rs62104577(T,C); rs11082743(C,T); rs143783625(C,T); rs11661691(T,G); rs79030588(G,A); rs148824289(A,C); rs4939855(C,T); rs13381179(C,T); rs116832427(G,A); rs12326672(C,A); rs12326673(A,G); rs8097220(A,G); rs13381473(C,T); rs11662738(C,T); rs183704174(G,A); rs16950480(G,A); rs573272(T,C); rs76504357(G,C); rs9947456(G,A); rs480460(C,T); rs1701878(A,G); rs145659565(G,A); rs192175584(C,T); rs2957173(A,T); rs7229796(T,C); rs2658744(A,G); rs510201(G,A); rs509229(T,C); rs374409610(G,T); rs1893530(C,T); rs572642(C,T); rs184266395(A,T); rs148648463(G,A); rs145754577(G,A); rs34120857(C,T); rs191900196(G,T); rs2849476(G,A); rs80331958(A,G); rs72925840(C,T); rs1788117(C,G); rs148700320(G,A); rs1788118(G,A); rs56205725(T,A); rs75928777(A,G); rs8087374(T,C); rs1788120(C,T); rs528306(C,T); rs115274355(T,C); rs507742(A,G); rs115993133(A,G); rs115579249(C,T); rs549201(C,T); rs552086(G,C); rs3794824(C,G); rs3794823(G,A); rs7231569(G,A); rs11660853(C,T); rs502089(C,T); rs10445490(G,C); rs511158(T,C); rs369761328(T,C); rs2939613(C,T); rs1701877(A,G); rs523373(C,A); rs487767(C,T); rs28737303(G,A); rs6507896(C,A); rs6507897(C,A); rs61580418(C,A); rs562009(T,C); rs561007(A,C); rs62104611(G,A); rs186378471(T,C); rs62104612(G,A); rs12960046(A,G); rs580326(A,C); rs12185343(C,A); rs192154350(G,A); rs484892(A,T); rs573978(C,T); rs75219584(T,G); rs112835793(C,T); rs9789092(C,G); rs148438466(C,T); rs62104613(C,T); rs522324(T,C); rs74969988(C,T); rs72912503(G,A); rs183569153(T,C); rs3965003(C,T); rs55858752(A,C); rs4939858(A,G); rs577081(A,G); rs577979(A,G); rs575408(C,G); rs515634(A,C); rs62104615(C,T); rs4567803(T,C); rs77317783(T,C); rs476201(G,C); rs11659570(C,T); rs192894656(G,C); rs2957171(T,G); rs530550(T,G); rs494752(G,C); rs1539965(G,A); rs2849477(A,G); rs8098926(G,C); rs186429099(G,A); rs74694639(T,C); rs527265(A,G); rs504246(A,C); rs498929(A,C); rs78865592(A,C); rs550258(T,C); rs1943012(G,A); rs7227713(A,T); rs370077109(A,G); rs4939861(C,T); rs9635952(T,C); rs556230(T,C); rs478682(C,A); rs2849478(C,T); rs2658743(T,A); rs528691(A,G); rs2939611(A,G); rs6507898(G,A); rs4939576(C,T); rs191965773(G,A); rs9956476(C,G); rs6507899(C,T); rs7505791(G,A); rs7505756(C,T); rs11664257(C,T); rs7239158(T,C); rs7506911(T,G); rs79525485(C,G); rs9284427(A,G); rs2078286(G,A); rs7228073(T,G); rs76197401(T,A); rs77037077(T,G); rs116542776(T,C); rs79348226(C,T); rs79104574(C,T); rs7506068(C,G); rs77839149(A,G); rs7242873(A,G); rs6507900(C,A); rs7506861(A,G); rs35834567(C,T); rs4939863(A,G); rs12458995(T,C); rs78791706(T,A); rs2001801(A,T); rs374902537(G,A); rs3809924(A,G); rs6507901(A,G); rs1876214(A,G); rs74950574(T,C); rs142155696(G,T); rs12457867(T,C); rs2337548(A,C); rs4939577(T,C); rs12961531(C,T); rs12962555(T,A); rs4939864(A,G); rs7504840(A,G); rs10775493(G,C); rs56175691(G,A); rs78150071(C,T); rs372159639(T,C); rs4939578(A,G); rs9949183(G,C); rs9964222(T,C); rs9954969(A,C); rs78571163(G,A); rs7235696(C,A); rs72912550(T,A); rs72642462(T,G); rs111675513(C,T); rs7504446(T,C); rs112575693(C,T); rs4939866(A,T); rs4939867(C,A); rs6507902(A,G); rs116125106(A,G); rs80176386(G,A); rs8094085(A,C); rs8099330(T,C); rs4939579(T,G); rs4939868(G,A); rs4939869(A,T); rs72924985(C,A); rs4939870(C,A); rs6507904(A,C); rs9956978(T,C); rs8088197(T,C); rs8087325(A,T); rs4939871(C,T); rs62102874(T,C); rs4939580(A,G); rs146166288(C,T); rs77549295(G,A); rs113837472(T,G); rs189304079(A,C); rs4939581(G,A); rs138268392(T,A); rs75062662(G,A); rs35710322(T,C); rs6507906(T,C); rs62102876(T,A); rs6507908(G,C); rs111955738(T,C); rs77451458(G,A); rs9949963(A,G); rs75491990(G,T); rs372211433(C,T); rs7505245(T,C); rs8093029(G,C); rs8088875(A,G); rs113284367(T,C); rs76051941(A,C); rs374157314(C,T); rs8086225(C,T); rs11663141(G,A); rs9950560(T,C); rs11663904(C,T); rs149663072(T,A); rs36126487(G,A); rs192795166(C,G); rs9952898(T,A); rs7244976(C,T); rs7244977(C,T); rs60182440(T,C); rs2097056(C,A); rs115534639(C,T); rs78334393(G,A); rs8089127(G,A); rs7407441(G,A); rs113472724(C,A); rs140885635(G,A); rs9967318(G,A); rs9967417(G,C); rs62102900(T,C); rs376516892(C,G); rs7230541(T,G); rs7245027(A,G); rs11082752(C,T); rs9960446(T,C); rs9961129(T,G); rs4359547(T,C); rs185608670(G,A); rs1943674(A,C); rs6417103(T,C); rs1943675(A,G); rs75663396(C,T); rs34904781(T,C); rs77414810(C,T); rs28889615(T,C); rs112532190(T,C); rs55746222(G,A); rs2156497(A,G); rs11533774(T,C); rs28862462(C,T); rs35755610(C,T); rs11082753(A,T); rs146060871(C,T); rs66622242(A,G); rs149796274(A,C); rs9951172(G,C); rs28447549(T,C); rs75946178(G,A) |
| ccdsGene name | CCDS11937.1 |
| cytoBand name | 18q21.1 |
| EntrezGene GeneID | 54808 |
| EntrezGene Description | dymeclin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DYM:NM_017653:exon16:c.A1778G:p.Q593R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6187 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7RTS9-2 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000692 |
| ESP Eur/Amr MAF | 0.001047 |
| ExAC AF | 0.0007726 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Sensorineural hearing loss;
Vestibular dysfunction;
[Eyes];
Nystagmus;
Upward gaze paresis;
Blepharoptosis;
Ophthalmoparesis, progressive, external;
Cataracts (less common)
CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy (less common)
ABDOMEN:
[Gastrointestinal];
Gastroparesis (less common);
Intestinal pseudo-obstruction (less common)
MUSCLE, SOFT TISSUE:
Proximal muscle weakness, mild;
Dysarthria;
Ragged red fibers seen on muscle biopsy;
Increased variation in fiber size;
Necrotic and atrophic fibers with centralized nuclei;
Multiple mitochondrial DNA (mtDNA) deletions (in most cases);
Decreased activity of cytochrome c oxidase (in most cases);
Subsarcolemmal accumulations of abnormally shaped mitochondria seen
on electron microscopy
NEUROLOGIC:
[Central nervous system];
Gait ataxia, progressive;
Ataxia worsens in the dark;
Positive Romberg sign;
Hyporeflexia;
Areflexia;
Myoclonus (less common);
Migraine;
Seizures (less common);
Cognitive impairment, mild;
Bilateral thalamic lesions on MRI;
Cerebellar white matter lesions on MRI;
Atrophic and degenerative changes in the spinal cord;
[Peripheral nervous system];
Sensory ataxic neuropathy;
Distal sensory impairment to vibration and proprioception;
Sensory axonal neuropathy;
Sural nerve biopsy shows loss of large and small myelinated axons;
[Behavioral/psychiatric manifestations];
Memory difficulties;
Lack of concentration;
Withdrawal;
Depression
LABORATORY ABNORMALITIES:
Mildly increased serum lactate;
Mildly increased serum creatine kinase
MISCELLANEOUS:
Young-adult onset (18-30 years) of sensory ataxia;
Later onset of ophthalmoparesis;
Highly variable phenotype
MOLECULAR BASIS:
Caused by mutation in the DNA polymerase-gamma gene (POLG, 174763.0002)
OMIM Title
*607461 DYMECLIN; DYM
OMIM Description
CLONING
Cohn et al. (2003) stated that DYM cDNA predicts a 669-residue protein
containing 6 transmembrane segments and a cytoplasmic N terminus.
Database analysis identified highly homologous proteins in many species.
EST database searching identified DYM transcripts derived from many
tissues, suggesting ubiquitous expression.
El Ghouzzi et al. (2003) reported that the DYM transcript was widely
distributed in normal cells and appeared particularly abundant in
chondrocytes and fetal brain.
By Northern blot analysis, Dimitrov et al. (2009) identified DYM as 3.1-
and 5.6-kb transcripts in primary chondrocytes and osteoblasts as well
as HeLa, SaOS2, and skin fibroblast cell lines. RNA dot-blot analysis
detected highest expression in cerebellum, kidney, lung, stomach, heart,
and pancreas with little to no expression in spleen, thymus, esophagus,
bladder, and thyroid gland. In situ hybridization of human embryonic and
fetal tissues showed that DYM was widely expressed in cortex,
hippocampus, and cerebellum. Fluorescence microscopy localized DYM to
the Golgi, and electron microscopy revealed that dymeclin associated
with the Golgi apparatus and with transitional vesicles of the ER-Golgi
interface. Permeabilization assays revealed that dymeclin is not a
transmembrane but a peripheral protein of the Golgi apparatus as it can
be completely released from the Golgi after permeabilization of the
plasma membrane. Time-lapse microscopy of living cells showed that
dymeclin shuttled between the cytosol and the Golgi apparatus in a
highly dynamic manner and recognized specifically a subset of mature
Golgi membranes.
GENE STRUCTURE
Cohn et al. (2003) stated that the DYM gene consists of 17 exons
distributed over more than 400 kb of genomic DNA. The initiating
methionine codon was identified in exon 2. The stop codon was in exon 17
and was followed by a polyadenylation signal (AATAAA) 228 bp into the
3-prime UTR. In the cDNA, the poly A followed 18 bp after the
polyadenylation signal.
MAPPING
Using a positional cloning strategy, Cohn et al. (2003) identified the
DYM transcript on chromosome 18q12-q21.1 as the gene mutant in
Smith-McCort dysplasia (SMC1; 607326) and Dyggve-Melchior-Clausen
dysplasia (DMC; 223800).
MOLECULAR GENETICS
Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia are similar
rare autosomal recessive osteochondrodysplasias. The radiologic features
and cartilage histology in DMC and SMC are identical. However, patients
with DMC exhibit significant developmental delay and mental retardation,
the major features that distinguish the 2 conditions. Cohn et al. (2003)
suggested that the 2 disorders are allelic because both map to
18q12-q21.1. By sequence analysis of the DYM gene, they demonstrated
mutations in patients with SMC (607461.0005-607461.0006) and DMC
(607461.0001-607461.0004). Affected members of 2 consanguineous DMC
families were homozygous for a stop codon mutation and a frameshift
mutation, respectively, demonstrating that DMC represents the DYM-null
phenotype.
Using a positional cloning strategy, El Ghouzzi et al. (2003) identified
mutations in the DYM gene in patients with Dyggve-Melchior-Clausen
syndrome. They detected 7 deleterious mutations, of which 4 were
nonsense, 2 splice site, and 1 frameshift, among 10 affected families.
Ultrastructural study of skin from an affected child showed dilated
rough endoplasmic reticulum, enlarged and aberrant vacuoles, and
numerous vesicles. El Ghouzzi et al. (2003) proposed that the gene
product, which they named dymeclin, may have a role in intracellular
digestion of proteins.
Neumann et al. (2006) reported 2 consanguineous families from Lebanon
and Georgia (Caucasus), respectively, with 2 patients each with DMC
confirmed by genetic analysis.
Dimitrov et al. (2009) showed that DYM mutations (see, e.g.,
607461.0004) associated with DMC resulted in mislocalization and
subsequent degradation of dymeclin. However, the DYM mutation (E87K;
607461.0006) associated with SMC did not result in mislocalization or
dymeclin degradation, suggesting that residual activity could explain
the absence of neurologic phenotype in SMC patients. Dimitrov et al.
(2009) concluded that DMC results from a loss-of-function of dymeclin.
MYO5B
| dbSNP name | rs546341(G,T); rs553040(T,C); rs149870629(C,T); rs553263(T,C); rs685591(G,C); rs670965(A,G); rs1942418(C,T); rs17713913(G,A); rs543468(G,C); rs1217604(C,G); rs570051(C,G); rs488042(T,C); rs488191(A,G); rs515811(G,T); rs111918224(G,C); rs138279601(C,T); rs4939898(C,T); rs12965607(T,G); rs560462(G,C); rs533064(A,T); rs646199(C,A); rs645232(C,T); rs79070209(G,A); rs4939596(G,A); rs498209(C,G); rs631052(T,G); rs495543(G,A); rs472449(G,A); rs616343(G,A); rs616331(G,A); rs578211(A,C); rs615827(T,C); rs10502902(T,C); rs613674(C,G); rs80183742(T,C); rs79109328(G,A); rs72642498(G,A); rs78814171(C,T); rs11662012(T,C); rs11659292(G,A); rs11659245(C,T); rs11659302(G,T); rs680052(G,C); rs11659307(C,G); rs11659310(C,G); rs11659330(C,T); rs11659336(C,G); rs112130537(A,T); rs1217625(T,C); rs77367228(T,C); rs4939900(C,T); rs4939901(A,G); rs4939902(A,G); rs113855445(A,T); rs11663885(T,C); rs111734531(A,G); rs9963703(T,C); rs79374597(C,T); rs3826580(T,C); rs3826579(G,A); rs28635912(C,G); rs28483032(C,T); rs113891295(C,G); rs533846(T,C); rs582210(G,T); rs9967578(T,C); rs9955644(G,A); rs9955491(C,G); rs72642500(A,G); rs17800351(C,T); rs17727301(T,C); rs72642501(T,G); rs11663034(A,G); rs11660022(T,C); rs9958667(G,A); rs4939597(C,T); rs948645(T,C); rs4939598(C,T); rs4939903(T,C); rs4939904(G,A); rs75885588(A,G); rs4939599(C,T); rs4939905(T,C); rs4939600(T,A); rs1217626(A,T); rs2276171(A,G); rs2276172(C,T); rs2276173(A,T); rs657424(A,C); rs139202442(C,T); rs645644(G,A); rs9947777(A,G); rs9948111(G,A); rs11873675(A,G); rs111736133(C,T); rs72642502(C,T); rs17657805(A,C); rs1217628(A,C); rs28521289(C,T); rs630665(C,T); rs487480(G,A); rs9951470(G,C); rs4939906(T,C); rs4939907(A,T); rs2276175(A,G); rs4939908(G,A); rs8098486(T,C); rs4939909(T,C); rs4939601(G,C); rs565517(A,T); rs596778(C,T); rs2276176(A,G); rs4939602(T,C); rs4939603(C,T); rs1217630(T,C); rs1237302(C,T); rs4939604(C,G); rs1228305(A,G); rs79834324(A,C); rs76923815(G,A); rs1237303(C,T); rs1217631(T,C); rs1217632(A,G); rs1217633(T,C); rs2276177(T,G); rs1217634(C,T); rs1217635(G,A); rs1217636(T,C); rs1217637(A,G); rs1217639(T,G); rs114169153(G,A); rs1787566(C,T); rs1310185(C,A); rs114187704(T,G); rs1310186(A,G); rs4939910(C,T); rs1942326(G,A); rs4939911(A,G); rs1787611(G,A); rs1787314(A,C); rs9947949(G,C); rs1787615(A,G); rs1787315(T,A); rs1617530(T,C); rs1617597(C,G); rs1787541(C,T); rs77543676(A,C); rs9709969(T,C); rs1621791(G,A); rs112141974(C,G); rs112291087(T,C); rs144689347(A,T); rs1787317(C,A); rs1787318(C,T); rs1787605(G,A); rs2679730(G,T); rs77055188(C,T); rs2969932(C,T); rs2915244(G,A); rs10502903(A,T); rs2848935(G,A); rs2156072(A,C); rs2679728(G,A); rs2679727(G,T); rs2187099(T,C); rs1539923(A,G); rs1621572(G,C); rs4939912(T,A); rs4939913(C,G); rs1787319(C,T); rs1787606(C,T); rs1557353(A,G); rs2969931(C,A); rs4939914(C,T); rs10083972(G,A); rs10221351(A,G); rs9304387(A,C); rs9304388(C,T); rs9304389(A,G); rs9304390(A,G); rs1615432(G,A); rs1787545(A,G); rs1787546(A,T); rs1787547(T,A); rs1619014(G,A); rs1787548(A,G); rs1787549(C,T); rs1787612(T,C); rs1787301(C,T); rs1787303(C,T); rs1787550(C,T); rs1787304(T,C); rs1787305(C,T); rs9959455(A,G); rs2915246(T,C); rs1942322(G,T); rs1942324(C,G); rs1787307(A,G); rs1787613(G,A); rs1787551(C,T); rs1787614(T,C); rs1787552(T,C); rs17800754(A,G); rs111821984(C,T); rs1787553(C,T); rs1787554(C,T); rs1614471(A,G); rs4939605(G,A); rs112228166(T,C); rs1616039(G,C); rs1787555(C,T); rs1787556(G,T); rs1787557(T,C); rs4939607(T,C); rs1787558(C,G); rs1787616(C,T); rs1787617(C,A); rs1787618(G,A); rs1787559(T,C); rs1787619(G,A); rs16951179(C,T); rs16951181(T,C); rs16951184(C,T); rs11659765(C,T); rs1787560(A,G); rs1787577(T,C); rs1787578(T,C); rs1787561(T,A); rs11876567(T,C); rs1539925(T,A); rs1539926(A,G); rs1787320(G,T); rs1787562(G,C); rs1787321(G,A); rs1787563(A,G); rs1612142(T,C); rs16951195(T,G); rs4939915(C,T); rs73438456(A,G); rs17714658(T,A); rs1787292(T,C); rs17727922(T,C); rs3132919(T,C); rs948643(A,G); rs190133933(G,C); rs17714688(C,T); rs75725470(A,C); rs17658306(C,T); rs948644(G,A); rs115059477(G,A); rs148714267(A,G); rs61737448(C,G); rs78973859(A,G); rs55754534(G,C); rs1612752(G,C); rs1787564(C,T); rs192349824(C,T); rs1787300(G,A); rs79629421(G,A); rs35199709(A,G); rs1787302(T,C); rs1217618(A,G); rs113562247(G,A); rs16951210(C,T); rs61054181(C,T); rs75963492(G,A); rs8097502(C,T); rs1217619(A,G); rs8084214(C,A); rs77380851(G,A); rs17714785(A,C); rs16951214(T,C); rs16951215(C,G); rs76895179(C,T); rs1217616(G,T); rs1217617(G,T); rs4939916(C,A); rs113980456(C,T); rs16951224(G,C); rs149361414(G,A); rs16951232(A,C); rs1787534(C,T); rs80311954(G,A); rs112787930(C,T); rs16951233(C,A); rs76982098(G,T); rs1787308(C,T); rs4939918(G,C); rs1623231(C,T); rs4939919(T,G); rs3018270(C,T); rs1217610(G,C); rs1217611(C,T); rs1217612(T,G); rs17658513(C,T); rs10502904(C,T); rs1235011(A,G); rs80317083(G,T); rs113393261(A,G); rs1217613(A,G); rs77263639(T,C); rs142147917(T,C); rs1790775(A,G); rs1790776(G,A); rs115078125(A,G); rs148138882(G,A); rs116711898(G,C); rs114635996(G,A); rs78653961(G,A); rs112855134(T,G); rs142321431(T,G); rs115278054(G,T); rs114322329(A,G); rs1228304(C,T); rs1217615(T,A); rs1787610(T,C); rs2298626(T,C); rs2298628(C,T); rs372101289(G,A); rs1623892(A,G); rs375912779(T,C); rs1787593(T,C); rs80187959(A,G); rs1787328(T,C); rs1787327(T,G); rs11663056(G,T); rs6507957(C,T); rs8086557(C,T); rs62098758(A,G); rs8087089(G,C); rs66656534(G,T); rs75982916(G,A); rs949265(C,A); rs949264(C,A); rs1625181(A,G); rs71357210(A,C); rs1626800(G,T); rs1790786(G,A); rs1790785(T,A); rs1790784(T,C); rs1790783(A,G); rs1631002(A,C); rs116024521(G,A); rs1790782(A,G); rs12457889(G,A); rs75214725(C,T); rs1787523(G,A); rs12967065(C,T); rs1787326(T,A); rs1790781(C,T); rs1790780(T,G); rs1790779(C,G); rs1787325(T,C); rs1787522(T,C); rs1787521(A,C); rs12962880(C,A); rs1790778(T,C); rs1787594(G,C); rs1787324(A,T); rs1787595(A,C); rs1942432(G,A); rs79393918(C,T); rs1942433(A,G); rs1623880(G,A); rs1787520(T,C); rs62100982(C,A); rs115696647(G,A); rs1627232(G,A); rs1787596(G,A); rs3744844(C,G); rs1787597(T,C); rs76277923(G,A); rs1787323(C,T); rs1790797(A,G); rs1787519(A,G); rs35991968(C,T); rs1790796(C,T); rs79124236(C,T); rs34659691(A,T); rs12457612(A,G); rs1787598(A,C); rs16951255(T,A); rs8094647(G,A); rs12458210(C,T); rs1787599(C,T); rs8095684(T,C); rs2721090(G,A); rs2969927(T,C); rs2954241(C,G); rs12458392(G,C); rs116476584(G,A); rs1787600(G,T); rs17658618(C,T); rs12954048(T,C); rs1790792(C,T); rs1790793(C,G); rs1787296(C,T); rs1787601(G,A); rs1787602(G,A); rs1787297(T,C); rs1787603(G,T); rs1787532(T,C); rs7243065(G,A); rs1790794(G,A); rs1790795(A,G); rs1787537(C,T); rs1787592(T,G); rs11082793(A,T); rs1787293(T,C); rs12969363(C,T); rs12970560(T,C); rs1787538(T,C); rs1787539(G,A); rs1787591(G,A); rs1787294(A,G); rs1617706(C,T); rs3017177(T,A); rs2954238(C,T); rs62100992(T,C); rs1787590(A,G); rs1787589(G,A); rs1790790(G,C); rs3132916(C,G); rs3107098(C,A); rs1790789(C,T); rs12962673(T,C); rs12962004(C,T); rs2945827(C,T); rs2969926(G,T); rs140112386(T,C); rs1632469(C,T); rs1631883(G,A); rs1631841(C,A); rs1787536(G,A); rs1787291(A,G); rs3107224(G,A); rs3112029(G,C); rs1787290(C,T); rs11874472(A,G); rs1616410(C,T); rs1787588(A,G); rs1787289(T,G); rs17715196(T,C); rs1787288(C,T); rs1787587(A,C); rs1631334(C,T); rs12959341(A,G); rs12964460(T,C); rs1790777(T,C); rs115396847(C,T); rs1787524(C,T); rs1787586(C,T); rs1787287(G,A); rs1787585(G,A); rs71357213(G,A); rs56984587(C,T); rs1974410(C,T); rs1787584(T,A); rs28445540(G,T); rs1787286(G,T); rs7229075(G,A); rs7229098(G,C); rs28472691(G,T); rs7228877(A,C); rs7229403(G,A); rs7230292(T,G); rs7229166(C,T); rs1787285(G,A); rs76675985(A,C); rs114190917(G,C); rs17658880(A,G); rs17658886(C,G); rs3928907(C,G); rs17715292(A,C); rs1787299(G,A); rs1557359(T,C); rs9675910(G,A); rs9958316(C,T); rs1787525(G,A); rs1787583(G,A); rs4939922(C,T); rs62098862(G,C); rs71357215(G,C); rs17801411(G,A); rs16951305(A,T); rs13381727(C,T); rs1787582(C,T); rs9954060(T,C); rs949262(A,G); rs1893453(T,C); rs2721085(T,A); rs3897687(T,G); rs148653321(C,G); rs1790800(A,G); rs73440570(C,T); rs9945925(C,T); rs9948273(C,A); rs1790799(C,T); rs1790798(G,T); rs7239281(A,G); rs1557357(C,G); rs3915948(G,C); rs7244316(G,A); rs3915600(G,A); rs17658998(C,G); rs62098864(G,A); rs34900254(C,T); rs16951323(C,T); rs17715399(T,C); rs17715416(A,G); rs17659034(T,C); rs149288536(A,C); rs4939608(T,A); rs17715451(T,C); rs181072057(C,A); rs9963579(T,G); rs1557355(T,C); rs113632742(T,C); rs8089039(A,G); rs8089939(G,A); rs77391250(T,C); rs11082794(A,T); rs7240811(T,C); rs6507958(A,T); rs7227513(T,C); rs12326253(G,A); rs12958094(C,A); rs8087263(A,G); rs2000723(T,A); rs9963529(T,G); rs2000900(T,G); rs4939923(T,C); rs11873518(C,T); rs4939924(C,T); rs375663249(G,A); rs75903847(C,A); rs12455767(A,T); rs4591251(T,C); rs115573094(A,T); rs115655890(G,A); rs16951349(T,C); rs114894841(A,G); rs16951350(G,A); rs148118196(G,A); rs116031459(A,C); rs61177844(T,C); rs16951354(G,A); rs7242679(G,A); rs7242307(A,G); rs6507959(A,G); rs114822671(C,T); rs6507960(C,T); rs6507961(G,A); rs8099383(T,C); rs138771718(C,T); rs114888210(G,A); rs111624748(A,G); rs73442509(G,A); rs73442512(A,C); rs16951355(C,T); rs7240377(C,A); rs73442518(C,T); rs79904768(C,T); rs57118453(G,A); rs113717204(G,C); rs8087760(A,G); rs8088022(C,T); rs8089410(T,C); rs8088706(G,C); rs115540721(A,G); rs8088632(A,G); rs8092665(G,T); rs4245233(T,C); rs73442531(C,A); rs113629297(A,G); rs57559574(A,G); rs73442535(A,G); rs11875730(C,T); rs7234247(C,G); rs58574581(T,C); rs74742380(T,G); rs7235775(C,T); rs60136151(T,C); rs7240708(G,T); rs4939928(A,G); rs7233028(T,G); rs7233322(T,C); rs9960655(T,C); rs73442557(C,T); rs10853589(T,C); rs7228145(G,A); rs80123507(G,A); rs7228300(G,A); rs7228713(A,G); rs7229122(G,A); rs73442565(C,T); rs73442567(C,T); rs9963530(A,T); rs60511379(G,A); rs73442570(C,T); rs60822182(T,G); rs75060740(C,T); rs4283318(T,C); rs9950823(A,G); rs73442578(G,C); rs12969222(T,G); rs9956599(A,C); rs148224324(C,T); rs61264058(T,G); rs9961643(T,C); rs60591504(T,C); rs9304393(T,C); rs78846740(T,G); rs11082798(G,A); rs17659350(T,C); rs9958692(C,G); rs28739434(G,A); rs4398183(T,G); rs9951370(T,C); rs4939610(G,A); rs4939930(C,T); rs7241763(G,A); rs73442597(T,C); rs6507962(C,G); rs7243216(G,A); rs4281814(G,T); rs7228893(C,T); rs8089249(A,G); rs8089596(C,T); rs17801759(A,G); rs4422066(A,T); rs59163993(A,G); rs10469004(T,C); rs72913831(T,C); rs59798863(G,C); rs115626119(T,A); rs4939612(T,C); rs8097126(T,A); rs6507963(T,A); rs8096121(A,G); rs141004722(A,C); rs59585590(A,T); rs149682556(C,T); rs114390927(T,A); rs12958677(C,G); rs9653020(C,A); rs112482253(C,A); rs4365387(T,C); rs151237181(C,T); rs11660336(G,A); rs1893983(C,A); rs116608268(G,A); rs4331418(C,G); rs8098733(T,C); rs8098154(C,T); rs4939613(T,A); rs1815928(G,A); rs116701598(A,C); rs148919317(C,T); rs114503216(T,C); rs11082799(G,A); rs76979703(A,G); rs7241126(T,G); rs138336084(G,A); rs12970975(C,G); rs73444722(A,C); rs12454026(G,A); rs8086954(A,C); rs60669253(A,G); rs11662612(G,A); rs7229010(T,A); rs73959844(C,T); rs74654443(T,C); rs73444729(C,G); rs72913861(C,A); rs60024710(A,G); rs60954036(A,G); rs1815941(G,T); rs1815940(T,C); rs4281815(G,T); rs10502905(G,A); rs73444740(A,G); rs4287668(C,T); rs4606829(A,G); rs7244899(G,A); rs60799755(G,A); rs73444754(A,G); rs1815939(T,A); rs1815938(A,G); rs73444757(C,A); rs75721002(T,A); rs1815937(C,T); rs1815936(C,T); rs73444760(A,T); rs1815934(T,G); rs12455913(C,T); rs4939932(C,T); rs4939933(C,T); rs184815583(G,A); rs1815933(C,G); rs1815932(G,A); rs7233446(C,T); rs7234190(G,C); rs115427667(C,T); rs7239417(G,A); rs73444767(T,C); rs1815931(C,T); rs73444770(T,C); rs1815930(T,C); rs9955800(A,G); rs1815929(T,G); rs73444775(G,A); rs73444779(T,C); rs12962799(A,G); rs4939614(G,C); rs181329126(T,C); rs4939615(T,C); rs9945639(C,T); rs115576270(C,T); rs9945666(A,G); rs377636961(T,C); rs4265917(C,T); rs73444788(G,A); rs2721080(C,A); rs2666932(T,A); rs73444792(C,G); rs2721081(G,A); rs2721082(G,A); rs3941597(C,A); rs2721083(C,A); rs2852096(T,C); rs138304995(G,T); rs17801873(C,G); rs2666931(C,T); rs2666930(G,T); rs2941747(T,C); rs2941746(G,C); rs2959534(G,A); rs17715957(A,G); rs187346887(A,T); rs17801897(A,T); rs2666928(A,T); rs116827850(C,T); rs73959848(T,C); rs79898963(T,G); rs2721091(C,T); rs76046479(C,A); rs2666927(A,G); rs72915715(T,G); rs73959850(A,T); rs73446607(G,A); rs17728885(C,A); rs3897890(A,G); rs2852095(G,A); rs17801939(A,G); rs114361672(C,T); rs59163572(T,A); rs17801957(A,G); rs2852104(C,A); rs2666926(C,T); rs2721086(G,A); rs115918299(T,C); rs74527226(A,G); rs112727105(A,G); rs2721087(G,A); rs2666925(C,A); rs2721079(T,C); rs112502026(T,A); rs77758274(T,C); rs115088082(G,A); rs2852103(A,C); rs2852102(G,C); rs76588922(T,C); rs112306361(T,G); rs79278781(T,C); rs76245700(C,G); rs111360042(T,C); rs2852101(T,C); rs115543226(A,G); rs114949773(T,C); rs2721088(T,C); rs77346305(T,C); rs112553253(T,C); rs116104251(C,A); rs2852100(C,T); rs2721089(G,A); rs114202995(A,G); rs58984742(T,C); rs56064131(T,G); rs111611887(G,A); rs2852099(C,T); rs78922823(C,G); rs2852098(C,T); rs76966530(C,T); rs57109291(G,A); rs79826463(G,C); rs2721084(T,C); rs80006744(C,T); rs2852097(C,T); rs2666935(G,A); rs76262010(T,A); rs113874545(T,G); rs115363228(A,C); rs77269149(C,G); rs78023300(G,A); rs76246669(G,A); rs16951443(T,G); rs73446635(A,C); rs2852090(C,T); rs113268907(T,C); rs16951444(A,T); rs16951446(A,G); rs61014316(C,G); rs79373100(C,T); rs57410122(C,T); rs79584162(C,A); rs113569576(G,C); rs3898016(A,G); rs114913205(A,G); rs3898017(T,C); rs113108018(A,G); rs114138643(T,A); rs73446645(C,T); rs78807555(C,A); rs2852091(C,T); rs16951447(A,G); rs11664789(C,T); rs79251985(T,C); rs142194489(G,A); rs113650962(T,A); rs73446649(C,T); rs41434445(C,T); rs16951451(G,A); rs79749731(G,A); rs16951452(A,G); rs113128623(G,C); rs73446652(T,C); rs116830981(G,A); rs112983768(T,A); rs79978187(C,T); rs73446655(T,C); rs11082801(T,C); rs12454692(C,A); rs16951453(T,C); rs116301688(G,A); rs16951455(C,T); rs75829616(C,T); rs2941748(C,T); rs16951456(T,C); rs11877042(T,C); rs55973431(C,T); rs11873930(G,C); rs11873938(C,T); rs112159384(A,G); rs11877128(T,C); rs16951461(T,A); rs73446665(A,G); rs2666933(T,C); rs116616094(A,G); rs76784184(A,T); rs73446666(T,C); rs77411044(T,C); rs114214522(A,T); rs112979422(C,A); rs115375172(C,G); rs79289086(C,G); rs66563656(T,G); rs76376415(C,A); rs73446672(C,T); rs16951464(T,C); rs16951467(C,T); rs114465091(C,T); rs16951469(A,G); rs55740515(G,C); rs2852094(G,A); rs56000363(T,G); rs112886413(A,G); rs115381241(G,A); rs77751047(C,T); rs16951471(A,C); rs75288100(T,C); rs16951477(G,C); rs16951480(A,G); rs76104509(A,G); rs114137581(G,A); rs74488749(C,T); rs75845837(G,T); rs16951482(C,T); rs115115504(C,T); rs78441534(C,T); rs73446685(C,T); rs73446686(C,T); rs75867576(G,A); rs73446687(T,C); rs73446688(G,A); rs2852093(C,T); rs112891814(C,T); rs17802069(G,A); rs16951484(A,G); rs116111442(G,C); rs16951486(A,G); rs16951488(T,G); rs74605163(A,C); rs113782925(G,A); rs16951490(G,T); rs16951494(T,G); rs76409902(T,C); rs77446050(G,A); rs79336804(C,A); rs80065326(C,T); rs73446698(T,A); rs112481693(T,C); rs115655232(C,A); rs1877170(G,C); rs11873585(C,T); rs11876744(T,C); rs11876777(T,C); rs115688550(A,C); rs11873736(A,C); rs11873823(G,C); rs11873766(A,C); rs55901816(T,C); rs56112383(G,C); rs114681086(G,A); rs55781418(G,A); rs111641250(T,C); rs76943101(G,A); rs34151822(C,A); rs141103757(G,A); rs184516606(T,G); rs111738958(G,A); rs111438058(G,A); rs8085101(T,C); rs76934289(C,T); rs75458599(G,A); rs72917846(T,C); rs1877171(G,A); rs60211550(A,G); rs78095453(C,T); rs74623953(A,C); rs112525513(T,A); rs67371714(C,G); rs8086061(G,C); rs8085876(A,G); rs8086129(C,T); rs8086287(C,T); rs72917852(G,A); rs61143368(G,A); rs60328586(C,T); rs58100385(C,G); rs4939935(A,G); rs61154515(G,T); rs73448725(A,G); rs57181716(C,T); rs8087268(G,T); rs8087386(G,T); rs8087466(C,G); rs57590770(C,T); rs72917866(C,A); rs72917867(C,A); rs112654711(T,A); rs11082802(C,T); rs112117850(T,C); rs74604886(T,G); rs76428660(A,G); rs1056030(G,A); rs79496364(T,C); rs2292380(A,T); rs2292381(C,T); rs112213502(A,G); rs2292382(G,T); rs78847958(G,A); rs112703964(C,G); rs16951520(C,G); rs74861239(G,C); rs113893312(G,A); rs34076760(G,T); rs112645171(A,T); rs59865407(T,C); rs76225237(C,T); rs60748915(A,T); rs7239831(A,G); rs115397735(C,T); rs72917870(C,T); rs72917871(C,T); rs72917872(C,T); rs8082713(A,G); rs67235664(G,C); rs11875844(A,G); rs74808128(G,C); rs16951529(A,C); rs111729088(G,T); rs113700273(C,T); rs16951532(G,A); rs4939616(T,C); rs16951535(C,G); rs8089226(T,C); rs72917883(C,T); rs72917884(G,C); rs112054577(C,T); rs75259958(T,G); rs17716413(C,A); rs60112557(C,T); rs78268095(T,G); rs16951538(C,G); rs56793364(C,A); rs61644566(C,T); rs116113423(A,G); rs7506978(G,C); rs60753795(C,T); rs111492114(G,A); rs17729161(C,T); rs7230622(G,A); rs7230623(G,A); rs72917893(G,A); rs7230413(A,G); rs60419005(C,T); rs72917900(T,C); rs73959870(A,G); rs7235033(C,A); rs7235513(G,A); rs72919803(C,G); rs72919804(G,A); rs113698010(T,G); rs191995922(T,C); rs73430304(C,T); rs73430307(T,C); rs77811265(T,C); rs73430309(G,A); rs73430312(A,T); rs76967376(C,A); rs73430313(A,G); rs79333957(A,T); rs952799(A,C); rs949931(A,G); rs115491317(A,G); rs73430315(A,C); rs57136853(G,A); rs4939938(T,C); rs4939939(C,T); rs4939940(A,G); rs7407945(G,A); rs9966423(T,C); rs9954152(A,C); rs9966699(T,C); rs12456122(C,A); rs10853590(T,C); rs111776301(T,C); rs9963499(C,G); rs9952643(T,C); rs9952908(T,C); rs1705548(G,C); rs1705494(C,A); rs2457965(C,A); rs2457966(A,G); rs2457967(T,C); rs6507964(G,T); rs1790433(C,G); rs7237077(T,C); rs1628233(G,A); rs1705543(C,A); rs1627219(G,A); rs17716496(T,G); rs12967269(G,C); rs1705542(T,C); rs114256115(G,A); rs907236(A,G); rs949187(C,T); rs7227756(C,T); rs1790432(G,T); rs949186(A,G); rs12326884(A,T); rs907235(T,C); rs907234(G,C); rs949185(A,T); rs907233(T,C); rs1790428(G,A); rs907232(A,G); rs1790427(T,C); rs17716544(G,A); rs1790426(A,G); rs1790425(T,A); rs75023094(C,T); rs949184(T,A); rs949183(A,C); rs73959882(A,G); rs187849500(G,T); rs4939943(G,C); rs1705535(T,C); rs34357790(C,A); rs1705534(G,A); rs1790441(T,G); rs1790442(A,T); rs1790443(T,C); rs59265785(C,T); rs1705533(G,A); rs1790444(G,C); rs1705532(G,A); rs1790445(A,G); rs1511151(C,T); rs55962226(C,A); rs2469479(A,C); rs2469478(C,T); rs1616331(C,T); rs1612024(G,A); rs8091678(A,G); rs2457975(A,T); rs11665048(G,A); rs34934575(G,A); rs949180(C,A); rs116726484(G,A); rs949181(G,A); rs868973(G,C); rs868972(G,C); rs868971(A,G); rs1705529(G,C); rs77329007(C,A); rs4939948(A,G); rs1790411(G,A); rs62101468(C,T); rs8094831(G,A); rs1705519(T,C); rs76183080(C,T); rs1705518(G,C); rs1705517(A,C); rs1790412(T,C); rs7231741(C,G); rs7236961(T,G); rs72919889(T,G); rs373942979(C,T); rs7233836(T,C); rs6507965(T,C); rs1705502(T,G); rs2276368(T,C); rs1616625(G,A); rs1397678(G,A); rs1705504(G,C); rs1790417(C,T); rs6507966(G,A); rs991654(A,T); rs12607904(A,C); rs1623594(G,A); rs12150790(T,C); rs7227820(T,C); rs7227007(C,T); rs956778(G,T); rs871621(C,G); rs871622(G,A); rs949182(C,T); rs869126(C,T); rs74586859(G,T); rs973655(T,C); rs973656(G,A); rs17802396(T,C); rs1705507(T,C); rs1790416(A,G); rs8098073(C,G); rs8097966(A,T); rs8098113(A,G); rs78772710(C,T); rs4095420(C,T); rs12965448(C,T); rs144507285(A,G); rs62101497(A,C); rs1705508(C,T); rs1985467(T,C); rs72921717(G,A); rs9949712(T,C); rs1628303(G,T); rs72921721(A,G); rs1511150(T,C); rs10502907(C,T); rs34571336(C,T); rs72921725(C,A); rs997837(T,C); rs1790465(T,C); rs1705509(A,C); rs1705510(A,G); rs1705511(C,G); rs1567526(G,A); rs148353660(G,A); rs1705512(A,G); rs1705513(C,T); rs77204803(A,G); rs1705514(T,C); rs1467087(T,C); rs17660456(C,G); rs17716831(G,A); rs75193001(C,G); rs4939617(A,G); rs11082805(T,G); rs4939949(C,G); rs1705528(G,A); rs1705527(T,C); rs1790463(A,C); rs1790462(C,G); rs11663203(G,A); rs74811752(G,A); rs1705525(G,A); rs146024425(T,C); rs1790461(C,T); rs1705524(A,G); rs1397679(A,C); rs57661994(T,C); rs4356569(G,C); rs4267424(G,A); rs4603663(C,T); rs1705515(T,C); rs7242823(A,C); rs11662087(G,A); rs11082807(A,C); rs11082808(C,T); rs11877056(A,G); rs1705520(T,C); rs1705521(T,C); rs1705522(T,C); rs1790415(T,C); rs7244611(T,A); rs12970477(G,A); rs1628154(T,A); rs139473034(C,T); rs1705523(A,T); rs34618434(T,C); rs115810637(A,G); rs4349244(G,A); rs1790414(C,T); rs1705544(A,G); rs9949319(T,C); rs1705545(C,A); rs1790413(G,A); rs4939950(G,A); rs4939951(T,C); rs8093558(G,A); rs8094659(T,C); rs1705546(C,G); rs1790449(A,G); rs10502908(T,C); rs1355409(G,A); rs1355410(C,T); rs1355411(T,C); rs8085880(C,T); rs12454494(C,A); rs12964072(T,C); rs114882831(C,T); rs4939953(T,C); rs4939954(G,C); rs2469480(C,T); rs10853592(C,T); rs11082809(G,C); rs6507968(G,C); rs6507969(G,A); rs6507970(A,G); rs8085772(G,A); rs62101529(G,A); rs8086036(G,T); rs8086076(G,T); rs8090334(G,C); rs8091290(T,C); rs12961521(G,T); rs2457977(C,G); rs4939955(A,G); rs12966211(G,C); rs12966222(G,A); rs10164183(T,C); rs10163781(A,C); rs1705547(T,G); rs10164196(T,C); rs9304394(A,G); rs1619740(G,A); rs1618185(C,T); rs1616442(C,G); rs1511154(T,G); rs1511155(T,A); rs143583120(T,C); rs951388(A,C); rs951387(G,A); rs66464140(G,A); rs1790440(C,T); rs1705492(A,C); rs11082810(A,C); rs145273397(C,T); rs68057311(A,C); rs1705493(T,C); rs1790439(T,C); rs1790438(T,C); rs1790436(A,G); rs8084741(G,C); rs8084995(G,T); rs1790435(A,G) |
| ccdsGene name | CCDS42436.1 |
| cytoBand name | 18q21.1 |
| EntrezGene GeneID | 4645 |
| EntrezGene Description | myosin VB |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO5B:NM_001080467:exon19:c.G2343C:p.K781N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7331 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9ULV0 |
| dbNSFP Uniprot ID | MYO5B_HUMAN |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.001636 |
| ESP Eur/Amr MAF | 0.002408 |
| ExAC AF | 2.548e-03,8.165e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Ears];
Hearing loss, profound congenital sensorineural
ABDOMEN:
[Gastrointestinal];
Enteropathy;
Diarrhea;
Intractable vomiting;
Feeding problems;
Small bowel biopsy shows crypt hyperplastic villus atrophy, inflammatory
infiltrate within the lamina propria, and disorganized surface epithelium
GENITOURINARY:
[Kidneys];
Renal tubular dysfunction
ENDOCRINE FEATURES:
Hyperinsulinism
LABORATORY ABNORMALITIES:
Hypoglycemia;
Generalized aminoaciduria;
Homozygous 122Kb deletion 11p15-p14
MOLECULAR BASIS:
Contiguous gene syndrome caused by homozygous deletion of approximately
122Kb on chromosome 11p15-p14
OMIM Title
*606540 MYOSIN VB; MYO5B
;;KIAA1119
OMIM Description
Myosins are molecular motors that, upon interaction with actin
filaments, utilize energy from ATP hydrolysis to generate mechanical
force. For further background information on myosins, see MYO1A
(601478).
CLONING
By screening for cDNAs with the potential to encode large proteins
expressed in brain, Hirosawa et al. (1999) identified a cDNA encoding
MYO5B, which they called KIAA1119. The deduced 1,260-amino acid protein
is 88% identical to rat Myr6. RT-PCR analysis detected wide expression
of KIAA1119, with highest levels in liver, followed by kidney.
GENE FUNCTION
In a hepatic epithelial cell line, Wakabayashi et al. (2005) showed that
MYO5B is required for polarization of hepatocytes and that polarization
is initiated upon delivery of RAB11A (605570)-MYO5B-containing membranes
to the surface.
Roland et al. (2007) demonstrated the interaction of MYO5B with RAB8A in
yeast 2-hybrid assays, and confirmed the interaction of MYO5B with
RAB11A and RAB8A in vivo using fluorescent resonant energy transfer
techniques.
Muller et al. (2008) noted that MYO5B is required for the recycling of
transferrin receptor (190010) back to the plasma membrane through an
endocytotic recycling compartment in nonpolarized, but not polarized,
cells.
MOLECULAR GENETICS
In patients with microvillus inclusion disease (MVID, DIAR2; 251850)
from 7 families, Muller et al. (2008) identified 7 different nonsense,
missense, splice site, or in-frame insertion mutations in the MYO5B
gene.
In 7 Navajo patients with microvillus inclusion disease, Erickson et al.
(2008) identified a homozygous P660L mutation (606540.0006) in exon 16
of the MYO5B gene. Erickson et al. (2008) suggested that the finding of
the homozygous P660L mutation 3 codons away from the homozygous R656L
(606540.0005) mutation, reported by Muller et al. (2008), may indicate
that this region of exon 16 encodes a critical folding domain of the
protein. and the substitution of the leucine for proline is highly
nonconservative and causes the substitution of the bulky aliphatic for
the small, fixed-turn amino acid.
Van der Velde et al. (2013) stated that their online MVID registry
contained information on 137 patients and included 41 unique MYO5B
mutations in 40 patients. The mutations included 16 missense mutations,
20 nonsense or splice site mutations, 4 insertion/deletions, and 1
duplication. The authors noted that although nonsense, splice site, and
insertion/deletion mutations were found in either the head or the tail
domain of the myosin Vb protein, all of the missense mutations, with the
exception of one, were located in the myosin Vb motor domain. The
authors noted that this is in contrast to randomly distributed missense
mutations described in other identified myosins. They distinguished 5
categories of mutations: (1) missense mutations in domains important for
actin interactions; (2) missense mutations in domains important for
nucleotide binding; (3) missense mutations in domains important for
allosteric rearrangements of the motor; (4) mutations that may lead to
protein misfolding; and (5) mutations leading to premature termination
of the protein.
MAPPING
Zhao et al. (1996) mapped the mouse Myo5b gene to chromosome 18. By
interspecific backcross analysis, Hasson et al. (1996) mapped the mouse
gene to chromosome 18 and predicted a localization of 18q21.1-q23 in
human. Scott (2001) mapped the MYO5B gene to chromosome 18q21 based on
similarity between the MYO5B sequence (GenBank GENBANK AB032945) and a
chromosome 18 clone (GenBank GENBANK AP001847).
MBD1
| dbSNP name | rs1142549(A,C); rs1142548(A,G); rs145606891(C,T); rs11663629(C,A); rs146051294(A,G); rs11872799(G,A); rs59616370(T,C); rs140994927(T,C); rs2851716(A,G); rs116860842(G,A); rs116201949(G,A); rs125555(G,C); rs141389875(G,A); rs140690(G,A); rs140688(C,T); rs140687(C,A); rs10775495(A,G); rs73434055(G,A); rs144836491(C,T); rs376111746(T,C); rs1530391(T,A); rs144029744(T,C); rs73434056(T,C); rs999198(A,G); rs999199(A,C); rs7240570(T,C); rs143641466(T,A); rs35888849(C,A); rs1562004(A,G); rs12957023(C,T) |
| ccdsGene name | CCDS11941.1 |
| cytoBand name | 18q21.1 |
| EntrezGene GeneID | 4152 |
| EntrezGene Description | methyl-CpG binding domain protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MBD1:NM_001204142:exon12:c.C1304T:p.T435I,MBD1:NM_015846:exon12:c.C1304T:p.T435I,MBD1:NM_015847:exon11:c.C1157T:p.T386I,MBD1:NM_001204140:exon12:c.C1211T:p.T404I,MBD1:NM_001204141:exon11:c.C1154T:p.T385I,MBD1:NM_015845:exon11:c.C1235T:p.T412I,MBD1:NM_001204139:exon12:c.C1304T:p.T435I,MBD1:NM_001204136:exon12:c.C1304T:p.T435I,MBD1:NM_001204137:exon13:c.C1379T:p.T460I,MBD1:NM_001204143:exon11:c.C1136T:p.T379I,MBD1:NM_002384:exon11:c.C1136T:p.T379I,MBD1:NM_001204151:exon10:c.C1235T:p.T412I,MBD1:NM_015844:exon11:c.C1136T:p.T379I,MBD1:NM_001204138:exon13:c.C1376T:p.T459I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6084 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DUR3 |
| dbNSFP KGp1 AF | 0.00137362637363 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.001377 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.0003822 |
OMIM Clinical Significance
Heme:
Compensated hemolysis;
Hemolysis on exposure to drugs and possibly viruses
Lab:
Mild hyperbilirubinemia;
Reticulocytosis;
Abnormal red cell membrane on EM;
Defective catabolism of red cell membrane phosphatides;
Excess cation permeability and ouabain-sensitive pumping
Inheritance:
Autosomal dominant
OMIM Title
*179780 DIPEPTIDASE 1; DPEP1
;;DIPEPTIDASE 1, RENAL;;
RENAL DIPEPTIDASE; RDP;;
DEHYDROPEPTIDASE I;;
MICROSOMAL DIPEPTIDASE; MDP;;
MEMBRANE-BOUND DIPEPTIDASE 1; MBD1
OMIM Description
DESCRIPTION
DPEP1 (EC 3.4.13.11) is a kidney membrane enzyme that hydrolyzes a
variety of dipeptides and is implicated in renal metabolism of
glutathione and its conjugates, e.g., leukotriene D4 (Kozak and Tate,
1982). DPEP1 is responsible for hydrolysis of the beta-lactam ring of
antibiotics, such as penem and carbapenem (Campbell et al., 1984).
Earlier, beta-lactamase enzymes were thought to occur only in bacteria,
where their probable function was in protecting the organisms against
the action of beta-lactam antibiotics. These antibiotics exhibit
selective toxicity against bacteria but virtual inertness against many
eukaryotic cells (Adachi et al., 1990).
CLONING
Adachi et al. (1990) isolated and characterized cDNA clones for human
DPEP1, which they called RDP. DNA and RNA blot analysis indicated the
existence of a single gene.
To isolate potential tumor/growth suppressor genes involved in Wilms
tumor, Austruy et al. (1993) constructed a cDNA library by cloning a
mature kidney cDNA subtracted with an excess of Wilms tumor mRNA. Clones
were selected according to a differential pattern of expression, i.e.,
positive with RNA from mature kidney and negative with RNA from several
Wilms tumors. By comparison of sequences of these clones with database
sequences, 1 clone was identified as DPEP1.
Nitanai et al. (2002) stated that RDP is a homodimer of identical
369-amino acid subunits. Each subunit has a calculated molecular mass of
about 42 kD, but N-glycosylation at 4 possible sites results in a highly
glycosylated peptide of about 63 kD. In addition, each RDP subunit has a
C-terminal glycosylphosphatidylinositol membrane anchor.
Habib et al. (2003) cloned mouse Dpep1, which they designated Mbd1.
Northern blot analysis detected 3 transcripts that were differentially
expressed in heart, lung, skeletal muscle, kidney, liver, and testis. No
Mbd1 expression was detected in brain and spleen. The transcripts likely
arise from the use of alternate poly(A) sites and variations in the
5-prime UTR.
BIOCHEMICAL FEATURES
Nitanai et al. (2002) determined the crystal structure of human RDP.
Each subunit appears to assume a barrel shape made up of 8 alpha helix
and beta sheet pairs. Each monomer requires 2 zinc ions that are ligated
to the catalytic residues (glu125, his198, and his219) at the bottom of
the enzymatic pocket. His152 is not ligated to zinc, but it is
responsible for recognition of a substrate or inhibitor. The pocket is
reinforced by 2 adjacent disulfide bonds and by 3 proline residues.
Cys361 is involved in a disulfide bridge between monomers.
GENE FUNCTION
Kera et al. (1999) measured dipeptidase activity in several human
postmortem tissues and in rat tissues using glycyl-D-alanine as
substrate. Highest activity in human tissues was detected in kidney
cortex, pancreas, and testis. Much lower activity was detected in
adrenal gland and liver, and very low activity was detected in lung,
spleen, cerebrum, and cerebellum. The enzyme was also found in serum and
urine from healthy volunteers. Activity in rats was similar, but was
much higher in lung. The distribution of enzyme activity in various
tissues changed in postnatal rats up to 8 weeks of age.
Habib et al. (2003) demonstrated that COS-7 cells transfected with mouse
Mbd1 were able to convert leukotriene D4 to leukotriene E4 and could
hydrolyze cystinyl-bis-glycine (cys-bis-gly) and beta-lactam. Inhibition
of Mbd1 by penicillamine indicated that it is a metallopeptidase.
GENE STRUCTURE
Satoh et al. (1993) determined that the DPEP1 gene contains 10 exons and
spans about 6 kb.
MAPPING
By FISH, Nakagawa et al. (1991) mapped the RDP gene to chromosome 16q24.
Austruy et al. (1993) used somatic cell hybrids carrying either
different human chromosomes or chromosome 16 segments to confirm and
refine the physical mapping of DPEP1 to 16q24.3. Two RFLPs were
described and used to show linkage of DPEP1 to D16S7; maximum lod score
was 5.8 at theta of 0.03.
ANIMAL MODEL
Habib et al. (1998) found that Mbd1-deficient mice retained partial
ability to degrade cys-bis-gly and to convert leukotriene D4 to
leukotriene E4 depending on the tissue examined. Habib et al. (2003)
suggested that tissue- and substrate-specific activities of Mbd2 (DPEP2;
609925) and Mbd3 (DPEP3; 609926) partially compensate for the loss of
Mbd1 in these mice.
C18orf54
| dbSNP name | rs7234566(G,T); rs1787822(T,C); rs35145966(C,T); rs144857966(T,C); rs116066037(G,T); rs1787837(C,A); rs1787836(A,G); rs1370367(T,C); rs7240534(C,T); rs1612076(A,G); rs7227253(T,A); rs145644447(A,G); rs191018372(T,G); rs146562554(G,A); rs1618800(A,G); rs150551052(G,A); rs148294758(A,G); rs1657904(C,T); rs370712699(T,G); rs1657905(T,A); rs1657907(G,C); rs143484872(G,A); rs148658061(T,C); rs6508289(C,T); rs6508290(A,G); rs140618781(C,A); rs8097147(A,G); rs61469746(C,T); rs3017293(C,T); rs35367184(G,A); rs59383547(A,C); rs115873573(A,G); rs1787835(G,A); rs1787834(A,C); rs1657909(A,T); rs35635051(A,T); rs7230556(T,C); rs139230235(A,C); rs114977883(G,A); rs7243152(G,T); rs9304461(G,C); rs371447958(G,C); rs9946193(A,G); rs187867814(T,C); rs368495601(A,G); rs1657910(G,T); rs55650283(T,G); rs28838401(T,A); rs9949916(G,T); rs9950152(G,A); rs1787833(A,G); rs190333034(G,T); rs1657911(G,C); rs7240120(A,C); rs6508292(C,G); rs7240890(G,C); rs7240944(C,A); rs7242250(T,C); rs9953620(A,G); rs4940324(C,G); rs4939759(C,T); rs13380938(T,C); rs8087762(G,A); rs9959563(C,T); rs181128653(C,T); rs8088269(A,G); rs148151573(G,T); rs8097231(A,C); rs4939760(T,A); rs4940325(T,G); rs4940326(C,T); rs149286794(A,G); rs148467431(G,T); rs12604412(A,G); rs11872614(A,G); rs11875851(T,C); rs71368966(T,C); rs34220352(T,A); rs11659776(A,G); rs140674963(G,A); rs368714519(G,A); rs4940327(G,A); rs16958125(C,T); rs16958129(G,A); rs191072344(A,C); rs8086822(C,T); rs139138184(T,G); rs8087515(G,T); rs143642739(G,A); rs4940328(T,A); rs4940329(G,T); rs148515769(A,C); rs4430819(T,C); rs4581772(G,T); rs12458588(G,T); rs3753057(G,A); rs3753054(A,G); rs3753053(T,C); rs116624237(C,T); rs16958153(A,G); rs114496881(G,C); rs3809947(A,T); rs3809948(A,G); rs1046699(T,G); rs149989260(G,C); rs185900646(C,T); rs1061830(C,T); rs1344883(C,T) |
| ccdsGene name | CCDS11956.1 |
| cytoBand name | 18q21.2 |
| EntrezGene GeneID | 162681 |
| EntrezGene Description | chromosome 18 open reading frame 54 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C18orf54:NM_001288981:exon3:c.A128G:p.K43R,C18orf54:NM_001288980:exon3:c.A128G:p.K43R,C18orf54:NM_173529:exon2:c.A128G:p.K43R,C18orf54:NM_001288982:exon1:c.A128G:p.K43R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8074 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IYD9-2 |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000681 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 8.945e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Achromatic retinal patches;
Retinal astrocytoma;
Optic gliomas;
[Mouth];
Pitted dental enamel;
Gingival fibroma
CARDIOVASCULAR:
[Heart];
Wolf-Parkinson-White syndrome;
Cardiac rhabdomyoma
RESPIRATORY:
[Lung];
Lymphangiomyomatosis, rare
GENITOURINARY:
[Kidneys];
Renal cysts;
Tumors of the kidney (may progress to malignancy in less than 2%)
SKELETAL:
Cystic areas of bone rarefaction, esp. phalanges
SKIN, NAILS, HAIR:
[Skin];
Facial angiofibroma (adenoma sebaceum);
White ash leaf-shaped macules;
Shagreen patch;
Subcutaneous nodules;
Cafe-au-lait spots;
Subungual fibromata
NEUROLOGIC:
[Central nervous system];
Hamartomatous lesions of the brain;
Subependymal nodules;
Cortical tubers;
Infantile spasms;
Seizures;
Mental retardation (30%);
Learning difficulties;
Intracranial calcification by x-ray or CT;
[Behavioral/psychiatric manifestations];
Attention deficit disorder;
Hyperactivity;
Autism
ENDOCRINE FEATURES:
Precocious puberty;
Hypothyroidism
NEOPLASIA:
Myocardial rhabdomyoma;
Multiple bilateral renal angiomyolipoma;
Ependymoma;
Renal carcinoma;
Giant cell astrocytoma;
Chordoma;
Benign tumors of the eye, heart, and lungs
LABORATORY ABNORMALITIES:
Increased frequency of premature centromere disjunction (PCD) in cultured
fibroblasts, esp. chromosome 3;
Allelic loss on 16p13.3 in angiomyolipoma, cardiac rhabdomyoma, cortical
tuber, and giant cell astrocytoma
MISCELLANEOUS:
Genetic heterogeneity (see 191100);
Many studies have reported that the phenotype of tuberous sclerosis-2
(TSC2) is more severe than that of tuberous sclerosis-1 (e.g., lower
IQ, more seizures, more macules, cust-like cortical tubers);
Highly variable phenotype;
One-third of cases are familial;
Majority of cases are sporadic;
Prevalence of 1 in 6,000 to 1 in 10,000;
Frequent new mutations (~60%) and/or gonadal mosaicism in TSC2
MOLECULAR BASIS:
Caused by mutation in the tuberin gene (TSC2, 191092.0001)
OMIM Title
*613258 CHROMOSOME 18 OPEN READING FRAME 54; C18ORF54
;;LAS2, MOUSE, HOMOLOG OF; LAS2
OMIM Description
CLONING
Liu et al. (2009) cloned a mouse Las2 cDNA, and by database analysis,
they identified human LAS2, or C18ORF54. The deduced 533-amino acid
human protein shares 65% identity with the 526-amino acid mouse protein.
Quantitative PCR of mouse tissues detected highest Las2 expression in
lung.
GENE FUNCTION
Using a genomewide association study, Liu et al. (2009) found that
germline nonsynonymous SNPs and insertion/deletion polymorphisms in the
Las2 gene were associated with susceptibility to lung adenoma in mice.
Loss of Las2 increased colony formation in the LM2 mouse lung
adenocarcinoma cell line and increased the tumorigenicity of LM2 cells
in nude mice. Examination of 384 human lung adenocarcinomas and matched
normal DNA revealed frequent allelic imbalance associated with 2
microdeletions around the LAS2 region in lung tumors. Of 6 tumors
showing this loss of heterozygosity, none had somatic mutations in LAS2
coding exons.
MAPPING
By genomic sequence analysis, Liu et al. (2009) mapped the C18ORF54 gene
to chromosome 18q21. They mapped the mouse gene to distal chromosome 18.
BOD1L2
| dbSNP name | rs11151997(G,T); rs28706382(T,C); rs12605919(C,T); rs12604265(T,C); rs139105324(T,C); rs71353994(A,G); rs9956688(G,A); rs8085797(A,G); rs8086063(A,G); rs7234572(C,A) |
| ccdsGene name | CCDS59322.1 |
| cytoBand name | 18q21.31 |
| EntrezGene GeneID | 284257 |
| snpEff Gene Name | AC100775.1 |
| EntrezGene Description | biorientation of chromosomes in cell division 1-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | BOD1L2:NM_001257964:exon1:c.G482T:p.G161V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IYS8 |
| dbNSFP Uniprot ID | BD1L2_HUMAN |
| dbNSFP KGp1 AF | 0.52793040293 |
| dbNSFP KGp1 Afr AF | 0.538617886179 |
| dbNSFP KGp1 Amr AF | 0.522099447514 |
| dbNSFP KGp1 Asn AF | 0.582167832168 |
| dbNSFP KGp1 Eur AF | 0.482849604222 |
| dbSNP GMAF | 0.472 |
| ExAC AF | 0.547 |
LOC100505549
| dbSNP name | rs540680(C,G); rs72942238(G,A); rs141102222(G,A); rs453189(T,C); rs411805(C,T); rs384019(T,C); rs441668(C,T); rs392303(T,A); rs4455054(A,G); rs139747662(G,A); rs12961923(G,A); rs393612(T,C); rs150311558(G,A); rs4527102(C,G); rs11877467(G,T); rs12968882(C,T); rs146985525(A,G); rs35463072(A,G); rs12454749(G,C); rs146608506(G,A); rs527143(C,T); rs2678244(C,G); rs184876936(G,A); rs185359876(G,C); rs7506792(G,A); rs62094186(C,T); rs422759(C,T); rs441946(A,G); rs141463813(T,C); rs385648(C,T); rs372552(A,G); rs12955402(G,A); rs35673807(G,A); rs549202(A,G); rs370781(T,C); rs577519(C,T); rs378777(C,T); rs7241054(C,T); rs1129621(A,T); rs11543269(C,T); rs1968274(T,C); rs17685852(A,G); rs4940950(C,A); rs317822(C,T); rs12958967(G,A); rs12327290(T,G); rs222581(C,T); rs11152025(G,A); rs8097764(G,A); rs167603(G,A); rs1609692(G,A); rs62094188(G,A); rs317823(G,A); rs35665103(T,G); rs369298568(T,C); rs7226404(A,C); rs11875799(T,C); rs317824(G,T); rs317825(C,T); rs12963741(C,T); rs12964254(A,G); rs34653195(G,T); rs76889037(C,T); rs17753176(A,T); rs12968116(C,T); rs35623014(C,T); rs7232795(T,C); rs7227893(G,A); rs317826(G,A); rs150771038(G,A); rs115167153(T,C); rs56950313(G,A); rs317827(C,T); rs55740540(G,A); rs371807(C,G); rs527815(T,C); rs1110965(C,A); rs17686020(A,G); rs1893673(T,C); rs116387349(A,C); rs62094219(C,T); rs62094220(C,T); rs76258995(C,T); rs79277091(C,T); rs180853250(T,C); rs62094223(T,C); rs72942301(C,T); rs62094224(T,C); rs62094225(G,A); rs373111(C,A); rs317850(G,T); rs167604(T,C); rs412615(C,T); rs1862919(G,A); rs12969748(C,T); rs72944108(G,A); rs2048951(C,T); rs317848(G,A); rs317847(A,T); rs4308033(G,T); rs4306606(G,A); rs9964678(A,G); rs317846(A,G); rs160992(G,A); rs4940499(A,G); rs317845(A,G); rs317844(A,G); rs12717119(G,A); rs317843(C,G); rs12717120(A,G); rs58094309(A,G) |
| ccdsGene name | CCDS11965.1 |
| cytoBand name | 18q21.31 |
| EntrezGene GeneID | 100505549 |
| snpEff Gene Name | ATP8B1 |
| EntrezGene Description | uncharacterized LOC100505549 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ATP8B1:NM_005603:exon23:c.G2789A:p.R930Q, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6051 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O43520 |
| dbNSFP Uniprot ID | AT8B1_HUMAN |
| dbNSFP KGp1 AF | 0.003663003663 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00131926121372 |
| dbSNP GMAF | 0.003673 |
| ESP Afr MAF | 0.012029 |
| ESP All MAF | 0.004075 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001553 |
LOC101927322
| dbSNP name | rs12458537(T,G); rs7505926(C,A) |
| cytoBand name | 18q21.32 |
| EntrezGene GeneID | 101927322 |
| snpEff Gene Name | MALT1 |
| EntrezGene Description | uncharacterized LOC101927322 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1584 |
MC4R
| dbSNP name | rs34114122(T,G) |
| cytoBand name | 18q21.32 |
| EntrezGene GeneID | 4160 |
| EntrezGene Description | melanocortin 4 receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04362 |
OMIM Clinical Significance
Limbs:
One or 2 grotesquely enlarged fingers
Inheritance:
No report of familial occurrence
OMIM Title
*155541 MELANOCORTIN 4 RECEPTOR; MC4R
;;MCR RECEPTOR
OMIM Description
CLONING
Gantz et al. (1993) cloned a fourth member of the melanocortin receptor
family of 7-transmembrane G-protein linked receptors. By Northern blot
analysis and in situ hybridization, the melanocortin-4 receptor (MC4R)
was found to be expressed primarily in the brain; its expression was
notably absent in the adrenal cortex, melanocytes, and placenta. The
profile of responses of MC4R, transfected into COS-1 cells and L cells,
to different melanocortins distinguished it from the previously
described melanocortin receptors. (See 155555, 202200, and 155540.) MC4R
is a 333-amino acid protein encoded by a single exon (Yeo et al., 1998).
GENE FUNCTION
Nonsense-mediated decay (NMD) inhibits the accumulation of nonsense- or
frameshift-mutated mRNA and thus minimizes the synthesis of truncated
proteins with potential dominant-negative effects. Brocke et al. (2002)
investigated the NMD sensitivity of nonsense-mutated transcripts of
MC4R. Nonsense-mutated variants of MC4R transcripts were stable and
expressed truncated proteins that were detectable in the lysates of
transfected cells. The authors hypothesized that the lack of necessity
for splicing in the naturally intronless MC4R gene may allow it to
escape from NMD.
By using a combination of pharmacologic, molecular genetic,
electrophysiologic, and feeding studies, Mineur et al. (2011) found that
activation of hypothalamic alpha-3 (118503)-beta-4 (118509) nicotinic
acetylcholine receptors leads to activation of proopiomelanocortin
(POMC; 176830) neurons. POMC neurons and subsequent activation of
melanocortin-4 receptors were critical for nicotinic-induced decreases
in food intake in mice. The study of Mineur et al. (2011) demonstrated
that nicotine decreases food intake and body weight by influencing the
hypothalamic melanocortin system and identified critical molecular and
synaptic mechanisms involved in nicotine-induced decreases in appetite.
Lim et al. (2012) showed that chronic stress in mice decreases the
strength of excitatory synapses on D1 dopamine receptor (DRD1;
126449)-expressing nucleus accumbens medium spiny neurons owing to
activation of the melanocortin-4 receptor. Stress-elicited increases in
behavioral measurements of anhedonia, but not increases in measurements
of behavioral despair, are prevented by blocking these melanocortin-4
receptor-mediated synaptic changes in vivo. Lim et al. (2012) concluded
that stress-elicited anhedonia requires a neuropeptide-triggered, cell
type-specific synaptic adaptation in the nucleus accumbens and that
distinct circuit adaptations mediate other major symptoms of
stress-elicited depression.
MAPPING
By means of fluorescence chromosomal in situ hybridization, Gantz et al.
(1993) localized the MC4R gene to 18q21.3. By fluorescence in situ
hybridization (FISH), Magenis et al. (1994) mapped the MC4R gene to
18q22. Using FISH and radiation hybrid mapping, Sundaramurthy et al.
(1998) localized the MC4R gene to 18q22.
MOLECULAR GENETICS
Yeo et al. (1998) and Vaisse et al. (1998) described a severely obese
child and adult, respectively, with a mutation in the MC4R gene. The
mutation was present in heterozygous state in each case, and other
members of the family were obese in a pattern consistent with autosomal
dominant inheritance. Molecular abnormalities have been identified in
autosomal recessive severe obesity involving the leptin gene
(164160.0001), the leptin receptor gene (601007.0002), the prohormone
convertase-1 gene (PC1; 162150.0001), and the proopiomelanocortin gene
(POMC; 176830.0001). Hypogonadotropic hypogonadism is found in
association with mutations in the leptin, leptin receptor, and PC1
genes, and hypoadrenalism is found with POMC and PC1 gene mutations;
short stature is associated with mutations in the leptin receptor gene.
There was no evidence of impaired adrenal function in the MC4R-deficient
subjects; sexual development and fertility were normal, and affected
subjects were tall, which was of interest given the increased linear
growth exhibited by heterozygous Mc4r-deficient mice.
By SSCP, Hinney et al. (1999) screened the coding region of the MC4R
gene in 306 extremely obese children and adolescents, 25 healthy
underweight students, 52 normal weight individuals, 51 inpatients with
anorexia nervosa (606788), and 27 patients with bulimia nervosa
(607499). Several mutations were identified, including a 4-bp deletion
(155541.0001) that resulted in a frameshift, yielding a truncated
protein. This mutation had been assumed to be associated with dominantly
inherited morbid obesity in humans. Both the index patient (body mass
index (BMI), 42.06 kg/m2; height, 171 cm; age, 19.6 years) and her
mother (BMI, 37.55 kg/m2; height, 164 cm; age, 42.5 years) were
heterozygous for this deletion. A tyr35-to-ter substitution
(155541.0003) was detected in 2 obese probands (BMI, 31.29 kg/m2 and
45.91 kg/m2, respectively); this mutation led to a truncated protein
that encompassed the N-terminal extracellular domain. Both carriers also
showed an asp37-to-val mutation (155541.0004). In both cases these
mutations were maternally transmitted, indicating they form a haplotype.
A male obese proband harbored 2 missense mutations, and 4 different
missense mutations were detected in 4 different male probands. All
mutations in the MC4R gene were only found in extremely obese
individuals whose BMIs were all greater than the 99th percentile. An
ile251-to-leu (I251L) polymorphism was found in similar frequencies in
all groups studied. The authors concluded that MC4R mutations are not
uncommon. While the data supported dominantly inherited obesity because
of the 3 obese probands with haploinsufficiency, the functional
significance of the missense mutations remained to be determined.
In a study of 306 index patients, Hinney et al. (1999) detected 3 obese
probands with haploinsufficiency mutations in the MC4R gene. Sina et al.
(1999) extended the mutation screen to another 186 extremely obese
children and adolescents and identified an additional haploinsufficiency
carrier, bringing the total number of mutation-carrying obese patients
identified to 4. They genotyped and phenotyped 43 family members of
these 4 index patients. A total of 19 mutation carriers were identified.
Extreme obesity was the predominating phenotype; however, moderate
obesity occurred in 3 of the carriers. No other specific phenotypic
abnormalities were detected. Female haploinsufficiency carriers were
heavier than male carriers in the respective families, a finding similar
to findings in Mc4r-knockout mice.
Farooqi et al. (2003) stated that MC4R deficiency is the most common
form of monogenic obesity. To define the clinical spectrum, mode of
inheritance, genotype-phenotype correlations, and pathophysiologic
mechanisms leading to obesity, they determined the nucleotide sequence
of the MC4R gene in 500 probands with severe childhood obesity. In 29
probands (5.8%), they found mutations in MC4R (155541.0010-155541.0019);
23 were heterozygotes and 6 were homozygotes. Mutation carriers had
severe obesity, increased lean mass, increased linear growth,
hyperphagia, and severe hyperinsulinemia; homozygotes were more severely
affected than heterozygotes. Subjects with mutations retaining residual
signaling capacity had a less severe phenotype. Thus, MC4R mutations are
inherited in a codominant manner. The correlation between the signaling
properties of these mutant receptors and energy intake emphasized the
key role of this receptor in the control of eating behavior.
Dubern et al. (2001) identified 4 dominantly inherited heterozygous
missense MC4R mutations in 4 of 63 unrelated children with severe
obesity. The same mutation was not found in any of the control subjects.
Expression of the obese phenotype was variable in mutation-positive
family members. Dubern et al. (2001) concluded that MC4R mutations may
be a nonnegligible cause of severe obesity in children with variable
expression and penetrance.
Jacobson et al. (2002) determined the prevalence of mutations in the
coding and flanking regions of the MC4R gene in severely obese and
normal-weight subjects from the Swedish Obese Subjects study, the
Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family
study, and a Memphis cohort. A total of 433 white and 95 black subjects
(94% females) were screened for mutations by direct sequencing. Three
previously described missense variants and 9 novel (3 missense, 6
silent) variants were detected. None of them showed significant
association with obesity or related phenotypes. In addition, 2 novel
deletions were found in 2 heterozygous obese women which were predicted
to encode a truncated nonfunctional receptor. No pathogenic mutations
were found among obese blacks or nonobese controls. Furthermore, none of
the null mutations found in other populations was present in this
sample. The authors concluded that their results do not support the
prevailing notion that sequence variation in the MC4R gene is a frequent
cause of human obesity.
In a cohort of 172 patients presenting with severe childhood obesity and
a family history of obesity, Lubrano-Berthelier et al. (2003) screened
for mutations in the coding region of the MC4R gene and identified 3
heterozygous MC4R mutations in 3 patients. A functional analysis of 14
MC4R mutations, including the 3 identified in this study, indicated that
all mutations altered the activation of the receptor by the endogenous
agonist alpha-MSH (see 176830). Lubrano-Berthelier et al. (2003) further
demonstrated that greater than 80% of childhood obesity-associated
heterozygous MC4R mutations led to intracellular retention of the
receptor.
Branson et al. (2003) sequenced the complete MC4R coding region and the
leptin-binding domain of the leptin receptor (LEPR; 601007) in 469
severely obese white subjects (370 women and 99 men). Normal-weight
controls were 15 women and 10 men without a history of dieting or a
family history of obesity. MC4R mutations, including 5 novel variants,
were found in 24 obese subjects (5.1%) and 1 control (4%). Twenty of the
24 obese subjects with an MC4R mutation were matched for age, sex, and
BMI with 120 of the 445 obese subjects without an MC4R mutation. All
mutation carriers reported binge eating, as compared with 14.2% of obese
subjects without mutations and none of the normal-weight subjects
without mutations. The prevalence of binge eating was similar among
carriers of mutations in the leptin-binding domain of LEPR and
noncarriers. No mutations were found in the region of POMC encoding
alpha-MSH, the ligand of MC4R. List and Habener (2003) commented on the
possible importance of ethnic background in the frequency of mutations
in MC4R in obesity. They also suggested that the findings of Branson et
al. (2003) be interpreted with caution, as they differed from earlier
findings of a binge-eating disorder prevalence of 5% among carriers of
MC4R mutations (Sina et al., 1999).
Hebebrand et al. (2004) compared the eating behavior of 43 obese
probands with functionally relevant MC4R mutations to wildtype controls.
No significant differences in binge-eating episodes between carriers of
the MC4R variants and wildtype controls were detected, and Hebebrand et
al. (2004) concluded that binge-eating episodes are not a distinct
feature of MC4R mutation carriers. This analysis was different from the
study of Branson et al. (2003) because Hebebrand et al. (2004) studied
only carriers of mutations that had been shown to be of functional
relevance in vitro and did not include carriers of silent variants in
the open reading frame, variants in untranslated regions (UTRs), or the
val103-to-ile (V103I) or I251L polymorphisms.
In detailed pharmacologic studies of 11 different missense mutations in
the MC4R gene associated with obesity, Nijenhuis et al. (2003) found
that all the mutant receptors were poorly expressed at the cell surface
and showed a decreased maximal response to agonist, indicating that the
mutations impair receptor function. The findings supported the
hypothesis that loss of function of MC4R contributes to obesity.
Santini et al. (2004) screened a population of Italian obese subjects
for MC4R variants, demonstrating a 1.7% prevalence of potentially
pathogenic mutations. They reported a novel heterozygous missense
mutation that impaired MC4R functional activity in vitro.
By means of transient transfection in vitro, Yeo et al. (2003) examined
the functional properties of 12 different mutations in human MC4R that
result in severe, familial, early-onset obesity. Of the 9 missense
mutants studied, 4 (including 155541.0013, 155541.0014, and 155541.0018)
were completely unable to generate cAMP in response to ligand and 5 were
partially impaired. Four (including 155541.0014 and 155541.0017) showed
impaired cell surface expression and 6 showed reduced ligand binding.
The mutant protein I316S (155541.0016) showed reduced affinity for
alpha-MSH but retained normal affinity for the antagonist agouti-related
protein (AGRP; 602311). None of the mutations inhibited signaling
through cotransfected wildtype receptors.
Valli-Jaakola et al. (2004) screened 2 Finnish cohorts, comprising 56
children with severe early-onset obesity (relative weight for height
greater than or equal to 70% before age 10) and 252 morbidly obese
adults (body mass index greater than 40 kg/m2) for MC4R mutations. They
identified a pathogenic mutation (S127L; 155541.0021) in 1 child,
causing severe early-onset obesity. They also identified a novel
polymorphism in the coding region and 2 novel variations outside the
coding region.
Hinney et al. (2003) performed a mutation screen of the coding region of
the MC4R gene in 808 extremely obese children and adolescents and 327
underweight or normal-weight controls. A total of 16 different missense,
nonsense, and frameshift mutations were found in the obese study group;
5 of these were novel. In vitro assays revealed that 9 of the 16
mutations led to impaired cAMP responses, compared with wildtype
receptor constructs. The association test based on functionally relevant
mutations was positive (P = 0.006, Fisher's exact test, one-sided). They
also screened a total of 1,040 parents of 520 of the aforementioned
obese young index patients to perform transmission disequilibrium tests.
The 11 parental carriers of functionally relevant mutations transmitted
the mutation in 81.8% (P = 0.033). The authors concluded that their
results supported the hypothesis that these MC4R mutations represent
major gene effects for obesity.
Lubrano-Berthelier et al. (2006) determined the prevalence of MC4R
mutations in a cohort of severely obese adults and the clinical
phenotype and the phenotype-genotype relationships of adult MC4R
mutation carriers. The prevalence of obesity specific MC4R mutations was
2.6%, (95% CI = 1.5-3.7). The prevalence of MC4R mutations was similar
in patients developing obesity in childhood (2.83%) and in patients with
a later onset of the disease (2.35%). Adult obese MC4R mutation carriers
did not present with binge eating or with any specific clinical
phenotype. The authors concluded that the severity of the functional
alterations of the mutated MC4Rs and, in particular, the intracellular
retention of the receptor correlated both with the severity and the
onset of the obesity in the mutation carriers.
Hinney et al. (2006) investigated the prevalence and spectrum of MC4R
mutations in 4,068 individuals of a German population-based study group
(KORA-S4) and 1,003 German obese adults (BMI greater than 30 kg/m2).
Sixteen (6 novel) coding nonsynonymous mutations were detected in 27
heterozygous individuals of KORA-S4. Four of the mutation alleles led to
impaired receptor function in vitro; however, none of these 6
heterozygous mutation carriers was obese. In the obese adults, 6 coding
nonsynonymous and a nonsense mutation were detected in 13 individuals.
Only the nonsense mutation allele entailed impaired receptor function.
The authors concluded that individuals heterozygous for nonsynonymous
MC4R mutation alleles entailing impaired function were not obese and
that nonsynonymous MC4R mutations causing impaired receptor function
were rare in German obese adults (2 in 1,003 = 0.2%).
By direct sequencing of the coding region of the MC4R gene in a cohort
of 289 Czech children and adolescents with early-onset obesity,
Hainerova et al. (2007) found a prevalence of 2.4% of MC4R homozygous
and heterozygous mutations. One novel variant (C84R) showed a
significant reduction in cAMP signal properties of the MC4R. There was a
similar response of MC4R mutation carriers and noncarriers to diet
management.
In a genomewide association study of 318,237 SNPs for insulin resistance
and related phenotypes in 2,684 Indian Asians and 11,955 individuals of
Indian Asian or European ancestry, Chambers et al. (2008) found
association between dbSNP rs12970134, located near the MC4R gene, and
waist circumference (p = 1.7 x 10(-9)). Homozygotes for the risk allele
had an approximately 2 cm greater waist circumference compared to
wildtype. The authors concluded that genetic variation near MC4R is
associated with a risk of adiposity and insulin resistance.
Loos et al. (2008) performed a metaanalysis of data from 4 European
population-based studies and 3 disease-case series, involving a total of
16,876 individuals of European descent, and found a significant
association between dbSNP rs17782313, located 188 kb downstream of the
MC4R gene, and BMI in adults (p = 2.8 x 10(-15)) and children (p = 1.5 x
10(-8)). In case-control analyses, the odds for severe childhood obesity
reached 1.30 (p = 8.0 x 10(-11)), and overtransmission of the risk
allele to obese offspring was observed in 660 families. The authors
concluded that common variants near the MC4R gene influence fat mass,
weight, and obesity risk at the population level.
Willer et al. (2009) performed a metaanalysis of 15 genomewide
association studies for BMI comprising 32,387 participants and followed
up top signals in 14 additional cohorts comprising 59,082 participants.
They strongly confirmed association with MC4R at SNP dbSNP rs17782313
with a per-allele change in BMI of 0.20 and an overall P value of 1.1 x
10(-20).
Hardy et al. (2010) genotyped variants in FTO (610966; dbSNP rs9939609)
and near MC4R (dbSNP rs17782313) in 1,240 men and 1,239 women born in
1946 and participating in the MRC National Survey of Health and
Development. Birth weight was recorded and height and weight were
measured or self-reported repeatedly at 11 time-points between ages 2
and 53 years. Hierarchical mixed models were used to test whether
genetic associations with weight or BMI standard deviation scores (SDS)
changed with age during childhood and adolescence (2-20 years) or
adulthood (20-53 years). The association between FTO dbSNP rs9939609 and
BMI SDS strengthened during childhood and adolescence (rate of change:
0.007 SDS/A-allele/year; P less than 0.001), reached a peak strength at
age 20 years (0.13 SDS/A-allele), and then weakened during adulthood
(-0.003 SDS/A-allele/year, P = 0.001). MC4R dbSNP rs17782313 showed
stronger associations with weight than BMI; its association with weight
strengthened during childhood and adolescence (0.005 SDS/C-allele/year;
P = 0.006), peaked at age 20 years (0.13 SDS/C-allele), and weakened
during adulthood (-0.002 SDS/C-allele/year, P = 0.05). Hardy et al.
(2010) concluded that genetic variants in FTO and MC4R showed similar
biphasic changes in their associations with BMI and weight,
respectively, strengthening during childhood up to age 20 years and then
weakening with increasing adult age.
CYTOGENETICS
It has been hypothesized that MC4R mutations found in association with
obesity result in a loss of MC4R gene function due to
haploinsufficiency. Cody et al. (1999) studied the molecular basis of
the phenotype of individuals with large deletions of 18q. Because of its
location at 18q21.3, the MC4R gene was hemizygous in approximately
one-third of the individuals in this study. If hemizygosity of the MC4R
gene results in haploinsufficiency-induced obesity, then individuals
with deletion of 18q whose deletions included the MC4R gene should be
obese in comparison with those individuals whose deletion did not
include the gene. The data of Cody et al. (1999) indicated no difference
in obesity among those deleted and not deleted for the gene. Thus, the
MC4R gene product must be haplosufficient, and the involvement of MC4R
in obesity may reflect a dominant-negative effect.
Heisler et al. (2002) found that genetic or pharmacologic blockade of
MC4R and MC3R (155540) is sufficient to attenuate the anorectic efficacy
of threshold doses of d-FEN (D-fenfluramine), suggesting that drugs
targeting these downstream melanocortin pathways may act in part in a
manner similar to d-FEN to decrease food intake and body weight with
fewer side effects.
ANIMAL MODEL
Huszar et al. (1997) found that inactivation of the melanocortin-4
receptor by gene targeting in mice resulted in a maturity-onset obesity
syndrome associated with hyperphagia, hyperinsulinemia, and
hyperglycinemia. This syndrome recapitulated several of the
characteristic features of the 'agouti' syndrome, which results from
ectopic expression of agouti protein (600201), a pigmentation factor
normally expressed in the skin. The findings identified a novel
signaling pathway in the mouse for body weight regulation and supported
a model in which the primary mechanism by which agouti induces obesity
is chronic antagonism of the melanocortin-4 receptor.
Marsh et al. (1999) found that the leptin resistance of obese Mc4r -/-
mice does not prevent their response to the anorectic actions of ciliary
neurotrophic factor (CNTF; 118945), corticotropin-releasing factor (CRF;
122560), or urocortin (UCN; 600945); or the orexigenic
(appetite-stimulating) actions of neuropeptide Y (NPY; 162640) or
peptide YY (PYY; 600781), indicating that these neuromodulators act
independently or downstream of Mc4r signaling. Marsh et al. (1999)
showed that homozygous Mc4r-deficient mice do not respond to the
anorectic action of a melanocyte-stimulating hormone (MSH)-like agonist,
suggesting that alpha-MSH (see 176830) inhibits feeding primarily by
activating Mc4r.
Kim et al. (2000) studied MC4R as a candidate gene for the control of
economically important growth and performance traits in the pig. They
found a missense mutation in a region highly conserved among
melanocortin receptor genes: a G-to-A transition at a position
corresponding to human codon 298, changing GAU (asp) to AAU (asn). The
asp298 allele was associated with less backfat thickness, slower growth
rate, and lower feed intake. In an association study of this MC4R
polymorphism in a large number of individual animals from several
different pig lines, they found a significant association of MC4R
genotypes with backfat, growth rate, and feed intake in a number of
lines. The authors considered it likely that the variant amino acid
residue of the MC4R mutation (or a closely linked mutation) causes a
significant change of the MC4R function.
Chen et al. (2000) evaluated the potential role of MC3R in energy
homeostasis by studying Mc3r-deficient (Mc3r -/-) mice and compared the
functions of Mc3r and Mc4r in mice deficient for both genes. Mice
lacking both Mc3r and Mc4r became significantly heavier than Mc4r -/-
mice. Chen et al. (2000) concluded that Mc3r and Mc4r serve nonredundant
roles in the regulation of energy homeostasis. Cummings and Schwartz
(2000) showed that these studies demonstrated that the 2 melanocortin
receptor isoforms reduce body weight through distinct and complementary
mechanisms. Mc4r regulates food intake and possibly energy expenditure,
whereas Mc3r influences feed efficiency and the petitioning of fuel
stores into fat.
Ste. Marie et al. (2000) studied Mc4r-null mice to determine whether
aberrant metabolism contributes to their late-onset obesity. The
consumption of the null mice was restricted to (i.e., pair-fed with)
that of wildtype mice. The null females maintained body weights
intermediate to those of wildtype and nonpair-fed null females, whereas
pair-feeding normalized the body weights of null male mice. These and
other findings indicated that Mc4r deficiency enhances caloric
efficiency, similar to that seen in the agouti obesity syndrome and in
Mc3r-null mice.
By a combination of genetic, pharmacologic, and anatomic approaches, Van
der Ploeg et al. (2002) showed that MC4R, implicated in the control of
food intake and energy expenditure, also modulates erectile function and
sexual behavior. Evidence was based on several findings: a highly
selective nonpeptide MC4R agonist augmented erectile activity initiated
by electrical stimulation of the cavernous nerve in wildtype, but not
Mc4r-null, mice; copulatory behavior was enhanced by administration of a
selective MC4R agonist and was diminished in mice lacking Mc4r; RT-PCR-
and non-PCR-based methods demonstrated MC4R expression in rat and human
penis, and rat spinal cord, hypothalamus, brainstem, and pelvic ganglion
(major autonomic relay center to the penis), but not in rat primary
corpus smooth muscle cavernosum cells; and in situ hybridization of
glans tissue from the human and rat penis revealed MC4R expression in
nerve fibers and mechanoreceptors in the glans of the penis.
Collectively, these data implicated MC4R in the modulation of penile
erectile function and provided evidence that MC4R-mediated proerectile
responses may be activated through neuronal circuitry in spinal cord
erectile centers and somatosensory afferent nerve terminals of the
penis. The results supported the existence of MC4R-controlled neuronal
pathways that control sexual function.
Xu et al. (2003) found that, like MC4R mutants, mouse mutants that
express decreased amounts of the brain-derived neurotrophic factor
(BDNF; 113505) receptor TrkB (600456) showed hyperphagia and
maturity-onset obesity, suggesting a role for BDNF in energy balance.
The authors found that BDNF is an anorexigenic factor that is highly
expressed in murine ventromedial hypothalamic (VMH) nuclei and is
regulated by feeding status. Deficiency in MC4R signaling reduced
expression of BDNF in the VMH, indicating that BDNF and its receptor
TrkB are downstream components in the MC4R-mediated control of energy
balance.
Balthasar et al. (2005) devised a strategy to target Mc4r reactivation
in specific neurons in Mc4r-null mice. They found that restoration of
Mc4r expression in the paraventricular hypothalamus and in a
subpopulation of amygdala neurons prevented 60% of the obesity observed
in Mc4r-null animals. Rescued animals reduced their food intake toward
normal. However, measures of oxygen consumption suggested that their
remaining obesity was due to low energy expenditure. Balthasar et al.
(2005) concluded that different melanocortin pathways control food
intake and energy expenditure.
SERPINB10
| dbSNP name | rs17072097(T,G); rs35743864(G,A); rs8097425(A,G); rs17072102(T,C); rs28558645(A,G); rs12454249(A,G); rs73478048(C,T); rs73478050(A,G); rs8085341(A,G); rs8084931(C,T); rs17072109(A,G); rs17072114(T,C); rs9320033(C,T); rs73478055(G,A); rs724557(A,T); rs724558(T,C); rs1944273(G,C); rs1944272(G,C); rs1944271(C,T); rs9955171(T,C); rs8098414(C,T); rs8085490(T,C); rs8099238(A,C); rs9955876(A,T); rs145764045(C,T); rs17072146(G,A); rs9967382(C,T); rs17072152(G,A); rs76497377(G,T); rs9947135(C,T); rs4350667(A,G); rs9947504(C,T); rs17072158(G,C); rs56079168(A,G); rs7236189(C,T); rs76521468(G,A); rs75492443(C,T); rs17072163(A,G); rs976142(C,T); rs976141(T,C); rs2042729(C,T); rs73961814(C,G); rs2162348(G,C); rs8096642(T,C); rs56207918(G,T); rs151119109(G,A); rs8097354(T,C); rs8093162(C,G); rs11876768(G,A); rs79988000(T,C); rs73961817(A,G); rs73961818(G,T); rs9957733(A,G); rs73961819(A,G); rs2114377(G,A); rs9960901(T,A); rs8090188(A,G); rs8093894(T,C); rs75622590(T,C); rs8094058(T,C); rs8089023(G,A); rs8090673(A,G); rs8095974(A,G); rs9955325(G,C); rs9955406(G,T); rs8086521(G,A); rs8091779(T,A); rs3786340(C,T); rs10163726(A,G); rs9951724(A,T); rs1544899(T,C); rs73961823(G,A); rs73480047(T,C); rs1544898(A,T); rs73480050(C,T); rs8084306(T,C); rs8084600(T,C); rs8096543(G,A); rs149477894(T,C); rs2078574(G,T); rs62097500(T,C); rs1989731(T,C); rs73480064(C,G); rs9964049(A,T); rs963075(C,T); rs17072204(G,A); rs28665012(C,T); rs73961827(A,T) |
| ccdsGene name | CCDS11990.1 |
| cytoBand name | 18q21.33 |
| EntrezGene GeneID | 5273 |
| EntrezGene Description | serpin peptidase inhibitor, clade B (ovalbumin), member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SERPINB10:NM_005024:exon4:c.C395T:p.T132I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5361 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0006914 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Absent eyebrows;
Absent eyelashes;
[Teeth];
Normal teeth
SKIN, NAILS, HAIR:
[Skin];
Normal sweating;
[Nails];
Onychodystrophy;
Micronychia;
Onycholysis;
[Hair];
Alopecia;
Brittle hair (in some patients);
Pili torti (in some patients);
Sparse body hair (in some patients);
Absent body hair
NEUROLOGIC:
[Central nervous system];
No mental retardation
METABOLIC FEATURES:
Normal sweating
MISCELLANEOUS:
Three families described (last curated January 2014)
MOLECULAR BASIS:
Caused by mutation in the keratin 85 gene (KRT85, 602767.0001)
OMIM Title
*602058 PROTEASE INHIBITOR 10; PI10
;;BOMAPIN;;
SERPIN PEPTIDASE INHIBITOR, CLADE B (OVALBUMIN), MEMBER 10; SERPINB10
OMIM Description
DESCRIPTION
The superfamily of high molecular weight serine proteinase inhibitors
(serpins) regulate a diverse set of intracellular and extracellular
processes such as complement activation, fibrinolysis, coagulation,
cellular differentiation, tumor suppression, apoptosis, and cell
migration. Serpins are characterized by a well-conserved tertiary
structure that consists of 3 beta sheets and 8 or 9 alpha helices (Huber
and Carrell, 1989). A critical portion of the molecule, the reactive
center loop connects beta sheets A and C. Protease inhibitor-10 (PI10;
SERPINB10) is a member of the ov-serpin subfamily, which, relative to
the archetypal serpin PI1 (107400), is characterized by a high degree of
homology to chicken ovalbumin, lack of N- and C-terminal extensions,
absence of a signal peptide, and a serine rather than an asparagine
residue at the penultimate position (summary by Bartuski et al., 1997).
CLONING
Riewald and Schleef (1995) cloned PI10, which they called bomapin, from
a human bone marrow cDNA library. The deduced 397-amino acid protein has
a calculated molecular mass of 45 kD and shares 48% sequence identity
with PAI2 (173390) and elastase inhibitor (SERPINB1; 130135), A single
2.3-kb PI10 transcript was highly expressed in human bone marrow cells
but was undetectable in all other analyzed human tissues.
GENE FUNCTION
Riewald and Schleef (1995) demonstrated that PI10 was able to form
SDS-stable complexes with thrombin and trypsin. They suggested that PI10
may play a role in the regulation of protease activities during
hematopoiesis.
MAPPING
Bartuski et al. (1997) found that the bomapin gene maps to 18q21.3 where
at least 5 other ov-serpins map.
FLJ44313
| dbSNP name | rs6565888(T,C); rs3813097(A,G) |
| cytoBand name | 18q23 |
| EntrezGene GeneID | 400658 |
| snpEff Gene Name | ZNF516 |
| EntrezGene Description | FLJ44313 protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001377 |
C2CD4C
| dbSNP name | rs374851541(G,A); rs34282976(A,G); rs1061150(A,G); rs7251812(C,T); rs2241407(T,C); rs8104383(T,C); rs2310958(A,G); rs7247159(A,G); rs12974729(A,G); rs12978500(C,A) |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 126567 |
| EntrezGene Description | C2 calcium-dependent domain containing 4C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Ears];
Low-set ears;
Anteriorly rotated ears;
[Eyes];
Visual inattention;
[Nose];
Hooked nose
RESPIRATORY:
[Lung];
Respiratory insufficiency in neonatal period
ABDOMEN:
[Liver];
Hepatomegaly;
Abnormal liver function tests;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Poor feeding
NEUROLOGIC:
[Central nervous system];
Spasticity;
Clonic seizures;
Severe psychomotor retardation;
Hydrocephalus;
Enlarged ventricles;
Calcifications;
Leukodystrophy;
Cerebral atrophy;
Cerebellar atrophy;
Brain stem atrophy;
Elevated white cell count in cerebrospinal fluid;
Elevated interferon levels in cerebrospinal fluid;
Elevated pterin levels (tetrahydrobiopterin, neopterin) in cerebrospinal
fluid
HEMATOLOGY:
Pancytopenia
IMMUNOLOGY:
No evidence of prenatal infection
LABORATORY ABNORMALITIES:
Increased serum alpha-interferon (IFNA1, 147660);
Increased CSF interferon;
CSF lymphocytosis
MISCELLANEOUS:
Onset in first year of life
MOLECULAR BASIS:
Caused by mutation in the ribonuclease H2, subunit A gene (RNASEH2A,
606034.0001)
OMIM Title
*610336 C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 4C; C2CD4C
;;NUCLEAR-LOCALIZED FACTOR 3; NLF3;;
KIAA1957
OMIM Description
CLONING
As part of a large-scale cDNA cloning project, Nagase et al. (2001)
cloned KIAA1957 from a human fetal brain cDNA library. KIAA1957 encodes
a predicted protein of 481 amino acids.
By analysis of human protein sequence databases with the sequence of
NLF1 (610343) and NLF2 (610344) as query, Warton et al. (2004)
determined that KIAA1957 shows approximately 30% homology with NLF1 and
NLF2. KIAA1957, NLF1, and NLF2 contain 2 homologous domains, one of
which is 100% identical among the 3 proteins and contains a predicted
nuclear localization sequence. KIAA1957 and its mouse ortholog share 88%
amino acid homology.
MAPPING
Using genomic sequence analysis, Nagase et al. (2001) mapped the
KIAA1957 gene to human chromosome 19.
GPX4
| dbSNP name | rs713041(T,C) |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 2879 |
| snpEff Gene Name | SBNO2 |
| EntrezGene Description | glutathione peroxidase 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UNKNOWN |
| Annovar Mutation type | unknown |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4036 |
| ESP Afr MAF | 0.314002 |
| ESP All MAF | 0.407977 |
| ESP Eur/Amr MAF | 0.45155 |
| ExAC AF | 0.571,2.461e-05 |
OMIM Clinical Significance
Heme:
Hemolytic anemia
Lab:
Glutathione reductase deficiency
Inheritance:
Autosomal recessive
OMIM Title
*138322 GLUTATHIONE PEROXIDASE 4; GPX4
;;PHOSPHOLIPID HYDROPEROXIDE GLUTATHIONE PEROXIDASE; PHGPX
OMIM Description
DESCRIPTION
GPX4 reduces phospholipid hydroperoxides within membranes and
lipoproteins and acts in conjunction with alpha-tocopherol to inhibit
lipid peroxidation. Lipid peroxidation is implicated in a number of
pathophysiologic processes, including inflammation and atherogenesis.
GPX4 is a selenoprotein whose production and activity are sensitive to
selenium (Se), which is incorporated into selenoproteins as
selenocysteine (summary by Sneddon et al., 2003).
CLONING
Using porcine Phgpx to screen a testis cDNA library, Esworthy et al.
(1994) cloned human GPX4, which they called PHGPX. The 3-prime UTR
contains a selenocysteine insertion sequence (SECIS) required for
insertion of selenocysteine at an opal codon (UGA). The deduced
197-amino acid protein has a calculated molecular mass of 19 kD. It has
putative active-site tryptophan and glutamic acid residues that are
predicted to interact with selenocysteine, and a tyrosine residue that
is phosphorylated in the porcine protein.
By fractionation and immunofluorescence microscopy of resting human
platelets, Januel et al. (2006) showed that GPX4 associated with
membranes, cytoplasm, and mitochondria, and that GPX4 activity showed an
identical distribution. Western blot analysis detected GPX4 at an
apparent molecular mass of 20 to 21 kD.
Roveri et al. (1992) found that rat Gpx4 was present primarily in
testis. Januel et al. (2006) stated that rat has mitochondrial and
nonmitochondrial forms of Gpx4.
Borchert et al. (2003) characterized the expression of 2 major isoforms
of Gpx4 in mouse tissues. One isoform, which they designated the
phospholipid (phGpx) form, was expressed in many tissues. The other,
designated the sperm nucleus (snGpx) isoform, was detected in mouse
testis and kidney, as well as in a human embryonic kidney cell line.
Subcellular fractionation and immunoelectron microscopy revealed
cytosolic localization. Immunohistochemical staining of mouse kidneys
showed staining for snGpx in cortical and medullary interstitial cells.
Analysis of the 5-prime flanking region common to both isoforms revealed
strong promoter activity. The snGpx4 promoter, which contains 334 bp of
intronic sequence, suppressed the activity of the common promoter.
BIOCHEMICAL FEATURES
To overcome inefficient selenocysteine-incorporating machinery in
recombinant systems, Scheerer et al. (2007) expressed recombinant human
cytosolic GPX4 containing a sec46-to-cys (U46C) mutation, which retains
residual catalytic activity, in E. coli. They solved the crystal
structure of this molecule to 1.55-angstrom resolution. X-ray data
indicated that the monomeric protein consisted of 4 alpha helices and 7
beta strands. The catalytic triad (cys46, gln81, and trp136) localized
at a flat impression on the protein surface extending into a
surface-exposed patch of basic amino acids (lys48, lys135, and arg152)
that also contained polar thr139. Mutation analysis confirmed the
functional importance of the catalytic triad. Like the wildtype enzyme,
the U46C mutant exhibited a strong tendency toward polymerization, which
was prevented by reductants. Site-directed mutagenesis suggested
involvement of the catalytic cys46 and surface-exposed cys10 and cys66
in polymer formation. In GPX4 crystals, these residues contacted
adjacent protein monomers.
GENE STRUCTURE
Kelner and Montoya (1998) determined that the human GPX4 gene spans 2.8
kb and contains 7 exons. Analysis of the gene sequence identified a
potential alternative tissue-specific first exon.
MAPPING
By Southern analysis of genomic DNA from human/hamster somatic cell
hybrids, Chu (1994) showed that the GPX4 gene is located on chromosome
19. By fluorescence in situ hybridization, Kelner and Montoya (1998)
assigned the gene to chromosome 19p13.3.
GENE FUNCTION
In human umbilical vein endothelial cells (HUVECs), Sneddon et al.
(2003) observed a dose-dependent increase in GPX4 mRNA and protein
levels with increasing Se concentration until the Se concentration
reached 76 nM. GPX4 enzyme activity was optimum at an even higher Se
concentration. Sneddon et al. (2003) noted that these findings
contrasted with findings in other tissues and cell types, suggesting
that Se regulates GPX4 in a tissue- and cell-type specific manner,
possibly reflecting the relative importance of GPX4 in individual
tissues. They also found that, in addition to Se, fatty acids,
cytokines, and redox state regulated GPX4 expression and activity, but
sometimes in different and opposing ways.
Activation of platelets by agonists such as thrombin (F2; 176930) leads
to a dramatic increase in cell surface expression of several receptors,
as well as changes in platelet shape, release of arachidonic acid from
phospholipids, and increased level of peroxides. Using fractionated
human platelets and confocal immunofluorescence microscopy, Januel et
al. (2006) found that GPX4 protein and enzymatic activity redistributed
from the cytosol to membranes following platelet activation. They
hypothesized that mobilization of GPX4 toward membranes protects
platelets against the burst of lipid hydroperoxides and limits the stage
of activation.
By yeast 3-hybrid screening of a mouse testis cDNA library, followed by
RNA mobility gel shift assays, Ufer et al. (2008) found that the
RNA-binding protein Grsf1 (604851) bound an AGGGGA motif in the 5-prime
UTR of mitochondrial Gpx4. Grsf1 upregulated Gpx4 UTR-dependent reporter
gene expression, recruited mitochondrial Gpx4 mRNA to translationally
active polysomes, and coimmunoprecipitated with Gpx4 mRNA. During
embryonic mouse brain development, Grsf1 and mitochondrial Gpx4 were
coexpressed, and knockdown of Grsf1 via small interfering RNA prevented
embryonic Gpx4 expression. Compared with mock controls, Grsf1-knockdown
embryos showed developmental retardation that paralleled increased
apoptosis and massive lipid peroxidation. Overexpression of
mitochondrial Gpx4 prevented the apoptotic changes and rescued
development in Grsf1-knockdown embryos. Ufer et al. (2008) concluded
that GRSF1 upregulates translation of GPX4 mRNA and that both proteins
are required for embryonic brain development.
MOLECULAR GENETICS
Villette et al. (2002) examined the 3-prime UTR of the GPX4 gene in 66
healthy Scottish volunteers and identified a T-C SNP at position 718,
near the predicted SECIS element. The distribution of this SNP was in
Hardy-Weinberg equilibrium, with 34% CC homozygotes, 25% TT homozygotes,
and 41% TC heterozygotes. Individuals of different genotypes exhibited
significant differences in the levels of lymphocyte 5-lipoxygenase total
products, with CC homozygotes showing 36% and 44% more products than TT
homozygotes and TC heterozygotes, respectively. Villette et al. (2002)
concluded that GPX4 has a regulatory role in leukotriene biosynthesis
and that the 718T-C SNP has functional effects.
- Spondylometaphyseal Dysplasia, Sedaghatian Type
In a deceased female infant with the Sedaghatian type of
spondylometaphyseal dysplasia (SMDS; 250220), Smith et al. (2014)
identified compound heterozygosity for mutations in the GPX4 gene
(138322.0001 and 138322.0002). In addition, in the unaffected
first-cousin Turkish parents of a deceased male infant with SMDS,
previously studied by Aygun et al. (2012), they detected heterozygosity
for a nonsense mutation (Y127X; 138322.0003). DNA was unavailable from
the affected child.
ANIMAL MODEL
Ran et al. (2004) stated that Gpx4 deletion in mice is embryonic lethal,
and that embryonic fibroblasts from Gpx4 +/- mice exhibit increased
lipid peroxidation, more cell death after exposure to oxidizing agents,
and growth retardation under high oxygen levels. They found that
expression of human GPX4 rescued the lethal phenotype of Gpx4 -/- mice.
Transgenic mice overexpressing human GPX4 showed reduced oxidative
injury after oxidative stress.
AMH
| dbSNP name | rs61736571(G,A); rs10407022(G,T) |
| ccdsGene name | CCDS12085.1 |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 268 |
| EntrezGene Description | anti-Mullerian hormone |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AMH:NM_000479:exon1:c.G129A:p.L43L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.00091 |
| ESP All MAF | 0.000308 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 9.807e-05 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Weight];
Obesity, early-onset
ABDOMEN:
[Gastrointestinal];
Malabsorption (small intestine);
Diarrhea;
Small intestine biopsy shows villous atrophy
ENDOCRINE FEATURES:
Hypoglycemia, reactive;
Hypocortisolemia;
Hypogonadotropic hypogonadism;
Primary amenorrhea;
Impaired processing of proopiomelanocortin (POMC, 176830)
LABORATORY ABNORMALITIES:
Increased plasma proinsulin;
Decreased or normal plasma insulin;
Increased plasma progastrin;
Increased plasma proglucagon
MISCELLANEOUS:
Phenotypic variability
MOLECULAR BASIS:
Caused by mutation in the proprotein convertase 1 gene (PC1, 162150.0001)
OMIM Title
*600957 ANTI-MULLERIAN HORMONE; AMH
;;MULLERIAN-INHIBITING SUBSTANCE; MIS;;
MULLERIAN-INHIBITING FACTOR; MIF
OMIM Description
DESCRIPTION
Male sex differentiation is mediated by 2 discrete hormones produced by
the fetal testis. Testosterone, produced by Leydig cells, virilizes the
external genitalia and promotes prostatic growth; anti-mullerian hormone
(AMH), also called mullerian-inhibiting substance (MIS) or factor (MIF),
results in regression of mullerian ducts which would otherwise
differentiate into the uterus and fallopian tubes.
CLONING
Picard et al. (1986) used mRNA prepared from fetal bovine testicular
tissue to construct a cDNA library. They isolated cDNAs encoding a
fragment of bovine AMH and showed by Northern blots that the gene was
expressed only in fetal testis and adult ovarian follicles.
Cate et al. (1986) isolated the human gene for MIF. The gene encodes a
560-amino acid polypeptide. The highly conserved C-terminal domain of
the protein shows marked homology with human transforming growth
factor-beta (190180) and the beta chain of porcine inhibin (147390).
BIOCHEMICAL FEATURES
Lee et al. (1997) demonstrated that measurements of serum
mullerian-inhibiting substance can be used to determine testicular
status in prepubertal children with nonpalpable gonads, thus
differentiating anorchia from undescended testes in boys with bilateral
cryptorchidism and serving as a measure of testicular integrity in
children with intersexual anomalies.
To determine the value of assessing serum AMH levels in the diagnosis of
intersex conditions, Rey et al. (1999) assayed levels in 107 patients
with ambiguous genitalia of various etiologies. In XY patients, AMH was
low when the intersex condition was caused by abnormal testicular
determination (including pure and partial gonadal dysgenesis) but was
normal or elevated in patients with impaired testosterone secretion,
whereas serum testosterone was low in both groups. AMH was also elevated
during the first year of life and at puberty in intersex states caused
by androgen insensitivity. In 46,XX patients with a normal male
phenotype or ambiguous genitalia in whom the diagnosis of female
pseudohermaphroditism had been excluded, AMH levels greater than 75
pmol/L were indicative of the presence of testicular tissue and
correlated with the mass of functional testicular parenchyma. The
authors concluded that serum AMH determination is a powerful tool to
assess Sertoli cell function in children with intersex states that can
help to distinguish between defects of male sexual differentiation
caused by abnormal testicular determination and those resulting from
isolated impairment of testosterone secretion or action.
Misra et al. (2003) examined the role of MIS determination in the
evaluation of 65 phenotypic females with mild virilization. Among the 28
subjects with MIS values above the normal female range, all had abnormal
gonadal tissue: ovotestes in 11, testes in 7, dysgenetic gonads in 7,
and MIS-secreting ovarian tumors in 3. Among the 37 children with serum
MIS in the normal female range, 19 had detectable MIS and 18 had
unmeasurable MIS. In the former group with measurable but normal female
MIS values, 16 subjects had ovaries, 1 had an ovotestis, and 1 had
dysgenetic gonads containing testicular elements. Of 18 children with
undetectable MIS values, 16 had ovaries and 2 had ovarian dysgenesis.
The authors concluded that elevation of serum MIS above the normal
female range was consistently associated with the presence of testicular
tissue or MIS-secreting tumors, mandating additional evaluation and
surgical exploration.
To investigate the correlation between AMH levels and age of onset of
menopause, van Disseldorp et al. (2008) measured AMH levels in 144
fertile normal volunteers and determined the mean AMH as a function of
age. The authors found good conformity between the observed distribution
of age at menopause and that predicted from declining AMH levels. Van
Disseldorp et al. (2008) concluded that the similarity between observed
and predictive distributions of age at menopause supported the
hypothesis that AMH levels are related to onset of menopause.
GENE FUNCTION
Forest (1997) commented that there is no evidence of any biologic action
of mullerian-inhibiting substance after birth. Its overproduction in
patients with sex-cord tumors does not seem to have any harmful effects.
Wang et al. (2005) found that motor neurons of adult male and female
mice synthesized Mis and expressed its receptors. Mis supported survival
of embryonic motor neurons in vitro at physiologic concentrations,
suggesting that mature motor neurons use MIS for communication or as an
autocrine factor. Wang et al. (2005) postulated that MIS may have a
hormone effect in developing males due to the delayed development of the
blood-brain barrier, possibly resulting in sex-specific differences in
motor neurons.
Anttonen et al. (2005) studied the role of factors regulating normal
granulosa cell function, i.e., AMH, inhibin-alpha (147380),
steroidogenic factor-1 (SF1; 184757), and GATA transcription factors
(e.g., GATA4, 600576) in the pathobiology and clinical behavior of
granulosa cell tumors (GCTs). The more aggressive GCTs retained a high
GATA4 expression, whereas the larger tumors lost the
proliferation-suppressing AMH expression. Anttonen et al. (2005)
concluded that the high GATA4 expression in GCTs may serve as a marker
of poor prognosis.
GENE STRUCTURE
Cate et al. (1986) determined that the human MIF gene has 5 exons.
MAPPING
Cohen-Haguenauer et al. (1987) mapped the gene for AMH to 19p13.3-p13.2,
using in situ hybridization and Southern blot analysis of a panel of
human-mouse and human-hamster somatic cell hybrids.
By study of cow-hamster and cow-mouse somatic cell hybrids, Rogers et
al. (1991) showed that the AMH and SPARC (182120) genes are syntenic in
cattle. SPARC maps to chromosome 5 in the human.
By linkage mapping, King et al. (1991) demonstrated that the Amh gene is
on mouse chromosome 10. This analysis identified a new region of linkage
homology between human 19p and mouse 10.
MOLECULAR GENETICS
Knebelmann et al. (1991) demonstrated a missense mutation in the AMH
gene in a patient with AMH-negative persistent mullerian duct syndrome
(see 600957.0001).
Imbeaud et al. (1994) performed molecular analysis of the AMH gene in 21
patients with persistent mullerian duct syndrome (PMDS; 261550) and
their families. In 6 patients with normal serum concentration of AMH,
the AMH was normal or contained only polymorphisms and silent mutations,
supporting the hypothesis that the condition is due to end-organ
resistance. In the 15 remaining patients with low or undetectable levels
of serum AMH, 9 novel mutations were discovered. When present in
homozygotes or compound heterozygotes, these mutations were associated
with the PMDS phenotype, the same mutation never being observed in 2
different families. The first 3 exons of the AMH gene appeared
particularly mutation-prone, although they are less GC rich than the 2
last exons and code for the N-terminal part of the AMH protein, which is
not in itself essential to bioactivity.
Guerrier et al. (1989) demonstrated that not all cases of PMDS are
caused by a defect of the AMH gene itself; some patients express a
normal amount of bioactive testicular AMH. PMDS, characterized by the
presence of mullerian derivatives in otherwise normally virilized males,
is sometimes due to mutations in the AMH gene which abrogate AMH
production by the immature Sertoli cells and sometimes due to mutations
in AMHR (600956), the AMH receptor gene (Imbeaud et al., 1995). These 2
forms of persistent mullerian duct syndrome are referred to as types 1
and 2, respectively.
Imbeaud et al. (1996) reported results of molecular studies on 38
families with PMDS. They identified the basis of the condition: namely,
16 AMH and 16 AMH receptor mutations in 32 families. Six of the patients
were postpubertal, and in these patients determination of the level of
anti-mullerian hormone was no longer informative, since AMH production
is normally repressed after puberty. In prepubertal patients, the type
of genetic defect leading to PMDS could be predicted from the level of
serum AMH, which is very low or undetectable in PMDS type I due to AMH
mutations and at the upper limit of normal in receptor mutations. AMH
mutations were extremely diverse, and were identified in 16 families,
including 9 previously reported families (Imbeaud et al., 1994). Imbeaud
et al. (1996) reported that exon 1 and the 3-prime half of exon 5 of the
AMH gene are the main sites of deleterious changes including short
deletions and missense mutations.
To investigate the role of the AMH signaling pathway in the
pathophysiology of polycystic ovary syndrome (PCOS; see 184700),
Kevenaar et al. (2008) studied the association of the AMH I49S and the
AMHR -482A-G polymorphisms with PCOS susceptibility and phenotype in 331
women with PCOS and 32 normoovulatory controls, all Dutch Caucasians.
Allele and genotype frequency of these polymorphisms in the Dutch
Caucasian population were determined using 3,635 population-based
controls. Kevenaar et al. (2008) found that genotype and allele
frequencies for the 2 polymorphisms were similar in PCOS women and
controls. However, within the group of PCOS women, carriers of the AMH
49S allele had polycystic ovaries less often (92.7 vs 99.5%, p =
0.0004), lower follicle numbers (p = 0.03), and lower androgen levels,
compared with noncarriers (p = 0.04). In addition, in vitro studies
demonstrated that the bioactivity of the AMH 49S protein is diminished
compared with the AMH 49I protein (p less than 0.0001). Kevenaar et al.
(2008) concluded that whereas these genetic variants do not influence
PCOS susceptibility, the AMH I49S polymorphism contributes to the
severity of the PCOS phenotype.
ANIMAL MODEL
Mishina et al. (1996) produced and examined AMHR2 (600956) knockout
mice. They observed that mutant males were internal
pseudohermaphrodites, having both male and female reproductive organs.
The phenotype of AMH/AMHR2 double-knockout mutant males was
indistinguishable from that of either single mutant. Furthermore, the
phenotypes of AMH/alpha-inhibin and AMHR2/alpha-inhibin double-knockout
mutant males were also identical, suggesting to the authors that AMH is
the only ligand of the AMHR2 receptor.
Arango et al. (1999) introduced mutations into conserved Sf1 (184757)-
and Sox9 (608160)-binding sites within the endogenous mouse Mis
promoter. Male mice homozygous for the mutant Sf1-binding site correctly
initiated Mis transcription in fetal testes, although at significantly
reduced levels. Surprisingly, sufficient Mis was produced to eliminate
the mullerian ducts. In contrast, males homozygous for the mutant
Sox9-binding site did not initiate Mis transcription, resulting in
pseudohermaphrodites. These studies suggested an essential role for SOX9
in the initiation of MIS transcription, whereas SF1 appeared to act as a
quantitative regulator of MIS transcript levels, perhaps for influencing
non-mullerian duct tissues. Comparative studies of MIS expression in
vertebrates indicated that the MIS promoter receives transcriptional
inputs that vary between species but result in the same functional
readout.
Wang et al. (2009) presented evidence suggesting that AMH (MIS) is an
important factor in the generation of variability of 'sex-linked bias,'
or subtle behavioral differences between males and females. Most neurons
in the adult mouse brain, spinal cord, and peripheral nervous system, as
well as embryonic spinal cord motor neurons, expressed the Amhr2
receptor. Only trace levels of Amh were detected in embryonic head,
indicating that the prime embryonic source is from the testes. Male
Amh-null or Amhr2-null mice showed subtle feminization of spinal cord
motor neurons, i.e., fewer numbers of lumbar lateral motor neurons
compared to wildtype males. However, androgen-dependent features were
unaffected. Male Amhr2-null or Amh-null mice had partial feminization of
exploratory behavior. Wang et al. (2009) suggested that Amh may be a
regulator of neuronal pathways. The authors noted that Amh levels vary
in the male population, which may underlie subtle sex-linked biases.
NOMENCLATURE
Because MIF is also used as the symbol for macrophage migration
inhibitory factor (153620), AMH, for anti-mullerian hormone, will be
considered the preferred symbol for the locus on chromosome 19.
RAX2
| dbSNP name | rs6510769(G,C); rs917545(G,A); rs917546(C,T); rs28673245(C,T) |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 84839 |
| snpEff Gene Name | MRPL54 |
| EntrezGene Description | retina and anterior neural fold homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.202 |
FEM1A
| dbSNP name | rs11085099(T,G); rs141938232(G,A); rs1044386(G,A); rs1044409(G,A) |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 55527 |
| EntrezGene Description | fem-1 homolog a (C. elegans) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3508 |
ZNRF4
| dbSNP name | rs2240743(C,T); rs2240744(G,A); rs420325(A,G); rs2240745(G,A); rs113345491(G,A); rs8111108(T,C) |
| ccdsGene name | CCDS42475.1 |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 148066 |
| EntrezGene Description | zinc and ring finger 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNRF4:NM_181710:exon1:c.C109T:p.P37S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8WWF5 |
| dbNSFP Uniprot ID | ZNRF4_HUMAN |
| dbNSFP KGp1 AF | 0.557234432234 |
| dbNSFP KGp1 Afr AF | 0.343495934959 |
| dbNSFP KGp1 Amr AF | 0.552486187845 |
| dbNSFP KGp1 Asn AF | 0.784965034965 |
| dbNSFP KGp1 Eur AF | 0.526385224274 |
| dbSNP GMAF | 0.4431 |
| ESP Afr MAF | 0.328488 |
| ESP All MAF | 0.449728 |
| ESP Eur/Amr MAF | 0.490577 |
| ExAC AF | 0.536 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Distal muscle atrophy
NEUROLOGIC:
[Central nervous system];
Spastic paraplegia;
Upper limbs may be affected;
Abnormal gait;
Hyperreflexia;
Extensor plantar responses;
Ataxia (in some patients);
Cerebellar atrophy (in some patients);
Spinal cord atrophy (1 family);
[Peripheral nervous system];
Axonal motor neuropathy
MISCELLANEOUS:
Onset usually in the first decade;
Later onset has been reported
MOLECULAR BASIS:
Caused by mutation in the patatin-like phospholipase domain-containing
protein 6 (PNPLA6, 603197.0001)
OMIM Title
*612063 ZINC FINGER AND RING FINGER PROTEIN 4; ZNRF4
;;SPERMATID-SPECIFIC RING ZINC FINGER PROTEIN; SPERIZIN
OMIM Description
CLONING
Fujii et al. (1999) cloned mouse Znrf4, which they called sperizin. The
deduced 326-amino acid protein contains a RING finger motif. Northern
blot analysis of adult mouse tissues detected sperizin in testis only.
Sperizin was not expressed in prepubertal testis. Fractionation of mouse
testicular cells revealed sperizin in the germ cell fraction, and
sperizin was not detected in testis with defective germ cell
differentiation. Fluorescence-tagged sperizin was expressed in the
cytoplasm of transfected HeLa cells.
MAPPING
By interspecific backcross analysis, Fujii et al. (1999) mapped the
mouse Znrf4 gene to a region of chromosome 17 that shares homology of
synteny with human chromosome 19p13.3.
CAPS
| dbSNP name | rs7249419(A,G); rs7248090(G,A); rs74174355(C,T); rs13004(A,G) |
| ccdsGene name | CCDS12156.1 |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 828 |
| EntrezGene Description | calcyphosine |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CAPS:NM_080590:exon3:c.A115G:p.R39G,CAPS:NM_004058:exon3:c.A115G:p.R39G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0007 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NF12 |
| dbNSFP KGp1 AF | 0.0380036630037 |
| dbNSFP KGp1 Afr AF | 0.126016260163 |
| dbNSFP KGp1 Amr AF | 0.0386740331492 |
| dbNSFP KGp1 Asn AF | 0.00874125874126 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.03811 |
| ESP Afr MAF | 0.135497 |
| ESP All MAF | 0.048593 |
| ESP Eur/Amr MAF | 0.00407 |
| ExAC AF | 0.027 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604667 CALCIUM-DEPENDENT ACTIVATOR PROTEIN FOR SECRETION; CADPS
;;CAPS;;
CADPS1;;
KIAA1121
OMIM Description
CLONING
Calcium-activated secretion in neuroendocrine cells is dependent on ATP
and cytosolic proteins such as NSF (601633), SNAPs (see 603215)
GTP-binding proteins, and components of a vesicle coat complex. Walent
et al. (1992) isolated a rat cytosolic factor, which they termed p145,
that reconstituted Ca(2+)-activated secretion via dense core vesicle
exocytosis in permeable neuroendocrine cells. The protein is a dimer of
145-kD subunits. By screening rat brain cDNA libraries with anti-p145,
Ann et al. (1997) obtained a cDNA encoding a protein of 1,289 amino
acids, which they designated Caps. Sequence analysis revealed an overall
hydrophilic protein with 2 potential coiled-coil regions. Northern blot
analysis on mRNA from human tissue revealed expression of a 5.6-kb
transcript in brain, pancreas, hypothalamus, pituitary, and adrenal, but
not in heart, placenta, lung, liver, skeletal muscle, or kidney. The
sequence of rat Caps is 75% similar and 54% identical to that of C.
elegans UNC31; loss-of-function UNC31 mutants exhibit multiple nervous
system defects.
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Hirosawa et al. (1999) cloned CADPS, which they designated
KIAA1121. RT-PCR ELISA detected high expression in whole adult brain,
intermediate expression in fetal brain and adult heart, lung, pancreas,
testis, and spinal cord, low expression in ovary, and little to no
expression in skeletal muscle, kidney, spleen, and adult and fetal
liver. Expression was high in thalamus and intermediate in all other
specific brain regions examined.
By screening a human pancreas cDNA library with mouse Cadps, Cisternas
et al. (2003) cloned CADPS. The deduced 1,274-amino acid protein
contains an N-terminal coiled-coil domain, followed by a C2 domain, a PH
domain, and a C-terminal coiled-coil domain. The C2 domain is expected
to mediate calcium and phospholipid binding. The mouse and human
proteins share 98% identity. Northern blot analysis detected a 5.6-kb
CADPS transcript highly expressed in adult brain and pancreas and fetal
brain, with lower expression in adult heart. Within specific brain
regions, CADPS was expressed strongly in cerebellum, cerebral cortex,
medulla, occipital pole, frontal and temporal lobes, and putamen and
more weakly in spinal cord. Semiquantitative PCR detected CADPS
expression in heart, brain, and pancreas.
GENE FUNCTION
Equilibrium dialysis studies by Ann et al. (1997) showed that rat Caps
is a calcium-binding protein.
By subcellular fractionation of isolated rat presynaptic nerve
terminals, or synaptosomes, Berwin et al. (1998) determined that Caps is
primarily associated with plasma membranes and large dense core vesicles
but not with small clear synaptic vesicles.
Vesicle exocytosis is a sequential multistep process that involves the
initial tethering of vesicles to the plasma membrane, followed by
membrane fusion. Membrane fusion requires SNARE complexes that bridge
the vesicle and plasma membrane to promote close membrane apposition and
bilayer mixing. Using rodent constructs, Daily et al. (2010) found that
Caps exhibited high affinity for syntaxin-1 (STX1A; 186590) and Snap25
(600322), which are neuronal SNARE components required for exocytosis,
and moderate affinity for Vamp2 (185881). Binding was optimum when the
SNARE proteins were integrated into liposomes. Daily et al. (2010)
concluded that CAPS promotes SNARE complex assembly and vesicle fusion
through direct binding to syntaxin-1, SNAP25, and VAMP2.
GENE STRUCTURE
Cisternas et al. (2003) determined that the CADPS gene contains 30 exons
and spans 475 kb. The 5-prime end of the gene contains a CpG island.
MAPPING
By radiation hybrid analysis, Hirosawa et al. (1999) mapped the human
CADPS gene to chromosome 3. Cisternas et al. (2003) mapped the CADPS
gene to chromosome 3p21.1 by genomic sequence analysis.
PSPN
| dbSNP name | rs2304198(G,A) |
| ccdsGene name | CCDS12164.1 |
| CosmicCodingMuts gene | PSPN |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 5623 |
| EntrezGene Description | persephin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PSPN:NM_004158:exon1:c.C30T:p.S10S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3962 |
| ESP Afr MAF | 0.243532 |
| ESP All MAF | 0.363525 |
| ESP Eur/Amr MAF | 0.162209 |
| ExAC AF | 0.254 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602921 PERSEPHIN; PSPN
OMIM Description
DESCRIPTION
Neurotrophic factors, including persephin, are important for the proper
development and maintenance of the nervous system. These factors promote
neuronal survival and can prevent the neuronal degeneration associated
with injury, toxin exposure, or neurodegenerative disease (summary by
Milbrandt et al., 1998).
CLONING
To identify genes related to the neurotrophic factors GDNF (600837) and
NRTN (602018), Milbrandt et al. (1998) carried out PCR using primers
based on regions that were similar in these 2 proteins. They isolated
human, mouse and rat genomic fragments encoding a protein that they
designated persephin, symbolized PSP. The predicted 156-amino acid human
protein contains a 21-residue signal peptide. On Western blots, mature
mouse PSP has a molecular mass of 10 to 12 kD. The human PSP protein
shares 80% sequence identity with rat and mouse PSP, and 38% and 30%
identity with NTRN and GDNF, respectively. Like other GDNF family
members, the PSP gene contains an intron interrupting the prodomain.
RT-PCR analysis revealed that rat PSP mRNA was expressed at low levels
and was inefficiently spliced, leading Milbrandt et al. (1998) to
suggest that regulation of transcript processing is an important means
of regulating PSP protein production.
GENE FUNCTION
Milbrandt et al. (1998) found that PSP resembled GDNF and NTRN in that
it exhibited neurotrophic activity on mesencephalic dopaminergic and
motor neurons. Like GDNF, PSP also had effects on kidney development, as
evidenced by its ability to promote ureteric bud branching. However, in
contrast to GDNF and NTRN, PSP did not support any of the peripheral
neurons examined. Milbrandt et al. (1998) suggested that PSP utilizes
different, or additional, receptor components than do other members of
the GDNF family.
MAPPING
By radiation hybrid mapping and somatic cell hybrid PCR, Chadwick et al.
(1998) mapped the PSPN gene to chromosome 19p13.3.
C3
| dbSNP name | rs17030(G,A); rs11569562(A,G); rs11569561(C,A); rs344555(T,C); rs2277984(C,T); rs2277983(T,C); rs11569560(G,A); rs11569558(C,T); rs11569557(C,T); rs344553(T,G); rs344552(T,C); rs11569555(T,C); rs34081046(C,T); rs344551(A,C); rs7951(G,A); rs11569584(T,G); rs11569551(G,A); rs344550(C,G); rs76061973(C,T); rs11569546(G,A); rs11569545(A,G); rs344549(T,C); rs1389625(A,G); rs1389623(G,A); rs2241393(G,C); rs11569538(C,G); rs344548(G,C); rs11569582(A,T); rs7257062(C,T); rs2241392(G,C); rs344547(C,T); rs237554(T,C); rs344546(G,A); rs344545(G,A); rs344544(A,C); rs344543(C,G); rs344542(A,G); rs344541(A,G); rs344540(G,A); rs344538(T,C); rs344536(C,T); rs344535(T,C); rs8108377(C,A); rs11569523(C,T); rs11085192(T,C); rs13345176(C,T); rs6417195(G,A); rs3745568(T,G); rs150237828(G,A); rs10414623(G,A); rs11085194(C,T); rs10402876(G,C); rs10406463(A,G); rs2287845(G,A); rs2355315(G,T); rs2253756(G,A); rs2355316(G,A); rs408004(G,A); rs366510(G,T); rs201763255(T,A); rs408744(T,A); rs594974(T,A); rs1895388(G,C); rs10221476(C,T); rs11666563(G,C); rs1833792(C,T); rs10415542(T,C); rs445750(G,A); rs111756342(C,T); rs392690(A,G); rs2547436(G,A); rs2642209(C,T); rs2642208(G,A); rs11569459(A,G); rs11569458(G,A); rs11569457(G,C); rs2642207(A,C); rs408290(G,C); rs433594(A,G); rs428453(C,G); rs432823(T,C); rs11569450(G,C); rs406514(G,A); rs113081409(C,T); rs451760(G,A); rs11085195(T,C); rs11672613(T,C); rs8107911(G,A); rs8112351(T,C); rs11569438(G,T); rs402756(A,G); rs58437379(T,C); rs11085196(C,A); rs11569429(C,T); rs11569428(G,T); rs11569426(C,T); rs2230205(C,T); rs2230204(C,T); rs116727573(G,A); rs189367(G,A); rs2230203(G,T); rs10411506(G,A); rs11569422(C,G); rs4807895(A,G); rs192458238(T,C); rs11085197(G,C); rs1047286(G,A); rs11569418(T,C); rs2642202(T,G); rs11569416(G,A); rs11569415(G,A); rs11569414(C,T); rs2547438(T,G); rs2230199(G,C); rs2250656(T,C); rs11569404(C,G); rs11569395(C,A) |
| ccdsGene name | CCDS32883.1 |
| CosmicCodingMuts gene | C3 |
| cytoBand name | 19p13.3 |
| EntrezGene GeneID | 718 |
| EntrezGene Description | complement component 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C3:NM_000064:exon27:c.C3431T:p.T1144M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6771 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P01024 |
| dbNSFP Uniprot ID | CO3_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Nephritis;
Membranous glomerulonephropathy
SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash;
Malar rash
HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia
IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of B cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells
LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Antiribonuclear protein positive;
Anti-SSB positive;
Anti-factor VIII positive
MISCELLANEOUS:
Onset in infancy or childhood
MOLECULAR BASIS:
Caused by mutations in the caspase 10 gene (CASP10, 601762.0001)
OMIM Title
*603966 ALDO-KETO REDUCTASE FAMILY 1, MEMBER C3; AKR1C3
;;ALDO-KETO REDUCTASE B; HAKRB;;
DIHYDRODIOL DEHYDROGENASE 3; DD3;;
3-@ALPHA-HYDROXYSTEROID DEHYDROGENASE, TYPE II;;
17-@BETA-HYDROXYSTEROID DEHYDROGENASE V; HSD17B5
OMIM Description
CLONING
The aldo-keto reductase family includes 3-alpha-hydroxysteroid
dehydrogenase (3-alpha-HSD) as well as dihydrodiol dehydrogenase
(AKR1C3) and human chlordecone reductase (CHDR, or AKR1C4; 600451).
Aldo-keto reductases catalyze the conversion of aldehydes and ketones to
alcohols by utilizing NADH and/or NADPH as a cofactor. 3-Alpha-HSD is a
versatile aldo-keto reductase, able to utilize a large array of
substrates. By screening a human liver expression library with an
antibody against rat 3-alpha-HSD, Qin et al. (1993) isolated cDNAs
encoding 4 distinct human aldo-keto reductases: HAKRa (AKR1C4), HAKRb,
HAKRc (AKR1C1; 600449), and HAKRd (AKR1C2; 600450). The predicted
323-amino acid HAKR proteins share more than 85% identity. Northern blot
analysis revealed that HAKRb is expressed as 1.4- and 1.2-kb mRNAs in
several human tissues.
Nagase et al. (1995) isolated KIAA0119, an HAKRb cDNA, from a human
immature myeloid cell line. Mills et al. (1998) isolated an identical
cDNA, which they designated HAKRe.
GENE FUNCTION
Khanna et al. (1995) reported that recombinant type I (AKR1C4) and type
II (AKR1C3) human 3-alpha-HSD proteins exhibited both reductase and
dehydrogenase activities.
GENE STRUCTURE
By sequence analysis, Khanna et al. (1995) demonstrated that the AKR1C3
and AKR1C4 genes contain 9 exons and span 15 to 20 kb. The sizes and
boundaries of the exons are identical in both genes.
MAPPING
By analysis of somatic cell hybrids, Nagase et al. (1995) mapped the
KIAA0119 gene to chromosome 10. Khanna et al. (1995) isolated 2 genes
encoding dihydrodiol dehydrogenase, referred to as type I or DDH1, and
type II or DDH2, as well as 1 gene for chlordecone reductase. However,
sequence analysis revealed that the type I gene of Khanna et al. (1995)
corresponded to either AKR1C1 or AKR1C2, the type II gene corresponded
to AKR1C3, and the CHDR gene corresponded to AKR1C4 (White, 1999). By a
combination of somatic cell hybrid analysis and fluorescence in situ
hybridization, Khanna et al. (1995) mapped all 3 genes to 10p15-p14.
MOLECULAR GENETICS
Qin et al. (2006) identified a functional polymorphism in the promoter
region of the HSD17B5 gene (-71G) that may contribute to testosterone
excess in a subset of patients with polycystic ovary syndrome (see
184700).
FLJ25758
| dbSNP name | rs10414331(T,C); rs12983790(G,A); rs10414215(C,T) |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 497049 |
| EntrezGene Description | MAP/microtubule affinity-regulating kinase 1 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1616 |
LOC100128573
| dbSNP name | rs111852362(G,A); rs11880122(A,G); rs11880140(A,G) |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 100128573 |
| snpEff Gene Name | ARHGEF18 |
| EntrezGene Description | uncharacterized LOC100128573 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01791 |
| ExAC AF | 0.039 |
FLJ22184
| dbSNP name | rs73500086(A,G); rs525420(A,G) |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 80164 |
| snpEff Gene Name | EVI5L |
| EntrezGene Description | putative uncharacterized protein FLJ22184 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08586 |
LYPLA2P2
| dbSNP name | rs28550929(T,C); rs62125157(C,T); rs28643572(A,C) |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 388499 |
| EntrezGene Symbol | LOC388499 |
| EntrezGene Description | lysophospholipase II pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02433 |
| ExAC AF | 0.007792 |
FBN3
| dbSNP name | rs2287937(C,G); rs143551340(G,A); rs147506230(G,C); rs12460243(G,A); rs11667975(G,T); rs6603135(G,T); rs12972954(T,C); rs78806879(C,G); rs11669144(G,A); rs17160128(A,G); rs7246924(A,C); rs77261076(G,A); rs11673355(C,T); rs11260050(G,A); rs111281472(G,A); rs76486281(C,T); rs28421148(A,G); rs74954996(C,A); rs17202210(C,G); rs78309858(C,G); rs60941879(C,T); rs138398260(G,A); rs4804258(A,G); rs35624673(C,T); rs10418055(A,G); rs10424096(A,G); rs73003698(A,G); rs77384136(G,A); rs73003701(C,G); rs150918051(T,C); rs76261579(G,A); rs73005512(G,C); rs144808655(A,G); rs10420783(G,A); rs7256904(G,T); rs7248720(T,C); rs7257948(C,A); rs8112016(C,T); rs113647357(A,G); rs146177619(C,T); rs142453019(A,G); rs150523803(G,A); rs7247713(C,T); rs35477781(A,C); rs12974407(T,G); rs4804259(C,A); rs112071796(A,C); rs113100512(G,T); rs4804261(G,A); rs7260038(G,A); rs7260089(C,T); rs6603136(C,A); rs6603137(A,T); rs6603138(G,A); rs8100055(C,T); rs8105684(A,G); rs111746847(C,T); rs8103218(C,T); rs3745393(C,T); rs3745394(G,A); rs3745395(C,T); rs8104066(C,T); rs8104079(C,G); rs8107185(G,T); rs12611311(A,G); rs12984484(A,G); rs10406623(T,C); rs10416205(C,T); rs141306449(G,A); rs61501857(T,C); rs2303168(C,T); rs3848570(C,T); rs2303169(T,C); rs35618038(G,A); rs62124727(T,A); rs77280459(T,C); rs7253442(T,C); rs10404241(G,A); rs12609798(C,T); rs12610395(A,G); rs12608618(G,A); rs8101778(G,C); rs62124731(T,C); rs17160147(G,C); rs17160149(A,C); rs73503752(C,T); rs73503753(A,T); rs73503755(A,G); rs28525575(T,G); rs113019969(G,A); rs111805079(G,A); rs111958793(T,C); rs150353903(T,C); rs138072164(A,G); rs112450238(A,G); rs113836633(T,C); rs151083198(C,T); rs17160151(C,T); rs7260399(G,A); rs11667465(A,G); rs115118410(T,C); rs6603139(T,C); rs79069797(C,T); rs12460643(A,G); rs7257658(G,T); rs9676439(T,A); rs78484880(G,C); rs140212866(G,A); rs3813782(G,A); rs116118704(G,A); rs149893915(G,A); rs35033566(T,C); rs45571440(G,A); rs35002391(C,T); rs12459760(G,A); rs10416843(A,G); rs8112982(C,T); rs12981294(A,G); rs12984611(C,T); rs8104453(A,G); rs34758775(T,C); rs61301669(T,C); rs6603140(C,T); rs62124735(C,G); rs11260051(G,A); rs6603141(A,G); rs10415092(C,T); rs8107566(C,G); rs77571385(G,A); rs17160153(T,C); rs8102671(T,G); rs7260602(G,A); rs7245429(G,T); rs7245552(G,T); rs34241327(C,T); rs146716479(G,A); rs73503784(G,A); rs12608849(G,A); rs10413994(A,G); rs10404258(C,T); rs115834286(C,T); rs12151307(A,G); rs145090095(C,T); rs3829817(C,T); rs3813781(G,C); rs3813780(C,T); rs61735544(C,T); rs78619893(G,T); rs61633950(T,C); rs45624733(C,T); rs12980768(T,C); rs74809476(G,A); rs115839582(C,G); rs76623041(G,A); rs8104517(T,C); rs35911979(C,T); rs8112549(G,T); rs11666861(A,C); rs11260052(A,G); rs11260053(C,T); rs11260054(A,G); rs59541369(G,A); rs11260055(C,T); rs4804059(A,C); rs11260056(A,G); rs35882466(T,C); rs10906991(C,T); rs10906992(T,C); rs7247355(T,C); rs12977723(G,T); rs7259018(A,G); rs35534815(C,T); rs56182050(G,A); rs4804060(G,A); rs4804061(T,C); rs141530818(G,A); rs12611329(T,C); rs4804263(A,G); rs4804062(C,T); rs8113458(T,C); rs8104354(C,T); rs139086008(G,C); rs10415836(C,T); rs12986396(A,G); rs3865463(G,A); rs3865464(T,A); rs4289098(G,A); rs10424520(C,A); rs4271691(T,C); rs67061735(C,G); rs56299108(G,C); rs112108346(G,T); rs369937429(C,T); rs8100537(T,A); rs8111372(A,G); rs7258713(G,A); rs2126971(A,G); rs113611719(G,A); rs116238778(G,C); rs56145610(T,C); rs143981897(G,A); rs77846381(G,T); rs899207(C,T); rs1382354(A,T); rs76556785(T,C); rs3813779(A,G); rs11672038(C,T); rs56316217(C,T); rs56121327(T,C); rs11880234(G,A); rs187636590(C,T); rs78004441(G,A); rs12981571(C,T); rs150421324(C,T); rs12975322(C,T); rs4804264(C,T); rs4804063(T,C); rs12974088(G,A); rs2086151(G,A); rs2086150(T,C); rs183041253(A,T); rs2086149(C,T); rs11666268(G,A); rs28438683(G,A); rs35101205(G,A); rs4804265(G,A); rs4804266(T,C); rs11881306(C,A); rs10422745(T,C); rs372176775(G,A); rs55782529(G,T); rs11883071(A,G); rs4804267(T,G); rs8109920(G,A); rs35427227(G,A); rs6603144(G,C); rs34071630(C,A); rs12460407(T,C); rs115429206(C,G); rs1038081(C,T); rs150870149(C,T); rs116463709(A,T); rs374913286(C,T); rs112174176(G,A); rs67706801(G,A); rs61300707(A,T); rs11881180(C,A); rs9676367(C,G); rs1564204(A,G); rs7250651(A,G); rs4527136(A,G); rs4527135(A,T); rs4536568(C,T); rs4637025(T,C); rs115670758(G,T); rs6603145(G,A); rs6603146(G,C); rs62126084(T,A); rs12104255(A,C); rs10419582(G,A); rs61729603(G,A); rs79793764(C,T); rs116450972(C,T); rs4804269(T,A); rs10422575(C,T); rs62126086(C,T); rs113429196(G,A); rs62126087(A,C); rs12986194(A,G); rs35988441(T,C); rs113312428(T,C); rs35025963(C,T); rs3813778(G,A); rs12327845(C,T); rs73009364(A,G); rs11260058(C,T); rs8112970(C,T); rs73505697(C,T); rs4804270(T,G); rs61375545(A,T); rs7255200(A,G); rs113031141(C,T); rs115248317(C,T); rs4275954(G,A); rs3813776(C,T); rs3813775(C,A); rs4804271(C,T); rs3813774(G,A); rs12974280(G,C); rs61744943(G,A); rs11673432(C,T); rs149726064(G,A); rs11671061(G,A); rs66928190(G,A); rs66925881(G,A); rs11671264(G,A); rs11666450(C,T); rs36124795(C,T); rs35202360(G,A); rs12975055(G,C); rs73505702(C,T); rs149219271(C,T); rs80029479(T,C); rs8112525(T,C); rs9749144(C,A); rs62123271(G,T); rs75077069(C,T); rs34100431(G,A); rs2061776(C,T); rs2061775(C,T); rs12980749(G,C); rs1531547(G,C); rs7246376(G,A); rs58173840(C,T); rs12460182(T,C); rs2336538(G,A); rs2336539(C,T); rs11672304(G,A); rs78742967(C,T); rs72993506(T,A); rs73922237(T,C); rs72993508(G,C); rs72993510(G,A); rs141368488(C,G); rs12162233(G,A); rs35525553(T,C); rs12162237(G,A); rs113989445(G,A); rs62123275(C,T); rs7256533(G,A); rs59201833(G,A); rs60558810(G,T); rs73922239(G,C); rs72993515(C,A); rs7260060(G,A); rs7507795(T,C); rs10412939(T,C); rs7252264(T,G); rs7252378(T,C); rs7252385(T,C); rs2004238(G,A); rs2004237(T,C); rs12459124(C,T); rs899208(T,C); rs2008549(A,G); rs899210(C,T); rs899211(C,T); rs62123279(G,A); rs56243829(C,T) |
| ccdsGene name | CCDS12196.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 84467 |
| EntrezGene Description | fibrillin 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FBN3:NM_032447:exon55:c.G6952A:p.A2318T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5569 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.000228 |
| ESP All MAF | 0.000386 |
| ESP Eur/Amr MAF | 0.000468 |
| ExAC AF | 0.0002778 |
ACTL9
| dbSNP name | rs4804079(G,T) |
| ccdsGene name | CCDS12207.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 284382 |
| EntrezGene Description | actin-like 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTL9:NM_178525:exon1:c.C679A:p.H227N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8TC94 |
| dbNSFP Uniprot ID | ACTL9_HUMAN |
| dbNSFP KGp1 AF | 0.584249084249 |
| dbNSFP KGp1 Afr AF | 0.603658536585 |
| dbNSFP KGp1 Amr AF | 0.538674033149 |
| dbNSFP KGp1 Asn AF | 0.674825174825 |
| dbNSFP KGp1 Eur AF | 0.525065963061 |
| dbSNP GMAF | 0.4164 |
| ESP Afr MAF | 0.448479 |
| ESP All MAF | 0.472013 |
| ESP Eur/Amr MAF | 0.48407 |
| ExAC AF | 0.549,8.141e-06 |
OR2Z1
| dbSNP name | rs56684959(G,C); rs28324(T,C) |
| cytoBand name | 19p13.2 |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04775 |
MBD3L1
| dbSNP name | rs2969292(T,C); rs2972588(C,T) |
| ccdsGene name | CCDS12209.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 85509 |
| EntrezGene Description | methyl-CpG binding domain protein 3-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MBD3L1:NM_145208:exon1:c.T447C:p.V149V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.09137 |
| ESP Afr MAF | 0.088743 |
| ESP All MAF | 0.076503 |
| ESP Eur/Amr MAF | 0.070233 |
| ExAC AF | 0.922 |
OR1M1
| dbSNP name | rs111953002(C,T); rs111340982(G,A); rs4804097(A,G) |
| ccdsGene name | CCDS32896.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 125963 |
| EntrezGene Description | olfactory receptor, family 1, subfamily M, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1M1:NM_001004456:exon1:c.C261T:p.T87T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0124 |
| ESP Afr MAF | 0.03064 |
| ESP All MAF | 0.011149 |
| ESP Eur/Amr MAF | 0.001163 |
| ExAC AF | 0.003537 |
OR7G2
| dbSNP name | rs4804400(T,C); rs4804401(A,C); rs12610094(A,G) |
| ccdsGene name | CCDS32897.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 390882 |
| EntrezGene Description | olfactory receptor, family 7, subfamily G, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7G2:NM_001005193:exon1:c.A957G:p.K319K, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3508 |
| ESP Afr MAF | 0.146164 |
| ESP All MAF | 0.281178 |
| ESP Eur/Amr MAF | 0.350349 |
| ExAC AF | 0.337 |
OR7G1
| dbSNP name | rs2195951(T,C); rs28599881(G,A); rs2217657(C,G); rs6511874(A,G) |
| ccdsGene name | CCDS32898.2 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 125962 |
| EntrezGene Description | olfactory receptor, family 7, subfamily G, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7G1:NM_001005192:exon1:c.A755G:p.Y252C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGA0 |
| dbNSFP Uniprot ID | OR7G1_HUMAN |
| dbNSFP KGp1 AF | 0.296245421245 |
| dbNSFP KGp1 Afr AF | 0.581300813008 |
| dbNSFP KGp1 Amr AF | 0.121546961326 |
| dbNSFP KGp1 Asn AF | 0.314685314685 |
| dbNSFP KGp1 Eur AF | 0.18073878628 |
| dbSNP GMAF | 0.2961 |
| ESP Afr MAF | 0.474807 |
| ESP All MAF | 0.29248 |
| ESP Eur/Amr MAF | 0.173256 |
| ExAC AF | 0.223 |
OR7G3
| dbSNP name | rs10424352(A,G); rs61730396(C,T); rs61751875(G,A); rs10407484(A,G); rs61745558(G,A); rs114119470(C,T); rs10414255(T,C); rs115923170(T,C) |
| ccdsGene name | CCDS32899.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 390883 |
| EntrezGene Description | olfactory receptor, family 7, subfamily G, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7G3:NM_001001958:exon1:c.T741C:p.V247V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4004 |
| ESP Afr MAF | 0.351112 |
| ESP All MAF | 0.425342 |
| ESP Eur/Amr MAF | 0.310814 |
| ExAC AF | 0.334 |
OR7D2
| dbSNP name | rs56246934(T,C); rs61733545(A,C); rs10423277(C,T); rs7246654(G,A); rs6511918(C,T) |
| ccdsGene name | CCDS32900.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 162998 |
| EntrezGene Description | olfactory receptor, family 7, subfamily D, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7D2:NM_175883:exon1:c.T207C:p.V69V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2328 |
| ESP Afr MAF | 0.111439 |
| ESP All MAF | 0.235276 |
| ESP Eur/Amr MAF | 0.298721 |
| ExAC AF | 0.262,8.132e-06 |
OR7D4
| dbSNP name | rs8109935(G,A); rs5020278(G,A); rs61729907(G,A) |
| ccdsGene name | CCDS32901.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 125958 |
| EntrezGene Description | olfactory receptor, family 7, subfamily D, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7D4:NM_001005191:exon1:c.C651T:p.S217S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1405 |
| ESP Afr MAF | 0.310486 |
| ESP All MAF | 0.157235 |
| ESP Eur/Amr MAF | 0.078721 |
| ExAC AF | 0.113 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, right ventricular;
Fibrofatty replacement of right ventricular myocardium;
Ventricular arrhythmia (sustained VT);
Syncope
SKIN, NAILS, HAIR:
[Skin];
Normal skin (no palmoplantar keratoderma);
[Hair];
Normal hair (no woolly hair)
MISCELLANEOUS:
Genetic heterogeneity;
Allelic to Naxos disease (601214)
MOLECULAR BASIS:
Caused by mutation in the junction plakoglobin gene (JUP, 173325.0002).
OMIM Title
*611538 OLFACTORY RECEPTOR, FAMILY 7, SUBFAMILY D, MEMBER 4; OR7D4
;;OLFACTORY RECEPTOR OR19-7;;
ODORANT RECEPTOR FAMILY SUBFAMILY D, MEMBER 4RT;;
OR19-B
OMIM Description
GENE FUNCTION
Keller et al. (2007) found that human odor receptor OR7D4 was
selectively activated in vitro by androstenone and the related odorous
steroid androstadienone, and that it did not respond to a panel of 64
other odors and 2 solvents. The chimpanzee OR7D4 ortholog differs from
the human OR7D4 reference sequence at 5 amino acid residues.
MAPPING
The human OR7D4 gene is situated in a cluster of 7 intact odorant
receptor genes on chromosome 19p13.2 (Keller et al., 2007).
MOLECULAR GENETICS
Keller et al. (2007) investigated whether genetic variation in human
odorant receptor genes partly accounts for variation in odor perception
between individuals by investigating the ligand specificity of OR7D4
variants in vitro and by testing whether variation in OR7D4 is
correlated with variation in the perception of androstenone and
androstadienone in human subjects. Two nonsynonymous polymorphisms in
complete linkage disequilibrium occurred at the highest frequency. These
led to 2 amino acid changes, R88W and T133M; Keller et al. (2007)
referred to the common allele of the receptor (the reference sequence)
as RT and to the other as WM. OR7D4 RT responded selectively to
androstenone and androstadienone but not to any other stimulus tested.
OR7D4 WM showed no response to any compound at tested concentrations.
Dose-response curves with RT and WM showed that the paired SNPs in the
WM variant, which affect amino acids in extracellular loop 2 and
intracellular loop 2, severely impaired function. Keller et al. (2007)
generated OR7D4 with each of the SNPs and found that OR7D4 R88W and
T133M retained an intermediate level of function, suggesting that both
residues are important for OR7D4 function. Human subjects with RT/WM or
WM/WM genotypes as a group were less sensitive to androstenone and
androstadienone and found both odors less unpleasant than the RT/RT
group. Androstenone is perceived by some individuals as offensive
('sweaty, urinous'), pleasant ('sweet, floral'), or odorless. Genotypic
variation in OR7D4 accounts for a significant proportion of the valence
(pleasantness or unpleasantness) and intensity variance in perception of
these steroidal odors. Keller et al. (2007) concluded that their results
demonstrated the first link between the function of a human odorant
receptor in vitro and odor perception.
OR7E24
| dbSNP name | rs12980833(C,T); rs2240927(C,T); rs2240928(C,T) |
| ccdsGene name | CCDS45955.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 26648 |
| EntrezGene Description | olfactory receptor, family 7, subfamily E, member 24 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7E24:NM_001079935:exon1:c.C578T:p.S193F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IFN5 |
| dbNSFP Uniprot ID | O7E24_HUMAN |
| dbNSFP KGp1 AF | 0.0714285714286 |
| dbNSFP KGp1 Afr AF | 0.0569105691057 |
| dbNSFP KGp1 Amr AF | 0.0359116022099 |
| dbNSFP KGp1 Asn AF | 0.113636363636 |
| dbNSFP KGp1 Eur AF | 0.065963060686 |
| dbSNP GMAF | 0.07163 |
| ESP Afr MAF | 0.04693 |
| ESP All MAF | 0.066378 |
| ESP Eur/Amr MAF | 0.075608 |
| ExAC AF | 0.074 |
COL5A3
| dbSNP name | rs10425011(A,G); rs13822(G,A); rs889129(T,A); rs10406152(T,C); rs2277969(C,T); rs2277968(C,T); rs114807947(G,A); rs28733115(T,G); rs59848316(C,T); rs184452849(C,T); rs78870141(C,T); rs16997011(T,A); rs746052(C,T); rs3745582(C,A); rs3786698(C,G); rs62104313(T,C); rs2059144(C,T); rs3815748(T,C); rs3815747(G,C); rs45476799(C,T); rs3815746(C,T); rs2277967(G,C); rs2277966(C,G); rs62638754(A,G); rs150954558(C,G); rs2277965(C,G); rs58525359(C,T); rs2287814(G,C); rs139060186(G,A); rs189808587(G,A); rs62104329(A,G); rs116615573(T,C); rs3745586(G,A); rs9749007(C,T); rs12972760(G,T); rs12973008(G,A); rs73003459(C,T); rs2287813(C,G); rs2287812(C,T); rs62638750(A,G); rs2287811(T,G); rs145390115(G,A); rs3815745(G,A); rs34006676(T,C); rs36094530(A,G); rs34115713(T,G); rs4621093(G,A); rs4410199(A,G); rs4293496(C,T); rs4299262(C,T); rs35465645(C,A); rs58911461(T,A); rs34316001(C,T); rs58973115(G,A); rs1971056(G,A); rs115373705(T,C); rs17209296(T,C); rs2287810(C,T); rs35571684(G,C); rs111596853(G,T); rs73502989(C,G); rs8109238(G,A); rs73003476(C,G); rs2161468(C,G); rs10425853(G,A); rs143805967(T,C); rs34613029(C,T); rs12610207(G,A); rs12609337(A,G); rs11879687(A,G); rs111360355(T,G); rs11878348(G,T); rs60587399(A,G); rs111618913(T,A); rs55752297(T,C); rs8109675(T,C); rs190995892(A,G); rs180805227(C,T); rs11672661(A,G); rs8110119(C,T); rs8103054(T,C); rs60051874(C,T); rs28592244(C,G); rs11670705(C,T); rs28539329(G,C); rs1862474(T,C); rs112317333(T,G); rs368043662(C,T); rs8113693(G,T); rs2287808(C,T); rs2287807(C,T); rs8101390(A,C); rs8100973(C,G); rs66985586(G,A); rs8101635(A,G); rs113718949(C,T); rs11085513(A,G); rs111945858(G,A); rs8107569(G,T); rs8107579(G,A); rs10417972(A,G); rs11879755(C,T); rs11883111(T,C); rs73005181(C,T); rs2287805(C,T); rs2287804(C,A); rs73005185(G,A); rs7259523(A,G); rs142013643(T,C); rs113907185(C,T); rs180840629(G,A); rs7248892(C,T); rs10411233(G,C); rs7251564(G,A); rs7252953(A,G); rs111742429(G,C); rs2010448(C,T); rs2010454(C,T); rs73005188(C,T); rs142090102(G,A); rs1974813(C,T); rs2277964(G,T); rs2277963(G,C); rs62638740(A,C); rs113672702(G,A); rs62104336(C,T); rs11669943(A,G); rs116330148(C,G); rs59632972(C,T); rs141030441(A,G); rs3745591(C,T); rs3745592(C,G); rs10415783(G,A); rs1559186(G,C); rs10411835(A,G); rs8104251(G,C); rs115580776(G,C); rs10409955(G,A); rs144857481(T,C); rs73007104(C,A); rs115047588(T,A); rs7254800(G,A); rs3745594(A,G); rs3745595(A,G); rs73007110(T,A); rs3745596(C,T); rs3745597(G,A); rs112064858(A,G); rs3745598(A,G); rs73007113(T,C); rs79612764(G,T); rs73504949(A,G); rs11085525(C,A); rs2878724(T,C); rs8102728(G,A); rs1946249(T,C); rs73007115(G,A); rs10415297(A,G); rs8108105(A,C); rs12980478(T,A); rs2287803(T,C); rs45553035(T,C); rs45525137(G,A); rs2287802(A,G); rs111376023(C,G); rs57490083(C,T); rs8100636(C,T); rs749260(C,A); rs749259(C,T); rs749261(C,G); rs61742765(C,G); rs142660839(A,G); rs73007122(C,T); rs12459949(A,G); rs4078706(T,C); rs8112026(T,C); rs113953093(G,A); rs889126(G,A); rs67479537(C,T); rs67560822(C,T); rs141626628(A,G); rs35143140(G,A); rs11085529(G,C); rs116608371(G,A); rs2303099(G,T); rs2303098(C,T); rs73007128(G,A); rs11085532(C,A); rs9789273(T,C); rs34480538(T,C); rs56391955(C,T); rs35637169(A,G); rs34196120(T,C); rs35678764(C,A); rs9749454(A,C); rs9797822(C,A); rs74892315(C,G); rs76280521(C,A); rs76715988(T,C); rs34729515(C,A) |
| ccdsGene name | CCDS12222.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 50509 |
| EntrezGene Description | collagen, type V, alpha 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL5A3:NM_015719:exon47:c.C3467T:p.P1156L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8744 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P25940 |
| dbNSFP Uniprot ID | CO5A3_HUMAN |
| dbNSFP KGp1 AF | 0.00274725274725 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.003404 |
| ESP All MAF | 0.00123 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0004473 |
OMIM Clinical Significance
Eyes:
Coloboma of iris, choroid and retina
Inheritance:
Autosomal dominant
OMIM Title
*120216 COLLAGEN, TYPE V, ALPHA-3; COL5A3
OMIM Description
Type V collagen is distributed in vertebrate tissues as a heterotrimer
of 3 different polypeptide chains, alpha-1 (COL5A1, 120215), alpha-2
(COL5A1, 120190), and alpha-3 (COL5A3), a heterotrimer of 2 copies of
alpha-1 and 1 copy of alpha-2, or a homotrimer of alpha-1 polypeptides.
For additional background information on collagen V, see 120215.
CLONING
By database searching, screening of cDNA libraries, and nested PCR,
Imamura et al. (2000) cloned full-length human and mouse COL5A3 cDNAs
encoding 1,745- and 1,739-amino acid proteins, respectively. COL5A3 is
most similar to the fibrillar procollagens COL5A1, COL11A1 (120280), and
COL11A2 (120290). Dot-blot analysis demonstrated particularly high
levels of COL5A3 expression in mammary gland, high levels in placenta,
uterus, fetal heart and lung, and moderately high levels in adult heart
and brain. Relatively high levels of COL5A1 and COL5A2 were found in
most of the same tissues, indicating the presence of heterotrimers of
the collagen V alpha chains in these tissues. An exception was adult
brain, in which the levels of COL5A3 were not matched by those of the
other two. Northern blot analysis detected particularly high expression
of an approximately 6.0-kb transcript in heart, placenta, and uterus.
Smaller bands of approximately 4.2 kb and 5.5 kb were found in brain and
lung, respectively. In situ hybridization of mouse embryos detected
Col5a3 expression primarily in the epimysial sheaths of developing
muscles and within nascent ligaments adjacent to forming bones and in
joints.
MAPPING
By radiation hybrid analysis, Imamura et al. (2000) mapped the COL5A3
gene to chromosome 19p13.2. By interspecific backcross analysis, they
mapped the mouse homolog to a region of syntenic homology on proximal
chromosome 9.
ILF3-AS1
| dbSNP name | rs143842626(T,C); rs76716359(C,G); rs4804514(G,T) |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 147727 |
| snpEff Gene Name | ILF3 |
| EntrezGene Description | ILF3 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
MIR6886
| dbSNP name | rs6413505(C,T); rs1003723(C,T) |
| ccdsGene name | CCDS12254.1 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 3949 |
| EntrezGene Symbol | LDLR |
| snpEff Gene Name | LDLR |
| EntrezGene Description | low density lipoprotein receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03765 |
| ESP Afr MAF | 0.140036 |
| ESP All MAF | 0.052437 |
| ESP Eur/Amr MAF | 0.007558 |
| ExAC AF | 0.019 |
SWSAP1
| dbSNP name | rs317926(A,G) |
| ccdsGene name | CCDS12259.1 |
| CosmicCodingMuts gene | C19orf39 |
| cytoBand name | 19p13.2 |
| EntrezGene GeneID | 126074 |
| snpEff Gene Name | C19orf39 |
| EntrezGene Description | SWIM-type zinc finger 7 associated protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SWSAP1:NM_175871:exon2:c.A512G:p.D171G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0317 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6NVH7 |
| dbNSFP Uniprot ID | CS039_HUMAN |
| dbNSFP KGp1 AF | 0.00869963369963 |
| dbNSFP KGp1 Afr AF | 0.0386178861789 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.044485 |
| ESP All MAF | 0.015301 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0044 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (in some patients)
HEAD AND NECK:
[Head];
Dolicocephaly (in some patients);
[Face];
High forehead;
Frontal bossing;
Malar flattening;
Micrognathia;
Retrognathia;
Prognathism (rare);
Facial asymmetry, mild (rare);
Deviation of maxilla, slight (rare);
Hypertrichosis of upper lip (rare);
[Ears];
Prominent earlobes (in some patients);
Bilateral sensorineural hearing loss (in some patients);
[Eyes];
High arched eyebrows;
Sparse eyebrows laterally (rare);
Downslanting palpebral fissures;
Epicanthal folds (in some patients);
Hypermetropia (in some patients);
Nystagmus, horizontal (rare);
[Nose];
Depressed nasal bridge;
Tubular nose (in some patients);
Deviation of nasal root (rare);
[Mouth];
High palate (in some patients)
ABDOMEN:
[Liver];
Elevated liver enzymes (in some patients);
[Pancreas];
Pancreatic atrophy (in some patients)
GENITOURINARY:
Genital tract abnormalities;
[Internal genitalia, male];
Cryptorchidism (rare);
[Internal genitalia, female];
Absent vagina;
Absent uterus;
Unicornuate uterus;
Uterus didelphis;
Ovarian cysts, multiple (rare);
[Kidneys];
Renal cysts;
Multicystic dysplastic kidneys (prenatal onset);
Hyperechogenic kidneys or renal cysts on prenatal ultrasound;
Bilateral ureteropelvic junction stenosis;
Hydronephrosis;
Pelvic dilation;
Urinary tract infections, recurrent;
Abnormal renal function;
Nonfunctioning kidney;
End-stage renal disease;
Unilateral renal agenesis;
Renal hypoplasia;
Normal kidneys (in some patients);
[Ureters];
Ureteral atresia;
[Bladder];
Hypoplastic bladder;
Thin bladder wall;
[Bladder];
Urethral stenosis (rare)
SKELETAL:
Joint mobility increased (in some patients);
Joint mobility decreased (rare);
[Spine];
Scoliosis (rare);
[Limbs];
Long slender arms and legs (rare);
Short arms and legs (rare);
[Hands];
Long thin hands (rare);
Long fingers (rare);
Short hands (rare);
[Feet];
Long thin feet (rare);
Long toes (rare);
Short feet (rare)
SKIN, NAILS, HAIR:
[Nails];
Onychodystrophy (rare);
Hyperconvex nails (rare);
Nail hypoplasia, mild (rare);
[Hair];
Sparse eyebrows laterally (rare);
Hypertrichosis of upper lip (rare)
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild to moderate;
Speech delay;
Autism or autistic features;
Seizures (in some patients);
Complex partial seizures (in some patients);
[Behavioral/psychiatric manifestations];
Schizophrenia (in some patients)
ENDOCRINE FEATURES:
Diabetes, maturity-onset, of the young (MODY)
MISCELLANEOUS:
Contiguous gene deletion syndrome
MOLECULAR BASIS:
Caused by deletion of 1.0-2.5Mb on chromosome 17q12
OMIM Title
*614536 SWIM-TYPE ZINC FINGER DOMAIN-CONTAINING PROTEIN 7-ASSOCIATED PROTEIN
1; SWSAP1
;;SWS1-ASSOCIATED PROTEIN 1;;
ZSWIM7-ASSOCIATED PROTEIN 1; ZSWIM7AP1;;
CHROMOSOME 19 OPEN READING FRAME 39; C19ORF39
OMIM Description
DESCRIPTION
Homologous recombination repair is a well-conserved cellular process for
the repair of DNA lesions that uses the intact sister chromatid as a
template. SWSAP1 forms a heterodimer with SWS1 (ZSWIM7; 614535) that
functions in homologous recombination repair (Liu et al., 2011).
CLONING
By PCR, Liu et al. (2011) cloned human SWSAP1. The deduced 229-amino
acid protein contains Walker A and Walker B nucleotide-binding boxes in
its N-terminal half, suggesting that it functions as an ATPase.
GENE FUNCTION
Liu et al. (2011) found that SWSAP1 affinity purified with SWS1 from
HEK293T cells. The heterodimeric SWS1-SWSAP1 complex had an apparent
molecular mass of about 40 kD. Expression of either epitope-tagged
SWSAP1 or SWS1 was enhanced upon coexpression. Conversely, knockdown of
either SWS1 or SWSAP1 expression via small interfering RNA led to a
dramatic decrease in the level of the other protein. SWSAP1 or the
SWSAP1-SWS1 complex hydrolyzed ATP in vitro, and activity was
significantly increased in the presence of single-stranded DNA compared
with double-stranded DNA. SWSAP1 or the SWS1-SWSAP1 complex, but not
SWS1 alone, bound DNA in an ATP-independent manner. Knockdown of SWS1 or
SWSAP1 increased cell sensitivity to the DNA damaging agent
methylmethane sulfonate (MMS) and reduced RAD51 (see 179617) foci
formation. Double knockdown of SWSAP1 and RAD51C (602774) further
increased MMS sensitivity and further reduced RAD51 foci formation
compared with SWSAP1 or RAD51C single-knockdown cells, indicating that
SWS1-SWSAP1 and RAD51 likely represent independent subpathways of
homologous recombination.
MAPPING
Hartz (2012) mapped the SWSAP1 gene to chromosome 19p13.2 based on an
alignment of the SWSAP1 sequence (GenBank GENBANK AK092438) with the
genomic sequence (GRCh37).
LOC284454
| dbSNP name | rs345638(T,C) |
| cytoBand name | 19p13.13 |
| EntrezGene GeneID | 284454 |
| snpEff Gene Name | ZSWIM4 |
| EntrezGene Description | uncharacterized LOC284454 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
MIR27A
| dbSNP name | rs895819(T,C) |
| cytoBand name | 19p13.13 |
| EntrezGene GeneID | 407018 |
| snpEff Gene Name | ZSWIM4 |
| EntrezGene Description | microRNA 27a |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3572 |
| ESP Afr MAF | 0.491071 |
| ESP All MAF | 0.377573 |
| ESP Eur/Amr MAF | 0.327889 |
| ExAC AF | 0.337 |
LOC113230
| dbSNP name | rs7258963(T,C) |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 113230 |
| snpEff Gene Name | AC022098.1 |
| EntrezGene Description | uncharacterized LOC113230 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | LOC113230:NM_001291291:exon2:c.T593C:p.V198A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.46978021978 |
| dbNSFP KGp1 Afr AF | 0.725609756098 |
| dbNSFP KGp1 Amr AF | 0.414364640884 |
| dbNSFP KGp1 Asn AF | 0.384615384615 |
| dbNSFP KGp1 Eur AF | 0.394459102902 |
| dbSNP GMAF | 0.4688 |
| ExAC AF | 0.357 |
OR7C1
| dbSNP name | rs73004304(C,G); rs77999564(C,T); rs16979912(A,G); rs10415312(C,T); rs10415562(C,T); rs17230134(T,C) |
| ccdsGene name | CCDS12317.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26664 |
| EntrezGene Description | olfactory receptor, family 7, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7C1:NM_198944:exon1:c.G739C:p.V247L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O76099 |
| dbNSFP Uniprot ID | OR7C1_HUMAN |
| dbNSFP KGp1 AF | 0.169413919414 |
| dbNSFP KGp1 Afr AF | 0.217479674797 |
| dbNSFP KGp1 Amr AF | 0.207182320442 |
| dbNSFP KGp1 Asn AF | 0.0314685314685 |
| dbNSFP KGp1 Eur AF | 0.224274406332 |
| dbSNP GMAF | 0.1694 |
| ESP Afr MAF | 0.24217 |
| ESP All MAF | 0.215285 |
| ESP Eur/Amr MAF | 0.201512 |
| ExAC AF | 0.18 |
OR7A5
| dbSNP name | rs60413369(G,A); rs62122652(C,G); rs56284724(C,T); rs2190686(T,C); rs61731995(T,C) |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26664 |
| EntrezGene Symbol | OR7C1 |
| EntrezGene Description | olfactory receptor, family 7, subfamily C, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03076 |
OR7A10
| dbSNP name | rs3752195(G,T); rs11880955(T,A); rs9305052(G,C); rs12972670(A,G); rs12985894(G,T) |
| ccdsGene name | CCDS32936.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 390892 |
| EntrezGene Description | olfactory receptor, family 7, subfamily A, member 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7A10:NM_001005190:exon1:c.C792A:p.A264A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2048 |
| ESP Afr MAF | 0.188153 |
| ESP All MAF | 0.214978 |
| ESP Eur/Amr MAF | 0.228721 |
| ExAC AF | 0.241 |
OR7A17
| dbSNP name | rs34590588(T,G); rs145127106(C,T); rs10401818(G,A); rs116182024(G,T) |
| ccdsGene name | CCDS12319.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26333 |
| EntrezGene Description | olfactory receptor, family 7, subfamily A, member 17 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7A17:NM_030901:exon1:c.A729C:p.S243S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.04362 |
| ESP Afr MAF | 0.113482 |
| ESP All MAF | 0.058127 |
| ESP Eur/Amr MAF | 0.029767 |
| ExAC AF | 0.038,8.132e-06,8.132e-06 |
OR7C2
| dbSNP name | rs11883178(G,A) |
| ccdsGene name | CCDS12320.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26658 |
| EntrezGene Description | olfactory receptor, family 7, subfamily C, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR7C2:NM_012377:exon1:c.G365A:p.R122H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0305 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O60412 |
| dbNSFP Uniprot ID | OR7C2_HUMAN |
| dbNSFP KGp1 AF | 0.0347985347985 |
| dbNSFP KGp1 Afr AF | 0.117886178862 |
| dbNSFP KGp1 Amr AF | 0.0193370165746 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0131926121372 |
| dbSNP GMAF | 0.03489 |
| ESP Afr MAF | 0.089424 |
| ESP All MAF | 0.03829 |
| ESP Eur/Amr MAF | 0.012093 |
| ExAC AF | 0.018 |
OR1I1
| dbSNP name | rs59166286(A,T); rs8105277(A,G); rs8104843(C,G); rs73008811(G,T); rs8108721(T,C); rs73008812(C,T); rs8105737(A,C); rs16980312(T,C); rs12975625(T,C); rs16980313(A,T) |
| ccdsGene name | CCDS32937.1 |
| CosmicCodingMuts gene | OR1I1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 126370 |
| EntrezGene Description | olfactory receptor, family 1, subfamily I, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR1I1:NM_001004713:exon1:c.A148T:p.I50F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O60431 |
| dbNSFP Uniprot ID | OR1I1_HUMAN |
| dbNSFP KGp1 AF | 0.160714285714 |
| dbNSFP KGp1 Afr AF | 0.0345528455285 |
| dbNSFP KGp1 Amr AF | 0.209944751381 |
| dbNSFP KGp1 Asn AF | 0.208041958042 |
| dbNSFP KGp1 Eur AF | 0.183377308707 |
| dbSNP GMAF | 0.1598 |
| ESP Afr MAF | 0.046074 |
| ESP All MAF | 0.127403 |
| ESP Eur/Amr MAF | 0.16907 |
| ExAC AF | 0.194 |
MIR6795
| dbSNP name | rs56061231(G,A) |
| ccdsGene name | CCDS12326.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 4854 |
| EntrezGene Symbol | NOTCH3 |
| snpEff Gene Name | NOTCH3 |
| EntrezGene Description | notch 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4642 |
| ESP Afr MAF | 0.283704 |
| ESP All MAF | 0.431339 |
| ESP Eur/Amr MAF | 0.285349 |
| ExAC AF | 0.642 |
OR10H2
| dbSNP name | rs2285955(G,A); rs4569397(T,A); rs2067083(C,T); rs11669315(G,A) |
| ccdsGene name | CCDS12333.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26538 |
| EntrezGene Description | olfactory receptor, family 10, subfamily H, member 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10H2:NM_013939:exon1:c.G114A:p.T38T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3609 |
| ESP Afr MAF | 0.27803 |
| ESP All MAF | 0.38994 |
| ESP Eur/Amr MAF | 0.447301 |
| ExAC AF | 0.406 |
OR10H3
| dbSNP name | rs1966357(A,C); rs11670007(G,A); rs11670326(C,T); rs2240228(G,A); rs2240229(G,A); rs16980824(C,T) |
| ccdsGene name | CCDS12334.1 |
| CosmicCodingMuts gene | OR10H3 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26532 |
| EntrezGene Description | olfactory receptor, family 10, subfamily H, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10H3:NM_013938:exon1:c.A21C:p.R7S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O60404 |
| dbNSFP Uniprot ID | O10H3_HUMAN |
| dbNSFP KGp1 AF | 0.64880952381 |
| dbNSFP KGp1 Afr AF | 0.815040650407 |
| dbNSFP KGp1 Amr AF | 0.646408839779 |
| dbNSFP KGp1 Asn AF | 0.353146853147 |
| dbNSFP KGp1 Eur AF | 0.765171503958 |
| dbSNP GMAF | 0.3517 |
| ESP Afr MAF | 0.196096 |
| ESP All MAF | 0.241658 |
| ESP Eur/Amr MAF | 0.265 |
| ExAC AF | 0.702,8.133e-06 |
OR10H5
| dbSNP name | rs61754873(G,T); rs4808381(T,C); rs3746151(C,T); rs67455341(C,A) |
| ccdsGene name | CCDS32940.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 284433 |
| EntrezGene Description | olfactory receptor, family 10, subfamily H, member 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10H5:NM_001004466:exon1:c.G431T:p.R144L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NGA6 |
| dbNSFP Uniprot ID | O10H5_HUMAN |
| dbNSFP KGp1 AF | 0.104853479853 |
| dbNSFP KGp1 Afr AF | 0.0914634146341 |
| dbNSFP KGp1 Amr AF | 0.129834254144 |
| dbNSFP KGp1 Asn AF | 0.0734265734266 |
| dbNSFP KGp1 Eur AF | 0.125329815303 |
| dbSNP GMAF | 0.1042 |
| ESP Afr MAF | 0.093509 |
| ESP All MAF | 0.120867 |
| ESP Eur/Amr MAF | 0.134884 |
| ExAC AF | 0.114,5.692e-05 |
OR10H1
| dbSNP name | rs28426969(C,T); rs61739573(G,A); rs4808383(C,G) |
| ccdsGene name | CCDS12335.1 |
| CosmicCodingMuts gene | OR10H1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 26539 |
| EntrezGene Description | olfactory receptor, family 10, subfamily H, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10H1:NM_013940:exon1:c.G468A:p.G156G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3205 |
| ESP Afr MAF | 0.495688 |
| ESP All MAF | 0.397893 |
| ESP Eur/Amr MAF | 0.347791 |
| ExAC AF | 0.33 |
OR10H4
| dbSNP name | rs16980821(C,T); rs16980994(C,A); rs16980822(A,G); rs11880184(A,G) |
| ccdsGene name | CCDS32941.1 |
| cytoBand name | 19p13.12 |
| EntrezGene GeneID | 126541 |
| EntrezGene Description | olfactory receptor, family 10, subfamily H, member 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR10H4:NM_001004465:exon1:c.C204T:p.S68S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2516 |
| ESP Afr MAF | 0.419655 |
| ESP All MAF | 0.299785 |
| ESP Eur/Amr MAF | 0.238372 |
| ExAC AF | 0.231 |
MRPL34
| dbSNP name | rs2288464(C,A); rs6903(C,T) |
| cytoBand name | 19p13.11 |
| EntrezGene GeneID | 64981 |
| snpEff Gene Name | ABHD8 |
| EntrezGene Description | mitochondrial ribosomal protein L34 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1501 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolongation of corrected QT interval (in some patients);
Long isoelectric ST segment (in some patients);
Late-onset T wave (in some patients);
Atrioventricular node block, 2:1, intermittent (in some patients);
Atrial fibrillation (in some patients)
MISCELLANEOUS:
Risk of sudden death with exertion
MOLECULAR BASIS:
Caused by mutation in the type IV voltage-gated sodium channel beta
subunit gene (SCN4B, 608256.0001)
OMIM Title
*611840 MITOCHONDRIAL RIBOSOMAL PROTEIN L34; MRPL34
OMIM Description
DESCRIPTION
Mitochondria have their own translation system for production of 13
proteins essential for oxidative phosphorylation. MRPL34 is 1 of more
than 70 protein components of mitochondrial ribosomes that are encoded
by the nuclear genome (Kenmochi et al., 2001).
CLONING
By searching databases using bovine Mrpl34 as query, followed by PCR of
human genomic DNA, Kenmochi et al. (2001) cloned MRPL34.
MAPPING
By radiation hybrid analysis and analysis of an integrated BAC-STS map,
Kenmochi et al. (2001) mapped the MRPL34 gene to chromosome 19p13.1.
TSSK6
| dbSNP name | rs7250893(A,G) |
| ccdsGene name | CCDS12403.1 |
| CosmicCodingMuts gene | TSSK6 |
| cytoBand name | 19p13.11 |
| EntrezGene GeneID | 83983 |
| EntrezGene Description | testis-specific serine kinase 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TSSK6:NM_032037:exon1:c.T690C:p.Y230Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4164 |
| ESP Afr MAF | 0.380855 |
| ESP All MAF | 0.44085 |
| ESP Eur/Amr MAF | 0.349522 |
| ExAC AF | 0.401 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Optic nerve atrophy;
Slow decrease in visual acuity;
Dyschromatopsia, blue-yellow;
Central scotoma
MISCELLANEOUS:
Onset in 1st to 3rd decade of life
OMIM Title
*610712 TESTIS-SPECIFIC SERINE/THREONINE KINASE 6; TSSK6
;;SMALL SERINE/THREONINE PROTEIN KINASE; SSTK;;
TSSK4
OMIM Description
DESCRIPTION
TSSK6 is a serine/threonine protein kinase that is required for
postmeiotic chromatin remodeling and male fertility (Spiridonov et al.,
2005).
CLONING
By searching databases using a protein kinase catalytic domain as query,
Spiridonov et al. (2005) identified TSSK6, which they called SSTK. EST
analysis suggested the existence of 3 TSSK6 splice variants that use 2
different polyadenylation sites. The deduced 273-amino acid TSSK6
protein has a calculated molecular mass of 30.3 kD and consists almost
entirely of the N and C lobes of a protein kinase domain. TSSK6
possesses several essential protein kinase features, including a
conserved active site, ATP-binding region, and potential activation loop
phosphorylation motif. Northern blot analysis detected high expression
of a 1.5-kb transcript in adult testis, with lower expression in colon,
small intestine, ovary, prostate, thymus, spleen, and peripheral blood
leukocytes. A 3-kb transcript was expressed in spinal cord and medulla
oblongata. RT-PCR analysis confirmed that highest TSSK6 expression was
in testis.
GENE FUNCTION
Using wildtype TSSK6 and TSSK6 mutants expressed and immunopurified from
293T cells for in vitro protein kinase assays, Spiridonov et al. (2005)
found that TSSK6 had protein kinase activity against myelin basic
protein (MBP; 159430), as well as autophosphorylation activity. Lys41
and asp135 of TSSK6 were essential for MBP phosphorylation. TSSK6
phosphorylation of MBP occurred almost entirely on serines, and further
studies using synthetic peptides showed that TSSK6 displayed highest
phosphorylation activity on peptides containing a common RxxSxxR
sequence. Coimmunoprecipitation analysis of TSSK6 expressed in 293T
cells showed that TSSK6 bound heat-shock proteins HSP90-1-beta (HSPCB;
140572), HSC70 (HSPA8; 600816), and HSP70-1 (HSPA1A; 140550). In vitro
phosphorylation studies showed that TSSK6 phosphorylated histones H1
(see 142711), H2A (see 613499), H2AX (H2AFX; 601772), and H3 (see
602810), but not H2B (see 602803), H4 (see 602822), or TP1 (TNP1;
190231).
GENE STRUCTURE
Spiridonov et al. (2005) determined that the TSSK6 gene contains 2
exons.
MAPPING
By genomic sequence analysis, Spiridonov et al. (2005) mapped the TSSK6
gene to chromosome 19. They mapped the mouse Tssk6 gene to chromosome 8.
Hao et al. (2004) reported that the TSSK6 gene, which they called TSSK4,
maps to chromosome 19p13.11, and that the mouse Tssk6 gene maps to
chromosome 8B3.3.
ANIMAL MODEL
Spiridonov et al. (2005) found that Tssk6-null female mice were fertile,
but Tssk6-null males were sterile and had reduced sperm counts,
decreased sperm motility, and a dramatic increase in the percentage of
sperm with abnormal morphology. Beginning at stage 10, Tssk6-null
elongating spermatids displayed abnormal sperm head development
characterized by increased space between the nuclear envelope and
condensing nucleus of the posterior head. Stage-12 Tssk6-null elongating
spermatids showed expansion of the perinuclear and subacrosomal space
and accumulation of electron dense matter between the membranes of the
head and nucleus. Spiridonov et al. (2005) concluded that Tssk6-null
spermatozoa have impaired DNA condensation.
LINC01233
| dbSNP name | rs2304139(A,C); rs2915918(C,G) |
| cytoBand name | 19p12 |
| EntrezGene GeneID | 100128139 |
| EntrezGene Symbol | LOC100128139 |
| EntrezGene Description | uncharacterized LOC100128139 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.124 |
LOC100996349
| dbSNP name | rs2306964(A,G); rs62621413(C,T); rs2306965(A,T) |
| cytoBand name | 19p12 |
| EntrezGene GeneID | 100996349 |
| EntrezGene Description | testis expressed 264 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.343 |
HAVCR1P1
| dbSNP name | rs180847354(G,A); rs61745938(T,C); rs10500223(A,G); rs919812(C,A); rs919813(A,G) |
| cytoBand name | 19p12 |
| EntrezGene GeneID | 100101266 |
| EntrezGene Description | hepatitis A virus cellular receptor 1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
LINC00906
| dbSNP name | rs111497063(A,G); rs116548670(C,T); rs150220105(C,A); rs113922833(T,C); rs60457694(A,G); rs111750185(G,A); rs113670426(A,G); rs111321343(A,G); rs12460607(A,C); rs113311560(G,A); rs112117614(G,A) |
| cytoBand name | 19q12 |
| EntrezGene GeneID | 148145 |
| EntrezGene Description | long intergenic non-protein coding RNA 906 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.003673 |
RGS9BP
| dbSNP name | rs259292(G,A); rs7251557(C,T); rs259293(C,T); rs10411566(G,A); rs10413184(C,T); rs259294(A,C); rs10417773(G,T) |
| cytoBand name | 19q13.11 |
| EntrezGene GeneID | 390916 |
| EntrezGene Symbol | NUDT19 |
| snpEff Gene Name | ANKRD27 |
| EntrezGene Description | nudix (nucleoside diphosphate linked moiety X)-type motif 19 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.461 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive, postnatal, due to gastroesophageal reflux (in some
patients)
HEAD AND NECK:
[Head];
Large anterior fontanel;
Delayed closure anterior fontanel;
Macrocephaly;
[Face];
Frontal bossing;
Forehead hyperpigmentation;
Prominent supraorbital ridge;
Midface hypoplasia;
Long, smooth philtrum;
[Eyes];
Hypertelorism;
Y-shaped sutural cataract (in some patients);
Punctate lenticular opacities;
Esotropia (in some patients);
Optic atrophy, bilateral (in some patients);
Double-ring sign of lens (in some patients);
[Nose];
Broad nasal bridge;
Anteverted nares;
[Mouth];
Wide mouth;
Thin upper lip;
Bifid uvula (in some patients);
Cleft palate (in some patients);
[Teeth];
Delayed eruption;
Dental caries (secondary teeth);
Hypoplastic teeth (secondary teeth)
CARDIOVASCULAR:
[Cardiac];
Valvular pulmonic stenosis (in some patients)
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Joint laxity;
Osteopenia (in some patients);
[Skull];
Ossification defects;
[Spine];
Scoliosis;
Posterior wedging of vertebral bodies;
[Pelvis];
High, narrow iliac wings;
[Feet];
Flat feet
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation (forehead);
Capillary hemangioma (forehead);
[Hair];
Coarse hair;
Brittle hair;
Sparse hair
MOLECULAR BASIS:
Caused by mutation in the human homolog A of the S. cerevisiae SEC23
gene (SEC23A, 610511.0001)
OMIM Title
*607814 REGULATOR OF G PROTEIN SIGNALING 9-BINDING PROTEIN; RGS9BP
;;RGS9-BINDING PROTEIN;;
RGS9 ANCHOR PROTEIN; R9AP
OMIM Description
CLONING
Hu and Wensel (2002) cloned bovine R9ap from a retina cDNA library and
identified the homologous human sequence by database analysis. The
deduced R9AP protein contains 235 amino acids and has a C-terminal
transmembrane domain. Northern blot analysis of several bovine and mouse
tissues detected R9ap expression only in retina. By fractionation and
Western blot analysis of bovine rod outer segment (ROS) membranes, Hu
and Wensel (2002) determined that R9ap associates with Rgs9 (604067) in
the ROS. Immunohistochemical analysis of mouse retina showed R9ap
staining in the ROS and minor staining in the outer plexiform layer.
GENE FUNCTION
By coimmunoprecipitation analysis, Hu and Wensel (2002) determined that
bovine R9ap associated with a heterotetrameric complex containing Rgs9,
Gnb5 (604447), and Gnat (see 139330) in detergent-solubilized ROS
membranes. R9ap interacted specifically with the N-terminal domain of
Rgs9. Hu and Wensel (2002) concluded that the C-terminal transmembrane
domain of R9ap functions as the membrane anchor for the other largely
soluble interacting partners.
Hu et al. (2003) determined that the formation of a membrane-bound
complex with bovine R9ap increased the GTPase-accelerating activity of
Rgs9 by a factor of 4.
MAPPING
By genomic sequence analysis, Hu and Wensel (2002) mapped the R9AP gene
to chromosome 19q13.11.
MOLECULAR GENETICS
Nishiguchi et al. (2004) identified a Guatemalan patient with bradyopsia
(608415) who was homozygous for a frameshift mutation, insertion of a C
at cDNA nucleotide 194 within codon 65 (R65) of the R9AP protein
(607814.0001).
CEBPA
| dbSNP name | rs12691(G,A); rs707656(G,C); rs1049969(T,C) |
| cytoBand name | 19q13.11 |
| EntrezGene GeneID | 1050 |
| EntrezGene Description | CCAAT/enhancer binding protein (C/EBP), alpha |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1442 |
OMIM Clinical Significance
Vascular:
Celiac artery compression;
Aberrant celiac artery
Abdomen:
Abdominal pain
Inheritance:
Autosomal dominant
OMIM Title
*116897 CCAAT/ENHANCER-BINDING PROTEIN, ALPHA; CEBPA
;;C/EBP-ALPHA;;
CEBP
OMIM Description
CLONING
The CCAAT/enhancer-binding protein bears sequence homology and
functional similarities to liver activator protein (LAP, or CEBPB;
189965) (Descombes et al., 1990). See Landschulz et al. (1989).
Using rat Cebp-alpha to screen a human liver cDNA library, followed by
screening a human placenta genomic library, Swart et al. (1997) cloned
full-length CEBP-alpha. The deduced 357-amino acid protein has an
N-terminal transactivation domain and a C-terminal DNA-binding and
dimerization domain. Northern blot analysis detected high expression of
a 2.7-kb CEBP-alpha transcript in human placenta, liver, and spleen.
Lower expression was detected in colon, smooth muscle, lung, and kidney
medulla, and no expression was detected in kidney cortex. CEBP-alpha was
also expressed in normal and psoriatic human skin, in cultured human
keratinocytes, and in rat aorta and liver. Immunohistochemical analysis
detected CEBP-alpha in nuclei of epidermal keratinocytes from normal
human skin and lesional psoriatic skin. Intense staining was detected in
suprabasal cells, hair follicle keratinocytes, and glandular sebocytes,
but not in cells of the inflammatory infiltrate or capillaries.
GENE STRUCTURE
Swart et al. (1997) determined that the CEBPA gene is intronless.
MAPPING
By means of somatic cell hybrids segregating either human or rat
chromosomes, Szpirer et al. (1992) mapped the CEBP gene to human
chromosome 19 and rat chromosome 1. These results provided further
evidence for conservation of synteny on these chromosomes (and on mouse
chromosome 7). Using human/hamster somatic cell hybrids containing
restricted fragments of human chromosome 19, Hendricks-Taylor et al.
(1992) mapped the CEBPA gene to chromosome 19q13.1, between the GPI
(172400) and TGFB1 (190180) genes. This position was confirmed by
fluorescence in situ hybridization. Birkenmeier et al. (1989) mapped the
Cebpa gene to mouse chromosome 7.
GENE FUNCTION
Miller et al. (1996) characterized the promoter of the human gene
encoding leptin (164160), a signaling factor expressed in adipose tissue
with an important role in body weight homeostasis. They found that CEBPA
modulates leptin expression and suggested a function for CEBPA in
treatment of human obesity.
Wang et al. (2001) found that CEBPA directly interacts with CDK2
(116953) and CDK4 (123829) and arrests cell proliferation by inhibiting
these kinases. A region between amino acids 175 and 187 of CEBPA was
determined to be responsible for direct inhibition of cyclin-dependent
kinases and caused growth arrest in cultured cells. CEBPA inhibited CDK2
activity by blocking the association of CDK2 with cyclins. The
activities of Cdk4 and Cdk2 were increased in mouse Cebpa knockout
livers, leading to increased proliferation.
The myeloid transcription factor CEBPA is crucial for normal
granulopoiesis, and dominant-negative mutations of the CEBPA gene are
found in a significant proportion of malignant cells from patients with
myeloblastic subtypes (M1 and M2) of acute myeloid leukemia (AML;
601626). Pabst et al. (2001) demonstrated that the AML1 (RUNX1;
151385)-ETO (CBFA2T1; 133435) fusion protein suppressed CEBPA
expression. Helbling et al. (2004) found that the leukemic
AML1-MDS1-EAI1 (AME; see 151385) fusion protein suppressed CEBPA
protein. In contrast to the AML1-ETO fusion, AME failed to suppress
CEBPA mRNA expression. Helbling et al. (2004) found that a putative
inhibitor of CEBPA translation, calreticulin (CRT; 109091), was strongly
activated after induction of AME in a cell line experimental system
(14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition
of CRT by small interfering RNA restored CEBPA levels. These results
identified CEBPA as a key target of the leukemic fusion protein AME and
suggested that modulation of CEBPA by CRT may represent a mechanism
involved in the differentiation block in AME leukemias.
Menard et al. (2002) showed that Cebpa was expressed in mouse cortical
progenitor cells and could induce expression of a reporter gene
containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a
neuron-specific gene.
Skokowa et al. (2006) found significantly decreased or absent LEF1
(153245) expression in arrested promyelocytes from patients with
congenital neutropenia (see 202700). Competitive binding and chromatin
immunoprecipitation (ChIP) assays showed that LEF1 directly bound to and
regulated CEBPA, suggesting that LEF1-dependent downregulation of CEBPA
in congenital neutropenia leads to a maturation block in promyelocytes
similar to that seen in CEBPA dominant-negative AML.
By peptide analysis of nuclear proteins that interacted with CEBPA,
Bararia et al. (2008) identified TIP60 (KAT5; 601409) as a CEBPA binding
partner. The interaction was confirmed by coprecipitation analysis and
protein pull-down assays. TIP60 enhanced the ability of CEBPA to
transactivate a TK (TK1; 188300) promoter containing 2 CCAAT sites, and
the histone acetyltransferase activity of TIP60 was required for its
cooperativity with CEBPA. Domain analysis revealed that TIP60 interacted
with the DNA-binding and transactivation domains of CEBPA.
Immunoprecipitation analysis showed that TIP60 was recruited to the
promoters of CEBPA and GCSFR (CSF3R; 138971) following
beta-estradiol-induced differentiation of K562 myelogenous leukemia
cells, which was concomitant with histone acetylation at the CEBPA and
GCSFR promoters.
Reddy et al. (2009) showed that microRNA-661 (MIR661; 613716)
downregulated expression of MTA1 (603526), a gene that is upregulated in
several cancers. They identified putative CEBP-alpha-binding sites in
the promoter region of the MIR661 gene. Reporter gene assays showed that
CEBP-alpha upregulated MIR661 expression in transfected HeLa and MDA-231
breast cancer cells. Expression of CEBP-alpha and MIR661 was inversely
proportional to that of MTA1 in breast cancer cell lines, and the level
of MTA1 protein was progressively upregulated with increasing metastatic
potential. Overexpression of MIR661 in MDA-231 breast cancer cells
inhibited cell motility, invasiveness, and anchorage-independent growth,
and it reduced their ability to form tumors in a xenograft model. Reddy
et al. (2009) concluded that CEBP-alpha downregulates MTA1 expression
and cancer cell growth by upregulating expression of MIR661.
Di Ruscio et al. (2013) presented data demonstrating that active
transcription regulates levels of genomic methylation. They identified a
novel nuclear nonpolyadenylated noncoding RNA (ncRNA) arising from the
CEBPA gene locus that is critical in regulating the local DNA
methylation profile. They termed this ncRNA 'extracoding CEBPA'
(ecCEBPA) because it encompasses the entire mRNA sequence in the
same-sense orientation. ecCEBPA binds to DNMT1 (126375) and prevents
CEBPA gene locus methylation. Deep sequencing of transcripts associated
with DNMT1 combined with genome-scale methylation and expression
profiling extended the generality of this finding to numerous gene loci.
Di Ruscio et al. (2013) concluded that these results delineated the
nature of DNMT1-RNA interactions and suggested strategies for
gene-selective demethylation of therapeutic targets in human diseases.
In mouse primary B cells, Di Stefano et al. (2014) found that transient
CEBPA expression followed by Oct4 (164177), Sox2 (184429), Klf4
(602253), and Myc (190080) (collectively known as OSKM) activation
induces a 100-fold increase in induced pluripotent stem (iPS) cell
reprogramming efficiency, involving 95% of the population. During this
conversion, pluripotency and epithelial-mesenchymal transition genes
become markedly upregulated, and 60% of the cells express Oct4 within 2
days. CEBPA acts as a pathbreaker as it transiently makes the chromatin
of pluripotency genes more accessible to DNaseI (125505). CEBPA also
induces the expression of the dioxygenase Tet2 (612839) and promotes its
translocation to the nucleus where it binds to regulatory regions of
pluripotency genes that become demethylated after OSKM induction. In
line with these findings, overexpression of Tet2 enhances OSKM-induced
B-cell reprogramming. Because the enzyme is also required for efficient
CEBPA-induced immune cell conversion, the data of Di Stefano et al.
(2014) indicated that TET2 provides a mechanistic link between iPS cell
reprogramming and B-cell transdifferentiation.
MOLECULAR GENETICS
In affected members of a family with acute myeloid leukemia (601626),
Smith et al. (2004) identified a germline 1-bp deletion (212delC) in the
CEBPA gene, resulting in the presence of 5 cytosine residues in a region
where 6 cytosine residues are present in the wildtype sequence. Overt
leukemia developed in the father at age 10 years, in the first-born son
at age 30 years, and in the last-born daughter at age 18 years.
- Somatic Mutations
Pabst et al. (2001) noted that in the hematopoietic system, CEBPA is
exclusively expressed in myelomonocytic cells. It is specifically
upregulated during granulocytic differentiation. No mature granulocytes
are observed in Cebpa-mutant mice, whereas all the other blood cell
types are present in normal proportions. In acute myeloid leukemia (AML;
601626), the most prominent abnormality is a block in differentiation of
granulocytic blasts. With this background information, Pabst et al.
(2001) studied samples from AML patients and demonstrated that CEBPA is
mutated in 16% of AML-M2 patients that lack the 8;21 translocation (ETO,
133435; RUNX1, 151385). They found that 5 mutations in the N terminus
truncated the full-length protein, but did not affect the 30-kD protein
initiated further downstream. The mutated proteins blocked wildtype
C/EBP-alpha DNA binding and transactivation of granulocyte target genes
in a dominant-negative manner, and failed to induce the granulocytic
differentiation. This was the first report of CEBPA mutations in human
neoplasia. Pabst et al. (2001) detected 5 deletions, 2 insertions, and 4
point mutations in the CEBPA gene (see, e.g., 116897.0001-116897.0003).
All deletions caused a shift into the same alternative reading frame, as
the number of missing basepairs was (3n+1). The mean age at diagnosis of
the patients with CEBPA mutations was 66 years. CEBPA mutations were
found in 7.3% of AML patients.
Snaddon et al. (2003) stated that the t(8;21) translocation is found in
10 to 15% of cases of AML, particularly those of the M2 subtype, where
it accounts for 40% of cases. Using a PCR-SSCP and sequencing approach,
they screened for CEBPA mutations in 99 patients with AML type M1 or M2.
They identified 9 somatic CEBPA mutations in 8 patients. All of the
mutations were clustered toward the C terminus of the protein. Two
patients carried biallelic mutations: one was homozygous for a 57-bp
insertion at nucleotide 1137 (116897.0004) and the other was compound
heterozygous for a 27-bp insertion at nucleotide 1096 (116897.0005) and
a 4-bp insertion (GGCC) at nucleotide 363 (116897.0006).
EVOLUTION
To explore the evolution of gene regulation, Schmidt et al. (2010) used
chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq)
to determine experimentally the genomewide occupancy of 2 transcription
factors, CEBPA and HNF4A (600281), in the livers of 5 vertebrates: Homo
sapiens, Mus musculus, Canis familiaris, Monodelphis domesticus
(short-tailed opossum), and Gallus gallus. Although each transcription
factor displayed highly conserved DNA binding preferences, most binding
was species-specific, and aligned binding events present in all 5
species were rare. Regions near genes with expression levels that are
dependent on a transcription factor were often bound by the
transcription factor in multiple species yet showed no enhanced DNA
sequence constraint. Binding divergence between species can be largely
explained by sequence changes to the bound motifs. Among the binding
events lost in one lineage, only half are recovered by another binding
event within 10 kb. Schmidt et al. (2010) concluded that their results
revealed large interspecies differences in transcriptional regulation
and provided insight into regulatory evolution.
NOMENCLATURE
According to the nomenclature proposed by Cao et al. (1991), the
CCAAT/enhancer-binding protein is C/EBP-alpha and NF-IL6 (LAP) is
C/EBP-beta, with the corresponding genes being CEBPA and CEBPB (189965).
CEBPB was formerly symbolized TCF5.
ANIMAL MODEL
Wang et al. (1995) found that mice homozygous for the targeted deletion
of the Cebpa gene did not store hepatic glycogen and died from
hypoglycemia within 8 hours after birth. In these mutant mice, the
amounts of glycogen synthase (138571) mRNA were 50 to 70% of normal and
the transcriptional induction of the genes for 2 gluconeogenic enzymes,
phosphoenolpyruvate carboxykinase (261680) and glucose-6-phosphatase
(613742), was delayed. The hepatocytes and adipocytes of the mutant mice
failed to accumulate lipid, and the expression of the gene for
uncoupling protein (113730), the defining marker of brown adipose
tissue, was reduced. The findings demonstrated that C/EBP-alpha is
critical for the establishment and maintenance of energy homeostasis in
neonates.
Flodby et al. (1996) made transgenic knockout mice in which the CEBPA
gene was selectively disrupted. The homozygous mutant Cebpa -/- mice
died, usually within the first 20 hours after birth and had defects in
the control of hepatic growth and lung development. Histologic analysis
revealed that these animals had severely disturbed liver architecture,
with acinar formation, in a pattern suggestive of either regenerating
liver or hepatocellular carcinoma. Pulmonary histology showed
hyperproliferation of type II pneumocytes and disturbed alveolar
architecture. Molecular analysis showed that accumulation of glycogen
and lipids in the liver and adipose tissue is impaired and that the
mutant animals are severely hypoglycemic. The authors found by Northern
blot analysis that levels of c-myc and c-jun RNAs are specifically
induced by several fold in the livers of these animals indicating an
active proliferative state. They found by immunohistology that
cyclin-stained cells are present in the liver of Cebpa -/- mice at a 5
to 10 times higher frequency than normal, also indicating abnormally
active proliferation. Flodby et al. (1996) suggested that CEBPA may have
an important role in the acquisition and maintenance of terminal
differentiation in hepatocytes.
Mice deficient in Cebpa have defective development of adipose tissue. Wu
et al. (1999) used fibroblasts from Cebpa -/- mice in combination with
retroviral vectors expressing Cebpa and peroxisome
proliferator-activated receptor-gamma (PPARG; 601487) to determine the
precise role of CEBPA in adipogenesis. The authors found that Cebpa -/-
fibroblasts underwent adipose differentiation through expression and
activation of Pparg. Cebpa-deficient adipocytes accumulated less lipid
and did not induce endogenous Pparg, indicating that cross-regulation
between CEBPA and PPARG is important in maintaining the differentiated
state. The cells also showed a complete absence of insulin (INS;
176730)-stimulated glucose transport, secondary to reduced gene
expression and tyrosine phosphorylation for the Ins receptor (147670)
and Ins receptor substrate-1 (147545). Wu et al. (1999) concluded that
CEBPA has multiple roles in adipogenesis and that cross-regulation
between PPARG and CEBPA is a key component of the transcriptional
control of this cell lineage.
CEBPA-AS1
| dbSNP name | rs34508287(G,C); rs16967952(G,A); rs41344151(G,A) |
| cytoBand name | 19q13.11 |
| EntrezGene GeneID | 80054 |
| snpEff Gene Name | CEBPA |
| EntrezGene Description | CEBPA antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.14 |
SCGB1B2P
| dbSNP name | rs140185735(G,A) |
| cytoBand name | 19q13.11 |
| EntrezGene GeneID | 643719 |
| EntrezGene Description | secretoglobin, family 1B, member 2, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007346 |
ZNF30
| dbSNP name | rs2651125(G,A); rs56330896(G,C); rs114521355(G,A); rs8103894(A,C); rs2545998(A,G); rs2651124(G,A); rs2545999(A,G); rs79484506(T,C); rs2546000(A,G); rs2546001(A,G); rs2651123(A,G); rs2651122(G,A); rs115767301(A,T); rs145488198(C,T); rs11880361(T,C); rs73036321(G,C); rs116601216(C,G); rs10422961(C,T); rs8112400(A,C); rs8101694(T,G); rs62122083(T,G); rs10406154(A,G); rs74413818(C,T); rs78972015(T,C); rs2859486(C,A); rs2546002(C,T); rs2651101(G,C); rs2651100(T,C); rs2651099(G,A); rs7253119(A,G); rs113009317(A,G); rs10420614(A,G); rs112849393(A,T); rs111315653(A,G); rs2546003(G,A); rs115801290(C,T); rs2431456(T,G); rs2431457(T,C); rs10414362(T,C); rs2546004(A,G); rs56012968(A,C); rs77348642(A,G); rs73593656(G,T); rs2546005(T,G); rs2651104(C,T); rs6510453(A,G); rs2546006(T,C); rs2546007(A,G); rs2546008(T,C); rs34802915(C,T); rs4805099(A,G); rs8111770(T,C); rs111920156(G,A); rs2546011(T,G); rs2546012(G,A); rs8100832(G,A); rs10411042(T,C); rs2546013(G,A); rs2546014(T,C); rs115643512(C,T); rs73929235(G,A); rs112158580(T,C); rs35376615(G,A); rs73593668(G,A); rs2546016(G,A); rs2546017(T,C); rs10422037(A,G); rs10421478(C,T); rs76732057(G,T); rs1811(A,G); rs62122088(A,G); rs2651109(T,C); rs142299823(G,T); rs61181887(C,T); rs1345658(G,A); rs765746(A,G); rs367569512(C,T); rs3761066(C,T); rs1053213(G,A); rs1053216(G,A) |
| ccdsGene name | CCDS46044.1 |
| cytoBand name | 19q13.11 |
| EntrezGene GeneID | 90075 |
| EntrezGene Description | zinc finger protein 30 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF30:NM_194325:exon5:c.C1432T:p.H478Y,ZNF30:NM_001099437:exon5:c.C1435T:p.H479Y,ZNF30:NM_001099438:exon5:c.C1435T:p.H479Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5252 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P17039 |
| dbNSFP Uniprot ID | ZNF30_HUMAN |
MIR6887
| dbSNP name | rs1688017(G,A) |
| ccdsGene name | CCDS12442.1 |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 5349 |
| EntrezGene Symbol | FXYD3 |
| snpEff Gene Name | FXYD3 |
| EntrezGene Description | FXYD domain containing ion transport regulator 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3035 |
| ESP Afr MAF | 0.316841 |
| ESP All MAF | 0.343226 |
| ESP Eur/Amr MAF | 0.356744 |
| ExAC AF | 0.36 |
FFAR2
| dbSNP name | rs61744093(G,A); rs113286222(C,T); rs55695970(G,A) |
| ccdsGene name | CCDS12461.1 |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 2867 |
| EntrezGene Description | free fatty acid receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FFAR2:NM_005306:exon1:c.G303A:p.A101A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01423 |
| ESP Afr MAF | 0.009986 |
| ESP All MAF | 0.006305 |
| ESP Eur/Amr MAF | 0.004419 |
| ExAC AF | 7.636e-03,4.879e-05 |
ETV2
| dbSNP name | rs2285419(G,A) |
| ccdsGene name | CCDS32995.2 |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 2116 |
| EntrezGene Description | ets variant 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ETV2:NM_014209:exon5:c.G268A:p.D90N, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0009 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A6NFN5 |
| dbNSFP KGp1 AF | 0.129578754579 |
| dbNSFP KGp1 Afr AF | 0.146341463415 |
| dbNSFP KGp1 Amr AF | 0.140883977901 |
| dbNSFP KGp1 Asn AF | 0.143356643357 |
| dbNSFP KGp1 Eur AF | 0.10290237467 |
| dbSNP GMAF | 0.1299 |
| ESP Afr MAF | 0.096987 |
| ESP All MAF | 0.083699 |
| ESP Eur/Amr MAF | 0.077059 |
| ExAC AF | 0.105 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Saccadic pursuit (rare)
SKELETAL:
[Spine];
Scoliosis;
[Feet];
Pes cavus
NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Difficulty walking;
Loss of independent ambulation approximately 30 years after onset;
Pyramidal signs;
Hyperreflexia;
Mild upper limb involvement;
Extensor plantar responses;
[Peripheral nervous system];
Distal sensory impairment in lower limbs;
Axonal neuropathy (in some patients)
MISCELLANEOUS:
Onset in childhood or adolescence (range 6 to 15 years);
Slow progression
MOLECULAR BASIS:
Caused by mutation in the DDHD domain-containing protein 1 gene (DDHD1,
614603.0001)
OMIM Title
*609358 ETS VARIANT GENE 2; ETV2
;;ETS-RELATED PROTEIN 71, MOUSE, HOMOLOG OF; ER71; ETSRP71
OMIM Description
CLONING
Brown and McKnight (1992) cloned mouse Etv2, which they designated Er71.
The deduced protein contains 335 amino acids and may represent a partial
sequence. Northern blot analysis of several mouse tissues detected a
1.7-kb transcript in adult testis and a 1.2-kb transcript in whole
day-8.5 mouse embryos. No expression was detected in any other tissue
examined.
De Haro and Janknecht (2005) determined that mouse Etv2 has 2 alternate
translation start sites, resulting in proteins of 336 or 358 amino
acids. Northern blot analysis detected a major 1.7-kb transcript and a
minor 1.5-kb transcript in mouse testis. RT-PCR found highest Etv2
expression in Sertoli cells. By database analysis, De Haro and Janknecht
(2005) identified a cDNA for human ETV2. The deduced protein contains
370 amino acids. De Haro and Janknecht (2005) also identified a human
ETV2 cDNA isolated from adult medulla that lacks exon 2 and encodes a
truncated protein with only the last 249 amino acids of full-length
ETV2.
GENE FUNCTION
Brown and McKnight (1992) found that mouse Er71, like Gabpa (600609) and
Er81 (ETV1; 600541), recognized the pentanucleotide DNA sequence
5-prime-CGGAA/T-3-prime.
By electrophoretic mobility shift assay, De Haro and Janknecht (2005)
found that the 2 isoforms of mouse Etv2 bound to the MMP1 (120353)
promoter with equal affinity and showed comparable activation of a
reporter gene driven by the MMP1 promoter.
GENE STRUCTURE
De Haro and Janknecht (2005) determined that the mouse Etv2 gene
contains 7 exons and spans 3 kb. The promoter region has no TATA box,
but it has a functional Sp1 (189906)-binding site. The human ETV2 gene
also contains 7 exons.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ETV2
gene to chromosome 19 (TMAP stSG50872).
De Haro and Janknecht (2005) mapped the mouse Etv2 gene to chromosome
7A3 in a region that shows homology of synteny to human chromosome
19q13.
SDHAF1
| dbSNP name | rs144661239(C,T); rs7925(A,G) |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 644096 |
| EntrezGene Description | succinate dehydrogenase complex assembly factor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005969 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
SKELETAL:
[Spine];
Platyspondyly;
Irregular end plates;
Kyphoscoliosis;
Lumbar scoliosis;
[Limbs];
Short and bowed lower limbs;
Enlarged knee joints;
Metaphyseal changes, mild, of knees and hips;
Osteoarthropathy, precocious;
[Hands];
Brachydactyly, mild
SKIN, NAILS, HAIR:
[Skin];
Acne;
[Hair];
Hirsutism
ENDOCRINE FEATURES:
Hyperandrogenism;
Premature pubarche (in 1 female patient);
Secondary amenorrhea
LABORATORY ABNORMALITIES:
Elevated androstenedione and testosterone;
Dehydroepiandrosterone (DHEA) at upper level of normal range;
DHEA sulfotransferase below limit of detection
MISCELLANEOUS:
Skeletal and endocrine features have not been fully characterized
in all of the patients reported
MOLECULAR BASIS:
Caused by mutation in the 3-prime-phosphoadenosine 5-prime-phosphosulfate
synthase 2 gene (PAPSS2, 603005.0001)
OMIM Title
*612848 SUCCINATE DEHYDROGENASE COMPLEX ASSEMBLY FACTOR 1; SDHAF1
OMIM Description
DESCRIPTION
The succinate dehydrogenase (SDH) complex, or complex II of the
mitochondrial respiratory chain, is composed of 4 individual subunits
(see SDHA, 600857). SDHAF1 is essential for SDH assembly but does not
physically associate with the complex in vivo (Ghezzi et al., 2009).
CLONING
Using PCR of genomic DNA, Ghezzi et al. (2009) cloned full-length
SDHAF1. The deduced 115-amino acid protein has an N-terminal
mitochondrial targeting sequence and an LYR motif characteristic of
proteins involved in Fe-S metabolism. Northern blot analysis detected
SDHAF1 in all tissues examined. Epitope-tagged SDHAF1 localized to
mitochondria in transfected COS-7 and HeLa cells. Western blot analysis
and subcellular fractionation suggested that SDHAF1 resides in the
mitochondrial matrix and that the mitochondrial targeting signal is not
removed following import into mitochondria.
GENE STRUCTURE
Ghezzi et al. (2009) determined that the SDHAF1 gene contains a single
exon.
MAPPING
By linkage and genomic sequence analysis, Ghezzi et al. (2009) mapped
the SDHAF1 gene to chromosome 19q12-q13.2.
MOLECULAR GENETICS
In affected members of Italian and Turkish families with mitochondrial
complex II deficiency (252011), Ghezzi et al. (2009) identified 2
different homozygous mutations in the SDHAF1 gene (612848.0001 and
612848.0002, respectively).
LOC644189
| dbSNP name | rs10426014(G,A); rs10402405(A,T); rs73614534(C,T) |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 644189 |
| snpEff Gene Name | ZFP82 |
| EntrezGene Description | acyl-CoA thioesterase 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3884 |
LOC728752
| dbSNP name | rs146765954(T,A); rs140234261(C,A); rs2967473(G,A) |
| cytoBand name | 19q13.12 |
| EntrezGene GeneID | 728752 |
| snpEff Gene Name | ZNF566 |
| EntrezGene Description | uncharacterized LOC728752 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005051 |
| ExAC AF | 0.001495 |
RYR1
| dbSNP name | rs4632259(T,C); rs79912670(A,G); rs919781(T,C); rs78371511(T,C); rs12972895(C,T); rs4802437(A,G); rs115997727(T,A); rs4801752(G,A); rs7248727(T,G); rs112184750(C,T); rs73044967(T,G); rs118007563(A,G); rs4802446(A,G); rs6508800(C,T); rs114566153(A,G); rs115367056(G,C); rs73554203(A,G); rs78121757(T,C); rs16972602(A,G); rs73554209(A,G); rs113026709(G,A); rs2229139(A,G); rs57132842(C,T); rs11665761(G,A); rs143569504(G,A); rs10407327(C,T); rs11083457(A,G); rs11083458(G,C); rs11083459(A,G); rs113082524(G,A); rs7249795(A,C); rs7254048(T,A); rs7253151(C,T); rs371223042(T,C); rs79165769(T,C); rs112774101(C,T); rs77893602(C,T); rs10406027(T,C); rs115050327(C,T); rs145971928(G,A); rs10411456(C,T); rs4802467(C,T); rs7256131(A,G); rs4802468(C,T); rs3745844(G,A); rs4802469(G,A); rs117954351(G,A); rs374547508(T,A); rs79884297(C,T); rs11083461(T,C); rs6508801(A,G); rs7246436(A,G); rs7246443(A,C); rs145743312(G,A); rs367546625(A,G); rs12980439(A,G); rs8104269(A,G); rs7250476(A,G); rs7254832(T,C); rs61586345(C,G); rs2288889(G,C); rs10422917(A,G); rs10423111(A,G); rs10424073(A,T); rs58037715(G,C); rs2071085(T,C); rs113248409(C,G); rs7252208(A,G); rs7252456(C,T); rs74771916(C,T); rs4802474(T,G); rs73930587(G,A); rs117163044(G,A); rs2304147(C,T); rs112123262(A,G); rs12979436(A,G); rs113253831(T,C); rs7246304(G,C); rs4802479(G,C); rs4802481(G,T); rs113151133(C,T); rs113501171(T,G); rs2304148(A,G); rs190617867(G,A); rs67515748(T,G); rs75609634(A,G); rs2304150(G,A); rs114945956(G,A); rs7259574(G,A); rs147579733(G,A); rs2228069(G,A); rs4801763(C,T); rs114470725(A,G); rs4802484(G,T); rs150137731(A,G); rs7258075(T,G); rs11083462(C,T); rs115751347(C,T); rs76563952(C,G); rs55741829(G,A); rs79093079(G,A); rs111805366(G,A); rs144279623(C,T); rs115083050(A,G); rs56082081(T,G); rs56356303(T,C); rs114390995(C,T); rs115163794(T,C); rs16972636(T,C); rs34694816(A,G); rs16972639(T,G); rs17707979(A,G); rs140921213(C,T); rs7259884(A,G); rs7245897(T,G); rs7246023(T,C); rs56278664(A,C); rs56373685(C,T); rs112210268(G,T); rs150745225(A,G); rs55845760(T,C); rs56942001(T,C); rs60228500(T,C); rs59112185(A,G); rs8104818(T,C); rs200289457(G,A); rs80306848(T,C); rs56271299(T,G); rs57257936(C,T); rs113108796(G,A); rs6508803(G,A); rs6508804(T,G); rs144645143(T,G); rs118185414(C,A); rs73541002(G,A); rs73542803(G,A); rs56363218(C,T); rs35880389(G,T); rs56081639(G,A); rs79672171(G,A); rs111484073(C,T); rs114675312(T,C); rs10409638(G,A); rs73030953(T,C); rs148448010(T,G); rs11882267(C,T); rs370971702(T,C); rs35566549(G,T); rs77886329(C,A); rs78962501(T,G); rs73030958(G,A); rs114203198(G,C); rs11882920(T,C); rs17708009(C,T); rs2228068(A,G); rs114488272(G,A); rs74852099(C,T); rs11882813(A,C); rs150263551(G,C); rs59052455(T,C); rs75917973(T,C); rs80096436(A,T); rs77003470(C,A); rs7246905(C,T); rs144967889(C,T); rs75181912(C,T); rs35968585(T,C); rs11880533(G,A); rs11880546(A,T); rs71356808(C,A); rs144614891(C,T); rs59167126(C,T); rs146617004(C,T); rs78549624(G,C); rs150503196(T,C); rs11879442(T,G); rs12373548(G,T); rs76462598(A,T); rs113637763(T,C); rs2163822(G,A); rs73030978(G,A); rs74890623(A,T); rs73030980(C,T); rs2228071(C,T); rs2229147(C,T); rs2234709(C,A); rs2228072(G,A); rs2071088(G,A); rs2960323(C,G); rs2960324(C,T); rs113750580(C,T); rs2163823(G,A); rs2116869(A,G); rs2163824(C,A); rs77022898(C,T); rs2915947(A,C); rs4802515(T,C); rs2229144(G,A); rs2915949(G,A); rs2915950(A,G); rs2960340(T,C); rs2915951(T,C); rs2915952(G,A); rs2915953(A,G); rs2960341(C,T); rs2960342(C,T); rs2960343(T,G); rs2915954(A,G); rs2915955(A,C); rs2229146(T,C); rs2960344(C,T); rs2960345(T,G); rs2915957(T,C); rs2915958(G,C); rs2915959(T,A); rs2960346(A,C); rs2960347(G,T); rs2960330(T,C); rs2960331(C,A); rs2960332(C,T); rs141608654(G,A); rs2960333(C,T); rs2960334(T,C); rs10469270(C,T); rs80203847(G,A); rs58360688(A,G); rs142259840(G,T); rs117201461(A,G); rs2960335(C,T); rs79974109(G,C); rs142792817(C,T); rs2960337(T,G); rs2960338(C,T); rs2071089(A,G); rs77374921(C,T); rs185224386(G,A); rs76697375(G,A); rs2915943(T,C); rs115308402(A,C); rs2304151(G,A); rs892052(G,A); rs73032604(T,G); rs61361030(C,T); rs2229145(C,T); rs2960327(T,G); rs111349451(C,A); rs112231089(G,A); rs2945047(C,A); rs2915945(T,C); rs3786829(T,C); rs58611824(C,T); rs2459635(G,A); rs1568191(T,C); rs1996410(A,C); rs2254484(T,C); rs2960354(C,T); rs908644(C,G); rs6508806(A,G); rs2960353(G,A); rs74716784(T,G); rs113883435(T,C); rs73032616(G,A); rs73032620(T,G); rs7250800(A,G); rs146752700(G,A); rs114862383(C,A); rs112592402(T,C); rs116226819(A,G); rs147933610(G,A); rs79117865(C,G); rs148689362(C,T); rs141164060(C,T); rs2071091(T,C); rs73032627(A,G); rs2459631(C,G); rs116534638(A,G); rs7245673(A,C); rs5029199(C,T); rs17795068(T,C); rs12981340(A,G); rs45555835(G,A); rs116792069(C,A); rs78884140(G,A); rs10500279(G,C); rs2960317(G,C); rs2960318(A,G); rs17722095(T,C); rs145757821(A,T); rs73933018(A,G); rs2960349(T,C); rs73032639(T,C); rs2960350(A,G); rs192685259(A,C); rs2960351(A,T); rs77021014(C,A); rs7249859(A,C); rs73550971(G,A); rs2459634(T,G); rs2176432(C,A); rs148836407(G,A); rs73032648(C,T); rs151229391(G,C); rs76161683(T,C); rs12973045(G,A); rs2945048(T,A); rs2960321(C,A); rs4802603(C,T); rs2960322(C,A); rs373072653(C,T); rs12974674(G,C); rs115207918(C,T); rs12327672(G,C); rs74891592(A,G); rs149507211(C,T); rs2907616(C,T); rs143449840(T,C); rs2960339(T,C); rs113183691(T,G); rs147725091(C,T); rs2960320(C,G); rs2907613(T,C); rs6508808(C,T); rs145435491(A,G); rs16972718(T,A); rs57231127(T,C); rs145402660(A,G); rs10853716(T,C); rs1966385(A,C); rs1966387(G,A); rs148571295(T,C); rs77866361(C,T); rs79487156(G,A); rs4802617(C,T); rs1468571(A,C); rs61435613(T,C); rs146998233(C,G); rs7254175(C,T); rs7254460(A,G); rs112131190(T,C); rs151070010(G,A); rs59812056(A,G); rs115347874(C,G); rs149788900(G,A); rs138351255(C,T); rs147021399(G,A); rs35458693(T,C); rs6508809(C,T); rs142134147(G,A); rs113613661(G,A); rs116321707(G,A); rs10408694(T,C) |
| ccdsGene name | CCDS33011.1 |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 6261 |
| EntrezGene Description | ryanodine receptor 1 (skeletal) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RYR1:NM_001042723:exon30:c.G4306A:p.V1436M,RYR1:NM_000540:exon30:c.G4306A:p.V1436M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.601 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| ExAC AF | 5.692e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Corneal dystrophy;
Corneal opacities;
[Teeth];
Delayed primary teeth eruption;
Failure of secondary teeth eruption
OMIM Title
*180901 RYANODINE RECEPTOR 1; RYR1
;;RYANODINE RECEPTOR, SKELETAL MUSCLE; RYDR;;
SKELETAL MUSCLE RYANODINE RECEPTOR; SKRR;;
SARCOPLASMIC RETICULUM CALCIUM RELEASE CHANNEL
OMIM Description
DESCRIPTION
The RYR1 gene encodes the skeletal muscle ryanodine receptor, which
serves as a calcium release channel of the sarcoplasmic reticulum as
well as a bridging structure connecting the sarcoplasmic reticulum and
transverse tubule (MacLennan et al., 1989).
See also RYR2 (180902) and RYR3 (180903), which encode the cardiac and
brain ryanodine receptors, respectively.
CLONING
MacLennan et al. (1989) and Zorzato et al. (1990) cloned cDNAs encoding
the rabbit and human ryanodine receptors. The human cDNA encodes a
5,032-amino acid protein with a molecular mass of 563.5 kD, which is
made without an N-terminal sequence. Sequence analysis predicts 10
potential transmembrane sequences in the C-terminal region and 2
additional potential transmembrane sequences closer to the center of the
molecule, which could form the calcium-conducting pore. The remainder of
the protein is hydrophilic and presumably constitutes the cytoplasmic
domain. Several potential calmodulin (see 114180)-binding sites were
observed between residues 2800 and 3050.
GENE FUNCTION
Eu et al. (2000) reported that ambient oxygen tension (pO2) dynamically
controls the redox state of 6 to 8 out of 50 thiols in each RYR1 subunit
and thereby tunes the response to NO. At physiologic pO2, nanomolar NO
activates the channel by S-nitrosylating a single cysteine residue.
Among sarcoplasmic reticulum proteins, S-nitrosylation is specific to
RYR1, and its effect on the channel is calmodulin (see 114180)
dependent. Neither activation nor S-nitrosylation of the channel occurs
at ambient pO2. The demonstration that channel cysteine residues
subserve coupled O2 sensor and NO regulatory functions, and that these
operate through the prototypic allosteric effector calmodulin, may have
general implications for the regulation of redox-related systems.
Calcium-induced calcium release is a general mechanism that most cells
use to amplify calcium signals. In heart cells, this mechanism is
operated between voltage-gated L-type calcium channels (LCCs; see
114205) in the plasma membrane and calcium release channels, commonly
known as ryanodine receptors, in the sarcoplasmic reticulum. The calcium
influx through LCCs traverses a cleft of roughly 12 nm formed by the
cell surface and the sarcoplasmic reticulum membrane, and activates
adjacent ryanodine receptors to release calcium in the form of calcium
sparks (Cheng et al., 1993). Wang et al. (2001) determined the kinetics,
fidelity, and stoichiometry of coupling between LCCs and ryanodine
receptors. They showed that the local calcium signal produced by a
single opening of an LCC, named a 'calcium sparklet,' can trigger about
4 to 6 ryanodine receptors to generate a calcium spark. The coupling
between LCCs and ryanodine receptors is stochastic, as judged by the
exponential distribution of the coupling latency. The fraction of
sparklets that successfully triggers a spark is less than unity and
declines in a use-dependent manner.
Ducreux et al. (2004) found that activation of RYR1 caused release of
interleukin-6 (IL6; 147620) from cultured human myotubes. Maximal
release was obtained 4 to 6 hours later, suggesting that IL6 was newly
transcribed and synthesized.
Epigenetic regulation of gene expression is a source of genetic
variation, which can mimic recessive mutations by creating
transcriptional haploinsufficiency. Germline epimutations and genomic
imprinting are typical examples. Genomic imprinting can be
tissue-specific, with biallelic expression in some tissues and
monoallelic expression in others or with polymorphic expression in the
general population. During the RYR1 mutation analysis of a cohort of
patients with recessive core myopathies, Zhou et al. (2006) discovered
that 6 (55%) of 11 patients had monoallelic RYR1 transcription in
skeletal muscle, despite being heterozygous at the genomic level. In
families for which parental DNA was available, segregation studies
showed that the nonexpressed allele was maternally inherited.
Transcription analysis in patients' fibroblasts and lymphoblastoid cell
lines indicated biallelic expression, which suggested tissue-specific
silencing. Transcription analysis of normal human fetal tissues showed
that RYR1 is monoallelically expressed in skeletal and smooth muscle,
brain, and eye in 10% of cases. In contrast, 25 normal adult human
skeletal muscle samples displayed only biallelic expression. Finally,
the administration of the DNA methyltransferase inhibitor
5-aza-deoxycytidine to cultured patient skeletal muscle myoblasts
reactivated the transcription of the silenced allele, which suggested
hypermethylation as a mechanism for RYR1 silencing. The data indicated
that RYR1 undergoes polymorphic, tissue-specific, and developmentally
regulated allele silencing and that this unveils recessive mutations in
patients with core myopathies. The data also suggested that imprinting
is a likely mechanism for this phenomenon and that similar mechanisms
could play a role in human phenotypic heterogeneity.
GENE STRUCTURE
Phillips et al. (1996) reported that the RYR1 gene contains 106 exons,
of which 2 are alternatively spliced. The length of the gene was
estimated to be approximately 160 kb. The numbering of the nucleotides
comprising the RYR1 cDNA and the numbering of amino acids encoded by
them were corrected to account for earlier errors and omissions.
BIOCHEMICAL FEATURES
- Crystal Structure
Tung et al. (2010) showed the 2.5-angstrom resolution crystal structure
of a region spanning 3 domains of RyR1, encompassing amino acid residues
1-559. The domains interact with each other through a predominantly
hydrophilic interface. Docking in RyR1 electron microscopy maps
unambiguously places the domains in the cytoplasmic portion of the
channel, forming a 240-kD cytoplasmic vestibule around the 4-fold
symmetry axis. Tung et al. (2010) pinpointed the exact locations of more
than 50 disease-associated mutations in full-length RyR1 and RyR2
(180902). The mutations can be classified into 3 groups: those that
destabilize the interfaces between the 3 amino-terminal domains, disturb
the folding of individual domains, or affect 1 of the 6 interfaces with
other parts of the receptor. Tung et al. (2010) proposed a model whereby
the opening of RyR coincides with allosterically couples motions within
the N-terminal domains. This process can be affected by mutations that
target various interfaces within and across subunits. Tung et al. (2010)
suggested that the crystal structure provides a framework to understand
the many disease-associated mutations in RyRs that have been studied
using functional methods, and would be useful for developing new
strategies to modulate RyR function in disease states.
MAPPING
By in situ hybridization, MacLennan et al. (1989) localized the RYR1
gene to chromosome 19cen-q13.2. By fluorescence in situ hybridization,
Trask et al. (1993) assigned the RYR1 gene to 19q13.1. MacKenzie et al.
(1990) mapped the RYR1 gene to 19q13.1, distal to GPI (172400) and MAG
(159460).
Using somatic cell hybrids, Harbitz et al. (1990) regionalized the
porcine Ryr1 gene (termed CRC by them) to chromosome 6p11-q21. The
authors noted homology of synteny with the genes on human chromosome 19.
Cavanna et al. (1990) demonstrated that the Ryr gene in the mouse maps
to chromosome 7. By in situ hybridization, Mattei et al. (1994) mapped
the mouse Ryr1 gene to 7A2-7A3.
MOLECULAR GENETICS
Robinson et al. (2006) provided a detailed review of mutations in the
RYR1 gene.
- Susceptibility to Malignant Hyperthermia
In several porcine breeds that exhibited inheritance of malignant
hyperthermia (145600), Otsu et al. (1991) and Fujii et al. (1991)
identified a mutation in the Ryr1 gene (R615C). In 1 of 35 Canadian
families with malignant hyperthermia, Gillard et al. (1991) identified
the same mutation, which is R614C (180901.0001) in humans.
In patients with malignant hyperthermia, Manning et al. (1998)
identified 4 adjacent mutations in the RYR1 gene: R2163C (180901.0010),
R2163H (180901.0011), V2168M (180901.0013), and T2206M (180901.0014).
Brandt et al. (1999) stated that 21 RYR1 mutations had been identified
in families with malignant hyperthermia, 4 of which were also associated
with central core myopathy. By screening for these 21 mutations in 105
MH families, including 10 families with central core disease (CCD;
117000), phenotyped by the IVCT according to the European protocol, the
authors determined the approximate mutation frequencies, with R614C (9%;
180901.0001) and G2434R (7%; 180901.0007) being the most common
mutations. Brandt et al. (1999) also detected 2 novel mutations, each in
a single pedigree. In the 109 individuals of the 25 families with RYR1
mutations, cosegregation between genetic result and IVCT was almost
perfect. Only 3 genotypes were discordant with the IVCT phenotypes,
suggesting a true sensitivity of 98.5% and a specificity of minimally
81.8% for this test. Screening of the transmembrane region of RYR1 did
not yield a new mutation, confirming the cytosolic portion of the
protein to be of main functional importance for pathogenesis.
Sambuughin et al. (2001) reported that malignant hyperthermia
susceptibility (MHS) had been found to be associated with 30 different
mutations in the RYR1 gene, all of which represent single-nucleotide
changes.
Monnier et al. (2005) reported the results of correlation studies
performed with molecular, pharmacologic, histologic, and functional data
obtained from 176 families, 129 referred to as 'confirmed' and 46 as
'potential' MHS families. Extensive molecular analysis allowed them to
identify a variant in 60% of the confirmed MHS families and resulted in
the characterization of 11 new variants in the RYR1 gene. Most of the
mutations clustered in the MH1 (52%) and MH2 (36%) domains of the RYR1
gene.
- Central Core Disease
In patients with central core disease (CCD; 117000), Zhang et al. (1993)
and Quane et al. (1993) identified mutations in the RYR1 gene
(180901.0003-180901.0005).
In 16 of 34 unrelated families with CCD, Monnier et al. (2001)
identified 12 different mutations in the C-terminal domain of RYR1.
Morphologic analysis of the patients' muscles showed different aspects
of cores. Three mutations led to in-frame deletions of 1 to 3 amino
acids (see, e.g., 180901.0018). According to a 4-transmembrane domain
model, the mutations concentrated mostly in the myoplasmic and luminal
loops linking, respectively, transmembrane domains T1 and T2 or T3 and
T4 of RYR1. Four neomutations in RYR1 were found in 4 families,
indicating that neomutations in RYR1 are not rare and may confound
genetic studies of families that present with congenital myopathies such
as central core disease.
Tilgen et al. (2001) screened the C-terminal domain of the RYR1 gene for
mutations in 50 European patients diagnosed clinically and/or
histologically as having CCD. Four novel missense mutations (see, e.g.,
180901.0019) were identified in 13 of 25 index patients. The mutations
clustered in exons 101 and 102 and replaced conserved amino acids.
Lymphoblasts derived from patients carrying these C-terminal RYR1
mutations exhibited a release of calcium from intracellular stores in
the absence of any pharmacologic activators of RYR; significantly
smaller thapsigargin-sensitive intracellular calcium stores, compared to
lymphoblasts from control individuals; and a normal sensitivity of the
calcium release to the RYR inhibitor dantrolene. The authors suggested
that the C-terminal domain of RYR1 may be a hotspot for mutations
leading to the CCD phenotype.
Zorzato et al. (2003) identified a patient with severe CCD and her
mother with mild CCD who were both heterozygous for a deletion (amino
acids 4863-4869; 180901.0024) in the pore-forming region of the
sarcoplasmic reticulum calcium release channel. The deleted amino acids
form part of the luminal loop connecting membrane-spanning segments M8
and M10 and are conserved in all known vertebrate RYR1 isoforms.
Lymphoblastoid cells carrying the RYR1 deletion exhibited an
'unprompted' calcium release from intracellular stores, resulting in
significantly smaller thapsigargin-sensitive intracellular Ca(2+) stores
compared with lymphoblastoid cells from controls. Blocking the RYR1 with
dantrolene restored the intracellular calcium stores to levels similar
to those found in controls. Single channel and [3H]ryanodine binding
measurements in HEK293 cells heterologously expressing mutant channels
revealed a reduced ion conductance and loss of ryanodine binding and
regulation by Ca(2+).
- Minicore/Centronuclear Myopathy with External Ophthalmoplegia
Monnier et al. (2003) and Jungbluth et al. (2005) identified biallelic
mutations in the RYR1 gene (see, e.g., 180901.0025-180901.0029) in
patients with minicore myopathy with external ophthalmoplegia (255320).
In 17 patients with a clinicopathologic diagnosis of centronuclear
myopathy (CNM), Wilmshurst et al. (2010) identified mutations in the
RYR1 gene (see, e.g., 180901.0035-180901.0037). The phenotype was
characterized by onset at birth, neonatal hypotonia and weakness,
delayed motor development, external ophthalmoplegia, and bulbar
involvement, similar to that observed in minicore myopathy with external
ophthalmoplegia. In addition to central nuclei, prominent
histopathologic findings included multiple internalized nuclei, type 1
fiber predominance and hypotrophy, relative type 2 hypertrophy, and
oxidative abnormalities in electron microscopic analysis, although frank
cores were not typically seen. Compound heterozygosity for a nonsense
and missense mutation was found in all except 3 patients, in whom a
second pathogenic allele could not be found. Twelve of the patients were
from South Africa, and haplotype analysis suggested founder effects for
some of the mutant alleles. The 17 patients were ascertained from a
larger group of 24 patients with a diagnosis of CNM, indicating that
RYR1 mutations can account for this subtype of myopathy. Wilmshurst et
al. (2010) postulated that disorder resulted from disturbed assembly
and/or malfunction of the excitation-contraction machinery.
- King-Denborough Syndrome
In a patient with King-Denborough syndrome (see 145600), D'Arcy et al.
(2008) identified a heterozygous mutation in the RYR1 gene
(180902.0038).
GENOTYPE/PHENOTYPE CORRELATIONS
Manning et al. (1998) tabulated the 17 mutations that had been
identified in the RYR1 gene in families with MHS and CCD. They estimated
that the 4 novel mutations they found accounted for approximately 11% of
MH cases. The 13 that had been identified before their study were
located in 2 regions, the N-terminal and central regions. Their study
and that of others indicated that the gene segment 6400-6700 is a
mutation hotspot. Two different amino acid substitutions had been
identified in each of 3 codons: 614, 2163, and 2458. Correlation
analysis of IVCT data available for pedigrees bearing these 17 RYR1
mutations showed an exceptionally good correlation between caffeine
threshold and tension values, whereas no correlation was observed
between halothane threshold and tension values. The findings indicated
that assessment of recombinant individuals on the basis of caffeine
response is justified, whereas assessment on the basis of halothane
response may be problematic, and suggested a link between the caffeine
threshold and tension values and the MH/CCD phenotype.
McCarthy et al. (2000) noted that the majority of RYR1 mutations
appeared to be clustered in the N-terminal amino acid residues 35-614
(referred to as the MH/CCD region-1) and the centrally located residues
2163-2458 (MH/CCD region-2). The only mutation identified outside of
these regions was a single mutation associated with a severe form of CCD
in the highly conserved C terminus of the gene, I4898T (180901.0012).
All of the RYR1 mutations result in amino acid substitutions in the
myoplasmic portion of the protein, with the exception of the mutation in
the C terminus, which resides in the luminal/transmembrane region. The
likely deciding factors in determining whether a particular RYR1
mutation results in MHS alone or MHS and CCD are sensitivity of the RYR1
mutant proteins to agonists; the level of abnormal channel-gating caused
by the mutation; the consequential decrease in the size of the
releasable calcium store and increase in resting concentration of
calcium; and the level of compensation achieved by the muscle with
respect to maintaining calcium homeostasis.
Robinson et al. (2002) stated that 15 RYR1 N-terminal mutations are
considered causative of MHS, and that 5 of these are also associated
with CCD. In an extensive U.K. population survey, they detected 8 of
these 15 mutations in 85 of 297 (29%) unrelated MH susceptibility cases,
with G2434R (180901.0007) detected in 53 cases (18%). R163C
(180901.0004), R2163H (180901.0011), and R2435H (180901.0003), RYR1
mutations associated with both CCD and MH, had more severe caffeine and
halothane response phenotypes than those associated with MH alone.
Mutations near the N terminus (R163C; G341R, 180901.0006) had a
relatively greater effect on response to caffeine than halothane, with a
significantly increased caffeine:halothane tension ratio compared to
G2434R of the central domain. All phenotypes were more severe in males
than females, and were also affected by muscle specimen size and
viability. Discordance between RYR1 genotype and IVCT phenotype was
observed in 7 families (9 individuals), with 5 false-positives and 4
false-negatives. The clinical and genetic data in this study
demonstrated that RYR1 mutations involved in CCD are those associated
with 1 end of the spectrum of MH IVCT phenotypes.
Ducreux et al. (2004) found that cultured human myotubes with the I4898T
mutation in the RYR1 gene (180901.0012), which is in the C-terminal
hydrophobic membrane-spanning region of the protein and causes CCD, had
a 4-fold increase in background levels of IL6 in the absence of RYR1
activation compared to controls; cells with the V2168M (180901.0013)
mutation, which causes MHS, had background IL6 levels similar to control
cells. In addition, cells with the CCD mutation had significantly less
agonist-induced calcium release from intracellular stores compared to
control cells or MHS cells. The findings indicated that mutations in the
C-terminal domain reduce the amount of calcium released via the RYR1
channel, resulting in altered excitation-contraction coupling. Release
of IL6, an inflammatory and pyrogenic cytokine, may affect signaling
pathways responsible for muscle fiber abnormalities in CCD.
Lyfenko et al. (2004) reviewed the dynamic alterations in myoplasmic
calcium metabolism in disorders caused by mutation in the RYR1 gene, and
discussed molecular mechanisms by which these genetic defects lead to
distinct clinical and histopathologic manifestations. Benkusky et al.
(2004) reviewed RYR1 and RYR2 mutations and their role in muscle and
heart disease, respectively.
POPULATION GENETICS
McCarthy et al. (2000) pointed out that the RYR1 G341R mutation
(180901.0006) is present in about 6% of Irish/English/French families,
but is rare in northern Europe. The R614C mutation (180901.0001) is more
common in German families (9%), while the V2168M (180901.0013) mutation
is common in Swiss families but relatively rare otherwise.
Monnier et al. (2005) found that the RYR1 R614C mutation is the most
prevalent mutation in French families with MHS, whereas it is poorly
represented in affected families from the U.K. In contrast, the G2434R
(180901.0007) and V2168M (180901.0013) mutations, which are the most
prevalent in MHS families from the U.K. (Robinson et al., 2002) and
Switzerland (Girard et al., 2001), respectively, are present at a much
lower level in affected French families.
ANIMAL MODEL
Takeshima et al. (1994) developed mice with a targeted mutation in the
Ryr1 gene. Homozygous mice died perinatally with gross abnormalities of
skeletal muscle. The contractile response to electrical stimulation
under physiologic conditions was totally abolished in mutant embryonic
muscle. However, ryanodine receptors other than Ryr1 seemed to exist,
because a response to caffeine was retained. Takeshima et al. (1994)
concluded that RYR1 is essential for both muscular maturation and
excitation-contraction coupling and that RYR1 function during
excitation-contraction coupling cannot be substituted by other receptor
subtypes.
Takeshima et al. (1995) demonstrated that the residual
caffeine-activated calcium release in Ryr1 null mice is likely mediated
by Ryr3 (180903).
Barone et al. (1998) generated double mutant mice carrying a targeted
disruption of both the Ryr1 and the Ryr3 (180903) genes. Skeletal
muscles from mice homozygous for both mutations did not contract in
response to caffeine or ryanodine. In addition, these muscles showed
very low tension when directly activated with micromolar ionized calcium
after membrane permeabilization, indicating either poor development or
degeneration of the myofibrils. This was confirmed by biochemical
analysis of contractile proteins. Electron microscopy confirmed small
size of myofibrils and showed complete absence of ryanodine receptors in
the junctional sarcoplasmic reticulum.
Chelu et al. (2006) found that mice with a homozygous for the Y522S
(180901.0031) mutation in the Ryr1 gene exhibited skeletal defects and
died during embryonic development or soon after birth. Heterozygous
mice, corresponding to the human occurrence of this mutation, were
susceptible to malignant hyperthermia and showed whole body contractions
and elevated core temperatures in response to isoflurane exposure or
heat stress. Skeletal muscles from heterozygous mice exhibit increased
susceptibility to caffeine- and heat-induced contractures in vitro. In
addition, the heterozygous expression of the mutation resulted in
enhanced RyR1 sensitivity to activation by temperature, caffeine, and
voltage but not uncompensated sarcoplasmic reticulum calcium leak or
store depletion.
Durham et al. (2008) found that skeletal muscle from heterozygous
Y522S-mutant mice displayed increased basal oxidative stress with
increased levels of reactive oxygen and nitrogen species compared to
wildtype mice. Further studies suggested that the reactive species
resulted from increased calcium release from the leaky mutant RyR1
channel in resting muscles. Increased calcium combined with increased
reactive nitrogen species produced S-nitrosylation of the mutant leaky
channel that further enhanced channel activity at increased
temperatures. Durham et al. (2008) postulated a destructive feed-forward
cycle of increased calcium release, increased temperature-sensitivity of
the mutant channel, and increased muscle contraction with elevated
temperature and heat stress. Over time, this cycle induced a myopathy
characterized by damaged mitochondria and decreased force generation.
Bellinger et al. (2009) found that the Ryr1 channel in skeletal muscle
from the mdx mouse, a model of Duchenne muscular dystrophy (DMD; 310200)
with disruption of the dystrophin gene (DMD; 300377), showed increased
inducible nitric oxide (NOS2A; 163730)-mediated S-nitrosylation of
cysteine residues, which depleted the channel complex of calstabin-1
(FKBP12; 186945). This resulted in leaky channels with increased calcium
flux. These changes were age-dependent and coincided with dystrophic
changes in muscle. Prevention of calstabin-1 depletion from Ryr1 with
S107, a compound that binds the Ryr1 channel and enhances binding
affinity, inhibited sarcoplasmic reticulum calcium leak, reduced
biochemical and histologic evidence of muscle damage, improved muscle
function, and increased exercise performance in mdx mice. Bellinger et
al. (2009) proposed that the increased calcium flux via a defective Ryr1
channel contributes to muscle weakness and degeneration in DMD by
increasing calcium-activated proteases.
IFNL4
| dbSNP name | rs74597329(T,G); rs4803222(G,C) |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 101180976 |
| snpEff Gene Name | IL28B |
| EntrezGene Description | interferon, lambda 4 (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | splicing |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| ExAC AF | 0.102,3.759e-04 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Macrocephaly;
Open fontanel;
Frontal bossing;
[Face];
Facial nerve palsy;
[Ears];
Narrowed auditory canal;
Sclerosis of semicircular canals;
[Eyes];
Vision loss, unilateral or bilateral;
Optic nerve atrophy
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Feeding problems
SKELETAL:
Dense bones;
Narrowed medullary space due to encroachment of cortical bone;
[Skull];
Macrocephaly;
Open fontanel;
Narrow optic canal;
Narrow auditory canal;
Sclerosis of semicircular canals;
Fully ossified ethmoid air cells;
Fully ossified sphenoid sinuses
HEMATOLOGY:
Anemia;
Thrombocytopenia
LABORATORY ABNORMALITIES:
Elevated lactate dehydrogenase
MOLECULAR BASIS:
Caused by mutation in the sorting nexin 10 gene (SNX10, 614780.0001)
OMIM Title
*615090 INTERFERON, LAMBDA-4; IFNL4
OMIM Description
DESCRIPTION
Interferon-lambda (IFNL) genes, such as INFL4, encode type III
interferons (IFNs) that induce antiviral activity, including suppression
of hepatitis C virus (HCV; see 609532) replication, through activation
of the JAK (see 147795)-STAT (see 600555) pathway and upregulation of
IFN-stimulated genes (e.g., ISG15; 147571). IFNL4 is only expressed in
individuals who have a frameshift variant (dbSNP ss469415590) that
'creates' the gene. In individuals without the variant, IFNL4 is a
pseudogene (Prokunina-Olsson et al., 2013).
CLONING
By stimulating primary hepatocytes with poly(I:C), a synthetic mimic of
double-stranded HCV RNA and an inducer of IFNL genes, followed by mRNA
sequence analysis, Prokunina-Olsson et al. (2013) observed a novel
transcribed region upstream of the IFNL3 gene (607402). Using 5-prime
RACE, they identified a transcription start site and a protein
translation start site. Exon 1 contains, at codon 22, a compound
dinucleotide variant (dbSNP ss469415590; TT to delT/G) comprised of a
1-nucleotide insertion/deletion polymorphism (delT; dbSNP rs67272382)
and a 1-nucleotide substitution (T-G; dbSNP rs74597329). PCR analysis of
primary hepatocyte cDNA showed that individuals homozygous for the
delT/G allele produced multiple protein-coding transcripts, whereas
individuals homozygous for the TT allele did not. Only a predicted
179-amino acid protein, designated IFNL4, showed homology to other
proteins, sharing 29% amino acid identity with IFNL3. The IFNL4 and
IFNL3 proteins are most related within sequences corresponding to the A
and F helices of IFNL3, which bind the primary IFNL receptor, IFNLR1
(607404). However, IFNL4 differs in the sequence corresponding to the D
helix of IFNL3, which binds the second chain of the IFNL receptor
complex, IL10RB (123889).
GENE STRUCTURE
Prokunina-Olsson et al. (2013) determined that the IFNL4 gene contains
at least 5 exons.
MAPPING
By sequence analysis, Prokunina-Olsson et al. (2013) mapped the IFNL4
gene to chromosome 19q13.13.
GENE FUNCTION
Prokunina-Olsson et al. (2013) showed that transient transfection of a
hepatoma cell line with IFNL4, INFL3, or IFNA (147660), induced
activation of STAT1 and STAT2 (600556). Confocal microscopy demonstrated
expression of IFNL4 in transfected hepatoma cells and in
poly(I:C)-stimulated primary hepatocytes of HCV-uninfected carriers of
the delT/G allele of dbSNP ss469415590, but not in an individual
homozygous for the TT allele.
MOLECULAR GENETICS
- Association with Hepatitis C Virus Clearance
Prokunina-Olsson et al. (2013) found that dbSNP ss469415590, which
'creates' the IFNL4 gene, was in high linkage disequilibrium with dbSNP
rs12979860, a genetic marker strongly associated with HCV clearance.
They showed that the delT/G allele of dbSNP ss469415590 was even more
strongly correlated with poor response to pegylated IFNA/ribavirin
treatment of chronic HCV than the T allele of dbSNP rs12979860 in
individuals of African ancestry. Prokunina-Olsson et al. (2013) proposed
that IFNL4 induces weak expression of ISGs, providing an antiviral
response that lowers the HCV load, but that it also reduces responses to
type I and type III IFNs that are necessary for efficient HCV clearance.
EVOLUTION
By genomic sequence analysis in 45 species, Prokunina-Olsson et al.
(2013) found that the delT/G allele of dbSNP ss469415590 is an ancestral
variant present in all species. The existence of IFNL4 protein could be
predicted only in macaques, apes, and humans. The TT allele of dbSNP
ss469415590, which is favorable for HCV clearance and treatment
response, appeared to be recently derived and was found in 93%, 68%, and
23% of Asian, European, and African populations, respectively, according
to HapMap samples.
IFNL1
| dbSNP name | rs143181120(C,G); rs30461(A,G) |
| ccdsGene name | CCDS12531.1 |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 282618 |
| snpEff Gene Name | IL29 |
| EntrezGene Description | interferon, lambda 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IFNL1:NM_172140:exon3:c.C375G:p.L125L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.004085 |
| ESP All MAF | 0.001384 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0002033 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation
METABOLIC FEATURES:
Recurrent hypoglycemic episodes
LABORATORY ABNORMALITIES:
Hypoglycemia;
Elevated plasma ACTH;
Low to undetectable plasma cortisol;
Normal plasma renin;
Normal plasma aldosterone
MOLECULAR BASIS:
Caused by mutation in the melanocortin-2 receptor accessory protein
gene (MRAP, 609196.0001)
OMIM Title
*607403 INTERFERON, LAMBDA-1; IFNL1
;;INTERLEUKIN 29; IL29
OMIM Description
DESCRIPTION
IL29, or IFNL1, belongs to the interferon-lambda family (also known as
type III interferons), whose members are distantly related to both type
I interferons (e.g., IFNA2; 147562) and members of the IL10 (124092)
family. IL29 has significant antiviral activity and immunoregulatory
properties and appears to inhibit T helper-2 (Th2) responses (Srinivas
et al., 2008).
CLONING
By genomic sequence analysis, Sheppard et al. (2003) identified genes
encoding IL28A (607401), IL28B (607402), and IL29. The deduced 200-amino
acid IL29 protein is 81% identical to IL28A and IL28B, but it shares
only low homology with IL10 (124092), IFNA2, and IL22 (605330). IL29 has
a conserved cysteine pattern and amphipathic profile similar to other
helical cytokine family members.
GENE FUNCTION
By RT-PCR analysis, Sheppard et al. (2003) determined that treatment of
mononuclear cells and other cell types with double-stranded RNA or viral
infection induced transcription of IL28 and IL29. Addition of IL28,
IL29, or IFNA2 also induced protection from virus challenge infection,
but IL28 and IL29 did not display antiproliferative activity. Luciferase
reporter analysis indicated that IL28 and IL29 signal through
IFN-stimulated response elements. However, IL28 and IL29 did not bind to
IFNAR1 (107450), but instead bound to and signaled through a novel
receptor, IL28RA (607404) partnered with IL10RB (123889). Sheppard et
al. (2003) proposed that IL28 and IL29 represent an evolutionary link
between type I IFNs and the IL10 family and may serve as an alternative
therapeutic choice to type I IFNs.
Using quantitative RT-PCR, ELISA, and intracellular FACS analysis of
mitogen-stimulated peripheral blood mononuclear cells, Srinivas et al.
(2008) showed that IFNL1 preferentially inhibited IL13 (147683) compared
with IL4 (147780) and IL5 (147850) Th2 cytokines, although significant
decreases of IL4 and IL5 were also detected. Srinivas et al. (2008)
concluded that IFNL1 is an inhibitor of Th2 cytokine responses,
primarily of IL13.
By screening human cells transfected with foreign DNA, Zhang et al.
(2011) observed expression of IFNL1, a type III IFN, rather than type I
IFN. Pull-down analysis with cytosolic proteins identified Ku70 (XRCC6;
152690) and Ku80 (XRCC5; 194364) as the DNA-binding proteins. Knockdown
and reporter analyses revealed that Ku70 functioned as a DNA sensor that
induced IFNL1 activation. Analysis of the IFNL1 promoter indicated that
positive-regulatory domain I and IFN-stimulated response element sites
were predominantly involved in DNA-mediated IFNL1 activation. Pull-down
assays showed that IFNL1 induction was associated with activation of
IRF1 (147575) and IRF7 (605047). Zhang et al. (2011) concluded that Ku70
mediates the induction of type III IFN by DNA, as may occur in viral
infections or DNA vaccination.
GENE STRUCTURE
By genomic sequence analysis, Sheppard et al. (2003) determined that the
IL29 gene contains 5 exons, in contrast to the related type I IFNs,
which are encoded by a single exon. Analysis of 5-prime regulatory
regions suggested the presence of DNA-binding elements involved in type
I IFN regulation.
MAPPING
By genomic sequence analysis, Sheppard et al. (2003) mapped the IL28A,
IL28B, and IL29 genes to chromosome 19q13.13, a localization distinct
from that of the related type I IFNs, which are colocalized on
chromosome 9.
EID2B
| dbSNP name | rs17795475(T,G); rs17641508(C,T); rs10403763(C,G); rs34110322(T,G); rs1123301(A,G) |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 126272 |
| EntrezGene Description | EP300 interacting inhibitor of differentiation 2B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2484 |
EID2
| dbSNP name | rs8101913(C,A) |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 163126 |
| EntrezGene Description | EP300 interacting inhibitor of differentiation 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.107 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataract, congenital;
Cataract, nuclear (in some patients);
Cataract, posterior polar (in some patients);
Cataract, anterior polar (in some patients);
Cataract, cortical (in some patients);
Glaucoma (in some patients)
MISCELLANEOUS:
Two Pakistani families with a homozygous CRYBB3 mutation have been
reported (last curated August 2014);
One 4-generation Caucasian Italian family with a heterozygous CRYBB3
mutation has been reported (last curated August 2014)
MOLECULAR BASIS:
Caused by mutation in the beta-B3 crystallin gene (CRYBB3, 123630.0001)
OMIM Title
*609773 CREBBP/EP300 INHIBITORY PROTEIN 2; CRI2
;;E1A-LIKE INHIBITOR OF DIFFERENTIATION 2; EID2
OMIM Description
CLONING
By EST database searching for homologs of E1A-like inhibitor of
differentiation-1 (CRI1, or EID1; 605984), Ji et al. (2003) identified a
partial sequence of CRI2 (EID2). They subsequently cloned a full-length
EID2 cDNA from a human heart cDNA library and identified and cloned the
mouse homolog. Human EID2 encodes a 236-amino acid protein that shares
55% and 78% sequence identity with EID1 and mouse Eid2, respectively,
with greatest similarity in the C terminus. Western blot analysis
demonstrated that EID2 is preferentially expressed in the nuclear
fraction. Northern blot analysis revealed ubiquitous expression in human
tissues, with highest expression in placenta and significant expression
in liver, brain, heart, skeletal muscle, and kidney. The expression
pattern differed in mouse, with more restricted expression in heart,
brain, kidney, and pancreas and no detectable expression in placenta.
GENE FUNCTION
In human skeletal myocytes, Ji et al. (2003) found that levels of EID2
message were highest in undifferentiated myoblasts and decreased with
differentiation. In mouse embryos, Eid2 protein was first detectable at
embryonic day 10.5 and showed highest expression at E11.5.
Using reporter gene constructs cotransfected with EID2 into human
primary skeletal muscle cells, Ji et al. (2003) found that EID2
inhibited the transcriptional activity of alpha-cardiac actin (102540)
and beta-myosin heavy chain (160760) promoters. Ji et al. (2003) found
that, like EID1, EID2 causes a significant reduction in MYOD (159970)
transcriptional activity and interacts with p300 (EP300; 602700). EID2
bound the C-terminal fragment of p300, which contains the HAT and C/H3
domains known to interact with EID1. In vitro p300 histone acetylase
assays using recombinant EID1 and EID2 showed that both proteins are
potent inhibitors of p300 function.
Lee et al. (2004) carried out a series of studies to investigate the
effect of EID2 on TGF-beta (TGFB1; 190180)-induced transcription, which
is dependent on SMAD proteins. They showed that EID2 inhibits TGFB1/SMAD
transcriptional responses. EID2 strongly suppressed TGFB1-induced
transcriptional activity of a SMAD3 fusion protein and, to a lesser
degree, suppressed that of SMAD2 (601366) and SMAD4 (600993) fusion
proteins, indicating that EID2 can directly suppress SMAD-mediated
transcriptional activation. Immunoprecipitation experiments showed that
the interaction of EID2 and SMADs does not occur in a ligand
(TGFB1)-dependent manner; however, treatment with TGFB1 increases the
interaction. Deletion mutant experiments revealed that the MH2 domain of
SMAD3, which is present in the C terminus, is required for interaction
with EID2. Truncation mutant experiments revealed that the internal
portion of EID2 is responsible for interaction with SMAD3 and therefore
may mediate EID2 suppressive activity on TGFB1-induced transcription.
Transfection of an EID2-specific siRNA lowered levels of endogenous EID2
protein and led to an increase in TGFB1-induced transcription. Although
EID2 expression had little effect on SMAD2/3 phosphorylation, it
inhibited SMAD3-SMAD4 complex formation, suggesting that this is the
primary mechanism by which EID2 suppresses SMAD-dependent transcription.
Lee et al. (2004) carried out Western blot analysis to investigate the
effect of EID2 on the level of expression of TGFB1-responsive genes. The
presence of EID2 inhibited TGFB1-induced expression of p21 (116899) and
p15 (600431), but had no effect on p27 (600778). TGFB1-induced
suppression of MYC (190080), CDK2 (116953) and CDK4 (123829) was
inhibited by EID2. In thymidine uptake assays, cells expressing EID2
were slightly resistant to TGFB1 growth inhibitory activity.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the CRI2
gene to chromosome 19 (TMAP STS-N99910).
By sequence analysis, Ji et al. (2003) mapped the mouse Cri2 gene to
chromosome 7.
MIR6796
| dbSNP name | rs3745198(C,G); rs3745199(C,G) |
| ccdsGene name | CCDS33027.1 |
| cytoBand name | 19q13.2 |
| EntrezGene GeneID | 23646 |
| EntrezGene Symbol | PLD3 |
| snpEff Gene Name | PLD3 |
| EntrezGene Description | phospholipase D family, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3719 |
| ESP Afr MAF | 0.078342 |
| ESP All MAF | 0.277561 |
| ESP Eur/Amr MAF | 0.379666 |
| ExAC AF | 0.354,3.766e-05 |
CBLC
| dbSNP name | rs112123644(C,T); rs2927450(C,G); rs35106910(A,C); rs41301961(T,G); rs111648890(G,A); rs200445340(T,C); rs10416628(G,A); rs2965124(G,A); rs4803756(A,G); rs114213981(G,A); rs144265733(C,T); rs148754840(C,T); rs2927448(G,T); rs114034879(T,G); rs116735164(T,A); rs28427198(T,G); rs2965123(A,G); rs10426226(G,A); rs139653078(G,A); rs2965122(G,A); rs28431193(T,C); rs2927447(T,C); rs28465377(G,A); rs2965121(G,A); rs2965119(C,G); rs113154274(C,T); rs2965118(C,G); rs10401942(C,T); rs2965117(A,G); rs377713423(G,A); rs149347774(C,T); rs899087(T,C); rs142887024(G,C); rs112287266(T,G); rs150894593(G,A); rs10423646(G,A); rs10424785(T,C); rs147360159(G,T); rs73570198(A,C); rs61750955(A,G); rs1903831(A,C); rs116023028(C,T); rs114699167(C,T); rs1903830(T,C); rs2889414(A,G); rs10419669(G,A); rs116614005(C,T); rs116490343(C,T); rs114427898(G,C); rs144103378(G,A); rs2965113(T,C); rs2967669(A,G); rs115493420(G,A); rs2965112(A,G); rs73572003(T,G); rs111794050(A,G); rs143695016(C,T); rs142527337(G,A); rs76701630(G,A); rs114075829(C,T); rs748913(G,C) |
| ccdsGene name | CCDS12643.1 |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 23624 |
| EntrezGene Description | Cbl proto-oncogene C, E3 ubiquitin protein ligase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CBLC:NM_012116:exon3:c.T554C:p.V185A,CBLC:NM_001130852:exon3:c.T554C:p.V185A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5469 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00228937728938 |
| dbNSFP KGp1 Afr AF | 0.010162601626 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.002296 |
| ExAC AF | 1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Dull facial expression
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, severe;
Limited verbal comprehension;
Speech limited to single word or no words;
Incomprehensible speech;
[Behavioral/psychiatric manifestations];
Dull facial expression;
Hyperactivity;
Easily frustrated;
Short attention span
MISCELLANEOUS:
Onset in early childhood
MOLECULAR BASIS:
Caused by mutation in the coiled-coil and C2 domain-containing 1A
gene (CC2D1A, 610055.0001)
OMIM Title
*608453 CAS-BR-M MURINE ECOTROPIC RETROVIRAL TRANSFORMING SEQUENCE C; CBLC
;;CBL3
OMIM Description
DESCRIPTION
CBL proteins, such as CBLC, are phosphorylated upon activation of a
variety of receptors that signal via protein tyrosine kinases. Through
interactions with proteins containing SRC (190090) homology-2 (SH2) and
SH3 domains, CBL proteins modulate downstream cell signaling (Keane et
al., 1999).
CLONING
By searching an EST database for CBL-like sequences, followed by
screening a pancreas carcinoma cell line cDNA library and 5-prime RACE,
Keane et al. (1999) cloned CBLC, which they designated CBL3. The deduced
474-amino acid protein has a calculated molecular mass of 52.5 kD. CBLC
contains an N-terminal phosphotyrosine-binding domain, a conserved C3HC4
zinc finger motif, and a short proline-rich region near the C terminus.
CBLC lacks the extensive proline-rich domain and leucine zipper motif
found in CBL (165360) and CBLB (604491). Keane et al. (1999) also
identified a splice variant that encodes a protein with a 46-amino acid
deletion in the phosphotyrosine-binding domain; this protein has a
calculated molecular mass of 47.5 kD. Northern blot analysis detected a
1.7- to 2.0-kb transcript expressed at high levels in liver, pancreas,
small intestine, colon, prostate, and trachea. Low expression was
detected in stomach, lung, and thyroid, and no expression was detected
in hematopoietic tissues. RNA dot blot analysis detected low but
ubiquitous expression, with highest levels in adrenal gland and salivary
gland in addition to the tissues identified by Northern blot analysis.
By searching an EST database for sequences similar to CBL, followed by
screening a kidney cDNA library and oligo capping to extend the 5-prime
sequence, Kim et al. (1999) cloned CBLC. Northern blot analysis detected
a 2.0-kb transcript highly expressed in colon and small intestine.
Expression was also observed in pancreas, placenta, liver, kidney, and
prostate, but not in brain, testis, and lymphoid tissues. Minor
transcripts of 4.0 and 6.0 kb were also detected in several tissues.
Western blot analysis found that endogenous CBLC migrated with an
apparent molecular mass of 52 kD in colon carcinoma cell lines.
Griffiths et al. (2003) found that mouse Cblc was expressed in
epithelial cells of the gastrointestinal tract, the epidermis, and the
respiratory, urinary, and reproductive systems.
GENE FUNCTION
By in vitro protein binding assays, Keane et al. (1999) determined that
both the long (CBLC-L) and short (CBLC-S) forms of CBLC bound to
recombinant fusion proteins containing the SH3 domains of LYN (165120)
and CRK (164762), but not with any other SH3-containing proteins.
Following EGF (131530) stimulation of cotransfected embryonic kidney
cells, CBLC-L, but not CBLC-S, was phosphorylated and immunoprecipitated
with EGFR (131550). CBLC-L also inhibited EGF-induced stimulation of
transcription by ERK2 (MAPK1; 176948) in a dose-dependent manner. CBLC-S
had no effect on MAPK signaling.
Kim et al. (1999) transfected embryonic kidney cells with CBLC and EGFR.
The amount of EGFR that coimmunoprecipitated with CBLC increased
following EGF stimulation. In vitro binding assays showed that CBLC
bound to the SH3 domain, but not the SH2 domain, of FYN (137025), and it
bound to the SH3 domain of GRB2 (108355) and the p85 regulatory subunit
of phosphatidylinositol 3-kinase (171833). CBLC and FYN
coimmunoprecipitated in transfected embryonic kidney cells only when
both proteins were present.
GENE STRUCTURE
Nau and Lipkowitz (2003) determined that the CBLC gene contains 11 exons
and spans about 23 kb. The mouse Cblc gene contains 10 exons and lacks
the intron that exists between human exons 8 and 9.
MAPPING
By somatic cell hybrid analysis and radiation hybrid analysis, Keane et
al. (1999) mapped the CBLC gene to chromosome 19q13.2. Using FISH, Kim
et al. (1999) mapped the CBLC gene to chromosome 19q13.2-q13.3. Southern
blot analysis indicated that CBLC is a single copy gene.
ANIMAL MODEL
Griffiths et al. (2003) found that Cblc-null mice were viable, healthy,
and fertile, and displayed no histologic abnormalities up to 18 months
of age. Proliferation of epithelial cells in the epidermis and
gastrointestinal tracts was unaffected by the loss of Cblc. Moreover,
Cblc was not required for attenuation of EGF-stimulated ERK activation
in primary keratinocytes.
BLOC1S3
| dbSNP name | rs59215448(G,A); rs6509200(T,A); rs111903160(C,T) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 388552 |
| snpEff Gene Name | TRAPPC6A |
| EntrezGene Description | biogenesis of lysosomal organelles complex-1, subunit 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01056 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataract, congenital;
Cataract, nuclear (in some patients);
Cataract, posterior polar (in some patients);
Cataract, anterior polar (in some patients);
Cataract, cortical (in some patients);
Glaucoma (in some patients)
MISCELLANEOUS:
Two Pakistani families with a homozygous CRYBB3 mutation have been
reported (last curated August 2014);
One 4-generation Caucasian Italian family with a heterozygous CRYBB3
mutation has been reported (last curated August 2014)
MOLECULAR BASIS:
Caused by mutation in the beta-B3 crystallin gene (CRYBB3, 123630.0001)
OMIM Title
*609762 BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 3; BLOC1S3
;;BLOC1, SUBUNIT 3; BLOS3;;
REDUCED PIGMENTATION, MOUSE, HOMOLOG OF; RP;;
HPS8 GENE; HPS8
OMIM Description
DESCRIPTION
BLOC1S3 is a component of the ubiquitously expressed BLOC1 multisubunit
protein complex. BLOC1 is required for normal biogenesis of specialized
organelles of the endosomal-lysosomal system, such as melanosomes and
platelet dense granules (Starcevic and Dell'Angelica, 2004).
CLONING
Using the BLOC1 subunit pallidin (PLDN; 604310) as bait in a yeast
2-hybrid screen of a HeLa cell cDNA library, Starcevic and Dell'Angelica
(2004) cloned BLOC1S3, which they called BLOS3. The deduced BLOS3
protein has a calculated molecular mass of 21.3 kD. However, Western
blot analysis detected endogenous HeLa cell BLOS3 at an apparent
molecular mass of 32 kD.
GENE FUNCTION
By mass spectrometry of BLOC1 proteins purified from bovine liver, mouse
liver, and HeLa cells, Starcevic and Dell'Angelica (2004) identified
BLOS3 as a subunit of BLOC1. Other BLOC1 subunits identified were
pallidin, muted (607289), dysbindin (DTNBP1; 607145), cappuccino
(605695), snapin (SNAPAP; 607007), BLOC1S1 (601444), and BLOC1S2
(609768). Coimmunoprecipitation and yeast 2-hybrid analyses confirmed
that these proteins interact within the BLOC1 complex.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the BLOC1S3
gene to chromosome 19 (TMAP RH48388). Starcevic and Dell'Angelica (2004)
mapped the mouse Bloc1s3 gene to chromosome 7A2.
MOLECULAR GENETICS
Using an autozygosity mapping strategy, Morgan et al. (2006) mapped
Hermansky-Pudlak syndrome (HPS8; 614077) in a large consanguineous
family to 19q13. Affected individuals displayed features of incomplete
oculocutaneous albinism and platelet dysfunction. Skin biopsy
demonstrated abnormal aggregates of melanosomes within basal epidermal
keratinocytes. Morgan et al. (2006) noted that the human homolog of the
rp gene, which is disrupted in a mouse model of Hermansky-Pudlak
syndrome, resides in this region. Sequencing of the single exon of the
BLOC1S gene demonstrated a 1-bp frameshift deletion, 448delC
(609762.0001).
ANIMAL MODEL
Starcevic and Dell'Angelica (2004) determined that the reduced
pigmentation (rp) mutation in mice, a model of Hermansky-Pudlak syndrome
(HPS; 203300), results from a 1-bp substitution (238C-T) in the Blos3
gene. The mutation introduces a premature termination codon (Q80X) in rp
mice. Mutant mRNA was not subject to nonsense-mediated mRNA decay. The
rp mutation did not completely disrupt BLOC1 assembly.
CD3EAP
| dbSNP name | rs967591(G,A) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 10849 |
| snpEff Gene Name | ERCC1 |
| EntrezGene Description | CD3e molecule, epsilon associated protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2466 |
| ESP Afr MAF | 0.165491 |
| ESP All MAF | 0.147142 |
| ESP Eur/Amr MAF | 0.137457 |
| ExAC AF | 0.129 |
OMIM Clinical Significance
Vascular:
Arterial thrombosis;
Venous thrombosis
Misc:
Recurrent fetal loss
Heme:
Immune thrombocytopenia
Immunology:
Autoantibodies against cellular phospholipid components;
Anticardiolipin antibodies;
Lupus anticoagulant antibodies
Inheritance:
Autosomal dominant
OMIM Title
*107325 CD3-EPSILON-ASSOCIATED PROTEIN; CD3EAP
;;CD3 ANTIGEN, EPSILON-ASSOCIATED PROTEIN;;
ANTISENSE ERCC1; ASE1;;
POLYMERASE I-ASSOCIATED FACTOR, 49-KD, MOUSE, HOMOLOG OF; PAF49
OMIM Description
CLONING
In the course of characterizing ERCC1 (126380), a DNA repair gene on
chromosome 19q13.2-q13.3, Hoeijmakers et al. (1989) found that its
3-prime terminus overlaps with the 3-prime end of another gene, which
they designated ASE1. This exceptional type of gene overlap is conserved
in the mouse and even in the yeast ERCC1 homolog, RAD10, suggesting an
important biologic function.
Yamamoto et al. (2004) purified the mouse polymerase I complex and
cloned the 49-kD polypeptide, Paf49. By database analysis, they
determined that Paf49 is the mouse homolog of human ASE1. The deduced
human ASE1 protein contains 510 amino acids.
GENE FUNCTION
By coimmunoprecipitation assays, Yamamoto et al. (2004) confirmed that
mouse Paf49 interacts with the polymerase I complex, specifically with
Paf53 and Taf1a (604903). Mutation analysis indicated that the N
terminus of Paf49 interacts with Paf53 and Taf1a, and the C terminus may
also contribute to a lesser extent to the interaction with Taf1a. In
exponentially growing mouse fibroblasts, Paf49 colocalized with the
ribosomal transcriptional activation factor Ubf (600673) within large
discrete nucleoli. When cells were cultured in serum-restricted medium,
some Paf49 dispersed into the nucleoplasm.
MAPPING
Hoeijmakers et al. (1989) identified the ASE1 gene (CD3EAP) on
chromosome 19q13.2-q13.3. Its 3-prime end overlaps the 3-prime end of
the ERCC1 gene.
C19orf83
| dbSNP name | rs2286756(G,T) |
| ccdsGene name | CCDS54280.1 |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 100287177 |
| EntrezGene Symbol | LOC100287177 |
| snpEff Gene Name | EML2 |
| EntrezGene Description | uncharacterized LOC100287177 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | splicing |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4261 |
| ExAC AF | 0.498,5.815e-05 |
LOC388553
| dbSNP name | rs145068014(C,T); rs16979992(G,C); rs10415988(C,T); rs145752347(C,T); rs148412205(G,A); rs10422883(A,G); rs113724427(G,C); rs10404220(G,A); rs75300785(C,A); rs10418603(G,T); rs75271991(G,A); rs78133855(A,C); rs12611358(G,A); rs140565511(C,T); rs4802274(A,G); rs143438195(C,T); rs8107659(G,T); rs10416076(G,A); rs11083781(C,T); rs114817925(G,C); rs191451754(A,C); rs10404730(A,C); rs918164(A,G); rs10419334(G,T); rs77185077(G,A); rs78898068(T,C); rs7260651(G,A); rs4802275(C,T); rs4802276(T,C); rs4802277(G,A); rs2341096(A,G); rs725660(C,A) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 388553 |
| snpEff Gene Name | AC074212.3 |
| EntrezGene Description | uncharacterized LOC388553 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.7077 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.021978021978 |
| dbNSFP KGp1 Afr AF | 0.0345528455285 |
| dbNSFP KGp1 Amr AF | 0.0303867403315 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0263852242744 |
| dbSNP GMAF | 0.02204 |
| ExAC AF | 0.017 |
IRF2BP1
| dbSNP name | rs3745926(T,C) |
| ccdsGene name | CCDS12678.1 |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 26145 |
| EntrezGene Description | interferon regulatory factor 2 binding protein 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | IRF2BP1:NM_015649:exon1:c.A1530G:p.L510L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3095 |
| ESP Afr MAF | 0.486752 |
| ESP All MAF | 0.288842 |
| ESP Eur/Amr MAF | 0.187456 |
| ExAC AF | 0.224 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Retrognathia;
[Mouth];
High-arched palate
CHEST:
[Breasts];
Widely-spaced nipples
SKELETAL:
Arthrogryposis
MUSCLE, SOFT TISSUE:
Hypotonia, severe;
Defects in mitochondria respiratory activities, mainly complexes I,
II, and IV;
Defects in lipoate-containing mitochondrial enzyme complexes
NEUROLOGIC:
[Central nervous system];
Encephalopathy;
Hypotonia, severe;
Absent primitive reflexes;
Cerebral atrophy;
Polymicrogyria;
Hypoplasia of the corpus callosum;
Hypoplasia of the medulla oblongata;
Cortical cytotoxic edema;
White matter abnormalities
METABOLIC FEATURES:
Lactic acidosis;
Metabolic acidosis
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios
LABORATORY ABNORMALITIES:
Increased serum and CSF lactate;
Increased serum and CSF glycine
MISCELLANEOUS:
Onset in utero;
Death in the perinatal period;
Two sibs have been reported (last curated July 2013)
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae IBA57 gene
(IBA57, 615316.0001)
OMIM Title
*615331 INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN 1; IRF2BP1
;;IRF2-BINDING PROTEIN 1
OMIM Description
DESCRIPTION
IRF2 (147576) belongs to a family of proteins that play a major role in
the transcriptional regulation of type I interferon (e.g., IFNA; 147660)
in response to viral infection and of genes that are regulated in
response to type I and type II (e.g., IFNG; 147570) interferons. IRF2BP1
and IRF2BP2 (615332) bind to the C-terminal repression domain of IRF2
and have properties of IRF2-dependent transcriptional corepressors
(Childs and Goodbourn, 2003).
CLONING
By yeast 2-hybrid screening of a placenta cDNA library using the
C-terminal repression domain of IRF2 as bait, Childs and Goodbourn
(2003) isolated cDNAs encoding IRF2BP1 and 2 isoforms of IRF2BP2. The
predicted 584-amino acid IRF2BP1 protein contains an N-terminal C4 zinc
finger motif and a C-terminal C3HC4 RING finger. Western blot analysis
of cytoplasmic and nuclear extracts of transfected cells showed that
IRF2BP1 and both IRF2BP2 isoforms localized to the nucleus.
GENE FUNCTION
Using yeast 2-hybrid analysis, Childs and Goodbourn (2003) showed that
IRF2BP1 and both IRF2BP2 isoforms interacted specifically with the 58
C-terminal amino acids of IRF2, but not with IRF1 (147575) or IRF9
(147574). The IRF2BP proteins failed to interact with themselves or with
each other, suggesting an inability to form dimers.
Coimmunoprecipitation analysis confirmed interaction of each IRF2BP with
IRF2. Functional analysis showed that transcription repression by the
IRF2BPs occurred through their recruitment to promoters by IRF2,
independently of histone deacetylation. An IRF2 isoform lacking val177
and val178 did not interact with the IRF2BP2s, suggesting that the
relative conformation of the DNA-binding domain and the C-terminal
region of IRF2 is crucial for transcriptional repression.
Using epitope tagging with coimmunoprecipitation analysis for
confirmation, Kimura (2008) identified IRF2BP1 as a JDP2
(608657)-binding protein. IRF2BP1 enhanced ubiquitination of JDP2, which
required the IRF2BP1 RING finger domain. IRF2BP1 repressed ATF2
(123811)-mediated transcriptional activation, as shown by luciferase
analysis, independently of IRF2BP1 ubiquitin ligase activity. Protein
pull-down assays showed that IRF2BP1 interacted with ATF2 directly.
MAPPING
Gross (2013) mapped the IRF2BP1 gene to chromosome 19q13.32 based on an
alignment of the IRF2BP1 sequence (GenBank GENBANK BC038222) with the
genomic sequence (GRCh37).
NANOS2
| dbSNP name | rs8111011(G,A); rs1422627(C,T) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 339345 |
| EntrezGene Description | nanos homolog 2 (Drosophila) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2016 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Low anterior hairline;
Micrognathia;
Short philtrum;
[Eyes];
Hyperopia;
Cataracts, rapid-onset;
Aphakic glaucoma;
[Mouth];
Full lips;
[Teeth];
Prominent widely-spaced incisors
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect
CHEST:
[Breasts];
Inverted nipples
SKELETAL:
Decreased bone density;
Delayed bone age;
[Spine];
Tethered spinal cord;
Compression deformities of the spine;
Scoliosis
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple;
[Hair];
Low anterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Central hypotonia;
Peripheral hypertonia
OMIM Title
*608228 NANOS, DROSOPHILA, HOMOLOG OF, 2; NANOS2
;;NOS2
OMIM Description
CLONING
Tsuda et al. (2003) cloned mouse Nanos2. The deduced protein contains a
zinc finger motif. Nanos2 expression was restricted to male mouse germ
cells.
Using quantitative PCR, Angeles Julaton and Reijo Pera (2011) detected
highest NANOS2 expression in adult and fetal testis. Weaker NANOS2
expression was detected in other fetal tissues, particularly in brain,
kidney, liver, lung, ovary, skeletal muscle, spleen, and thymus. NANOS2
was also detected in adult ovary and spleen, with little to no
expression in other adult tissues. Western blot analysis detected NANOS2
at an apparent molecular mass of 24 kD in adult and fetal testis and
ovary.
MAPPING
Hartz (2013) mapped the NANOS2 gene to chromosome 19q13.32 based on an
alignment of the NANOS2 sequence (GenBank GENBANK BC042883) with the
genomic sequence (GRCh37).
ANIMAL MODEL
Tsuda et al. (2003) found that Nanos2-null mice were viable and showed
no apparent abnormalities, but Nanos2-null testes had defects in
spermatogenesis. The weight of testes in 4-week-old mutant males was
reduced to about 30% of normal, and no germ cells were detected.
Morphologic examination revealed apoptotic germ cells after embryonic
day 15.5, and apoptosis continued until the germ cells had completely
disappeared by 4 weeks of age. In contrast, female gonads were
morphologically and functionally normal, and homozygous female mice were
fertile.
Using Nanos2-null mice, Suzuki and Saga (2008) showed that Nanos2
suppressed meiosis in male mouse germ cells by preventing Stra8 (609987)
expression, which was required for premeiotic DNA replication, after
Cyp26b1 (605207) downregulation. Forced expression of Nanos2 in female
germ cells resulted in inhibition of meiosis and induction of male-type
differentiation, indicating that Nanos2 activates a male-specific
genetic program.
MIR769
| dbSNP name | rs190748158(G,A) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 768217 |
| snpEff Gene Name | CCDC61 |
| EntrezGene Description | microRNA 769 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.005421 |
| ESP All MAF | 0.001651 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 5.463e-04,8.154e-06 |
CCDC8
| dbSNP name | rs10412551(G,A); rs11880658(C,T); rs140574202(C,T); rs4802310(T,C) |
| cytoBand name | 19q13.32 |
| EntrezGene GeneID | 83987 |
| EntrezGene Description | coiled-coil domain containing 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1942 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
Multiple epiphyseal dysplasia;
Early onset osteoarthritis;
[Spine];
Endplate irregularities (thoracic-lumbar vertebrae);
Schmorl's nodes;
Anterior osteophytes (thoracic-lumbar vertebrae);
[Pelvis];
Hip arthralgia;
[Limbs];
Knee arthralgia;
Irregular epiphyses (knee)
MISCELLANEOUS:
Onset in childhood;
MED is a heterogeneous disorder (see MED1 (132400), MED2 (600204),
MED3 (600969), MED4 (226900), MED5 (608078), and MED with diabetes
mellitus (226980))
MOLECULAR BASIS:
Caused by mutation in the collagen IX, alpha-1 polypeptide gene (COL9A1,
120210.0001)
OMIM Title
*614145 COILED-COIL DOMAIN-CONTAINING PROTEIN 8; CCDC8
OMIM Description
CLONING
By searching for genes in a potential 3M syndrome locus on chromosome
19q, Hanson et al. (2011) identified CCDC8. The deduced 538-amino acid
protein has a calculated molecular mass of 59 kD. It has an N-terminal
domain that shares significant similarity with the N-terminal region of
PNMA (see 604010), and this is followed by an alanine-rich region that
contains a coiled-coil domain, and a second coiled-coil domain at the C
terminus. CCDC8 also contains potential sites for amidation,
glycosylation, phosphorylation, and myristoylation. RT-PCR analysis
detected variable CCDC8 expression in all tissues examined. Western blot
analysis detected endogenous CCDC8 at an apparent molecular mass of
about 90 kD, suggesting extensive posttranslational modification.
Database analysis revealed orthologs of CCDC8 in placental mammals only.
GENE FUNCTION
Hanson et al. (2011) observed a strong correlation between the tissue
distribution of CCDC8 and that of OBSL1 (610991) and CUL7 (609577),
which are also implicated in 3M syndromes (6122921 and 273750,
respectively). Immunoprecipitation analysis of cotransfected HEK293
cells revealed that OBSL1 interacted with both CCDC8 and CUL7, but CCDC8
did not interact with CUL7. Hanson et al. (2011) proposed that OBSL1 may
act as an adaptor protein linking CUL7 and CCDC8.
GENE STRUCTURE
Hanson et al. (2011) stated that CCDC8 is a single-exon gene.
MAPPING
By database analysis, Hanson et al. (2011) mapped the CCDC8 gene to
chromosome 19q13.2-q13.32.
MOLECULAR GENETICS
By autozygosity mapping followed by exome sequencing of 3 Asian patients
with 3M syndrome-3 (3M3; 614205), Hanson et al. (2011) identified 2
different homozygous 1-bp duplications in the CCDC8 gene (614145.0001
and 614145.0002). Both mutations were predicted to result in truncation,
consistent with a loss of function. The phenotype was characterized by
poor growth and characteristic dysmorphic features, including fleshy
tipped nose, frontal bossing, triangular face, pointed chin, short
thorax, and prominent heels. The findings supported the hypothesis that
the 3M syndrome results from defects in a pathway controlling human
growth.
TPRX1
| dbSNP name | rs12462705(G,A); rs12462695(C,A); rs111411093(C,T); rs78381908(T,C) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 284355 |
| EntrezGene Description | tetra-peptide repeat homeobox 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4545 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Dystonia, episodic, primary affects hands and feet;
Migraines (less common);
Seizures (rare)
MISCELLANEOUS:
Variable age at onset (range childhood to late adult);
Episodes typically last 2 to 5 minutes and occur daily or several
times per month;
Episodes not triggered by alcohol, caffeine, or stress;
Reduced penetrance (89%)
OMIM Title
*611166 TETRAPEPTIDE REPEAT HOMEOBOX 1; TPRX1
OMIM Description
DESCRIPTION
Homeobox genes, such as TPRX1, are characterized by the presence of a
conserved DNA sequence, the homeobox, which encodes a DNA-binding
domain, the homeodomain (Booth and Holland, 2007).
CLONING
Using PRD (see 167410)-class homeodomains to query a genome database,
Booth and Holland (2007) identified TPRX1. The deduced protein contains
58 repeated copies of a 4-amino acid motif (variants of pro-ile-pro-gly)
C-terminal to the homeodomain. EST database analysis indicated that
TPRX1 is expressed in testis, eye, and brain.
GENE STRUCTURE
Booth and Holland (2007) determined that the TPRX1 gene contains 2 exons
and spans over 2.4 kb.
MAPPING
By genomic sequence analysis, Booth and Holland (2007) mapped the TPRX1
gene to chromosome 19q13.32. They identified a duplicate TPRX copy, that
is likely a pseudogene, 35.1 kb away and on the other side of the CRX
gene (602225). They also identified 2 truncated retrotransposed
pseudogenes on chromosome 10q22.3.
FTL
| dbSNP name | rs2230267(T,C) |
| ccdsGene name | CCDS33070.1 |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 2512 |
| EntrezGene Description | ferritin, light polypeptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FTL:NM_000146:exon2:c.T163C:p.L55L, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4963 |
| ESP Afr MAF | 0.473899 |
| ESP All MAF | 0.480471 |
| ESP Eur/Amr MAF | 0.457093 |
| ExAC AF | 0.498 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Long philtrum;
Micrognathia;
Flat philtrum;
[Ears];
Low-set ears;
Poorly formed pinnae;
[Eyes];
Upward slanting palpebral fissures;
Esotropia;
[Nose];
Short nose;
Hypoplastic alae nasi;
[Mouth];
Thin upper lip;
Cleft palate
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
Pulmonary stenosis;
Truncus arteriosus
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Sprengel deformity;
Fused ribs;
Missing ribs
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
Small penis;
[External genitalia, female];
Small labia majora;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Polycystic kidneys;
Absent kidneys;
Abnormal collecting system
SKELETAL:
[Spine];
Dysplastic sacrum;
Absent vertebrae;
Hemivertebrae;
Scoliosis;
[Pelvis];
Hypoplastic acetabulae;
Constricted iliac base;
Large obturator foramina;
Vertical ischial axis;
[Limbs];
Short thighs;
Bilateral, often asymmetric involvement of femora;
Hypoplastic to absent femora;
Variable fibular involvement;
Variable humeri hypoplasia;
Radioulnar synostosis;
Radiohumeral synostosis;
Limited elbow movement;
Limited shoulder movement;
[Feet];
Talipes equinovarus;
Short third, fourth, fifth metatarsals;
Preaxial polydactyly;
Toe syndactyly
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Majority of cases are sporadic;
Prenatal history of maternal diabetes in 35% of cases
OMIM Title
*134790 FERRITIN LIGHT CHAIN; FTL
OMIM Description
DESCRIPTION
The iron storage protein ferritin is a complex of 24 L-ferritin (FTL)
and H-ferritin (FTH1; 134770) subunits in ratios that vary in different
cell types. FTH subunits exhibit ferroxidase activity, converting Fe(2+)
to Fe(3+), so that iron may be stored in the ferritin mineral core,
which prevents undesirable reactions of Fe(2+) with oxygen. FTL subunits
are devoid of catalytic activity but are thought to facilitate
nucleation and mineralization of the iron center (summary by Sammarco et
al., 2008).
CLONING
Studies of ferritin synthesis in cell-free systems by Watanabe and
Drysdale (1981) suggested that the H and L subunits in human and rat are
derived from different mRNA molecules.
Brown et al. (1983) noted that mammalian liver and spleen ferritin
(relative mass about 450 kD) consists of 24 subunits of 2 species, the
heavy subunit (relative mass, 21 kD) and the light subunit (relative
mass, 19 kD). They presented evidence that, in rat, the 2 subunits are
coded by separate mRNAs and that a family of genes encodes the light
subunit.
Cazzola et al. (1997) stated that the human ferritin L chain contains
174 residues and has an apparent molecular mass of 19 kD. They found
that serum ferritin, with an apparent molecular mass of 23 kD, was a
glycosylated form of intracellular ferritin L chain.
Curtis et al. (2001) reported that the human ferritin light chain
contains 175 residues and that the peptide folds into 5 alpha-helical
domains designated A through E.
MAPPING
By study of human/Chinese hamster hybrid cells and use of a
radioimmunoassay specific for human ferritin, Caskey et al. (1983)
showed that chromosome 19 encodes the structural gene for ferritin. By
in situ hybridization, McGill et al. (1984) confirmed the assignment of
the light chain gene to chromosome 19 but concluded that the heavy chain
is encoded by 1p. By study of hamster-human and mouse-human hybrid
cells, some with translocations involving chromosome 19, Worwood et al.
(1985) concluded that light subunits of ferritin (rich in human spleen
ferritin) are coded by a gene in segment 19q13.3-qter and that the gene
for the heavy subunit (rich in human heart ferritin) is located on
chromosome 11. By miniaturized restriction enzyme analysis of sorted
chromosomes, Lebo et al. (1985) demonstrated ferritin light-chain genes
on at least 3 chromosomes.
Munro et al. (1988) reviewed information on the ferritin genes. They
pointed out that in both the rat and the human, several ferritin
pseudogenes can be recognized not only because they are flanked by
5-prime and 3-prime direct repeats representing the site of their
retroinsertion into the chromatin, but also because they differ from
functional genes by the absence of introns and by the presence of
polyadenylic acid tails that have been inserted onto the 3-prime end of
the messenger transcription of the functional gene. They cited the
evidence of Santoro et al. (1986) and of Hentze et al. (1986) that there
is only one expressed H and one expressed L gene in the human genome.
By typing the progeny of 2 sets of genetic crosses, Filie et al. (1998)
determined the map location of loci containing sequences related to the
ferritin light chain gene in the mouse. Twelve loci were positioned on
11 different chromosomes. One of these genes mapped to a position on
chromosome 7 predicted to contain the expressed Flt1 gene on the basis
of the previously determined position of the human homolog on
19q13.3-q13.4.
GENE FUNCTION
Human ferritins expressed in yeast normally contain little iron, which
led Shi et al. (2008) to hypothesize that yeast, which do not express
ferritins, might also lack the requisite iron chaperones needed for
delivery of iron to ferritin. In a genetic screen to identify human
genes that, when expressed in yeast, could increase the amount of iron
loaded into ferritin, Shi et al. (2008) identified poly(rC) binding
protein-1 (PCBP1; 601209). PCBP1 bound to ferritin in vivo, and bound
iron and facilitated iron loading into ferritin in vitro. Depletion of
PCBP1 in human cells inhibited ferritin iron loading and increased
cytosolic iron pools. Thus, Shi et al. (2008) concluded that PCBP1 can
function as a cytosolic iron chaperone in the delivery of iron to
ferritin.
Using reporter genes expressed in HEK293 cells, Sammarco et al. (2008)
determined that expression of both FTL and FTH increased in the presence
of excess iron under normoxic culture conditions (20% oxygen). However,
expression of FTL, but not FTH, increased in the presence of excess iron
under hypoxic culture conditions (1% oxygen). Sammarco et al. (2008)
concluded that expression of FTL and FTH are differentially regulated.
Mancias et al. (2014) used quantitative proteomics to identify a cohort
of novel and known autophagosome-enriched proteins, including cargo
receptors, in human cells. Like known cargo receptors, nuclear receptor
coactivator-4 (NCOA4; 601984) was highly enriched in autophagosomes, and
associated with autophagy-8 (ATG8)-related proteins that recruit
cargo-receptor complexes into autophagosomes (see, e.g., GABARAPL2,
607452). Unbiased identification of NCOA4-associated proteins revealed
ferritin heavy chain (see FTH1, 134770) and FTL, components of an
iron-filled cage structure that protects cells from reactive iron
species but is degraded via autophagy to release iron. Mancias et al.
(2014) found that delivery of ferritin to lysosomes required NCOA4, and
an inability of NCOA4-deficient cells to degrade ferritin led to
decreased bioavailable intracellular iron. Mancias et al. (2014)
concluded that their work identified NCOA4 as a selective cargo receptor
for autophagic turnover of ferritin (ferritinophagy), which is critical
for iron homeostasis, and provided a resource for further dissection of
autophagosomal cargo-receptor connectivity.
MOLECULAR GENETICS
- Hyperferritinemia-Cataract Syndrome
Beaumont et al. (1995) identified a mutation in the iron-responsive
element (IRE) in the 5-prime noncoding region of the FTL gene
(134790.0001) in the hyperferritinemia-cataract syndrome (HHCS; 600886).
Camaschella et al. (2000) reported a father and daughter with only
modest hyperferritinemia and subclinical cataract in whom they
identified a mutation in the IRE of FTL (51G-C; 134790.0009).
In 17 unrelated patients with hyperferritinemia, 1 of whom had bilateral
cataract, Kannengiesser et al. (2009) identified heterozygosity for a
missense mutation in the FTL N terminus (T30I; 134790.0017).
- Neurodegeneration with Brain Iron Accumulation 3
Curtis et al. (2001) identified an adenine insertion after nucleotide
460 of the FTL gene (134790.0010) that is predicted to alter C-terminal
residues of the FTL gene product in patients with neurodegeneration with
brain iron accumulation-3 (NBIA3; 606159), also known as
neuroferritinopathy.
- L-ferritin Deficiency
In a healthy 52-year-old woman with low serum L-ferritin, Cremonesi et
al.(2004) identified a heterozygous mutation in the ATG start codon of
the FTL gene (M1V; 134790.0018), predicted to disable protein
translation and expression. The findings suggested that L-ferritin has
no effect on systemic iron metabolism, and suggested that
haploinsufficiency of L-ferritin does not cause neurologic or
hematologic clinical effects.
In a 23-year-old woman with autosomal recessive serum L-ferritin
deficiency, Cozzi et al.(2013) identified a homozygous truncating
mutation in the FTL gene (E104X; 134790.0019). The FTL gene was chosen
for sequencing because the patient had undetectable serum ferritin
levels. The patient had childhood generalized epilepsy, mild cognitive
impairment, alopecia, and restless legs syndrome, but no hematologic
abnormalities. Cozzi et al. (2013) stated that this was the first
patient reported with complete loss of FTL.
GENOTYPE/PHENOTYPE CORRELATIONS
The phenotype resulting from FTL mutations depends on the location of
the mutation(s) within the FTL gene. In patients with the
hyperferritinemia-cataract syndrome, mutations most commonly occur
within the iron-response element (IRE) stem loop of the FTL mRNA,
resulting in decreased affinity for iron-response protein binding and
overproduction of FTL protein. This excess ferritin aggregates in the
ocular lens. Patients with neurodegeneration with brain iron
accumulation-3 have truncating mutations in exon 4 of the FTL gene,
resulting in frameshifts and accumulation of ferritin-containing
spherical inclusions in the brain and other organs. One control
individual with haploinsufficiency of the FTL gene had low levels of
serum ferritin, but no hematologic or neurologic abnormalities,
indicating that haploinsufficiency of FTL is not pathogenic (Cremonesi
et al., 2004). Finally, 1 patient with childhood idiopathic generalized
epilepsy, mild neurocognitive impairment, and restless legs syndrome has
been reported to have complete loss of FTL; this patient had no
hematologic abnormalities (summary by Cozzi et al., 2013).
ANIMAL MODEL
Vidal et al. (2008) found that transgenic mice expressing human FTL with
the 498insTC mutation (134790.0014) developed histologic and behavioral
features that mimicked human hereditary ferritinopathy. Expression of
the transgene caused behavioral and motor dysfunction, leading to
shorter life span. Histologic and immunohistochemical analysis revealed
that, by 8 weeks of age, transgenic mice developed nuclear and
intracytoplasmic inclusions in neurons and glia throughout the central
nervous system and in postmitotic cells in most peripheral tissues.
Nuclear inclusions were made up of accumulated ferric iron,
detergent-insoluble ferritin, ubiquitinated proteins, and elements of
the proteasome. Nuclear inclusions became enlarged and almost completely
occupied the nucleus, displacing chromatin up against the nuclear
membrane.
LHB
| dbSNP name | rs1056917(A,G) |
| ccdsGene name | CCDS12748.1 |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 3972 |
| EntrezGene Description | luteinizing hormone beta polypeptide |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LHB:NM_000894:exon3:c.T285C:p.G95G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4238 |
| ESP Afr MAF | 0.278484 |
| ESP All MAF | 0.354913 |
| ESP Eur/Amr MAF | 0.39407 |
| ExAC AF | 0.604 |
OMIM Clinical Significance
GU:
Ambiguous external genitalia;
Male hypogonadism (.0001);
Male infertility;
Male pseudohermaphroditism
Misc:
Normal sexual development and fertility in female heterozygotes
Lab:
Defective lutropin beta chain;
Elevated plasma LH;
Elevated plasma FSH;
Low plasma testosterone;
46,XY chromosomes
Inheritance:
Autosomal dominant (19q13.2)
OMIM Title
+152780 LUTEINIZING HORMONE, BETA POLYPEPTIDE; LHB
;;LUTROPIN, BETA CHAIN;;
INTERSTITIAL CELL STIMULATING HORMONE, BETA CHAIN;;
CHORIONIC GONADOTROPIN, BETA POLYPEPTIDE 4; CGB4
MALE PSEUDOHERMAPHRODITISM DUE TO DEFECTIVE LH MOLECULE, INCLUDED
OMIM Description
DESCRIPTION
The glycoprotein hormone family to which luteinizing hormone belongs
includes follicle-stimulating hormone (FSH; 136530), thyroid-stimulating
hormone (TSH; 188540), and chorionic gonadotropin (CG; 118860). Each of
these hormones consists of a noncovalent dimer of alpha and beta
subunits. The alpha subunit is the same for all 4 hormones (see CGA,
118850), and the beta subunits define the endocrine function of the
dimer (Talmadge et al., 1983).
CLONING
Talmadge et al. (1984) stated that the LH-beta subunit encodes a deduced
121-amino acid protein, 6 amino acids longer than described by Sairam
and Li (1975). Luteinizing hormone is made in the pituitary and has a
central role in promoting spermatogenesis and ovulation by stimulating
the testes and ovaries to synthesize steroids (Talmadge et al., 1984).
MAPPING
Restriction enzyme mapping indicates that the genes for the beta chains
of chorionic gonadotropin and for luteinizing hormone are contiguous.
Both CGB (118860) and LHB have been assigned to chromosome 19q13.2
(Mohrenweiser et al., 1991).
GENE FUNCTION
Park et al. (1976) described a 27-year-old 'woman' who had a 46,XY
karyotype, ambiguous external genitalia, and elevated plasma LH, with
slightly elevated FSH and low testosterone in plasma. Her plasma
testosterone level increased 15- to 20-fold after stimulation with human
CG. The authors postulated that the secretion of an abnormal LH molecule
that was immunoreactive but biologically inactive, i.e., a CRM+
mutation, was responsible. One might expect that an abnormal LH molecule
would produce hypergonadotropic hypogonadism. Indeed, Axelrod et al.
(1979) described hypogonadism in a male with immunologically active,
biologically inactive luteinizing hormone.
One of the major structural differences between the LHB and CGB subunits
is the C-terminal region. Beyond residue 114, LHB has a hydrophobic
heptapeptide stretch, whereas CGB contains a 31-residue hydrophilic
C-terminal peptide (CTP) that is O-glycosylated. The CGB subunit is
secreted quantitatively as a monomer and assembles efficiently, whereas
secretion and assembly of LHB is inefficient. Muyan et al. (1996) tested
the function of the heptapeptide and CTP domains by fusing them to their
counterparts at residues 114 of CGB or LHB subunits. The secretion and
assembly of these chimeras were examined in transfected Chinese hamster
ovary (CHO) cells. Removal of the heptapeptide enhanced the amount of
LHB subunit secreted 4-fold compared with intact LHB. Fusion of this
heptapeptide to CGB 114, i.e., CGB lacking the CTP, decreased the amount
of secreted subunit 2-fold compared with wildtype human CGB. These data
supported the hypothesis that the C-terminal regions of LHB and CGB
subunits play a role in the intracellular behavior of the corresponding
heterodimers.
Both the LHB and FSHB genes are expressed in gonadotropes, but LHB is
more dependent on GNRH (152760) input than is FSHB (Albanese et al.,
1996).
Curtin et al. (2001) tested direct pituitary effects of the androgen
dihydrotestosterone (DHT) to modulate the rat LH-beta promoter. The
LH-beta promoter (-617 to +44 bp)-luciferase construct was stimulated in
L-beta-T2 cells 7- to 10-fold by GNRH. Androgen treatment had little
effect on basal promoter activity but suppressed GNRH stimulation by
approximately 75%. GNRH stimulation of the LH-beta promoter requires
interactions between a complex distal response element containing 2
specificity protein-1 (Sp1) binding sites and a CArG box, and a proximal
element with 2 bipartite binding sites for steroidogenic factor-1
(184757) and early growth response protein-1 (EGR-1; 128990) (Weck et
al., 2000; Kaiser et al., 2000). The distal response element does not
bind androgen receptor (AR; 313700), but AR reduces Sp1 binding to this
region.
Concentrations of LH and FSH are known to increase during normal
pubertal development. Phillips et al. (1997) examined the median charge
of serum LH and FSH using agarose in 81 normal children at pubertal
stages I to V. In pubertal girls there were no significant differences
in the median charge of LH. In boys there was a significant (p less than
0.01) shift to more acidic isoforms of LH by pubertal stage II. Further
changes were not found later in puberty. Except for LH at pubertal stage
I, where the median charge was similar for both sexes, the median charge
was more basic (p less than 0.001) for LH in girls compared with boys at
all 5 pubertal stages. The authors concluded that while there are few
qualitative changes in the gonadotropins during normal female puberty,
there is a dramatic shift to more acidic isoforms of LH early in male
puberty.
Reproduction depends on regulated expression of the LH-beta gene. Tandem
copies of regulatory elements that bind early growth response protein-1
(Egr1; 128990) and steroidogenic factor-1 (SF1; 184757) are located in
the proximal region of the LH-beta promoter and make essential
contributions to its activity as well as mediate responsiveness to GNRH
(152760). Located between these tandem elements is a single site capable
of binding the homeodomain protein Pitx1 (602149). Quirk et al. (2001)
reassessed the requirement for a Pitx1 element in the promoter of the
LH-beta gene using homologous cell lines and transgenic mice. Their
analysis indicated a striking requirement for the Pitx1 regulatory
element. When assayed by transient transfection using a
gonadotrope-derived cell line, an LH-beta promoter construct harboring a
mutant Pitx1 element displayed attenuated transcriptional activity but
retained responsiveness to GNRH. In contrast, analysis of wildtype and
mutant expression vectors in transgenic mice indicated that LH-beta
promoter activity is completely dependent on the presence of a
functional Pitx1 binding site. The authors concluded that collectively,
their data reinforce the concept that activity of the LH-beta promoter
is determined, in part, through highly cooperative interactions between
SF1, Egr1, and Pitx1. While Egr1 can be regarded as a key downstream
effector of GNRH, and Pitx1 as a critical partner that activates SF1,
they suggested that their data firmly establish that the Pitx1 element
plays a vital role in permitting these functions to occur in vivo.
Manna et al. (2002) synthesized recombinant forms of wildtype and
variant LH in human embryonic kidney (HEK) 293 cells. Although the
mutations in variant LH-beta did not significantly affect the affinity
of LH receptor (152790) binding, variant LH had higher in vitro
biopotency than wildtype LH, in terms of LTC1 mouse Leydig tumor cell
cAMP and progesterone production, and steroidogenic acute regulatory
protein expression. In addition, in HEK293 cells expressing the human LH
receptor, variant LH demonstrated 1.8-fold higher response of inositol
trisphosphate (IP3) production than wildtype LH. Furthermore, HEK293
cells expressing the ELK1 trans-reporting plasmids displayed 2.7-fold
greater luciferase response to variant LH than wildtype LH, documenting
stimulation of the mitogen-activated protein kinase (MAPK) pathway. The
in vivo half-life of variant LH was clearly faster than that of wildtype
LH and human chorionic gonadotropin when injected into rat circulation.
Analysis by matrix-assisted laser desorption ionization mass
spectrometry demonstrated clear differences in structures of
carbohydrate side chains attached to the 2 forms of recombinant LHs,
including incomplete processing of high mannose glycans in variant LH,
suggesting different pathways in its intracellular trafficking.
Before ovulation in mammals, a cascade of events resembling an
inflammatory and/or tissue remodeling process is triggered by LH in the
ovarian follicle. Many LH effects, however, are thought to be indirect
because of the restricted expression of its receptor (LHR; 152790) to
mural granulosa cells (Peng et al., 1991). Park et al. (2004)
demonstrated that LH stimulation in wildtype mouse ovaries induces the
transient and sequential expression of the epidermal growth factor
family members amphiregulin (104640), epiregulin (602061), and
betacellulin (600345). Incubation of follicles with these growth factors
recapitulates the morphologic and biochemical events triggered by LH,
including cumulus expansion and oocyte maturation. Thus, Park et al.
(2004) concluded that these EGF-related growth factors are paracrine
mediators that propagate the LH signal throughout the follicle.
MOLECULAR GENETICS
Roy et al. (1996) described a novel genetic variant of LH, due to a
1502G-A transition in the LHB gene, causing replacement of glycine by
serine at amino acid 102 in the LH beta subunit (152780.0003).
Subsequently, Liao et al. (1998) and Ramanujam et al. (1999, 2000)
identified associations between this variant in both male and female
infertility. To determine the effect of this beta subunit gene mutation
on LH functions in vitro, Liao et al. (2002) used site-directed
mutagenesis to construct the variant LH beta subunit gene. They tested
its bioactivities when expressed in CHO cells cotransfected with the
variant beta subunit and native alpha subunit genes as compared with
wildtype LH. The amino acid replacement did not result in the change of
efficiency of dimerization of the alpha and beta subunits. However,
variant LH had significantly lower receptor-binding activity and lower
biopotency for progesterone production than wildtype LH at the higher
concentrations of LH.
An association between some variants of luteinizing hormone and
ovulatory disorders, including infertility, is observed in Japan.
Takahashi et al. (2003) searched for other polymorphisms and
interactions with the LHB variant as a potential basis for the
association with ovulatory disorders in 3 Japanese groups: 43 females
with ovulatory disorders, 79 females with normal ovulation, and 23
healthy males. PCR-amplified LH beta subunit gene sequencing detected 5
novel silent polymorphisms. The 1036C-A transition allele was most
frequent (0.945), with no homozygotes for wildtype observed, and was
detected significantly more often in patients with polycystic ovary
syndrome (184700), endometriosis (131200), premature ovarian failure,
and luteal insufficiency compared to healthy women. Three other novel
alleles (894C-T, 1098C-T, and 1423C-T) were found significantly more
frequently in women with ovulatory disorders, as was the overall
incidence of point mutations. There was linkage disequilibrium in the
presence of the LHB variant; 87.5% of women with the LHB variant and
ovulatory disorders also had silent polymorphisms, although the silent
polymorphisms were infrequent in the subset without ovulatory disorders.
Takahashi et al. (2003) concluded that the silent polymorphisms could
influence the LHB variant association with ovulatory disorders in the
Japanese population.
ANIMAL MODEL
Ma et al. (2004) found that targeted disruption of the Lhb gene in mice
did not affect embryonic development and viability, but it resulted in
postnatal defects in gonadal growth and function, resulting in
infertility. Mutant males had decreased testis size, prominent Leydig
cell hypoplasia, defects in expression of genes encoding steroid
biosynthesis pathway enzymes, reduced testosterone levels, and blockage
of spermatogenesis at the round spermatid stage. Mutant female mice were
hypogonadal and demonstrated decreased levels of serum estradiol and
progesterone. Ovarian histology demonstrated normal thecal layer,
defective folliculogenesis with many degenerating antral follicles, and
absence of corpora lutea. FSH levels were unaffected in null mice, and
the phenotype could be rescued by exogenous human chorionic
gonadotropin, indicating that LH responsiveness of the target cells was
not irreversibly lost.
SNAR-G2
| dbSNP name | rs3810177(T,C) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 100170228 |
| snpEff Gene Name | CGB1 |
| EntrezGene Description | small ILF3/NF90-associated RNA G2 |
| EntrezGene Type of gene | snRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3228 |
CGB1
| dbSNP name | rs10853805(A,C) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 114335 |
| snpEff Gene Name | CGB2 |
| EntrezGene Description | chorionic gonadotropin, beta polypeptide 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3792 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts
CARDIOVASCULAR:
[Heart];
Cardiomyopathy, hypertrophic
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
MUSCLE, SOFT TISSUE:
Distal muscle weakness, occurs initially;
Proximal muscle weakness occurs later;
Limb-girdle muscle weakness;
Foot drop;
Hyporeflexia at ankle joints;
EMG shows myopathic changes;
Neck muscle weakness;
Trunk muscle weakness;
Velopharyngeal muscle weakness;
Muscle biopsy shows dystrophic changes;
Fiber size variation;
Fiber splitting;
Accumulation of intrasarcoplasmic granulofilamentous aggregates that
are immunoreactive to desmin and alpha-beta-crystallin;
Autophagic vacuoles;
Z-disks with abnormal homogeneous material
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset;
Slowly progressive;
Clinical variability;
Two patients without cardiomyopathy or cataracts have been reported
MOLECULAR BASIS:
Caused by mutation in the alpha-B-crystallin gene (CRYAB, 123590.0001)
OMIM Title
*608823 CHORIONIC GONADOTROPIN, BETA POLYPEPTIDE 1; CGB1
OMIM Description
DESCRIPTION
The placental hormone chorionic gonadotropin (CG) is a member of a
glycoprotein hormone family that includes the pituitary hormones
luteinizing hormone (LH; 152780), follicle-stimulating hormone (FSH;
136530), and thyroid-stimulating hormone (TSH; 188540). Each of these
hormones consists of a noncovalent dimer of alpha and beta subunits. The
alpha subunit is the same for all 4 hormones (see CGA; 118850), and the
beta subunits define the endocrine function of the dimer (Talmadge et
al., 1983).
CLONING
By restriction digest analysis, Talmadge et al. (1983) determined that
the 7 CGB genes are extremely similar but not identical. Bo and Boime
(1992) determined that most of the sequence variation among the CGB
genes occurs in the nontranslated region of exon 1. They stated that
CGB1 and CGB2 (608824) were thought to be pseudogenes; however, RT-PCR
of first trimester placenta RNA and placenta polysomal RNA detected both
CGB1 and CGB2. Expression in polysomal RNA suggested that the
transcripts are translated. Northern blot analysis detected lower
expression of these transcripts in comparison to those of other CGBs;
transcripts were smaller owing to the use of a cryptic splice site. The
open reading frames were also significantly different than those of
other CGBs.
GENE STRUCTURE
Jameson and Lindell (1988) determined that each of the CGB genes
contains 3 exons. Otani et al. (1988) determined that the CGB promoter
regions contain no CAAT or TATAA boxes. Policastro et al. (1983)
observed that CGB1 contains a noncanonic donor splice sequence at the
exon 1-intron 1 boundary.
MAPPING
Talmadge et al. (1983) mapped the CGB1 gene to a gene cluster that
contains 7 CGB genes and LHB (152780). This gene cluster is located on
chromosome 19q13.32. Jameson and Lindell (1988) determined that the CGB
gene cluster spans 68 kb.
CGB8
| dbSNP name | rs35930240(A,T) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 94115 |
| snpEff Gene Name | CGB5 |
| EntrezGene Description | chorionic gonadotropin, beta polypeptide 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.04717 |
| ESP All MAF | 0.044737 |
| ESP Eur/Amr MAF | 0.043683 |
C19orf73
| dbSNP name | rs2232003(T,C) |
| ccdsGene name | CCDS42589.1 |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 55150 |
| EntrezGene Description | chromosome 19 open reading frame 73 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C19orf73:NM_018111:exon1:c.A316G:p.S106G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9NVV2 |
| dbNSFP Uniprot ID | CS073_HUMAN |
| dbNSFP KGp1 AF | 0.702380952381 |
| dbNSFP KGp1 Afr AF | 0.776422764228 |
| dbNSFP KGp1 Amr AF | 0.718232044199 |
| dbNSFP KGp1 Asn AF | 0.517482517483 |
| dbNSFP KGp1 Eur AF | 0.786279683377 |
| dbSNP GMAF | 0.298 |
| ESP Afr MAF | 0.254225 |
| ESP All MAF | 0.220003 |
| ESP Eur/Amr MAF | 0.202767 |
| ExAC AF | 0.753 |
ADM5
| dbSNP name | rs73588418(C,G); rs60730355(G,T); rs61201794(C,T); rs10425688(C,T); rs201107314(A,G); rs45492293(A,G) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 199800 |
| snpEff Gene Name | PRMT1 |
| EntrezGene Description | adrenomedullin 5 (putative) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.006887 |
LOC101928378
| dbSNP name | rs10418141(C,A); rs2290286(C,T); rs7256094(C,T); rs7257463(T,A) |
| ccdsGene name | CCDS12782.1 |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 53635 |
| EntrezGene Symbol | PTOV1 |
| snpEff Gene Name | PNKP |
| EntrezGene Description | prostate tumor overexpressed 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2631 |
SNAR-F
| dbSNP name | rs12973086(C,A); rs35925366(T,A); rs35405362(T,C) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 100126781 |
| EntrezGene Description | small ILF3/NF90-associated RNA F |
| EntrezGene Type of gene | snRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2466 |
CLEC11A
| dbSNP name | rs1053020(T,G) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 6320 |
| EntrezGene Description | C-type lectin domain family 11, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3411 |
MGC45922
| dbSNP name | rs2411334(A,G) |
| cytoBand name | 19q13.33 |
| EntrezGene GeneID | 284365 |
| snpEff Gene Name | AC010325.1 |
| EntrezGene Description | uncharacterized LOC284365 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3884 |
| ExAC AF | 0.486 |
CLDND2
| dbSNP name | rs78557740(C,G) |
| cytoBand name | 19q13.41 |
| EntrezGene GeneID | 125875 |
| snpEff Gene Name | NKG7 |
| EntrezGene Description | claudin domain containing 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02847 |
ERVV-1
| dbSNP name | rs144326310(G,A) |
| cytoBand name | 19q13.41 |
| EntrezGene GeneID | 147664 |
| EntrezGene Description | endogenous retrovirus group V, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 4.591E-4 |
ZNF818P
| dbSNP name | rs114094934(A,C); rs10853858(A,G); rs10853859(A,G); rs62117782(C,T); rs59782712(A,C); rs7247982(A,G); rs1136205(G,A); rs9788(A,G) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 390963 |
| EntrezGene Description | zinc finger protein 818, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009642 |
VN1R2
| dbSNP name | rs61576844(T,G); rs2965248(C,T); rs2965249(T,C); rs200264390(A,G); rs113873413(C,T); rs201104873(C,T) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 317701 |
| snpEff Gene Name | ZNF677 |
| EntrezGene Description | vomeronasal 1 receptor 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2268 |
| ExAC AF | 0.174 |
VN1R4
| dbSNP name | rs148896466(C,G) |
| ccdsGene name | CCDS33099.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 317703 |
| EntrezGene Description | vomeronasal 1 receptor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | VN1R4:NM_173857:exon1:c.G73C:p.V25L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7Z5H5 |
| dbNSFP Uniprot ID | VN1R4_HUMAN |
| dbNSFP KGp1 AF | 0.0425824175824 |
| dbNSFP KGp1 Afr AF | 0.15243902439 |
| dbNSFP KGp1 Amr AF | 0.0220994475138 |
| dbNSFP KGp1 Asn AF | 0.00699300699301 |
| dbNSFP KGp1 Eur AF | 0.00791556728232 |
| dbSNP GMAF | 0.0427 |
| ESP Afr MAF | 0.160236 |
| ESP All MAF | 0.054898 |
| ESP Eur/Amr MAF | 0.00093 |
| ExAC AF | 0.017 |
BIRC8
| dbSNP name | rs34683072(G,A); rs35700345(C,T); rs8109165(G,A); rs35880972(C,T); rs61744061(G,A); rs2865248(A,G); rs7260390(T,A); rs75354845(C,G); rs78399115(C,T); rs10401943(T,A) |
| ccdsGene name | CCDS12863.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 112401 |
| EntrezGene Description | baculoviral IAP repeat containing 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | BIRC8:NM_033341:exon1:c.C674T:p.A225V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.059 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96P09 |
| dbNSFP Uniprot ID | BIRC8_HUMAN |
| dbNSFP KGp1 AF | 0.0265567765568 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.0469613259669 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0435356200528 |
| dbSNP GMAF | 0.02663 |
| ESP Afr MAF | 0.014526 |
| ESP All MAF | 0.033523 |
| ESP Eur/Amr MAF | 0.043256 |
| ExAC AF | 0.039 |
MIR1283-1
| dbSNP name | rs57111412(A,G) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 100302265 |
| snpEff Gene Name | MIR515-2 |
| EntrezGene Description | microRNA 1283-1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2268 |
| ESP Afr MAF | 0.40051 |
| ESP All MAF | 0.178058 |
| ESP Eur/Amr MAF | 0.080681 |
| ExAC AF | 0.154 |
MIR519D
| dbSNP name | rs116796400(A,G) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 574480 |
| snpEff Gene Name | MIR517A |
| EntrezGene Description | microRNA 519d |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.002755 |
| ESP Afr MAF | 0.013712 |
| ESP All MAF | 0.004175 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001322 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly (about 3 SD below the mean)
NEUROLOGIC:
[Central nervous system];
Developmental delay, severe;
Hypotonia;
Seizures;
Myoclonic seizures;
Hypsarrhythmia;
Simplified gyral pattern;
Thin corpus callosum;
Delayed myelination;
Apoptosis of neurons
ENDOCRINE FEATURES:
Diabetes mellitus, infantile;
Few and small islets of Langerhans;
Hypogonadism (1 patient)
MISCELLANEOUS:
Two families have been reported (as of September 2011);
Death before age 3 years
MOLECULAR BASIS:
Caused by mutation in the immediate-early response 3-interacting protein
1 (IER3IP1, 609382.0001)
OMIM Title
*614247 MICRO RNA 519D; MIR519D
;;miRNA519D;;
MIRN519D
OMIM Description
DESCRIPTION
MicroRNAs (MiRNAs), such as MIR519D, are noncoding RNAs of approximately
22 nucleotides that function as posttranscriptional regulators. They do
so predominantly by binding to complementary sequences in the 3-prime
UTRs of target mRNAs and altering mRNA stability and translational
efficiency (Hou et al., 2011).
GENE FUNCTION
Hou et al. (2011) showed that MIR519D was downregulated in human
hepatocellular carcinomas (HCCs) and that expression of MIR519D could
suppress growth in the QGY-7703 human HCC cell line. Bioinformatic
analysis revealed a potential MIR519D-binding site in the 3-prime UTR of
MKI67 (176741), which is associated with cellular proliferation and
cancer progression. Overexpression of MIR519D significantly
downregulated MKI67 and reduced colony formation by QGY-7703 cells.
RT-PCR revealed an overall increase in MKI67 expression and a decrease
in MIR519D expression in 10 HCCs compared with adjacent normal tissue.
MAPPING
Hartz (2011) mapped the MIR519D gene to chromosome 19q13.42 based on an
alignment of the mature MIR519D sequence (CAAAGUGCCUCCCUUUAGAGUG) with
the genomic sequence (GRCh37).
MIR520H
| dbSNP name | rs56013413(G,A) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 574493 |
| snpEff Gene Name | MIR517C |
| EntrezGene Description | microRNA 520h |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | miRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0831 |
| ESP Afr MAF | 0.209184 |
| ESP All MAF | 0.084904 |
| ESP Eur/Amr MAF | 0.030455 |
| ExAC AF | 0.047 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKELETAL:
[Hands];
Amyotrophy of the intrinsic hand muscles;
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Muscle weakness, distal;
Muscle atrophy, distal
NEUROLOGIC:
[Central nervous system];
Unstable gait;
[Peripheral nervous system];
Decreased motor nerve conduction velocities;
Areflexia;
Hyporeflexia
MISCELLANEOUS:
Onset in first or second decade;
One family (4 affected members) has been reported (last curated July
2012)
MOLECULAR BASIS:
Caused by mutation in the receptor expression-enhancing protein 1
gene (REEP1, 609139.0006)
OMIM Title
*614755 MICRO RNA 520H; MIR520H
;;miRNA520H
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs), such as MIR520H, regulate gene expression
posttranscriptionally by pairing with complementary nucleotide sequences
in the 3-prime UTRs of target mRNAs (Wang et al., 2010).
GENE FUNCTION
Wang et al. (2010) identified an MIR520H target sequence in the ABCG2
(603756) transcript. Expression of an MIR520H mimic in PANC-1 human
pancreatic cancer cells reduced ABCG2 mRNA and protein expression and
reduced cell migration. MIR520H had no effect on PANC-1 cell
proliferation, cell cycle, or apoptosis.
MAPPING
Hartz (2012) mapped the MIR520H gene to chromosome 19q13.42 based on an
alignment of the MIR520H stem-loop sequence
(UCCCAUGCUGUGACCCUCUAGAGGAAGCACUUUCUGUUUGUUGUCUGAGAAAAAACAAAGUGCUUCCCUUUAGAGUUACUGUUUGGGA)
with the genomic sequence (GRCh37). The MIR520G gene, which encodes a
mature miRNA nearly identical to that encoded by the MIR520H gene, is
located about 20 kb from MIR520H.
MIR4752
| dbSNP name | rs4112253(G,C) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 100616171 |
| snpEff Gene Name | LILRB2 |
| EntrezGene Description | microRNA 4752 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1928 |
| ExAC AF | 0.106 |
LENG9
| dbSNP name | rs10423424(C,G); rs61747214(G,A) |
| ccdsGene name | CCDS12895.2 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 94059 |
| EntrezGene Description | leukocyte receptor cluster (LRC) member 9 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LENG9:NM_198988:exon1:c.G1496C:p.R499P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96B70 |
| dbNSFP Uniprot ID | LENG9_HUMAN |
| dbNSFP KGp1 AF | 0.561355311355 |
| dbNSFP KGp1 Afr AF | 0.829268292683 |
| dbNSFP KGp1 Amr AF | 0.533149171271 |
| dbNSFP KGp1 Asn AF | 0.351398601399 |
| dbNSFP KGp1 Eur AF | 0.559366754617 |
| dbSNP GMAF | 0.4389 |
| ESP Afr MAF | 0.255107 |
| ESP All MAF | 0.387538 |
| ESP Eur/Amr MAF | 0.455434 |
| ExAC AF | 0.539,8.176e-06 |
LOC101928804
| dbSNP name | rs2304224(G,T) |
| ccdsGene name | CCDS12904.1 |
| CosmicCodingMuts gene | KIR2DL1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 101928804 |
| snpEff Gene Name | KIR2DL1 |
| EntrezGene Description | uncharacterized LOC101928804 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | KIR2DL1:NM_014218:exon1:c.G13T:p.V5F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6IST4 |
| dbNSFP KGp1 AF | 0.18543956044 |
| dbNSFP KGp1 Afr AF | 0.0792682926829 |
| dbNSFP KGp1 Amr AF | 0.162983425414 |
| dbNSFP KGp1 Asn AF | 0.117132867133 |
| dbNSFP KGp1 Eur AF | 0.316622691293 |
| dbSNP GMAF | 0.185 |
| ESP Afr MAF | 0.105983 |
| ESP All MAF | 0.242245 |
| ESP Eur/Amr MAF | 0.312277 |
| ExAC AF | 0.235 |
RDH13
| dbSNP name | rs4029(A,G); rs4806637(A,G); rs10666(A,G); rs1626971(C,T); rs1671221(G,A); rs754235(T,C); rs116526674(C,T); rs115818785(G,A); rs775821(G,A); rs17296594(G,A); rs3745913(C,T); rs114935525(G,A); rs146678400(A,G); rs150332635(G,A); rs2305543(G,A); rs201701999(C,T); rs80309968(T,C); rs4806467(C,G); rs139123052(T,C); rs62122054(G,C); rs775824(T,C); rs775825(C,T); rs10418948(C,T); rs115911234(A,G); rs116216690(A,G); rs6509916(A,G); rs114411619(C,G); rs775826(A,G); rs775827(C,T); rs775828(G,A); rs62122055(G,T); rs775829(T,G); rs4588108(T,A); rs4447548(G,C); rs2124090(G,T); rs2124089(G,C); rs61215036(C,A); rs139481320(G,A); rs1671170(A,T); rs11084387(G,A); rs11672111(G,C); rs11672139(G,A); rs76119016(G,A); rs73059044(T,C); rs113400937(G,A); rs10424361(T,C); rs10423151(G,A); rs10424374(T,C); rs1654444(T,G); rs10424969(T,G); rs141300342(G,T); rs8101745(T,C); rs28591280(A,C); rs1671172(C,T); rs147161892(G,A); rs148588179(C,T); rs116646788(G,A); rs114476684(T,C); rs114184798(G,A); rs12608988(G,A); rs199574409(G,A); rs201546457(A,C); rs12608979(C,T); rs12609004(G,T); rs73615874(A,G); rs116644211(C,T); rs1654445(A,T); rs10418395(C,T); rs148641945(C,T); rs11668339(G,A); rs140039120(G,T); rs145692399(T,C); rs2365720(C,A); rs115036600(T,C); rs185241843(T,C); rs150089876(T,G); rs149283501(C,A); rs144491427(T,C); rs139724258(A,G); rs1654446(A,G); rs1654447(A,G); rs114180071(T,C); rs1671176(A,C); rs115813890(A,G); rs115499123(G,C); rs1654448(A,G); rs62122059(G,A); rs142437057(T,A); rs1654449(A,G); rs7245554(G,A); rs116249398(C,T); rs1654452(A,G); rs1654453(T,G); rs116836547(A,G); rs28616112(G,A); rs1671169(G,A); rs1654454(G,A); rs1654459(G,A); rs57718148(C,T); rs116960457(G,A); rs59276232(G,T); rs57387991(C,A); rs4806640(A,T); rs58314744(C,T); rs1654460(T,C); rs73059063(G,T); rs1654463(G,T); rs1654464(T,C); rs1654465(T,C); rs1654466(G,A); rs11084389(C,T) |
| ccdsGene name | CCDS42627.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 112724 |
| EntrezGene Description | retinol dehydrogenase 13 (all-trans/9-cis) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RDH13:NM_138412:exon5:c.G205A:p.E69K,RDH13:NM_001145971:exon4:c.G418A:p.E140K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.743 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NBN7 |
| dbNSFP Uniprot ID | RDH13_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.004668 |
| ESP All MAF | 0.001606 |
| ESP Eur/Amr MAF | 0.000119 |
| ExAC AF | 0.0006528 |
TMEM190
| dbSNP name | rs77912983(G,A) |
| ccdsGene name | CCDS33113.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 147744 |
| EntrezGene Description | transmembrane protein 190 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM190:NM_139172:exon5:c.G414A:p.T138T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.05647 |
| ESP Afr MAF | 0.064487 |
| ESP All MAF | 0.067364 |
| ESP Eur/Amr MAF | 0.068837 |
| ExAC AF | 0.055 |
MIR6805
| dbSNP name | rs56312243(C,T) |
| ccdsGene name | CCDS12924.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 6158 |
| EntrezGene Symbol | RPL28 |
| snpEff Gene Name | RPL28 |
| EntrezGene Description | ribosomal protein L28 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03765 |
| ESP Afr MAF | 0.025494 |
| ESP All MAF | 0.047634 |
| ESP Eur/Amr MAF | 0.058927 |
| ExAC AF | 0.036 |
ZNF784
| dbSNP name | rs751729(G,A) |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 147808 |
| EntrezGene Description | zinc finger protein 784 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2663 |
ZNF580
| dbSNP name | rs12981222(C,T); rs11233(G,A) |
| ccdsGene name | CCDS12931.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 51157 |
| EntrezGene Description | zinc finger protein 580 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF580:NM_001163423:exon2:c.C465T:p.C155C,ZNF580:NM_207115:exon2:c.C465T:p.C155C,ZNF580:NM_016202:exon1:c.C465T:p.C155C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1685 |
| ExAC AF | 0.113 |
ZNF581
| dbSNP name | rs11084406(A,G) |
| ccdsGene name | CCDS12932.1 |
| cytoBand name | 19q13.42 |
| EntrezGene GeneID | 51545 |
| EntrezGene Description | zinc finger protein 581 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZNF581:NM_016535:exon2:c.A510G:p.E170E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.05556 |
| ESP Afr MAF | 0.03586 |
| ESP All MAF | 0.106797 |
| ESP Eur/Amr MAF | 0.14314 |
| ExAC AF | 0.101 |
NLRP5
| dbSNP name | rs12462690(G,A); rs60062723(G,A); rs183807248(C,T); rs112676366(C,T); rs513926(G,T); rs512864(C,A); rs200004072(A,T); rs200772594(C,G); rs74706913(A,G); rs13344734(A,G); rs73066196(G,A); rs73066197(A,T); rs184075209(T,G); rs10404266(T,C); rs201590660(T,G); rs73066202(A,G); rs73068103(C,T); rs35669530(C,T); rs1560691(C,T); rs141325452(C,T); rs4801657(C,T); rs4801658(T,C); rs12463158(C,T); rs10424794(G,A); rs4801660(A,G); rs146838444(G,A); rs117776002(A,T); rs117241160(C,A); rs117570814(C,A); rs645588(C,A); rs645540(C,T); rs72629146(C,A); rs150034375(T,C); rs62123586(C,T); rs73068129(A,C); rs7252935(G,A); rs62123587(G,A); rs62123589(C,T); rs12462844(T,C); rs16986872(C,T); rs12460573(C,T); rs12460633(G,A); rs12460592(C,G); rs76148349(C,T); rs57612823(T,C); rs61386341(A,G); rs60616806(T,A); rs61274775(G,A); rs17676833(G,A); rs34981810(T,C); rs34154649(A,G); rs17608485(A,G); rs17608522(T,C); rs387220(A,C); rs62120412(T,G); rs62120413(T,C); rs62120414(C,A); rs16986875(A,G); rs16986877(A,G); rs628370(T,G); rs1612449(A,G); rs62120416(C,A); rs12462984(G,C); rs12460940(T,C); rs10424286(T,C); rs56289104(A,G); rs35014286(C,G); rs34037352(T,C); rs67449072(C,T); rs17608620(C,T); rs35940209(C,T); rs28711142(A,G); rs56226758(A,G); rs4561578(C,G); rs2903527(A,G); rs73617470(A,T); rs34233636(C,T); rs3097883(T,C); rs3097882(A,T); rs306431(C,T); rs167385(T,C); rs306429(A,C); rs3103605(T,G); rs67697300(T,C); rs7253464(T,C); rs3097879(A,T); rs78993976(A,G); rs306425(A,T); rs73619241(C,T); rs306427(G,T); rs306428(A,G); rs10410222(C,T); rs306445(T,C); rs141359540(C,T); rs77160688(A,G); rs10402653(C,T); rs78240861(A,C); rs57362808(C,T); rs306446(C,T); rs2574764(G,A); rs144473292(G,A); rs216681(C,T); rs8108335(G,A); rs62120426(G,A); rs1529718(A,G); rs117149740(C,T); rs2451833(T,C); rs2082448(C,T); rs142252791(G,A); rs10404343(C,T); rs879523(A,C); rs892056(A,G); rs12976763(C,G); rs3103611(A,G); rs199500921(G,A); rs200541204(A,G); rs1808663(C,T); rs397977(C,T); rs144685875(C,G); rs392991(A,G); rs490494(T,C); rs10853883(C,A); rs3097877(T,C); rs3097876(T,C); rs73619261(G,A); rs113926310(G,C); rs185742431(C,T); rs388295(C,A); rs73619264(C,T); rs111611972(G,A); rs143360222(A,T); rs73619265(T,G); rs2163827(C,A); rs59794747(G,A); rs7247800(A,G); rs55837102(C,T); rs627690(G,C); rs574342(G,A); rs61302387(G,A); rs393160(G,A); rs553964(C,T); rs521700(T,C); rs11084421(G,T); rs55948400(C,G); rs549015(T,C); rs11084422(C,T); rs10402135(G,A); rs16986899(T,C); rs306447(A,G); rs28460835(A,T); rs73619288(C,T); rs73619290(G,A); rs58521241(G,A); rs10416480(C,A); rs113789766(G,A); rs2569425(A,G); rs61732213(G,T); rs150501753(G,A); rs77863650(C,T); rs8109087(A,G); rs10420406(T,C); rs7255920(A,G); rs117748533(C,T); rs447762(C,T); rs170061(C,T); rs306442(A,C); rs407673(G,C); rs56881541(T,C); rs147674223(A,G); rs148023389(G,A); rs191040(T,C); rs10407520(C,T); rs112183520(C,T); rs148809154(G,A); rs191039(C,G); rs114892663(C,T); rs139293807(G,A); rs115086126(T,C); rs10416123(T,C); rs306439(T,C); rs9967622(C,A); rs9304771(C,A); rs306438(C,T); rs10416484(G,C); rs167386(T,G); rs10421588(C,T); rs533606(C,T); rs10421870(A,G); rs306437(G,A); rs306436(G,A); rs306435(C,T); rs3103055(C,T); rs61673854(C,G); rs4439865(G,A); rs3097875(A,G); rs306434(C,T); rs12459806(C,T); rs191038(C,G); rs7251102(A,G); rs306433(T,C); rs10411686(C,T); rs306432(A,C); rs189119491(G,A); rs2101392(C,T); rs10419239(C,T); rs12462825(T,C); rs111462776(C,T); rs73620942(C,A); rs543992(A,G); rs511176(C,T); rs11880713(G,A); rs11880721(G,A); rs113942299(T,C); rs2574762(A,G); rs79626027(G,A); rs7256266(A,G); rs61107968(T,C); rs2637113(T,C); rs4239486(G,A); rs2637112(T,G); rs2637111(G,A); rs2637110(A,G); rs2867224(A,C); rs1654395(A,G); rs1654394(A,G); rs59114397(G,A); rs7245707(A,T); rs2631650(A,G); rs1654393(C,A); rs1654392(C,T); rs113923491(C,T); rs28417059(A,G); rs443580(C,T); rs514565(C,A); rs57288454(G,A); rs35553570(G,C); rs78747812(G,A); rs392801(G,A); rs3103057(G,A); rs386127(A,T); rs444974(A,G); rs376974(C,T); rs367934(C,T); rs444555(G,A); rs3103058(A,G); rs73625335(G,T); rs55913574(A,G); rs75719876(G,C); rs2637107(G,A); rs10403937(C,T); rs693105(A,G); rs145479613(C,T); rs1612594(C,T); rs10221468(G,C); rs453819(C,T); rs1684853(C,T); rs398599(T,C); rs8106943(T,C); rs437136(C,T); rs17714301(C,A); rs114781937(C,T); rs386875(G,A); rs379192(G,A); rs55809430(C,T); rs111444316(G,A); rs79705438(G,A); rs689292(A,C); rs689311(G,A); rs403404(A,G); rs397730(C,T); rs9807815(C,T); rs59417225(G,T); rs10409555(G,A); rs36118060(G,A) |
| ccdsGene name | CCDS12938.1 |
| cytoBand name | 19q13.43 |
| EntrezGene GeneID | 126206 |
| EntrezGene Description | NLR family, pyrin domain containing 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NLRP5:NM_153447:exon7:c.A1066G:p.R356G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5243 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P59047 |
| dbNSFP Uniprot ID | NALP5_HUMAN |
| dbNSFP KGp1 AF | 0.0 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.000487 |
| ESP All MAF | 0.000798 |
| ESP Eur/Amr MAF | 0.000951 |
| ExAC AF | 0.0008077 |
ZIM3
| dbSNP name | rs142739045(C,G); rs184655309(G,A); rs73060874(C,T); rs113785943(G,A); rs17305549(C,T); rs59231549(C,T); rs4801433(T,C); rs7251328(A,G); rs368695053(T,C); rs7252632(T,C); rs141971869(T,C); rs10418374(A,G); rs143777789(G,C); rs138432980(G,A); rs142827872(C,T); rs4801199(C,A); rs4801200(A,T); rs2370135(T,C); rs7256529(C,T); rs12609596(T,C); rs76943613(G,A); rs111797761(G,A); rs2370134(C,T); rs17305556(G,A); rs17305563(A,T); rs10407445(C,T); rs12459570(A,T); rs2887656(G,A); rs12461894(T,C); rs28672911(C,T); rs12459627(C,T); rs141314603(A,G); rs8107902(A,T); rs77161334(C,T); rs12973761(C,T); rs7254420(C,A); rs4427915(A,T); rs4432357(T,A); rs7250354(A,T); rs2370133(C,A); rs2370132(T,C); rs8105078(G,A); rs10417543(C,G); rs11084488(T,C); rs58537382(T,C); rs59976893(T,C); rs77434521(T,G); rs10426157(T,G); rs8112993(A,G); rs8113009(A,C); rs10408197(T,C); rs6510045(A,G); rs78500647(T,C); rs8106383(G,A); rs12986338(G,T) |
| ccdsGene name | CCDS33125.1 |
| cytoBand name | 19q13.43 |
| EntrezGene GeneID | 114026 |
| EntrezGene Description | zinc finger, imprinted 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZIM3:NM_052882:exon5:c.A650G:p.H217R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8542 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96PE6 |
| dbNSFP Uniprot ID | ZIM3_HUMAN |
| ExAC AF | 1.626e-05 |
VN1R1
| dbSNP name | rs76997017(T,C); rs61744949(G,T); rs28649880(G,A) |
| cytoBand name | 19q13.43 |
| EntrezGene GeneID | 57191 |
| EntrezGene Description | vomeronasal 1 receptor 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02801 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Weight];
Obesity
HEAD AND NECK:
[Eyes];
Retinitis pigmentosa;
Retinal dystrophy
GENITOURINARY:
[External genitalia, male];
Hypogenitalism;
Hypospadias;
[Kidneys];
Structural renal abnormalities;
Lobulated kidneys;
Cystic kidneys
SKELETAL:
[Hands];
Polydactyly;
[Feet];
Syndactyly
NEUROLOGIC:
[Central nervous system];
Learning disabilities;
Mental retardation
ENDOCRINE FEATURES:
Diabetes mellitus
MOLECULAR BASIS:
Caused by mutation in the MKKS gene (MKKS, 604896.0003)
OMIM Title
*605234 VOMERONASAL 1 RECEPTOR 1; VN1R1
;;V1R-LIKE 1; V1RL1;;
VOMERONASAL RECEPTOR 1;;
V3R-RELATED GENE;;
VNR19I1;;
ZVNH1;;
ZVNR1
OMIM Description
CLONING
Pheromones elicit specific behavioral responses and physiologic
alterations in recipients of the same species. In mammals, these
chemical signals are recognized within the nasal cavity by sensory
neurons that express pheromone receptors. In rodents, these receptors
are thought to be represented by 2 large multigene families, comprising
the V1r and V2r genes, which encode 7-transmembrane proteins. Although
pheromonal effects have been demonstrated in humans (Stern and
McClintock, 1998), V1R or V2R counterparts of the rodent genes had not
been demonstrated until the report of Rodriguez et al. (2000).
Capitalizing on the absence of introns within V1r coding regions, they
took a genomic approach to cloning human V1R homologs. This approach
yielded 8 different sequences that shared homologies with rodent V1r
sequences; 7 of these had multiple frameshifts and/or stop codons in
their coding sequence, indicating that they most likely represent
pseudogenes. One gene, termed V1RL1 (for V1r-like gene-1), had an
uninterrupted open reading frame encoding a polypeptide of 313 amino
acids that shared strong homology with mouse and rat V1r family members.
By Southern blot analysis, Rodriguez et al. (2000) consistently found
V1RL1 mRNA expression in the olfactory mucosa, and detected expression
in brain, lung, and kidney with poor reproducibility, thought to reflect
very low expression levels in these tissues. Sequencing 11 genetically
unrelated, ethnically diverse individuals, they found 2 single
nucleotide polymorphisms (SNPs), each resulting in an amino acid change.
Multiple polymorphisms between different mouse strains had been
demonstrated (Rodriguez et al., 1999) in the gene V1rb2. In rodents,
pheromone detection is thought to be mediated mainly by the vomeronasal
organ (VNO), a specialized structure located at the base of the nasal
septum. Although a VNO-like structure is present during early human
embryogenesis, it appears to regress after birth to become vestigial in
adults. The VNO may, however, not be the exclusive site of pheromone
detection.
Using a differential screening strategy to compare transcripts expressed
by main olfactory epithelium (MOE) and VNO neurons, Pantages and Dulac
(2000) identified a novel gene family they named the V3Rs. The V3Rs
encode 7-transmembrane domain receptors predicted to function as
pheromone receptors. Using Southern blot analysis and genomic library
screening, Pantages and Dulac (2000) estimated that the V3R family
includes about 100 to 120 receptor genes in mouse. Pantages and Dulac
(2000) identified a human V3R sequence containing a complete open
reading frame and predicted to generate a fully functional transcript
and receptor. Using in situ hybridization, Pantages and Dulac (2000)
detected V3R family expression restricted to the apical portion of the
VNO neuroepithelium. Within the VNO, V3R-positive neurons are distinct
from neurons expressing the pheromone receptor families V1R and V2R.
Individual V3R genes were expressed by small and nonoverlapping subsets
of VNO neurons, and Pantages and Dulac (2000) hypothesized that
individual VNO neurons express only 1 receptor gene.
EVOLUTION
Pantages and Dulac (2000) presented a phylogenetic tree of human and
mouse V1R, V3R, and T2R sequences.
MAPPING
Rodriguez et al. (2000) noted that a BLAST search of the GenBank
database revealed that 2 sequenced cosmids mapping to 19q13.4 (GenBank
GENBANK AC004076, GENBANK AC003005) encompass the V1RL1 gene.
ANIMAL MODEL
Del Punta et al. (2002) used chromosome engineering technology to delete
in the germline of mice an approximately 600-kb genomic region that
contains a cluster of 16 intact V1r genes. These genes comprise 2 of the
12 described V1r gene families and represent approximately 12% of the
V1r repertoire. The mutant mice displayed deficits in a subset of
vomeronasal organ-dependent behaviors: the expression of male sexual
behavior and maternal aggression was substantially altered.
Electrophysiologically, the epithelium of the vomeronasal organ of such
mice did not respond detectably to specific pheromonal ligands. Del
Punta et al. (2002) concluded that the behavioral impairment and
chemosensory deficit support a role for V1r receptors as pheromone
receptors.
FKBP1AP1
| dbSNP name | rs8111062(A,G); rs964795(A,G) |
| cytoBand name | 19q13.43 |
| EntrezGene GeneID | 84914 |
| EntrezGene Symbol | ZNF587 |
| snpEff Gene Name | ZNF587 |
| EntrezGene Description | zinc finger protein 587 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02571 |
MIR4754
| dbSNP name | rs975947(C,T) |
| cytoBand name | 19q13.43 |
| EntrezGene GeneID | 101929096 |
| EntrezGene Symbol | LOC101929096 |
| snpEff Gene Name | RPS5 |
| EntrezGene Description | uncharacterized LOC101929096 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3632 |
| ExAC AF | 0.169 |
ZCCHC3
| dbSNP name | rs1046560(T,C); rs143206307(C,T); rs1046561(A,C) |
| cytoBand name | 20p13 |
| EntrezGene GeneID | 85364 |
| EntrezGene Description | zinc finger, CCHC domain containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4688 |
| ESP Afr MAF | 0.3864 |
| ESP All MAF | 0.413506 |
| ESP Eur/Amr MAF | 0.426002 |
| ExAC AF | 0.427,8.525e-06 |
SOX12
| dbSNP name | rs6050323(C,G); rs6050344(G,C) |
| cytoBand name | 20p13 |
| EntrezGene GeneID | 6666 |
| EntrezGene Description | SRY (sex determining region Y)-box 12 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1731 |
OMIM Clinical Significance
Endocrine:
Diabetes mellitus, insulin-dependent
Inheritance:
Autosomal locus and allelic heterogeneity
OMIM Title
*601947 SRY-BOX 12; SOX12
;;SRY-BOX 22; SOX22
OMIM Description
CLONING
Jay et al. (1997) cloned SOX22, a novel member of the SRY
(480000)-related HMG box (SOX) gene family. The predicted 315-amino acid
protein contains several domains that are present in other paralogous
SOX proteins. SOX22 mRNA was expressed in various fetal and adult organs
and tissues, suggesting that this gene plays roles in both
differentiation and maintenance of several cell types.
MAPPING
Jay et al. (1997) mapped the SOX22 gene to chromosome 20p13 by
fluorescence in situ hybridization.
C20orf141
| dbSNP name | rs78096730(C,T); rs6107195(T,C) |
| cytoBand name | 20p13 |
| EntrezGene GeneID | 128653 |
| EntrezGene Description | chromosome 20 open reading frame 141 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005969 |
| ESP Afr MAF | 0.013699 |
| ESP All MAF | 0.004186 |
| ESP Eur/Amr MAF | 0.0 |
MRPS26
| dbSNP name | rs1100(G,A) |
| cytoBand name | 20p13 |
| EntrezGene GeneID | 64949 |
| snpEff Gene Name | GNRH2 |
| EntrezGene Description | mitochondrial ribosomal protein S26 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1625 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature, final adult height 150-160cm
HEAD AND NECK:
[Head];
Brachycephaly;
Large fontanelle;
Delayed closure of fontanelle;
[Face];
Tall forehead;
Bitemporal narrowing;
Short philtrum;
Midface hypoplasia;
[Ears];
Hearing loss, conductive;
Hearing loss, sensorineural;
[Eyes];
Myopia;
Upslanting palpebral fissures;
Ptosis;
Short palpebral fissures;
[Mouth];
Thin upper lip;
[Neck];
Long neck
CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Mitral regurgitation;
Bicuspid aortic valve;
Aortic regurgitation;
[Vascular];
Patent ductus arteriosus;
Hypertension;
Vessel calcification (hands & feet)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum
ABDOMEN:
[External features];
Umbilical hernia
GENITOURINARY:
[External genitalia, male];
Hypospadias;
Inguinal hernia
SKELETAL:
Delayed bone age;
Epiphyseal dysplasia;
Premature osteoarthritis;
[Spine];
Scoliosis;
[Pelvis];
Decreased hip extension;
Degenerative hip disease;
[Limbs];
Decreased extension (elbows and knees);
Prominent deltoid insertion of humerus;
Small, flat epiphyses (distal radius);
Cubitus valgus;
Hyperextensible elbows;
[Hands];
Absent distal flexion creases;
Fifth finger clinodactyly;
Camptodactyly (progressive);
Pseudoepiphyses (middle phalanges);
Thumb subluxation;
Short forth metacarpal;
[Feet];
Severe metatarsus adductus;
2-3 toe syndactyly
SKIN, NAILS, HAIR:
[Skin];
Absent distal flexion creases (fingers)
NEUROLOGIC:
[Central nervous system];
cranial nerve palsy, intermittent, transient
NEOPLASIA:
Meningioma
MISCELLANEOUS:
Progressive degenerative hip disease requiring replacement in 2nd
to 4th decade
OMIM Title
*611988 MITOCHONDRIAL RIBOSOMAL PROTEIN S26; MRPS26
;;MRPS13
OMIM Description
DESCRIPTION
Mitochondria have their own translation system for production of 13
proteins essential for oxidative phosphorylation. MRPS26 is 1 of more
than 70 protein components of mitochondrial ribosomes that are encoded
by the nuclear genome (Kenmochi et al., 2001).
CLONING
By database analysis, Goldschmidt-Reisin et al. (1998) identified mouse,
rat, and human MRPS26, which they called MRPS13. The deduced human
protein contains a 27-amino acid N-terminal mitochondrial import signal.
By proteolytic digestion of whole bovine 28S subunits, followed by
peptide analysis and EST database analysis, Koc et al. (2001) identified
full-length human MRPS26. The deduced 205-amino acid MRPS26 protein has
a calculated molecular mass of 24.2 kD. Removal of the predicted
31-amino acid N-terminal mitochondrial localization signal results in a
mature protein of 20.8 kD. Koc et al. (2001) identified MRPS26 orthologs
in mouse and Drosophila, but not in C. elegans, yeast, or E. coli. Mouse
and human MRPS26 share 71.4% amino acid identity.
MAPPING
By radiation hybrid analysis and analysis of an integrated BAC-STS map,
Kenmochi et al. (2001) mapped the MRPS26 gene to chromosome 20p13.
UBOX5-AS1
| dbSNP name | rs864140(G,A) |
| cytoBand name | 20p13 |
| EntrezGene GeneID | 100134015 |
| snpEff Gene Name | UBOX5 |
| EntrezGene Description | UBOX5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2025 |
BFSP1
| dbSNP name | rs6105762(T,G); rs41276390(C,G); rs6080717(G,A); rs6080718(T,C); rs6136118(C,T); rs115901456(T,C); rs114244890(C,T); rs2239653(C,T); rs2239654(C,T); rs2239655(A,T); rs6044849(C,T); rs761020(G,A); rs6034836(A,C); rs79258065(A,G); rs6080719(C,T); rs6044850(A,G); rs6136119(G,A); rs6136120(C,T); rs6044851(C,T); rs6136121(A,G); rs111832882(T,C); rs62202670(T,C); rs116838142(A,G); rs78697579(C,T); rs16999345(T,G); rs6111548(C,T); rs11905530(C,G); rs6080720(G,A); rs76186660(T,C); rs147718368(A,G); rs6111549(T,C); rs2235585(T,C); rs6080721(C,T); rs13043260(C,G); rs13044625(T,C); rs6075216(A,T); rs182663198(A,G); rs76673557(C,T); rs2269037(C,T); rs2269039(T,C); rs6075217(G,A); rs2269040(T,G); rs57004524(G,A); rs6111551(T,C); rs76624484(C,T); rs74181967(C,T); rs2269042(T,C); rs13037434(G,C); rs2269043(T,C); rs2269044(G,A); rs73253996(C,T); rs6111552(G,C); rs74420760(T,C); rs201938(C,T); rs2023508(A,G); rs79776981(A,T); rs4052812(A,T); rs6034837(T,C); rs7270359(C,G); rs6034838(G,A); rs6034839(G,A); rs111334922(A,G); rs201937(C,A); rs79923008(C,T); rs76607515(A,G); rs56967283(C,T); rs3828011(A,G); rs3790329(G,A); rs6044855(T,G); rs17717798(T,C); rs77653098(G,A); rs1016211(C,A); rs2072957(C,T); rs2281207(G,A); rs41276392(G,T); rs35579921(G,A); rs73105002(A,G); rs73107003(G,A); rs6111553(G,A); rs6080725(C,T); rs79869377(C,T); rs6034840(T,A); rs6111555(G,A); rs75293132(G,A); rs2284920(A,G); rs2284921(C,T); rs6080726(A,C); rs6080727(G,C); rs6080728(C,T); rs2269047(A,G); rs1559958(A,G); rs1559956(C,T); rs145106444(T,C); rs6105766(T,C); rs7272051(G,T); rs79342281(T,C); rs75176655(T,C); rs115344961(A,G); rs76704447(A,G); rs80082806(A,G); rs79084462(C,T); rs75570616(G,A); rs6044856(G,A); rs75626514(A,T); rs6044857(A,G); rs2023224(G,A); rs1474677(C,T); rs2269049(A,T); rs76731532(G,A); rs6044859(C,T); rs142199127(A,G); rs62202685(G,A); rs8119609(A,G); rs11700353(T,C); rs73599751(T,C); rs76030610(A,G); rs141889423(T,C); rs62202686(G,A); rs6044861(T,C); rs2235586(C,G); rs73599752(G,C); rs73262332(T,C); rs78115630(G,A); rs113532316(G,A); rs34902028(T,C); rs73898303(A,G); rs6044862(G,A); rs7262745(C,T); rs7262975(G,C); rs6034842(T,C); rs3790328(G,A); rs2300928(G,A); rs57329866(G,A); rs76661547(G,C); rs55810689(T,C); rs6044868(C,T); rs60503938(T,C); rs59229626(G,T); rs60584985(A,T); rs201934(G,C); rs201933(A,G); rs201932(T,G); rs201931(G,T); rs114140988(G,C); rs16999368(T,C); rs16999369(C,G); rs201930(T,C); rs201929(A,G); rs201928(C,T); rs62202688(T,C); rs143243476(C,T); rs147292136(C,T); rs725148(C,T); rs2328178(A,G); rs58874627(C,T); rs16999380(T,C); rs75225013(G,A); rs73599756(G,C); rs56240681(A,G); rs2424081(C,T); rs6044874(A,G); rs6105774(C,T); rs57258654(G,T); rs6111562(G,T); rs2424082(A,G); rs117681625(C,T); rs2424083(G,T); rs2424084(G,C); rs79439439(T,A); rs11905481(G,A); rs6105776(G,A); rs1575203(A,T); rs1575204(T,C); rs56314666(C,T); rs78374864(G,A); rs144247464(A,G); rs144566848(C,T); rs6034848(G,A); rs6034849(G,A); rs6034850(C,T); rs2328179(T,C); rs6136131(C,T); rs6111567(G,A); rs16999401(A,C); rs911356(A,G); rs35198546(G,C); rs6044883(A,G); rs1407194(T,C); rs4814625(T,G); rs16999416(G,A); rs6080736(C,G); rs6034852(G,A); rs6080737(C,T); rs11087213(A,G); rs6034854(T,C); rs74181970(G,A); rs6105777(G,T); rs6111573(A,C); rs4813271(C,A); rs6080738(G,A); rs35786923(T,C); rs6080739(G,A); rs6044885(T,C); rs6034855(T,C); rs148804825(G,A); rs2180823(C,T); rs6034856(G,A); rs35384212(T,G) |
| ccdsGene name | CCDS13126.1 |
| cytoBand name | 20p12.1 |
| EntrezGene GeneID | 631 |
| EntrezGene Description | beaded filament structural protein 1, filensin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | BFSP1:NM_001195:exon6:c.T812C:p.I271T,BFSP1:NM_001278607:exon6:c.T479C:p.I160T,BFSP1:NM_001278608:exon8:c.T395C:p.I132T,BFSP1:NM_001278606:exon7:c.T395C:p.I132T,BFSP1:NM_001161705:exon6:c.T437C:p.I146T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8382 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000915750915751 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 9.183E-4 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000349 |
| ExAC AF | 0.0003578 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
SKIN, NAILS, HAIR:
[Skin];
Palmar telangiectasias (described in 1 family)
NEUROLOGIC:
[Central nervous system];
Cerebral cavernous malformations;
Seizures;
Recurrent headaches;
Hemorrhagic stroke
MISCELLANEOUS:
Genetic heterogeneity (see 116800 for summary);
Sporadic cases often single lesions versus multiple lesions in familial
cases
MOLECULAR BASIS:
Caused by mutation in the CCM2 gene (CCM2, 607929.0001)
OMIM Title
*603307 BEADED FILAMENT STRUCTURAL PROTEIN 1; BFSP1
;;CYTOSKELETAL PROTEIN, 115-KD; CP115;;
FILENSIN
OMIM Description
DESCRIPTION
The beaded filament is a cytoskeletal structure, which is abundant in
the fiber cells of the ocular lens. BFSP1 and BFSP2 (603212) are major
components of the beaded filament (Hess et al., 1995).
CLONING
By PCR of human lens cDNA using primers based on sequences conserved
between rat and bovine filensin, Hess et al. (1995) isolated a partial
cDNA encoding human filensin, which they called CP115. Northern blot
analysis indicated that filensin was expressed as a 2.4-kb mRNA only in
human lens. Hess et al. (1998) reported the sequence of a cDNA
corresponding to the entire human filensin coding region. The sequence
of the predicted 665-amino acid human protein is 62% and 50% identical
to those of bovine and chicken filensin, respectively. However, it has
less than 26% identity to other members of the intermediate filament
(IF) family (see 148070). Sequence analysis revealed that, like other IF
proteins, filensin contains a central rod domain flanked by an
N-terminal head domain and C-terminal tail domain, although the filensin
central rod domain is uniquely short. Using yeast 2-hybrid analysis,
Hess et al. (1998) demonstrated that filensin formed heterodimers with
BFSP2 but not with any other IF protein tested.
GENE STRUCTURE
Hess et al. (1998) determined that the BFSP1 gene contains 7 introns and
spans approximately 35 kb. The number (6) and positions of the introns
in the region encoding the central rod domain generally correspond to
those of type III IF genes.
MAPPING
By analysis of somatic cell hybrids, Hess et al. (1995) mapped the
filensin gene to chromosome 20. Using fluorescence in situ
hybridization, radiation hybrid mapping, and analysis of YAC clones,
Rendtorff et al. (1998) refined the map position to 20p12.1-p11.23.
MOLECULAR GENETICS
Ramachandran et al. (2007) sequenced the BFSP1 gene in 11 affected and 8
unaffected members of a large consanguineous Indian family with
juvenile-onset cortical cataract mapping to chromosome 20p (CTRCT33;
611391) and identified homozygosity for a 3,343-bp deletion encompassing
exon 6 (603307.0001) in all affected individuals.
SNORD17
| dbSNP name | rs753213(A,T) |
| ccdsGene name | CCDS13130.1 |
| cytoBand name | 20p11.23 |
| EntrezGene GeneID | 692086 |
| snpEff Gene Name | SNX5 |
| EntrezGene Description | small nucleolar RNA, C/D box 17 |
| EntrezGene Type of gene | snoRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2645 |
| ESP Afr MAF | 0.130137 |
| ESP All MAF | 0.239449 |
| ESP Eur/Amr MAF | 0.287544 |
| ExAC AF | 0.31 |
LOC100270804
| dbSNP name | rs7262320(G,T); rs7262363(C,T); rs859025(C,T); rs16979653(A,G) |
| cytoBand name | 20p11.23 |
| EntrezGene GeneID | 100270804 |
| snpEff Gene Name | RP5-1068E13.3 |
| EntrezGene Description | uncharacterized LOC100270804 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1579 |
SCP2D1
| dbSNP name | rs374964954(A,G); rs1053834(C,T); rs1053839(C,T) |
| ccdsGene name | CCDS13139.1 |
| cytoBand name | 20p11.23 |
| EntrezGene GeneID | 100128496 |
| EntrezGene Symbol | C20orf78 |
| snpEff Gene Name | C20orf79 |
| EntrezGene Description | chromosome 20 open reading frame 78 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SCP2D1:NM_178483:exon1:c.A130G:p.S44G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.105 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UJQ7 |
| dbNSFP Uniprot ID | CT079_HUMAN |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 7.7e-05 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0001626 |
INSM1
| dbSNP name | rs6137007(T,G); rs7272722(A,C) |
| cytoBand name | 20p11.23 |
| EntrezGene GeneID | 3642 |
| EntrezGene Description | insulinoma-associated 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.009183 |
OMIM Clinical Significance
Skel:
Skeletal dysplasia;
Severely retarded ossification of epiphyses, pelvis, hands, and feet
Limbs:
Abnormal modeling of bones of hands and feet
Neuro:
No mental retardation
Inheritance:
Autosomal recessive
OMIM Title
*600010 INSULINOMA-ASSOCIATED 1; INSM1
;;IA1
OMIM Description
CLONING
By differential screening of human insulinoma and glucagonoma cDNA
libraries, Goto et al. (1992) cloned INSM1, which they called IA1. The
3-prime UTR has 2 polyadenylation signals. The deduced 510-amino acid
protein has a calculated molecular mass of 52.9 kD. IA1 has an
N-terminal domain with 4 classical prohormone dibasic conversion sites
and an amidation signal sequence. The C-terminal domain contains 5
putative C2H2-type zinc finger DNA-binding motifs. Northern blot
analysis detected a 3.0-kb transcript in all human and rodent
insulinomas examined, but not in any normal tissues. IA1 was also
expressed in several tumor cell lines of neuroendocrine origin.
Lan et al. (1994) cloned and sequenced the entire IA1 gene and its
5-prime upstream region from a human liver genomic library. In vitro
translation studies showed that IA1 cDNA and IA1 genomic DNA yielded
identical protein products of approximately 61 kD.
Xie et al. (2002) cloned mouse Insm1 from a beta-cell cDNA library. The
deduced 521-amino acid protein is 86% identical to human INSM1, and both
proteins contain proline-rich regions and multiple zinc finger
DNA-binding motifs. Northern blot analysis revealed that mouse Insm1
expression began at embryonic day 10.5, decreased after day 13.5, was
barely detectable at day 18.5. In mouse brain, Insm1 was strongly
expressed for 2 weeks after birth, but it showed little to no expression
thereafter. Fluorescence-tagged Insm1 was expressed exclusively in
nuclei of transfected cells.
By in situ hybridization and immunohistologic analysis, Gierl et al.
(2006) found widespread expression of mouse Insm1 in the developing
central and peripheral nervous system and pancreas. It was also present
in adult pancreatic islets.
GENE FUNCTION
Clinical studies by Lan et al. (1994) demonstrated that IA1 is a
sensitive marker for neuroendocrine differentiation of human lung
tumors.
By yeast 2-hybrid analysis, in vitro pull-down experiments, nuclear
colocalization, and coimmunoprecipitation assays, Xie et al. (2002)
showed the mouse Insm1 interacted with Cap (SORBS1; 605264).
Using a chromatin immunoprecipitation assay, Liu et al. (2006) found
that INSM1 bound the promoter region of mouse Neurod1 (601724) following
transfection in HEK293 cells. Yeast 2-hybrid analysis of a human fetal
brain cDNA library showed that cyclin D1 (CCND1; 168461) bound INSM1,
and in vitro and in vivo pull-down assays confirmed the interaction.
Coimmunoprecipitation assays of mammalian cells revealed that INSM1
interacted with HDAC1 (601241) and HDAC3 (605166) and that the
interaction was mediated through cyclin D1. Cyclin D1 cooperated with
INSM1 to suppress Neurod1 promoter activity, and overexpression of
cyclin D1 and HDAC3 significantly enhanced the transcriptional
repression activity of INSM1 on the Neurod1 promoter. A chromatin
immunoprecipitation assay showed that HDAC3 occupied the same region of
the Neurod1 promoter by forming a transcription complex with INSM1. Liu
et al. (2006) concluded that INSM1 recruits cyclin D1 and HDACs, which
confer transcriptional repressor activity.
GENE STRUCTURE
Lan et al. (1994) determined that the IA1 gene is intronless.
Examination of the 5-prime upstream region demonstrated several
tissue-specific regulatory elements. Xie et al. (2002) determined that
the mouse Insm1 gene is also intronless.
MAPPING
By fluorescence in situ hybridization, Lan et al. (1994) mapped the
INSM1 gene to chromosome 20p11.2. Xie et al. (2002) mapped the mouse
Insm1 gene to chromosome 2.
ANIMAL MODEL
Gierl et al. (2006) found that homozygous Insm1-null mouse embryos were
normal in size and well developed until embryonic day 12.5. However,
after day 12.5, Insm1-null embryos were recovered at lower than the
expected frequency, and at birth, Insm1-null mice appeared unable to
breathe and died. Creating Insm1-null mice on a mixed genetic background
reduced the embryonic lethality. Endocrine precursors formed in the
pancreas of Insm1-null mice, but only few insulin (INS; 176730)-positive
beta cells were generated. Instead, endocrine precursors accumulated and
expressed none of the pancreatic hormones. A similar change was observed
in the developing intestine, where endocrine precursors formed but did
not differentiate correctly. Accumulation of proteins that participate
in secretion and vesicle transport is a hallmark of endocrine cell
differentiation, and Insm1-null mice showed reduced expression of genes
encoding such proteins. Gierl et al. (2006) concluded that INSM1
controls a gene expression program for hormones and proteins of the
secretory machinery.
NKX2-2
| dbSNP name | rs41309908(A,T) |
| cytoBand name | 20p11.22 |
| EntrezGene GeneID | 4821 |
| EntrezGene Description | NK2 homeobox 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03765 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604612 NK2 HOMEOBOX 2; NKX2-2
;;NK2, DROSOPHILA, HOMOLOG OF, B; NKX2B;;
NKX2.2, MOUSE, HOMOLOG OF
OMIM Description
CLONING
The morphogenesis of the central nervous system is thought to be
established by an integrated network of regulatory factors. Vertebrate
homologs of Drosophila segmentation and homeotic (Hox) genes are among
the numerous regulatory genes expressed at high levels in the central
nervous system. Homeobox-containing genes are a large family of
transcription factors that are distinguished by a 60-amino acid
evolutionarily conserved DNA-binding homeodomain. See 142950 for
additional background information on homeobox genes.
By screening a cosmid DNA library at low stringency with a probe from
the homeobox-containing TTF1 (600635), Price et al. (1992) obtained a
partial mouse cDNA for Nkx2.2. By RNAase mapping experiments, they found
that Nkx2.2 transcripts are in localized domains of the brain during
mouse embryogenesis. Hartigan and Rubenstein (1996) isolated a complete
cDNA clone for Nkx2.2 which encodes a 273-amino acid protein. By
immunofluorescence experiments, Sussel et al. (1998) determined that,
within the pancreas, Nkx2.2 is expressed in insulin-producing beta
cells, glucagon-producing alpha cells, and pancreatic polypeptide
(PP)-secreting cells of the islet, but not in somatostatin-producing
delta cells.
By screening pools of PAC DNA with PCR primers for mouse Nkx2.2, Furuta
et al. (1998) isolated a human NKX2B cDNA, which encodes a protein that
shows 98% sequence identity to mouse Nkx2.2.
GENE FAMILY
Holland et al. (2007) stated that the NKX2-2 and NKX2-8 (603245) genes
are collectively orthologous to Drosophila vnd and comprise the Nk2.2
gene family.
GENE STRUCTURE
Furuta et al. (1998) determined that the NKX2B gene contains 2 exons
that span approximately 2.5 kb.
MAPPING
By FISH, Furuta et al. (1998) mapped the NKX2B gene to chromosome 20p11.
Wang et al. (2000) stated that linkage of the Nkx2.1 and Nkx2.9 genes on
mouse chromosome 12 and of the Nkx2.4 (NKX2D; 607808) and Nkx2.2 genes
on mouse chromosome 2 suggests that these gene pairs represent
paralogous clusters, as initially defined for duplicated Hox gene
clusters in vertebrates. Each Nkx2 protein is more related to its
duplicated partner on another chromosome than to its linked partner.
This supports a model in which an ancient gene was duplicated to form a
tandem gene pair, which was then duplicated to another chromosomal locus
at a later time, forming a paralogous pair.
GENE FUNCTION
Ding et al. (2003) presented evidence suggesting that Nkx2.2 acts
downstream of Shh (600725) and upstream of Lmx1b (602575) in a signaling
cascade to direct the development, specification, and/or differentiation
of 5-HT (5-hydroxytryptamine) neurons in the central nervous system in
mice.
MOLECULAR GENETICS
Furuta et al. (1998) found no association between NKX2B mutations and
maturity-onset diabetes of the young in 57 unrelated Japanese subjects.
ANIMAL MODEL
Mice homozygous for a targeted disruption in the Nkx2.2 gene die within
a few days of birth with severe hyperglycemia (Sussel et al., 1998).
PAX1
| dbSNP name | rs190760065(G,C) |
| cytoBand name | 20p11.22 |
| EntrezGene GeneID | 5075 |
| EntrezGene Description | paired box 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.001837 |
OMIM Clinical Significance
Heme:
Bleeding disorder
Skin:
Easy bruising
Nose:
Recurrent epistaxes
GU:
Hypermenorrhea
Lab:
Primary release defect of platelets;
Low platelet membrane sialyltransferase activity
Inheritance:
Autosomal dominant
OMIM Title
*176640 PRION PROTEIN; PRNP
;;PRP;;
PRION-RELATED PROTEIN; PRIP
OMIM Description
DESCRIPTION
The PRNP gene encodes the prion protein, which has been implicated in
various types of transmissible neurodegenerative spongiform
encephalopathies. The human prion diseases occur in inherited, acquired,
and sporadic forms. Approximately 15% are inherited and associated with
coding mutations in the PRNP gene. Inherited prion diseases include
familial Creutzfeldt-Jakob disease (CJD; 123400), Gerstmann-Straussler
disease (GSD; 137440), and fatal familial insomnia (FFI; 600072).
Acquired prion diseases include iatrogenic CJD, kuru (245300), variant
CJD (vCJD) in humans, scrapie in sheep, and bovine spongiform
encephalopathy (BSE) in cattle. Prion diseases are also referred to as
transmissible spongiform encephalopathies (TSE). Variant CJD is believed
to be acquired from cattle infected with BSE. However, the majority of
human cases of prion disease occur as sporadic CJD (sCJD) (Collinge et
al., 1996; Parchi et al., 2000; Hill et al., 2003).
CLONING
Oesch et al. (1985) isolated a cDNA clone corresponding to a pathogenic
PrP fragment from a scrapie-infected hamster brain cDNA library.
Southern blotting with PrP cDNA revealed a single gene with the same
restriction patterns in normal and scrapie-infected brain DNA. A single
PrP-related gene was also detected in murine and human DNA. Proteinase K
digestion yielded PrP 27-30 in infected brain extract, but completely
degraded the PrP-related protein in normal brain extract.
Kretzschmar et al. (1986) isolated a PRNP cDNA from a human retina cDNA
library. The 253-amino acid protein shared 90% amino acid sequence
identity with the hamster protein. Northern blot analysis detected a
2.5-kb mRNA in a variety of human neuroectodermal cell lines.
Basler et al. (1986) determined that the pathogenic PrP protein in
scrapie and normal cellular PrP are encoded by the same gene. The PrP
coding sequence encodes an amino-terminal signal peptide. The primary
structure of PrP encoded by the gene of a healthy animal did not differ
from that encoded by a cDNA from a scrapie-infected animal, suggesting
that the different properties of PrP from normal and scrapie-infected
brains are due to posttranslational events.
GENE STRUCTURE
Puckett et al. (1991) determined that the PRNP gene contains 2 exons.
The region 5-prime of the transcriptional start site has GC-rich
features commonly seen in housekeeping genes.
Mahal et al. (2001) characterized the promoter region of PRNP. The
region is highly GC-rich, lacks a canonical TATA box, contains a CCAAT
box, and has a number of putative binding sites for transcription
factors SP1 (189906), AP1 (165160), and AP2 (107580).
MAPPING
Sparkes et al. (1986) mapped the human PRNP gene to chromosome
20pter-p12 by a combination of somatic cell hybridization and in situ
hybridization. Liao et al. (1986) mapped it to the same region using
spot blotting of DNA from sorted chromosomes. By in situ hybridization,
Robakis et al. (1986) also assigned the PRNP locus to 20p.
By analysis of interstitial 20p deletions, Schnittger et al. (1992)
demonstrated the following order of loci: pter--PRNP--SCG1
(118920)--BMP2A (112261)--PAX1 (167411)--cen. Puckett et al. (1991)
identified a RFLP with a high degree of heterozygosity in the 5-prime
region of the PRNP gene, which might serve as a useful marker for the
pter-p12 region of chromosome 20.
GENE FUNCTION
The nonpathogenic cellular human prion protein, PrPc, is a glycoprotein
that contains a single disulfide bond, is N-glycosylated, and is
attached to the plasma membrane by a C-terminally linked glycosyl
phosphatidylinositol anchor. PrPc has a largely alpha-helical structure,
whereas the pathogenic PrP(Sc) isoform is rich in beta-pleated sheets
(Vanik and Surewicz, 2002).
Mouillet-Richard et al. (2000) used the murine 1C11 neuronal
differentiation model to search for PrPc-dependent signal transduction
through antibody-mediated crosslinking. The 1C11 clone is a committed
neuroectodermal progenitor with an epithelial morphology that lacks
neuron-associated functions. Upon induction, 1C11 cells develop a
neural-like morphology, and may differentiate either into serotonergic
or noradrenergic cells. The choice between the 2 differentiation
pathways depends on the set of inducers used. Ligation of PrPc with
specific antibodies induced a marked decrease in the phosphorylation
level of the tyrosine kinase FYN (137025) in both serotonergic and
noradrenergic cells. The coupling of PrPc to FYN was dependent upon
caveolin-1 (601047). Mouillet-Richard et al. (2000) suggested that
clathrin (see 118960) might also contribute to this coupling. The
ability of the 1C11 cell line to trigger PrPc-dependent FYN activation
was restricted to its fully differentiated serotonergic or noradrenergic
progenies. Moreover, the signaling activity of PrPc occurred mainly at
neurites. Mouillet-Richard et al. (2000) suggested that PrPc may be a
signal transduction protein.
A form of PrP with an altered protease-resistant conformation, PrP(Sc),
is believed to be the infectious agent, or to constitute the major
component of it, in transmissible forms of prion disease. Fischer et al.
(2000) identified plasminogen (173350), a proprotease implicated in
neuronal excitotoxicity, as a PrP(Sc)-binding protein. Binding is
abolished if the conformation of the PrP(Sc) is disrupted by 6-molar
urea or guanidine. The isolated lysine-binding site-1 of plasminogen
(kringles I-III) retains this binding activity, and binding can be
competed for with lysine. Plasminogen does not bind to PrPc; thus
plasminogen represents the first endogenous factor discriminating
between normal and pathologic prion protein. Fischer et al. (2000)
suggested that this unexpected property may be exploited for diagnostic
purposes.
In the absence of translocation accessory factors, PRNP is exclusively
synthesized in a type I or type II transmembrane topology and not as a
GPI-anchored plasma membrane protein, the most abundant PRNP isoform.
PRNP contains 4 N-terminal octapeptide repeats (ORs) with similarity to
BCL2 (151430) homology domains. Bounhar et al. (2001) showed that
expression of PRNP containing the 4 ORs or of BCL2 protects primary
human neurons against BAX (600040)-induced cell death. Treatment with
brefeldin A or monensin abolished the neuroprotective effects of PRNP,
indicating that PRNP must traffic past the cis-Golgi to mediate
protection. Truncated PRNP lacking the GPI-anchor signal peptide
sequence was also neuroprotective, suggesting that PRNP acts in the
cytosol where BAX is localized. Mutation analysis indicated that the
D178N (176640.0010) PRNP variant lacks neuroprotective function, whereas
the T183A (176640.0022) variant only partially inhibits neuroprotective
function. Bounhar et al. (2001) concluded that a transmembrane or
secreted form of PRNP mediates the neuroprotective function and that
mutations causing loss of function may be involved in the
pathophysiology of prion diseases.
Steele et al. (2006) found that mouse Prnp levels correlated with
differentiation of multipotent neural precursors into mature neurons in
vitro and that Prnp levels positively influenced neuronal
differentiation in a dose-dependent manner.
Lauren et al. (2009) identified the cellular prion protein (PrP-C) as an
amyloid-beta oligomer (104760) receptor by expression cloning.
Amyloid-beta oligomers bind with nanomolar affinity to PrP-C, but the
interaction does not require the infectious PrP-Sc conformation.
Synaptic responsiveness in hippocampal slices from young adult PrP-null
mice was normal, but the amyloid-beta oligomer blockade of long-term
potentiation was absent. Anti-PrP antibodies prevented
amyloid-beta-oligomer binding to PrP-C and rescued synaptic plasticity
from oligomeric amyloid-beta in hippocampal slices. Lauren et al. (2009)
concluded that PrP-C is a mediator of amyloid-beta-oligomer-induced
synaptic dysfunction, and that PrP-C-specific pharmaceuticals may have
therapeutic potential for Alzheimer disease.
Sonati et al. (2013) described rapid neurotoxicity in mice and
cerebellar organotypic cultured slices exposed to ligands targeting the
alpha-1 and alpha-3 helices of the PrPc globular domain. Ligands
included 7 distinct monoclonal antibodies, monovalent Fab(1) fragments,
and recombinant single-chain variable fragment miniantibodies. Similar
to prion infections, the toxicity of the globular domain ligands
required neuronal PrPc, was exacerbated by PrPc overexpression, was
associated with calpain activation and was antagonized by calpain
inhibitors. Neurodegeneration was accompanied by a burst of reactive
oxygen species, and was suppressed by antioxidants. Furthermore, genetic
ablation of the superoxide-producing enzyme NOX2 (300481) protected mice
from globular domain ligand toxicity. Sonati et al. (2013) also found
that neurotoxicity was prevented by deletions of the octopeptide repeats
within the flexible tail. These deletions did not appreciably compromise
globular domain antibody binding, suggesting that the flexible tail is
required to transmit toxic signals that originate from the globular
domain and trigger oxidative stress and calpain activation. Supporting
this view, various octapeptide ligands were not only innocuous to both
cerebellar organotypic cultured slices and mice, but also prevented the
toxicity of globular domain ligands while not interfering with their
binding. Sonati et al. (2013) concluded that PrPc consists of 2
functionally distinct modules, with the globular domain and the flexible
tail exerting regulatory and executive functions, respectively.
Octapeptide ligands also prolonged the life of mice expressing the toxic
PrPc mutant PrP(delta-94-134), indicating that the flexible tail
mediates toxicity in 2 distinct PrPc-related conditions. Sonati et al.
(2013) suggested that flexible tail-mediated toxicity may play a role in
other prion pathologies, such as familial Creutzfeldt-Jakob disease
(123400) in humans bearing supernumerary octapeptides.
- Prions, A New Class of Infectious Agent
Prusiner (1982, 1987) suggested that prions represent a new class of
infectious agent that lacks nucleic acid. The term prion, which was
devised by Prusiner (1982), comes from 'protein infectious agent.'
Prusiner (1994) reviewed the pathogenesis of transmissible spongiform
encephalopathies and noted that a protease-resistant isoform of the
prion protein was important in the pathogenesis of these diseases.
Collinge et al. (1990) suggested that 'prion disease,' whether familial
or sporadic, is a more appropriate diagnostic term.
One interpretation has been that the prion is a sialoglycoprotein whose
synthesis is stimulated by the infectious agent that is the primary
cause of this disorder. Manuelidis et al. (1987) presented evidence
suggesting that the PrP peptide is not the infectious agent in CJD.
Pablos-Mendez et al. (1993) reviewed the 'tortuous history of prion
diseases' and suggested an alternative to the idea that prions are
infectious, namely, that they are cytotoxic metabolites. The authors
suggested that studies of the processing of the metabolite PrP and
trials of agents that enhance the appearance of this protein would be
useful ways to test their hypothesis. Their model predicted that
substances capable of blocking the catabolism of PrP would lead to its
accumulation. Increasing PrP synthesis in transgenic mice shortens the
latency in experimental scrapie. The hypothesis of Pablos-Mendez et al.
(1993) suggested an intracellular derailment of the degradative rather
than the synthetic pathway of PrP.
It has been suggested that the infectious, pathogenic agent of the
transmissible spongiform encephalopathies is a protease-resistant,
insoluble form of the PrP protein that is derived posttranslationally
from the normal, protease-sensitive PrP protein (Beyreuther and Masters,
1994). Kocisko et al. (1994) reported the conversion of normal PrP
protein to the protease-resistant PrP protein in a cell-free system
composed of purified constituents. This selective conversion from the
normal to the pathogenic form of PrP required the presence of
preexisting pathogenic PrP. The authors showed that the conversion did
not require biosynthesis of new PrP protein, its amino-linked
glycosylation, or the presence of its normal
glycosylphosphatidylinositol anchor. The findings provided direct
evidence that the pathogenic PrP protein can be formed from specific
protein-protein interactions between it and the normal PrP protein.
Lasmezas et al. (1997) reported that all 30 mice inoculated by
intracerebral injection of a BSE-infected brain homogenate developed
neurologic symptoms and neurologic death within 2 years. However, 55% of
the mice showed no detectable pathologic protease-resistant isoforms
(referred to as 'PrPres'). Neuropathologic findings of BSE were limited
to the PrPres-positive mice. PrPres-negative mice were able to transmit
the disease to a second series of mice, indicating that they were
infected with a TSE agent. During serial passages, the PrPres protein
eventually appeared in almost all affected mice. Lasmezas et al. (1997)
concluded that the PrPres protein adapted to a new species host over
time, and suggested that an additional infectious agent may be involved
in the transmission of BSE.
Mestel (1996) reviewed the evidence for and against the existence of
infectious proteins. Prusiner (1996) provided a comprehensive review of
the molecular biology and genetics of prion diseases. Collinge (1997)
likewise reviewed this topic and tabulated 12 pathogenetic mutations in
the PRNP gene that had been reported to that time. Noting that the
ability of a protein to encode a disease phenotype represents a
nonmendelian form of transmission important in biology, Collinge (1997)
commented that it would be surprising if evolution had not used this
method for other proteins in a range of species. He referred to the
identification of prion-like mechanisms in yeast (Wickner, 1994; Ter
Avanesyan et al., 1994). Horwich and Weissman (1997) reviewed the
central role of prion protein in the group of related transmissible
neurodegenerative diseases. The data demonstrated that prion protein is
required for the disease process, and that the conformational conversion
of the prion protein from its normal soluble alpha-helical conformation
to an insoluble beta-sheet state is intimately tied to the generation of
disease and infectivity.
Lindquist (1997) pointed out that 'some of the most exciting concepts in
science issue from the unexpected collision of seemingly unrelated
phenomena.' The case in point she discussed was the suggestion by
Wickner (1994) that 2 baffling problems in yeast genetics could be
explained by a hypothesis similar to the prion hypothesis. Two yeast
mutations provided a convincing case that the inheritance of phenotype
can sometimes be based upon the inheritance of different protein
conformations rather than upon the inheritance of different nucleic
acids. Thus, yeast may provide important new tools for the study of
prion-like processes. Furthermore, she suggested that prions need not be
pathogenic; self-promoted structural changes in macromolecules lie at
the heart of a wide variety of normal biologic processes, not only
epigenetic phenomena, such as those associated with altered chromatin
structures, but also some normal, developmentally regulated events.
Hegde et al. (1999) demonstrated that transmissible and genetic prion
diseases share a common pathway of neurodegeneration. Hegde et al.
(1999) observed that the effectiveness of accumulated PrP(Sc), an
abnormally folded isoform, in causing neurodegenerative disease depends
upon the predilection of host-encoded PrP to be made in a transmembrane
form, termed PrP-Ctm. Furthermore, the time course of PrP(Sc)
accumulation in transmissible prion disease is followed closely by
increased generation of PrP-Ctm. Thus, the accumulation of PrPsc appears
to modulate in trans the events involved in generating or metabolizing
PrP-Ctm. Hegde et al. (1999) concluded that together these data
suggested that the events of PrP-Ctm-mediated neurodegeneration may
represent a common step in the pathogenesis of genetic and infectious
prion diseases.
Like other proteins that traffic through the endoplasmic reticulum,
misfolded prion protein undergoes retrograde transportation to the
cytosol for degradation by the proteasome. Accumulation of even small
amounts of cytosolic prion protein was strongly neurotoxic in cultured
cells and transgenic mice. Mice developed normally but acquired severe
ataxia with cerebellar degeneration and gliosis. Ma et al. (2002)
concluded that their work established a mechanism for converting
wildtype PrP to a highly neurotoxic species that is distinct from the
self-propagating PrP(Sc) isoform, and suggested a potential common
framework for seemingly diverse prion protein neurodegenerative
disorders. Ma and Lindquist (2002) reported that prion protein
retrogradely transported out of the endoplasmic reticulum produced both
amorphous aggregates and a PrP(Sc)-like conformation in the cytosol. The
distribution between these forms correlated with the rate of appearance
in the cytosol. Once conversion to the PrP(Sc)-like conformation
occurred, it was sustained. Thus, PrP has an inherent capacity to
promote its own conformation conversion in mammalian cells. Ma and
Lindquist (2002) suggested that these observations might explain the
origin of PrP(Sc).
Noting that PrP(Sc) possesses partial protease resistance and high
beta-sheet content, unlike the protease-sensitive, alpha-helix-rich
PrPc, Paramithiotis et al. (2003) suggested that PrP(Sc) possesses
unique conformational epitopes. The conformational conversion of the
protein from PrPc to PrP(Sc) in disease is likely to be accompanied by
molecular surface exposure of previously sequestered amino acid side
chains which may serve as immunologic epitopes. Paramithiotis et al.
(2003) found that induction of beta-sheet structures was associated with
increased solvent accessibility, and thus molecular surface exposure, of
tyrosine. They immunized rabbits with tyr-tyr-arg-NH2 peptides and found
that the antibody specifically recognized PrP(Sc), but not PrPc, from
multiple species, as assessed by immunoprecipitation, plate capture
immunoassay, and flow cytometry. Paramithiotis et al. (2003) suggested
that studies of conformational protein changes in prion diseases may
provide a prototype for other disorders of protein misfolding, including
other neurologic disorders.
Deleault et al. (2003) investigated the biochemical amplification of
protease-resistant PrP(Sc)-like protein, also referred to as PrP(res),
using a modified version of the protein-misfolding cyclic amplification
method. They reported that stoichiometric transformation of PrPc to
PrP(Sc) in vitro requires specific RNA molecules. Notably, whereas
mammalian RNA preparations stimulate in vitro amplification of PrP(Sc),
RNA preparations from invertebrate species do not. The findings of
Deleault et al. (2003) suggested that host-encoded stimulatory RNA
molecules may have a role in the pathogenesis of prion disease and may
provide practical approaches to improving the sensitivity of diagnostic
techniques based on PrP(Sc) amplification.
Legname et al. (2004) produced recombinant mouse PrP in E. coli that
polymerized into amyloid fibrils, representing a subset of
beta-sheet-rich structures. Fibrils consisting of recombinant mouse
PrP(89-230) were inoculated intracerebrally into transgenic mice
expressing murine PrP(89-231). The mice developed neurologic dysfunction
between 380 and 660 days after inoculation. Brain extracts showed
protease-resistant PrP by Western blotting; these extracts transmitted
disease to wildtype mice and transgenic mice overexpressing PrP, with
incubation times of 150 and 90 days, respectively. Neuropathologic
findings suggested that a novel prion strain was created. Legname et al.
(2004) concluded that their results provide compelling evidence that
prions are infectious proteins.
Yin et al. (2007) presented evidence indicating that pathogenic mutant
Prnp proteins bind more glycosaminoglycans (GAG) at an N-terminus
binding motif compared to wildtype Prnp, and furthermore that GAG
promote the aggregation of mutant Prnp. Point mutations in the PRNP gene
caused conformational changes in the region between residues 109 and
136, resulting in the exposure of a normally buried GAG-binding motif.
Yin et al. (2007) hypothesized that these conformational changes, which
enhance GAG binding, may contribute to pathogenesis of inherited prion
diseases.
- Pathogenic Formation of Amyloid-like Fibrils
Tagliavini et al. (1991) found that a portion of the PrP protein was the
major component of amyloid plaque cores isolated from 2 patients from a
large Indiana kindred with Gerstmann-Straussler disease caused by a
phe198-to-ser (F198S; 176640.0011) mutation in the PRNP gene. The PrP
protein fragment was an 11-kD degradation product whose N terminus
corresponded to residue 58 of the amino acid sequence. The amyloid
fractions also contained larger PrP fragments with apparently intact N
termini. Tagliavini et al. (1991) concluded that the GSD disease process
is characterized by proteolytic cleavage of PrP, generating an
amyloidogenic peptide that polymerizes into insoluble fibrils.
Forloni et al. (1993) found that a PrP peptide containing amino acid
residues 106-126 has a high intrinsic ability to polymerize into
amyloid-like fibrils in vitro. Chronic exposure of primary rat
hippocampal neurons in cell culture to micromolar concentrations of a
peptide corresponding to this peptide resulted in increased neuronal
death. Forloni et al. (1993) suggested that the neurotoxic effect of the
peptide involves an apoptotic mechanism. Tagliavini et al. (1993) found
that PrP peptide 106-126 formed straight fibrils similar to those seen
in GSD brains, whereas PrP peptide 127-147 formed twisted fibrils
resembling scrapie-associated fibrils. Both types of fibrils showed
Congo red staining and X-ray diffraction patterns consistent with
amyloid.
Le et al. (2001) showed that PrP 106-126, a peptide that had been
detected in some Alzheimer disease (see 605055) brain lesions, uses
formyl peptide receptor-like-1 (FPRL1; 136538) to induce monocyte
migration and the release of proinflammatory cytokines implicated in the
neurotoxicity observed in prion disease.
Tagliavini et al. (2001) characterized amyloid peptides purified from
brain tissue of a GSD patient with the ala117-to-val (D117V;
176640.0004) mutation. The major peptide extracted from amyloid fibrils
was a 7-kD PRNP fragment. Sequence analysis and mass spectrometry showed
that this peptide was truncated at the N and C termini, spanning
approximately from residues 88 to 148, and was generated from the mutant
allele. Additional N- and C-terminal fragments were identified; however,
apart from a peptide spanning residues 191 to 205, which formed a
morphologically distinct type of fibril, only the 7-kD peptides were
fibrillogenic in vitro. Tagliavini et al. (2001) proposed that the
full-length 253-amino acid PRNP protein may be deposited extracellularly
in GSD patients and be partially proteolytically degraded, creating a
protease-resistant core of 7 kD.
Salmona et al. (2003) synthesized several PrP peptides, including a 7-kD
fragment spanning approximately residues 82-146 that had been identified
as the major amyloid component in GSD brains. The fragments formed
aggregates consisting of 9.8-nm-diameter amyloid-like fibrils with a
beta-pleated structure that were partially resistant to protease
digestion. The peptide induced an increase in plasma membrane
microviscosity of primary neurons, which the authors suggested may be
relevant to disease pathogenesis. Scrambling of C-terminal amino acid
sequences modified the ability of the 7-kD peptide to aggregate and form
fibrils, suggesting that the properties of fragment 82-146 are dependent
on the integrity of C-terminal regions of the PrP protein.
Cobb et al. (2007) used site-directed spin labeling and EPR spectroscopy
to examine the molecular architecture of pathogenic recombinant D178N
human PrP90-231, which undergoes autocatalytic conversion to the amyloid
state (Legname et al., 2004). The conformational conversion of PrP
involves major refolding of the alpha-helical region. The core of the
amyloid maps to C-terminal residues from 160 to 220, which form
single-molecule layers that stack on top of one another with parallel
in-register alignment of beta-strands.
- Identification of Different Pathogenic PrP(Sc) Protein Strains
In a study of 19 cases of sporadic CJD, Parchi et al. (1996) identified
2 forms of the pathogenic PrP(Sc): type 1 (21 kD) and type 2 (19 kD),
which are generated after partial digestion by proteinase K at different
N-terminal regions. Three major bands that contained the diglycosylated,
monoglycosylated, and unglycosylated forms of each of the 2 subtypes
were seen on Western analysis. PrP(Sc) type 1 was found in 11 of 13
met129 homozygotes; PrP(Sc) type 2 was found in the other 2 met129
homozygotes, in all 3 129met/val heterozygotes, and in all 3 val/val129
homozygotes. No significant variation in the pattern of electrophoretic
mobility of each type of PrP(Sc) was seen among the different brain
regions tested. The more typical CJD phenotype characterized by duration
less than 6 months, periodic sharp waves on EEG, and myoclonus, was
associated with met129 homozygosity and the type 1 protein, whereas
atypical forms, characterized by slower disease course, absence of sharp
wave patterns on EEG, and/or absence of myoclonus, were associated with
different genotypes at codon 129 and the type 2 protein. Patients with
the type 2 PrP(Sc) variant had more severe subcortical involvement on
neuropathologic examination. Parchi et al. (1996) proposed a
classification of sCJD based on 129 polymorphism genotype and subtype of
PrP(Sc) protein.
Collinge et al. (1996) confirmed the presence of PrP(Sc) types 1 (21-kD)
and 2 (19-kD) in 26 cases of sCJD. They also identified 2 additional
PrP(Sc) types with differing molecular mass, types 3 and 4, in
iatrogenic and 'new variant' cases of CJD, respectively. All 10 patients
with vCJD were homozygous for met129. Type 4 was highly glycosylated and
was similar to that seen in experimentally transmitted bovine spongiform
encephalopathy in mice and macaques, and to naturally acquired BSE in
domestic cats. The report of Collinge et al. (1996) was reviewed by
Aguzzi and Weissmann (1996), who concluded that Collinge et al. (1996)
had provided further evidence that the BSE agent had been transmitted to
man. Ironside et al. (1996) reviewed the neuropathologic and clinical
features of the 'new variant' of CJD that was related to BSE.
Deslys et al. (1997) found that a French patient with new variant CJD
first reported by Chazot et al. (1996) had PrP immunostaining and
electrophoretic patterns (type 4 as defined by Collinge et al., 1996)
similar to those seen in vCJD patients from the U.K., suggesting that
vCJD is a unique, and homogeneous, disease variant.
In a study of 300 cases of sCJD, Parchi et al. (1999) found that 71.6%
of all patients were homozygous for met129, 11.75% were met/val
heterozygous, and 16.7% were val homozygous. PrP(Sc) type 1 was
identified in 95% of met homozygotes, 3.7% of met/val heterozygotes, and
1.4% of val homozygotes, whereas type 2 was identified in 14% met/met,
31.4% met/val, and 54.6% val/val. The relative proportion of each of the
3 PrP(Sc) glycosylation forms, showed significant heterogeneity. Parchi
et al. (1999) delineated 6 subtypes of sCJD according to PrP(Sc) type,
codon 129 genotype, and disease phenotype. Seventy percent of patients
showed the classic phenotype, PrP(Sc) type 1, and at least 1 met allele
at codon 129.
Parchi et al. (2000) determined that 1 of the 2 PrP(Sc) isoforms, 21-kD
type 1 and 19-kD type 2, was present in each of 32 patients with prion
disease, including 17 with sporadic CJD, 5 with iatrogenic CJD, 6 with
familial CJD, 4 with variant CJD, and 2 with fatal familial insomnia.
All cases of vCJD were met129 homozygous. Protein sequencing showed that
types 1 and 2 PrP(Sc) had N-terminal regions beginning at residues gly82
and ser97, respectively, corresponding to the proteinase K cleavage
sites. In addition to these main variants, all cases, except 1 FFI,
showed additional minor PrP(Sc) species with different N-termini. Parchi
et al. (2000) noted that the type 2 PrP(Sc) protein was associated with
all 4 cases of variant CJD, and did not differ from the type 2 PrP(Sc)
associated with sporadic CJD. This finding suggested that the type 3
variant identified by Collinge et al. (1996) actually corresponds to
their type 2 variant.
Wadsworth et al. (1999) identified further PrP(Sc) strain-specific
protein conformations influenced by metal ion binding. They showed that
metal ion chelation of certain PrP(Sc) types caused a change in protein
conformation and exposure of new proteolytic sites for proteinase K. The
findings represented a novel mechanism for posttranslational
modification of PrP and the generation of multiple prion strains.
In 89 cases of sCJD and 30 cases of vCJD, Hill et al. (2003) identified
the 4 types of PrP(Sc) previously described by Collinge et al. (1996).
All cases with 21-kD type 1 were homozygous for met129, whereas the
19-kD type 2 protein was seen in individuals of all codon 129 genotypes.
Type 3 PrP(Sc) had a slightly smaller molecular mass compared to type 4
PrP(Sc), was seen in iatrogenic and sporadic disease, and was generally
associated with codon 129 genotypes containing a val allele. Type 4
PrP(Sc) was unique to vCJD, was associated only with homozygosity for
met129, and had a distinct glycosylation pattern. In addition, Hill et
al. (2003) referred to a type 5 PrP(Sc) seen in vCJD-infected mice, and
a type 6 PrP(Sc) in a single case of sCJD. The authors presented a
classification scheme that incorporated PrP(Sc) type, effects of metal
ion chelation on PrP(Sc), codon 129 genotype, and clinical and
neuropathologic features.
Telling et al. (1996) found that the PrP(Sc) protein found in fatal
familial insomnia was 19 kD after deglycosylation, whereas that from
other inherited and sporadic prion diseases was 21 kD. Brain extracts
from FFI patients transmitted disease to transgenic mice expressing a
chimeric human-mouse PrP gene about 200 days after inoculation, and
induced formation of the 19-kD PrP(Sc) fragment, whereas extracts from
the brains of familial and sporadic Creutzfeldt-Jakob disease patients
produced the 21-kD PrP(Sc) fragment in these mice. Telling et al. (1996)
concluded that the conformation of PrP(Sc) functions as a template in
directing the formation of nascent PrP(Sc), and suggested a mechanism to
explain strains of prions where diversity is encrypted in the
conformation of PrP(Sc) rather than by mutations in the PRNP gene.
Bruce et al. (1997) found that mice inoculated with tissue from 3 human
cases of vCJD showed clinical and neuropathologic features similar to
that seen in mice with BSE, suggesting that the same strain of agent is
involved in both diseases.
Among 32 cases of sCJD, Zanusso et al. (2004) found that 18 cases and 14
cases had di-, mono-, and unglycosylated PrP(Sc) corresponding to the
21-kD type 1 PrP(Sc) and 19-kD type 2 PrP(Sc), respectively. All the
met/val129 genotypes were represented in both groups. All cases with
type 1 PrP(Sc) and cases with type 2 PrP(Sc) and the met/met129 genotype
also had a 16- to 17-kD unglycosylated PrP fragment. Cases with type 2
PrP(Sc) who were met/val129 or val/val129 had an additional 18-kD
unglycosylated PrP fragment. The findings highlighted the presence of
multiple PrP(Sc) conformations in sCJD.
Head et al. (2004) noted that the nomenclature of PrP(Sc) has been
controversial, with several classification schemes proposed (Parchi et
al., 1996; Collinge et al., 1996; Hill et al., 2003). In 59 cases of
variant CJD, Head et al. (2004) found that the biochemical features of
the PrP(Sc) protein were remarkably stereotyped, consisting
predominantly of the diglycosylated 19-kD type 2 protein. In addition,
all vCJD cases were homozygous for met129. There was much greater
variation among 165 cases of sporadic CJD, in which monoglycosylated or
unglycosylated forms of both PrP(Sc) type 1 (66% of cases) or type 2
(34% of cases) were detected. In addition, patients with sCJD
represented all 3 genotypes of the 129 codon: 67% were met/met, 19% were
met/val, and 14% were val/val. The type 2 isoform did not differ in
mobility between sCJD and vCJD, suggesting that it represented a single
conformation. Analysis of 17 different anatomic brain regions of 6 cases
of sCJD showed regional variation in PrP(Sc) type. In contrast, all 5
vCJD cases showed uniform type 2 PrP(Sc) mobility in all 17 regions.
Head et al. (2004) concluded that the distinct and stereotyped findings
in vCJD were consistent with exposure of susceptible individuals (met129
homozygotes) to a single strain of prion by a defined route, likely
oral. In sCJD, PrP(Sc) replication may be an error-prone process,
resulting in the formation of different forms of PrP(Sc) which are then
replicated.
Haik et al. (2004) studied the biochemical features of PrP(Sc) in 4
patients with inherited prion disease associated with the D178N
mutation: 2 with fatal familial insomnia (176640.0010) and 2 with
familial CJD (176640.0007). The 2 disorders differ at the codon 129
polymorphism in the mutated allele, with met129 in FFI and val129 in
CJD. Western blot analysis showed heterogeneity of the PrP(Sc) protein
between patients with the same mutation and in different brain regions
of the same patient. The findings indicated that a pathologic mutation
in the PRNP gene was capable of inducing PrP(Sc) diversity both between
and within affected individuals. In a response to Haik et al. (2004),
Head and Ironside (2004) noted that prion diversity had been identified
in sporadic, inherited, and acquired forms of CJD, suggesting that it
may be a fundamental aspect of prion diseases in general.
Using a rapid coculture system, Nishida et al. (2005) demonstrated that
a neural cell line free of immune system cells supported substantial CJD
agent interference without pathologic prion protein (PrPres). In
addition, an attenuated Creutzfeldt-Jakob disease agent (SY-CJD)
prevented superinfection by sheep-derived Chandler (Ch) and 22L scrapie
agents. However, only 22L and not Ch prevented the virulent
human-derived agent (FU-CJD) infection, even though both scrapie strains
provoked abundant PrPres. Nishida et al. (2005) concluded that this
relationship between particular strains of sheep- and human-derived
agents is likely to affect their prevalence and epidemic spread.
Zanusso et al. (2007) reported an atypical case of sCJD associated with
a novel prion protein conformation. The patient was a 69-year-old woman
with rapid progression of behavioral disturbances and dementia,
resulting in akinetic mutism and death approximately 13 months after
disease onset. Postmortem examination showed spongiform degeneration,
intracellular prion protein deposition, and axonal swellings filled with
PrP-positive amyloid-like fibrils. Biochemical analysis detected a novel
prion protein tertiary structure, which was predominantly
unglycosylated. No mutation in the PRNP gene was found, and all bank
voles inoculated with brain suspension from the patient developed
disease.
Cali et al. (2009) studied 34 patients with sCJD who were met129
homozygotes. Detailed protease K and antibody studies found that 9 (26%)
had PrPSc type 1 only, 5 (15%) had PrPSc type 2 only, and 20 (59%) had
both PrPSc types 1 and 2 either mixed in the same anatomic region or
separate in different regions. In those with the mixed type 1 and 2
PrPSc, the type 1 PrPSc dominated in all brain regions examined,
especially in the cerebellum and subcortical regions. Clinically, those
with the mixed type 1 and 2 had an average disease duration that was
intermediate between the other 2 groups. Histologic studies also showed
a mixed pattern between that observed for either type in isolation.
Further characterization using different antibodies and a conformational
stability immunoassay indicated that the coexistence of types 1 and 2 in
the same anatomic region may allow PrPSc types 1 and 2 to take on
conformational characteristics of each other. Cali et al. (2009)
concluded that sCJD with both types 1 and 2 should be considered as a
separate disease entity.
MOLECULAR GENETICS
Mead (2006) provided a detailed review of the genetics of prion
diseases.
In affected members of a family with inherited Creutzfeldt-Jakob disease
(123400) Owen et al. (1989, 1990) identified a 144-bp insertion in the
PRNP gene (176640.0001), resulting in 6 extra octapeptide repeats in the
N-terminal region of the protein. Collinge et al. (1989) identified a
0.15-kb insertion similar to that reported by Owen et al. (1989) in 2
affected members of a family with Gerstmann-Straussler disease (137440).
Goldfarb et al. (1992) reported the interesting observation that when
the val129 allele was present on the same chromosome as the
asp178-to-asn mutation (D178N), the phenotype was that of CJD
(176640.0007), whereas the met129/asn178 allele (176640.0010) segregated
with fatal familial insomnia (600072). In inherited prion diseases,
mutant isoforms spontaneously assume conformations depending on the
mutation. An interaction between methionine or valine at position 129
and asparagine at position 178 might result in 2 abnormal isoforms that
differ in conformation and pathogenic consequences.
Gajdusek (1991) provided a chart of the PRNP mutations identified: 5
different mutations causing single amino acid changes and 5 insertions
of 5, 6, 7, 8, or 9 octapeptide repeats. He also provided a table of 18
different amino acid substitutions that have been identified in the
transthyretin gene (TTR; 176300) resulting in amyloidosis and drew a
parallel between the behavior of the 2 classes of disorders.
Palmer and Collinge (1993) reviewed mutations and polymorphisms in the
prion protein gene. Windl et al. (1999) diagrammed the known pathogenic
mutations in the coding region of PRNP.
Windl et al. (1999) searched for mutations and polymorphisms in the
coding region of the PRNP gene in 578 patients with suspect prion
diseases referred to the German Creutzfeldt-Jakob disease surveillance
unit over a period of 4.5 years. Among 40 reported pathogenic missense
mutations in the PRNP gene, the D178N mutation was the most common. In
all of these cases, D178N was coupled with methionine at codon 129,
resulting in the typical fatal familial insomnia genotype. Two novel
missense mutations and several silent polymorphisms were found.
Mead et al. (2001) analyzed the PRNP locus for tightly linked
susceptibility factors for prion disease. They identified 56 polymorphic
sites within 25 kb of the PRNP open reading frame, including sites
within the PRNP promoter and the PRNP 3-prime untranslated region. These
were characterized in 61 CEPH families, demonstrating extensive linkage
disequilibrium around PRNP and the existence of 11 major European PRNP
haplotypes. A common haplotype was overrepresented in patients with
sporadic Creutzfeldt-Jakob disease. They could demonstrate that, in
addition to the strong susceptibility conferred by codon 129, there was
a significant independent association between sporadic CJD and a
polymorphism upstream of PRNP. Although their sample size was
necessarily small, no association was found between these polymorphisms
and variant CJD or iatrogenic CJD, in keeping with their having distinct
disease mechanisms. Cousens et al. (2001) described a cluster of variant
CJD near the Leicestershire village of Queniborough in the U.K.. Mead et
al. (2001) could find no evidence of a PRNP founder susceptibility
effect in that cluster.
Rivera et al. (1989) described a 13-year-old male with a severe
progressive neurologic disorder whose karyotype showed a pseudodicentric
chromosome resulting from a telomeric fusion 15p;20p. In lymphocytes the
centromeric constriction of the abnormal chromosome was always that of
chromosome 20, whereas in fibroblasts both centromeres were alternately
constricted. The authors suggested that centromere inactivation resulted
from a modified conformation of the functional DNA sequences preventing
normal binding to centromere-specific proteins. They also postulated
that the patient's disorder, reminiscent of a spongy glioneuronal
dystrophy as seen in Creutzfeldt-Jakob disease, may be secondary to the
presence of a mutation in the prion protein.
- Exclusion of PRNP Mutations in Neurodegenerative Diseases
Schellenberg et al. (1991) sought the missense mutations at codons 102,
117, and 200 of the PRNP gene, as well as the PRNP insertion mutations,
which are associated with CJD and GSD, in 76 families with Alzheimer
disease (see 104300), 127 presumably sporadic cases of Alzheimer
disease, 16 cases of Down syndrome (190685), and 256 normal controls;
none was positive for any of these mutations.
Jendroska et al. (1994) used histoblot immunostaining in an attempt to
detect pathologic prion protein in 90 cases of various movement
disorders including idiopathic Parkinson disease (PD; 168600), multiple
system atrophy, diffuse Lewy body disease (127750),
Steele-Richardson-Olszewski syndrome (260540), corticobasal
degeneration, and Pick disease (172700). No pathologic prion protein was
identified in any of these brain specimens, although it was readily
detected in 4 controls with Creutzfeldt-Jakob disease.
Perry et al. (1995) used SSCP to screen for mutations at the prion locus
in 82 Alzheimer disease patients from 54 families (including 30 familial
cases), as well as in 39 age-matched controls. They found a 24-bp
deletion around codon 68 which removed 1 of the 5 gly-pro rich
octarepeats in 2 affected sibs and 1 offspring in a late-onset Alzheimer
disease family. However, the other affected individuals within the same
pedigree did not share this deletion, which was also detected in 3
age-matched controls in 6 unaffected members from a late-onset Alzheimer
disease family. Another octarepeat deletion was detected in 3 other
individuals from the same Alzheimer disease family, of whom 2 were
affected. No other mutations were found. Perry et al. (1995) concluded
that there was no evidence for association between prion protein
mutations and Alzheimer disease in their survey.
GENOTYPE/PHENOTYPE CORRELATIONS
Mastrianni et al. (2001) suggested that each PRNP mutation produces a
different prion strain with a unique clinicopathologic phenotype. They
identified 4 patients with familial CJD caused by the V201I mutation
(176640.0014) and demonstrated transmissibility of the disease into
transgenic mice. Although the clinical presentations of the patients
were variable, the protein accumulation patterns in the brains of the
patients and in the mice were similar to one another and to sporadic
CJD, but differed from the patterns produced by E200K (176640.0006),
D178N (176640.0010), and met129 (176640.0005).
POPULATION GENETICS
Soldevila et al. (2003) found a wide variation in the frequency of the
V129 and M129 alleles of the PRNP gene (176640.0005) in different
geographic areas. They studied 616 chromosomes from control individuals
of all major continental groups, and 6 individuals affected by either
CJD or fatal familial insomnia. In addition to the M129V polymorphism,
they studied E219K (176640.0019). They found that the V129 allele was
highly represented in some populations from the Americas, and that M129
and V129 occurred in similar frequencies in Africa. The M129
susceptibility allele was found at high frequencies in Old World
populations, at very high frequencies in the Pacific (approximately 81%)
and Central and East Asia (up to 93%), but at low frequency
(approximately 30%) in Native Americans. The protective K219 allele was
restricted to Asian and Pacific populations. Thus, susceptibility
alleles exhibit marked geographic differences in frequency and presumed
differences in probability to develop prion diseases.
Kuru is an acquired prion disease largely restricted to the Fore
linguistic group of the Papua New Guinea Highlands that was transmitted
during endocannibalistic feasts (Mead et al., 2003). Heterozygosity for
a common polymorphism in the human prion protein gene confers relative
resistance to prion diseases. Elderly survivors of the kuru epidemic,
who had multiple exposures at mortuary feasts, are, in marked contrast
to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru
imposed strong balancing selection on the Fore, essentially eliminating
PRNP 129 homozygotes. Worldwide PRNP haplotype diversity and coding
allele frequencies suggested that strong balancing selection at this
locus occurred during the evolution of modern humans. Mead et al. (2003)
raised the possibility that cannibalism, which some evidence suggests
was widespread in many prehistoric populations, may have provided the
setting for selection pressure as protection against prion disease.
Kreitman and Di Rienzo (2004) and Soldevila et al. (2005) suggested that
the findings reported by Mead et al. (2003) were due to ascertainment
bias and did not reflect balancing selection. In an analysis of 174
individuals worldwide who were genotyped for the PRNP 129 polymorphism,
Soldevila et al. (2006) found no evidence for selective forces other
than purifying selection. The findings disputed the hypothesis suggested
by Mead et al. (2003).
Zan et al. (2006) found that the frequency of the 129V allele was 0.3%
in a population of 436 Han Chinese individuals. They presented further
evidence that the pattern of genetic variation in the PRNP gene was not
consistent with balancing selection in this population.
Kovacs et al. (2005) examined the phenotype, distribution, and frequency
of genetic TSEs or prion diseases in different countries/geographic
regions. Genetic TSE patients with insertion mutations in the PRNP gene
represented a separate group. Point and insertion mutations in the PRNP
gene varied significantly in frequency between countries. The most
common mutation was E200K (176640.0006). Absence of a positive family
history was noted in a significant proportion of cases in all mutation
types. Patients with FFI or GSS developed disease earlier than those
with genetic CJD. Cases with basepair insertions and the CJD phenotype,
GSS, or FFI had a longer duration of illness compared to cases with
point mutations and genetic CJD. Given the low prevalence of family
history, Kovacs et al. (2005) suggested that the term 'genetic TSE' is
preferable to 'familial TSE.'
Kovacs et al. (2005) retrospectively analyzed data from 109 confirmed
cases of prion disease identified in Hungary from 1994 to 2004.
Seventeen of 27 cases who had genetic analysis had the common E200K
mutation. Another 10 patients lacking PRNP analysis had a positive
family history of prion disease. Estimates of the mean annual incidence
(0.27 per million) and proportion (25.6%) of genetic prion disease in
Hungary was unusually high and thought to be related to the migration of
ancestors from Slovakia where the frequency of E200K is high.
ANIMAL MODEL
The structural gene encoding mouse prion (Prnp) has been mapped to
chromosome 2. A second murine locus, Prni, which is closely linked to
Prnp, determines the length of the incubation period for scrapie in mice
(Carlson et al., 1986). Yet another gene controlling scrapie incubation
times, symbolized Pid1, is located on mouse chromosome 17. Scott et al.
(1989) demonstrated that transgenic mice harboring the prion protein
gene from the Syrian hamster, when inoculated with hamster scrapie
prions, exhibited scrapie infectivity, incubation times, and prion
protein amyloid plaques characteristic of the hamster. Hsiao et al.
(1994) found that 2 lines of transgenic mice expressing high levels of
the mutant P101L prion protein developed a neurologic illness and
central nervous system pathology indistinguishable from experimental
murine scrapie. Amino acid 102 in human prion protein corresponds to
amino acid 101 in mouse prion protein; hence, the P101L murine mutation
was the equivalent of the pro102-to-leu mutation (176640.0002) that
causes Gerstmann-Straussler disease in the human. Hsiao et al. (1994)
reported serial transmission of neurodegeneration to mice who expressed
the P101L transgene at low levels and Syrian hamsters injected with
brain extracts from the transgenic mice expressing high levels of mutant
P101L prion protein. Although the high-expressing transgenic mice
accumulated only low levels of infectious prions in their brains, the
serial transmission of disease to inoculated recipients argued that
prion formation occurred de novo in the brains of these uninoculated
animals and provided additional evidence that prions lack a foreign
nucleic acid.
Studies on PrP knockout mice have been reported by Bueler et al. (1994),
Manson et al. (1994), and Sakaguchi et al. (1996). Sakaguchi et al.
(1996) reported that the PrP knockout mice produced by them were
apparently normal until the age of 70 weeks, at which point they
consistently began to show signs of cerebellar ataxia. Histologic
studies revealed extensive loss of Purkinje cells in the majority of
cerebellar folia. Atrophy of the cerebellum and dilatation of the fourth
ventricle were noted. Similar pathologic changes were not noted in the
PrP knockout mice produced by Bueler et al. (1994) and by Manson et al.
(1994). Sakaguchi et al. (1996) noted that the difference in outcome may
be due to strain differences or to differences in the extent of the
knockout within the PrP gene. Notably, in all 3 lines of PrP knockout
mice described, susceptibility to prion infection was lost.
Mallucci et al. (2002) generated transgenic mice in which PrP was
depleted at age 9 weeks, after normal neurologic development. The mice
remained healthy without evidence of neurodegeneration or
neuropathologic findings for up to 15 months post-knockout. None of the
knockout mice developed scrapie symptoms after inoculation with
pathogenic prion. Neurophysiologic evaluation showed significant
reduction of after hyperpolarization potentials (AHP) in hippocampal CA1
cells, suggesting a direct role for PrP in the modulation of neuronal
excitability. Mallucci et al. (2002) concluded that loss of PrP function
is not a pathogenic mechanism in prion disease.
Based on their studies in PrP-null mice, Collinge et al. (1994)
concluded that prion protein is necessary for normal synaptic function.
They postulated that inherited prion disease may result from a
dominant-negative effect with generation of PrP(Sc), the
posttranslationally modified form of cellular PrP, ultimately leading to
progressive loss of functional PrPc. Tobler et al. (1996) reported
changes in circadian rhythm and sleep in PrP-null mice and stressed that
these alterations show intriguing similarities with the sleep
alterations in fatal familial insomnia.
Mice devoid of PrP develop normally, but are resistant to scrapie;
introduction of a PrP transgene restores susceptibility to the disease.
To identify the regions of PrP necessary for this activity, Shmerling et
al. (1998) prepared PrP knockout mice expressing PrPs with
amino-proximal deletions. Surprisingly, PrP with deletion of residues
32-121 or 32-134, but not with shorter deletions, caused severe ataxia
and neuronal death limited to the granular layer of the cerebellum as
early as 1 to 3 months after birth. The defect was completely abolished
by introducing 1 copy of a wildtype PrP gene. Shmerling et al. (1998)
speculated that these truncated PrPs may be nonfunctional and compete
with some other molecule with a PrP-like function for a common ligand.
Flechsig et al. (2000) expressed a truncated transgene of Prnp lacking
codons 32-93, thereby eliminating all 5 octarepeats, in Prnp -/- mice.
These reconstituted mice were also susceptible to scrapie. However, the
incubation period was longer and prion titers in brain and spleen were
30-fold lower than in wildtype mice. Histopathologic analysis detected
no changes in brain. In the cervical spinal cord, on the other hand,
there was astrogliosis and loss of neurons. Flechsig et al. (2000)
concluded that the octarepeats are not essential for sustaining prion
replication and disease, but they do affect the level of prion
accumulation and pathogenesis in the brain.
Hegde et al. (1998) studied the role of different topologic forms of PrP
in transgenic mice expressing PrP mutations that alter the relative
ratios of the topologic forms. One form is fully translocated into the
ER lumen and is termed PrP-Sec. Two other forms span the ER membrane
with orientation of either the carboxy-terminal to the lumen (PrP-Ctm)
or the amino-terminal to the lumen (PrP-Ntm). F2-generation mice
harboring mutations that resulted in high levels of PrP-Ctm showed onset
of neurodegeneration at 58 +/- 11 days. Overexpression of PrP was not
the cause. Neuropathology showed changes similar to those found in
scrapie, but without the presence of PrP(Sc). The level of expression of
PrP-Ctm correlated with severity of disease.
Supattapone et al. (1999) reported that expression of a redacted PrP of
106 amino acids with 2 large deletions in transgenic (Tg) mice deficient
for wildtype PrP (Prnp -/-) supported prion propagation. Rocky Mountain
laboratory (RML) prions containing full-length PrP-Sc produced disease
in Tg(PrP106)Prnp -/- mice after approximately 300 days, while
transmission of RML106 prions containing PrP-Sc106 created disease in
Tg(PrP106)Prnp -/- mice after approximately 66 days on repeated passage.
This artificial transmission barrier for the passage of RML prions was
diminished by the coexpression of wildtype mouse PrPc in Tg(PrP106)Prnp
+/- mice that developed scrapie in approximately 165 days, suggesting
that wildtype mouse PrP acts in trans to accelerate replication of
RML106 prions. Purified PrP-Sc106 was protease resistant, formed
filaments, and was insoluble in nondenaturing detergents.
Chiesa et al. (1998) generated lines of transgenic mice that expressed a
mutant prion protein containing 14 octapeptide repeats, the human
homolog of which (see 176640.0001) is associated with an inherited prion
dementia. This insertion was the largest identified to that time in the
PRNP gene and was associated with a prion disease characterized by
progressive dementia and ataxia, and by the presence of PrP-containing
amyloid plaques in the cerebellum and basal ganglia (Owen et al., 1992;
Duchen et al., 1993; Krasemann et al., 1995). Mice expressing the mutant
protein developed a neurologic illness with prominent ataxia at 65 or
240 days of age, depending on whether the transgene array was,
respectively, homozygous or hemizygous. Starting from birth, mutant PrP
was converted into a protease-resistant and detergent-insoluble form
that resembled the scrapie isoform of PrP, and this form accumulated
dramatically in many brain regions throughout the lifetime of the mice.
As PrP accumulated, there was massive apoptosis of granule cells in the
cerebellum.
Supattapone et al. (2001) removed additional sequences from PrP106 and
identified a 61-residue peptide, designated PrP61, which spontaneously
adopted an insoluble, protease-resistant conformation when expressed in
neuroblastoma cells. Synthetic PrP61 was found to form beta-sheets and
amyloid fibers. Transgenic mice that expressed PrP61 developed rapidly
progressive neurologic disease with PrP accumulation and degenerating
neurons. Although PrP61 is a good model for mutant PrP
neurodegeneration, it was not found to be infectious.
Kuwahara et al. (1999) established hippocampal cell lines from Prnp -/-
and Prnp +/+ mice. The cultures were established from 14-day-old mouse
embryos. All 6 cell lines studied belonged to the neuronal precursor
cell lineage, although they varied in their developmental stages.
Kuwahara et al. (1999) found that serum removal from the cell culture
caused apoptosis in the Prnp -/- cells but not in Prnp +/+ cells.
Transduction of the prion protein or the BCL2 gene suppressed apoptosis
in Prnp -/- cells under serum-free conditions. Prnp -/- cells extended
shorter neurites than Prnp +/+ cells, but expression of PRP increased
their length. Kuwahara et al. (1999) concluded that these findings
supported the idea that the loss of function of wildtype prion protein
may partly underlie the pathogenesis of prion diseases. The authors were
prompted to try transduction of the BCL2 gene because BCL2 had
previously been shown to interact with prion protein in a yeast 2-hybrid
system. Their results suggested some interaction between BCL2 and PRP in
mammalian cells as well.
In scrapie-infected mice, prions are found associated with splenic but
not circulating B and T lymphocytes and in the stroma, which contains
follicular dendritic cells. Formation and maintenance of mature
follicular dendritic cells require the presence of B cells expressing
membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble
lymphotoxin-beta receptor results in the disappearance of mature
follicular dendritic cells from the spleen. Montrasio et al. (2000)
demonstrated that this treatment abolished splenic prion accumulation
and retards neuroinvasion after intraperitoneal scrapie inoculation.
Montrasio et al. (2000) concluded that their data provided evidence that
follicular dendritic cells are the principal sites for prion replication
in the spleen.
Polymorphisms in the prion protein gene are known to affect prion
disease incubation times and susceptibility in both humans and mice.
However, studies with inbred lines of mice showed that large differences
in incubation times occur even with the same amino acid sequence of the
prion protein, suggesting that other genes may contribute to the
observed variation. To identify these loci, Lloyd et al. (2001) analyzed
1,009 animals from an F2 intercross between 2 strains of mice with
significantly different incubation periods when challenged with RML
scrapie prions. Interval mapping identified 3 highly significantly
linked regions on chromosomes 2, 11, and 12; composite interval mapping
suggested that each of these regions includes multiple linked
quantitative trait loci. Suggestive evidence for linkage was obtained on
chromosomes 6 and 7.
The incubation period and the neuropathology of transmissible spongiform
encephalopathies have been extensively used to distinguish prion
isolates (or strains) inoculated into panels of inbred mouse strains.
Such studies have shown that the bovine spongiform encephalopathy (BSE)
agent is indistinguishable from the agent causing variant
Creutzfeldt-Jakob disease (vCJD), but differs from isolates of sporadic
CJD, reinforcing the idea that the vCJD epidemic in Britain results from
consumption of contaminated beef products. Manolakou et al. (2001)
presented a mouse model for genetic and environmental factors that
modify the incubation period of BSE cross-species transmission. They
used 2 mouse strains that carried the same PrP allele but displayed a
100-day difference in their mean incubation period following
intracerebral inoculation with primary BSE isolate. They reported
genetic effects on incubation period that map to 4 chromosomal regions
in the mouse; in addition, they found significant factors of host
environment, namely, the age of the host's mother, the age of the host
at infection, and an interaction between the X chromosome and the
cytoplasm in the host.
Miele et al. (2002) identified 3 genes involved in mitochondrial
physiology that were differentially expressed in the postnatal
developing brains of normal mice and Prnp -/- mice. Further analysis
showed that compared to the hippocampal CA1 regions of Prnp +/+ mice,
those of Prnp -/- mice contained 40% fewer mitochondria, unusual
mitochondrial morphology, and significantly increased activity of
mitochondrial manganese-dependent antioxidant superoxide dismutase
(SOD2; 147460), suggesting greater levels of oxidative assault. These
results suggested that there is a relationship between normal cellular
PrP expression and quality and quantity of mitochondria.
Dominant-negative inhibition occurs when the product of the mutant or
variant allele interferes with a function of the wildtype allelic
protein. Naturally occurring polymorphic variants of PrP, Q171R and
E219K (176640.0019), known to render sheep and humans resistant to
scrapie and Creutzfeldt-Jakob disease, respectively, were found to act
as dominant negatives in scrapie-infected neuroblastoma cells (Kaneko et
al., 1997; Zulianello et al., 2000). Based on these findings, Perrier et
al. (2002) undertook studies on dominant-negative PrP using transgenic
mice expressing mutant PrP with either Q167R or Q218K or coexpressing
mutant and wildtype PrP and injected with Rocky Mountain Laboratory
prions. They found that expression of dominant-negative PrP at the same
level as wildtype PrP dramatically slowed scrapie PrP formation.
Moreover, dominant-negative PrP was not converted into scrapie PrP, and
its expression, even at high levels, had no deleterious effects on the
mice.
In a murine scrapie model, White et al. (2003) investigated whether
anti-PrP monoclonal antibodies show similar inhibitory effects on prion
replication in vivo. White et al. (2003) found that peripheral PrP(Sc)
levels and prion infectivity were markedly reduced, even when the
antibodies were first administered at the point of near maximal
accumulation of PrP(Sc) in the spleen. Furthermore, animals in which the
treatment was continued remained healthy for over 300 days after
equivalent untreated animals had succumbed to the disease.
Meier et al. (2003) reported that in wildtype mice, the expression of
PrPc rendered soluble and dimeric by fusion to the Fc-gamma tail of
human IgG1 (PrP-Fc2) delayed PrPsc accumulation, agent replication, and
onset of disease following inoculation with infective prions. In
infected PrP-expressing brains, PrP-Fc2 relocated to lipid rafts and
associated with PrPsc without acquiring protease resistance, indicating
that PrP-Fc2 resists conversion. Accordingly, mice expressing PrP-Fc2
but lacking endogenous PrPc were resistant to scrapie, did not
accumulate PrP-Fc2sc, and did not transmit disease to others. These
results indicated that various PrP isoforms engage in a complex in vivo,
whose distortion by PrP-Fc2 affects prion propagation and scrapie
pathogenesis. The unique properties of PrP-Fc2 suggested that soluble
PrP derivatives may represent a novel class of prion replication
antagonists.
Using a panel of recombinant antibody antigen-binding fragments (Fabs)
recognizing different epitopes of the cellular prion (PrPc) protein,
Peretz et al. (2001) identified a set of Fabs able to inhibit the
formation of the pathogenic prion protein PrPsc in mouse neuroblastoma
cells infected with PrPsc. Fab D18, recognizing residues 132-156
incorporating helix A of PrPc, eliminated PrPsc from mouse neuroblastoma
cells in vitro at a rate that abolishes prion propagation as well as
preexisting PrPsc from the cells. In vivo, mouse neuroblastoma cells
treated with Fab D18, or with some but not all other PrPc-binding Fabs,
and inoculated intracerebrally into mouse brains protected the animals
from disease. Peretz et al. (2001) proposed that Fab D18 operates
mechanistically by blocking or modifying the interaction of PrPc with
PrPsc at the face of the protein opposite from the residues thought to
participate in binding an auxiliary molecule, referred to as 'protein X'
by Kaneko et al. (1997), that is essential for prion propagation. Peretz
et al. (2001) suggested that residues 132-140 of PrPc are the logical
target for the development of antiprion drugs. Peretz et al. (2001)
concluded that specific antibodies may be a powerful weapon against
neurodegenerative diseases associated with the accumulation of misfolded
proteins.
Prinz et al. (2003) found that in mice deficient in Cxcr5 (601613), the
follicular dendritic cells (FDCs) are juxtaposed to major splenic nerves
and the transfer of intraperitoneally-administered prions into the
spinal cord is accelerated. Neuroinvasion velocity correlated
exclusively with the relative locations of FDCs and nerves; transfer of
Cxcr5 -/- bone marrow to wildtype mice induced perineural FDCs and
enhanced neuroinvasion, whereas reciprocal transfer to Cxcr5 -/- mice
abolished them and restored normal efficiency of neuroinvasion.
Suppression of lymphotoxin signaling depleted FDCs, abolished splenic
infectivity, and suppressed acceleration of pathogenesis in Cxcr5 -/-
mice. Prinz et al. (2003) concluded that prion neuroimmune transition
occurs between FDCs and sympathetic nerves, and that relative
positioning of FDCs and nerves controls the efficiency of peripheral
prion infection.
Mallucci et al. (2003) generated double transgenic mice that expressed
PrP in neuronal and nonneuronal cells until approximately 12 weeks of
age, when depletion of neuronal PrP occurred. Inoculation of the
transgenic mice with infective scrapie prions resulted in CNS infection
that was halted when PrP was depleted, resulting in long-term survival
of the mice compared to controls. Moreover, there was a reversal of
spongiosis and a prevention of neuronal loss in the transgenic animals.
This occurred despite the accumulation of extraneuronal PrPsc in glial
cells. Mallucci et al. (2003) concluded that the propagation of
nonneuronal PrPsc is not pathogenic, and that arresting the continued
conversion of PrPc to PrPsc within neurons during scrapie infection
prevents prion neurotoxicity.
Chesebro et al. (2005) found that in scrapie-infected transgenic mice
expressing PrP lacking the glycosylphosphatidylinositol membrane anchor,
abnormal protease-resistant PrPres (PrPsc) was deposited as amyloid
plaques, rather than the usual nonamyloid form of PrPres. Although
PrPres amyloid plaques induced brain damage reminiscent of Alzheimer
disease (see 104300), clinical manifestations were minimal. In contrast,
combined expression of anchorless and wildtype PrP produced accelerated
clinical scrapie. Thus, Chesebro et al. (2005) concluded that the PrP
GPI anchor may play a role in the pathogenesis of prion diseases.
Using flow cytometry, Zhang et al. (2006) found that Prnp was expressed
on the surface of long-term hematopoietic bone marrow stem cells in
mice. Stem cells from Prnp-null bone marrow exhibited impaired self
renewal. When treated with a cell cycle-specific myelotoxic agent,
animals reconstituted with Prnp-null stem cells exhibited increased
sensitivity to hematopoietic cell depletion. Ectopic expression of Prnp
in Prnp-null bone marrow cells rescued the defect in hematopoietic
engraftment. Zhang et al. (2006) concluded that PRNP is a marker for
hematopoietic stem cells and supports their self-renewal.
Trifilo et al. (2006) investigated extraneural manifestations in
scrapie-infected transgenic mice expressing prion protein lacking the
glycophosphatidylinositol membrane anchor. In the brain, blood, and
heart, both abnormal protease-resistant prion protein and prion
infectivity were readily detected by immunoblot and by inoculation into
nontransgenic recipients. The titer of infectious scrapie in blood
plasma exceeded 10(7) 50% infectious doses per ml. Trifilo et al. (2006)
found that the heart of these transgenic mice contained
protease-resistant prion protein-positive amyloid deposits that led to
myocardial stiffness and cardiac disease.
Asante et al. (2006) found that transgenic mice expressing human
met/val129 and inoculated with type 4 PrP(Sc) did not develop
characteristic vCJD neuropathology. Depending on the source of the
inoculum, which was derived from human and bovine prion isolates, the
mice developed 4 different disease phenotypes. Mice challenged with vCJD
prions had higher rates of infection than BSE-challenged mice. The
findings suggested that PRNP 129 heterozygotes may be more susceptible
to infection with human-passaged vCJD prions than primary infection with
bovine-derived prions.
Steele et al. (2008) found that Hsf1 (140580)-knockout mice died
significantly faster after inoculation with prion proteins compared to
wildtype mice with intact Hsf1 genes. However, both Hsf1-knockout and
wildtype mice showed a similar timing in onset of behavioral
abnormalities and pathologic changes after inoculation. The findings
suggested a protective role for HSF1 in prion pathogenesis and establish
that it is specific to disease progression as distinct from disease
onset.
Heikenwalder et al. (2008) generated symmetrical soft-tissue granulomas
in mice with and without Prnp and found that, following intraperitoneal
inoculation of prions, they could only detect prion in Prnp +/+
granuloma and spleen homogenates. Immunohistochemical analysis
demonstrated expression of Mfge8 (602281), a marker of FDCs, in spleen
but not in granulomas, indicating that, in addition to FDCs, stromal
Ltbr (600979)-positive mesenchymal cells can express prions.
Heikenwalder et al. (2008) concluded that granulomas can act as
clinically silent reservoirs of prion infectivity and that
lymphotoxin-dependent prion replication can occur in inflammatory
stromal cells that are distinct from FDCs.
Jackson et al. (2009) found that mice expressing a mutant murine D177N
Prnp protein, which is equivalent to the FFI-associated D178N mutation
(176640.0010) in humans, developed biochemical, physiologic, behavioral,
and neuropathologic abnormalities that were similar to FFI in humans and
different from other animal prion diseases. Pathologic brain changes in
homozygous mice included atrophy of neural nuclei, enlarged ventricles,
vacuolization and reactive gliosis in the deep cerebellar white matter,
and neuronal loss and gliosis of the thalamus. There were very low
amounts of proteinase K-resistant PrP, as seen in human FFI. Mutant mice
showed age-related changes in behavior reflecting sleep interruption.
Injection of a brain homogenate from mutant animals into wildtype
animals resulted in a similar pathology in serial recipients, indicating
that the disorder was transmissible and that a single amino acid change
in Prnp is sufficient for the spontaneous generation of prion
infectivity. Prnp-null mice who were injected remained normal,
indicating that physiologic amounts of Prnp protein are required for
disease transmission. The disease induced by the D177N mutant protein
was distinct from scrapie, indicating that the FFI-associated mutant
represents a unique strain of prion infectivity.
Prion incubation periods in experimental animals vary inversely with
expression level of cellular prion protein. Sandberg et al. (2011)
demonstrated that prion propagation in brain proceeds via 2 distinct
phases: a clinically silent exponential phase not rate-limited by prion
protein concentration that rapidly reaches a maximal prion titer,
followed by a distinct switch to a plateau phase. The latter determines
time to clinical onset in a manner inversely proportional to prion
protein concentration. These findings demonstrated an uncoupling of
infectivity and toxicity. Sandberg et al. (2011) suggested that prions
themselves are not neurotoxic but catalyze the formation of such species
from PrPC. Production of neurotoxic species is triggered when prion
propagation saturates, leading to a switch from autocatalytic production
of infectivity (phase 1) to a toxic (phase 2) pathway.
HISTORY
Aguzzi and Brandner (1999) reviewed 'the genetics of prions,' and raised
the question of whether this is a contradiction in terms since the
prion, which they defined as an enigmatic agent that causes
transmissible spongiform encephalopathies, is a paradigm of nongenetic
pathology. The protein-only hypothesis, originally put forward by
Griffith (1967), says that prion infectivity is identical to scrapie
protein, an abnormal form of the cellular protein, now referred to as
PRNP. Replication occurs by the scrapie prion recruiting cellular prion
and converting it into further scrapie prion. The newly formed scrapie
prion will join the conversion cycle and lead to a chain reaction of
events that results in an ever-faster accumulation of scrapie prion.
This hypothesis gained widespread recognition and acceptance after
Prusiner (1982) purified the pathologic protein and Weissmann and his
colleagues (Oesch et al., 1985; Basler et al., 1986) cloned the gene
that encodes the scrapie protein as well as its normal cellular
counterpart PRNP. Even more momentum was achieved when Weissmann's group
(Bueler et al., 1993) showed that genetic ablation of Prnp protects mice
from experimental scrapie on exposure to prions, as predicted by the
protein-only hypothesis. Aguzzi and Brandner (1999) considered the
finding of linkage between familial forms of prion diseases and
mutations in the prion gene to be an important landmark (Hsiao et al.,
1989).
Lloyd et al. (2001) pointed out that the identification of quantitative
trait loci (QTLs) for prion disease incubation time cast doubt on the
validity of the genetic models used in epidemiologic studies, which may
result in overly optimistic predictions of the size of the 'new variant'
CJD epidemic. These models assume that only methionine homozygous
individuals are susceptible to 'new variant' CJD. This in itself appears
unlikely because the other acquired human prion diseases, iatrogenic CJD
and kuru, occur in all codon 129 genotypes as the epidemic evolves, with
codon 129 heterozygotes having the longest mean incubation periods. By
definition, the patients identified to date with 'new variant' CJD are
those with the shortest incubation periods for BSE. These in turn, given
that no unusual history of dietary, occupational, or other exposure to
BSE has been identified, would be expected to be predominantly those
individuals with short incubation time alleles at these multiple genetic
loci in addition to having the codon 129 methionine homozygous PRNP
genotype.
Brown et al. (2003) proposed a possible method to prevent human
infection from processed meat contaminated by BSE, which involved
subjecting the food product to short pressure pulses at high
temperatures under commercially practical conditions. The authors spiked
hot dogs with hamster-adapted scrapie brain and used Western blots of
prion protein as indicators of infectivity levels. Brown et al. (2003)
noted that the effect of high pressure on reducing the bacterial load in
foodstuffs (thus enhancing preservation) was first examined at the end
of the 19th century, but was largely neglected until the late 1980s,
when reliable high-pressure equipment was developed and introduced into
commerce.
SSTR4
| dbSNP name | rs3746726(T,G); rs2567609(T,C); rs3746728(C,T); rs2567608(T,C) |
| ccdsGene name | CCDS42856.1 |
| CosmicCodingMuts gene | SSTR4 |
| cytoBand name | 20p11.21 |
| EntrezGene GeneID | 6754 |
| EntrezGene Description | somatostatin receptor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SSTR4:NM_001052:exon1:c.T850G:p.F284V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P31391 |
| dbNSFP Uniprot ID | SSR4_HUMAN |
| dbNSFP KGp1 AF | 0.296703296703 |
| dbNSFP KGp1 Afr AF | 0.229674796748 |
| dbNSFP KGp1 Amr AF | 0.309392265193 |
| dbNSFP KGp1 Asn AF | 0.258741258741 |
| dbNSFP KGp1 Eur AF | 0.362796833773 |
| dbSNP GMAF | 0.2966 |
| ESP Afr MAF | 0.233999 |
| ESP All MAF | 0.334615 |
| ESP Eur/Amr MAF | 0.386163 |
| ExAC AF | 0.348 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Vascular];
Cerebrovascular ischemic attacks;
Cerebrovascular hemorrhagic attacks;
Hypertension
SKIN, NAILS, HAIR:
[Skin];
Livedo racemosa (usually on trunk and/or lower extremities);
Erythematous, irregular netlike pattern of vessels;
HISTOLOGY:;
Intimal proliferation of small arteries;
Occlusion of small arteries
NEUROLOGIC:
[Central nervous system];
Cerebrovascular ischemic attacks, transient (proceed secondary neurologic
findings);
Headaches;
Visual changes;
Hemiplegia;
Dysarthria;
Facial palsy;
Seizures;
Tremor;
Cognitive decline
LABORATORY ABNORMALITIES:
Associated with serum anti-phospholipid antibodies in about 50% of
patients
MISCELLANEOUS:
Incidence of 4 per million per year;
Secondary features include arterial hypertension and renal involvement;
Women are more often affected;
Onset in young adulthood;
Progressive disorder;
One family with confirmed CECR1 mutation has been reported (last curated
August 2014)
MOLECULAR BASIS:
Caused by mutation in the cat eye syndrome chromosome region, candidate
1 gene (CECR1, 607575.0010)
OMIM Title
*182454 SOMATOSTATIN RECEPTOR 4; SSTR4
OMIM Description
CLONING
Rohrer et al. (1993) cloned and characterized a fourth human
somatostatin receptor, SSTR4, which is specifically expressed in human
fetal and adult brain and lung tissue. SSTR4 shared structural features
with the superfamily of receptors having 7 transmembrane segments. It
had a 1,167-bp open reading frame encoding a protein of 388 amino acids
with a predicted molecular size of 42 kD. Its amino acid sequence showed
58, 43, and 41% identity with the sequences of SSTR1 (182451), SSTR2
(182452), and SSTR3 (182453), respectively.
MAPPING
Yasuda et al. (1993) mapped somatostatin receptor-4 (designated SSTR5 in
the publication) to 20p11.2 by fluorescence in situ hybridization to
metaphase chromosomes. Fluorescence in situ hybridization using a probe
for SSTR4 in combination with probes for neuroendocrine convertase-2
(NEC2; 162151), thrombomodulin (THBD; 188040), and brain glycogen
phosphorylase (PYGB; 138550) established the following order:
20pter--NEC2--SSTR4--THBD--PYGB--cen.
Demchyshyn et al. (1993) also cloned the SSTR4 gene, determined its
sequence similarity to the other SSTR genes, and studied its
pharmacologic and biochemical properties. By PCR amplification of hybrid
human/hamster somatic cell lines, they demonstrated that chromosome 20
is the only chromosome with which the SSTR4 gene segregated.
By interspecific backcross analysis, Brinkmeier and Camper (1997) mapped
the Sstr4 gene to mouse chromosome 2.
THBD
| dbSNP name | rs1962(C,T); rs1042580(T,C); rs11696919(T,C) |
| cytoBand name | 20p11.21 |
| EntrezGene GeneID | 7056 |
| EntrezGene Description | thrombomodulin |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.241 |
OMIM Clinical Significance
Heme:
Bleeding diathesis;
Thrombocytopenia
Lab:
Platelet antibody
Inheritance:
Autosomal dominant form
OMIM Title
*188040 THROMBOMODULIN; THBD
;;THRM;;
CD141 ANTIGEN; CD141
OMIM Description
DESCRIPTION
The THBD gene encodes thrombomodulin, an endothelial cell surface
glycoprotein that forms a 1:1 complex with the coagulation factor
thrombin (F2; 176930). Binding of thrombin to this high-affinity
receptor alters its specificity toward several substrates, ultimately
acting as an antithrombotic factor. The F2:THBD complex activates
protein C (PROC; 612283) approximately 1,000 times faster than thrombin
alone, and activated protein C degrades clotting factors V (F5; 612309)
and VIII (F8; 300841). In addition, THBD can inhibit procoagulant
functions of thrombin, such as platelet activation or fibrinogen
clotting. THBD can also promote antithrombin III (SERPINC1; 107300)
inhibition of thrombin. Thus, thrombomodulin converts thrombin into a
physiologic anticoagulant (summary by Esmon (1987) and Anastasiou et
al., 2012).
CLONING
Wen et al. (1987) presented the complete cDNA sequence of human
thrombomodulin. The sequence encodes a 60.3-kD protein of 575 amino
acids. The predicted protein sequence includes a signal peptide of about
21 amino acids, an amino terminal ligand-binding domain of about 223
amino acids, an epidermal growth factor (EGF) homology region (see
131530) of 236 amino acids, a serine/threonine-rich segment of 34 amino
acids, a membrane-spanning domain of 23 amino acids, and a cytoplasmic
tail of 38 amino acids. The EGF homology region consists of 6 tandemly
repeated EGF-like domains. The organization of thrombomodulin is similar
to that of LDL receptor (606945), and the protein is homologous to a
large number of other proteins that also contain EGF-like domains,
including factor VII (613878), factor IX (300746), factor X (613872),
factor XII (610619), protein C, tissue plasminogen activator (173370),
and urokinase (191840).
GENE STRUCTURE
Jackman et al. (1987) reviewed the structure of the thrombomodulin gene
and commented on the lack of introns.
MAPPING
By molecular hybridization to sorted chromosomes, Wen et al. (1987)
localized the structural gene for thrombomodulin to chromosome 20. By in
situ hybridization, Espinosa et al. (1989) localized the THBD gene to
20p12-cen. By FISH, Yasuda et al. (1993) assigned the THBD gene to
20p11, proximal to NEC2 (162151) and SSTR5 (182455) which are located at
20p11.2. By radiation hybrid mapping, Maglott et al. (1996) localized
the THBD gene to a region corresponding to 20p11.2.
GENE FUNCTION
Ishii and Majerus (1985) demonstrated thrombomodulin in human plasma and
urine. The physiologic significance of circulating and urinary
thrombomodulin was obscure.
Malignant primary tumors of the pericardium such as primary pericardial
mesothelioma are very rare. Thrombomodulin has been identified on the
pleural mesothelioma cells. Okura et al. (1996) described the case of a
25-year-old man who was found to have a pericardial mesothelioma
secreting thrombomodulin. Very little clot formation in the pericardial
space may have been the result of the anticoagulant effect of
thrombomodulin.
Using microarray technology to identify CLOCK (601851)-controlled genes
in human and murine vascular endothelial cells, Takeda et al. (2007)
found that thrombomodulin was upregulated by CLOCK in these cells. Thbd
mRNA and protein showed a clear circadian oscillation in murine heart
and lung. A heterodimer of CLOCK and BMAL2 (ARNTL2; 614517) bound
directly to the E-box of the THBD promoter, resulting in activation. The
phase of circadian oscillation of Thbd mRNA expression was altered by
temporal feeding restriction in mice, suggesting that gene expression is
regulated by the peripheral clock system. In addition, this circadian
oscillation of Thbd was not seen in Clock mutant mice. The data
suggested that there is a peripheral clock in vascular endothelial cells
that regulates THBD gene expression, and that the oscillation of this
expression may contribute to the circadian variation of cardiovascular
events.
In in vitro cellular studies, Delvaeye et al. (2009) demonstrated that
thrombomodulin binds to C3b (see 120700) and factor H (CFH; 134370) and
negatively regulates complement by accelerating factor I (CFI;
217030)-mediated inactivation of C3b in the presence of cofactors. By
promoting activation of the plasma procarboxypeptidase B (CPB2; 603101),
thrombomodulin also accelerates the inactivation of anaphylatoxins C3a
and C5a. Thus, thrombomodulin provides protection against complement
activation.
As part of an effort to clarify the nomenclature for monocytes and
dendritic cells (DCs) in blood, Ziegler-Heitbrock et al. (2010) reported
that CD141 is a marker for 1 of 2 types of myeloid DCs. CD141-positive
myeloid DCs represent an immature or precursor stage of circulating DCs.
MOLECULAR GENETICS
- Thrombophilia Due to Thrombomodulin Defect
The role of thrombomodulin in thrombosis (THPH12; 614486) is
controversial. Although there have been several reports of THBD
mutations in patients with venous thrombosis, clear functional evidence
for the pathogenicity of these mutations is lacking. In a review,
Anastasiou et al. (2012) noted that thrombomodulin has a major role in
capillary beds and that THBD variation may not be associated with large
vessel thrombosis. It is likely that genetic or environmental risk
factors in addition to THBD variation are involved in the pathogenesis
of venous thrombosis. However, variation in the THBD gene may be
associated with increased risk for arterial thrombosis and myocardial
infarction. This association may be attributed to the fact that
thrombomodulin modulates inflammatory processes, complement activity,
and fibrinolysis.
Late fetal loss can be associated with placental insufficiency and
coagulation defects. Thrombomodulin and the endothelial protein C
receptor (EPCR; 600646) are glycoprotein receptors expressed mainly on
the endothelial surface of blood vessels and also in the placenta; they
both play a key physiologic role in the protein C anticoagulant pathway.
Franchi et al. (2001) investigated the possibility that defects in these
proteins play an important role in the pathogenesis of late fetal loss.
They performed a case-control study in 95 women with unexplained late
fetal loss (after 20 weeks); the control group comprised 236 women who
had given birth to at least 1 healthy baby and had no history of late
fetal loss or obstetrical complications. In the 95 patients, they found
5 mutations in the THBD gene and 2 in the EPCR gene; in the 236 control
subjects, they found 3 mutations in the THBD gene and 1 in the EPCR
gene. The relative risk for late fetal loss for carriers of mutation in
either the THBD or EPCR gene was estimated by an odds ratio of 4.0.
To evaluate the contribution of THBD gene mutations to venous
thrombosis, Faioni et al. (2002) examined 38 patients with recurrent,
documented thrombotic events at a young age and a positive family
history. Twelve individuals with low levels of soluble thrombomodulin in
plasma were also studied. Two mutations were identified: -33G-A
(188040.0004), in a severely thrombophilic patient, and D468Y
(188040.0001). The allelic frequency of an ala455-to-val polymorphism
(A455V; 188040.0008) was identical in patients and controls. Faioni et
al. (2002) concluded that mutations in the THBD gene are a very rare
cause of severe thrombophilia.
Tang et al. (2013) studied venous thrombosis in the Chinese population,
examining 1,304 individuals diagnosed with a first venous thrombosis and
1,334 age- and sex-matched healthy participants. Resequencing of THBD in
60 individuals with venous thrombosis and in 60 controls, and a
functional assay, showed that a common variant, c.-151G-T (188040.0010),
in the 5-prime UTR significantly reduced the gene expression and could
cause a predisposition to venous thrombosis. This variant was then
genotyped in a case-control study, and results indicated that
heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29)
increased risk of venous thrombosis. The THBD c.-151G-T variant was
further investigated in a family analysis involving 176 first-degree
relatives from 38 index families. First-degree relatives with this
variant had a 3.42-fold increased risk of venous thrombosis, and their
probability of remaining thrombosis-free was significantly lower than
that of relatives without the variant. In addition, 5 rare mutations
that might be deleterious were also identified in thrombophilic
individuals by sequencing.
- Susceptibility to Atypical Hemolytic Uremic Syndrome 6
In 7 (4.6%) of 153 patients with atypical hemolytic uremic syndrome
(AHUS6; 612926), Delvaeye et al. (2009) identified 6 different
heterozygous mutations in the THBD gene (see, e.g.,
188040.0005-188040.0007). In vitro functional expression studies showed
that cells transfected with mutant THBD were less effective in
converting C3b to iC3b on the cell surface after complement activation,
and were thus not as well protected against complement activation.
ANIMAL MODEL
Isermann et al. (2003) found that disruption of the mouse thrombomodulin
gene leads to embryonic lethality caused by a defect in the placenta.
They showed that the abortion of thrombomodulin-deficient embryos is
caused by tissue factor (134390)-initiated activation of the blood
coagulation cascade at the fetomaternal interface. Activated coagulation
factors induced cell death and growth inhibition of placental
trophoblast cells by 2 distinct mechanisms. The death of giant
trophoblast cells was caused by the conversion of fibrinogen to fibrin
(see 134820) and subsequent formation of fibrin degradation products. In
contrast, the growth arrest of trophoblast cells is not mediated by
fibrin, but is a likely result of engagement of the protease-activated
receptors PAR2 (600933) and PAR4 (602779) by coagulation factors.
Isermann et al. (2003) concluded that their findings show a novel
function for the thrombomodulin-protein C system in controlling the
growth and survival of trophoblast cells in the placenta. This function
is essential for the maintenance of pregnancy.
PYGB
| dbSNP name | rs7269584(T,G); rs6050486(A,G); rs6050487(C,G); rs2145125(G,C); rs79783587(T,C); rs1555329(G,A); rs67049380(A,G); rs6107017(A,G); rs6050488(T,C); rs3787078(A,G); rs3787080(C,G); rs79311385(A,G); rs6107019(C,T); rs6037069(C,T); rs74967589(A,G); rs2180596(C,A); rs3787081(G,A); rs77769033(A,G); rs112319672(T,G); rs2180597(G,T); rs6115106(T,C); rs8125980(G,C); rs66650433(A,G); rs11087508(A,G); rs67352161(A,G); rs116672236(T,C); rs77507457(G,T); rs4815398(A,G); rs6115107(A,G); rs113949969(T,A); rs79986863(A,G); rs79719043(A,G); rs77959670(C,T); rs74749140(T,C); rs6132824(T,C); rs6050490(C,T); rs6132825(A,T); rs74407052(C,G); rs6138553(G,A); rs111631271(C,T); rs73101756(G,A); rs6115109(G,A); rs8125437(T,G); rs8118763(G,T); rs2281558(G,T); rs2474762(A,G); rs2500413(T,C); rs2474763(A,G); rs11699953(C,G); rs67864609(C,T); rs6037071(A,G); rs111856937(C,T); rs7274104(G,C); rs6050493(T,G); rs7274130(C,T); rs6050494(A,G); rs6050495(C,T); rs6138554(C,T); rs2474764(T,A); rs6138555(G,A); rs6138556(C,T); rs28881233(A,T); rs4619688(C,G); rs2983489(C,A); rs186515826(A,G); rs6115113(C,T); rs6037073(T,C); rs2474765(G,T); rs2474766(A,G); rs6115115(A,G); rs2474767(T,C); rs6115118(G,A); rs73101777(C,T); rs6050502(T,C); rs6050503(A,G); rs6050504(A,G); rs148747294(G,A); rs2387734(C,T); rs183317672(G,A); rs2474769(C,T); rs1555331(C,G); rs6050505(T,C); rs75840140(T,C); rs13038092(A,G); rs111540814(T,C); rs61272267(T,A); rs8184820(T,C); rs6050507(G,A); rs6050508(C,G); rs73341190(T,C); rs7269045(A,G); rs6050509(C,T); rs6050510(C,T); rs6037075(C,A); rs6050511(T,C); rs2281559(C,T); rs6050512(A,G); rs8124539(C,T); rs7273544(G,A); rs7274919(C,T); rs115495326(G,A); rs143383097(C,T); rs6050513(A,G); rs2227894(C,T); rs45587239(C,T); rs6050515(C,G); rs113189330(C,T); rs2424698(C,T); rs2260997(G,T); rs11697384(A,G); rs6515626(A,G); rs2424699(G,A); rs2261109(T,C); rs2261115(G,A); rs2261698(A,G); rs2261720(T,G); rs2227890(A,G); rs2261747(G,A); rs2261753(G,A); rs2261784(G,C); rs2261785(C,T); rs2261794(T,G); rs2261795(T,C); rs2261796(T,G); rs2145126(G,A); rs7272959(G,A); rs910996(A,G); rs73103606(A,C); rs2257705(T,C); rs143142471(C,T); rs2227892(T,C); rs2257712(T,C); rs112054282(T,G); rs2257461(A,G); rs2257464(C,T); rs2257233(G,T); rs2257809(C,T); rs2424700(A,G); rs6107022(C,T); rs67184896(C,T); rs910997(G,A); rs2424701(C,T); rs1077889(A,G); rs56291736(A,G); rs753009(C,T); rs3002702(T,C); rs2257982(A,G); rs2257985(G,T); rs113856180(A,G); rs2257988(T,C); rs2424703(G,A); rs2257991(T,C); rs2258053(C,G); rs2257432(T,C); rs6115130(A,G); rs2258066(C,T); rs2258135(C,A); rs2258201(G,C); rs2474777(T,C); rs6107023(G,T); rs6107024(C,T); rs2281562(G,A); rs2258617(C,T); rs13042337(G,A); rs13043183(T,G) |
| ccdsGene name | CCDS13171.1 |
| cytoBand name | 20p11.21 |
| EntrezGene GeneID | 5834 |
| EntrezGene Description | brain |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PYGB:NM_002862:exon14:c.C1640T:p.S547L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7486 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P11216 |
| dbNSFP Uniprot ID | PYGB_HUMAN |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 1.626e-05,8.132e-06 |
OMIM Clinical Significance
GU:
Renal colic;
Renal oxalate stones
Lab:
Hyperglycinuria
Inheritance:
Autosomal dominant
OMIM Title
*138550 GLYCOGEN PHOSPHORYLASE, BRAIN TYPE; PYGB
OMIM Description
CLONING
Newgard et al. (1988) cloned the cDNA encoding a new isozyme of glycogen
phosphorylase (1,4-D-glucan:orthosphosphate D-glucosyltransferase; EC
2.4.1.1) from a cDNA library prepared from a human brain astrocytoma
cell line. Blot-hybridization analysis showed that the message is
preferentially expressed in human brain, but is also found at a low
level in human fetal liver and adult liver and muscle tissues. The
protein sequence deduced from the nucleotide sequence was 862 amino
acids long compared with 846 and 841 amino acids for the liver (PYGL;
613741) and muscle (PYGM; 608455) isozymes, respectively. The greater
length of brain phosphorylase was found to be due entirely to an
extension at the c-terminal portion of the protein. Muscle and brain
isozymes shared greater similarities with each other than either did
with the liver sequence.
MAPPING
Newgard et al. (1988) found by spot-blot hybridization of brain
phosphorylase cDNA to laser-sorted human chromosome fractions and
Southern blot analysis of hamster/human hybrid cell line DNA that the
exact homolog of the cloned glycogen phosphorylase maps to chromosome
20, but that a slightly less homologous gene is found on chromosome 10
as well. The liver and muscle genes had previously been localized to
chromosomes 14 and 11, respectively. The findings suggested to Newgard
et al. (1988) that the phosphorylase genes evolved by duplication and
translocation of a common ancestral gene, leading to divergence of
elements controlling gene expression and of structural features of the
phosphorylase proteins that confer tissue-specific functional
properties.
By fluorescence in situ hybridization, Yasuda et al. (1993) mapped the
PYGB gene to 20p11, proximal to SSTR4 (182454), which is located at
20p11.2. The gene in the mouse maps to chromosome 2 (Glaser et al.,
1989).
ID1
| dbSNP name | rs111423898(C,G); rs6060263(T,C); rs15817(A,G); rs73235783(C,T); rs2811(A,G) |
| cytoBand name | 20q11.21 |
| EntrezGene GeneID | 3397 |
| EntrezGene Description | inhibitor of DNA binding 1, dominant negative helix-loop-helix protein |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04086 |
OMIM Clinical Significance
Neuro:
Seizures
Radiology:
Band heterotopias, resembling subependymal nodules of tuberous sclerosis
on MRI
Inheritance:
Autosomal dominant with female predominance
OMIM Title
*600349 INHIBITOR OF DNA BINDING 1; ID1
;;INHIBITOR OF DIFFERENTIATION 1
OMIM Description
DESCRIPTION
ID proteins contain a helix-loop-helix (HLH) motif and regulate
tissue-specific transcription within several cell lineages. They do not
bind DNA directly, but inhibit lineage commitment by binding basic
helix-loop-helix (bHLH) transcription factors through their HLH motif.
ID proteins contribute to cell growth, senescence, differentiation, and
angiogenesis.
CLONING
Hara et al. (1994) identified 2 human Id-related genes, ID1 and ID2.
Nehlin et al. (1997) found that an ID1-prime isoform is generated by a
failure of the gene to splice its 1 intron, resulting in the replacement
of the last 13 C-terminal amino acids with 7 different amino acids. A
2.2-kb sequence from the 5-prime region of ID1 was sufficient to direct
transcription of a reporter gene, but it did not confer the
growth-regulated expression normally seen with ID1.
By Northern blot analysis of mouse tissues, Singh et al. (2001) found
high expression of Id1 in heart, lung and kidney, and lower expression
in brain and liver.
GENE FUNCTION
During B-cell differentiation, Id inhibitory proteins, particularly ID1
and ID2 (600386), are expressed at high levels in pro-B cells (Sun et
al., 1991; Wilson et al., 1991) and are downregulated as cells
differentiate into pre-B and mature B cells, presumably for the purpose
of releasing the bHLH proteins (e.g., E2A; 147141) that are important
for differentiation. Sun (1994) hypothesized that blocking
downregulation of the ID genes would interfere with B-cell development.
To test this hypothesis, the author established lines of transgenic mice
that constitutively expressed the mouse Id1 gene in lymphoid cells. A
severe defect in B-cell development occurred in these mice,
demonstrating that the activity of bHLH proteins and the downregulation
of the Id1 gene are crucial for B-cell differentiation to proceed. The
fact that the effect is observed by manipulating Id1 gene transcription
indicates that the Id1 gene is controlled primarily at the
transcriptional level.
All normal vertebrate diploid cells have only a limited capacity to
proliferate, a phenomenon that is known as replicative senescence. Human
diploid fibroblasts derived from embryonic tissue gradually lose the
ability to initiate DNA synthesis in response to external stimuli and
cease proliferation after 50 to 80 population doublings. Hara et al.
(1994) showed that Id-related genes are expressed transiently during
both early and late G1 phase and that senescent human diploid
fibroblasts fail to express these Id-related genes in response to serum
stimulation.
Hara et al. (1994) found that human ID1 and ID2 mRNAs were barely
detectable in quiescent early passage fibroblasts; serum coordinately
induced both mRNAs, with 2 peaks of expression, in early and late G1.
Antisense oligomers complementary to ID1 and ID2 mRNA prevented early
passage fibroblasts from entering the S phase of the cell cycle. In
senescent cells, serum barely induced the ID1 and ID2 mRNAs, although
the level of MYC expression induced was similar in early passage and
senescent cells.
Singh et al. (2001) found that Id1 mRNA expression paralleled that of
Znf289 (606908) during mouse mammary gland development. Both Id1 and
Znf289 are expressed during ductal and lobuloalveolar morphogenesis when
there is extensive proliferation of mammary epithelial cells. Both are
downregulated in differentiated, growth-arrested lactating epithelial
cells.
The protein ID1 is a negative transcriptional regulator of CDKN2A
(600160), which is associated with the development of malignant melanoma
(Ohtani et al., 2001). Polsky et al. (2001) examined 21 melanocytic
lesions at various stages of malignant progression from common
melanocytic nevi to metastatic melanomas for ID1 and CDKN2A expression.
Upregulation of ID1 expression was limited to the earliest stages of
melanoma, suggesting that ID1 is important in early melanoma
development.
Volpert et al. (2002) identified Id1 target genes by differential
display of genes expressed by wildtype and Id1 null embryonic mouse
fibroblasts. They identified several genes involved in diverse biologic
functions, such as matrix remodeling, intracellular signaling, and
angiogenesis. They further characterized the effect of Id1 disruption on
thrombospondin-1 (THBS1; 188060), an inhibitor of neovascularization,
and found that Id1 is a potent repressor of Tsp1 transcription.
By in vivo selection, transcriptomic analysis, functional verification,
and clinical validation, Minn et al. (2005) identified a set of genes
that marks and mediates breast cancer metastasis to the lungs. Some of
these genes serve dual functions, providing growth advantages both in
the primary tumor and in the lung microenvironment. Others contribute to
aggressive growth selectivity in the lung. Among the lung metastasis
signature genes identified, several, including ID1, were functionally
validated. Those subjects expressing the lung metastasis signature had a
significantly poorer lung metastasis-free survival, but not bone
metastasis-free survival, compared to subjects without the signature.
Kebebew et al. (2004) characterized the expression and distribution of
the ID1 protein in normal, hyperplastic, and neoplastic human thyroid
tissue. They also evaluated the effect of the ID1 gene on thyroid cancer
cell growth and markers of thyroid cell differentiation. Normal thyroid
tissue had the lowest level of ID1 protein expression. Anaplastic
thyroid cancer had the highest level compared to benign and malignant
thyroid tissues. ID1 protein expression was higher in malignant thyroid
tissue than in hyperplastic thyroid tissue. They found no significant
association between the level of ID1 protein expression and patient age,
sex, tumor-node-metastasis stage, tumor size, primary tumor versus lymph
node metastasis, primary tumor versus recurrent tumors, and extent of
tumor differentiation. Inhibiting ID1 mRNA expression in thyroid cancer
cell lines using ID1 antisense oligonucleotides resulted in growth
inhibition and decreased thyroglobulin (TG; 188450) and sodium-iodide
symporter (NIS; 601843) mRNA expression. The authors concluded that ID1
is overexpressed in hyperplastic and neoplastic thyroid tissue and
directly regulates the growth of thyroid cancer cells of follicular cell
origin, but is not a marker of aggressive phenotype in differentiated
thyroid cancer.
Using mouse models of pulmonary metastasis, Gao et al. (2008) identified
bone marrow-derived endothelial progenitor cells as critical regulators
of the angiogenic switch from micrometastasis to macrometastasis. Gao et
al. (2008) showed that tumors induced the expression of the
transcription factor Id1 in endothelial progenitor cells and that
suppression of Id1 after metastatic colonization blocked endothelial
progenitor cell mobilization, caused angiogenesis inhibition, impaired
pulmonary macrometastases, and increased survival of tumor-bearing
animals.
Gumireddy et al. (2009) showed that the transcriptional regulators KLF17
(ZNF393; 609602) and ID2 were inversely expressed in human and mouse
mammary tumor cell lines and in primary human breast cancers, with KLF17
predominantly expressed in cells and tumors of low metastatic potential,
and ID2 predominantly expressed in cells and tumors with high metastatic
potential. Electrophoretic mobility shift, chromatin
immunoprecipitation, and reporter gene assays showed that mouse Klf17
bound directly to 1 of 2 CACCC boxes in the 5-prime UTR of the mouse Id2
gene and suppressed its expression. Knockdown of KLF17 via short hairpin
RNA caused epithelial-to-mesenchymal transition and increased metastasis
in vivo, and dual knockdown of KLF17 and ID2 normalized these effects.
Ding et al. (2010) demonstrated that liver sinusoidal endothelial cells
(LSECs) constitute a unique population of phenotypically and
functionally defined Vegfr3 (136352)+/Cd34 (142230)-/Vegfr2
(191306)+/VE-cadherin (601120)+/factorVIII (300841)+/Cd45 (151460)-
endothelial cells, which through the release of angiocrine trophogens
initiate and sustain liver regeneration induced by 70% partial
hepatectomy. After partial hepatectomy, residual liver vasculature
remains intact without experiencing hypoxia or structural damage, which
allows study of physiologic liver regeneration. Using this model, Ding
et al. (2010) showed that inducible genetic ablation of Vegfr2 in the
LSECs impairs the initial burst of hepatocyte proliferation (days 1-3
after partial hepatectomy) and subsequent reconstitution of the
hepatovascular mass (days 4-8 after partial hepatectomy) by inhibiting
upregulation of the endothelial cell-specific transcription factor Id1.
Accordingly, Id1-deficient mice also manifested defects throughout liver
regeneration, owing to diminished expression of LSEC-derived angiocrine
factors, including hepatocyte growth factor (HGF; 142409) and Wnt2
(147870). Notably, in in vitro cocultures, Vegfr2-Id1 activation in
LSECs stimulated hepatocyte proliferation. Indeed, intrasplenic
transplantation of Id1 wildtype or Id1-null LSECs transduced with Wnt2
and Hgf reestablished an inductive vascular niche in the liver sinusoids
of the Id1-null mice, initiating and restoring hepatovascular
regeneration. Therefore, Ding et al. (2010) concluded that in the early
phases of physiologic liver regeneration, VEGFR2-ID1-mediated inductive
angiogenesis in LSECs through release of angiocrine factors WNT2 and HGF
provokes hepatic proliferation. Subsequently, VEGFR2-ID1-dependent
proliferative angiogenesis reconstitutes liver mass.
Ding et al. (2014) combined an inducible endothelial cell-specific mouse
gene deletion strategy and complementary models of acute and chronic
liver injury to show that divergent angiocrine signals from liver
sinusoidal endothelial cells stimulate regeneration after immediate
injury and provoke fibrosis after chronic insult. The profibrotic
transition of vascular niche results from differential expression of
stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 (162643) in
liver sinusoidal endothelial cells. After acute injury, CXCR7
upregulation in liver sinusoidal endothelial cells acts with CXCR4 to
induce transcription factor ID1 (600349), deploying proregenerative
angiocrine factors and triggering regeneration. Inducible deletion of
Cxcr7 in sinusoidal endothelial cells from the adult mouse liver
impaired liver regeneration by diminishing Id1-mediated production of
angiocrine factors. By contrast, after chronic injury inflicted by
iterative hepatotoxin (carbon tetrachloride) injection and bile duct
ligation, constitutive Fgfr1 (136350) signaling in liver sinusoidal
endothelial cells counterbalanced Cxcr7-dependent proregenerative
response and augmented Cxcr4 expression. This predominance of Cxcr4 over
Cxcr7 expression shifted angiocrine response of liver sinusoidal
endothelial cells, stimulating proliferation of desmin (125660)-positive
hepatic stellate-like cells and enforcing a profibrotic vascular niche.
Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice
restored the proregenerative pathway and prevented Fgfr1-mediated
maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7
activation in liver sinusoidal endothelial cells abrogated fibrogenesis.
Ding et al. (2014) demonstrated that in response to liver injury,
differential recruitment of proregenerative CXCR7-ID1 versus profibrotic
FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration
and fibrosis.
GENE STRUCTURE
Nehlin et al. (1997) found that the ID1 gene contains 2 exons.
MAPPING
By somatic cell hybrid analysis and fluorescence in situ hybridization,
Mathew et al. (1995) mapped the ID1 gene to chromosome 20q11.
ANIMAL MODEL
Id proteins may control cell differentiation by interfering with DNA
binding of transcription factors. Lyden et al. (1999) demonstrated that
the targeted disruption of Id1 and Id3 (600277) in mice results in
premature withdrawal of neuroblasts in the cell cycle and expression of
neural-specific differentiation markers. Lyden et al. (1999) crossed Id1
+/- and Id3 +/- mice. Offspring lacking 1 to 3 Id alleles in any
combination were indistinguishable from wildtype, but no animals lacking
all 4 Id alleles were born. By embryonic day 12.5, double knockout
embryos exhibited cranial hemorrhage, and no double knockout embryos
survived beyond embryonic day 13.5. The Id1-Id3 double knockout mice
displayed vascular malformations in forebrain and absence of branching
and sprouting of blood vessels in the neuroectoderm. As angiogenesis
both in the brain and in tumors requires invasion of avascular tissue by
endothelial cells, Lyden et al. (1999) examined Id knockout mice for
their ability to support the growth of tumor xenografts. Three different
tumors failed to grow and/or metastasize in mice carrying only 1 Id1
allele, and any tumor growth present showed poor vascularization and
extensive necrosis. Thus, Lyden et al. (1999) concluded that Id genes
are required to maintain the timing of neuronal differentiation in the
embryo and invasiveness of the vasculature. Because the Id genes are
expressed at very low levels in adults, they make attractive targets for
antiangiogenic drug design. Lyden et al. (1999) also concluded that the
premature neuronal differentiation in Id1-Id3 double knockout mice
indicates that ID1 or ID3 is required to block the precisely timed
expression and activation of positively acting bHLH proteins during
murine development.
In the developing heart, Id1, Id2 (600386), and Id3 are detected in the
endocardial cushion mesenchyme from embryonic days 10.5 through 16.5,
but Id4 (600581) is absent. Fraidenraich et al. (2004) showed that Id1
to Id3 are also expressed in the epicardium and endocardium but are
absent in the myocardium. Id1 to Id3 expression becomes confined in the
leaflets of the cardiac valves as the atrioventricular endocardial
cushion tissue myocardializes. Id1 and Id3 expression persists in the
cardiac valves, endocardium, endothelium, and epicardium at postnatal
day 7. Fraidenraich et al. (2004) found that double and triple Id
knockout embryos displayed severe cardiac defects and died at
midgestation. Embryo size was reduced by 10 to 30%. Knockout embryos
displayed ventricular septal defects associated with impaired
ventricular trabeculation and thinning of the compact myocardium.
Trabeculae had disorganized sheets of myocytes surrounded by
discontinuous endocardial cell lining. Cell proliferation in the
myocardial wall was defective. Fraidenraich et al. (2004) showed that
midgestation lethality of embryos was rescued by the injection of 15
wildtype embryonic stem (ES) cells into mutant blastocysts. Myocardial
markers altered in Id mutant cells were restored to normal throughout
the chimeric myocardium. Intraperitoneal injection of ES cells into
female mice before conception also partially rescued the cardiac
phenotype with no incorporation of ES cells. Insulin-like growth
factor-1 (IGF1; 147440), a long-range secreted factor, in combination
with Wnt5a (164975), a locally secreted factor, were thought likely to
account for complete reversion of the cardiac phenotype. Fraidenraich et
al. (2004) concluded that ES cells have the potential to reverse
congenital defects through Id-dependent local and long-range effects in
a mammalian embryo.
FOXS1
| dbSNP name | rs6121246(C,T) |
| cytoBand name | 20q11.21 |
| EntrezGene GeneID | 2307 |
| EntrezGene Description | forkhead box S1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2328 |
| ESP Afr MAF | 0.439254 |
| ESP All MAF | 0.289814 |
| ESP Eur/Amr MAF | 0.21319 |
| ExAC AF | 0.204 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature, disproportionate;
Final adult height 38-49 inches;
Small-normal birth length;
[Weight];
Normal birth weight
HEAD AND NECK:
[Head];
Normal head circumference;
[Face];
Prominent forehead;
[Nose];
Short nose
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Superiorly curved clavicles
SKELETAL:
Joint laxity;
[Spine];
Increased lumbar lordosis;
Lower thoracic kyphosis;
Oval vertebral bodies (infancy);
Anterior beaking (childhood);
Gibbus deformity;
Narrow thoracolumbar interpediculate distance;
[Limbs];
Acromesomelia;
Bowed forearms;
Limited elbow extension;
Short tubular bones;
Bowed radius;
Progressive shortening of humerus in first year;
Progressive shortening of radius in first year;
Progressive shortening of ulna in first year;
Metaphyseal flaring of long bones;
[Hands];
Short, broad fingers;
Short, broad metacarpals (progressive shortening in first year);
Short, broad phalanges (progressive shortening in first year);
Broad middle and proximal phalanges;
Cone-shaped epiphyses;
[Feet];
Short toes;
Large halluces;
Short, broad phalanges;
Short, broad metatarsals
SKIN, NAILS, HAIR:
[Skin];
Loose, redundant skin on fingers;
[Nails];
Short nails
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Disproportionately short limbs often noted at birth;
Short limbs become more apparent during childhood
MOLECULAR BASIS:
Caused by mutation in the natriuretic peptide receptor B gene (NPR2,
108961.0001)
OMIM Title
*602939 FORKHEAD BOX S1; FOXS1
;;FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 18; FKHL18;;
FORKHEAD-RELATED ACTIVATOR 10; FREAC10
OMIM Description
CLONING
The 'forkhead' family of transcription factors belongs to the winged
helix class of DNA-binding proteins. By screening an adipose tissue
library with a mixture of conserved forkhead domains from several gene
family members, Cederberg et al. (1997) isolated cDNAs corresponding to
a gene that they designated freac10, or FKHL18. Dot blot analysis of
mRNA from 50 human tissues revealed that FKHL18 is expressed
predominantly in the aorta and, to a lesser degree, in the kidney.
MAPPING
By analysis of a somatic cell hybrid panel and by fluorescence in situ
hybridization, Cederberg et al. (1997) mapped the FKHL18 gene to
20q11.1-q11.2.
TSPY26P
| dbSNP name | rs3813922(G,T) |
| cytoBand name | 20q11.21 |
| EntrezGene GeneID | 128854 |
| snpEff Gene Name | PLAGL2 |
| EntrezGene Description | testis specific protein, Y-linked 26, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2259 |
| ExAC AF | 0.075 |
AHCY
| dbSNP name | rs4239(T,A); rs17091693(G,C); rs17091698(T,C); rs74729960(G,A); rs35038733(C,G); rs6088456(G,A); rs819133(T,G); rs17091701(G,A); rs73261430(C,G); rs864702(A,G); rs150066229(G,A); rs17091705(G,A); rs34602355(C,T); rs819134(G,A); rs866027(G,A); rs149906760(C,T); rs1205352(A,G); rs148385378(G,A); rs875650(T,A); rs4456777(C,T); rs112893730(G,A); rs1205354(T,C); rs1205355(A,G); rs1205356(G,C); rs1205357(C,T); rs7271501(G,C); rs7273572(G,A); rs819159(A,T); rs819158(G,A); rs819157(C,T); rs819156(A,C); rs819155(G,A); rs115339231(C,G); rs115531003(A,G); rs73261454(G,A); rs146834796(C,T); rs60735957(T,G); rs819152(C,G); rs56718957(G,A); rs56681478(G,A); rs819151(G,A); rs819150(G,A); rs819149(C,G); rs819148(G,A); rs75630818(T,C); rs819147(C,T); rs11906980(G,A); rs1205366(T,C); rs60847955(G,C); rs819146(G,T); rs57180376(G,T); rs1093783(C,T); rs1093782(G,T); rs139928143(C,A); rs8118727(C,A); rs55938811(G,A); rs112310554(A,G); rs1205333(G,A); rs142449184(C,T); rs183805006(C,T); rs141539073(G,A); rs147234327(T,C); rs1205350(G,A) |
| ccdsGene name | CCDS13233.1 |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 191 |
| EntrezGene Description | adenosylhomocysteinase |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | AHCY:NM_000687:exon9:c.C1000T:p.R334C,AHCY:NM_001161766:exon9:c.C916T:p.R306C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6073 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P23526 |
| dbNSFP Uniprot ID | SAHH_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.00174825174825 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.001362 |
| ESP All MAF | 0.000538 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001708 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Dry conjunctival mucosae;
Lacrimal gland aplasia/hypoplasia;
Absent lacrimal gland puncta;
[Mouth];
Xerostomia;
Salivary gland aplasia/hypoplasia;
Absent parotid papillae;
[Teeth];
Dental caries
OMIM Title
*180960 S-ADENOSYLHOMOCYSTEINE HYDROLASE; AHCY
;;SAHH
OMIM Description
DESCRIPTION
The AHCY gene encodes S-adenosylhomocysteine hydrolase (EC 3.3.1.1),
which catalyzes the hydrolysis of S-adenosylhomocysteine to adenosine
and homocysteine (summary by Baric et al., 2004).
CLONING
Coulter-Karis and Hershfield (1989) isolated cDNA clones for human AHCY
from a placental cDNA library. The deduced 432-amino acid protein has a
molecular mass of 47.6 kD with 97% identity to the rat protein.
GENE FUNCTION
Baric et al. (2004) noted that S-adenosylhomocysteine hydrolase
catalyzes the hydrolysis of S-adenosylhomocysteine to adenosine and
homocysteine. In eukaryotes, this is the major route for disposal of the
S-adenosylhomocysteine formed as a common product of each of many
S-adenosylmethionine-dependent methyltransferases. The reaction is
reversible, but under normal conditions the removal of both adenosine
and homocysteine is sufficiently rapid to maintain the flux in the
direction of hydrolysis. Physiologically, S-adenosylhomocysteine
hydrolysis serves not only to sustain the flux of methionine sulfur
toward cysteine, but is believed also to play a critical role in the
regulation of biologic methylations.
EVOLUTION
Hershfield and Francke (1982) noted that in ADA deficiency (see 102700),
adenosine and deoxyadenosine accumulate and, respectively, inhibit and
inactivate S-adenosylhomocysteine hydrolase. The fact that both SAHH and
ADA are on chromosome 20 suggests an evolutionary relationship. SAHH,
which is a eukaryotic enzyme, probably arose after ADA, which occurs
also in prokaryotes. Evolution of SAHH may have required the
simultaneous occurrence of ADA to avoid the adverse effects of adenosine
and deoxyadenosine. Alternatively, tandem reduplication of a portion of
the ADA gene encoding a binding domain for adenosine may have occurred
and further changes may have led to the SAHH gene. SAHH is a major high
affinity cytoplasmic adenosine-binding protein.
MAPPING
By analysis of human-Chinese hamster hybrids, Hershfield and Francke
(1982) assigned the AHCY gene to chromosome 20.
By study of rearranged human chromosomes in human-rodent cell hybrids,
Mohandas et al. (1984) assigned the SAHH locus to 20cen-q13.1 and the
ADA gene (608958) to 20q13.1-qter. Eiberg and Mohr (1985) looked at
linkage of ADA and SAHH in their Danish family data; 8 families were
informative for polymorphism of these enzymes. The data gave a maximum
lod score of 1.59 at theta = 0.15 for males and females combined. In an
informative South African family, Bissbort et al. (1987) found a
recombination fraction of about 0.18 between SAHH and ADA. Combined with
the published findings in Danish families, the recombination fraction
for the pooled data was calculated to be 0.4 in men, 0.08 in women, and
0.13 in the sexes taken together.
MOLECULAR GENETICS
Bissbort et al. (1983) found that the SAHH gene is polymorphic in
southwest Germany with 2 common alleles: SAHH*1 and SAHH*2, with
frequencies of 0.96 and 0.04, respectively. In the Japanese population,
Akiyama et al. (1984) estimated the gene frequencies of SAHH*1 and
SAHH*2 to be 0.953 and 0.047, respectively, similar to the results
reported by Bissbort et al. (1983).
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
By starch gel electrophoresis, Arredondo-Vega et al. (1989) identified 2
variant alleles in erythrocyte AHCY. In a British population, the gene
frequencies were 0.024 for AHCY*2 and 0.006 for AHCY*3. Variant isozyme
patterns could not be distinguished by isoelectric focusing.
Among 237 red blood cell samples from unrelated individuals in Croatia,
Kloor et al. (2006) identified 4 different electromorphic SAHH variants.
SAHH*4 was a new variant, present at a frequency of 0.015. Gene
frequencies for SAHH*1, SAHH*2, and SAHH*3 were 0.941, 0.032, and 0.006,
respectively. The authors identified a 'silent' allele with
significantly decreased enzyme activity, which they designated SAHH*0.
The frequency of SAHH*0 was 0.006, yielding an expected incidence for
homozygous individuals with SAHH deficiency of 1 in 30,000 in this
population.
- Hypermethioninemia with S-Adenosylhomocysteine Hydrolase
Deficiency
In a Croatian boy with S-adenosylhomocysteine hydrolase deficiency,
Baric et al. (2004) identified compound heterozygosity for 2 mutations
in the AHCY gene (180960.0001 and 180960.0002). In discussing the basis
of the pathologic effects of S-adenosylhomocysteine hydrolase
deficiency, Baric et al. (2004) pointed to the numerous
S-adenosylmethionine-dependent methyltransferases, which are inhibited
to a greater or lesser extent by S-adenosylhomocysteine. They pointed
out that changes in DNA methylation patterns are heritable and could
negatively affect tissue-specific gene expression during embryogenesis
and after birth. Because the silencing of genes by inappropriate
methylation is the functional equivalent of somatic mutations, the
heritability of DNA methylation patterns suggests that restoration of
'normal' genomic methylation patterns may not occur.
HMGB3P1
| dbSNP name | rs146102159(C,T) |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 128872 |
| EntrezGene Description | high mobility group box 3 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0528 |
MYH7B
| dbSNP name | rs3761144(C,G); rs34174778(C,G); rs35828152(A,G); rs35552264(A,T); rs13041792(G,A); rs7268769(A,G); rs3787212(G,A); rs3761143(C,T); rs3761142(C,T); rs139949758(T,C); rs187578141(C,T); rs6088662(T,G); rs73905016(C,G); rs146671827(T,G); rs113293741(T,G); rs10427446(C,G); rs143348189(A,G); rs184388741(G,A); rs6060130(C,T); rs55909363(C,T); rs55696836(G,A); rs11698868(C,T); rs149920054(T,C); rs4911165(A,C); rs6088664(G,A); rs6088665(C,G); rs80170004(G,A); rs76110461(C,T); rs73905018(A,G); rs6119548(A,G); rs17401737(C,A); rs7260770(G,A); rs4911455(A,C); rs6579204(A,G); rs7263251(T,C); rs6058149(A,G); rs6120772(C,T); rs57945863(A,C); rs75635914(C,T); rs57513710(C,T); rs6060132(G,A); rs6058150(G,T); rs114406087(C,T); rs147927753(G,A); rs6120775(T,C); rs147089290(C,T); rs6060133(T,C); rs75866240(C,T); rs56255027(G,C); rs77485149(G,A); rs73905019(C,A); rs74599371(G,A); rs79197732(C,T); rs184525880(T,C); rs1475070(C,T); rs7261969(C,T); rs76191812(G,A); rs6060135(A,G); rs185694661(G,A); rs6088666(A,G); rs6087657(G,A); rs77437249(G,A); rs6120778(T,C); rs201494323(C,T); rs6060137(C,T); rs17310782(C,T); rs11906160(G,A); rs6060139(T,C); rs6060140(G,A); rs6088667(T,G); rs1885118(T,C); rs191959576(A,C); rs73905025(G,A); rs55641088(C,T); rs7269138(T,C); rs2425006(T,G); rs733086(A,G); rs2077574(A,T); rs734308(A,G); rs2425007(A,G); rs4911166(G,A); rs4911456(G,A); rs112203644(G,C); rs60893848(G,A); rs2425008(G,C); rs8118978(A,C); rs6119558(T,C); rs3746446(T,C); rs45522831(C,T); rs183060273(C,T); rs7261167(G,A); rs11905413(G,A); rs143368271(C,T); rs1885120(C,G); rs1885114(A,G); rs2425009(T,C); rs6060143(T,C); rs189879552(G,T); rs142914233(C,T); rs146127955(A,C); rs6120785(A,G); rs185144383(G,C); rs2425010(C,T); rs2425011(T,C); rs7268266(T,C); rs73905030(C,A); rs372433127(G,A); rs79841934(C,T); rs73905031(T,C); rs2425013(C,T); rs2425014(T,C); rs2425015(A,G); rs6120788(C,T); rs73095129(G,A); rs3746438(C,T); rs6058154(G,A); rs7271157(C,T); rs3746435(G,C); rs73905035(C,T); rs80109502(G,A); rs148157021(C,T); rs114205213(A,C); rs36003887(G,A); rs55666478(C,T); rs61745054(A,G); rs4911167(A,G) |
| ccdsGene name | CCDS42869.1 |
| CosmicCodingMuts gene | MYH7B |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 57644 |
| EntrezGene Description | myosin, heavy chain 7B, cardiac muscle, beta |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYH7B:NM_020884:exon17:c.C1348T:p.R450C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5825 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | A7E2Y1 |
| dbNSFP Uniprot ID | MYH7B_HUMAN |
| dbNSFP KGp1 AF | 0.0018315018315 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00395778364116 |
| dbSNP GMAF | 0.001837 |
| ESP Afr MAF | 0.000725 |
| ESP All MAF | 0.004392 |
| ESP Eur/Amr MAF | 0.006201 |
| ExAC AF | 0.00509 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Sensorineural hearing loss (reported in 1 patient);
[Eyes];
Hypertelorism (reported in 1 patient);
[Nose];
Broad nasal root (reported in 1 patient)
MUSCLE, SOFT TISSUE:
Muscle weakness
NEUROLOGIC:
[Central nervous system];
Seizures;
Psychomotor retardation, mild to moderate;
Hypotonia;
Acute encephalopathy;
Cerebral atrophy (reported in 1 patient);
Cerebellar atrophy (reported in 1 patient);
Delayed myelination (reported in 1 patient);
[Behavioral/psychiatric manifestations];
Hyperactivity (reported in 1 patient)
LABORATORY ABNORMALITIES:
Decreased aminoacylase-1 activity;
Increased urinary N-acetylated amino acids
MISCELLANEOUS:
Variable phenotype;
Some patients are asymptomatic and detected only by newborn screening;
Seizures may occur with illness;
Patients may show normal development
MOLECULAR BASIS:
Caused by mutation in the aminoacylase-1 gene (ACY1, 104620.0001).
OMIM Title
*609928 MYOSIN, HEAVY CHAIN 7B, CARDIAC MUSCLE, BETA; MYH7B
;;MYOSIN HEAVY CHAIN 14; MYH14;;
KIAA1512
OMIM Description
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned MYH7B, which they designated
KIAA1512. The deduced 1,692-amino acid protein shares 71% identity with
MYH7 (160760). RT-PCR ELISA detected high MYH7B expression in heart,
skeletal muscle, testis, adult and fetal brain, and all specific adult
brain regions examined. Slightly lower expression was detected in ovary
and kidney, and intermediate expression was detected in lung, pancreas,
spleen, and adult and fetal liver.
By screening genomic cosmid libraries for myosin heavy chain genes,
followed by cDNA hybridization and PCR amplification, Desjardins et al.
(2002) cloned MYH7B, which they called MYH14. The deduced protein
contains several class II myosin consensus sequences and has a tail
region of about 1,100 amino acids with homology to both class II myosins
and dimerization domains of leucine zipper proteins. In its N-terminal
catalytic domain, MYH14 has novel surface loop sequences, including
substitutions in the aliphatic sequence of loop 1 and paired prolines in
loop 2. Desjardins et al. (2002) compared the motor domain of MYH14 with
those of other MYHs and concluded that MYH14 is a slow-twitch myosin.
Database analysis identified MYH14 ESTs in libraries obtained from whole
embryo, pooled human tissue cDNA, and well-differentiated endometrial
adenocarcinoma.
By scanning mouse myosin genes for intronic microRNAs (miRNAs), van
Rooij et al. (2009) identified Mir499 (613614) within intron 19 of the
Myh7b gene. Northern blot analysis showed that Mir499 and Myh7b were
highly expressed in mouse heart and the slow-twitch soleus muscle, but
not in the fast-twitch gastrocnemius/plantaris, tibialis anterior, and
extensor digitorum longus muscles.
GENE STRUCTURE
Desjardins et al. (2002) determined that the MYH7B gene contains at
least 40 coding exons and spans about 24 kb.
Van Rooij et al. (2009) identified an miRNA, Mir499 (613614), within
intron 19 of the mouse Myh7b gene.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the MYH7B gene
to chromosome 20. Desjardins et al. (2002) confirmed this localization
by genomic sequence analysis.
GENE FUNCTION
Van Rooij et al. (2009) found that expression of Myh7b and its
intronically encoded miRNA, Mir499, was upregulated in mouse heart by
hypothyroidism caused by inhibition of triiodothyronine (T3; see 188450)
synthesis. This upregulation was reversed by T3 administration. Gain-
and loss-of-function experiments in mice showed that expression of Myh7b
and Mir499 was controlled by the dominant miRNA in mouse heart, Mir208a
(611116).
MIR499B
| dbSNP name | rs3746444(A,G) |
| ccdsGene name | CCDS42869.1 |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 100616134 |
| snpEff Gene Name | MYH7B |
| EntrezGene Description | microRNA 499b |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1814 |
| ESP Afr MAF | 0.181441 |
| ESP All MAF | 0.195146 |
| ESP Eur/Amr MAF | 0.201145 |
| ExAC AF | 0.199 |
MMP24-AS1
| dbSNP name | rs7280(A,G) |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 101410538 |
| snpEff Gene Name | EIF6 |
| EntrezGene Description | MMP24 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4968 |
C20orf173
| dbSNP name | rs11167267(G,T); rs224395(A,G); rs1810741(T,C); rs1810742(A,G); rs147932385(G,A); rs224396(T,G); rs6060448(G,C); rs224397(T,C); rs138105994(C,T); rs224399(A,G); rs224400(A,T); rs224401(A,G); rs17092750(A,T); rs7261862(T,C); rs182903490(G,A); rs6060450(G,A) |
| cytoBand name | 20q11.22 |
| EntrezGene GeneID | 140873 |
| snpEff Gene Name | RP3-477O4.5 |
| EntrezGene Description | chromosome 20 open reading frame 173 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intergenic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3039 |
LINC00657
| dbSNP name | rs9620(C,T); rs6142494(T,C); rs6121135(G,T); rs6142495(C,T); rs7265718(T,G); rs2982537(T,C); rs3171389(C,T); rs7261967(G,A) |
| cytoBand name | 20q11.23 |
| EntrezGene GeneID | 647979 |
| EntrezGene Description | long intergenic non-protein coding RNA 657 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1919 |
MAFB
| dbSNP name | rs56049320(A,T); rs3577(G,A) |
| cytoBand name | 20q12 |
| EntrezGene GeneID | 9935 |
| EntrezGene Description | v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07576 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Mouth];
Bifid uvula (in some patients)
CARDIOVASCULAR:
[Vascular];
Ascending aortic aneurysm;
Ascending aortic dissection;
Arterial aneurysm and/or dissection (abdominal aorta, carotid, and
coronary arteries);
Arterial tortuosity, generalized;
Vascular rupture during pregnancy;
Loss of elastic fibers of aortic wall;
Deposition of mucopolysaccharide-like material in the media;
Erdheim cystic medial necrosis
ABDOMEN:
[Gastrointestinal];
Bowel rupture (some)
GENITOURINARY:
[External genitalia, female];
Inguinal hernia (some);
[Internal genitalia, female];
Uterine hemorrhage (some)
SKELETAL:
Joint laxity
SKIN, NAILS, HAIR:
[Skin];
Velvety skin;
Translucent skin;
Atrophic scars (rare);
Skin hyperextensibility (rare);
Easy bruisability
MISCELLANEOUS:
Average age of onset earlier with TGFBR1 mutations;
Men present with vascular disease earlier than women (23 vs 39 years);
Survival worse in men than women
MOLECULAR BASIS:
Caused by mutation in the transforming growth factor, beta receptor
I gene (TGFBR1, 190181.0004)
OMIM Title
*608968 V-MAF MUSCULOAPONEUROTIC FIBROSARCOMA ONCOGENE FAMILY, PROTEIN B;
MAFB
;;KRML, MOUSE, HOMOLOG OF; KRML
OMIM Description
DESCRIPTION
MAF family members, such as MAFB, are basic region/leucine zipper
transcription factors that affect transcription positively or
negatively, depending on their partner proteins and the context of the
target promoter (Wang et al., 1999).
CLONING
Wang et al. (1999) identified the MAFB gene, which they called KRML,
within a region of chromosome 20 deleted in malignant myeloid disorders.
By PCR of genomic DNA, followed by screening a bone marrow cDNA library
and EST database analysis, they obtained 3 full-length cDNAs that differ
only in their utilization of alternate polyadenylation signals. The
common deduced protein contains 323 amino acids and has a calculated
molecular mass of 35.8 kD. MAFB has a pro-ser-thr-rich acidic
transcription activation domain at its N terminus, followed by 2
histidine repeats, an extended homology region, a basic DNA-binding
domain, and a C-terminal leucine zipper domain containing hydrophobic
residues that form the zipper heptad repeats (LLLLYL). MAFB shares 84%
amino acid identity with its murine homolog. Northern blot analysis
detected ubiquitous expression of MAFB. A 3.0-kb transcript was
expressed in all tissues analyzed, and a 1.8-kb transcript was expressed
predominantly in bone marrow and skeletal muscle, with low-level
expression in heart.
GENE STRUCTURE
Wang et al. (1999) determined that the MAFB gene consists of a single
exon and spans about 3 kb.
MAPPING
By sequence analysis, Wang et al. (1999) mapped the MAFB gene to
chromosome 20q11.2-q13.1.
GENE FUNCTION
Using a yeast 2-hybrid screen and in vitro protein-binding assays,
Petersen et al. (2004) demonstrated that human MAFB interacted directly
with the intracellular domain (ICD) of mouse Lrp1 (107770). Mutation
analysis indicated that the leucine zipper motif of MAFB was required
for this interaction. Murine Mafb and the isolated ICD colocalized in
the nucleus of cotransfected human embryonic kidney cells. The ICD also
localized in the cytoplasm. MAFB stimulated expression of a reporter
gene that was constructed with 3 upstream copies of the Maf recognition
element (MARE) followed by a TATA-like promoter. Cotransfection of the
Lrp1 ICD with MAFB reduced the transactivation potential of MAFB.
Garzon et al. (2006) identified MAFB as a putative target of MIRN130A
(610175) and, using RT-PCR and Western blot analysis, found that MAFB
mRNA and protein were upregulated during megakaryocytic differentiation.
Transfection of a human megakaryocytic leukemia cell line with MIRN130A
precursor reduced expression of a reporter gene containing the 3-prime
UTR of MAFB, and overexpression of MIRN130A in a myelogenous leukemia
cell line reduced MAFB protein levels.
Aziz et al. (2009) reported that combined deficiency for the
transcription factors MafB and c-Maf enables extended expansion of
mature monocytes and macrophages in culture without loss of
differentiated phenotype and function. Upon transplantation, the
expanded cells are nontumorigenic and contribute to functional
macrophage populations in vivo. Small hairpin RNA inactivation showed
that continuous proliferation of MafB/c-Maf-deficient macrophages
requires concomitant upregulation of 2 pluripotent stem cell-inducing
factors, KLF4 (602253) and c-Myc (190080). Aziz et al. (2009) concluded
that MafB/c-Maf deficiency renders self-renewal compatible with terminal
differentiation. It thus appears possible to amplify functional
differentiated cells without malignant transformation or stem cell
intermediates.
MOLECULAR GENETICS
For discussion of a possible association between variation in the MAFB
gene and susceptibility to nonsyndromic cleft lip/palate, see 119530.
In 11 simplex cases and affected individuals from 2 pedigrees with
multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et
al. (2012) identified heterozygosity for missense mutations in the MAFB
gene (see, e.g., 608968.0001-608968.0006). The mutations were clustered
within a 51-bp region of the single exon of MAFB. All but the 3 youngest
simplex cases had renal disease, and 5 patients had undergone renal
transplantation; however, because affected adults from the 2 families
did not manifest renal dysfunction, Zankl et al. (2012) concluded that
MAFB mutations are also responsible for MCTO in the absence of renal
disease.
ANIMAL MODEL
Wang et al. (1999) noted that mutations in the murine Mafb gene are
responsible for the mouse mutant Kreisler (kr), a developmental defect
of the hindbrain.
Artner et al. (2007) stated that homozygous Mafb-mutant mice die at
birth: kr mice of renal failure and Mafb -/- mice of central apnea. They
observed that Mafb -/- mouse embryos had reduced numbers of pancreatic
alpha and beta cells, whereas the total number of endocrine cells was
unchanged. Production of alpha cells was delayed until embryonic day
13.5 in mutant embryos and coincident with the onset of Mafa (610303)
expression.
LOC101927242
| dbSNP name | rs56115289(G,A) |
| cytoBand name | 20q13.12 |
| EntrezGene GeneID | 101927242 |
| snpEff Gene Name | C20orf62 |
| EntrezGene Description | uncharacterized LOC101927242 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07851 |
STK4-AS1
| dbSNP name | rs3761190(A,G); rs2284269(G,A) |
| cytoBand name | 20q13.12 |
| EntrezGene GeneID | 100505826 |
| snpEff Gene Name | STK4 |
| EntrezGene Description | STK4 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3802 |
ZNF663P
| dbSNP name | rs4810507(G,A) |
| cytoBand name | 20q13.12 |
| EntrezGene GeneID | 100130934 |
| snpEff Gene Name | RP5-981L23.1 |
| EntrezGene Description | zinc finger protein 663, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1465 |
MKRN7P
| dbSNP name | rs279730(T,C); rs24236(C,T); rs1000383(G,A); rs279729(A,G); rs6094349(C,T); rs975102(T,C) |
| cytoBand name | 20q13.12 |
| EntrezGene GeneID | 7686 |
| snpEff Gene Name | RP5-981L23.2 |
| EntrezGene Description | makorin ring finger protein 7, pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1341 |
TRERNA1
| dbSNP name | rs6125876(C,A) |
| cytoBand name | 20q13.13 |
| EntrezGene GeneID | 100887755 |
| snpEff Gene Name | RP4-710H13.2 |
| EntrezGene Description | translation regulatory long non-coding RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3834 |
MOCS3
| dbSNP name | rs112247357(A,G); rs74274627(C,T); rs6013047(T,C) |
| cytoBand name | 20q13.13 |
| EntrezGene GeneID | 27304 |
| snpEff Gene Name | DPM1 |
| EntrezGene Description | molybdenum cofactor synthesis 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
SUMO1P1
| dbSNP name | rs6097643(G,A); rs12151887(C,G); rs11699573(T,C); rs6068699(G,A); rs116095814(G,C) |
| cytoBand name | 20q13.2 |
| EntrezGene GeneID | 391257 |
| EntrezGene Description | SUMO1 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.101 |
MC3R
| dbSNP name | rs3746619(C,A); rs3827103(G,A) |
| cytoBand name | 20q13.2 |
| EntrezGene GeneID | 4159 |
| EntrezGene Description | melanocortin 3 receptor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2084 |
| ESP Afr MAF | 0.456423 |
| ESP All MAF | 0.214286 |
| ESP Eur/Amr MAF | 0.090233 |
| ExAC AF | 0.152 |
OMIM Clinical Significance
Limbs:
One or 2 grotesquely enlarged fingers
Inheritance:
No report of familial occurrence
OMIM Title
*155540 MELANOCORTIN 3 RECEPTOR; MC3R
;;MC3 RECEPTOR
OMIM Description
CLONING
Gantz et al. (1993) identified a third melanocortin receptor that
recognizes the core heptapeptide sequence of melanocortins. (See 155555
and 202200 for MC1 and MC2, respectively.) This receptor is expressed in
the brain, placenta, and gut tissues, but not in the adrenal cortex or
melanocytes.
Cooke et al. (2008) noted that the 361-amino acid MC3R protein is a G
protein-coupled receptor with 7 transmembrane domains.
GENE STRUCTURE
Cooke et al. (2008) stated that the MC3R gene contains 1 coding exon.
MAPPING
Gantz et al. (1993) mapped the MC3R gene to chromosome 20q13.2-q13.3 by
fluorescence in situ hybridization. By fluorescence in situ
hybridization, Magenis et al. (1994) assigned the MC3R gene to 20q13.2;
they assigned the homologous gene in the mouse to chromosome 2 by study
of an intersubspecific backcross mapping panel. It is noteworthy that
the gene for this neural receptor maps to the same region as the locus
for benign neonatal epilepsy (EBN1; 121200) in the human and near the
El-2 epilepsy susceptibility locus in the mouse. Through study of an
interspecific backcross, Malas et al. (1994) also demonstrated that the
mouse homolog maps to chromosome 2.
GENE FUNCTION
Heisler et al. (2002) found that genetic or pharmacologic blockade of
MC4R (155541) and MC3R is sufficient to attenuate the anorectic efficacy
of threshold doses of d-FEN (D-fenfluramine), suggesting that drugs
targeting these downstream melanocortin pathways may act in part in a
manner similar to d-FEN to decrease food intake and body weight with
fewer side effects.
MOLECULAR GENETICS
Familial genetic studies of noninsulin-dependent diabetes mellitus
(NIDDM; 125853) of different human populations, including French
Caucasians, suggested evidence for linkage of NIDDM and chromosome 20q13
(see 603694), where the MC3R gene maps. Hani et al. (2001) assessed the
MC3R gene for variations in a large cohort of French families with NIDDM
and identified thr6-to-lys (T6L) and val81-to-ile (V81I; 155540.0003)
variants in the MC3R gene. These 2 variants, which were in complete
linkage disequilibrium, were also present in nondiabetic controls. Based
on association and familial linkage disequilibrium test results, the
authors stated that these MC3R gene-coding variants were not associated
with diabetes or obesity. Hani et al. (2001) concluded that these
variants were marginally associated with insulin and glucose levels
during oral glucose tolerance testing in normoglycemic subjects.
In a 13-year-old obese (see BMIQ9; 602025) girl and her father, Lee et
al. (2002) identified a heterozygous mutation (I183N; 155540.0001) in
the MC3R gene. Functional characterization of the I183N mutant by Tao
and Segaloff (2004) showed a complete lack of signaling in response to
agonist stimulation.
Feng et al. (2005) analyzed the MC3R gene in 190 overweight and 160
nonoverweight children and found that 29 (8.2%) children were double
homozygous for T6L and V81I variants. The double homozygous children
(lys/lys and ile/ile) were significantly heavier (p less than 0.0001),
had more body fat (p less than 0.001), and had greater plasma leptin (p
less than 0.0001) and insulin concentrations (p less than 0.001) and
greater insulin resistance (p less than 0.008) than wildtype or
heterozygous children. Both sequence variants were more common in
African American than in Caucasian children.
Rutanen et al. (2007) studied the T6L and V81I MC3R polymorphisms in a
cross-sectional study of 216 middle-aged nondiabetic Finnish subjects
who were offspring of type 2 diabetic patients. Carriers of the lys6 and
ile81 alleles had significantly lower rates of lipid oxidation and
higher rates of glucose oxidation in the fasting state than subjects
with the thr/thr6 and val/val81 genotypes. Rutanen et al. (2007)
concluded that SNPs of MC3R may regulate substrate oxidation and
first-phase insulin secretion.
Mencarelli et al. (2008) sequenced the MC3R gene in 290 obese
individuals and 215 normal-weight controls and identified 3 heterozygous
mutations present in 3 obese individuals, respectively, that were not
present in controls (see, e.g., 155540.0002). Although there were only a
limited number of family members available for study, there appeared to
be cosegregation of the mutations with the obese phenotype.
Using genomewide linkage and positional mapping of tuberculosis-affected
sib pairs in South Africans of mixed racial origin and in Africans from
northern Malawi, Cooke et al. (2008) identified a novel putative
tuberculosis susceptibility locus on chromosome 20q13.31-q33 (MTBS3;
612929). Detailed SNP mapping of chromosome 20q13.31-q33 in a
case-control study of West African subjects revealed evidence of disease
association with SNPs in the MC3R and CTSZ (603169) genes. Homozygosity
for the A allele of a +241G-A SNP in the MC3R gene (dbSNP rs3827103),
which produces the V81I substitution in the protein (Cooke, 2009),
conferred resistance to tuberculosis. In contrast, homozygosity for the
C allele of a T-C SNP in the 3-prime UTR of the CTSZ gene (dbSNP
rs34069356) was associated with susceptibility to tuberculosis.
ANIMAL MODEL
Genetic and pharmacologic studies defined a role for MC4R in the
regulation of energy homeostasis. MC3R is expressed at high levels in
the hypothalamus. Chen et al. (2000) evaluated the potential role of
MC3R in energy homeostasis by studying Mc3r-deficient (Mc3r -/-) mice
and compared the functions of Mc3r and Mc4r in mice deficient for both
genes. At the age of 4 to 6 months, Mc3r -/- mice had increased fat
mass, reduced lean mass, and higher feed efficiency than wildtype
littermates, despite being hypophagic and maintaining normal metabolic
rates. (Feed efficiency is the ratio of weight gain to food intake.)
Consistent with increased fat mass, Mc3r -/- mice were hyperleptinemic,
and male Mc3r -/- mice developed mild hyperinsulinemia. They did not
show significantly altered corticosterone or total thyroxine (T4)
levels. Mice lacking both Mc3r and Mc4r became significantly heavier
than Mc4r -/- mice. Chen et al. (2000) concluded that Mc3r and Mc4r
serve nonredundant roles in the regulation of energy homeostasis.
Cummings and Schwartz (2000) showed that these studies demonstrated that
the 2 melanocortin receptor isoforms reduce body weight through distinct
and complementary mechanisms. Mc4r regulates food intake and possibly
energy expenditure, whereas Mc3r influences feed efficiency and the
petitioning of fuel stores into fat.
FAM209A
| dbSNP name | rs111909024(G,A) |
| ccdsGene name | CCDS33493.1 |
| cytoBand name | 20q13.31 |
| EntrezGene GeneID | 200232 |
| snpEff Gene Name | C20orf106 |
| EntrezGene Description | family with sequence similarity 209, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FAM209A:NM_001012971:exon2:c.G475A:p.V159I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0024 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5JX71 |
| dbNSFP Uniprot ID | CT106_HUMAN |
| dbNSFP KGp1 AF | 0.0196886446886 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.0359116022099 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0395778364116 |
| dbSNP GMAF | 0.01974 |
| ESP Afr MAF | 0.004539 |
| ESP All MAF | 0.022221 |
| ESP Eur/Amr MAF | 0.031279 |
| ExAC AF | 0.024 |
MIR4532
| dbSNP name | rs113808830(C,T); rs73177830(G,A) |
| cytoBand name | 20q13.31 |
| EntrezGene GeneID | 100616353 |
| EntrezGene Description | microRNA 4532 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03122 |
| ExAC AF | 0.016 |
DPH3P1
| dbSNP name | rs57610632(T,C) |
| ccdsGene name | CCDS13506.1 |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 100132911 |
| snpEff Gene Name | COL9A3 |
| EntrezGene Description | diphthamide biosynthesis 3 pseudogene 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DPH3P1:NM_080750:exon1:c.T162C:p.I54I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.04545 |
| ESP Afr MAF | 0.114162 |
| ESP All MAF | 0.060885 |
| ESP Eur/Amr MAF | 0.037712 |
| ExAC AF | 0.036 |
HAR1A
| dbSNP name | rs73312551(T,C); rs750696(C,T); rs750697(G,A); rs750698(T,G); rs750699(C,T) |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 768097 |
| EntrezGene Symbol | HAR1B |
| snpEff Gene Name | HAR1F |
| EntrezGene Description | highly accelerated region 1B (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | misc_RNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2732 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial weakness;
[Eyes];
Ptosis (less common);
Absence of ophthalmoparesis;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory muscle weakness may occur
MUSCLE, SOFT TISSUE:
Muscle biopsy shows 60-80-nm tubular aggregates arranged in hexagonal
arrays in type 2 fibers
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor milestones (in some);
Proximal muscle weakness due to defect at the neuromuscular junction;
Proximal muscle atrophy;
Distal muscle weakness may also occur;
Easy fatigability;
Muscle cramps;
Gowers sign;
Waddling gait;
Decremental compound motor action potential (CMAP) response to repetitive
nerve stimulation seen on EMG;
Increased jitter seen on single fiber EMG
IMMUNOLOGY:
Absence of acetylcholine receptor (AChR) autoantibodies
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Onset in first decade;
Favorable response to acetylcholinesterase inhibitors;
Distinct disorder from acquired limb-girdle myasthenia (159400)
and congenital limb-girdle myasthenia (254300)
MOLECULAR BASIS:
Caused by mutation in the glutamine:fructose-6-phosphate aminotransferase
1 gene (GFPT1, 138292.0001)
OMIM Title
*610556 HIGHLY ACCELERATED REGION GENE 1A; HAR1A
;;HAR1F
OMIM Description
CLONING
Using expressed sequence tag (EST) analysis, Pollard et al. (2006)
identified the HAR1A gene as HAR1F, one of a pair of overlapping
divergently transcribed genes (see also HAR1B, 610557) that contain the
'human accelerated region' HAR1. Pollard et al. (2006) found that the
protein-coding potential of the HAR1A RNA is poor or absent, but that it
forms a stable RNA structure.
GENE STRUCTURE
Pollard et al. (2006) determined that the HAR1A gene contains 2 exons.
MAPPING
By genomic sequence analysis, Pollard et al. (2006) mapped the HAR1A
gene to chromosome 20q13.33.
EVOLUTION
Pollard et al. (2006) devised a ranking of regions in the human genome
that show significant evolutionarily acceleration. The most dramatic of
these 'human accelerated regions' is HAR1. Pollard et al. (2006) found
that the 118-bp HAR1 region contains 18 substitutions since the
human-chimpanzee ancestor, but that only 2 bases have changed between
chimpanzee and chicken. Resequencing in 4 primates further confirmed
that all 18 substitutions were likely to have occurred in the human
lineage. Resequencing in a 24-person diversity panel indicated that all
18 substitutions are fixed in the human population. Based on further
experiments, Pollard et al. (2006) concluded that the changes in HAR1
clearly occurred on the human lineage but probably took place more than
1 million years ago.
GENE FUNCTION
Using RNA in situ hybridization of human embryonic brain sections,
Pollard et al. (2006) detected HAR1A expression at 7 and 9 weeks'
gestation in the dorsal telencephalon but not in other parts of the
forebrain. Within the early developing cortex, HAR1F was selectively
expressed in a subset of cells located close to the pial surface in the
marginal zone, indicating its expression in Cajal-Retzius neurons. It
was codetected with reelin (600514), a specific marker of these neurons.
HAR1A was not expressed in interneurons expressing GABA. HAR1 expression
was maintained until at least 17 to 19 weeks' gestation. HAR1A was also
found to be expressed in the upper cortical plate, presumably
corresponding to neurons finishing their radial migration. At later
gestational stages (24 weeks), expression of HAR1A was no longer
detectable in Cajal-Retzius cells. At 17 to 24 weeks' gestation, HAR1A
expression was observed in hippocampal primordium, the dentate gyrus,
the developing cerebellar cortex, and a few hindbrain nuclei such as the
olivar complex. In situ hybridization of adult brain sections revealed
that expression of HAR1A was highest in cerebellum and was also
prominent in forebrain structures including the cortex, hippocampus,
thalamus, and hypothalamus. Expression in was also detected in ovary and
testis by quantitative real-time PCR.
MIR3196
| dbSNP name | rs744591(C,A) |
| ccdsGene name | CCDS13512.1 |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 100423014 |
| snpEff Gene Name | NKAIN4 |
| EntrezGene Description | microRNA 3196 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4669 |
| ExAC AF | 0.337 |
FLJ16779
| dbSNP name | rs6062869(C,T); rs911054(C,G); rs76183812(C,A); rs116769520(G,A); rs910894(G,A); rs114865282(T,C); rs910893(G,A); rs910892(C,T); rs77235784(A,G); rs149017561(G,A); rs149049261(G,T); rs77907969(C,T); rs6011704(T,C); rs6122109(A,C); rs6062427(G,A); rs145545601(G,A); rs4809513(T,C); rs2281566(C,A); rs1884819(C,T); rs75838425(G,C); rs3589(C,T) |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 100192386 |
| snpEff Gene Name | NKAIN4 |
| EntrezGene Description | uncharacterized LOC100192386 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3815 |
COL20A1
| dbSNP name | rs4809522(T,G); rs4809523(T,C); rs4809524(A,G); rs4809525(G,A); rs79607342(G,A); rs111980331(G,A); rs6090346(G,A); rs112920247(G,A); rs28589973(C,A); rs28694305(G,A); rs112364255(T,C); rs111855042(C,T); rs9917458(C,T); rs6090349(A,T); rs4809526(G,A); rs372703402(G,A); rs116356658(A,G); rs111674249(A,G); rs75941628(C,T); rs6062880(C,T); rs6089874(C,T); rs7263455(G,A); rs144961858(T,G); rs74827289(G,C); rs34493170(G,A); rs6011726(C,T); rs7347209(C,T); rs4809287(A,G); rs6011728(G,C); rs111950139(T,C); rs4809529(C,T); rs75513393(T,C); rs147670144(G,C); rs755041(A,G); rs911067(T,C); rs113536487(T,C); rs6090357(C,T); rs369836351(A,T); rs6011731(A,G); rs3803935(C,T); rs11697902(T,C); rs6062890(G,A); rs55690903(A,G); rs80291285(C,A); rs74397198(G,A); rs7265034(A,C); rs3746381(C,T); rs6089881(G,C); rs6062891(C,T); rs6011732(A,T); rs3746382(A,G); rs1884820(G,C); rs1884821(T,C); rs11700044(C,T); rs57333838(C,A); rs4809289(C,T); rs6062894(C,T); rs111347131(C,T); rs6011733(G,A); rs6011734(G,T); rs192749239(C,G); rs113461066(G,A); rs117049320(G,A); rs112017476(G,C); rs112826399(G,A); rs3746383(G,T); rs6089885(T,C); rs75644446(C,T); rs150129155(C,T); rs58149550(C,T); rs79012842(C,T); rs4809536(T,C); rs8126037(T,C); rs112825381(C,T); rs6010903(A,G); rs2180614(T,C); rs2180615(T,C); rs76283480(A,G); rs6011740(T,C); rs112810599(C,T); rs111601765(G,A); rs911069(A,G); rs6010905(G,A); rs911043(G,T); rs76725394(T,C) |
| ccdsGene name | CCDS46628.1 |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 57642 |
| EntrezGene Description | collagen, type XX, alpha 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | COL20A1:NM_020882:exon34:c.C3650T:p.T1217I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6125 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.002474 |
| ESP All MAF | 0.00081 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.0003431 |
SLC2A4RG
| dbSNP name | rs2427536(G,A) |
| ccdsGene name | CCDS13537.1 |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 56731 |
| EntrezGene Description | SLC2A4 regulator |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC2A4RG:NM_020062:exon3:c.G372A:p.P124P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | low |
| dbSNP GMAF | 0.0404 |
| ESP Afr MAF | 0.016818 |
| ESP All MAF | 0.056855 |
| ESP Eur/Amr MAF | 0.077344 |
| ExAC AF | 0.945 |
ABHD16B
| dbSNP name | rs45471398(A,C); rs6011193(C,G) |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 140701 |
| snpEff Gene Name | TPD52L2 |
| EntrezGene Description | abhydrolase domain containing 16B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07025 |
UCKL1-AS1
| dbSNP name | rs817316(A,G); rs817317(A,T); rs817318(T,C); rs79599197(T,C) |
| ccdsGene name | CCDS13547.1 |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 100113386 |
| snpEff Gene Name | ZNF512B |
| EntrezGene Description | UCKL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2658 |
LINC00176
| dbSNP name | rs3829704(C,T); rs3764735(A,G); rs816939(A,C); rs2427596(C,G) |
| cytoBand name | 20q13.33 |
| EntrezGene GeneID | 284739 |
| snpEff Gene Name | PRPF6 |
| EntrezGene Description | long intergenic non-protein coding RNA 176 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.14 |
LIPI
| dbSNP name | rs1136522(T,C); rs7279700(C,T); rs7278737(G,T); rs13048561(A,G); rs1556276(A,G); rs1556277(T,C); rs8127547(T,C); rs12627315(T,C); rs74666896(C,G); rs9982308(C,T); rs192028411(G,A); rs59313234(C,A); rs13050849(A,G); rs13050985(A,C); rs114220546(A,G); rs4816961(C,A); rs115781158(C,T); rs13050925(T,G); rs148532356(G,A); rs11701744(G,T); rs914111(T,C); rs146873872(A,G); rs12482507(C,T); rs144390386(T,G); rs77472061(G,A); rs12627550(T,C); rs62208642(C,G); rs2822409(G,C); rs2822410(T,G); rs2822411(A,C); rs144242377(A,G); rs8131606(G,A); rs2822413(T,C); rs143584807(G,T); rs2246835(T,C); rs1115648(A,G); rs2403729(G,A); rs1115649(G,A); rs11909528(C,T); rs2187063(A,G); rs62208643(C,T); rs2155969(C,T); rs2155970(A,C); rs183604764(G,A); rs2822419(T,A); rs2155971(G,A); rs77558352(T,C); rs75726603(A,G); rs2187064(C,G); rs74719747(G,A); rs116411749(C,A); rs1970046(C,A); rs2263412(A,G); rs8130103(T,A); rs2032283(C,T); rs2032284(G,A); rs190847847(G,T); rs116237252(C,T); rs12627207(C,T); rs10854284(G,A); rs8131402(C,T); rs8132149(C,A); rs77507320(T,C); rs6516620(C,T); rs6516621(C,T); rs189287692(G,A); rs2032285(C,T); rs1573435(T,C); rs8127852(G,A); rs73155594(G,A); rs8129727(A,C); rs8129739(A,T); rs8133316(T,G); rs76164511(A,C); rs2822424(T,A); rs2822425(A,G); rs2822426(A,C); rs1475568(C,G); rs1475569(T,A); rs75079489(A,G); rs77373846(C,A); rs79050674(A,T); rs9636758(G,C); rs114619712(C,A); rs75329126(G,A); rs78117642(C,T); rs2096926(G,A); rs8130994(C,T); rs74379744(G,A); rs77139775(A,G); rs78620963(G,A); rs115393629(G,T); rs116793008(T,G); rs114415583(A,T); rs76706671(C,A); rs78498290(C,T); rs78113034(A,G); rs114300579(C,T); rs79945912(A,T); rs12482173(T,A); rs182519841(C,G); rs76430290(C,T); rs140965924(G,T); rs9636759(A,G); rs76896236(G,A); rs11909472(C,T); rs7277797(A,T); rs7276350(G,A); rs7277426(C,T); rs7281965(T,C); rs55938121(T,G); rs60607364(C,T); rs7278182(C,T); rs144037378(A,C); rs115720581(A,G); rs58601465(C,T); rs114760253(C,G); rs193075461(G,T); rs77521194(T,A); rs62209377(C,T); rs115608011(C,T); rs2155961(T,C); rs12482474(A,T); rs146284737(A,G); rs116259201(G,T); rs7283799(A,T); rs59554421(A,T); rs114311432(T,C); rs7275510(A,T); rs9980668(G,A); rs73162690(G,A); rs12483666(A,T); rs1124254(T,G); rs73162696(G,A); rs7276941(A,G); rs2822427(C,A); rs2822428(T,C); rs141540334(T,C); rs146169744(C,T); rs11910353(C,T); rs2822429(C,T); rs914112(A,G); rs2212711(C,T); rs145260608(G,A); rs2822430(A,C); rs11909656(C,T); rs2822431(C,T); rs2822432(C,T); rs7283442(T,A); rs2822433(G,T); rs914113(T,C); rs993752(C,A); rs11087929(G,C); rs11087930(A,C); rs73894171(G,A); rs6516632(T,C); rs6516633(C,T); rs73894172(T,C); rs2212712(A,G); rs7276034(G,A); rs9976636(C,T); rs2212713(C,T); rs62209378(A,C); rs79917237(A,G); rs2822434(A,G); rs6516634(C,G); rs60457222(T,C); rs7283108(T,C); rs57726121(A,G); rs140068278(G,A); rs7283069(T,C); rs73894174(A,G); rs143638770(C,A); rs2822435(C,T); rs2822436(A,G); rs13051215(T,A); rs9984592(A,G); rs34283087(A,C); rs9976011(T,C); rs8131931(T,C); rs4306779(A,G); rs74694896(T,C); rs147642111(A,G); rs142241847(T,C); rs13052831(G,A); rs13047430(A,T); rs73346025(T,G); rs13050803(T,G); rs75699809(G,A); rs2155963(C,T); rs12627429(C,A); rs9974739(T,C); rs28850941(G,A); rs147553078(T,C); rs2212714(G,A); rs2226729(T,A); rs9977811(G,A); rs76041056(C,G); rs34992986(A,G); rs112116463(G,A); rs73346033(A,G); rs13051245(G,A); rs12482146(T,C); rs12483692(C,G); rs75730972(A,G); rs2155964(T,C); rs73346040(T,C); rs145166585(T,C); rs73346044(C,A); rs73346045(T,A); rs1981365(C,T); rs114084862(A,T); rs9983384(G,A); rs115356762(T,G); rs143630220(G,T); rs148172494(G,C); rs145640490(C,G); rs143208223(C,T); rs137861507(C,A); rs141966023(A,C); rs138955940(G,A); rs144428328(G,A); rs142729848(T,G); rs148843169(C,T); rs147868026(T,G); rs7283595(C,T); rs7282646(G,T); rs117690986(T,C); rs112278281(C,T); rs113235923(C,T); rs141531603(T,C); rs115899878(T,C); rs111663456(G,A); rs1739485(G,T); rs79995355(T,C); rs9983711(G,A); rs431864(C,T); rs389322(T,C); rs75826784(T,C); rs116700095(T,C); rs144720655(C,T); rs140239750(T,C); rs73346061(G,A); rs76522857(A,C); rs4263189(T,C); rs8129587(G,T); rs116889243(G,A); rs11908737(G,A); rs117647974(G,A); rs454923(T,C); rs8134368(C,T); rs117355127(T,C); rs9975152(C,G); rs454065(T,C); rs115130325(G,A); rs435506(G,A); rs435081(T,G); rs114201703(T,A); rs2822437(T,C); rs8130145(G,A); rs115201811(A,G); rs2822438(T,C); rs4597625(A,T); rs114936113(A,C); rs13046897(A,C); rs113400488(C,A); rs73346081(C,A); rs149088118(C,T); rs143106869(T,C); rs2403759(C,T); rs13046593(C,G); rs74923977(G,A); rs145683340(A,C); rs74734528(T,A); rs2822439(C,T); rs73346087(G,A); rs409070(G,T); rs138995996(G,A); rs111545715(C,T); rs425131(A,C); rs111878015(T,C); rs62226901(A,C); rs11909217(C,T); rs140868104(G,A); rs9981966(A,C); rs114599259(C,A); rs13052706(T,C); rs75113550(C,T); rs78063679(T,C); rs187299413(T,C); rs77737444(A,C); rs141278719(C,T); rs115898605(G,A); rs189799676(A,G); rs113752687(G,C); rs59390056(A,G); rs9983425(T,C); rs143844869(T,C); rs144002648(A,C); rs76138468(C,T); rs57804003(T,A); rs73346096(G,A); rs417044(A,G); rs28496553(G,T); rs78217374(A,C); rs408805(G,A); rs11911585(G,A); rs399963(C,A); rs9983840(G,C); rs2403760(T,C); rs142610065(C,A); rs62226903(G,A); rs432135(T,C); rs7281467(A,C); rs143200096(T,C); rs377414(C,G); rs77733186(C,T); rs116398579(A,C); rs146028684(A,C); rs428714(A,G); rs144738390(C,G); rs73164287(G,A); rs115656641(T,G); rs413234(C,T); rs79462758(A,G); rs140812638(A,C); rs190512262(C,A); rs9975472(G,A); rs13048747(C,A); rs427098(A,C); rs79776703(G,T); rs114123770(C,T) |
| ccdsGene name | CCDS13564.1 |
| cytoBand name | 21q11.2 |
| EntrezGene GeneID | 149998 |
| EntrezGene Description | lipase, member I |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LIPI:NM_198996:exon2:c.G227A:p.C76Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7103 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | G1JSG6 |
| dbNSFP KGp1 AF | 0.00732600732601 |
| dbNSFP KGp1 Afr AF | 0.0182926829268 |
| dbNSFP KGp1 Amr AF | 0.0138121546961 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.019065 |
| ESP All MAF | 0.009688 |
| ESP Eur/Amr MAF | 0.004884 |
| ExAC AF | 0.004944 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Coarse facies;
[Ears];
Sensorineural hearing loss;
Meniere syndrome;
[Eyes];
Conjunctiva shows dilated blood vessels;
Fundi show dilated blood vessels with corkscrew-like tortuosity;
[Nose];
Enlarged nasal tip;
Depressed nasal bridge;
[Mouth];
Thick lips
SKIN, NAILS, HAIR:
[Skin];
Angiokeratoma corporis diffusum;
Hyperkeratosis;
Dry skin;
Maculopapular eruption, diffuse;
Telangiectasia on lips and oral mucosa
MUSCLE, SOFT TISSUE:
Lymphedema
NEUROLOGIC:
[Central nervous system];
Intellectual impairment, mild;
Vertigo;
MRI may show atrophy of the cerebrum;
White mater abnormalities in the posterior periventricular region;
[Peripheral nervous system];
Peripheral axonal neuropathy;
Distal limb muscle weakness;
Distal sensory impairment of all modalities;
Sural nerve biopsy shows decreased density of myelinated fibers and
axonal degeneration
LABORATORY ABNORMALITIES:
Decreased or absent alpha-N-acetylgalactosaminidase protein;
Decreased or absent alpha-N-acetylgalactosaminidase activity;
Diverse tissue cell types (vascular endothelial cells, adipocytes,
Schwann cells, leukocytes) have membrane-lined cytoplasmic vacuoles
with amorphous and filamentous material;
Glycoamino aciduria;
Increased urinary O-linked sialopeptides
MISCELLANEOUS:
Adult onset;
Allelic disorder to Schindler disease (609241)
MOLECULAR BASIS:
Caused by mutation in the alpha-N-acetylgalactosaminidase gene (NAGA,
104170.0002)
OMIM Title
*609252 LIPASE I; LIPI
;;LPD LIPASE; LPDL;;
PRED5
OMIM Description
CLONING
By screening a testis cDNA library using mouse Lpdl as probe, Wen et al.
(2003) cloned human LIPI, which they called LPDL. The deduced 460-amino
acid protein contains a hydrophobic leader sequence with a putative
cleavage site after amino acid 15, a central lipase consensus sequence
(GxSxG), a central 12-amino acid lipase lid sequence, and several
conserved cysteines. The GxSxG sequence includes the active site ser159,
which forms a putative catalytic triad with asp183 and his258. LPDL
shares 71% amino acid identity with mouse Lpdl, 44% identity with LPDLR
(LIPH; 607365), and 34% identity with phospholipase PLA1A (607460).
Northern blot analysis of several human and mouse tissues detected
strong expression of a 2.0-kb transcript only in testis. In situ
hybridization of 2-week-old mice detected Lpdl expression in testis,
with weaker expression in hepatocytes. In testis of adult mice, Lpdl was
expressed in the cytoplasm of primary spermatocytes, but not in mature
sperm or in Leydig cells.
GENE STRUCTURE
Wen et al. (2003) determined that the LIPI gene contains 10 exons and
spans more than 100 kb. Exon 3 encodes the lipase consensus sequence
GxSxG. The mouse Lipi gene contains 10 exons and spans 110 kb.
MAPPING
By genomic sequence analysis, Wen et al. (2003) mapped the LIPI gene to
chromosome 21q11.2, centromeric to the STCH gene (601100). They mapped
the mouse Lipi gene to chromosome 16B1.
MOLECULAR GENETICS
Wen et al. (2003) identified 2 Caucasians with hypertriglyceridemia
(145750) who were heterozygous for a mutation in the LIPI gene that
resulted in substitution of tyrosine for a conserved cysteine at codon
55 (C55Y; 609252.0001). They identified 2 other coding SNPs that were
associated with variation in plasma HDL cholesterol in independent
normolipidemic populations.
ANIMAL MODEL
Mice homozygous for the lipid defect (lpd) mutation have a phenotype
that includes hepatic steatosis and hypertriglyceridemia. Wen et al.
(2003) determined that the lpd mutation is a deletion of exon 10 in the
Lpdl gene.
LINC00515
| dbSNP name | rs915861(G,T) |
| cytoBand name | 21q21.3 |
| EntrezGene GeneID | 282566 |
| snpEff Gene Name | MRPL39 |
| EntrezGene Description | long intergenic non-protein coding RNA 515 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0854 |
CLDN17
| dbSNP name | rs35531957(C,T) |
| ccdsGene name | CCDS13586.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 26285 |
| EntrezGene Description | claudin 17 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN17:NM_012131:exon1:c.G244A:p.A82T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0108 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P56750 |
| dbNSFP Uniprot ID | CLD17_HUMAN |
| dbNSFP KGp1 AF | 0.10119047619 |
| dbNSFP KGp1 Afr AF | 0.0142276422764 |
| dbNSFP KGp1 Amr AF | 0.10773480663 |
| dbNSFP KGp1 Asn AF | 0.178321678322 |
| dbNSFP KGp1 Eur AF | 0.0963060686016 |
| dbSNP GMAF | 0.1015 |
| ESP Afr MAF | 0.030413 |
| ESP All MAF | 0.068584 |
| ESP Eur/Amr MAF | 0.08814 |
| ExAC AF | 0.094 |
CLDN8
| dbSNP name | rs13433507(G,A); rs9647055(G,A); rs686364(A,G); rs61743791(G,A) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 9073 |
| EntrezGene Description | claudin 8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03168 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Limbs];
Ankle contractures
MUSCLE, SOFT TISSUE:
Muscle amyotrophy
NEUROLOGIC:
[Central nervous system];
Delayed motor development (in some patients);
[Peripheral nervous system];
Proximal and distal asymmetric muscle weakness of the upper and lower
limbs;
Gait difficulties;
Frequent falls;
Areflexia;
Decreased motor nerve conduction velocities;
Decreased nerve amplitudes;
Sural nerve biopsy shows axonal loss;
Thinly myelinated nerve fibers;
Onion bulb formation;
De- and remyelination;
Distal sensory impairment
MISCELLANEOUS:
Onset usually in early childhood;
Adult onset may occur;
Variable severity;
Motor impairment more significant than sensory impairment;
Progressive disorder;
Some patients may become wheelchair-bound;
Trauma may accelerate symptoms
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae Fig4 gene (FIG4,
609390.0001)
OMIM Title
*611231 CLAUDIN 8; CLDN8
OMIM Description
DESCRIPTION
Claudins, such as CLDN8, are components of epithelial cell tight
junctions. Tight junctions regulate movement of solutes and ions through
the paracellular space and prevent mixing of proteins and lipids in the
outer leaflet of the apical and basolateral plasma membrane domains
(Acharya et al., 2004).
GENE FUNCTION
Using immunofluorescence microscopy, Kiuchi-Saishin et al. (2002)
localized Cldn8 to the thin ascending loop of Henle, distal tubule, and
collecting duct of mouse kidney. By immunofluorescence of mouse kidney
sections, Li et al. (2004) found that Cldn8 was expressed primarily at
the tight junction along the entire aldosterone-sensitive distal nephron
and in the late segments of the thin descending limbs of long-looped
nephrons.
Yu et al. (2003) generated Madin-Darby canine kidney cells with
inducible expression of mouse Cldn8. Induction of Cldn8 was associated
with downregulation of endogenous Cldn2 (300520). Cldn8 expression
reduced paracellular permeability to monovalent inorganic and organic
cations and to divalent cations, but not to anions or neutral
substrates. The results were consistent with a model in which CLDN2
encodes a highly cation-permeable channel, whereas CLDN8 acts primarily
as a cation barrier. Yu et al. (2003) suggested that CLDN8 plays an
important role in the paracellular cation barrier of the distal renal
tubule.
Using immunofluorescence microscopy, Acharya et al. (2004) showed that
Cldn4 (602909), Cldn8, and Cldn12 (611232) localized to the bladder
epithelium of rat, mouse, and rabbit. These claudins specifically
localized to tight junctions of the superficial umbrella cell layer,
consistent with the high-resistance, low-permeability barrier function
of this cell type.
Using immunohistochemical analysis, Dube et al. (2007) found that CLDN1
(603718), CLDN3 (602910), CLDN4 (602909), and CLDN8 were associated with
the blood-epididymal barrier of the epididymal duct. In all 3 epididymal
segments, CLDN1, CLDN3, and CLDN4 localized to tight junctions, along
the lateral margins of adjacent principal cells, and at the interface
between basal and principal cells. In contrast, CLDN8 localized to tight
junctions in all 3 segments, along the lateral margins of principal
cells in the caput, and at the interface between basal and principal
cells in the corpus.
MAPPING
By genomic sequence analysis, Katoh and Katoh (2003) mapped the CLDN8
gene to chromosome 21q22.11, where it is clustered with CLDN17.
KRTAP24-1
| dbSNP name | rs2832752(G,C); rs117273560(A,T); rs2832753(T,C); rs78287602(C,T); rs77638540(C,T); rs1557291(A,C) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 643803 |
| EntrezGene Description | keratin associated protein 24-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1313 |
KRTAP25-1
| dbSNP name | rs2832759(A,G); rs8127420(A,G) |
| ccdsGene name | CCDS46640.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 100131902 |
| EntrezGene Description | keratin associated protein 25-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP25-1:NM_001128598:exon1:c.T156C:p.G52G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1561 |
| ExAC AF | 0.142 |
KRTAP26-1
| dbSNP name | rs2236427(C,A); rs150667938(A,C); rs12483584(G,T); rs3804007(G,T); rs3804008(A,C); rs78731676(C,T) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 388818 |
| EntrezGene Description | keratin associated protein 26-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3196 |
KRTAP27-1
| dbSNP name | rs2244485(G,A); rs117534873(C,T) |
| ccdsGene name | CCDS33532.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 643812 |
| EntrezGene Description | keratin associated protein 27-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP27-1:NM_001077711:exon1:c.C296T:p.A99V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI81 |
| dbNSFP Uniprot ID | KR271_HUMAN |
| dbNSFP KGp1 AF | 0.308608058608 |
| dbNSFP KGp1 Afr AF | 0.164634146341 |
| dbNSFP KGp1 Amr AF | 0.350828729282 |
| dbNSFP KGp1 Asn AF | 0.22027972028 |
| dbNSFP KGp1 Eur AF | 0.448548812665 |
| dbSNP GMAF | 0.309 |
| ESP Afr MAF | 0.222197 |
| ESP All MAF | 0.396202 |
| ESP Eur/Amr MAF | 0.485349 |
| ExAC AF | 0.406 |
KRTAP13-2
| dbSNP name | rs76283726(C,A); rs3804010(G,C); rs61748317(G,A); rs8129087(C,T) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337959 |
| EntrezGene Description | keratin associated protein 13-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01653 |
KRTAP13-1
| dbSNP name | rs1985418(C,A); rs9636833(G,C) |
| ccdsGene name | CCDS13590.2 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 140258 |
| EntrezGene Description | keratin associated protein 13-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP13-1:NM_181599:exon1:c.C90A:p.Y30X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.00732600732601 |
| dbNSFP KGp1 Afr AF | 0.0284552845528 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.007346 |
| ESP Afr MAF | 0.029278 |
| ESP All MAF | 0.009995 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.002797 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Microcephaly (head circumference 3-11 S.D. below mean);
[Face];
Sloping forehead;
[Ears];
Congenital hearing loss (1 family)
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild to severe;
Delayed motor development;
Delayed language development;
Seizures (less common);
Agenesis of the corpus callosum (less common);
Small cerebral cortex;
Simplified cortical gyration pattern;
Enlarged ventricles;
Cortical dysplasia (2 patients);
[Behavioral/psychiatric manifestations];
Hyperactivity;
Attention deficit
MISCELLANEOUS:
Onset at birth;
Some patients may show mild decrease in head circumference over time
MOLECULAR BASIS:
Caused by mutation in the abnormal spindle-like, microcephaly-associated
gene (ASPM, 605481.0001)
OMIM Title
*608718 KERATIN-ASSOCIATED PROTEIN 13-1; KRTAP13-1
;;KAP13.1
OMIM Description
DESCRIPTION
Hair keratins and hair keratin-associated proteins (KAPs), such as
KRTAP13-1, are the main structural proteins of hair fibers (Rogers et
al., 2002).
CLONING
By searching databases using nonhuman KAP sequences as queries, followed
by screening a human scalp cDNA library, Rogers et al. (2002) cloned
KRTAP13-1, which they called KAP13.1. The deduced 172-amino acid protein
has a molecular mass of 18.3 kD. It has a high cysteine content (12.2
mol percent), classifying KAP13.1 as a high sulfur KAP. Both mouse and
human KAP13.1 contain C-terminal pentameric repeats. Mouse Kap13.1 also
contains a decameric repeat that is only partially conserved in human
KAP13.1. In situ hybridization detected KAP13.1 expression in the cortex
and dermal papillae of plucked beard follicles.
MAPPING
Rogers et al. (2002) mapped the KRTAP13-1 gene within a KAP gene cluster
on chromosome 21q22.1.
KRTAP13-4
| dbSNP name | rs2226548(G,A) |
| ccdsGene name | CCDS13592.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 284827 |
| EntrezGene Description | keratin associated protein 13-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP13-4:NM_181600:exon1:c.G175A:p.A59T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI77 |
| dbNSFP Uniprot ID | KR134_HUMAN |
| dbNSFP KGp1 AF | 0.524725274725 |
| dbNSFP KGp1 Afr AF | 0.660569105691 |
| dbNSFP KGp1 Amr AF | 0.646408839779 |
| dbNSFP KGp1 Asn AF | 0.291958041958 |
| dbNSFP KGp1 Eur AF | 0.554089709763 |
| dbSNP GMAF | 0.4757 |
| ESP Afr MAF | 0.364276 |
| ESP All MAF | 0.396586 |
| ESP Eur/Amr MAF | 0.41314 |
| ExAC AF | 0.569 |
KRTAP15-1
| dbSNP name | rs2832873(C,A) |
| ccdsGene name | CCDS13593.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 254950 |
| EntrezGene Description | keratin associated protein 15-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP15-1:NM_181623:exon1:c.C127A:p.L43M, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI76 |
| dbNSFP Uniprot ID | KR151_HUMAN |
| dbNSFP KGp1 AF | 0.52793040293 |
| dbNSFP KGp1 Afr AF | 0.668699186992 |
| dbNSFP KGp1 Amr AF | 0.646408839779 |
| dbNSFP KGp1 Asn AF | 0.297202797203 |
| dbNSFP KGp1 Eur AF | 0.554089709763 |
| dbSNP GMAF | 0.4729 |
| ESP Afr MAF | 0.355651 |
| ESP All MAF | 0.393972 |
| ESP Eur/Amr MAF | 0.413605 |
| ExAC AF | 0.57 |
KRTAP19-1
| dbSNP name | rs375731942(T,G) |
| ccdsGene name | CCDS13594.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337882 |
| EntrezGene Description | keratin associated protein 19-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP19-1:NM_181607:exon1:c.A189C:p.G63G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000154 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.0001955 |
KRTAP19-2
| dbSNP name | rs7280687(A,G) |
| ccdsGene name | CCDS13595.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337969 |
| EntrezGene Description | keratin associated protein 19-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP19-2:NM_181608:exon1:c.T13C:p.Y5H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0015 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LHN2 |
| dbNSFP Uniprot ID | KR192_HUMAN |
| dbNSFP KGp1 AF | 0.0224358974359 |
| dbNSFP KGp1 Afr AF | 0.0934959349593 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02204 |
| ESP Afr MAF | 0.067635 |
| ESP All MAF | 0.02322 |
| ESP Eur/Amr MAF | 0.000465 |
| ExAC AF | 0.006937 |
KRTAP19-3
| dbSNP name | rs2251071(G,C) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337970 |
| snpEff Gene Name | KRTAP19-2 |
| EntrezGene Description | keratin associated protein 19-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4715 |
KRTAP19-4
| dbSNP name | rs2298437(T,C) |
| ccdsGene name | CCDS33534.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337971 |
| EntrezGene Description | keratin associated protein 19-4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP19-4:NM_181610:exon1:c.A143G:p.Y48C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI73 |
| dbNSFP Uniprot ID | KR194_HUMAN |
| dbNSFP KGp1 AF | 0.570970695971 |
| dbNSFP KGp1 Afr AF | 0.835365853659 |
| dbNSFP KGp1 Amr AF | 0.671270718232 |
| dbNSFP KGp1 Asn AF | 0.325174825175 |
| dbNSFP KGp1 Eur AF | 0.536939313984 |
| dbSNP GMAF | 0.4298 |
| ESP Afr MAF | 0.251929 |
| ESP All MAF | 0.364293 |
| ESP Eur/Amr MAF | 0.42186 |
| ExAC AF | 0.583 |
KRTAP19-6
| dbSNP name | rs1023364(T,A) |
| ccdsGene name | CCDS13598.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337973 |
| EntrezGene Description | keratin associated protein 19-6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP19-6:NM_181612:exon1:c.A153T:p.G51G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2727 |
| ESP Afr MAF | 0.217431 |
| ESP All MAF | 0.265647 |
| ESP Eur/Amr MAF | 0.290349 |
| ExAC AF | 0.715,8.132e-06 |
KRTAP6-3
| dbSNP name | rs9305426(A,C) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337968 |
| EntrezGene Description | keratin associated protein 6-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP6-3:NM_181605:exon1:c.A152C:p.Y51S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI67 |
| dbNSFP Uniprot ID | KRA63_HUMAN |
| dbNSFP KGp1 AF | 0.527014652015 |
| dbNSFP KGp1 Afr AF | 0.617886178862 |
| dbNSFP KGp1 Amr AF | 0.671270718232 |
| dbNSFP KGp1 Asn AF | 0.300699300699 |
| dbNSFP KGp1 Eur AF | 0.569920844327 |
| dbSNP GMAF | 0.4738 |
| ESP Afr MAF | 0.402179 |
| ESP All MAF | 0.391127 |
| ESP Eur/Amr MAF | 0.385465 |
| ExAC AF | 0.597,8.134e-06 |
KRTAP22-1
| dbSNP name | rs198915(T,A) |
| ccdsGene name | CCDS13601.1 |
| CosmicCodingMuts gene | KRTAP22-1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337979 |
| EntrezGene Description | keratin associated protein 22-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP22-1:NM_181620:exon1:c.T77A:p.L26H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3MIV0 |
| dbNSFP Uniprot ID | KR221_HUMAN |
| dbNSFP KGp1 AF | 0.816391941392 |
| dbNSFP KGp1 Afr AF | 0.880081300813 |
| dbNSFP KGp1 Amr AF | 0.958563535912 |
| dbNSFP KGp1 Asn AF | 0.604895104895 |
| dbNSFP KGp1 Eur AF | 0.866754617414 |
| dbSNP GMAF | 0.1841 |
| ESP Afr MAF | 0.138448 |
| ESP All MAF | 0.110026 |
| ESP Eur/Amr MAF | 0.095465 |
| ExAC AF | 0.886,2.033e-04 |
KRTAP20-1
| dbSNP name | rs116971075(A,T) |
| ccdsGene name | CCDS13603.1 |
| CosmicCodingMuts gene | KRTAP20-1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337975 |
| EntrezGene Description | keratin associated protein 20-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP20-1:NM_181615:exon1:c.A23T:p.Y8F, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0023 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI63 |
| dbNSFP Uniprot ID | KR201_HUMAN |
| dbNSFP KGp1 AF | 0.0274725274725 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0359116022099 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0606860158311 |
| dbSNP GMAF | 0.02755 |
| ESP Afr MAF | 0.014299 |
| ESP All MAF | 0.040674 |
| ESP Eur/Amr MAF | 0.054186 |
| ExAC AF | 0.036,1.952e-04 |
KRTAP21-3
| dbSNP name | rs2833031(C,T) |
| ccdsGene name | CCDS54481.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 100288323 |
| EntrezGene Description | keratin associated protein 21-3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP21-3:NM_001164435:exon1:c.G170A:p.C57Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.279761904762 |
| dbNSFP KGp1 Afr AF | 0.434959349593 |
| dbNSFP KGp1 Amr AF | 0.157458563536 |
| dbNSFP KGp1 Asn AF | 0.493006993007 |
| dbNSFP KGp1 Eur AF | 0.0765171503958 |
| dbSNP GMAF | 0.2801 |
| ESP Afr MAF | 0.429913 |
| ESP All MAF | 0.162943 |
| ESP Eur/Amr MAF | 0.046826 |
| ExAC AF | 0.101 |
KRTAP21-2
| dbSNP name | rs12053674(C,G) |
| ccdsGene name | CCDS13605.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337978 |
| EntrezGene Description | keratin associated protein 21-2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP21-2:NM_181617:exon1:c.G26C:p.C9S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI59 |
| dbNSFP Uniprot ID | KR212_HUMAN |
| dbNSFP KGp1 AF | 0.202838827839 |
| dbNSFP KGp1 Afr AF | 0.325203252033 |
| dbNSFP KGp1 Amr AF | 0.0469613259669 |
| dbNSFP KGp1 Asn AF | 0.367132867133 |
| dbNSFP KGp1 Eur AF | 0.0738786279683 |
| dbSNP GMAF | 0.2034 |
| ESP Afr MAF | 0.32887 |
| ESP All MAF | 0.142934 |
| ESP Eur/Amr MAF | 0.047674 |
| ExAC AF | 0.097,8.134e-06 |
KRTAP8-1
| dbSNP name | rs2833101(G,A); rs1892667(T,G); rs145220071(G,A); rs7278128(A,G) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337879 |
| EntrezGene Description | keratin associated protein 8-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3526 |
KRTAP7-1
| dbSNP name | rs9305443(C,A); rs9982910(G,T); rs9982675(A,C); rs9982755(A,G); rs9982775(A,G) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337878 |
| snpEff Gene Name | AP000244.1 |
| EntrezGene Description | keratin associated protein 7-1 (gene/pseudogene) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02709 |
KRTAP11-1
| dbSNP name | rs112534515(G,T) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 337880 |
| EntrezGene Description | keratin associated protein 11-1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.00551 |
| ESP Afr MAF | 0.00386 |
| ESP All MAF | 0.011231 |
| ESP Eur/Amr MAF | 0.015007 |
| ExAC AF | 0.011 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural, prelingual;
Hearing loss affects all frequencies
NEUROLOGIC:
[Central nervous system];
Vestibular dysfunction;
Vertigo
MISCELLANEOUS:
Onset usually at birth, but may occur later;
Allelic disorder to autosomal dominant nonsyndromic sensorineural
deafness (DFNA11, 601317) and Usher syndrome type IB (276900)
MOLECULAR BASIS:
Caused by mutation in the myosin VIIA gene (MYO7A, 276903.0007)
OMIM Title
*600064 KERATIN-ASSOCIATED PROTEIN 11-1; KRTAP11-1
;;HAIR FOLLICLE-SPECIFIC GENE 1; HACL1
OMIM Description
CLONING
From a cDNA library of mouse skin, Huh et al. (1994) isolated a
hair-follicle-specific gene which they designated Hacl1. The gene was
expressed specifically in skin, and its mRNA level was correlated with
the active state of hair follicles in developmental and regenerative
processes of hair. Its mRNA was approximately 1 kb. The deduced amino
acid sequence showed 6 direct repeats of a decapeptide on the C-terminal
side. In situ hybridization showed that the gene is expressed
specifically in the keratogenous zone of the cortical cells of the hair
shaft.
MAPPING
By genomic sequence analysis, Pruett et al. (2004) mapped the mouse
Krtap11-1 gene to distal chromosome 16 and the human KRTAP11-1 gene to
chromosome 21q22.11, a region of conserved linkage.
KRTAP19-8
| dbSNP name | rs7279142(C,T); rs2833198(A,G) |
| ccdsGene name | CCDS42917.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 728299 |
| EntrezGene Description | keratin associated protein 19-8 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KRTAP19-8:NM_001099219:exon1:c.G181A:p.A61T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q3LI54 |
| dbNSFP Uniprot ID | KR198_HUMAN |
| dbNSFP KGp1 AF | 0.105769230769 |
| dbNSFP KGp1 Afr AF | 0.20325203252 |
| dbNSFP KGp1 Amr AF | 0.243093922652 |
| dbNSFP KGp1 Asn AF | 0.0716783216783 |
| dbNSFP KGp1 Eur AF | 0.00263852242744 |
| dbSNP GMAF | 0.1056 |
| ESP Afr MAF | 0.154127 |
| ESP All MAF | 0.053313 |
| ESP Eur/Amr MAF | 0.001862 |
| ExAC AF | 0.059 |
C21orf119
| dbSNP name | rs112644530(A,C); rs11702306(C,T); rs114692905(T,C); rs78714580(T,A) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 84996 |
| EntrezGene Description | chromosome 21 open reading frame 119 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.118 |
| ExAC AF | 0.076 |
IL10RB-AS1
| dbSNP name | rs999788(C,T) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 100288432 |
| snpEff Gene Name | IFNAR2 |
| EntrezGene Description | IL10RB antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2906 |
KCNE2
| dbSNP name | rs41260744(G,A); rs4817649(C,T); rs34532322(G,A); rs4816481(G,A); rs75101266(C,G); rs7281066(A,C); rs34281709(G,A); rs41314675(A,G); rs72550224(C,A); rs1010668(T,G); rs10854373(C,T); rs7278141(G,A); rs11700409(G,C); rs7278436(G,T); rs56307674(C,T); rs9984281(A,G); rs9305548(C,T); rs74315448(T,C) |
| ccdsGene name | CCDS13635.1 |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 9992 |
| EntrezGene Description | potassium voltage-gated channel, Isk-related family, member 2 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=9992&%3Brs=74315448|http://omim.org/entry/603796#0003 |
| Annovar Function | KCNE2:NM_172201:exon2:c.T170C:p.I57T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.747 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9Y6J6 |
| dbNSFP Uniprot ID | KCNE2_HUMAN |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=9992&%3Brs=74315448|http://omim.org/entry/603796#0003 |
| dbNSFP KGp1 AF | 0.00503663003663 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0034965034965 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.005051 |
| ESP Afr MAF | 0.000681 |
| ESP All MAF | 0.000384 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 0.0008782 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Brachycephaly;
Cranium bifidum, anterior;
[Eyes];
Hypertelorism;
Telecanthus;
Myopia (in some patients);
Ptosis (in some patients);
Corneal dermoid cyst (rare);
Glaucoma (rare);
Optic nerve hypoplasia, segmental (rare);
Persistent primary vitreous (rare);
[Nose];
Bifid nose;
Nostril notching;
Broad nasal tip;
Separation of nostrils;
[Mouth];
Carp-shaped mouth (in some patients);
Cleft lip;
Cleft palate
RESPIRATORY:
[Airways];
Upper airway obstruction, severe (in some patients)
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism (in some patients)
SKELETAL:
[Skull];
Persistent craniopharyngeal canal (rare);
Vertical clivus (in some patients);
[Limbs];
Patellar hypoplasia or aplasia (in some patients);
Tibial hypoplasia;
[Hands];
Preaxial polydactyly;
Preaxial polysyndactyly;
[Feet];
Preaxial polydactyly;
Talipes equinovarus
SKIN, NAILS, HAIR:
[Skin];
Vertical creases of plantar surface between first and second toes;
[Nails];
Clubbed, thickened nails of halluces (1 patient)
NEUROLOGIC:
[Central nervous system];
Encephalocele;
Agenesis of corpus callosum;
Hypoplasia of corpus callosum;
Ventricular dilatation;
Mental retardation;
Periventricular nodular heterotopia;
Choroid plexus cyst;
Septum pellucidum deficient or cavum;
Calcification of the falx;
Interhemispheric lipoma;
Absent olfactory bulbs;
Enlarged sella turcica;
Absence of anterior pituitary;
Fenestrated basilar artery;
Persistent falcine venous sinus;
Retrocerebellar cyst;
Seizures
ENDOCRINE FEATURES:
Hypopituitarism (in some patients)
MISCELLANEOUS:
Brain anomalies variable;
Four unrelated patients with ZSWIM6 mutations have been described
(last curated September 2014)
MOLECULAR BASIS:
Caused by mutation in the zinc finger SWIM domain-containing protein
6 (ZSWIM6, 615951.0001)
OMIM Title
*603796 POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 2;
KCNE2
;;MINIMUM POTASSIUM ION CHANNEL-RELATED PEPTIDE 1; MIRP1;;
MINK-RELATED PEPTIDE 1
OMIM Description
CLONING
Abbott et al. (1999) cloned and characterized KCNE2, a potassium channel
gene encoding MinK-related peptide-1 (MiRP1), a small integral membrane
subunit that assembles with the HERG gene product (KCNH2; 152427), a
pore-forming protein, to alter its function. Unlike channels formed only
with HERG, mixed complexes resemble native cardiac I(Kr) channels in
their gating, unitary conductance, regulation by potassium, and
distinctive biphasic inhibition by the class III antiarrhythmic E-4031.
MiRP1 is a small, 123-amino acid protein containing consensus sequences
for 2 N-linked glycosylation sites (asn6 and asn29) and 2 protein kinase
C-mediated phosphorylation sites (thr71 and ser74). Northern blot
analysis detected MiRP1 expression in heart and muscle.
MAPPING
Abbott et al. (1999) stated that the KCNE2 gene has been mapped to
chromosome 21q22.1 (GenBank GENBANK AP000052). They noted that KCNE1
(176261), the gene encoding MinK, was previously mapped to this site.
The 2 genes are arrayed in opposite orientation, separated by 79 kb.
Their open reading frames share 34% identity, and both are contained in
a single exon. This suggests that the KCNE2 and KCNE1 genes are related
through gene duplication and divergent evolution.
GENE FUNCTION
Roepke et al. (2009) demonstrated that both KCNE2 and KCNQ1 (607542)
were expressed and partially colocalized in human and mouse thyroid
glands with the basolaterally located Na(+)/I(-) symporter (NIS) that
mediates active I(-) transport, the first step in thyroid hormone
biosynthesis. Thyroid follicular epithelia in Kcne2 -/- mice showed
abnormal architecture, and Kcne2-deficient thyrocytes were flattened and
less abundant compared to wildtype. Using the rat thyroid-derived FRTL5
cell line, the authors detected endogenous expression of KCNQ1 and KCNE2
proteins that was upregulated by thyroid-stimulating hormone (TSH; see
188540) or its major downstream effector cAMP in the cell membrane
fraction. The authors identified a TSH-stimulated K(+) current in FRTL5
cells that bore the signature linear current-voltage relationship of
KCNQ1-KCNE2 channels and was inhibited by a KCNQ1-specific antagonist.
Kcne2 -/- pups nursing from Kcne2 -/- dams had an 87% reduction in
thyroid I(-) accumulation compared to wildtype pups. Roepke et al.
(2009) concluded that the potassium channel subunits KCNQ1 and KCNE2
form a TSH-stimulated constitutively active thyrocyte K(+) channel that
is required for normal thyroid hormone biosynthesis.
MOLECULAR GENETICS
To assess the potential role of MiRP1 in disturbances of heart rhythm,
Abbott et al. (1999) screened 250 patients (20 with drug-induced
arrhythmia and 230 with inherited or sporadic arrhythmias) with no
mutations in the known arrhythmia genes KCNQ1 (607542), HERG, SCN5A
(600163), and KCNE1. A control population of 1,010 individuals was also
evaluated. Three missense mutations associated with long QT syndrome
(LQT6; 613693) and ventricular fibrillation were identified in the KCNE2
gene (603796.0001-603796.0003). In addition, in 18 of 1,260 individuals
screened, an A-to-G polymorphism at nucleotide 22 produced a thr8-to-ala
substitution in the putative extracellular domain of MiRP1. This change
was found in 1 patient with quinidine-induced arrhythmia, 1 with
inherited or sporadic arrhythmia, and 16 controls. Channels formed with
mutant MiRP1 subunits and HERG showed slower activation, faster
deactivation, and increased drug sensitivity. One variant (603796.0001),
associated with clarithromycin-induced arrhythmia, increases channel
blockade by the antibiotic. A mechanism for acquired arrhythmia was
revealed in which genetically based reduction in potassium currents
remains clinically silent until combined with additional stressors.
These findings support a theory for arrhythmogenesis that invokes
superimposition of genetic and environmental factors acting in concert
to diminish progressively the capacity of cardiac ion channels to
terminate each action potential in normal fashion.
Splawski et al. (2000) screened 262 unrelated individuals with LQT
syndrome for mutations in the 5 defined genes (KCNQ1, KCNH2, SCN5A,
KCNE1, and KCNE2) and identified mutations in 177 individuals (68%).
KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%,
respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%,
3%, and 2%, respectively).
Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in
541 consecutive unrelated patients with LQT syndrome (average QTc, 482
ms). In 272 (50%) patients, they identified 211 different pathogenic
mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each
in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more
than 1,400 reference alleles. Among the mutation-positive patients, 29
(11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different
LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients
with multiple mutations were younger at diagnosis, but they did not
discern any genotype/phenotype correlations associated with location or
type of mutation.
In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used
DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2
genes for mutations and SNPs. Most of the patients (84%) showed a
complex molecular pattern, with an identified mutation associated with 1
or more SNPs located in several LQTS genes; 4 of the patients also had a
second mutation in a different LQTS gene (biallelic digenic inheritance;
see, e.g., 603796.0005).
ANIMAL MODEL
In a canine model of ischemic cardiomyopathy, Jiang et al. (2004)
observed an increase in the rapid delayed rectifier current, I(Kr),
density and a marked reduction in the KCNE2 protein level, although the
protein level of KCNH2, the I(Kr) pore-forming alpha subunit, was not
altered. Jiang et al. (2004) suggested that in the canine ventricle,
KCNE2 may associate with KCNH2 and suppress its current amplitude. In
aging rat ventricle, the pacemaker current density was increased, and
there was a significant increase in the Kcne2 protein level, whereas
changes in the main alpha-subunit (HCN2; 602781) of the pacemaker
current channel were not significant. Jiang et al. (2004) suggested that
in aging rat ventricle, Kcne2 may associate with Hcn2 and enhance its
current amplitude.
Roepke et al. (2009) performed targeted disruption of Kcne2 in mice and
observed impaired thyroid iodide accumulation up to 8-fold, impaired
maternal milk ejection, halved mild tetraiodothyronine (T4) content, and
halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism,
alopecia, goiter, and cardiac abnormalities including hypertrophy,
fibrosis, and reduced fractional shortening. The alopecia, dwarfism, and
cardiac abnormalities were alleviated by triiodothyroinine (T3) and T4
administration to pups, by supplementing dams with T4 before and after
they gave birth, or by feeding the pups exclusively from Kcne2 +/+ dams;
conversely, these symptoms were elicited in Kcne2 +/+ pups by feeding
exclusively from Kcne2 -/- dams.
C21orf140
| dbSNP name | rs61740755(G,C) |
| cytoBand name | 21q22.11 |
| EntrezGene GeneID | 101928147 |
| EntrezGene Symbol | LOC101928147 |
| snpEff Gene Name | AP000322.54 |
| EntrezGene Description | uncharacterized protein ENSP00000386791 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | C21orf140:NM_001282537:exon1:c.C394G:p.Q132E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.0805860805861 |
| dbNSFP KGp1 Afr AF | 0.0121951219512 |
| dbNSFP KGp1 Amr AF | 0.0635359116022 |
| dbNSFP KGp1 Asn AF | 0.185314685315 |
| dbNSFP KGp1 Eur AF | 0.0540897097625 |
| dbSNP GMAF | 0.08081 |
| ExAC AF | 0.073 |
CLIC6
| dbSNP name | rs76648061(G,C); rs74590375(C,G); rs74814002(T,A); rs79480381(C,T); rs115360995(A,G); rs113486028(A,G); rs76372104(A,T); rs75349331(G,A); rs75792337(G,A); rs59349099(T,C); rs1013559(T,A); rs28360610(A,G); rs7281533(T,C); rs62213791(T,A); rs8127812(C,T); rs8131533(A,C); rs1009925(T,C); rs2154443(G,A); rs2834575(G,A); rs118136616(C,T); rs2409531(A,G); rs2154444(T,G); rs11909168(G,A); rs116007846(T,C); rs7281040(C,T); rs7276506(C,T); rs2834576(C,A); rs2834577(C,T); rs2834578(C,T); rs2834579(G,A); rs2236610(C,G); rs2834580(A,G); rs7275340(G,A); rs118087975(A,G); rs2834581(A,G); rs13051128(C,T); rs56037873(G,T); rs143071838(A,G); rs62213793(C,T); rs2834582(C,T); rs717578(T,C); rs717579(A,G); rs762244(T,A); rs1075704(G,T); rs733014(G,A); rs2834585(T,C); rs2834586(G,A); rs2834587(G,C); rs2834588(A,C); rs35509244(G,A); rs56181027(G,A); rs55898205(C,G); rs73196808(C,G); rs1557271(T,C); rs60291063(G,C); rs116861658(T,C); rs2154447(A,G); rs2186287(C,A); rs36041034(A,G); rs2834590(G,A); rs2186288(G,A); rs7280979(T,C); rs7280196(G,A); rs2834591(T,C); rs13051939(G,A); rs12627157(C,T); rs2834592(G,A); rs4816498(A,T); rs73196816(G,A); rs13049495(A,G); rs73196818(C,T); rs16992167(C,A); rs35169899(C,T); rs2834593(T,C); rs62213847(T,C); rs2834596(C,T); rs2070367(G,A); rs6517252(A,T); rs6517253(A,G); rs6517254(C,T); rs2070368(T,C); rs2834597(G,A); rs11702251(G,T); rs3819041(C,G); rs8129452(A,G); rs2014474(T,C); rs138663268(G,A); rs58668017(T,C); rs116045263(A,G); rs12329815(T,C); rs2834599(C,T); rs11911845(T,C); rs56739017(G,A); rs2154446(C,T); rs60010589(A,T); rs115008561(G,A); rs190033895(G,A) |
| ccdsGene name | CCDS13638.1 |
| cytoBand name | 21q22.12 |
| EntrezGene GeneID | 54102 |
| EntrezGene Description | chloride intracellular channel 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLIC6:NM_053277:exon6:c.G1919A:p.R640K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6575 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96NY7 |
| dbNSFP Uniprot ID | CLIC6_HUMAN |
| dbNSFP KGp1 AF | 0.00915750915751 |
| dbNSFP KGp1 Afr AF | 0.0365853658537 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.009183 |
| ESP Afr MAF | 0.031094 |
| ESP All MAF | 0.01061 |
| ESP Eur/Amr MAF | 0.000116 |
| ExAC AF | 0.003277 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Low anterior hairline (in some patients);
[Ears];
Minor ear anomalies (in some patients);
[Eyes];
Strabismus (in some patients);
Blepharoptosis (in some patients);
[Teeth];
Malocclusion, class I/II (in some patients)
SKELETAL:
[Skull];
Coronal synostosis, unilateral or bilateral;
Sagittal synostosis;
[Hands];
Transverse palmar crease (in some patients);
Brachydactyly (in some patients);
[Feet];
Hallux valgus (in some patients);
Syndactyly between adjacent toes (in some patients)
SKIN, NAILS, HAIR:
[Hair];
Low anterior hairline (in some patients)
NEUROLOGIC:
[Central nervous system];
Learning disability (in some patients);
Developmental delay (in some patients);
Asperger syndrome (rare);
Autism (rare);
Prominent ventricles (in some patients);
Prominent CSF spaces (in some patients);
Agenesis of corpus callosum, partial or complete (rare)
MOLECULAR BASIS:
Caused by mutation in the transcription factor-12 gene (TCF12, 600480.0001)
OMIM Title
*615321 CHLORIDE INTRACELLULAR CHANNEL 6; CLIC6
;;CLIC1-LIKE; CLIC1L;;
PARCHORIN, RABBIT, HOMOLOG OF
OMIM Description
DESCRIPTION
At its C-terminal end, CLIC6 shares significant similarity with chloride
intracellular channels (CLICs; see 602872). However, CLIC6 has a long
N-terminal domain that is absent in other CLIC proteins (Friedli et al.,
2003).
CLONING
By RT-PCR, EST sequencing, and screening a heart cDNA library, Friedli
et al. (2003) obtained 2 splice variants of human CLIC6. The full-length
variant encodes a deduced 704-amino acid protein with a long N-terminal
domain, followed by 5 CLIC signature motifs and a transmembrane domain.
The N-terminal domain contains a 10-amino acid motif (consensus
AEGPAGDSVD) repeated 14 times. The shorter CLIC6 variant lacks exon 2
and encodes a deduced 687-amino acid protein. Friedli et al. (2003) also
cloned mouse Clic6, which lacks exon 2 and has significant differences
with exon 1 compared with human CLIC6. Exons 3 through 7 of human and
mouse CLIC6 encode sequences with 95% amino acid identity, but the
proteins share only 56% identity if exon 1 is included. The deduced
mouse protein contains only 1 motif similar to the 14 repeats found in
human CLIC6. In contrast, the rabbit ortholog of CLIC6, parchorin, has
an N-terminal repeat region similar to that of human CLIC6. RT-PCR and
Northern blot analyses of human tissues detected CLIC6 transcripts of
about 5 kb in lung and stomach and of about 6 kb in heart and muscle. In
mouse, Clic6 was expressed in brain, stomach, lung, kidney, testis, eye,
and day-9.5 mouse embryo.
GENE STRUCTURE
Friedli et al. (2003) determined that the CLIC6 gene contains 7 exons
and spans 48.8 kb. Exon 1 contains a 408-nucleotide segment that is GC
rich (76%), and exon 2 is alternatively spliced.
MAPPING
By genomic sequence analysis, Friedli et al. (2003) mapped the CLIC6
gene to chromosome 21q22.12, between the RCAN1 gene (602917) and the
RUNX1 gene (151385).
RUNX1-IT1
| dbSNP name | rs58980844(C,T); rs8126714(C,T); rs57214149(T,C); rs11701383(G,A) |
| ccdsGene name | CCDS13639.1 |
| cytoBand name | 21q22.12 |
| EntrezGene GeneID | 80215 |
| snpEff Gene Name | RUNX1 |
| EntrezGene Description | RUNX1 intronic transcript 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09963 |
HLCS
| dbSNP name | rs14407(C,T); rs73398120(T,C); rs73902720(G,T); rs9967991(G,A); rs73398122(A,G); rs149641058(C,T); rs13050215(A,G); rs2845804(A,C); rs3787739(C,T); rs3787740(T,C); rs147089807(G,A); rs3787741(G,A); rs79912201(C,A); rs2850103(C,A); rs2850104(C,A); rs2850105(A,G); rs114499760(G,A); rs115405267(G,A); rs116222192(C,T); rs2073418(T,C); rs2073419(G,A); rs2073420(C,T); rs74993434(G,A); rs116404220(C,G); rs16994424(C,T); rs2000549(C,T); rs2000550(C,A); rs2845805(A,C); rs2850106(T,G); rs2850107(G,A); rs57661928(G,C); rs75888019(T,C); rs61517864(C,T); rs2835453(C,T); rs2070523(G,C); rs6517380(T,C); rs4817820(T,C); rs149736764(C,T); rs2835454(C,T); rs10154119(C,T); rs56129442(G,A); rs2835455(T,A); rs2073421(C,A); rs73210783(G,A); rs113804566(T,G); rs2835457(T,C); rs116466122(G,A); rs2073422(A,C); rs114059033(T,C); rs2835458(G,T); rs7276595(G,A); rs116063726(G,A); rs78648145(C,T); rs116374110(T,A); rs17814272(C,T); rs6517381(C,T); rs60006581(A,G); rs2835459(A,T); rs144478601(C,A); rs146431826(T,G); rs4817821(G,C); rs16994438(C,G); rs3787749(C,T); rs8130689(G,T); rs3787750(G,T); rs73210788(C,T); rs8127710(T,C); rs115601169(G,A); rs114543309(C,A); rs59068235(C,T); rs74568769(T,C); rs9981318(C,T); rs9981651(G,A); rs73210790(G,A); rs79831813(T,C); rs7509790(G,A); rs73210791(G,A); rs8129637(T,C); rs116746174(A,G); rs1015017(C,T); rs9985116(C,T); rs73902726(C,A); rs9305605(T,C); rs145287784(A,G); rs13049750(G,A); rs7283417(G,A); rs4501027(T,C); rs9979967(C,T); rs7278768(C,G); rs79448421(G,T); rs73210796(G,A); rs60796757(G,A); rs4816549(G,A); rs71332551(T,C); rs12627476(C,T); rs12627519(G,A); rs113989441(G,A); rs6517382(T,C); rs7280602(C,G); rs36038593(T,C); rs7276860(C,A); rs2032320(G,A); rs2016223(T,C); rs999372(G,C); rs999373(G,A); rs116439232(G,A); rs3827185(C,T); rs3787751(T,C); rs1467857(T,C); rs74657780(T,C); rs73212604(C,T); rs73212605(G,C); rs9977855(G,A); rs9977713(A,G); rs73212607(A,T); rs8132225(T,C); rs73902731(T,C); rs35352430(A,G); rs79809750(T,C); rs56224528(C,T); rs55782146(C,T); rs116006580(C,A); rs34820991(C,T); rs2105752(C,T); rs73212663(A,T); rs9647072(G,T); rs766212(C,T); rs8129544(A,C); rs35524379(G,A); rs9977488(T,C); rs116676297(C,T); rs35737292(C,T); rs75973031(C,T); rs3787752(G,A); rs3827187(A,G); rs13050751(A,G); rs13052249(T,C); rs13047304(C,T); rs13047322(C,T); rs3787753(C,A); rs3787754(G,T); rs8127309(A,G); rs3787755(C,G); rs73212666(T,C); rs762369(A,G); rs13052574(C,A); rs73212667(C,T); rs73212668(C,T); rs2236434(C,G); rs187809137(C,T); rs8130179(A,G); rs57777181(T,C); rs73398179(G,A); rs73212670(G,A); rs116128874(C,T); rs61287652(G,A); rs1010385(C,T); rs73212671(T,G); rs8132325(A,G); rs8133029(A,G); rs2835460(T,C); rs13053024(G,A); rs115415596(G,C); rs112342872(G,A); rs745147(T,G); rs1041832(A,G); rs1984020(C,A); rs2835461(A,G); rs2835463(C,T); rs2835464(G,C); rs2835465(C,T); rs1029247(T,C); rs17228878(C,A); rs9978519(G,A); rs58534350(C,T); rs765321(G,T); rs2835466(A,G); rs111302162(G,C); rs16994503(G,C); rs2835468(A,G); rs16994508(C,T); rs8134293(G,T); rs8134067(C,A); rs8134086(A,C); rs112799820(G,A); rs2835469(A,G); rs73902735(G,A); rs7279818(G,C); rs2835471(G,A); rs73902736(G,A); rs148790802(T,C); rs7280357(G,A); rs78780077(G,A); rs2835472(G,C); rs2835474(G,A); rs73902739(C,T); rs116014259(C,A); rs12627335(C,T); rs1023409(C,A); rs74491975(G,A); rs12627703(A,G); rs2156419(G,A); rs3787756(A,G); rs3787757(G,A); rs1041437(C,T); rs3787759(G,C); rs6517384(A,G); rs79748030(A,C); rs3787760(G,A); rs7283871(G,C); rs2898305(T,C); rs2898306(A,G); rs111294666(G,T); rs112908943(C,G); rs7280746(T,C); rs74495662(C,A); rs7276082(G,C); rs7276265(G,A); rs113240125(C,T); rs73385218(C,T); rs10154239(C,T); rs79270002(G,A); rs56196910(T,C); rs113331369(T,A); rs67763267(T,A); rs56693235(G,T); rs2835476(A,C); rs73902742(A,T); rs12626955(G,A); rs2835477(A,T); rs79712988(T,A); rs7279278(T,C); rs112762286(C,T); rs78341590(T,C); rs4817822(T,C); rs73902746(G,C); rs62223785(G,A); rs16994521(C,T); rs60706135(T,C); rs8127560(T,C); rs67674700(C,G); rs3787763(G,A); rs139199455(C,T); rs2835478(A,C); rs78920764(C,T); rs2898307(A,G); rs144801019(C,G); rs2835479(G,T); rs76794540(C,A); rs201941377(C,A); rs56410700(T,C); rs16994530(G,A); rs11702134(C,T); rs12627666(A,T); rs2835480(T,G); rs56257944(G,A); rs55823704(G,A); rs2835481(T,C); rs73902750(G,A); rs73902751(G,A); rs116439412(G,A); rs2065303(A,T); rs2835482(C,T); rs73385247(T,C); rs9647169(A,G); rs12152092(G,A); rs79533197(C,T); rs56382534(A,G); rs55939706(G,A); rs75473182(T,C); rs2835483(T,C); rs2835484(G,C); rs73212691(C,T); rs2835485(G,A); rs76031744(C,A); rs2835486(A,C); rs2835487(A,G); rs2835488(G,A); rs2835489(C,T); rs76149794(C,T); rs185543317(A,T); rs8134687(T,C); rs1968034(G,C); rs1968035(C,A); rs17192962(A,G); rs2835491(T,G); rs2835493(G,A); rs2409842(T,C); rs377377704(G,A); rs2835495(C,T); rs2835496(T,C); rs2835497(A,G); rs10451759(T,G); rs2835498(G,A); rs2835500(T,C); rs17284196(G,C); rs7281668(C,G); rs76091776(C,T); rs2835501(A,C); rs11088365(T,G); rs2835502(G,C); rs2835503(C,T); rs12627303(A,G); rs12627662(G,C); rs112613370(G,C); rs114857143(C,T); rs113227979(A,G); rs111922523(G,A); rs144244177(A,G); rs7275322(T,C); rs115764338(T,C); rs2835505(G,T); rs2835506(T,C); rs8130235(C,A); rs11088366(A,T); rs140862258(G,A); rs1892912(T,G); rs13050480(A,C); rs7280984(T,C); rs3787764(G,A); rs3787765(C,G); rs79936191(G,A); rs75444750(G,A); rs2835507(G,A); rs59639440(T,C); rs77919773(C,T); rs6517385(G,A); rs75070416(G,A); rs62223830(C,T); rs7278053(G,A); rs2835508(C,T); rs79964423(G,A); rs116689579(G,A); rs55872312(T,G); rs6517386(C,G); rs35693831(C,A); rs8133376(C,T); rs7282868(C,T); rs2835509(T,G); rs6517388(T,C); rs6517389(G,A); rs8130485(C,G); rs8134083(C,G); rs4146071(C,T); rs1892913(A,G); rs78771762(G,A); rs77386678(C,A); rs2835511(G,A); rs34592171(G,A); rs2835513(C,T); rs138527463(C,T); rs11701035(G,A); rs11909707(G,A); rs2835515(G,A); rs148435541(T,C); rs3827188(C,G); rs115063063(C,T); rs2835516(C,T); rs2835517(C,G); rs2835518(A,G); rs115344053(C,A); rs8131697(G,T); rs8131323(A,G); rs11700783(G,A); rs117513334(T,C); rs73385297(G,A); rs34473124(T,A); rs76264291(T,C); rs8131843(C,T); rs12627285(T,C); rs4402840(C,A); rs2898312(T,C); rs2835519(A,G); rs57059082(A,C); rs2835520(G,A); rs2835521(A,G); rs73902776(G,A); rs73902778(T,C); rs8129291(C,T); rs12482724(A,G); rs9305606(A,G); rs9305607(T,A); rs9305608(G,C); rs181809068(G,A); rs4817823(C,A); rs4817824(T,A); rs8131621(A,G); rs4817825(T,G); rs13048483(G,A); rs3787767(G,A); rs3787768(T,C); rs148582850(G,T); rs73902781(A,T); rs11088368(T,G); rs112086529(T,C); rs7278010(G,A); rs7278191(G,A); rs75421902(G,A); rs62223858(C,T); rs8134282(T,C); rs59719220(G,A); rs7283004(C,T); rs61394091(C,T); rs4817826(C,T); rs11702434(C,T); rs112399470(C,A); rs78282766(G,A); rs13047682(A,G); rs2835523(A,G); rs2276230(A,G); rs13049458(C,T); rs111447600(C,T); rs8129140(A,G); rs2835524(C,T); rs7278981(G,A); rs2835525(G,A); rs2835526(C,T); rs6517390(A,C); rs113405071(G,A); rs2835527(A,G); rs2835528(G,A); rs2835529(C,T); rs60319560(C,T); rs61205494(C,T); rs9941899(C,T); rs115830729(G,A); rs13045992(T,C); rs1009778(G,A); rs186339131(A,G); rs143993094(C,T); rs7278038(A,T); rs114037647(G,A); rs80192854(T,C); rs725719(G,A); rs114327751(T,C); rs55887820(T,C); rs151165109(C,T); rs116563877(C,T); rs62225462(G,C); rs7279810(C,T); rs12626368(G,A); rs7276758(T,C); rs377444965(T,C); rs7276185(C,G); rs73389361(C,A); rs59642134(G,A); rs8132874(T,C); rs8132538(G,A); rs8132327(A,C); rs116403840(G,A); rs2835530(T,C); rs142994906(T,C); rs8126803(T,C); rs115998268(T,C); rs55774658(T,C); rs115715506(T,C); rs6517391(C,T); rs115650690(C,T); rs11911767(A,C); rs112268280(C,G); rs115524798(T,C); rs115232075(C,T); rs116750349(C,G); rs2845817(A,G); rs35822038(G,A); rs116784854(T,C); rs2845818(A,C); rs2835531(T,C); rs2835532(A,G); rs74945403(T,C); rs928845(T,C); rs113601081(C,A); rs6517394(C,G); rs2845819(T,C); rs8134742(C,T); rs114608505(T,C); rs16994586(C,T); rs2835533(T,A); rs2835534(A,T); rs2845811(C,T); rs114798710(C,T); rs2409865(A,T); rs2256034(T,G); rs138490961(G,A); rs74448937(A,G); rs189853831(G,A); rs141414469(T,G); rs73905404(A,G); rs2850118(T,C); rs59000754(C,T); rs2850119(T,C); rs2850120(G,C); rs2245325(A,G); rs79681988(G,T); rs74589113(T,A); rs2245349(C,T); rs2245353(G,A); rs56030686(A,T); rs55804329(T,A); rs2845812(C,T); rs2845813(C,A); rs2245447(C,A); rs2245524(C,A); rs2845816(A,G); rs762370(A,G); rs376528719(C,T); rs2835535(A,G); rs192456516(C,A); rs28420273(C,T); rs56408051(C,T); rs73905405(G,A); rs16994594(C,T); rs2073424(G,A); rs73905407(C,G); rs2073425(C,T); rs35066001(T,C); rs2282501(G,A); rs4817828(G,A); rs116772968(T,C); rs2409867(C,A); rs2409868(T,C); rs73905408(C,T); rs55954735(G,A); rs3787771(T,C); rs8132547(G,A); rs16994604(G,A); rs73905410(T,C); rs2835537(C,T); rs2835538(C,T); rs8134448(T,C); rs2835539(C,T); rs1065758(G,A); rs61732502(C,T); rs2230182(G,A); rs61732504(C,A); rs73904770(T,C); rs116148792(T,C); rs73904771(T,C); rs111843214(C,G); rs8126740(C,G); rs3827189(C,T); rs56071327(A,G); rs4816550(T,C); rs8129682(T,C); rs7282361(T,C); rs2409869(G,A); rs13050453(T,G); rs2835540(G,T); rs1012961(T,C); rs1012962(G,C); rs1986063(A,G); rs57883789(T,G); rs79482882(A,G); rs79811784(C,G); rs6517395(G,T); rs74449038(T,C); rs2845822(C,T); rs7283846(C,T); rs7276076(T,C); rs2835541(G,T); rs2835542(G,C); rs12627541(G,C); rs3827190(G,A); rs13047776(C,G); rs13048613(T,G); rs113605204(T,G); rs57661443(G,A); rs60634357(G,A); rs7276518(G,A); rs7276605(A,C); rs114633029(C,T); rs7280892(A,C); rs7280923(A,C); rs7281321(A,G); rs73387887(G,C); rs997627(C,A); rs1892916(T,C); rs7277523(G,T); rs115044869(A,G); rs7277447(A,G); rs2835543(C,T); rs2835544(G,A); rs2835545(G,A); rs4816551(C,T); rs2835546(A,C); rs373661026(C,T); rs16997934(C,A); rs2835547(T,G); rs2835548(T,A); rs2835549(T,C); rs60570221(C,T); rs2835550(C,T); rs2835551(C,T); rs9978381(T,C); rs6517396(G,A); rs76233378(T,C); rs2845814(G,A); rs369888(C,T); rs2250250(A,G); rs2032086(A,G); rs2843633(C,A); rs2032087(C,A); rs61027540(T,C); rs58870626(G,A); rs376553697(T,C); rs4817832(C,T); rs1007421(C,T); rs3035106(A,G); rs1007423(G,T); rs4817833(A,G); rs4816552(G,A); rs4816553(G,T); rs12626945(G,A); rs28873986(C,T); rs116206011(C,G); rs412162(C,T); rs73901977(G,C); rs76330918(C,T); rs727961(A,G); rs59683906(T,A); rs12482985(A,G); rs58365567(C,T); rs35980239(G,A); rs11701986(C,T); rs9981774(G,A); rs445437(C,G); rs1571700(A,G); rs1571701(C,G); rs1571702(T,C); rs4816555(G,A); rs4817835(T,C); rs73901979(G,T); rs12626528(G,C); rs12626531(G,A); rs12626619(T,G); rs12626655(T,C); rs28690635(G,T); rs58557562(G,A); rs8126588(G,A); rs10439668(T,C); rs35634082(T,C); rs12483456(C,A); rs762373(G,A); rs762374(G,A); rs762375(C,G); rs762376(C,T); rs9974970(C,T); rs1137981(C,T); rs1893653(C,G); rs2154529(A,G); rs183464197(T,C); rs35662085(A,G); rs13049080(G,C); rs4817836(T,G); rs73901981(G,A); rs141830357(C,T); rs74450243(A,T); rs13052315(A,G); rs10084551(T,C); rs56979531(T,C); rs10084553(T,G); rs28694191(C,T); rs13049125(A,G); rs13049535(G,A); rs9976746(C,T); rs13050438(T,C); rs4817838(C,A); rs4817839(G,A); rs2409870(C,T); rs1893654(T,C); rs67456731(C,T); rs1893655(T,G); rs8129634(A,G); rs73901987(A,G); rs73901988(C,G); rs8130063(A,G); rs12483284(A,G); rs9983516(T,C); rs13050617(G,A); rs13050516(C,A); rs11702480(G,A); rs11700650(T,C); rs55981408(T,C); rs28610288(A,C); rs9975027(C,T); rs73901992(T,C); rs9978378(T,C); rs2154530(G,A); rs8127236(C,T); rs8127595(G,A); rs7276371(C,T); rs7276406(A,C); rs28593435(T,C); rs7280358(A,C); rs11909178(C,G); rs11909152(A,G); rs9636908(T,C); rs181984990(G,A); rs9636909(C,G); rs2835552(C,T); rs7281251(A,G); rs7282422(T,C); rs2835553(G,A); rs77048259(G,A); rs2016215(G,A); rs2016219(T,C); rs2835554(T,C); rs4817840(T,G); rs4816557(G,A); rs2835555(C,T); rs2835556(A,G); rs2835557(G,T); rs6517397(A,G); rs7282108(A,C); rs28530(C,G); rs2409871(G,A); rs8130102(G,A); rs75424330(G,C); rs1893656(G,A); rs112817264(A,G); rs115646655(A,G); rs13051479(T,C); rs391554(C,T); rs2850121(T,A); rs2843961(G,A); rs8131293(C,T); rs73196097(T,A); rs59668379(A,G); rs148362612(C,T); rs58844217(G,A); rs59943709(C,T); rs59089170(G,A); rs58296537(G,C); rs57564744(T,C); rs61087329(C,T); rs57113705(G,A); rs73196100(A,G); rs112704922(T,C); rs55786952(A,C); rs78465198(A,C); rs55776054(T,A); rs58128008(A,C); rs73198004(C,T) |
| ccdsGene name | CCDS13647.1 |
| cytoBand name | 21q22.13 |
| EntrezGene GeneID | 3141 |
| EntrezGene Description | holocarboxylase synthetase (biotin-(proprionyl-CoA-carboxylase (ATP-hydrolysing)) ligase) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HLCS:NM_001242785:exon9:c.G1672A:p.E558K,HLCS:NM_000411:exon9:c.G1672A:p.E558K,HLCS:NM_001242784:exon9:c.G1672A:p.E558K, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5986 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P50747 |
| dbNSFP Uniprot ID | BPL1_HUMAN |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.004312 |
| ESP All MAF | 0.002845 |
| ESP Eur/Amr MAF | 0.002093 |
| ExAC AF | 0.002358 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Small for gestational age;
Failure to thrive
HEAD AND NECK:
[Eyes];
Pigmentary retinopathy (rare)
CARDIOVASCULAR:
[Heart];
Low-output cardiomyopathy;
Dilated cardiomyopathy;
Cardiac failure
RESPIRATORY:
Respiratory failure
ABDOMEN:
[Liver];
Hepatic dysfunction
MUSCLE, SOFT TISSUE:
Hypotonia;
Generalized weakness;
Slowly progressive limb-girdle myopathy;
Muscle pain;
Rhabdomyolysis, episodic
NEUROLOGIC:
[Central nervous system];
Poor spontaneous movements;
Delayed psychomotor development;
[Peripheral nervous system];
Sensorimotor axonopathy
METABOLIC FEATURES:
Lactic acidosis
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Hydrops fetalis;
[Maternal];
HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)
LABORATORY ABNORMALITIES:
Hypoketotic hypoglycemia;
Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase,
long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase;
Increased serum acylcarnitines;
Hyperammonemia;
Myoglobinuria;
Abnormal liver enzymes
MISCELLANEOUS:
Three major clinical forms are apparent;
Rapidly progressive neonatal onset with early death;
Infantile onset with hepatic involvement;
Childhood or adolescent onset, protracted, with myopathy and neuropathy;
Sudden infant death may occur;
Symptoms may be aggravated by acute illness;
Most patients die from heart failure
MOLECULAR BASIS:
Caused by mutation in the alpha subunit of the hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA
thiolase/enoyl-CoA hydratase (HADHA, 600890.0003);
Caused by mutation in the beta subunit of the hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA
thiolase/enoyl-CoA hydratase (HADHB, 143450.0001)
OMIM Title
*609018 HOLOCARBOXYLASE SYNTHETASE; HLCS
;;HCS
OMIM Description
DESCRIPTION
Holocarboxylase synthetase (EC 6.3.4.10) covalently links biotin to
propionyl-CoA carboxylase (PCCA; 232000), pyruvate carboxylase (PC;
608786), alpha-methylcrotonyl-CoA carboxylase (MCCC1; 609010), and
acetyl-CoA carboxylase (ACACA; 200350).
CLONING
Suzuki et al. (1994) cloned a human holocarboxylase synthetase cDNA and
showed that antiserum against the recombinant protein immunoprecipitated
the enzyme. Human HLCS shows homology with E. coli BirA, which acts as
both a biotin-(acetyl-CoA-carboxylase) ligase and a biotin repressor in
E. coli, suggesting a functional relationship between the 2 proteins.
Leon-Del-Rio et al. (1995) isolated a cDNA encoding human HLCS by
complementation of the E. coli BirA mutant defective in biotin ligase.
The predicted 726-amino acid protein has a molecular mass of
approximately 81 kD. Northern blot analysis detected a 5.8-kb major
transcript in all human tissues tested, with highest expression in
skeletal muscle, kidney, and pancreas. Several minor transcripts were
also detected. Several forms of the mRNA are generated by alternative
splicing, and as a result, 2 mRNA molecules bear different putative
translation initiation sites. A sequence upstream of the first
translation initiation site encoded a peptide structurally similar to
mitochondrial presequences, but it lacked an in-frame ATG codon to
direct its translation. Leon-Del-Rio et al. (1995) anticipated that
alternative splicing most likely mediates the mitochondrial versus
cytoplasmic expression, although the elements required for directing the
enzyme to the mitochondria remained to be confirmed.
GENE FUNCTION
Narang et al. (2004) showed that the majority of HCS localized to the
nucleus rather than to cytoplasm, based on immunofluorescence studies
with antibodies to peptides and full-length HCS and based on expression
of recombinant HCS. Subnuclear fractionation indicated that HCS was
associated with chromatin and the nuclear lamina, the latter in a
discontinuous distribution in high salt-extracted nuclear membranes.
During mitosis, HCS resolved into ring-like particles, which colocalized
with lamin B (LMNB1; 150340). Nuclear HCS retained its biotinylating
activity and was shown to biotinylate purified histones in vitro.
Fibroblasts from patients with HCS deficiency were severely deficient in
histone biotinylation in addition to being deficient in carboxylase
activity. Narang et al. (2004) proposed that the role of HCS in histone
modification may be linked to participation of biotin in the regulation
of gene expression or cell division, and that affected patients may have
additional disease beyond that due to the effect on carboxylases.
MAPPING
By fluorescence in situ hybridization, Suzuki et al. (1994) mapped the
HLCS gene to chromosome 21q22.1. The assignment to chromosome 21 was
confirmed by PCR analysis of a DNA panel of human/hamster hybrid somatic
cells. By fluorescence in situ hybridization, Zhang et al. (1997) also
mapped the HLCS gene to 21q22.1 in human and to chromosome 16 in the
mouse.
MOLECULAR GENETICS
In sibs with HLCS deficiency, Suzuki et al. (1994) demonstrated compound
heterozygosity for 2 mutations in the HLCS gene (609018.0001;
609018.0002).
In 9 patients with multiple carboxylase deficiency, Dupuis et al. (1996)
identified 6 novel point mutations in the HLCS gene (see, e.g.,
609018.0003). Two of the mutations were frequent. Aoki et al. (1999)
reported 7 mutations (3 missense, 2 single-bp deletions, a 3-base
in-frame deletion, and a 68-bp deletion) identified in the cDNA of 7
holocarboxylase synthetase deficiency patients from Europe and the
Middle East.
In a large-scale analysis of mutations in the HLCS gene in patients with
biotin-responsive multiple carboxylase deficiency, Yang et al. (2001)
found no panethnically prevalent mutations; the arg508-to-trp
(609018.0004), gly581-to-ser (609018.0005), and val550-to-met
(609018.0006) mutations were found in both Japanese and non-Japanese
populations; the IVS10+5G-A mutation (609018.0007) was predominant and
probably a founder mutation in European patients; and the 780delG
(609018.0001), leu237-to-pro (609018.0002), and 665insA (609018.0008)
mutations were unique in Japanese patients. Mutations found
predominantly among Japanese patients severely affected enzyme activity,
whereas most of the mutations found in the non-Japanese patients
retained residual HLCS activity.
In 4 patients with HLCS deficiency (2 Italian, 1 Iranian, and 1
Australian/Maori), Morrone et al. (2002) identified 6 mutations in the
HLCS gene, including 2 novel mutations. Five of the mutations were
localized within the HLCS biotin-binding domain, whereas one (L216R;
609018.0009) was located in the N-terminal region outside of the
putative biotin-binding domain. This mutation, previously reported in
heterozygous state, was detected for the first time in a patient with
homozygous status. The patient's severe clinical phenotype and partial
responsiveness to biotin supported a genotype-phenotype correlation
through the involvement of residues of the N-terminal region involved in
substrate specificity recognition or regulation of the HLCS enzyme.
Suzuki et al. (2005) reviewed the mutations and polymorphisms that have
been found in the HLCS gene and their clinical relevance.
LOC101928398
| dbSNP name | rs75893216(G,C); rs463032(C,T); rs455328(G,A); rs455426(G,C); rs1893203(C,T) |
| cytoBand name | 21q22.2 |
| EntrezGene GeneID | 101928398 |
| snpEff Gene Name | TMPRSS3 |
| EntrezGene Description | uncharacterized LOC101928398 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1056 |
BRWD1-IT2
| dbSNP name | rs115796978(G,T); rs4624474(T,C); rs9981349(A,G); rs1888488(C,T) |
| cytoBand name | 21q22.2 |
| EntrezGene GeneID | 257357 |
| snpEff Gene Name | NCRNA00257 |
| EntrezGene Description | BRWD1 intronic transcript 2 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01928 |
| ExAC AF | 0.001477 |
PLAC4
| dbSNP name | rs116763337(C,T); rs3804026(A,T); rs4818219(A,G); rs59066201(A,C); rs61736857(C,T); rs61735054(C,T); rs75611608(C,A); rs9977003(A,G); rs7844(G,C); rs9015(A,T); rs77315286(G,T); rs151273283(G,A); rs73902942(G,A); rs185410921(G,C); rs16998089(G,A); rs76961289(A,G); rs62217945(C,T); rs56862917(C,A); rs11909439(C,T); rs144837128(C,T); rs146756105(G,A); rs7278659(A,G); rs369137740(G,A); rs77865052(G,T); rs73902946(T,A); rs74742373(G,A); rs3949725(A,T); rs77922633(G,C); rs141536296(G,A); rs8130833(A,G) |
| ccdsGene name | CCDS13668.1 |
| cytoBand name | 21q22.2 |
| EntrezGene GeneID | 191585 |
| snpEff Gene Name | BACE2 |
| EntrezGene Description | placenta-specific 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 9.183E-4 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataract, posterior polar (in some patients);
Cataract, lamellar (in some patients);
Cataract, nuclear (in some patients);
Cataract, complete (in some patients);
Cataract, congenital (in some patients);
Cataract, juvenile-onset (in some patients);
Retinal dystrophy (rare)
MISCELLANEOUS:
One consanguineous family with homozygosity for a CRYAB mutation has
been reported (last curated April 2013)
MOLECULAR BASIS:
Caused by mutation in the gene encoding alpha-B crystallin (CRYAB,
123590.0002)
OMIM Title
*613770 PLACENTA-SPECIFIC GENE 4; PLAC4
OMIM Description
CLONING
By screening placenta cDNA libraries for sequences abundantly expressed
in placenta and choriocarcinomas, Kido et al. (1993) isolated PLAC4,
which they called D21S418E. Northern blot analysis detected a 10-kb
transcript in human term placenta, but not in brain, kidney, liver,
lung, pancreas, heart, skeletal muscle, or myometrium. PLAC4 was not
expressed in unstimulated choriocarcinoma cell lines, but stimulation
with a cAMP analog induced expression of 10- and 7.5-kb transcripts. In
situ hybridization localized PLAC4 to syncytiotrophoblasts. PLAC4 was
not expressed in cytotrophoblast cells nor in cells in the villous core.
MAPPING
By somatic cell hybrid analysis, Kido et al. (1993) mapped the PLAC4
gene to chromosome 21q22.3.
GENE FUNCTION
Tsui et al. (2010) found that analysis of PLAC4 can aid in the
noninvasive prenatal detection of trisomy 21 (190685) using maternal
plasma samples. PLAC4 is transcribed from chromosome 21 in the placenta
and is specific for the fetus in maternal plasma. One analytic method,
termed the RNA-SNP approach, measures the ratio of alleles for a SNP in
placenta-derived mRNA molecules in maternal plasma. The RNA-SNP approach
detected the deviated RNA-SNP allelic ratio in PLAC4 mRNA caused by an
imbalance in chromosome 21 dosage. In a study of 153 pregnant women, the
diagnostic sensitivity and specificity using this method was 100% and
89.7%, respectively. In fetuses homozygous for the SNP, a second
analytic approach was used, which quantifies circulating PLAC4 mRNA
concentrations. Trisomy 21 pregnancies showed significantly increased
plasma PLAC mRNA compared to unaffected pregnancies. The sensitivity and
specificity of this method were 91.7% and 81.0% using real-time PCR, and
83.3% and 83.5% using digital PCR. The overall findings suggested that
the synergistic use of these 2 methods will increase the yield of
correct diagnosis of trisomy 21 using noninvasive methods.
LRRC3
| dbSNP name | rs9982752(A,G); rs2838563(A,G); rs4818719(C,T); rs3804034(A,G) |
| cytoBand name | 21q22.3 |
| EntrezGene GeneID | 81543 |
| EntrezGene Description | leucine rich repeat containing 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2378 |
KRTAP10-4
| dbSNP name | rs457322(C,T); rs12627028(C,T) |
| ccdsGene name | CCDS13712.1 |
| cytoBand name | 21q22.3 |
| EntrezGene GeneID | 54084 |
| EntrezGene Symbol | TSPEAR |
| EntrezGene Description | thrombospondin-type laminin G domain and EAR repeats |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1258 |
KRTAP10-5
| dbSNP name | rs145497498(C,A); rs2020221(C,T) |
| ccdsGene name | CCDS13712.1 |
| cytoBand name | 21q22.3 |
| EntrezGene GeneID | 54084 |
| EntrezGene Symbol | TSPEAR |
| snpEff Gene Name | KRTAP10-4 |
| EntrezGene Description | thrombospondin-type laminin G domain and EAR repeats |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01102 |
SSR4P1
| dbSNP name | rs7279120(A,T); rs2838769(G,A); rs915814(G,A) |
| cytoBand name | 21q22.3 |
| EntrezGene GeneID | 728039 |
| snpEff Gene Name | ADARB1 |
| EntrezGene Description | signal sequence receptor, delta pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0 |
CCT8L2
| dbSNP name | rs5747988(A,G); rs150667617(G,A) |
| ccdsGene name | CCDS13738.1 |
| cytoBand name | 22q11.1 |
| EntrezGene GeneID | 150160 |
| EntrezGene Description | chaperonin containing TCP1, subunit 8 (theta)-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CCT8L2:NM_014406:exon1:c.T375C:p.A125A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1478 |
| ESP Afr MAF | 0.056968 |
| ESP All MAF | 0.062971 |
| ESP Eur/Amr MAF | 0.066047 |
| ExAC AF | 0.892 |
CECR6
| dbSNP name | rs11160(G,A); rs9605217(G,C); rs7289082(A,G); rs9606619(C,T); rs12170331(G,A); rs45618234(G,A); rs35597091(G,A); rs56758753(C,T); rs55654777(G,A); rs974396(A,G); rs80064237(G,A); rs738033(G,T); rs9605220(A,G) |
| cytoBand name | 22q11.1 |
| EntrezGene GeneID | 27439 |
| snpEff Gene Name | IL17RA |
| EntrezGene Description | cat eye syndrome chromosome region, candidate 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1901 |
LINC00528
| dbSNP name | rs12158080(A,G); rs73148873(G,C); rs10048897(T,C); rs454566(A,G); rs5992834(G,A); rs5992835(G,A); rs391085(T,C); rs5992836(A,T); rs73148875(T,C) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 200298 |
| snpEff Gene Name | BID |
| EntrezGene Description | long intergenic non-protein coding RNA 528 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02617 |
DGCR10
| dbSNP name | rs62230772(T,C) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 100506454 |
| EntrezGene Symbol | LOC100506454 |
| snpEff Gene Name | DGCR5 |
| EntrezGene Description | uncharacterized LOC100506454 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | antisense |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3278 |
DGCR2
| dbSNP name | rs5993478(G,A); rs117455748(G,A); rs2073776(C,T); rs6623(C,T); rs114514552(G,A); rs10160(A,G); rs41277588(A,G); rs2072123(A,G); rs5992353(C,A); rs2283641(C,T); rs9618453(C,G); rs2073775(T,C); rs2073774(T,C); rs115140378(C,G); rs6518515(A,G); rs6518517(A,G); rs118036702(G,T); rs715590(A,G); rs715598(C,G); rs117496675(G,C); rs60933748(T,C); rs1001896(G,A); rs2871009(T,C); rs376732751(T,C); rs114869872(T,C); rs2871010(C,T); rs5992354(T,C); rs2074004(C,T); rs2074003(G,C); rs190163619(C,T); rs6518518(C,T); rs5993480(G,T); rs117220916(C,T); rs5993481(A,G); rs8138035(A,G); rs5993482(A,G); rs5992356(G,A); rs116547990(T,C); rs5993483(C,A); rs113139469(T,G); rs5993485(G,A); rs117636177(T,C); rs112749344(G,A); rs149085651(G,A); rs45472592(T,A); rs58321659(C,T); rs5993487(A,G); rs61099651(G,A); rs2238736(A,G); rs150691855(T,C); rs2107298(G,C); rs2238738(C,A); rs114944502(C,T); rs2238739(A,G); rs62221717(G,A); rs2238741(C,G); rs2238742(T,C); rs115736039(T,A); rs2238743(T,G); rs2238745(C,T); rs2238746(A,G); rs2238747(A,G); rs5993488(G,A); rs9617765(A,G); rs45511793(C,A); rs2238748(T,C); rs114872214(G,A); rs1557844(T,C); rs1557845(A,G); rs115603832(G,A); rs2239396(C,G); rs2238749(G,T); rs17810768(C,T); rs5993490(G,T); rs117349060(G,A); rs17743576(T,C); rs5993492(T,C); rs5993493(C,T); rs5993494(A,G); rs114797005(C,G); rs2238750(A,G); rs2238752(C,T); rs117558618(T,C); rs362076(T,C); rs7286581(T,A); rs148731177(T,C); rs117839378(T,G); rs62221720(T,C); rs361585(T,C); rs147120955(A,G); rs1557847(A,G); rs6518523(G,T); rs2107299(G,A); rs5993501(T,C); rs11913040(T,C); rs11912407(G,A); rs148206438(C,T); rs5993502(A,G); rs5993503(T,C); rs187602491(G,A); rs62221721(A,G); rs5993504(A,G); rs5993505(C,T); rs5993506(C,T); rs5993507(A,G); rs115412990(G,A); rs5993508(G,C); rs184473767(A,G); rs62221745(C,T); rs28615873(T,C); rs928908(G,A); rs928909(A,C); rs928910(T,C); rs2525031(G,A); rs115028093(A,C); rs5993509(C,T); rs5993511(T,G); rs2854654(C,T); rs2525033(A,T); rs8138482(C,T); rs60317557(T,C); rs55944437(T,C); rs2027794(A,G); rs2027795(A,G); rs59837434(G,A); rs2238755(T,C); rs2800960(C,T); rs2800969(C,T); rs112529676(G,A); rs62221748(T,C); rs2793077(T,A); rs2800980(C,T); rs2793076(G,A); rs2800985(C,T); rs2854655(A,G); rs2793075(C,A); rs2793073(C,T); rs2793072(G,A); rs2793071(C,A); rs112030417(C,T); rs118189100(A,G); rs2854657(G,C); rs117135183(G,C); rs2525034(T,C); rs114033727(C,G); rs112482772(G,A); rs2800990(A,G); rs2793069(C,A); rs2153604(A,G); rs146351204(C,T); rs2525035(T,C); rs114068644(G,A); rs2525036(T,C); rs5993523(T,C); rs5993524(G,C); rs5993525(A,G); rs2854659(A,T); rs62221750(T,C); rs2525037(T,C); rs73158843(T,C); rs2525038(C,A); rs2793064(G,A); rs57259441(C,G); rs73158846(T,A); rs2800954(G,A); rs2800958(T,C); rs73388723(A,G); rs2800959(C,G); rs2793063(A,G); rs144546077(G,A); rs56262811(G,A); rs9604929(G,A); rs2158335(C,G); rs114491955(A,C); rs62221752(T,C); rs55696481(C,T); rs2800964(G,A); rs2800966(C,T); rs60970018(G,A); rs2800967(T,C); rs2525039(G,C); rs2154188(C,G); rs116658684(C,T); rs2800970(T,C); rs2800971(T,C); rs2800972(A,G); rs73158856(A,G); rs62221754(G,A); rs2189490(C,T); rs2189491(A,T); rs2096055(A,T); rs2096054(G,A); rs111330742(T,C); rs73158859(T,C); rs5993531(C,T); rs2066240(G,A); rs2105421(G,C); rs1034727(C,T); rs738905(T,A); rs2096377(T,G); rs2800981(G,A); rs2525079(T,C); rs2854661(C,G); rs5993533(A,G); rs1936953(C,G); rs113453892(A,G); rs1936952(A,C); rs2525075(T,A); rs115133094(C,T); rs2525076(T,C); rs2800986(G,A); rs115142889(G,A); rs117232487(C,T); rs807741(T,G); rs807742(T,C); rs807743(C,G); rs807744(A,T); rs807745(G,A); rs62221755(C,G); rs115198383(G,T); rs145692051(C,A); rs62221756(T,C); rs807749(G,T); rs811107(A,C); rs807750(A,G); rs807751(A,G); rs117290908(C,T); rs807752(G,T); rs807753(T,C) |
| ccdsGene name | CCDS33598.1 |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 9993 |
| EntrezGene Description | DiGeorge syndrome critical region gene 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intronic |
| dbNSFP LR score | 0.6153 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.00915750915751 |
| dbNSFP KGp1 Afr AF | 0.0345528455285 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.009183 |
| ESP Afr MAF | 0.027968 |
| ESP All MAF | 0.008894 |
| ESP Eur/Amr MAF | 0.000502 |
| ExAC AF | 0.002322 |
OMIM Clinical Significance
Limbs:
Amelia of arms;
Severe underdevelopment of legs
Inheritance:
Autosomal recessive
OMIM Title
%601362 DIGEORGE SYNDROME/VELOCARDIOFACIAL SYNDROME COMPLEX 2
;;DGS2
OMIM Description
The DiGeorge syndrome (DGS; 188400) and velocardiofacial syndrome (VCFS;
192430) may present many clinical problems, including cardiac defects,
hypoparathyroidism, T-cell immunodeficiency, and facial dysmorphism.
They are frequently associated with deletions within 22q11.2 (accounting
in part for the designation CATCH22), but a number of cases have no
detectable molecular defect of this region. Daw et al. (1996) stated
that a number of single case reports with deletions of 10p suggested
genetic heterogeneity of DGS. They compared the regions of hemizygosity
in 4 patients with terminal deletions of 10p (1 patient with
hypoparathyroidism and 3 with DGS) and 1 patient with VCFS and a large
interstitial deletion. Fluorescence in situ hybridization (FISH)
analysis demonstrated that these patients had overlapping deletions at
the 10p13/10p14 boundary. A YAC contig spanning the shortest region of
deletion overlap (SRO) was assembled and allowed the size of the SRO to
be approximated to 2 Mb. As with deletions of 22q11, phenotypes varied
considerably between affected patients. Daw et al. (1996) concluded that
the results strongly support the hypothesis that haploinsufficiency of a
gene or genes within 10p (DGS2 locus) can cause the DGS/VCFS spectrum of
malformations.
Schuffenhauer et al. (1998) performed FISH and PCR analyses in 12
patients with 10p deletions, 9 of them with features of DGS, and in a
familial translocation 10p;14q associated with midline defects. The
critical DGS2 region was defined by 2 DGS patients and mapped within a
1-cM interval including D10S547 and D10S585. The other 7 DGS patients
were hemizygous for both loci. The breakpoint of the reciprocal
translocation 10p;14q mapped at a distance of at least 12 cM distal to
the critical DGS2 region. Interstitial and terminal deletions described
in these patients were in the range of 10 to 50 cM and enabled the
tentative mapping of loci for ptosis and hearing loss, features that are
not part of the DGS clinical spectrum.
Bartsch et al. (1999) sought evidence for chromosomal microdeletions at
10p14-p13 in patients with the DGS/VCFS phenotype. In a series of
patients studied in Dresden, all with normal karyotypes, 22q11
microdeletions were found in 12, and no patient was found to have a
deletion of the critical region of 10p. Another series studied in Munich
included 22 patients with an unequivocal diagnosis of DGS and no
detectable deletion of 22q11. These patients had at least 2 of the 3
major DGS signs: conotruncal heart defect, T-cell deficiency, and
hypocalcemia/hypoparathyroidism. FISH analysis showed a dizygous pattern
in all of the patients, indicating no deletions at the 10p critical
region. On the basis of this study, Bartsch et al. (1999) suggested that
FISH service laboratories need not implement a screen for 10p
microdeletions among DGS/VCFS patients.
Lichtner et al. (2000) reported clinical and molecular deletion analysis
of a patient described by Hasegawa et al. (1997) and a new case, both
with the HDR phenotype: hypoparathyroidism, deafness, and renal
dysplasia (146255). They were found to have partial monosomy for 10p due
to terminal deletions with breakpoints between D10S585 and D10S1720. By
comparison with data previously published on patients with
DiGeorge/velocardiofacial syndrome associated with 10p monosomy,
Lichtner et al. (2000) concluded that this is a contiguous gene
syndrome. Hemizygosity for a proximal region can cause cardiac defects
and T cell deficiency; hemizygosity for a more distal region can cause
hypoparathyroidism, sensorineural deafness, and renal dysplasia.
Villanueva et al. (2002) determined that a genomic sequence including
the nebulette gene (NEBL; 605491) was heterozygously deleted in cell
lines derived from 2 female DGS2 patients with the proximal deletion of
chromosome 10p14-p13, which is associated with cardiac and craniofacial
abnormalities. One patient showed a cardiac defect, immune deficiency,
cleft palate, facial dysmorphia, and developmental delay. The other
showed microcephaly, microphthalmia, and hypotelorism. The NEBL gene was
not deleted in cell lines derived from 2 patients with the more distal
deletion of 10p14-p13, which is associated with HDR syndrome.
DGCR11
| dbSNP name | rs1051248(G,C); rs715539(A,C); rs2012929(A,G); rs2000996(A,G); rs62221693(G,A); rs115917550(G,A); rs41277590(G,A); rs2240102(T,C); rs62221712(G,A); rs73384864(T,C) |
| ccdsGene name | CCDS33598.1 |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 25786 |
| snpEff Gene Name | DGCR2 |
| EntrezGene Description | DiGeorge syndrome critical region gene 11 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2291 |
LINC01311
| dbSNP name | rs2298271(C,T); rs2298270(G,T) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 100652736 |
| EntrezGene Symbol | LOC100652736 |
| snpEff Gene Name | SLC25A1 |
| EntrezGene Description | uncharacterized LOC100652736 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1419 |
CLDN5
| dbSNP name | rs885985(G,A) |
| ccdsGene name | CCDS13763.2 |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 7122 |
| EntrezGene Description | claudin 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CLDN5:NM_001130861:exon1:c.C109T:p.Q37X,CLDN5:NM_003277:exon2:c.C109T:p.Q37X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.465659340659 |
| dbNSFP KGp1 Afr AF | 0.221544715447 |
| dbNSFP KGp1 Amr AF | 0.549723756906 |
| dbNSFP KGp1 Asn AF | 0.501748251748 |
| dbNSFP KGp1 Eur AF | 0.55672823219 |
| dbSNP GMAF | 0.4651 |
| ExAC AF | 0.432 |
OMIM Clinical Significance
Neuro:
Amyotrophic lateral sclerosis
Misc:
Juvenile onset;
Slow progression
Inheritance:
Autosomal recessive
OMIM Title
*602101 CLAUDIN 5; CLDN5
;;TRANSMEMBRANE PROTEIN DELETED IN VELOCARDIOFACIAL SYNDROME; TMVCF
OMIM Description
CLONING
Using exon trapping, Sirotkin et al. (1997) identified a novel short
fragment cDNA within the region of 22q11 that is commonly deleted in
patients with velocardiofacial syndrome (VCFS; 192430). They cloned a
corresponding full-length cDNA from a human infant brain library. The
gene, termed transmembrane protein deleted in velocardiofacial syndrome
(TMVCF), encodes a 219-amino acid protein with a predicted mass of 23
kD. The amino acid sequence has strong homology to the rat RVP.1 (rat
ventral prostate) protein, a prostate-specific protein whose function is
unknown. Computer analyses predicted 2 transmembrane domains.
Tight junctions (TJs) constitute continuous seals around cells that
serve as a physical barrier preventing solutes and water from passing
freely through the paracellular space. Claudins are components of TJ
strands. By sequence analysis, Morita et al. (1999) determined that
TMVCF is a member of the claudin family and designated it claudin-5.
When expressed in mammalian cells, an epitope-tagged claudin-5 was
concentrated at TJs.
Coyne et al. (2003) determined that human bronchi and bronchioles
express CLDN1 (603718), CLDN3 (602910), CLDN4 (602909), CLDN5, and CLDN7
(609131). CLDN1 and CLDN4 localized to the apical TJ region and in
lateral intercellular junctions, with staining surrounding basal cells
that anchor the columnar epithelium to the basal lamina. In contrast,
CLDN3 and CLDN5 localized exclusively to the apical-most region of the
TJs. CLDN7 colocalized with ZO1 (TJP1; 601009) in lateral intercellular
junctions, with little or no staining near TJs.
GENE FUNCTION
Following overexpression in mouse fibroblasts and human airway
epithelium, Coyne et al. (2003) found that claudins concentrated at cell
borders when cells achieved confluence. Mouse fibroblasts expressing
CLDN5 formed TJ strands composed primarily of particles and particle
arrays, similar to those seen in gap junctions, whereas fibroblasts
expressing CLDN1, CLDN3, or both formed TJ strands that lacked particle
arrays. Coyne et al. (2003) determined that CLDN1 and CLDN3 decreased
solute permeability in overexpressing cells, while CLDN5 increased
permeability. CLDN1 and CLDN3 existed predominantly in monomeric form in
human airway epithelium and in an airway epithelium cell line. In
contrast, CLDN5 existed predominantly in pentameric and hexameric
configurations. Coimmunoprecipitation studies revealed specific
heterophilic interactions that could form between these 3 claudins.
GENE STRUCTURE
Analysis of genomic DNA by Sirotkin et al. (1997) revealed that the
TMVCF gene contains no introns.
MAPPING
By use of yeast artificial chromosomes, Sirotkin et al. (1997) localized
the TMVCF gene between polymorphic markers D22S944 and D22S941 on
chromosome 22q11, both of which are deleted in more than 80% of VCFS
patients.
In the course of comparative mapping of the human 22q11 region in mice,
Puech et al. (1997) demonstrated that the Tmvcf gene is located on mouse
chromosome 16.
ANIMAL MODEL
In mice with experimental autoimmune encephalitis (EAE), a mouse model
of a central nervous system inflammatory disease, Argaw et al. (2009)
observed widespread breakdown of the blood-brain barrier (BBB)
associated with upregulation of astrocyte-derived Vegf (192240) and
decreased expression of Cldn5 and occludin (Ocln; 602876) in the
microvascular endothelium. VEGF was found to specifically downregulate
CLDN5 and OCLN mRNA and protein in cultured human brain microvessel
endothelial cells. Microinjection of VEGF in mouse cerebral cortex
disrupted Cldn5 and Ocln and induced loss of barrier function.
Functional studies revealed that expression of recombinant Cldn5
protected brain microvascular endothelial cell cultures from a
VEGF-induced increase in permeability, whereas recombinant Ocln
expressed under the same promoter was not protective. The findings
implicated VEGF-mediated disruption of endothelial CLDN5 as a
significant mechanism of BBB breakdown in the inflamed central nervous
system.
LINC00895
| dbSNP name | rs8138364(C,G); rs114135176(C,T) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 150185 |
| EntrezGene Description | long intergenic non-protein coding RNA 895 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1152 |
SEPT5-GP1BB
| dbSNP name | rs192285693(C,T) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 100526833 |
| snpEff Gene Name | GP1BB |
| EntrezGene Description | SEPT5-GP1BB readthrough |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 9.183E-4 |
| ExAC AF | 0.001797 |
ARVCF
| dbSNP name | rs9265(C,A); rs165655(G,A); rs165840(C,T); rs13056165(G,A); rs12329964(G,A); rs150464268(C,T); rs165824(G,A); rs165815(C,T); rs2073744(A,G); rs62223685(G,A); rs2518823(T,C); rs71313932(G,C); rs146960902(G,A); rs887199(A,G); rs1110477(C,T); rs1110478(C,T); rs1110479(T,C); rs12627876(C,T); rs2518824(G,T); rs887200(C,T); rs2240718(T,G); rs150842244(C,A); rs12158201(C,T); rs887204(G,A); rs12628032(C,T); rs9618723(C,T); rs2073748(G,A); rs2073747(A,G); rs2240717(A,G); rs9606202(G,A); rs2240716(C,T); rs2518825(G,T); rs2238780(C,G); rs1990277(G,A); rs2238781(G,T); rs2238782(A,G); rs9618724(C,T); rs758374(T,C); rs9606203(C,A); rs2238783(C,G); rs73150831(G,T); rs2238784(G,A); rs73150834(C,T); rs917478(T,C); rs917479(T,G); rs62223687(C,T); rs4819526(T,C); rs62223688(T,C); rs2238787(G,A); rs9606204(C,A); rs887201(C,G); rs756653(G,A); rs2012714(C,T); rs12485043(C,T); rs4819527(C,T); rs2073746(T,C); rs56138370(G,A); rs2238788(C,T); rs2238789(A,G); rs73150839(G,A); rs2238790(G,A); rs2238791(C,A); rs2238792(C,T); rs12165361(C,T); rs1034564(C,T); rs1034565(C,T); rs1034566(C,T); rs2531693(C,G); rs35845824(G,A); rs2073745(G,A); rs732596(C,T); rs7285377(G,T); rs2238793(C,G); rs2531694(A,C); rs4819852(G,A); rs2106140(G,A); rs2159268(G,C); rs2256984(T,C); rs2073743(C,G); rs2073742(A,G); rs2073741(C,T); rs9617857(G,T); rs9618725(T,C); rs12171109(G,A); rs2079701(A,G); rs6518596(G,A); rs886162(G,C); rs887202(A,G); rs887203(A,G); rs877118(C,T); rs1989843(G,A); rs1990276(G,C); rs2157730(C,T); rs8135174(T,C); rs2238794(C,G); rs2238795(G,C); rs2238797(C,T); rs2531696(C,T); rs2531697(T,C); rs4819853(A,G); rs138720731(T,C); rs55902548(G,T); rs1978233(T,G); rs2079702(G,A); rs9605047(G,T); rs62223726(C,T); rs2531714(C,G); rs2531698(G,A) |
| ccdsGene name | CCDS13771.1 |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 421 |
| EntrezGene Description | armadillo repeat gene deleted in velocardiofacial syndrome |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ARVCF:NM_001670:exon12:c.C1993T:p.R665C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5116 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.000457875457875 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 4.591E-4 |
| ESP Afr MAF | 0.000227 |
| ESP All MAF | 0.000231 |
| ESP Eur/Amr MAF | 0.000233 |
| ExAC AF | 4.149e-04,1.627e-05 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Short philtrum;
Frontal bossing;
[Ears];
Prominent ears;
Conductive hearing loss;
[Eyes];
Blepharophimosis;
Upslanting palpebral fissures;
[Nose];
Prominent nose;
[Mouth];
Thin lips;
Small mouth
CARDIOVASCULAR:
[Heart];
Tetralogy of Fallot
SKELETAL:
[Hands];
Long fingers;
Partial cutaneous syndactyly (2-3 fingers);
Fifth finger camptodactyly;
Fifth finger clinodactyly
SKIN, NAILS, HAIR:
[Skin];
Prominent veins (especially over scalp and limbs);
[Hair];
Sparse hair
MUSCLE, SOFT TISSUE:
Sparse subcutaneous fat
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios
OMIM Title
*602269 ARMADILLO REPEAT GENE DELETED IN VCFS; ARVCF
OMIM Description
CLONING
To identify genes in chromosome 22q11 that may contribute to the
phenotype of velocardiofacial syndrome (VCFS; 192430), Sirotkin et al.
(1997) used cDNA selection and cDNA library screening to clone the
full-length human 'armadillo repeat gene deleted in VCFS' (ARVCF) cDNA.
ARVCF encodes a 962-amino acid protein that contains 2 motifs involved
in protein-protein interactions: a coiled-coil domain near the N
terminus and 10 tandem armadillo repeats in the central region.
Comparison of the ARVCF sequence with protein databases showed that the
structure of ARVCF is most closely related to the catenin family.
Members of this family play important roles in the formation of adherens
junction complexes. These data suggest that ARVCF is involved in
protein-protein interactions at adherens junctions. Unlike other catenin
family members, ARVCF contains a nuclear localization signal (NLS),
suggesting that ARVCF functions as a nuclear protein. Northern blotting
showed that ARVCF is ubiquitously expressed as a 4.0- to 4.3-kb
transcript in fetal and adult tissues, and Southern blotting revealed
that ARVCF is conserved in vertebrates and Drosophila.
MAPPING
Sirotkin et al. (1997) mapped the ARVCF gene to chromosome 22 by
fluorescence in situ hybridization and to chromosome 22q11 using
physical mapping methods. ARVCF is located within the region of 22q11
that is hemizygous in all VCFS/DGS patients who have interstitial
deletions. Based on the physical location and potential functions of
ARVCF, Sirotkin et al. (1997) suggested that hemizygosity of ARVCF plays
a role in the etiology of some of the phenotypes associated with VCFS.
By FISH and analysis of a somatic cell hybrid mapping panel, Bonne et
al. (1998) confirmed the mapping of the ARVCF gene to chromosome 22q11.
MOLECULAR GENETICS
Frisch et al. (2001) found an association between anorexia nervosa (AN;
606788) and the COMT val158 allele (V158M; 116790.0001) in a
family-based study of 51 Israeli-Jewish AN trios. Gabrovsek et al.
(2004) could not replicate this finding in a combined sample of 372
European AN families, suggesting that the findings of Frisch et al.
(2001) were specific to a particular population and that val158 is in
linkage disequilibrium with other molecular variations in the COMT gene,
or its vicinity, which were the direct cause of genetic susceptibility
to anorexia nervosa. Michaelovsky et al. (2005) studied 85
Israeli-Jewish AN trios, including the original sample of Frisch et al.
(2001), comprising 66 anorexia nervosa restricting (AN-R) and 19
binge-eating/purging patients. They performed a family-based
transmission disequilibrium test (TDT) for 7 SNPs in the COMT-ARVCF
region including the V158M polymorphism. TDT analysis of 5-SNP
haplotypes in the AN-R group revealed overall statistically significant
transmission disequilibrium for 'haplotype B' (COMT 186C, 408G, 472G
[val158] and ARVCF 659C[pro220] and 524T[val175]) (P less than 0.001),
while 'haplotype A' (COMT 186T, 408C, 472A[met158] and ARVCF
659T[leu220] and 524C[ala175]) was preferentially not transmitted (P =
0.01). Haplotype B was associated with increased risk (RR of 3.38),
while haplotype A exhibited a protective effect (RR of 0.40) for AN-R.
Preferential transmission of the risk alleles and haplotypes from
parents was mostly contributed by fathers.
ANIMAL MODEL
Duplications of human chromosome 22q11.2 (608363) are associated with
elevated rates of mental retardation, autism, and many other behavioral
phenotypes. Suzuki et al. (2009) determined the developmental impact of
overexpression of a 190-kb segment of human 22q11.2, which includes the
genes TXNRD2 (606448), COMT (116790), and ARVCF, on behaviors in
bacterial artificial chromosome (BAC) transgenic mice. BAC transgenic
mice and wildtype mice were tested for their cognitive capacities,
affect- and stress-related behaviors, and motor activity at 1 and 2
months of age. BAC transgenic mice approached a rewarded goal faster
(i.e., incentive learning), but were impaired in delayed rewarded
alternation during development. In contrast, BAC transgenic and wildtype
mice were indistinguishable in rewarded alternation without delays,
spontaneous alternation, prepulse inhibition, social interaction,
anxiety-, stress-, and fear-related behaviors, and motor activity.
Compared with wildtype mice, BAC transgenic mice had a 2-fold higher
level of COMT activity in the prefrontal cortex, striatum, and
hippocampus. Suzuki et al. (2009) suggested that overexpression of this
22q11.2 segment may enhance incentive learning and impair the prolonged
maintenance of working memory, but has no apparent affect on working
memory per se, affect- and stress-related behaviors, or motor capacity.
High copy numbers of this 22q11.2 segment may contribute to a highly
selective set of phenotypes in learning and cognition during
development.
LINC00896
| dbSNP name | rs654389(G,C); rs75367243(G,A); rs627235(C,T); rs17818762(C,T) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 150197 |
| snpEff Gene Name | AC007663.1 |
| EntrezGene Description | long intergenic non-protein coding RNA 896 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4743 |
POM121L4P
| dbSNP name | rs5751736(A,T); rs5760036(C,T) |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 266697 |
| EntrezGene Description | POM121 transmembrane nucleoporin-like 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F5H5H7 |
| dbNSFP KGp1 AF | 0.623626373626 |
| dbNSFP KGp1 Afr AF | 0.782520325203 |
| dbNSFP KGp1 Amr AF | 0.610497237569 |
| dbNSFP KGp1 Asn AF | 0.520979020979 |
| dbNSFP KGp1 Eur AF | 0.604221635884 |
| dbSNP GMAF | 0.376 |
| ExAC AF | 0.658,4.686e-05 |
YDJC
| dbSNP name | rs710177(A,G) |
| ccdsGene name | CCDS33613.1 |
| CosmicCodingMuts gene | YDJC |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 150223 |
| EntrezGene Description | YdjC homolog (bacterial) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | YDJC:NM_001017964:exon1:c.T99C:p.A33A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | low |
| dbSNP GMAF | 0.432 |
| ESP Afr MAF | 0.387156 |
| ESP All MAF | 0.378311 |
| ESP Eur/Amr MAF | 0.373801 |
| ExAC AF | 0.426 |
SDF2L1
| dbSNP name | rs5998835(T,C); rs61739341(G,A); rs73166641(G,A) |
| ccdsGene name | CCDS13792.1 |
| cytoBand name | 22q11.21 |
| EntrezGene GeneID | 150223 |
| EntrezGene Symbol | YDJC |
| EntrezGene Description | YdjC homolog (bacterial) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SDF2L1:NM_022044:exon3:c.G482A:p.R161H, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7859 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HCN8 |
| dbNSFP Uniprot ID | SDF2L_HUMAN |
| dbNSFP KGp1 AF | 0.00869963369963 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.0165745856354 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0145118733509 |
| dbSNP GMAF | 0.008724 |
| ESP Afr MAF | 0.005674 |
| ESP All MAF | 0.011687 |
| ESP Eur/Amr MAF | 0.014767 |
| ExAC AF | 0.011 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Reduced visual acuity;
Halos around lights;
Glare;
Gray, crumb-like granular deposits in anterior third of stroma;
Granular deposits replace epithelial basement membrane;
Deeper, fusiform lattice deposits develop later;
Foreign body sensation if erosions occur;
Recurrent erosions uncommon;
Histopathology shows hyaline changes consistent with granular dystrophy
in the anterior stroma;
Histopathology shows fusiform amyloid deposits in the deeper stroma
as seen in lattice dystrophy
MISCELLANEOUS:
Deposits may recur in graft after corneal transplantation;
Allelic to Groenouw type 1 corneal dystrophy (121900), Thiel-Behnke
corneal dystrophy (602082), lattice type 1 corneal dystrophy (122200),
lattice type IIIA corneal dystrophy (608471), and Reis-Bucklers
type corneal dystrophy (608470)
MOLECULAR BASIS:
Caused by mutations in the transforming growth factor, beta-induced,
68kD gene (TGFBI, 601692.0004)
OMIM Title
*607551 STROMAL CELL-DERIVED FACTOR 2-LIKE 1; SDF2L1
;;SDF2-LIKE 1
OMIM Description
CLONING
While investigating radiation-induced gene expression in mouse
hepatocellular carcinoma cells, Fukuda et al. (2001) isolated a clone
showing similarity to Sdf2 (602934), and they obtained the full-length
mouse cDNA. Using this cDNA as probe, they cloned SDF2L1 from a human
testis cDNA library. The deduced human and mouse proteins contain 221
amino acids and share 88% sequence identity. SDF2L1 has an N-terminal
hydrophobic signal sequence and an endoplasmic reticulum (ER)
retention-like motif (HDEL) at the C terminus. SDF2 and SDF2L1 show
significant similarity to the central hydrophilic regions of POMT1
(607423), POMT2 (607439), the O-mannosyltransferase family of S.
cerevisiae and C. albicans, and the rt protein of Drosophila. Northern
blot analysis detected ubiquitous expression of Sdf2l1 in mouse tissues,
with strong expression in testis, ovary, and uterus, and weak expression
in heart and skeletal muscle. Northern blot analysis of human tissues
revealed strong expression in testis, moderate expression in pancreas,
spleen, prostate, small intestine, and colon, and low expression in
brain and skeletal muscle.
GENE FUNCTION
Fukuda et al. (2001) noted that several ER resident proteins are stress
proteins that increase expression in an 'unfolded protein response' that
is activated by disruption of protein synthesis or calcium homeostasis.
They found that Sdf2l1 was upregulated in a mouse hepatocellular
carcinoma cell line following treatment with tunicamycin, an N-linked
glycosylation inhibitor, or with A23187, a calcium ionophore. Heat
stress weakly increased Sdf2l1 expression, and cycloheximide, a protein
synthesis inhibitor, had no effect.
GENE STRUCTURE
Fukuda et al. (2001) determined that the SDF2L1 gene contains 3 exons
and spans about 2 kb.
MAPPING
By genomic sequence analysis, Fukuda et al. (2001) mapped the SDF2L1
gene to chromosome 22q11.2.
VPREB1
| dbSNP name | rs11089977(A,G); rs11089978(T,C); rs5995719(C,T); rs5995720(G,A); rs6001563(A,G) |
| cytoBand name | 22q11.22 |
| EntrezGene GeneID | 7441 |
| EntrezGene Description | pre-B lymphocyte 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| dbNSFP LR score | 0.0 |
| snpEff Effect | start_lost |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.0892857142857 |
| dbNSFP KGp1 Afr AF | 0.189024390244 |
| dbNSFP KGp1 Amr AF | 0.0414364640884 |
| dbNSFP KGp1 Asn AF | 0.129370629371 |
| dbNSFP KGp1 Eur AF | 0.0171503957784 |
| dbSNP GMAF | 0.08953 |
| ESP Afr MAF | 0.194507 |
| ESP All MAF | 0.077195 |
| ESP Eur/Amr MAF | 0.017093 |
| ExAC AF | 0.058 |
OMIM Clinical Significance
INHERITANCE:
Isolated cases
GROWTH:
[Height];
Short stature (of varying degrees);
[Other];
Poor growth in infancy;
Failure to thrive
HEAD AND NECK:
[Face];
Flat face;
Long philtrum;
[Ears];
Low-set ears;
Dysmorphic ears;
[Eyes];
Hypertelorism;
Strabismus;
Epicanthal folds;
Narrow palpebral fissures;
Downslanting palpebral fissures;
Thick eyebrows;
Synophrys;
Long eyelashes (in some patients);
[Nose];
Broad nose;
[Mouth];
Thin upper lip;
High-arched palate;
Cupid's bow, exaggerated (in some patients)
ABDOMEN:
[Gastrointestinal];
Constipation (in some patients)
SKELETAL:
Delayed bone age (in some patients);
[Hands];
Short fingers;
Fifth finger clinodactyly;
Short middle phalanges;
Tapering fingers (in some patients);
[Feet];
Short toes
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple (in some patients);
[Hair];
Thick eyebrows;
Hairy elbows;
Hypertrichosis, patchy (in some patients);
Hypertrichosis, generalized (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia;
Slim, muscular build (in some patients);
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures (1 patient);
Wide-based gait;
Speech delay;
[Behavioral/psychiatric manifestations];
Aggressive behavior;
Autistic features
MISCELLANEOUS:
Hairy elbows become apparent in infancy and regress during adolescence;
Facial appearance becomes more apparent with age
MOLECULAR BASIS:
Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia
gene (MLL, 159555.0001)
OMIM Title
*605141 PRE-B-LYMPHOCYTE GENE 1; VPREB1
;;VPREB; IGVPB;;
IMMUNOGLOBULIN IOTA POLYPEPTIDE CHAIN; IGI
OMIM Description
CLONING
A gene designated VPREB has been found to be highly conserved in many
mammalian species (Kudo and Melchers, 1987; Bauer et al., 1988). Its
structure, which has been determined in mouse and man, shows regional
homologies to variable regions of heavy and light chains of
immunoglobulin. VPREB in mouse and man, and lambda-5 in mouse, are
expressed in pre-B lymphocytes, but not in mature B cells or in other
blood cell lineages. Neither gene is rearranged during B-cell
development.
MAPPING
In the mouse Vpreb is situated 4.6 kb upstream of another gene, called
lambda-5 (IGLL1; 146770), which shows strong regional homologies to
lambda light-chain genes (Kudo and Melchers, 1987). Both genes are
located on mouse chromosome 16, which also carries the lambda
light-chain genes. By Southern blot analysis of restriction
enzyme-digestive DNAs from a panel of mouse-human somatic cell hybrids,
Bauer et al. (1988) demonstrated that the human equivalent of VPREB is
located in band 22q11.2, distal to BCR2 and proximal to BCR4. The order
of loci on chromosome 22 is centromere--BCR2, IGVPB,
V(lambda-1)--BCR4--C(lambda)--BCR1--BCR3--SIS.
GENE FUNCTION
The VpreB and lambda-5 genes encode the iota and omega polypeptide
chains, respectively (Pillai and Baltimore, 1988), which associate with
the Ig-mu chain to form a molecular complex that is expressed on the
surface of pre-B cells. This complex presumably regulates Ig gene
rearrangements in the early steps of B-cell differentiation. In the
mouse the 2 genes are simultaneously expressed in pre-B cells, are only
4.6 kb apart, and belong to the same transcription unit. A primary
transcript is synthesized from which the pre-B and lambda-5 mRNAs are
derived by alternative splicing. In the human, however, Mattei et al.
(1991) concluded that the 2 genes are separate: the pre-B homolog lies
proximal to the BCR (151410) breakpoint in chronic myeloid leukemia
(CML; 608232) and the lambda-5 homolog lies distal to the breakpoint in
CML.
MIR650
| dbSNP name | rs5996397(C,G) |
| cytoBand name | 22q11.22 |
| EntrezGene GeneID | 723778 |
| snpEff Gene Name | IGLV3-9 |
| EntrezGene Description | microRNA 650 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | IG_V_gene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1469 |
| ESP Afr MAF | 0.307668 |
| ESP All MAF | 0.202647 |
| ESP Eur/Amr MAF | 0.156635 |
| ExAC AF | 0.150,8.158e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
SKELETAL:
[Feet];
Pes cavus;
Hammertoes;
Foot deformities
MUSCLE, SOFT TISSUE:
Neurogenic atrophy seen on muscle biopsy
NEUROLOGIC:
[Central nervous system];
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Lower limbs more severely affected than upper limbs;
Distal sensory impairment;
Areflexia;
Decreased motor nerve conduction velocities;
Sural nerve biopsy shows thin myelination;
Loss of large myelinated fibers
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Variable age at onset (range childhood to adult)
MOLECULAR BASIS:
Caused by mutation in the pleckstrin homology domain-containing protein,
family G, member 5 gene (PLEKHG5, 611101.0002)
OMIM Title
*615379 MICRO RNA 650; MIR650
;;miRNA650
OMIM Description
DESCRIPTION
MicroRNAs (miRNAs), such as MIR650, are small noncoding regulatory RNAs
that bind to complimentary sites in the 3-prime UTRs of target mRNAs and
either inhibit their translation or direct their degradation (Zhang et
al., 2010).
GENE FUNCTION
Zhang et al. (2010) found that expression of MIR650 in 60 paired gastric
cancer tissues was associated with significant lymphatic and distant
metastasis, but not with tumor size, stage, differentiation, or
invasion. Overexpression of MIR650 promoted growth in NCI-N87 gastric
cancer cells in culture and increased the frequency of tumor formation
and tumor size in xenografts of NCI-N87 cells in nude mice. Conversely,
inhibition of MIR650 reduced cell growth and clonogenicity.
Bioinformatic analysis predicted an MIR650-binding site in the 3-prime
UTR of ING4 (608524), a tumor suppressor gene. Transfection of MIR650
precursor into HEK293 cells reduced protein content of ING4, whereas
inhibition of MIR650 increased expression of a reporter gene containing
the ING4 3-prime UTR.
GENE STRUCTURE
Mraz et al. (2012) reported that the MIR650 gene is located within the
leader exon (exon 1) of the immunoglobulin (Ig) lambda light chain
variable genes of the V2 family (see 147240). By expression analysis in
chronic lymphocytic leukemia (CLL) samples and bioinformatic analysis,
they found that MIR650 and its host gene used the same promoter region
for their transcription. However, since MIR650 could also be expressed
in cell types other than B cells, Mraz et al. (2012) suggested that the
promoter serves as a potent enhancer element for MIR650.
MAPPING
Hartz (2013) mapped the MIR650 gene to chromosome 22q11.22 based on
alignment of the mature MIR650 sequence (AGGAGGCAGCGCUCUCAGGAC) with the
genomic sequence (GRCh37).
DDT
| dbSNP name | rs79966373(C,G); rs79213832(A,G); rs1006771(G,T) |
| ccdsGene name | CCDS13820.1 |
| cytoBand name | 22q11.23 |
| EntrezGene GeneID | 100037417 |
| EntrezGene Symbol | DDTL |
| EntrezGene Description | D-dopachrome tautomerase-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08356 |
| ESP Afr MAF | 0.172688 |
| ESP All MAF | 0.095488 |
| ESP Eur/Amr MAF | 0.061911 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
OMIM Title
*602750 D-DOPACHROME TAUTOMERASE; DDT
OMIM Description
DESCRIPTION
D-dopachrome tautomerase (DDT) converts D-dopachrome into
5,6-dihydroxyindole (summary by Nishihira et al., 1998).
CLONING
By screening a liver library with a rat D-dopachrome tautomerase cDNA,
Nishihira et al. (1998) identified cDNAs encoding human DDT. The
sequence of the predicted 118-amino acid DDT protein is 80% identical to
that of the rat protein. The molecular mass of recombinant DDT expressed
in bacterial cells was 13 kD by SDS-PAGE. Northern blot analysis
revealed that DDT was expressed as a 0.6-kb mRNA in all tissues tested,
with the strongest expression in liver.
GENE FUNCTION
Using site-directed mutagenesis, Nishihira et al. (1998) showed that the
N-terminal proline is essential for D-dopachrome tautomerization.
GENE STRUCTURE
Esumi et al. (1998) found that the DDT gene in human and mouse is
identical in exon structure to the MIF gene (153620). Both genes have 2
introns that are located at equivalent positions relative to a 2-fold
repeat in protein structure. Although in similar positions, the introns
are in different phases relative to the open reading frame. Other
members of this superfamily exist in nematodes and a plant, and a
related gene in C. elegans shares an intron position with MIF and DDT.
MAPPING
In addition to similarities in structure, the genes for DDT and MIF are
closely linked on human chromosome 22 and mouse chromosome 10. Esumi et
al. (1998) demonstrated the close linkage by anaphase fluorescence in
situ hybridization in the human. The DDT gene was mapped in the mouse by
interspecific backcross analysis.
POM121L9P
| dbSNP name | rs113852497(G,A); rs71318973(G,T) |
| cytoBand name | 22q11.23 |
| EntrezGene GeneID | 644079 |
| EntrezGene Symbol | BCRP1 |
| EntrezGene Description | breakpoint cluster region pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02433 |
MYO18B
| dbSNP name | rs114839997(G,A); rs5761163(A,G); rs133852(T,C); rs2743840(T,C); rs6004750(C,T); rs133854(T,G); rs6004751(C,T); rs115646552(A,C); rs133856(A,C); rs133858(C,G); rs147872874(A,C); rs133859(G,A); rs133860(C,T); rs144929260(C,A); rs133863(T,C); rs114888135(C,T); rs11090409(T,G); rs133865(T,C); rs6004753(C,T); rs6004754(G,A); rs6004755(A,G); rs6004756(G,A); rs11704164(C,T); rs2331155(T,C); rs2331156(T,C); rs2331157(T,C); rs133867(C,T); rs9620553(T,C); rs11704257(C,A); rs13058625(G,A); rs133869(T,A); rs9613013(A,G); rs5761165(C,T); rs112723336(T,G); rs59102982(C,T); rs133871(A,G); rs6004757(C,T); rs133872(C,G); rs133873(T,A); rs133874(A,G); rs133875(A,C); rs133876(G,A); rs12158009(C,T); rs61734946(C,G); rs3859865(G,A); rs133882(T,C); rs2331158(C,G); rs200574321(T,C); rs133885(G,A); rs133886(A,C); rs118015847(A,G); rs133887(G,A); rs133888(A,C); rs133889(G,C); rs16980690(C,G); rs133890(C,G); rs133891(A,G); rs12628806(T,A); rs133892(C,T); rs133893(C,T); rs133894(A,G); rs133896(G,A); rs61654192(T,G); rs2743843(G,A); rs16986612(G,C); rs75663127(T,C); rs145010398(C,T); rs4822648(T,C); rs5761167(T,A); rs4820654(A,G); rs78152601(C,G); rs4822649(C,A); rs4822650(T,C); rs133901(T,C); rs133902(C,T); rs41281569(A,G); rs2748221(T,C); rs6004762(C,T); rs2743845(G,A); rs133903(C,A); rs3859866(G,C); rs713816(T,C); rs713822(G,A); rs148939294(C,T); rs9608422(C,T); rs2073256(G,A); rs115557121(G,T); rs113027771(G,A); rs3859868(G,A); rs3859869(A,G); rs10222224(T,C); rs76110871(T,C); rs9624894(C,T); rs3848859(G,C); rs9613017(A,G); rs9624895(A,T); rs5752203(C,T); rs7286923(G,A); rs7288662(C,T); rs9624896(C,T); rs9613018(T,C); rs12170856(G,A); rs5761170(T,C); rs9624897(G,C); rs2076706(G,T); rs139026709(C,T); rs9613019(T,C); rs117194914(G,A); rs5761171(T,C); rs9624898(A,C); rs5752204(G,C); rs5761172(T,G); rs201070289(G,A); rs10427982(C,T); rs377313496(G,A); rs5761174(C,T); rs6519624(G,A); rs6519625(G,A); rs28729695(G,A); rs5752205(G,A); rs115281310(G,A); rs17624687(C,T); rs12158659(G,A); rs8138167(T,A); rs8142661(C,T); rs9613020(G,A); rs13058364(T,G); rs4822651(T,C); rs4822652(T,C); rs4822653(A,G); rs8139077(T,C); rs8135105(C,G); rs13053299(T,C); rs3859870(T,C); rs9613021(G,T); rs5996972(G,A); rs12484281(T,C); rs5752207(G,A); rs4822654(A,G); rs5761183(C,T); rs5761184(A,G); rs5752208(A,T); rs5996973(C,T); rs5996976(C,T); rs3859871(A,G); rs3859872(C,T); rs3859873(C,A); rs3848860(C,T); rs3931452(C,T); rs73401952(C,T); rs4822655(A,G); rs4822656(G,C); rs6004765(A,G); rs78964073(C,T); rs2331159(T,C); rs73401958(A,G); rs4820655(G,C); rs73401960(G,A); rs116612158(G,A); rs13053185(C,G); rs5761186(T,C); rs60992305(G,A); rs5996978(A,G); rs2038326(T,C); rs738636(T,C); rs738637(A,G); rs738638(G,C); rs5761188(A,G); rs5761189(T,A); rs5761190(G,T); rs5761191(G,C); rs5761192(C,T); rs5761193(G,A); rs4592957(T,A); rs5761194(A,T); rs12169768(G,T); rs5761196(T,G); rs5761200(A,G); rs5761201(A,G); rs5752210(T,C); rs5761202(C,T); rs140383394(G,C); rs4820656(G,A); rs4822657(T,C); rs8140133(G,A); rs738640(A,G); rs79080767(C,A); rs9624901(T,C); rs9624902(T,C); rs1807605(C,A); rs115082199(C,T); rs2877299(C,T); rs738642(C,G); rs738643(T,C); rs738644(G,A); rs5761204(C,T); rs5761205(T,G); rs6004767(C,T); rs146806961(C,T); rs4820657(T,C); rs16980756(C,T); rs5752211(T,C); rs2038327(G,C); rs57240776(G,A); rs9624903(A,T); rs2038328(C,A); rs112744374(G,A); rs75700316(C,T); rs116620174(A,G); rs6519627(G,A); rs9624904(A,G); rs5752213(T,A); rs77928433(G,A); rs5761207(G,A); rs5752214(T,C); rs58821819(T,C); rs5761209(G,A); rs910519(C,T); rs910521(T,G); rs5761210(T,C); rs146358824(C,T); rs77872464(G,T); rs9637321(C,T); rs76253872(A,G); rs4822658(G,C); rs78985115(A,G); rs9637345(A,G); rs9637346(T,C); rs4822659(T,C); rs75239319(C,T); rs13313869(C,G); rs77286836(G,A); rs5761218(A,C); rs5761219(A,T); rs76847710(C,T); rs5761220(G,C); rs16980773(A,G); rs2331160(A,G); rs5761221(C,T); rs761704(G,A); rs5761222(C,A); rs6004770(G,A); rs5761223(G,A); rs5761224(A,T); rs5761226(A,G); rs5761227(A,C); rs117817321(G,C); rs5761230(T,G); rs5761231(C,T); rs113540987(C,T); rs5761232(G,A); rs9620561(C,G); rs5752216(A,C); rs3926777(G,A); rs56070130(C,T); rs5752217(G,A); rs8135106(C,T); rs5761233(A,G); rs78395145(C,T); rs2012615(G,A); rs8135237(C,T); rs5752218(C,A); rs5752219(C,T); rs8136123(A,G); rs8139428(C,T); rs5761234(G,C); rs5752220(G,A); rs5761235(A,G); rs5761236(T,G); rs5761237(G,T); rs5761238(T,C); rs188607560(C,T); rs5761239(C,T); rs58639907(C,A); rs60504311(A,G); rs16980793(A,G); rs78532043(G,A); rs78147578(A,G); rs74619342(A,G); rs74378433(T,A); rs5761240(G,C); rs5761241(A,G); rs5761242(A,G); rs5761243(C,T); rs16980795(G,A); rs8137100(A,G); rs8135602(G,C); rs139753819(C,T); rs61055087(G,T); rs57344074(T,C); rs58171116(T,C); rs5752221(G,A); rs115876665(T,A); rs4411820(C,T); rs9608425(A,T); rs5752222(G,A); rs5752224(A,G); rs5761247(T,C); rs5761248(T,C); rs115558223(C,T); rs73401998(C,A); rs2331161(T,C); rs5761249(G,A); rs5761250(C,T); rs3859874(G,A); rs78373009(T,C); rs5996979(A,G); rs60861270(G,T); rs61708982(G,A); rs117058083(A,G); rs3859875(G,A); rs151160893(A,G); rs116481116(G,T); rs5752225(T,C); rs1018469(C,T); rs5761252(T,C); rs5761253(T,C); rs59220162(T,C); rs5996980(T,G); rs116889854(A,G); rs16980808(C,A); rs6004775(G,T); rs6004776(T,C); rs12160521(A,G); rs12165643(C,A); rs6004777(C,T); rs5761255(G,T); rs7289872(T,C); rs74820441(A,G); rs5761256(A,G); rs6004778(A,G); rs5996981(G,A); rs5761258(C,T); rs5996982(T,C); rs5752226(T,C); rs4820658(G,A); rs16980810(C,T); rs12166618(A,G); rs113471547(C,T); rs3859876(C,T); rs58118432(A,G); rs3859877(C,T); rs8143030(T,C); rs9624909(C,T); rs2331162(G,A); rs9624910(C,G); rs3859878(T,C); rs3884707(G,T); rs73403707(G,A); rs75369921(G,A); rs75323252(C,T); rs5761260(G,A); rs3848861(G,A); rs41281575(T,C); rs7284564(G,A); rs5996984(T,C); rs7286591(A,G); rs73403713(G,A); rs6004784(C,T); rs58245059(G,A); rs12166240(A,G); rs12166250(A,G); rs16980831(A,G); rs12166358(A,G); rs138050393(G,A); rs13056293(T,C); rs13056441(C,T); rs73879558(G,A); rs8137635(C,G); rs142708659(C,T); rs6004787(C,T); rs5761263(T,A); rs9624913(A,G); rs9620562(G,A); rs6004788(T,C); rs3859879(A,G); rs11090413(C,T); rs6004789(G,A); rs4822660(G,A); rs58869406(G,A); rs4822661(C,T); rs2331163(G,A); rs3887776(C,T); rs695423(A,G); rs2072002(A,G); rs695445(A,G); rs2072014(G,A); rs2748219(T,C); rs3859880(T,C); rs12167251(T,C); rs116611428(C,T); rs695550(G,A); rs3925154(A,C); rs6519629(G,T); rs12170588(T,C); rs5761265(A,C); rs4820659(T,C); rs4822663(G,A); rs17626577(C,T); rs9624917(G,A); rs17705141(G,A); rs17705165(A,T); rs2269630(C,T); rs2269631(A,G); rs73169000(G,T); rs2748238(T,C); rs2269632(T,C); rs2269633(G,A); rs5761266(T,C); rs5761268(C,A); rs5761269(A,G); rs5761271(A,G); rs6004793(A,G); rs5752231(C,T); rs5761272(G,A); rs6004794(G,C); rs2072010(C,A); rs2072011(G,A); rs2072012(T,C); rs2859407(C,T); rs2072018(G,C); rs148448252(C,T); rs5761273(C,T); rs5761274(C,G); rs8141828(T,G); rs2748237(G,C); rs147064352(G,A); rs9613026(G,A); rs2859409(T,C); rs9613027(A,G); rs2748236(A,G); rs2859410(T,C); rs5752232(C,G); rs2859411(T,C); rs2859412(T,G); rs695665(C,T); rs5752233(A,G); rs17632483(C,G); rs5996988(G,A); rs6004798(C,T); rs739278(C,T); rs3859881(C,T); rs695547(G,T); rs3848862(C,G); rs5752235(A,G); rs2748235(T,C); rs2748234(G,A); rs5761279(G,T); rs9624920(A,G); rs9624921(C,T); rs695748(T,C); rs57139988(A,C); rs59662024(C,T); rs5752236(C,T); rs115416053(C,T); rs695353(A,G); rs695350(G,T); rs5752238(G,A); rs116504007(A,T); rs74689200(C,T); rs115582921(A,G); rs695613(A,G); rs695538(T,A); rs60640813(C,T); rs695352(A,G); rs695589(C,T); rs695427(A,G); rs695403(G,A); rs141660262(T,A); rs16980878(C,T); rs695351(A,G); rs12168416(G,T); rs149248954(G,A); rs695312(T,C); rs12157749(C,T); rs76851922(G,A); rs76923261(A,T); rs3091379(A,C); rs5996991(T,A); rs6004804(G,C); rs5752239(A,G); rs12169347(G,A); rs2859415(A,C); rs187367042(T,G); rs12166783(G,A); rs16980905(A,T); rs114043990(C,T); rs2285190(A,G); rs141599386(G,A); rs2285191(G,A); rs12330121(C,T); rs5996993(T,C); rs2285192(A,C); rs2285193(G,A); rs2285194(C,T); rs11090417(G,A); rs2301492(A,C); rs2269634(G,A); rs2269635(C,A); rs2269636(T,C); rs77138731(A,G); rs74953901(G,A); rs1573755(C,A); rs113754242(G,C); rs695821(A,G); rs16980942(A,T); rs17633130(C,T); rs695785(A,G); rs8137161(G,T); rs8141976(A,G); rs5761292(C,T); rs5761293(T,C); rs4822666(A,C); rs4822667(G,T); rs695428(G,C); rs5752240(C,T); rs1158340(T,C); rs1158341(C,T); rs5761294(A,G); rs5761295(A,G); rs695408(A,G); rs148501064(C,T); rs695463(G,A); rs2301494(A,G); rs695443(A,C); rs695784(A,G); rs695513(T,C); rs739280(G,A); rs695431(C,A); rs2301497(G,A); rs2301498(A,G); rs739281(T,C); rs2285196(T,C); rs695540(A,G); rs73879581(T,C); rs695407(G,A); rs112894412(A,T); rs695430(A,G); rs695824(C,G); rs695670(C,T); rs695317(A,G); rs115684277(G,A); rs7287246(A,T); rs2157538(C,T); rs4822669(A,G); rs73407512(G,C); rs6004809(C,T); rs5761300(T,C); rs6004810(A,G); rs4822670(A,G); rs4822671(A,G); rs739282(T,C); rs138636785(C,T); rs2285197(G,A); rs2285198(G,T); rs4820661(A,G); rs16980979(T,C); rs76435293(A,G); rs16980985(A,C); rs58271461(G,A); rs35761934(T,C); rs9620565(G,A); rs6004814(C,T); rs7364149(A,G); rs6004815(A,G); rs973523(A,G); rs2331164(G,A); rs8140616(C,T); rs2072003(A,T); rs2072004(T,A); rs2066935(A,G); rs114017805(A,G); rs8137311(G,A); rs6004818(G,A); rs11913129(A,C); rs5761303(C,T); rs5761304(C,G); rs2072016(G,A); rs2072017(T,C); rs5761306(T,G); rs9306417(G,C); rs34284508(C,T); rs75554421(C,T); rs2027881(C,T); rs6004822(T,C); rs2331165(G,A); rs2301501(A,G); rs2301502(A,G); rs2301503(G,C); rs5761307(C,T); rs9620568(A,G); rs9613035(A,G); rs11914063(C,T); rs5752242(T,C); rs80225275(G,A); rs141511648(C,G); rs5761308(A,G); rs2247775(C,T); rs737817(T,C); rs2285200(G,A); rs2247902(G,T); rs2331192(G,A); rs2331193(A,T); rs2331194(T,C); rs5996999(T,C); rs2269628(A,G); rs5997000(T,C); rs114051787(C,A); rs2269629(C,T); rs1476053(A,G); rs2285201(C,T); rs2285202(A,G); rs5761310(C,T); rs77665011(G,A); rs5761311(A,C); rs12165370(C,G); rs739283(T,A); rs5761312(A,G); rs9624926(A,G); rs79031933(G,A); rs75931834(A,C); rs115172431(C,T); rs763493(A,G); rs763489(A,T); rs763491(G,A); rs763494(A,G); rs763490(A,G); rs78243796(C,T); rs2157539(A,G); rs5761313(G,T); rs5761314(C,T); rs728175(C,G); rs5761315(C,T); rs6004831(A,G); rs9608428(G,A); rs5997002(A,G); rs80051947(C,T); rs9608429(A,G); rs6004832(A,G); rs117544445(G,C); rs739284(A,G); rs739285(G,A); rs114954424(A,G); rs146629510(T,C); rs115710984(C,G); rs5761316(G,A); rs9608430(C,T); rs1006208(C,T); rs1006209(T,C); rs2301504(T,C); rs1006210(A,C); rs6004833(A,G); rs6004835(A,C); rs5761322(T,G); rs2269637(A,T); rs142385726(A,G); rs5752245(A,C); rs10427827(A,G); rs10427777(G,A); rs969975(A,G); rs9613039(C,T); rs16981069(T,C); rs34639859(C,T); rs35446166(T,C); rs2227235(T,C); rs6004838(T,C); rs12627770(C,T); rs2227236(G,C); rs2285204(A,G); rs67028235(C,T); rs144459454(C,T); rs28628482(T,C); rs60524122(C,T); rs8136253(C,T); rs147897769(T,G); rs5997003(A,G); rs2269638(A,G); rs78113389(T,C); rs1013815(T,G); rs5761324(A,G); rs1034461(G,A); rs1012480(T,C); rs1012481(C,T); rs7292253(C,T); rs34476419(T,C); rs144765478(C,T); rs2301505(G,C); rs9624932(C,T); rs12106591(C,T); rs3948759(C,A); rs9613041(A,G); rs9620572(A,G); rs76519149(C,T); rs5997004(A,T); rs2331195(G,A); rs9613042(G,C); rs2285205(A,G); rs2285206(A,C); rs9613043(A,T); rs2269640(C,T); rs9613044(A,G); rs9613045(T,C); rs7291115(G,A); rs11704814(C,T); rs62227570(C,T); rs2285207(A,T); rs9613046(C,T); rs5997006(T,G); rs6004846(G,A); rs9613048(C,G); rs2877304(T,C); rs2072006(A,G); rs2072007(A,G); rs2072008(C,T); rs2269641(A,G); rs6004849(T,C); rs2249582(A,G); rs115141226(C,T); rs9613049(C,T); rs9608432(A,T); rs9613050(G,T); rs117483066(C,T); rs6004851(A,G); rs882432(T,C); rs4822675(A,C); rs5997008(C,A); rs5761327(G,C); rs111619871(A,G); rs8140409(C,G); rs6004853(C,T); rs4820663(A,C); rs140907873(C,T); rs12386328(G,T); rs5997009(G,A); rs78845954(G,A); rs1894677(G,A); rs713734(A,G); rs77901613(C,T); rs9613055(T,C); rs9306419(C,T); rs6004856(A,G); rs66495114(C,T); rs7292234(G,A); rs7284984(A,C); rs17708465(G,C); rs4822676(C,T); rs4820664(T,G); rs4822677(C,G); rs75617736(T,A); rs6004859(C,A); rs9608435(A,G); rs9613059(G,A); rs7287781(C,A); rs6004862(A,T); rs9620576(T,C); rs61174692(C,T); rs6004864(T,C); rs6004865(A,C); rs6004866(A,G); rs9620577(G,A); rs6004867(C,T); rs6004868(T,C); rs9613060(G,A); rs9613061(A,G); rs6004869(T,G); rs9306420(G,T); rs76710082(C,T); rs9613062(G,A); rs5761336(T,C); rs9613063(C,T); rs6004874(G,A); rs17635540(G,A); rs6004875(G,A); rs6004876(G,A); rs2157537(T,C); rs16981143(T,C); rs9613066(C,T); rs190300263(G,A); rs6004877(A,G); rs9608439(G,A); rs9608440(C,T); rs9608441(A,G); rs56395914(G,A); rs12172625(C,T); rs7292258(G,A); rs6004879(C,T); rs9608443(T,C); rs7292853(G,A); rs7285082(C,T); rs4822678(T,C); rs916423(G,A); rs916424(T,A); rs12166988(G,A); rs916425(C,T); rs5752250(G,A); rs5752251(G,A); rs916426(A,G); rs9608444(C,T); rs6004881(C,G); rs5761340(C,T); rs16981163(G,A); rs5761341(T,G); rs5761342(T,C); rs73154161(G,A); rs5761343(T,C); rs5761344(T,A); rs7286230(T,C); rs6004882(C,G); rs4820666(A,G); rs4820667(T,C); rs2331196(C,T); rs34145275(C,A); rs2331197(T,C); rs2331198(G,A); rs2331199(G,T); rs6004883(C,T); rs2331200(G,A); rs113944211(A,G); rs1155189(C,T); rs9613069(A,C); rs12485050(G,A); rs916427(G,A); rs916428(G,T); rs4822679(A,G); rs5761347(A,G); rs9613070(T,C); rs9613071(C,T); rs9613072(C,T); rs744003(G,T); rs2009111(T,C); rs2003833(C,T); rs4049335(C,A); rs9608446(C,A); rs9613074(G,A); rs8139267(C,T); rs8138415(G,A); rs8135240(T,C); rs8139900(A,G); rs4822680(G,C); rs5761348(T,G); rs8136667(C,T); rs5752252(C,T); rs1155481(T,G); rs9620582(G,C); rs5761350(G,A); rs73404443(G,A); rs76858690(C,T); rs9613077(G,A); rs17709720(C,G); rs7287184(C,A); rs5761351(C,T); rs8139384(A,G); rs8139008(C,G); rs73883015(A,T); rs9613078(C,T); rs8135941(A,G); rs9613079(G,C); rs2016904(A,G); rs1004535(C,T); rs5752253(C,G); rs2027882(G,A); rs6004885(C,A); rs5761352(G,A); rs132494(C,G); rs2027883(A,G); rs9680735(A,G); rs1001022(T,C); rs9613081(G,A); rs35817879(A,G); rs1033588(A,G); rs5997020(C,G); rs16981208(C,G); rs6004887(G,T); rs187485816(G,A); rs17636976(C,T); rs6004890(A,G); rs12485167(T,C); rs9306421(A,G); rs12166654(T,C); rs9613082(T,G); rs9613083(G,A); rs7288885(A,G); rs7287272(G,A); rs141771956(A,T); rs5997021(G,A); rs6004891(C,T); rs6004893(G,C); rs34940781(G,A); rs8137747(C,T); rs8137855(C,T); rs12484097(A,C); rs5997022(C,G); rs6004895(C,A); rs6004896(G,A); rs6004897(G,C); rs55911721(C,A); rs111345326(G,A); rs5761354(C,T); rs6519633(C,T); rs5761355(C,T); rs5019557(T,G); rs5752254(C,T); rs73879804(C,A); rs1983666(T,C); rs6004900(G,A); rs111663192(G,T); rs1033589(C,A); rs114297323(G,A); rs138229563(A,T); rs5752256(G,T); rs74337878(T,A); rs761670(C,T); rs79264632(C,G); rs73404472(G,A); rs4822682(C,T); rs55704193(A,T); rs71321074(A,G); rs4820668(C,T); rs4822683(A,G); rs75341279(G,T); rs28606436(T,C); rs111426852(T,C); rs7290026(A,G); rs186229976(C,T); rs7284759(A,C); rs5997024(A,G); rs16981226(A,G); rs41531549(G,C); rs7284395(G,A); rs2236005(A,G); rs6004901(G,C); rs7284177(G,A); rs117354193(A,G); rs16981230(G,A); rs142465597(A,G); rs17295779(G,C); rs16981234(T,C); rs56342861(C,A); rs11912784(G,A); rs11913497(T,C); rs56338632(T,C); rs75784362(C,T); rs73154188(C,T); rs116580424(C,T) |
| ccdsGene name | CCDS54507.1 |
| cytoBand name | 22q12.1 |
| EntrezGene GeneID | 84700 |
| EntrezGene Description | myosin XVIIIB |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MYO18B:NM_032608:exon3:c.T95C:p.V32A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.7884 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | F5GYU7 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000251 |
| ESP Eur/Amr MAF | 0.000365 |
| ExAC AF | 0.0002452 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive
RESPIRATORY:
[Nasopharynx];
[Airways];
Reactive airway disease;
Asthma;
[Lung];
Pneumonia
ABDOMEN:
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea, chronic
SKIN, NAILS, HAIR:
[Skin];
Eczema
IMMUNOLOGY:
Lymphadenopathy;
Recurrent sinopulmonary infections;
Herpes simplex virus infection, mucocutaneous;
Defective CD95-induced apoptosis of peripheral blood lymphocytes;
No response to pneumococcal vaccination;
Defective T cell activation;
Defective B cell activation;
Defective natural killer cell (NK) activation;
Decreased cellular caspase-8 levels
MOLECULAR BASIS:
Caused by mutation in the caspase 8 gene (CASP8, 601763.0001)
OMIM Title
*607295 MYOSIN XVIIIB; MYO18B
OMIM Description
CLONING
Nishioka et al. (2002) identified MYO18B within a region of chromosome
22q that shows frequent loss of heterozygosity in advanced nonsmall cell
lung carcinomas and small cell lung carcinomas. The full-length cDNA
encodes a deduced 2,567-amino acid protein with a calculated molecular
mass of about 285 kD. MYO18B has an N-terminal head (motor) domain, a
neck region containing an IQ motif, and a C-terminal tail containing a
short coiled-coil domain that allows dimerization to form a 2-headed
structure. The head region contains a consensus ATP-binding site, part
of an actin-binding region, and a GPA (gly-pro-ala) motif that is
believed to interact with F actin (see 102610). MYO18B shares 40%
identity with the human and mouse MYSPDZ (TIAF1) proteins. Northern blot
analysis revealed an 8-kb transcript expressed only in skeletal muscle
and heart. Quantitative PCR detected wider expression, including
expression in adult and fetal lung. Examination of several lung cell
lines indicated expression in both lung epithelial cells and
fibroblasts.
GENE FUNCTION
Nishioka et al. (2002) found that MYO18B was inactivated in
approximately half of the primary lung cancers and cell lines examined.
The causes of the reduced expression varied and included deletion,
mutation, promoter methylation, and histone deacetylation.
GENE STRUCTURE
Nishioka et al. (2002) determined that the MYO18B gene contains 43 exons
and spans 286 kb.
MAPPING
By genomic sequence analysis, Nishioka et al. (2002) mapped the MYO18B
gene to chromosome 22q12.1, between the ADRBK2 gene (109636) and the
SEZ6L gene (607021), in a region that shows frequent loss of
heterozygosity in lung cancer.
MIR548J
| dbSNP name | rs4822739(C,G); rs12161068(T,C) |
| cytoBand name | 22q12.1 |
| EntrezGene GeneID | 100313914 |
| snpEff Gene Name | TPST2 |
| EntrezGene Description | microRNA 548j |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1276 |
| ESP Afr MAF | 0.162628 |
| ESP All MAF | 0.080971 |
| ESP Eur/Amr MAF | 0.045226 |
| ExAC AF | 0.087,8.200e-06 |
RFPL1S
| dbSNP name | rs71329487(A,G); rs174718(C,G); rs147060264(G,A); rs56355388(G,A) |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 10740 |
| snpEff Gene Name | RFPL1 |
| EntrezGene Description | RFPL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1171 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CHEST:
[Ribs and sternum];
Pectus carinatum;
Pectus excavatum
SKELETAL:
[Limbs];
[Hands];
Preaxial polydactyly;
Bifid thumb;
Triphalangeal thumb;
Soft tissue syndactyly between all fingers (in 1 family);
[Feet];
Soft tissue syndactyly between all toes (in 1 family);
Preaxial polydactyly
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate (in 1 patient)
MISCELLANEOUS:
Variable phenotype;
F syndrome (102510) has many overlapping features;
Two families reported (last curated September 2012)
OMIM Title
*605972 RET FINGER PROTEIN-LIKE 1, ANTISENSE; RFPL1S
;;RFP-LIKE 1, ANTISENSE
OMIM Description
DESCRIPTION
Natural antisense RNAs (NARs) such as RFPL1S affect diverse activities
in both prokaryotic and eukaryotic cells. For example, NARs regulate
basic fibroblast growth factor (FGF2; 134920) negatively in frog and
human oocytes (summary by Seroussi et al., 1999).
CLONING
By analysis of a cosmid genomic clone from 22q12-q13 and by PCR,
Seroussi et al. (1999) obtained cDNAs encoding RET finger protein (RFP;
602165)-like-1 (RFPL1; 605968), RFPL2 (605969), and RFPL3 (605970), as
well as antisense RFPL1S and RFPL3S (605971). Northern blot analysis
revealed expression of a 6-kb RFPL1S transcript that was strongly
expressed in adult and fetal brain.
GENE STRUCTURE
Seroussi et al. (1999) determined that the antisense RFPL1S transcript
contains 2 exons and a large intron.
RFPL1
| dbSNP name | rs16987627(T,C); rs67660453(G,C); rs7285081(G,A); rs6006149(G,T); rs191323199(A,G); rs2106107(C,T); rs67613029(T,A); rs114051853(G,A); rs5763240(T,C); rs12485237(A,G); rs3804076(T,C); rs10211999(C,T); rs12484086(C,T); rs13053624(A,T) |
| ccdsGene name | CCDS13857.2 |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 10740 |
| EntrezGene Symbol | RFPL1S |
| EntrezGene Description | RFPL1 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | RFPL1:NM_021026:exon1:c.T280C:p.W94R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O75677 |
| dbNSFP Uniprot ID | RFPL1_HUMAN |
| dbNSFP KGp1 AF | 0.151556776557 |
| dbNSFP KGp1 Afr AF | 0.290650406504 |
| dbNSFP KGp1 Amr AF | 0.118784530387 |
| dbNSFP KGp1 Asn AF | 0.0297202797203 |
| dbNSFP KGp1 Eur AF | 0.168865435356 |
| dbSNP GMAF | 0.1515 |
| ESP Afr MAF | 0.222197 |
| ESP All MAF | 0.192296 |
| ESP Eur/Amr MAF | 0.176977 |
| ExAC AF | 0.152,4.960e-03 |
OMIM Clinical Significance
INHERITANCE:
Autosomal dominant
CHEST:
[Ribs and sternum];
Pectus carinatum;
Pectus excavatum
SKELETAL:
[Limbs];
[Hands];
Preaxial polydactyly;
Bifid thumb;
Triphalangeal thumb;
Soft tissue syndactyly between all fingers (in 1 family);
[Feet];
Soft tissue syndactyly between all toes (in 1 family);
Preaxial polydactyly
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate (in 1 patient)
MISCELLANEOUS:
Variable phenotype;
F syndrome (102510) has many overlapping features;
Two families reported (last curated September 2012)
OMIM Title
*605968 RET FINGER PROTEIN-LIKE 1; RFPL1
;;RFP-LIKE 1
OMIM Description
CLONING
By analysis of a cosmid genomic clone from 22q12-q13 and by PCR,
Seroussi et al. (1999) obtained cDNAs encoding RET finger protein (RFP;
602165)-like-1 (RFPL1), RFPL2 (605969), and RFPL3 (605970), as well as
antisense RFPL1S (605972) and RFPL3S (605971). The deduced 287-amino
acid RFPL1 protein is 91 to 94% identical to RFPL2 and RFPL3. Exon 1 of
RFPL1 encodes a putative RING-like motif, which is 29% identical to that
of RFP, and exon 2 encodes a B30-2 domain, which is 41% identical to
that of RFP. Northern blot analysis revealed expression of a 1.5-kb
RFPL1 transcript that was abundant in prostate and less abundant in
adult brain, fetal liver, and fetal kidney. A 1.2-kb transcript strongly
expressed in testis and a 6-kb transcript strongly expressed in adult
and fetal brain appeared to represent RFPL3S and RFPL1S, respectively.
Analysis of a family with Opitz syndrome (300000) and unrelated normal
individuals resulted in the detection of a polymorphic
protein-truncating allele of RFPL1 that was not associated with the OS
phenotype.
GENE STRUCTURE
The RFPL1 gene comprises 2 exons (Seroussi et al., 1999).
GENE FUNCTION
Using microarray expression analysis, Bonnefont et al. (2008) found that
the human RFPL1, RFPL2, and RFPL3 genes are transactivated by the
corticogenic transcription factor PAX6 (607108). Real-time PCR
demonstrated that RFPL1,2,3 are highly expressed in embryonic stem
cell-derived neurogenesis and in fetal neocortex.
MAPPING
The RFPL1 gene resides in a cluster with RFPL2 and RFPL3 on chromosome
22q12.2-q13.3 (Seroussi et al., 1999; Bonnefont et al., 2008).
EVOLUTION
Bonnefont et al. (2008) observed that high RFPL1,2,3, transcript levels
occurred at the onset of neurogenesis in differentiating human embryonic
stem cells and in the developing human neocortex, whereas the unique
murine RFPL gene is expressed in liver but not in neural tissue. Study
of the evolutionary history of the RFPL gene family revealed that the
RFPL1,2,3 gene ancestor emerged after the Euarchonta-Glires split.
Subsequent duplication events led to the presence of multiple RFPL1,2,3
genes in Catarrhini approximately 34 million years ago, resulting in an
increase in gene copy number in the hominoid lineage. In Catarrhini,
RFPL1,2,3 expression profile diverged toward the neocortex and
cerebellum over the liver. Importantly, humans showed a striking
increase in cortical RFPL1,2,3 expression in comparison to cerebellum,
and to chimpanzee and macaque neocortex. Acceleration in RFPL protein
evolution was also observed with signs of positive selection in the
RFPL1,2,3 cluster and 2 neofunctionalization events (acquisition of a
specific RFPL-Defining Motif in all RFPLs and of an N-terminal 29-amino
acid sequence in Catarrhinian RFPL1,2,3). Thus, Bonnefont et al. (2008)
proposed that the recent emergence and multiplication of the RFPL1,2,3
genes contribute to changes in primate neocortex size and/or
organization.
SDC4P
| dbSNP name | rs4820859(T,C) |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 376844 |
| snpEff Gene Name | MTMR3 |
| EntrezGene Description | syndecan 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03306 |
SEC14L6
| dbSNP name | rs41282475(T,C); rs6518696(T,C); rs6518697(A,G); rs7289828(G,T); rs41282477(C,T); rs6518698(T,C); rs8135119(A,G); rs56968636(G,C); rs5753179(T,C); rs73394239(T,A); rs5753183(C,T); rs5749116(C,G); rs112068496(T,G); rs7287003(G,C); rs7286807(A,G); rs5749117(T,C); rs9621016(C,T); rs9621017(C,T); rs35102600(C,T); rs12170920(G,A); rs10428025(A,G); rs60308761(A,G); rs8138980(C,T); rs5749118(C,T); rs7289983(T,G); rs5997676(T,C); rs5753186(A,G); rs4820862(A,G); rs4820864(A,G); rs115481536(G,A); rs5753187(T,A); rs2899151(T,C); rs2412991(T,C); rs5997677(G,T); rs7285565(A,G); rs9608972(T,C); rs1107844(T,C); rs111483347(C,T); rs2079311(C,T); rs764218(A,G); rs764217(G,C); rs2097871(A,G); rs5753190(T,C); rs5753191(G,A); rs5753192(C,A); rs377702316(G,A); rs5994317(G,A); rs5753193(C,G); rs5753194(G,A); rs5749120(G,A); rs4820865(A,G); rs5749122(A,G); rs5749123(G,A); rs11704402(C,T); rs372196098(C,T); rs71331244(C,G); rs140241421(A,G); rs4820866(G,A); rs5997678(T,C); rs5753201(C,G); rs141325068(G,C); rs376763758(G,A); rs188359278(C,T); rs181839987(A,G); rs186440570(G,A); rs188899276(T,C); rs139968908(C,T); rs144327589(C,T); rs146883899(C,T); rs139043294(G,A); rs143992907(C,T) |
| ccdsGene name | CCDS54518.1 |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 730005 |
| EntrezGene Description | SEC14-like 6 (S. cerevisiae) |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SEC14L6:NM_001193336:exon7:c.A542C:p.N181T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.6968 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
MIR3928
| dbSNP name | rs5997893(A,G) |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 100500901 |
| snpEff Gene Name | RNF185 |
| EntrezGene Description | microRNA 3928 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.315 |
| ExAC AF | 0.499 |
LOC54944
| dbSNP name | rs113370862(G,T); rs62236171(G,A); rs5997959(G,A); rs79323513(A,G); rs138363368(A,G); rs75042792(G,A); rs137969440(C,T); rs79873898(G,A); rs9609263(A,C); rs1005624(T,C); rs9609264(C,G) |
| cytoBand name | 22q12.2 |
| EntrezGene GeneID | 54944 |
| EntrezGene Symbol | FLJ20464 |
| snpEff Gene Name | PATZ1 |
| EntrezGene Description | uncharacterized protein FLJ20464 |
| EntrezGene Type of gene | unknown |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
H1F0
| dbSNP name | rs6000898(T,C); rs1894644(T,C); rs149530054(G,A); rs1894645(G,T); rs1894646(G,C) |
| cytoBand name | 22q13.1 |
| EntrezGene GeneID | 3005 |
| snpEff Gene Name | GCAT |
| EntrezGene Description | H1 histone family, member 0 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2819 |
OMIM Clinical Significance
INHERITANCE:
Multifactorial
SKELETAL:
[Pelvis];
Congenital hip dislocation;
Positive Ortolani sign
MISCELLANEOUS:
Preponderance of affected females (80%) to males;
Positive family history in 12-33% patients;
Incidence 1-1.5/1,000 live births
OMIM Title
*142708 H1 HISTONE FAMILY, MEMBER 0; H1F0
;;H1.0;;
H1-0 HISTONE;;
H1FV
OMIM Description
For background information on histones, histone gene clusters, and the
H1 histone family, see HIST1H1A (142709).
CLONING
Doenecke and Tonjes (1986) cloned the human H1.0 gene.
Marzluff et al. (2002) noted that H1F0 is a replacement H1 histone whose
transcription is independent of DNA replication. Unlike the transcripts
for replication-dependent histones, transcripts for replacement
histones, including that for H1F0, are polyadenylated. Marzluff et al.
(2002) stated that H1F0 is expressed at high levels during terminal
differentiation.
GENE FUNCTION
See HIST1H1A (142709) for functional information on H1 histones.
MAPPING
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic
cell hybrids, Albig et al. (1993) demonstrated that the H1.0 gene maps
to chromosome 22. By fluorescence in situ hybridization, they localized
the gene to 22q13.1. Thus, unlike the other H1 genes mapped by Albig et
al. (1993), H1.0 lies outside the histone gene cluster on chromosome 6.
By genomic sequence analysis, Marzluff et al. (2002) determined that
nearly all replication-dependent histone genes are clustered on
chromosomes 6p22-p21, 1q21, and 1q42. In contrast,
replication-independent histone genes, such as H1F0, lie outside of
these clusters.
TOMM22
| dbSNP name | rs5750668(T,C); rs1056610(T,C); rs116369871(C,A); rs3205205(G,T); rs1056661(A,G); rs5750669(T,A); rs144615628(C,T) |
| cytoBand name | 22q13.1 |
| EntrezGene GeneID | 56993 |
| snpEff Gene Name | JOSD1 |
| EntrezGene Description | translocase of outer mitochondrial membrane 22 homolog (yeast) |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3145 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Deafness, sensorineural, severe to profound affecting all frequencies
MISCELLANEOUS:
Prelingual onset
MOLECULAR BASIS:
Caused by mutation in the otoancorin gene (OTOA, 607038.0001)
OMIM Title
*607046 TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 22, YEAST, HOMOLOG OF;
TOMM22
;;TOM22
OMIM Description
DESCRIPTION
The translocase of outer mitochondrial membrane (TOM) complex is a
multisubunit complex involved in the recognition, unfolding, and
translocation of preproteins from the cytosol into the mitochondria.
CLONING
By EST database searching with yeast Tom22 as the probe, followed by PCR
on a liver cDNA library, Yano et al. (2000) obtained cDNAs encoding
mouse and human TOMM22. The deduced 142-amino acid human protein, which
is approximately 33% similar to the yeast proteins, contains an
N-terminal negatively charged region, an internal hydrophobic
transmembrane region, and a C-terminal region with a glutamine-rich
segment. Immunoblot analysis and fluorescence microscopy showed
expression of a 21-kD mitochondrial membrane protein with its N and C
termini exposed to the cytosol and intermembrane space of the
mitochondrial outer membrane, respectively.
Saeki et al. (2000) also cloned and characterized TOMM22, which they
termed 1C9-2. Western blot analysis showed ubiquitous expression in
tissues and cell lines. An association between the rat Tomm22 protein,
which is 94% identical to the human protein, and Tomm40 (608061) was
observed. Saeki et al. (2000) concluded that the components of the
mitochondrial import machinery are evolutionarily conserved.
GENE FUNCTION
Functional analysis by Yano et al. (2000) indicated that the N terminus
of TOMM22 mediates import of preproteins. Immunoprecipitation and
pulse-chase analysis pointed to an association of the cytosolic domain
of TOMM22 and TOMM20 (601848) and their cooperation in protein import.
GENE STRUCTURE
Using sequence analysis, Saeki et al. (2000) determined that the TOMM22
gene contains 4 exons.
MAPPING
By genomic sequence analysis, Saeki et al. (2000) mapped the TOMM22 gene
to chromosome 22q12-q13.
ATF4
| dbSNP name | rs4894(A,C) |
| ccdsGene name | CCDS13996.1 |
| cytoBand name | 22q13.1 |
| EntrezGene GeneID | 468 |
| EntrezGene Description | activating transcription factor 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ATF4:NM_001675:exon1:c.A65C:p.Q22P,ATF4:NM_182810:exon2:c.A65C:p.Q22P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P18848 |
| dbNSFP Uniprot ID | ATF4_HUMAN |
| dbNSFP KGp1 AF | 0.253205128205 |
| dbNSFP KGp1 Afr AF | 0.262195121951 |
| dbNSFP KGp1 Amr AF | 0.262430939227 |
| dbNSFP KGp1 Asn AF | 0.157342657343 |
| dbNSFP KGp1 Eur AF | 0.315303430079 |
| dbSNP GMAF | 0.2534 |
| ESP Afr MAF | 0.270086 |
| ESP All MAF | 0.302245 |
| ESP Eur/Amr MAF | 0.318721 |
| ExAC AF | 0.304 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Macrocephaly
NEUROLOGIC:
[Central nervous system];
Megalencephaly;
Ataxia;
Spasticity;
Seizures;
Delay in motor development;
Mild mental retardation;
Diffuse swelling of cerebral white matter;
Large subcortical cysts in frontal and temporal lobes;
Diffuse spongiform leukoencephalopathy;
Vacuolizing myelinopathy
MISCELLANEOUS:
Onset in infancy;
Slow course of functional deterioration compared to severity of MRI
findings
MOLECULAR BASIS:
Caused by mutation in the MLC1 gene (MLC1, 605908.0001)
OMIM Title
*604064 ACTIVATING TRANSCRIPTION FACTOR 4; ATF4
;;CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN 2; CREB2;;
TAX-RESPONSIVE ENHANCER ELEMENT B67; TAXREB67
OMIM Description
DESCRIPTION
ATF4 belongs to the large ATF/CREB family of transcription factors.
These proteins bind DNA via their basic region and dimerize via their
leucine zipper domain to form a variety of homo- and heterodimers to
regulate gene transcription (De Angelis et al., 2003).
CLONING
An activating transcription factor (ATF)-binding site is a promoter
element present in a wide variety of viral and cellular genes, including
E1A-inducible adenoviral genes and cAMP-inducible cellular genes. Hai et
al. (1989) identified cDNAs encoding 8 different human ATF
consensus-binding proteins, including a partial cDNA corresponding to
ATF4. They found that members of this family share significant sequence
similarity within a leucine zipper DNA-binding motif and an adjacent
basic region; the proteins show little similarity outside of these
regions.
The cAMP response element (CRE) is an octanucleotide motif that mediates
diverse transcriptional regulatory effects. By screening a Jurkat T-cell
line expression library for the ability to bind CRE, Karpinski et al.
(1992) isolated a full-length cDNA corresponding to ATF4, which they
called CREB2 (CRE-binding protein-2). The predicted protein contains 351
amino acids. Northern blot analysis revealed that the 1.5-kb CREB2 mRNA
was expressed in all human tumor cell lines and mouse organs tested.
MAPPING
Hartz (2014) mapped the ATF4 gene to chromosome 22q13.1 based on an
alignment of the ATF4 sequence (GenBank GENBANK BC008090) with the
genomic sequence (GRCh37).
GENE FUNCTION
Karpinski et al. (1992) found that, unlike CREB (123810), which
activates transcription from CRE-containing promoters, CREB2 functions
as a specific repressor of CRE-dependent transcription. The
transcriptional repressor activity resides within the C-terminal leucine
zipper and basic domain region of the CREB2 protein.
The p40tax gene product of human T-cell leukemia virus type 1 (HTLV-1)
activates HTLV-1 viral transcription in trans through tax-responsive
enhancers in the long terminal repeats. Tsujimoto et al. (1991)
identified ATF4 as TAXREB67, a protein that binds to the tax-responsive
enhancer element in HTLV-1.
Using a yeast 2-hybrid assay, He et al. (2001) found that mouse Nrf2
(NFE2L2; 600492) interacted with rat Atf4. Coimmunoprecipitation and
mammalian 2-hybrid analyses confirmed the interaction. An Nrf2-Atf4
dimer bound a stress response element (StRE) sequence from an Nrf2
target gene, Ho1 (HMOX1; 141250). CdCl2, an Ho1 inducer, increased
expression of Atf4 in mouse hepatoma cells prior to induction of Ho1. A
dominant-negative Atf4 mutant inhibited basal and CdCl2-induced
expression of an StRE-dependent construct in hepatoma cells, but it only
inhibited basal expression in a human mammary epithelial cell line. He
et al. (2001) concluded that ATF4 regulates HO1 expression in a
cell-specific manner, possibly in a complex with NRF2.
Siu et al. (2002) presented evidence that ATF4 binds nutrient-sensing
response element-1 (NSRE1) in the human asparagine synthetase (ASNS;
108370) gene and activates ASNS transcription in response to nutrient
stress.
Bagheri-Yarmand et al. (2003) found that expression of Atf4 was high in
virgin mouse mammary glands and in pregnant mammary glands, but it was
dramatically reduced during lactation and higher after weaning.
Transgenic mice overexpressing Atf4 in mammary epithelium showed
decreased proliferation and impaired differentiation of alveolar
epithelial cells during pregnancy and lactation. In addition, Atf4
overexpression induced apoptosis and accelerated involution of the
mammary gland, suggesting a role for ATF4 in the regulation of normal
mammary gland involution.
De Angelis et al. (2003) showed that human ATF4 and RBP3 (E2F1; 189971)
dimerized in vitro and in vivo and that RBP3 enhanced ATF4
transactivating activity. Expression of both proteins increased during
differentiation of a mouse myogenic cell line.
ATF4 has 2 upstream ORFs (uORFs) that are conserved in vertebrates. The
more 3-prime uORF, uORF2, extends into the coding region of full-length
ATF4. Independently, Lu et al. (2004) and Vattem and Wek (2004) found
that scanning ribosomes initiated translation at both uORFs of mouse
Atf4, and that ribosomes that translated uORF1 efficiently reinitiated
translation at downstream AUGs. In unstressed mouse fibroblasts, low
levels of phosphorylated Eif2 (see EIF2S1; 603907) favored early
capacitation of reinitiating ribosomes, directing them to the inhibitory
uORF2 downstream of uORF1, which precluded translation of Atf4 and
repressed the integrated stress response. In stressed cells, high levels
of phosphorylated Eif2 delayed capacitation of reinitiating ribosomes,
favoring reinitiation at the Atf4 coding sequence over uORF2, which
permitted Atf4 expression and activated the integrated stress response.
Using Rsk2 (300075) -/- mice, Yang et al. (2004) showed that RSK2 is
required for osteoblast differentiation and function. They identified
the transcription factor ATF4 as a critical substrate of RSK2 that is
required for the timely onset of osteoblast differentiation, for
terminal differentiation of osteoblasts, and for osteoblast-specific
gene expression. Additionally, RSK2 and ATF4 were found to
posttranscriptionally regulate the synthesis of type I collagen (see
120150), the main constituent of the bone matrix. Accordingly, Atf4
deficiency in mice resulted in delayed bone formation during embryonic
development and low bone mass throughout postnatal life. Yang et al.
(2004) concluded that ATF4 is a critical regulator of osteoblast
differentiation and function and that lack of ATF4 phosphorylation by
RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome
(303600).
Blais et al. (2004) determined that EIF2-alpha (EIF2S1), PERK (EIF2AK3;
604032), ATF4, and GADD34 (PPP1R15A; 611048) are involved in an
integrated adaptive response to hypoxic stress in HeLa cells.
Sayer et al. (2006) performed a yeast 2-hybrid screen of a human fetal
brain expression library and identified ATF4 as a direct interaction
partner of CEP290 (NPHP6; 610142). The protein-interaction domains
mapped to the N-terminal third of CEP290, encoded by exons 2 through 21,
and the C-terminal two-thirds of ATF4. To confirm that CEP290 and ATF4
interact physiologically in vivo, Sayer et al. (2006) performed
coimmunoprecipitation experiments using bovine retina extracts.
Immunoblot analysis demonstrated that endogenous ATF4 can be
immunoprecipitated using an antibody to CEP290 but not using a control
IgG. Reverse coimmunoprecipitation experiments showed that antibody to
ATF4 can also precipitate endogenous CEP290.
Lin et al. (2010) showed that although Skp2 (601436) inactivation on its
own does not induce cellular senescence, aberrant protooncogenic signals
as well as inactivation of tumor suppressor genes do trigger a potent,
tumor-suppressive senescence response in mice and cells devoid of Skp2.
Notably, Skp2 inactivation and oncogenic stress-driven senescence
neither elicit activation of the p19(Arf) (see 600160)-p53 (191170)
pathway nor DNA damage, but instead depend on Aft4, p27 (600778), and
p21 (116899). Lin et al. (2010) further demonstrated that genetic Skp2
inactivation evokes cellular senescence even in oncogenic conditions in
which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex
inhibitor can trigger cellular senescence in p53/Pten (601728)-deficient
cells and tumor regression in preclinical studies. Lin et al. (2010)
concluded that their findings provided proof-of-principle evidence that
pharmacologic inhibition of Skp2 may represent a general approach for
cancer prevention and therapy.
ANIMAL MODEL
Tanaka et al. (1998) used gene targeting to generate mice lacking Atf4.
They found that Atf4-deficient mice exhibited severe microphthalmia. The
Atf4-deficient eyes revealed a normal gross lens structure up to
embryonic day 14.5, after which the lens degenerated due to apoptosis
without the formation of lens secondary fiber cells. Retinal development
was normal in the mutant mice. The lens-specific expression of Atf4 in
the mutant mice led not only to the recovery of lens secondary fibers
but also to the induction of hyperplasia of these fibers. Tanaka et al.
(1998) concluded that ATF4 is essential for the later stages of lens
fiber cell differentiation.
Xiao et al. (2013) found that Atf4-null mice exhibited significantly
reduced fasting plasma triglyceride (TG) and very low density
lipoprotein (VLDL)-TG levels, as well as improved postprandial TG
profiles in a fat tolerance test, compared with wildtype mice. Atf4-null
mice also exhibited significantly lower fasting blood glucose levels and
enhanced glucose tolerance. Atf4 depletion reduced hepatic expression of
lipogenic genes without significantly affecting expression of genes
involved in fatty acid oxidation or VLDL-TG production. Furthermore,
reduced hepatic lipogenesis in Atf4-null mice prevented steatosis and
hypertriglyceridemia in response to drinking high fructose (30%) water.
In contrast, overexpression of Atf4 in primary mouse hepatocytes was
associated with increased TG synthesis and secretion secondary to
augmented lipogenesis. Xiao et al. (2013) concluded that ATF4 is a
significant factor in regulating hepatic lipid metabolism in response to
nutritional cues.
NOMENCLATURE
The ATF4 gene, which Karpinski et al. (1992) referred to as CREB2,
should not be confused with the ATF2 gene (123811), which was formerly
known as CREB2.
CACNA1I
| dbSNP name | rs3747178(C,T); rs5757730(A,G); rs5757731(C,G); rs5757732(C,T); rs5757733(T,G); rs5750851(T,C); rs73422185(G,C); rs5750852(T,C); rs2413600(T,C); rs3788556(T,C); rs144587111(C,A); rs5757734(T,C); rs73885275(C,T); rs132567(G,A); rs76560316(C,T); rs73885276(C,A); rs73422193(T,C); rs5757736(G,A); rs111500207(C,T); rs8139773(A,G); rs138483265(G,A); rs28631967(A,G); rs132570(C,A); rs132571(A,C); rs5750853(C,T); rs3788557(C,T); rs132572(T,G); rs132574(T,G); rs4353751(C,G); rs132575(A,G); rs132576(A,C); rs132577(A,T); rs74488486(G,T); rs132579(C,T); rs132580(T,C); rs4522708(G,A); rs4374(A,G); rs2413601(A,T); rs147775516(T,C); rs149905361(G,A); rs112285158(C,T); rs5995754(G,A); rs132582(C,T); rs713971(C,T); rs116081189(T,C); rs3788562(G,C); rs132583(C,G); rs2413602(A,G); rs117863931(C,T); rs183575468(G,A); rs2003151(C,T); rs132585(G,A); rs73885279(A,G); rs5757742(T,C); rs5757743(C,T); rs62228488(A,G); rs62228489(A,G); rs1076614(C,T); rs9619822(G,A); rs1883123(C,T); rs713733(G,A); rs5995755(A,G); rs56189860(G,A); rs5750857(G,T); rs5995756(T,C); rs5757746(G,A); rs5757747(T,C); rs73885281(G,A); rs5995757(T,C); rs6001638(T,C); rs6001639(C,A); rs1534883(T,C); rs56123210(G,A); rs77221970(G,A); rs3788566(G,T); rs3788567(G,T); rs5995759(T,C); rs926231(C,G); rs56317205(G,A); rs9306337(A,G); rs713860(T,C); rs1008677(C,T); rs73169382(C,A); rs9611205(G,A); rs5757748(T,A); rs11705236(G,A); rs8140185(C,T); rs3788568(G,T); rs738168(A,C); rs5995760(A,G); rs17401961(G,A); rs5750859(G,A); rs9306338(C,T); rs10212085(G,A); rs3788569(A,G); rs2072714(C,T); rs2072715(A,G); rs1883124(G,C); rs12628643(C,T); rs5995761(T,C); rs5757751(A,G); rs78634990(G,A); rs136803(C,G); rs136805(T,C); rs12170452(A,G); rs136811(T,A); rs136812(T,G); rs73424155(G,A); rs3788571(C,T); rs136813(C,T); rs5757752(G,C); rs140690741(C,T); rs5750860(C,T); rs5750861(C,A); rs5750862(G,A); rs73424163(A,G); rs5757754(G,A); rs55898159(T,C); rs73424168(G,C); rs9607661(T,C); rs73424170(C,T); rs5757756(C,A); rs136814(G,T); rs941431(G,A); rs136815(T,C); rs73424175(C,T); rs73424176(G,A); rs909679(G,A); rs136816(C,T); rs2092179(T,C); rs136817(C,T); rs136818(T,C); rs142759686(A,C); rs73424187(C,T); rs136819(A,G); rs136820(T,C); rs57831008(C,T); rs136822(T,C); rs7288937(G,T); rs7364249(A,G); rs7364282(T,C); rs136823(T,C); rs113087791(G,C); rs2010746(C,G); rs136824(C,G); rs713938(A,G); rs11705208(C,T); rs470071(G,A); rs136825(A,G); rs136827(A,G); rs5757759(A,G); rs5750866(G,A); rs5757760(C,T); rs926334(G,T); rs56859827(G,A); rs136828(A,G); rs136829(T,C); rs136830(T,C); rs136832(C,T); rs76439214(C,T); rs9611209(T,C); rs136834(T,C); rs136835(A,C); rs136844(A,G); rs114024717(C,T); rs136845(G,A); rs9607663(C,T); rs8140771(G,A); rs136846(T,C); rs78617552(G,A); rs732381(A,T); rs12158982(G,A); rs141359252(C,T); rs136848(T,G); rs5757761(T,C); rs136849(T,C); rs136850(T,C); rs136851(T,C); rs199526648(C,T); rs5995764(G,A); rs113038998(C,T); rs136852(T,C); rs136854(C,T); rs136855(A,G); rs5750868(G,A); rs9619825(T,C); rs136856(C,T); rs136857(T,C); rs5757762(G,A); rs5757763(A,G); rs136858(C,T); rs5750869(T,C); rs4821909(T,C); rs8141262(C,T); rs148279787(A,G); rs4821910(T,C); rs5750870(G,A); rs5757764(C,T); rs5757765(T,C); rs4820386(C,T); rs2235341(T,G); rs2235342(T,C); rs738315(T,C); rs73888114(A,G); rs5750871(A,G); rs5757766(T,C); rs11704439(T,G); rs714031(T,C); rs4820387(A,G); rs4820388(C,G); rs9619826(C,T); rs5757768(G,A); rs8136019(C,T); rs3788576(G,A); rs909680(C,T); rs9607667(C,T); rs114034999(T,A); rs150847273(A,G); rs17001423(C,G); rs113876343(C,T); rs75082737(C,T) |
| ccdsGene name | CCDS46710.1 |
| cytoBand name | 22q13.1 |
| EntrezGene GeneID | 8911 |
| EntrezGene Description | calcium channel, voltage-dependent, T type, alpha 1I subunit |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CACNA1I:NM_001003406:exon9:c.G1642A:p.A548T,CACNA1I:NM_021096:exon10:c.G1747A:p.A583T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.618 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9P0X4-3 |
| dbNSFP KGp1 AF | 0.00320512820513 |
| dbNSFP KGp1 Afr AF | 0.00406504065041 |
| dbNSFP KGp1 Amr AF | 0.00276243093923 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00527704485488 |
| dbSNP GMAF | 0.003214 |
| ESP Afr MAF | 0.000277 |
| ESP All MAF | 0.001249 |
| ESP Eur/Amr MAF | 0.001711 |
| ExAC AF | 0.0005391 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Low anterior hairline;
Micrognathia;
Short philtrum;
[Eyes];
Hyperopia;
Cataracts, rapid-onset;
Aphakic glaucoma;
[Mouth];
Full lips;
[Teeth];
Prominent widely-spaced incisors
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect
CHEST:
[Breasts];
Inverted nipples
SKELETAL:
Decreased bone density;
Delayed bone age;
[Spine];
Tethered spinal cord;
Compression deformities of the spine;
Scoliosis
SKIN, NAILS, HAIR:
[Skin];
Sacral dimple;
[Hair];
Low anterior hairline
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Central hypotonia;
Peripheral hypertonia
OMIM Title
*608230 CALCIUM CHANNEL, VOLTAGE-DEPENDENT, T TYPE, ALPHA-1I SUBUNIT; CACNA1I
;;KIAA1120
OMIM Description
DESCRIPTION
Voltage-dependent calcium channels control the rapid entry of Ca(2+)
into a variety of cell types and are therefore involved in both
electrical and cellular signaling. T-type channels, such as CACNA1I, are
activated by small membrane depolarizations and can generate burst
firing and pacemaker activity.
CLONING
By searching a database for T-type alpha-1 sequences, followed by PCR of
a brain cDNA library, Mittman et al. (1999) cloned CACNA1I. The deduced
2,016-amino acid protein shows a membrane topology with 4 domains, each
consisting of 6 membrane-spanning segments, a pore loop, and cytoplasmic
and extracellular connecting loops. The N and C termini are cytoplasmic.
The putative extracellular loops contain 5 potential N-glycosylation
sites and 17 cysteines that may contribute to proper protein
conformation. The long intracellular interdomain loops contain 28
potential phosphorylation sites. The membrane-spanning segments of
CACNA1I are 84% identical to the membrane-spanning segments of CACNA1G
(604065) and CACNA1H (607904).
By screening a database for sequences weakly homologous to alpha-1
calcium channel subunits, followed by PCR of a brain cDNA library,
Monteil et al. (2000) cloned CACNA1I. The deduced 1,981-amino acid
protein has a calculated molecular mass of about 220.8 kD. Northern blot
analysis detected a 10.5-kb transcript almost exclusively in brain.
Northern and mRNA dot blot analyses detected expression in most
individual brain regions examined, and dot blot analysis also detected
expression in adrenal gland and thyroid gland.
By screening brain cDNA libraries using rat Cacna1i as probe, followed
by genomic sequence analysis and PCR, Gomora et al. (2002) cloned
CACNA1I, which they called Ca(v)3.3. The deduced 2,188-amino acid
protein differs from those reported by Mittman et al. (1999) and Monteil
et al. (2000) in that it has a C-terminal extension containing a leucine
zipper motif.
GENE FUNCTION
By functional expression in human embryonic kidney cells, Monteil et al.
(2000) determined that CACNA1I was activated at a more positive voltage
than CACNA1G. Activation and inactivation kinetics were up to 6 times
slower in CACNA1I-transfected cells than in CACNA1G-transfected cells,
while deactivation kinetics were faster and showed little voltage
dependence. Other characteristics of CACNA1I currents included a slower
recovery from inactivation, lower sensitivity to Ni(2+), and a larger
channel conductance. Monteil et al. (2000) concluded that CACNA1I is a
T-type channel with distinct channel properties.
Gomora et al. (2002) determined that the full-length 2,188-amino acid
CACNA1I protein and 2 CACNA1I constructs with truncated C termini showed
similar kinetics of channel activation, inactivation, deactivation, and
recovery. A major difference was that the 2,188-amino acid protein
generated 2-fold more current than the truncated isoforms. A fraction of
the CACNA1I channels did not gate as low voltage-activated channels but
required stronger depolarizations to open. A strong depolarizing
prepulse increased the fraction of channels that gated at low voltage.
The C-terminally truncated CACNA1I isoforms were less affected by a
prepulse. Gomora et al. (2002) concluded that CACNA1I is similar to high
voltage-activated Ca(2+) channels in that depolarizing prepulses can
regulate its activity and its C terminus plays a role in modulating
channel activity.
By action potential clamp studies, Chemin et al. (2002) found
significant differences in the biochemical properties of CACNA1G,
CACNA1H, and CACNA1I following transient transfection in human embryonic
kidney cells. Using firing activities recorded in dissociated rat
cerebellar Purkinje neurons and thalamocortical relay neurons as
voltage-clamp waveforms, they showed that CACNA1I currents contributed
to sustained electrical activities, while CACNA1G and CACNA1H currents
generated short burst firing. Chemin et al. (2002) hypothesized that
each of the T-channel pore-forming subunits displays specific gating
properties that uniquely contribute to neuronal firing and that CACNA1I
channels provide pacemaker activity.
GENE STRUCTURE
Mittman et al. (1999) determined that the CACNA1I gene contains at least
36 exons and spans more than 115 kb. Exon 1 is untranslated. Mittman et
al. (1999) stated that alternative splicing occurs in at least 2 exons.
Gomora et al. (2002) identified an additional exon in the CACNA1I gene,
exon 37, which encodes a C-terminal extension.
MAPPING
By genomic sequence analysis, Mittman et al. (1999) and Monteil et al.
(2000) mapped the CACNA1I gene to chromosome 22q12.3-q13.2. Gomora et
al. (2002) stated that the CACNA1I gene maps to chromosome 22q13.1.
LOC100130899
| dbSNP name | rs6001722(G,A); rs6001723(A,G); rs9611253(T,A); rs9611254(T,C); rs7285314(G,A); rs9607683(A,G); rs17001585(A,G) |
| cytoBand name | 22q13.1 |
| EntrezGene GeneID | 100130899 |
| snpEff Gene Name | FAM83F |
| EntrezGene Description | uncharacterized LOC100130899 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2153 |
DNAJB7
| dbSNP name | rs77018551(A,G); rs112440129(G,A); rs148881292(G,A); rs103197(A,G) |
| ccdsGene name | CCDS14007.1 |
| cytoBand name | 22q13.2 |
| EntrezGene GeneID | 150353 |
| snpEff Gene Name | XPNPEP3 |
| EntrezGene Description | DnaJ (Hsp40) homolog, subfamily B, member 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02938 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Mild facial weakness (less common)
MUSCLE, SOFT TISSUE:
Proximal muscle weakness;
Hip girdle muscle weakness;
Shoulder girdle muscle weakness;
Asymmetric muscle involvement;
Prominent involvement of the quadriceps femoris muscles;
Quadriceps atrophy;
Prominent involvement of the biceps brachii muscles;
Biceps brachii atrophy;
Myalgia;
Calf hypertrophy (less common);
EMG shows myopathic changes;
Skeletal muscle biopsy shows dystrophic changes;
Muscle biopsy shows disruption of the sarcolemmal membrane;
MRI shows increased connective tissue and fat
LABORATORY ABNORMALITIES:
Normal or increased serum creatine kinase
MISCELLANEOUS:
Intrafamilial variability;
Variable severity;
Range of onset 11 to 50 years;
Progressive disorder;
Patients may become wheelchair-bound after about 12 years;
Allelic disorder to Miyoshi muscular dystrophy 3 (MMD3, 613319)
MOLECULAR BASIS:
Caused by mutation in the transmembrane protein 16E gene (TMEM16E,
608662.0003)
OMIM Title
*611336 DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 7; DNAJB7
;;DJ5;;
HSC3
OMIM Description
DESCRIPTION
DNAJB7 belongs to the evolutionarily conserved DNAJ/HSP40 family of
proteins, which regulate molecular chaperone activity by stimulating
ATPase activity. DNAJ proteins may have up to 3 distinct domains: a
conserved 70-amino acid J domain, usually at the N terminus; a
glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain
containing 4 motifs resembling a zinc finger domain (Ohtsuka and Hata,
2000).
CLONING
By searching EST databases for J domain-containing proteins, Ohtsuka and
Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse
DnajB7. The predicted type II transmembrane protein contains 220 amino
acids with an N-terminal J domain.
LDOC1L
| dbSNP name | rs6007169(G,C); rs3747218(G,C); rs9819(C,T); rs77560341(T,G); rs3747220(G,A); rs3827400(T,C); rs3827401(A,G); rs131154(C,G); rs77074261(A,C); rs131155(A,G); rs131156(T,C); rs105248(C,G); rs131157(A,G); rs131158(A,G); rs131159(C,T); rs131163(A,G); rs5765680(G,C); rs148791568(C,G) |
| cytoBand name | 22q13.31 |
| EntrezGene GeneID | 84247 |
| EntrezGene Description | leucine zipper, down-regulated in cancer 1-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1488 |
LOC730668
| dbSNP name | rs28698504(G,A); rs4078329(C,A); rs28659885(C,A); rs184557290(A,G); rs28591189(T,C); rs114983752(C,G) |
| cytoBand name | 22q13.31 |
| EntrezGene GeneID | 730668 |
| EntrezGene Description | dynein heavy chain -like pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1736 |
PKDREJ
| dbSNP name | rs41279831(T,C); rs8135363(T,C); rs56017104(A,G); rs6007728(C,T); rs6008357(T,G); rs12158566(G,A); rs6007729(C,T); rs6007730(C,T); rs6007732(A,T); rs6008361(G,A); rs6008362(G,A); rs6008365(G,A); rs4508712(A,G); rs6007740(G,A); rs141748832(G,A); rs145798089(A,G); rs35272610(C,T); rs36125344(G,C); rs6008384(T,C); rs34798212(A,G); rs7291444(T,G); rs112258541(C,A); rs6519993(A,G); rs9627324(A,G); rs7287371(A,G); rs8143066(G,A); rs6519994(G,A); rs6007747(A,G); rs6008394(C,T); rs6007748(A,G) |
| cytoBand name | 22q13.31 |
| EntrezGene GeneID | 10343 |
| EntrezGene Description | polycystin (PKD) family receptor for egg jelly |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0753 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Chronic otitis media;
[Eyes];
Ectopia lentis;
[Nose];
Nasal polyposis;
Chronic sinusitis;
Pansinusitis
RESPIRATORY:
[Airways];
Unilateral bronchiectasis;
Bilateral bronchiectasis;
Bronchiolitis;
Bronchitis;
Bronchial obstruction;
Bacterial infections of the respiratory tract;
[Lung];
Emphysema
SKIN, NAILS, HAIR:
[Skin];
Localized cutaneous necrobiosis lipoidica;
Pigmentary abnormalities;
Deep skin ulcers
LABORATORY ABNORMALITIES:
Normal CD8+/CD4+ ratio
MISCELLANEOUS:
Reduced life expectancy
MOLECULAR BASIS:
Caused by mutation in the transporter, ATP-binding cassette, major
histocompatibility complex, 2 gene (TAP2, 170261.0004)
OMIM Title
*604670 POLYCYSTIN AND SEA URCHIN REJ HOMOLOG-LIKE; PKDREJ
OMIM Description
CLONING
By searching cDNA and genomic databases for sequences similar to PKD1
(601313), PKD2 (173910), and the sea urchin sperm receptor for egg jelly
(suREJ), Hughes et al. (1999) identified an intronless gene, which they
designated PKDREJ, on cosmids located on chromosome 22q13. By screening
a testis cDNA library, the authors obtained a PKDREJ cDNA encoding a
deduced 2,253-amino acid protein. The PKDREJ protein is 64% identical
and 78% similar to the mouse Pkdrej protein. Hydrophobicity analysis
indicated that the structure of PKDREJ, with 11 transmembrane regions,
is similar to that of PKD1. Northern blot analysis showed expression of
an approximately 8-kb PKDREJ transcript exclusively in testis,
coincident with the timing of sperm maturation.
MAPPING
By radiation hybrid analysis, Veldhuisen et al. (1999) mapped the PKDREJ
gene to chromosome 22q13.3.
EVOLUTION
Sperm-egg interaction is a crucial step in fertilization, but the
interacting sperm-egg proteins that mediate this process remained
elusive. Rapid evolution of some fertilization proteins had been
observed in a number of species, including evidence of positive
selection in the evolution of components of the mammalian egg coat. The
rapid evolution of the egg coat proteins could strongly select for
changes on the sperm receptor, to maintain the interaction. Hamm et al.
(2007) presented evidence that positive selection has driven the
evolution of PKDREJ, a candidate sperm receptor of mammalian egg coat
proteins. They sequenced PKDREJ from a panel of 14 primates, including
humans, and conducted a comparative maximum-likelihood analysis of
nucleotide changes and found evidence of positive selection. An
additional panel of 48 humans were surveyed for nucleotide polymorphisms
at the PKDREJ locus. The regions predicted to have been subject to
adaptive evolution among primates showed several amino acid
polymorphisms among humans. The distribution of polymorphisms suggested
that balancing selection may maintain diverse PKDREJ alleles in some
populations. Unknown was whether there are functional differences
associated with these diverse alleles.
GTSE1-AS1
| dbSNP name | rs8140182(T,C); rs11704614(A,G); rs7286885(G,A); rs12159855(G,C) |
| cytoBand name | 22q13.31 |
| EntrezGene GeneID | 150384 |
| snpEff Gene Name | TTC38 |
| EntrezGene Description | GTSE1 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09045 |
LOC90834
| dbSNP name | rs7291527(T,C); rs138826(A,G); rs4823961(G,A); rs138827(T,C); rs138829(T,C); rs4824095(A,T) |
| ccdsGene name | CCDS14080.1 |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 90834 |
| snpEff Gene Name | BRD1 |
| EntrezGene Description | uncharacterized protein BC001742 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.05693 |
PIM3
| dbSNP name | rs4077129(T,C); rs1801645(C,T); rs114867023(C,T) |
| ccdsGene name | CCDS33678.1 |
| CosmicCodingMuts gene | PIM3_ENST00000360612 |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 415116 |
| EntrezGene Description | pim-3 oncogene |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PIM3:NM_001001852:exon6:c.T899C:p.V300A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q86V86 |
| dbNSFP Uniprot ID | PIM3_HUMAN |
| dbNSFP KGp1 AF | 0.781135531136 |
| dbNSFP KGp1 Afr AF | 0.768292682927 |
| dbNSFP KGp1 Amr AF | 0.814917127072 |
| dbNSFP KGp1 Asn AF | 0.795454545455 |
| dbNSFP KGp1 Eur AF | 0.76253298153 |
| dbSNP GMAF | 0.2195 |
| ESP Afr MAF | 0.23508 |
| ESP All MAF | 0.245571 |
| ESP Eur/Amr MAF | 0.250931 |
| ExAC AF | 0.722,8.184e-06 |
OMIM Clinical Significance
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Facial weakness;
[Eyes];
Ptosis (less common);
Absence of ophthalmoparesis;
[Neck];
Neck muscle weakness
RESPIRATORY:
Respiratory muscle weakness may occur
MUSCLE, SOFT TISSUE:
Muscle biopsy shows 60-80-nm tubular aggregates arranged in hexagonal
arrays in type 2 fibers
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor milestones (in some);
Proximal muscle weakness due to defect at the neuromuscular junction;
Proximal muscle atrophy;
Distal muscle weakness may also occur;
Easy fatigability;
Muscle cramps;
Gowers sign;
Waddling gait;
Decremental compound motor action potential (CMAP) response to repetitive
nerve stimulation seen on EMG;
Increased jitter seen on single fiber EMG
IMMUNOLOGY:
Absence of acetylcholine receptor (AChR) autoantibodies
LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase
MISCELLANEOUS:
Onset in first decade;
Favorable response to acetylcholinesterase inhibitors;
Distinct disorder from acquired limb-girdle myasthenia (159400)
and congenital limb-girdle myasthenia (254300)
MOLECULAR BASIS:
Caused by mutation in the glutamine:fructose-6-phosphate aminotransferase
1 gene (GFPT1, 138292.0001)
OMIM Title
*610580 ONCOGENE PIM3; PIM3
;;SERINE/THREONINE PROTEIN KINASE PIM3
OMIM Description
DESCRIPTION
PIM3 belongs to a family of protooncogenes that encode serine/threonine
protein kinases (Mikkers et al., 2004).
CLONING
By screening for genes upregulated in premalignant lesions in mouse
liver, followed by screening a human hepatoma cell line cDNA library,
Fujii et al. (2005) cloned PIM3. The deduced 326-amino acid protein has
a calculated molecular mass of 35.9 kD. PIM3 shares 95% amino acid
identity with rodent Pim3 and 57.1% and 44.0% amino acid identity with
human PIM1 (164960) and PIM2 (300295), respectively. Northern blot
analysis detected a 2.4-kb transcript in heart, skeletal muscle, brain,
spleen, kidney, placenta, lung, and peripheral blood leukocytes.
Expression was not detected in colon, thymus, liver, and small
intestine. Immunohistochemical analysis showed no expression of PIM3 in
normal liver, but it localized diffusely in large regenerative nodules
and adenomatous hyperplasia, lesions with precancerous potential,
adjacent to hepatocellar carcinoma areas. PIM3 was expressed in all
hepatoma cell lines examined.
GENE FUNCTION
EWS/ETS fusion proteins (see 133450) form a group of structurally
related oncoproteins found specifically in Ewing family tumors. Deneen
et al. (2003) identified Pim3 among several genes upregulated in a mouse
fibroblast cell line expressing human EWS/ETS proteins and in human
Ewing family tumor cell lines. Ectopic expression of rat Pim3 promoted
anchorage-independent growth in mouse fibroblasts, and coexpression of a
kinase-deficient Pim3 mutant attenuated EWS/ETS-mediated tumorigenesis
in immunodeficient mice.
Fujii et al. (2005) found that downregulation of PIM3 using small
interfering RNA (siRNA) significantly retarded cell proliferation in
human hepatoma cell lines.
By immunohistochemical analysis, Li et al. (2006) detected PIM3
expression in human pancreatic cancer tissue and pancreatic cancer cell
lines, but not in normal pancreatic tissue. Ablation of PIM3 expression
by siRNA promoted apoptosis in a human pancreatic cancer cell line,
reduced phosphorylation of BAD (603167) at ser112, and reduced BCLXL
(600039) protein expression.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PIM3
gene to chromosome 22 (TMAP WI-11798).
ANIMAL MODEL
Mikkers et al. (2004) generated compound Pim-deficient mice lacking
Pim1, Pim2, and Pim3. These mice were viable and fertile, but their body
size was reduced at birth and throughout postnatal life. Proliferation
of hematopoietic cells in response to growth factors was impaired in
vitro and in vivo. In addition, Pim proteins were required for efficient
cell cycle induction of peripheral T cells in response to synergistic
T-cell receptor (see 186790) and interleukin-2 (IL2; 147680) signaling.
DENND6B
| dbSNP name | rs67248662(G,C); rs371843726(G,A); rs73439311(G,A); rs35759545(C,T); rs62241228(T,C); rs373469067(T,G); rs35812349(A,G); rs62241230(C,T); rs11553141(T,C); rs73439316(C,T); rs78060754(C,T); rs73439320(A,G); rs62241231(G,A); rs62241232(G,A); rs67488807(T,C); rs62241233(T,C); rs62241235(C,T); rs62241236(G,T); rs62241237(C,T); rs114288684(C,T); rs73439323(T,C); rs62241238(G,A); rs62241239(C,A); rs72490267(G,A); rs111715507(C,T); rs62241241(A,G); rs62241242(A,C); rs112558821(T,C); rs73439331(G,A); rs75339271(C,T); rs67447900(A,G); rs62241243(T,C); rs4074135(T,C) |
| ccdsGene name | CCDS46732.1 |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 414918 |
| snpEff Gene Name | FAM116B |
| EntrezGene Description | DENN/MADD domain containing 6B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DENND6B:NM_001001794:exon10:c.C842T:p.S281L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5551 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8NEG7 |
| dbNSFP Uniprot ID | F116B_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 8e-05 |
| ESP Eur/Amr MAF | 0.000119 |
| ExAC AF | 2.456e-05 |
ADM2
| dbSNP name | rs112907082(C,T); rs13056677(G,A); rs2236031(C,T); rs876278(C,G); rs761745(T,C); rs62239483(G,C); rs4342045(G,A); rs9628167(C,T); rs141276299(C,T) |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 79924 |
| EntrezGene Description | adrenomedullin 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.01791 |
| ExAC AF | 0.003337 |
ODF3B
| dbSNP name | rs74795169(C,T) |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 440836 |
| EntrezGene Description | outer dense fiber of sperm tails 3B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retained_intron |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03306 |
KLHDC7B
| dbSNP name | rs131779(A,G); rs5770887(T,C); rs41281529(C,T); rs7291641(C,T); rs131778(A,G) |
| ccdsGene name | CCDS14097.2 |
| CosmicCodingMuts gene | KLHDC7B |
| cytoBand name | 22q13.33 |
| EntrezGene GeneID | 113730 |
| EntrezGene Description | kelch domain containing 7B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | KLHDC7B:NM_138433:exon1:c.A1598G:p.H533R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96G42 |
| dbNSFP Uniprot ID | KLD7B_HUMAN |
| dbNSFP KGp1 AF | 0.591575091575 |
| dbNSFP KGp1 Afr AF | 0.567073170732 |
| dbNSFP KGp1 Amr AF | 0.530386740331 |
| dbNSFP KGp1 Asn AF | 0.590909090909 |
| dbNSFP KGp1 Eur AF | 0.637203166227 |
| dbSNP GMAF | 0.4086 |
| ESP Afr MAF | 0.41968 |
| ESP All MAF | 0.376026 |
| ESP Eur/Amr MAF | 0.353699 |
| ExAC AF | 0.617 |
LOC100288814
| dbSNP name | rs5934730(G,T); rs5934731(C,T) |
| cytoBand name | Xp22.2 |
| EntrezGene GeneID | 100288814 |
| snpEff Gene Name | AC002365.1 |
| EntrezGene Description | uncharacterized LOC100288814 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LOC100288814:NM_001195081:exon1:c.G129T:p.S43S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4045 |
| ExAC AF | 0.459 |
ATXN3L
| dbSNP name | rs4830842(C,T) |
| ccdsGene name | CCDS48080.1 |
| cytoBand name | Xp22.2 |
| EntrezGene GeneID | 100093698 |
| EntrezGene Symbol | LOC100093698 |
| EntrezGene Description | unknown transcript |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | ATXN3L:NM_001135995:exon1:c.G995A:p.G332D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H3M9 |
| dbNSFP Uniprot ID | ATX3L_HUMAN |
| dbNSFP KGp1 AF | 0.62447257384 |
| dbNSFP KGp1 Afr AF | 0.732876712329 |
| dbNSFP KGp1 Amr AF | 0.495901639344 |
| dbNSFP KGp1 Asn AF | 0.704819277108 |
| dbNSFP KGp1 Eur AF | 0.196825396825 |
| dbSNP GMAF | 0.3755 |
| ESP Afr MAF | 0.237533 |
| ESP All MAF | 0.475692 |
| ESP Eur/Amr MAF | 0.338669 |
| ExAC AF | 0.478 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Prominent forehead;
[Face];
Dysmorphic features
SKELETAL:
[Hands];
Broad thumbs
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients);
Obsessive behaviour (in some patients)
MISCELLANEOUS:
Variable features;
Two families have been reported (as of curation date April 2014)
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-specific protease 9, X chromosome
gene (USP9X, 300072.0001)
OMIM Title
*300920 ATAXIN 3-LIKE; ATXN3L
OMIM Description
DESCRIPTION
The reversible and covalent attachment of ubiquitin (see 191339) to
lysine residues by ubiquitin ligases (see 605532) regulates the
function, trafficking, and stability of many proteins. Members of the
Josephin family of deubiquitinating enzymes (see 615323), such as
ATXN3L, oppose the activity of ubiquitin ligases (Weeks et al., 2011).
CLONING
Weeks et al. (2011) reported that the deduced ATXN3L protein has a
190-amino acid N-terminal Josephin-type cysteine protease domain and a
flexible C-terminal domain. The Josephin domain contains the catalytic
triad of cys14, his119, and asn134, and it shares 85% identity with the
Josephin domain of ATXN3 (607047).
GENE FUNCTION
Weeks et al. (2011) found that the isolated Josephin domain of ATXN3L
showed higher deubiquitinating activity than that of ATXN3 against a
synthetic fluorescent ubiquitin substrate and against unanchored
lys48-linked or lys63-linked polyubiquitin chains. Mutation of 3 ATXN3
residues elevated ATXN3 activity to near that displayed by ATXN3L.
BIOCHEMICAL FEATURES
Weeks et al. (2011) determined the crystal structure of the ATXN3L
Josephin domain complexed to ubiquitin at 2.6-angstrom resolution. The
asymmetric crystal unit contained 4 copies of the Josephin-ubiquitin
complex, and each Josephin domain adopted the same overall fold as the
ATXN3 Josephin domain. The shape was similar to that of a hitchhiker's
hand, with a helical hairpin forming the protruding thumb and the
remainder forming the closed fist, with the active site located at the
thumb-fist interface. Ubiquitin positioned snugly at this interface near
the catalytic triad, but it engaged in only weak interactions with
residues in the Josephin domain.
GENE STRUCTURE
Weeks et al. (2011) determined that ATXN3L is an intronless gene.
MAPPING
Hartz (2014) mapped the ATXN3L gene to chromosome Xp22.2 based on an
alignment of the ATXN3L sequence (GenBank GENBANK AB050195) with the
genomic sequence (GRCh37).
EVOLUTION
By database analysis, Weeks et al. (2011) identified the ATXN3L gene
only in primates. ATXN3L appeared to have arisen relatively recently,
just prior to the first major division between hominids and Old World
monkeys.
UBE2E4P
| dbSNP name | rs140143052(T,C) |
| cytoBand name | Xp22.2 |
| EntrezGene GeneID | 286480 |
| snpEff Gene Name | GS1-257G1.1 |
| EntrezGene Description | ubiquitin-conjugating enzyme E2E 4 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retrotransposed |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.005441 |
INE2
| dbSNP name | rs57459975(C,T); rs10521650(G,A); rs5936053(G,A) |
| cytoBand name | Xp22.2 |
| EntrezGene GeneID | 11238 |
| EntrezGene Symbol | CA5B |
| snpEff Gene Name | CA5B |
| EntrezGene Description | carbonic anhydrase VB, mitochondrial |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02781 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
SKELETAL:
[Pelvis];
Hip contractures;
[Limbs];
Knee contractures;
Ankle contractures;
[Feet];
Vertical tali;
Flat feet
NEUROLOGIC:
[Central nervous system];
Gait difficulties due to contractures of the lower limbs
MISCELLANEOUS:
One family has been reported (last curated May 2012);
Nonprogressive disorder;
Affected individuals remain ambulatory
OMIM Title
*300165 INACTIVATION ESCAPE 2; INE2
OMIM Description
CLONING
In a screen for genes that escape X inactivation, Esposito et al. (1997)
found 2 novel genes, INE1 (300164) and INE2. The INE2 cDNA contained no
significant open reading frame; however, a poly(A) signal and
polyadenylation were present. Northern blot analysis demonstrated a 2-kb
mRNA in human adult brain. INE2 has no corresponding sequence on the Y
chromosome.
MAPPING
Esposito et al. (1997) used fluorescence in situ hybridization to map
the INE2 gene to Xp22.2.
YY2
| dbSNP name | rs2382759(T,C) |
| ccdsGene name | CCDS14201.1 |
| cytoBand name | Xp22.12 |
| EntrezGene GeneID | 404281 |
| snpEff Gene Name | MBTPS2 |
| EntrezGene Description | YY2 transcription factor |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4498 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
MUSCLE, SOFT TISSUE:
Muscle weakness;
Muscle atrophy;
Muscle pain, exercise-induced;
Muscle stiffness, exercise-induced;
Exercise intolerance;
Muscle biopsy shows increased subsarcolemmal vacuolar glycogen accumulation;
Muscle biopsy shows mitochondrial paracrystalline inclusions;
Muscle biopsy shows decreased muscle-specific phosphorylase kinase
activity
LABORATORY ABNORMALITIES:
Increased serum creatine kinase;
Myoglobinuria, exercise-induced
MISCELLANEOUS:
Variable age at onset (childhood to adult);
Most patients have adult onset of symptoms
MOLECULAR BASIS:
Caused by mutation in the muscle-specific phosphorylase kinase subunit
A1 gene (PHKA1, 311870.0001)
OMIM Title
*300570 TRANSCRIPTION FACTOR YY2; YY2
;;ZNF631
OMIM Description
CLONING
By database searching, Nguyen et al. (2004) identified and subsequently
cloned from a HeLa cell cDNA library a novel cDNA encoding a protein
with significant homology to the transcription factor YY1 (600013). The
cDNA, called YY2, encodes a deduced 372-amino acid protein with several
Kruppel-like zinc fingers in the C-terminal region. The YY2 and YY1
proteins share 56.2% overall sequence identity and 86.4% identity in the
zinc finger regions. Northern blot analysis of HeLa cell RNA revealed a
major YY2 transcript of approximately 7.3 kb and several minor bands.
Western blot analysis detected a YY2 protein of about 58 kD and
expression of YY2 in all human tissues and cell lines tested except
colon.
GENE FUNCTION
Using electrophoretic mobility shift assays (EMSA), Nguyen et al. (2004)
found that YY2 can bind to and regulate some promoters known to be
controlled by YY1, including CSF3 (138970), p53 (191170), MYC (190080),
FOS (164810), and CXCR4 (162643). YY2 did not bind to YY1-binding sites
in several other promoters tested. Using YY2 deletion mutant
experiments, Nguyen et al. (2004) identified a potent activation domain
in the N terminus of YY2 (amino acids 32-102), a repression domain in
the C terminus (amino acids 237-372), and possibly additional repression
domains in the region between amino acids 102 and 237. Reporter gene
assays demonstrated that YY2 activates transcription of p53 and FOS
promoters but at lower rather than higher concentrations in FOS. It also
activates MYC and CXCR4 transcription at low concentrations but
represses their transcriptional activity at high concentrations.
MAPPING
By sequence analysis, Nguyen et al. (2004) mapped the YY2 gene to
chromosome Xp22.2-p22.1.
ZNF645
| dbSNP name | rs5951426(C,A); rs6629461(C,T) |
| ccdsGene name | CCDS14205.1 |
| cytoBand name | Xp22.11 |
| EntrezGene GeneID | 100873065 |
| EntrezGene Symbol | LOC100873065 |
| EntrezGene Description | uncharacterized LOC100873065 |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | ZNF645:NM_152577:exon1:c.C498A:p.D166E, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N7E2 |
| dbNSFP Uniprot ID | ZN645_HUMAN |
| dbNSFP KGp1 AF | 0.382760699216 |
| dbNSFP KGp1 Afr AF | 0.616564417178 |
| dbNSFP KGp1 Amr AF | 0.222929936306 |
| dbNSFP KGp1 Asn AF | 0.28801843318 |
| dbNSFP KGp1 Eur AF | 0.0574229691877 |
| dbSNP GMAF | 0.3827 |
| ESP Afr MAF | 0.32073 |
| ESP All MAF | 0.317807 |
| ESP Eur/Amr MAF | 0.111772 |
| ExAC AF | 0.222 |
VENTXP1
| dbSNP name | rs5944523(C,T); rs5944524(A,G); rs5944525(C,T); rs5944526(C,T); rs16997824(T,C) |
| cytoBand name | Xp21.3 |
| EntrezGene GeneID | 139538 |
| snpEff Gene Name | RP11-702C7.1 |
| EntrezGene Description | VENT homeobox pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02418 |
SMEK3P
| dbSNP name | rs16987899(G,A); rs5926442(C,T); rs5926772(G,A); rs151016097(G,A); rs12842916(A,G); rs73628812(C,T); rs5971193(C,G) |
| cytoBand name | Xp21.3 |
| EntrezGene GeneID | 139420 |
| snpEff Gene Name | GS1-309P15.2 |
| EntrezGene Description | SMEK homolog 3, suppressor of mek1 (Dictyostelium) pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.052 |
DCAF8L2
| dbSNP name | rs5926895(A,G); rs45553337(G,A) |
| ccdsGene name | CCDS59162.1 |
| CosmicCodingMuts gene | DCAF8L2 |
| cytoBand name | Xp21.3 |
| EntrezGene GeneID | 347442 |
| snpEff Gene Name | RP11-501H19.4 |
| EntrezGene Description | DDB1 and CUL4 associated factor 8-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DCAF8L2:NM_001136533:exon1:c.A1033G:p.T345A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1892 |
| ESP Afr MAF | 0.135649 |
| ESP All MAF | 0.291667 |
| ESP Eur/Amr MAF | 0.370556 |
| ExAC AF | 0.296 |
DCAF8L1
| dbSNP name | rs73628870(C,T); rs148204863(G,C); rs61735182(T,C) |
| cytoBand name | Xp21.3 |
| EntrezGene GeneID | 139425 |
| EntrezGene Description | DDB1 and CUL4 associated factor 8-like 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09553 |
MAGEB4
| dbSNP name | rs2071311(A,G); rs2856733(G,C) |
| ccdsGene name | CCDS14221.1 |
| CosmicCodingMuts gene | MAGEB4 |
| cytoBand name | Xp21.2 |
| EntrezGene GeneID | 4115 |
| EntrezGene Description | melanoma antigen family B, 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEB4:NM_002367:exon1:c.A750G:p.V250V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.188 |
| ESP Afr MAF | 0.104879 |
| ESP All MAF | 0.103683 |
| ESP Eur/Amr MAF | 0.103002 |
| ExAC AF | 0.856 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Face];
Mild dysmorphic features;
Hypotonic midface;
Prominent jaw;
[Ears];
Thick ears;
Upturned lobes;
[Eyes];
Hypertelorism;
Upslanted palpebral fissures;
Synophrys;
[Nose];
Short nose;
Thickened alae nasi and columella;
[Mouth];
Open mouth;
Tented upper lip;
[Teeth];
Crowded dentition
SKELETAL:
Hyperextensible joints
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate;
Seizures (1 family);
[Behavioral/psychiatric manifestations];
Autistic features;
Hyperactivity
MISCELLANEOUS:
Carrier females may have mild features
MOLECULAR BASIS:
Caused by mutation in the IL1 receptor accessory protein-like 1 gene
(IL1RAPL, 300206.0001)
OMIM Title
*300153 MELANOMA ANTIGEN, FAMILY B, 4; MAGEB4
OMIM Description
Genes of the MAGE family direct the expression of tumor antigens that
are recognized on a human melanoma by autologous cytolytic T
lymphocytes. See MAGEA1 (300016).
CLONING
Lurquin et al. (1997) identified the MAGEB4 gene within a cluster of 4
MAGE-related genes in Xp21.3. See MAGEB1 (300097). RT-PCR analysis found
that MAGEB4 is expressed in testis. The deduced MAGEB3 protein has 346
amino acids.
MAPPING
The MAGEB4 gene maps within the MAGEB gene cluster on chromosome Xp21.3
(Lurquin et al., 1997).
See 300016 for a discussion of the high frequency of genes on the X
chromosome encoding proteins with the MAGE domain as well as other
cancer-testis antigen genes (Ross et al., 2005).
FAM47B
| dbSNP name | rs6632131(A,C) |
| cytoBand name | Xp21.1 |
| EntrezGene GeneID | 170062 |
| EntrezGene Description | family with sequence similarity 47, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4462 |
| ESP Afr MAF | 0.354216 |
| ESP All MAF | 0.305753 |
| ESP Eur/Amr MAF | 0.278125 |
| ExAC AF | 0.353,1.674e-05 |
FAM47C
| dbSNP name | rs1995914(A,C) |
| ccdsGene name | CCDS35227.1 |
| cytoBand name | Xp21.1 |
| EntrezGene GeneID | 442444 |
| EntrezGene Description | family with sequence similarity 47, member C |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FAM47C:NM_001013736:exon1:c.A2771C:p.N924T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5HY64 |
| dbNSFP Uniprot ID | FA47C_HUMAN |
| dbNSFP KGp1 AF | 0.298372513562 |
| dbNSFP KGp1 Afr AF | 0.705882352941 |
| dbNSFP KGp1 Amr AF | 0.169811320755 |
| dbNSFP KGp1 Asn AF | 0.0680147058824 |
| dbNSFP KGp1 Eur AF | 0.0592286501377 |
| dbSNP GMAF | 0.2975 |
| ESP Afr MAF | 0.219671 |
| ESP All MAF | 0.357353 |
| ESP Eur/Amr MAF | 0.116379 |
| ExAC AF | 0.202,3.253e-05 |
FTH1P18
| dbSNP name | rs112906128(G,A); rs185811149(C,T) |
| cytoBand name | Xp21.1 |
| EntrezGene GeneID | 441490 |
| EntrezGene Description | ferritin, heavy polypeptide 1 pseudogene 18 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FTH1P18:NM_001271682:exon1:c.C345T:p.R115R, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | unprocessed_pseudogene |
| snpEff Impact | modifier |
LOC100132831
| dbSNP name | rs66771561(T,G) |
| cytoBand name | Xp11.4 |
| EntrezGene GeneID | 100132831 |
| snpEff Gene Name | RP11-169L17.5 |
| EntrezGene Description | A20-binding inhibitor of NF-kappaB activation 2 pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.136 |
DUSP21
| dbSNP name | rs1045031(T,C) |
| ccdsGene name | CCDS14264.1 |
| cytoBand name | Xp11.3 |
| EntrezGene GeneID | 63904 |
| EntrezGene Description | dual specificity phosphatase 21 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DUSP21:NM_022076:exon1:c.T557C:p.M186T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H596 |
| dbNSFP Uniprot ID | DUS21_HUMAN |
| dbNSFP KGp1 AF | 0.195901145268 |
| dbNSFP KGp1 Afr AF | 0.517647058824 |
| dbNSFP KGp1 Amr AF | 0.0457142857143 |
| dbNSFP KGp1 Asn AF | 0.0340501792115 |
| dbNSFP KGp1 Eur AF | 0.0255376344086 |
| dbSNP GMAF | 0.1953 |
| ESP Afr MAF | 0.421904 |
| ESP All MAF | 0.249266 |
| ESP Eur/Amr MAF | 0.061831 |
| ExAC AF | 0.117 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Tall, thin habitus
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Long, thin face;
Prominent forehead;
Maxillary hypoplasia;
Prominent jaw;
[Nose];
High nasal bridge;
[Mouth];
High-arched palate
CHEST:
[External features];
Pectus excavatum;
Pectus carinatum;
Narrow chest
SKELETAL:
[Spine];
Kyphosis;
Scoliosis;
[Hands];
Long hands;
Long fingers;
[Feet];
Long feet
MUSCLE, SOFT TISSUE:
Poor musculature
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild to severe;
[Behavioral/psychiatric manifestations];
Autistic features
VOICE:
Hypernasal voice
MOLECULAR BASIS:
Caused by mutation in the UPF3, B, yeast homolog gene (UPF3B, 300298.0001)
OMIM Title
*300678 DUAL-SPECIFICITY PHOSPHATASE 21; DUSP21
;;LMWDSP21
OMIM Description
DESCRIPTION
Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous
subgroup of the type I cysteine-based protein-tyrosine phosphatase
superfamily. DUSPs are characterized by their ability to dephosphorylate
both tyrosine and serine/threonine residues. They have been implicated
as major modulators of critical signaling pathways. DUSP21 contains the
consensus DUSP C-terminal catalytic domain but lacks the N-terminal CH2
domain found in the MKP (mitogen-activated protein kinase phosphatase)
class of DUSPs (see 600714) (summary by Patterson et al., 2009).
CLONING
By EST database analysis, Hood et al. (2002) identified DUSP21, which
they called LMWDSP21. The deduced 190-amino acid DUSP21 protein has a
calculated molecular mass of 21.5 kD and contains the DUSP consensus
motif and the conserved PTP signature motif and catalytic domain without
the N-terminal CH2 domain. DUSP21 shares 70% and 44% amino acid identity
with DUSP18 (611446) and DUSP14 (606618), respectively. Expression array
and Northern blot analysis of human tissues detected DUSP21 expression
in testis only. DUSP21 localized to both the nucleus and cytoplasm in
transfected simian kidney cells.
GENE FUNCTION
Hood et al. (2002) demonstrated that DUSP21 displayed in vitro
phosphotyrosine activity using phosphotyrosine analog pNPP as a
substrate. Using synthetic MAPK phosphopeptides, they showed that DUSP21
displayed a preference for phosphotyrosine and dually phosphorylated
peptides over a phosphothreonine peptide, with higher activity against
JNK (MAPK8; 601158) and ERK (MAPK3; 601795) compared to p38 (MAPK14;
600289). However, in vivo assay of DUSP21 transfected into COS cells
failed to detect DUSP21 phosphatase activity against any of the MAPK
substrates tested.
GENE STRUCTURE
Hood et al. (2002) determined that the DUSP21 gene contains 1 exon.
MAPPING
By genomic sequence analysis, Hood et al. (2002) mapped the DUSP21 gene
to chromosome Xp11.4-p11.23.
LINC01186
| dbSNP name | rs851244(A,G) |
| cytoBand name | Xp11.3 |
| EntrezGene GeneID | 101927574 |
| EntrezGene Symbol | LOC101927574 |
| snpEff Gene Name | RP1-30G7.2 |
| EntrezGene Description | uncharacterized LOC101927574 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03023 |
ZNF674-AS1
| dbSNP name | rs6611255(T,C); rs5905550(A,G) |
| cytoBand name | Xp11.23 |
| EntrezGene GeneID | 401588 |
| snpEff Gene Name | ZNF674 |
| EntrezGene Description | ZNF674 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3089 |
INE1
| dbSNP name | rs73630263(G,C); rs5953007(C,T); rs4339766(G,A) |
| ccdsGene name | CCDS14275.1 |
| cytoBand name | Xp11.23 |
| EntrezGene GeneID | 8552 |
| snpEff Gene Name | UBA1 |
| EntrezGene Description | inactivation escape 1 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.08041 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
SKELETAL:
[Pelvis];
Hip contractures;
[Limbs];
Knee contractures;
Ankle contractures;
[Feet];
Vertical tali;
Flat feet
NEUROLOGIC:
[Central nervous system];
Gait difficulties due to contractures of the lower limbs
MISCELLANEOUS:
One family has been reported (last curated May 2012);
Nonprogressive disorder;
Affected individuals remain ambulatory
OMIM Title
*300164 INACTIVATION ESCAPE 1; INE1
OMIM Description
CLONING
X chromosome inactivation provides dosage compensation for the
expression level of X-linked genes from the single X in males and the 2
in females. Although most genes on the X chromosome undergo
inactivation, several human genes have been shown to be expressed from
both the active and the inactivated X chromosome. Esposito et al. (1997)
screened EST cDNA clones that mapped to locations on the X for those
that escaped inactivation. They found 2 novel genes, INE1 and INE2
(300165). The INE1 cDNA contained an open reading frame encoding a
51-amino acid polypeptide with a single zinc finger domain. Northern
blot analysis revealed that INE1 was expressed in a wide variety of
human tissues. Unlike some genes that escape X inactivation, INE1 does
not have a Y chromosome homolog.
MAPPING
Esposito et al. (1997) used fluorescence in situ hybridization to map
the INE1 gene to Xp11.4-11.3.
MAGIX
| dbSNP name | rs12843494(C,T); rs5906744(A,G); rs5905720(G,C); rs183982494(C,T) |
| ccdsGene name | CCDS48106.1 |
| cytoBand name | Xp11.23 |
| EntrezGene GeneID | 79917 |
| EntrezGene Description | MAGI family member, X-linked |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGIX:NM_024859:exon3:c.C204T:p.S68S,MAGIX:NM_001099681:exon3:c.C204T:p.S68S,MAGIX:NM_001099682:exon3:c.C204T:p.S68S, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0013 |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbNSFP KGp1 AF | 0.0644966847498 |
| dbNSFP KGp1 Afr AF | 0.0123456790123 |
| dbNSFP KGp1 Amr AF | 0.0225988700565 |
| dbNSFP KGp1 Asn AF | 0.0289855072464 |
| dbNSFP KGp1 Eur AF | 0.0533707865169 |
| dbSNP GMAF | 0.06469 |
| ESP Afr MAF | 0.022525 |
| ESP All MAF | 0.075303 |
| ESP Eur/Amr MAF | 0.104221 |
| ExAC AF | 0.11 |
USP27X
| dbSNP name | rs112059598(G,A) |
| cytoBand name | Xp11.23 |
| EntrezGene GeneID | 389856 |
| snpEff Gene Name | AF238380.3 |
| EntrezGene Description | ubiquitin specific peptidase 27, X-linked |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.03869 |
GSPT2
| dbSNP name | rs974285(C,T) |
| cytoBand name | Xp11.22 |
| EntrezGene GeneID | 23708 |
| EntrezGene Description | G1 to S phase transition 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2189 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Mouth];
Oral thrush;
[Pharynx];
Absent tonsils
RESPIRATORY:
[Lung];
Pneumonia
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Chronic diarrhea
SKIN, NAILS, HAIR:
[Skin];
Candidal diaper rash;
Erythematous skin rashes
NEUROLOGIC:
[Central nervous system];
Recurrent bacterial meningitis
IMMUNOLOGY:
Frequent bacterial, fungal and viral infections;
Specific antibody production very poor;
Natural killer cells, reduced numbers and cytotoxicity;
Absent T lymphocytes;
Thymic hypoplasia;
Lymphoid depletion;
Lymph nodes are small and poorly developed
LABORATORY ABNORMALITIES:
Low absolute lymphocyte count;
Agammaglobulinemia
MISCELLANEOUS:
Death within first year of life
MOLECULAR BASIS:
Caused by mutation in the interleukin receptor gamma chain gene (IL2RG,
308380.0001)
OMIM Title
*300418 G1- TO S-PHASE TRANSITION 2; GSPT2
;;GST2, YEAST, HOMOLOG OF; GST2;;
PEPTIDE CHAIN RELEASE FACTOR 3B; ERF3B
OMIM Description
DESCRIPTION
GSPT2 is closely related to GSPT1 (139259), a GTP-binding protein that
plays an essential role at the G1- to S-phase transition of the cell
cycle in yeast and human cells. GSPT1 is a positive regulator of
translational accuracy and, in a binary complex with eRF1 (600285),
functions as a polypeptide chain release factor (summary by Hoshino et
al., 1998).
CLONING
Hoshino et al. (1998) cloned mouse Gspt2. The deduced 632-amino acid
protein has a 2-domain structure with a unique N-terminal region and a
conserved C-terminal eukaryotic elongation factor 1-alpha (130590)-like
domain. Mouse Gspt2 shares 81% identity with human GSPT1. RT-PCR
analysis revealed expression in all tissues examined, with relative
abundance in brain. In contrast to Gspt1, Gspt2 expression in Swiss 3T3
cells did not fluctuate with the cell cycle or upon phorbol ester
stimulation.
GENE FUNCTION
By coimmunoprecipitation and yeast 2-hybrid analyses, Hoshino et al.
(1998) determined that mouse Gspt2 interacts with human eRF1. By
mutation analysis, they found that both the N and C termini of Gspt2 are
required for this interaction.
MAPPING
By radiation hybrid analysis, Hansen et al. (1999) mapped the GSPT2 gene
to chromosome Xp11.23-p11.21.
MIR8088
| dbSNP name | rs73634264(C,G) |
| cytoBand name | Xp11.22 |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.01874 |
| ExAC AF | 0.001161 |
PFKFB1
| dbSNP name | rs3765479(G,A); rs12392887(A,G); rs113983235(G,A); rs55688372(G,C); rs6651976(A,G); rs12014660(G,A); rs2005463(T,C); rs201795827(G,A); rs4826364(T,C); rs4826365(A,C); rs5960382(C,T); rs12171767(T,C); rs12171770(T,C); rs147354935(T,C); rs7058927(A,G); rs185887725(C,T); rs112549768(A,G); rs149761567(A,G) |
| ccdsGene name | CCDS14364.1 |
| CosmicCodingMuts gene | PFKFB1 |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 5207 |
| EntrezGene Description | 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | PFKFB1:NM_001271805:exon7:c.C640T:p.R214C,PFKFB1:NM_001271804:exon8:c.C769T:p.R257C,PFKFB1:NM_002625:exon8:c.C835T:p.R279C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.5781 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | B4DUN5 |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000379 |
| ESP Eur/Amr MAF | 0.000595 |
| ExAC AF | 0.002127 |
OMIM Clinical Significance
Misc:
Early onset
Neuro:
Parkinsonism;
Mental retardation;
Tremor at rest;
Cogwheel rigidity;
Shuffling gait;
Seizures
Head:
Megalencephaly;
Frontal bossing
Radiology:
No basal ganglion calcification
Inheritance:
X-linked (Xq28)
OMIM Title
*311790 6-@PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 1; PFKFB1
;;PFKFB, LIVER;;
PFRX
OMIM Description
DESCRIPTION
Fructose-2,6-bisphosphate is an intracellular regulatory molecule that
controls glycolysis in all eukaryotic tissues by integrating hormonal
and metabolic signals. The synthesis and degradation of fructose
2,6-bisphosphate are catalyzed by 6-phosphofructo-2-kinase (EC
2.7.1.105) and fructose-2,6-bisphosphatase (EC 3.1.3.46), respectively.
In liver, these 2 activities belong to the same polypeptide encoded by
the gene PFKFB1, which also encodes the muscle isozyme (summary by
Hilliker et al., 1991).
CLONING
Darville et al. (1987) isolated a full-length cDNA encoding the rat
liver enzyme. Algaier and Uyeda (1988) isolated a partial cDNA for the
human liver enzyme.
MAPPING
By Southern analysis of human-rodent hybrid cell DNAs, Olson et al.
(1989) demonstrated that the PFKFB1 gene is located on Xcen-q13. They
also demonstrated a 2-allele RFLP useful for the localization of the
gene by genetic linkage analysis.
Batra et al. (1997) mapped the PFKFB1 gene to Xp11.21 within a YAC
contig clustered around ALAS2 (301300).
HISTORY
Hilliker et al. (1991) determined by in situ hybridization using probes
generated by the polymerase chain reaction (PCR) that the human PFKFB1
gene is located on Xq27-q28 and the rat Pfkfb1 gene on Xq22-q31.
MTRNR2L10
| dbSNP name | rs5960403(G,T); rs10521478(G,A); rs149160326(G,A); rs148291933(A,G); rs141417276(G,A) |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 101060042 |
| EntrezGene Symbol | LOC101060042 |
| EntrezGene Description | X antigen family member 3-like |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.02842 |
MAGEH1
| dbSNP name | rs11545211(G,A) |
| ccdsGene name | CCDS14369.1 |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 28986 |
| EntrezGene Description | melanoma antigen family H, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEH1:NM_014061:exon1:c.G492A:p.G164G, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2539 |
| ESP Afr MAF | 0.07588 |
| ESP All MAF | 0.207611 |
| ESP Eur/Amr MAF | 0.282699 |
| ExAC AF | 0.293 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
CARDIOVASCULAR:
[Vascular];
Systolic hypertension, mild
NEUROLOGIC:
[Central nervous system];
Seizures;
[Behavioral/psychiatric manifestations];
Irritability
LABORATORY ABNORMALITIES:
Hyponatremia;
Decreased serum osmolality;
Inappropriately increased urine osmolality;
Increased urinary sodium;
Decreased serum BUN;
Mildly decreased serum creatinine;
Decreased plasma renin activity;
Normal aldosterone;
Euvolemia;
Undetectable serum arginine vasopressin, or antidiuretic hormone (ADH,
AVP, 192340)
MISCELLANEOUS:
Onset within first 3 months of life;
Normal neonatal course;
Caused by constitutive activation of the AVPR2 receptor
MOLECULAR BASIS:
Caused by mutation in the arginine vasopressin receptor 2 gene (AVPR2,
300538.0021)
OMIM Title
*300548 MELANOMA ANTIGEN, FAMILY H, 1; MAGEH1
;;MAGEH
OMIM Description
CLONING
By searching databases for genes belonging to the MAGE gene family (see
MAGEA1; 300016), Chomez et al. (2001) identified several novel MAGE
genes, including MAGEH1. The deduced 219-amino acid protein contains a
central conserved MAGE domain, but it differs from other MAGE proteins
in its N and C termini. MAGEH1 was expressed at various levels in all
normal tissues examined.
Tcherpakov et al. (2002) found that Mageh1 was expressed as a
cytoplasmic protein in a rat neural precursor cell line.
GENE FUNCTION
Tcherpakov et al. (2002) found that the intracellular domain of nerve
growth factor receptor (NGFR; 162010) interacted with necdin (NDN;
602117) and Mageh1 in rodent neural tissue, and the interaction was
enhanced by ligand stimulation. Rat neural precursor cells transfected
with necdin or Mageh1 exhibited accelerated differentiation in response
to NGF (see 162030).
MAPPING
By genomic sequence analysis, Chomez et al. (2001) mapped the MAGEH1
gene to a MAGE gene cluster on chromosome Xp11.23-p11.21.
FOXR2
| dbSNP name | rs2375465(T,C) |
| ccdsGene name | CCDS35308.1 |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 139628 |
| EntrezGene Description | forkhead box R2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FOXR2:NM_198451:exon1:c.T857C:p.V286A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q6PJQ5 |
| dbNSFP Uniprot ID | FOXR2_HUMAN |
| dbNSFP KGp1 AF | 0.857745629898 |
| dbNSFP KGp1 Afr AF | 0.317948717949 |
| dbNSFP KGp1 Amr AF | 0.861386138614 |
| dbNSFP KGp1 Asn AF | 1.0 |
| dbNSFP KGp1 Eur AF | 0.953883495146 |
| dbSNP GMAF | 0.1421 |
| ESP Afr MAF | 0.499609 |
| ESP All MAF | 0.198618 |
| ESP Eur/Amr MAF | 0.027051 |
| ExAC AF | 0.927 |
SPIN3
| dbSNP name | rs5960234(A,C); rs5914035(C,T); rs5960235(G,A); rs912956(C,T); rs5914036(A,G); rs10521485(G,A); rs6612746(T,G); rs1325856(C,T) |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 169981 |
| EntrezGene Description | spindlin family, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intergenic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | nonsense_mediated_decay |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.09311 |
ZXDB
| dbSNP name | rs1057328(G,T); rs1997715(G,A) |
| ccdsGene name | CCDS35313.1 |
| cytoBand name | Xp11.21 |
| EntrezGene GeneID | 158586 |
| EntrezGene Description | zinc finger, X-linked, duplicated B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZXDB:NM_007157:exon1:c.G1167T:p.P389P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0 |
| ESP Afr MAF | 0.007823 |
| ESP All MAF | 0.003029 |
| ESP Eur/Amr MAF | 0.000297 |
| ExAC AF | 0.999,9.759e-04 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Coarse facies;
Low frontal hairline;
Midface hypoplasia;
[Ears];
Low-set ears;
[Eyes];
Hypertelorism;
Prominent eyebrows;
Pale optic discs;
[Nose];
Depressed nasal bridge;
Broad nasal tip;
[Mouth];
High-arched palate;
[Neck];
Short neck
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Prominent sternum;
Inferior rib flaring;
Thin ribs;
Anterior rib cupping
SKELETAL:
Spondyloepimetaphyseal dysplasia;
Delayed bone age;
Joint contractures;
[Skull];
Wormian bones;
[Spine];
Exaggerated thoracic kyphosis;
Platyspondyly;
Odontoid hypoplasia;
[Pelvis];
Flared iliac wings;
Short, hypoplastic femoral necks;
Coxa vara;
Cone-shaped capital femoral epiphyses;
[Limbs];
Widened metaphyses;
Small flattened epiphyses (distal femora and proximal tibiae);
Peg-like central prominence of distal tibial metaphyses;
[Hands];
Brachydactyly;
Large, broad hands;
Metaphyseal cupping (metacarpals and phalanges);
[Feet];
Brachydactyly;
Large, broad feet
SKIN, NAILS, HAIR:
[Hair];
Low frontal hairline;
Prominent eyebrows
NEUROLOGIC:
[Central nervous system];
Progressive mental retardation;
Small corpus callosum;
Delayed myelination;
Widened subarachnoid spaces;
Seizures
MISCELLANEOUS:
Normal development in first 6-12 months, followed by facial coarsening
and progressive delay in physical and mental development
OMIM Title
*300236 ZINC FINGER-ENCODING GENE, X-LINKED, DUPLICATED, B; ZXDB
OMIM Description
DESCRIPTION
The ZXDB gene is one of a pair of duplicated zinc finger genes on
chromosome Xp11.21 (Greig et al., 1993); see also ZXDA (300235).
CLONING
During a mapping study of Xp11.21, Greig et al. (1993) identified the
ZXDA and ZXDB genes. By screening a human fetal brain cDNA library with
an ZXDA genomic clone, Greig et al. (1993) isolated partial ZXDA and
ZXDB cDNAs. A comparison between 1.2 kb of ZXDA coding sequence, which
is contained within a single exon, and the corresponding sequence of
ZXDB revealed 98.7% nucleotide sequence identity. Southern blot analysis
detected sequences homologous to the ZXDA and ZXDB genes in a number of
placental mammalian species. These data suggest that the ZXDA and ZXDB
genes arose from a very ancient and highly conserved gene duplication.
The predicted partial ZXDA and ZXDB proteins contain 10 tandem zinc
finger motifs. Northern blot analysis showed approximately 6.5-kb ZXDA
and ZXDB transcripts. RT-PCR detected ZXDA and ZXDB expression in all
human tissues examined, namely heart, lung, muscle, fibroblasts, and
lymphoblasts, with ZXDB expressed more highly than ZXDA in every tissue.
Both the ZXDA and ZXDB genes are subject to X inactivation.
GENE STRUCTURE
Both the ZXDA and ZXDB genes are intronless (Greig et al., 1993).
MAPPING
Using a panel of somatic cell hybrids, Greig et al. (1993) confirmed the
mapping of the ZXDA and ZXDB genes to Xp11.21. The ZXDA and ZXDB genes
are located within approximately 400 kb of each other.
FRMD8P1
| dbSNP name | rs73629451(G,A); rs746509(G,A) |
| cytoBand name | Xq12 |
| EntrezGene GeneID | 83957 |
| snpEff Gene Name | RP3-475B7.3 |
| EntrezGene Description | FERM domain containing 8 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1215 |
HEPH
| dbSNP name | rs5919015(T,C); rs1028348(C,T); rs13440529(T,A); rs5965105(G,A); rs17301659(A,T); rs55881476(A,G); rs57349482(C,T); rs67613711(T,C); rs60273039(G,A); rs137910006(C,A); rs5965106(C,A); rs5964495(T,C); rs7054364(C,A); rs5918591(A,G); rs12689282(G,C); rs143095255(A,G); rs61264194(A,G); rs1989028(G,C); rs2206204(C,T); rs142249679(T,A); rs146228794(G,A); rs5965109(T,G); rs5964497(G,T); rs5964498(T,G); rs5919020(G,T); rs7062799(T,G); rs6624875(C,T); rs6624876(T,C); rs5964499(C,T); rs760866(A,T); rs5964500(T,A); rs2206203(T,G); rs2223446(G,A); rs7059116(T,A); rs1011526(G,A); rs5965110(C,T); rs7891437(A,G); rs7878370(T,C); rs193005941(G,A); rs1264215(A,G); rs1264213(C,G); rs5964501(T,C); rs1264212(A,T); rs1264218(C,T); rs806607(T,C); rs809363(A,G); rs7052942(A,G); rs7053202(A,G); rs73630913(G,T); rs73630914(G,C); rs806609(A,T); rs806610(A,G); rs1264216(T,G); rs189522458(G,A); rs5965112(G,A); rs28848546(G,A); rs1090845(T,C); rs5965113(G,C); rs145380788(A,G); rs1090844(C,T); rs1090843(A,G); rs1091486(C,T); rs1090841(G,A); rs1090840(G,A); rs1090839(A,G); rs1090838(T,C); rs149062526(G,T); rs7066319(A,G); rs10482096(G,A); rs1090835(A,G); rs73630915(A,G); rs1090834(T,A); rs149700407(C,T); rs58864384(G,A); rs1090833(T,C); rs1090831(A,G); rs1068535(A,G); rs143861028(G,A); rs1068534(C,G); rs707295(A,G); rs707296(T,C); rs699863(C,T); rs708966(A,G); rs708967(C,A); rs1090752(G,T); rs1068533(A,G); rs1090842(T,C); rs707302(A,C); rs707301(G,A); rs5965118(G,A); rs7887070(A,T); rs1068538(G,T); rs1068537(C,T); rs1068536(A,G); rs707298(T,C); rs73630916(G,A); rs707300(G,A); rs7055870(G,A); rs806538(A,G); rs806537(A,T); rs708968(G,T); rs708969(A,T); rs12012117(T,A); rs12015027(G,T); rs5918594(G,A); rs7064668(C,T); rs651494(C,T); rs61741156(A,T); rs185549884(G,C); rs5918595(G,A); rs4827365(A,G); rs1456803(G,A); rs1456804(G,A); rs5919024(T,G); rs2198868(G,A); rs2198869(G,T); rs1350239(C,T); rs1456806(G,C); rs2054180(C,T) |
| ccdsGene name | CCDS14385.1 |
| cytoBand name | Xq12 |
| EntrezGene GeneID | 9843 |
| EntrezGene Description | hephaestin |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | HEPH:NM_138737:exon16:c.A2761T:p.R921W,HEPH:NM_014799:exon15:c.A1798T:p.R600W,HEPH:NM_001282141:exon13:c.A2032T:p.R678W,HEPH:NM_001130860:exon16:c.A2608T:p.R870W, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9254 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | E9PHN8 |
| dbNSFP KGp1 AF | 0.000602772754671 |
| dbNSFP KGp1 Afr AF | 0.0020325203252 |
| dbNSFP KGp1 Amr AF | 0.0 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 6.046E-4 |
| ESP Afr MAF | 0.019817 |
| ESP All MAF | 0.007195 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001619 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Long, narrow face;
Long philtrum;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Microcornea;
Congenital cataract;
Microphthalmia;
Laterally curved eyebrows;
Thick eyebrows;
Vision loss;
Glaucoma, secondary;
Microcornea;
Persistent hyperplasia of primary vitreous;
Ptosis;
Blepharophimosis;
Exotropia;
[Nose];
Broad nasal tip;
High nasal bridge;
Bifid nasal tip;
[Mouth];
Cleft palate;
Submucous cleft palate;
Bifid uvula;
[Teeth];
Canine radiculomegaly;
Delayed dentition;
Persistent primary teeth;
Oligodontia;
Malocclusion;
Supernumerary teeth;
Fused teeth;
Root dilacerations (extension)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Mitral valve prolapse
GENITOURINARY:
[Internal genitalia, female];
Septate vagina
SKELETAL:
[Feet];
2-3 toe syndactyly;
Hammer toe (2-4 toes)
SKIN, NAILS, HAIR:
[Hair];
Laterally curved eyebrows;
Thick eyebrows
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
MOLECULAR BASIS:
Caused by mutations in the BCL6 corepressor gene (BCOR, 300485.0002)
OMIM Title
*300167 HEPHAESTIN; HEPH
OMIM Description
CLONING
Iron is essential for many cellular functions; consequently,
disturbances of iron homeostasis, leading to either iron deficiency or
iron overload, can have significant clinical consequences. Through study
of the 'sex-linked anemia' (sla) mouse, Vulpe et al. (1999) identified a
key component in intestinal iron transport, shedding light on the
mechanism by which dietary iron is absorbed into the body. The sla mouse
has a block in intestinal iron transport (Grewal, 1962). Mice carrying
the sla mutation develop moderate to severe microcytic hypochromic
anemia. Although these mice take up iron from the intestinal lumen into
mature epithelial cells normally, the subsequent exit of iron into the
circulation is diminished (Bannerman, 1976). As a result, iron
accumulates in enterocytes and is lost during turnover of the intestinal
epithelium (Edwards et al., 1977).
A project coincident to the report of Vulpe et al. (1999) led to the
discovery of an sla candidate gene, termed 'hephaestin' (Heph) after the
Greek god of metal working. Vulpe et al. (1999) noted several mouse and
human ESTs with homology to ceruloplasmin (CP; 117700), a serum
multi-copper ferroxidase, and they assembled a complete mouse cDNA that
encoded a protein 50% identical to mouse ceruloplasmin. All type I, II,
and III copper binding sites in ceruloplasmin were conserved in the
predicted hephaestin protein, as were all cysteine residues involved in
disulfide bond formation. In contrast to ceruloplasmin, hephaestin
contains a predicted C-terminal transmembrane domain, which suggested a
membrane-bound protein with a ceruloplasmin-like domain located in an
extra-cytosolic compartment or in the extracellular space. Vulpe et al.
(1999) found that Heph expression contrasts that of Cp, which is highly
expressed in liver and expressed to a lesser extent in other tissues,
including brain and lung, but is not expressed in intestine, where the
highest expression of Heph is found. In situ hybridization studies
indicated that intestinal expression of Heph is limited to villi, with
almost no signal observed in crypt cells. Iron absorption occurs in
villi.
GENE FUNCTION
Hephaestin represents a link between copper and iron metabolism in
mammals and offers a basis for the iron-deficiency anemia associated
with copper deficiency. Copper deficiency results in the decreased
absorption of dietary iron, which enters intestinal epithelium normally
but cannot exit into the circulation. Indeed, intestinal iron
accumulation in copper-deficient swine is similar to the iron
accumulation seen in sla mice (Lee et al., 1968). The administration of
copper, but not iron, to copper-deficient pigs alleviates the anemia and
facilitates the egress of iron from tissues, including intestine.
Copper and iron are similarly linked in systemic iron metabolism. The
congenital absence of ceruloplasmin in humans leads to iron accumulation
in many tissues; see aceruloplasminemia (604290).
MAPPING
Falconer and Isaacson (1962) mapped the sla locus to the central span of
the mouse X chromosome, 3 cM centromeric of 'Tabby' (Ta) and 10 cM
telomeric of 'bent tail' (Bn). Anderson et al. (1998) refined the
assignment to a critical region between markers DXMit45 and DXMit16.
Using radiation hybrid mapping, Vulpe et al. (1999) determined that the
human HEPH gene maps within 14.55 cR of DXS1194 in Xq11-q12 (lod score =
7.81), a region with homology of synteny to the mouse sla region.
ANIMAL MODEL
Vulpe et al. (1999) found that sla mice have a deletion of 582
nucleotides from the Heph gene, predicting an in-frame omission of 194
amino acids in the gene product. On the basis of its homology with
ceruloplasmin, Vulpe et al. (1999) proposed that hephaestin is a
ferroxidase necessary for iron release from intestinal epithelial cells.
Since it contains only 1 putative membrane-spanning domain, it is
unlikely to be a transmembrane iron carrier itself; hephaestin may
interact with an iron-transport protein to facilitate the movement of
iron across the membrane.
Mechanisms of brain and retinal iron homeostasis became subjects of
increased interest after the discovery of elevated iron levels in brains
of patients with Alzheimer disease (104300) and retinas of patients with
age-related macular degeneration (see 603075). To determine whether Cp
and its homolog Heph are important for retinal iron homeostasis, Hahn et
al. (2004) studied retinas from mice deficient in ceruloplasmin and/or
hephestin. In normal mice, Cp and Heph localized to Muller glia and
retinal pigment epithelium, a blood-brain barrier. Mice deficient in
both Cp and Heph, but not each individually, had a striking,
age-dependent increase in iron of the retinal pigment epithelium and
retina. The iron storage protein ferritin (see 134790) was also
increased in the doubly null retinas. After retinal iron levels had
increased, mice null for both Cp and Heph had age-dependent retinal
pigment epithelium hypertrophy, hypoplasia, and death, photoreceptor
degeneration, and subretinal neovascularization, providing a model of
some features of the human retinal diseases aceruloplasmine mia and
age-related macular degeneration. These pathologic changes indicated
that ceruloplasmin and hephestin are critical for central nervous system
iron homeostasis and that loss of both in the mouse leads to
age-dependent retinal neurodegeneration, providing a model that can be
used to test therapeutic efficacy of iron chelators and antiangiogenic
agents.
OTUD6A
| dbSNP name | rs144122625(A,G); rs4844103(G,A); rs144185857(C,A) |
| ccdsGene name | CCDS14395.1 |
| cytoBand name | Xq13.1 |
| EntrezGene GeneID | 139562 |
| EntrezGene Description | OTU domain containing 6A |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OTUD6A:NM_207320:exon1:c.A278G:p.K93R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.006 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q7L8S5 |
| dbNSFP Uniprot ID | OTU6A_HUMAN |
| dbNSFP KGp1 AF | 0.0271247739602 |
| dbNSFP KGp1 Afr AF | 0.0622317596567 |
| dbNSFP KGp1 Amr AF | 0.00558659217877 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.02721 |
| ESP Afr MAF | 0.080877 |
| ESP All MAF | 0.030874 |
| ESP Eur/Amr MAF | 0.002379 |
| ExAC AF | 0.008235 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant;
X-linked recessive
GROWTH:
[Height];
Short stature (female);
[Other];
Intrauterine growth retardation (male)
HEAD AND NECK:
[Head];
Microcephaly (male and female);
Large fontanelles (male and females);
[Face];
Short philtrum (female);
Micrognathia (male and female);
Triangular face (male);
[Ears];
Small ears (female);
Posteriorly rotated ears (female);
[Eyes];
Short palpebral fissure (male);
Downslanting palpebral fissure (male);
[Nose];
Choanal atresia (male);
[Mouth];
Soft tissue growths at angle of mouth (female);
Thin upper lip (female);
Cleft palate
CARDIOVASCULAR:
[Heart];
Patent ductus arteriosus (male);
Atrial septal defect (male);
Interrupted aortic arch (male);
Ventricular septal defect (male)
RESPIRATORY:
[Airways];
Tracheal stenosis (male)
CHEST:
[External features];
Broad chest (male);
[Breasts];
Widely spaced nipples (male)
ABDOMEN:
[Biliary tract];
Absent gallbladder (male)
GENITOURINARY:
[External genitalia, male];
Hypospadias;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis (male)
SKELETAL:
[Skull];
Widened sutures (male);
Absent/hypoplastic frontal sinuses (female);
[Pelvis];
Narrow iliac wings (female);
[Limbs];
Cortical thickening of long bones (female);
[Hands];
Small hands (male and female);
Brachydactyly (female);
Fifth finger clinodactyly (female);
Excessive number of fingerprint arches (female);
Cortical thickening of metacarpals (female);
[Feet];
Small feet (male and female);
Flat feet (female);
Small toenails (male)
SKIN, NAILS, HAIR:
[Nails];
Small toenails (male)
NEUROLOGIC:
[Central nervous system];
Developmental delay (female);
IQ 85-115 (female);
Cerebellar hypoplasia (male);
Decreased brain volume (female);
Extra superior temporal gyrus (female)
PRENATAL MANIFESTATIONS:
[Placenta and umbilical cord];
Two-vessel umbilical cord (male)
LABORATORY ABNORMALITIES:
Hypocalcemia (male);
Normal calcium (female);
Normal parathyroid hormone (female);
Skewed X-inactivation in females
MISCELLANEOUS:
Males are more severely affected than females;
Males died in neonatal period
OMIM Title
*300714 OTU DOMAIN-CONTAINING PROTEIN 6A; OTUD6A
;;DUBA2;;
HIN6 PROTEASE
OMIM Description
DESCRIPTION
Deubiquitinating enzymes (DUBs; see 603478) are proteases that
specifically cleave ubiquitin (191339) linkages, negating the action of
ubiquitin ligases. DUBA2 belongs to a DUB subfamily characterized by an
ovarian tumor (OTU) domain.
CLONING
Kayagaki et al. (2007) identified ovarian tumor domain (OTU)-containing
protein 6A (OTUD6A) in a small interfering RNA (siRNA)-based screen for
OTU deubiquitinating enzyme (DUB) family members. The 1,689-basepair
mRNA contains an open reading frame (ORF) predicting a 288-amino acid
protein.
MAPPING
The OTUD6A gene maps to chromosome Xq13.1 (Kayagaki et al., 2007).
P2RY4
| dbSNP name | rs41310667(C,T); rs56217451(T,C); rs3829708(G,T); rs3829709(A,C); rs1152187(T,G) |
| ccdsGene name | CCDS14398.1 |
| cytoBand name | Xq13.1 |
| EntrezGene GeneID | 5030 |
| EntrezGene Description | pyrimidinergic receptor P2Y, G-protein coupled, 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | P2RY4:NM_002565:exon1:c.G1043A:p.W348X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.0102471368294 |
| dbNSFP KGp1 Afr AF | 0.00609756097561 |
| dbNSFP KGp1 Amr AF | 0.0166666666667 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.00663129973475 |
| dbSNP GMAF | 0.01028 |
| ESP Afr MAF | 0.006258 |
| ESP All MAF | 0.014106 |
| ESP Eur/Amr MAF | 0.018579 |
| ExAC AF | 0.013 |
OMIM Clinical Significance
Ears:
Congenital severe sensorineural hearing loss
Misc:
Mild delayed manifestation in carrier females
Inheritance:
X-linked form
OMIM Title
*300038 PYRIMIDINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 4; P2RY4
;;P2Y4;;
NUCLEOTIDE RECEPTOR, URIDINE; NRU; UNR
OMIM Description
CLONING
Nguyen et al. (1995) detected genes encoding novel G protein-coupled
receptors (GPCRs) by PCR amplification of human genomic DNA using
degenerate oligonucleotides based on the sequences encoding
transmembrane spanning domains of the opioid receptors, matostatin
receptors, and related GPCRs. They identified a full-length genomic
clone containing an intronless open reading frame of 1095 bp encoding a
protein of 365 amino acids, features characteristic of GPCRs. The
encoded protein, UNR, has greatest overall identity (54%) with human P2U
purinoceptor (P2RY2; 600041). The greatest degree of amino acid identity
occurs within the putative 7-transmembrane domain, where it demonstrates
74% identity. Dendrogram analysis of the G protein-coupled P2
purinoceptors and UNR indicated that these receptors belong to a family
that may be more aptly named nucleotide receptors.
Communi et al. (1995) likewise cloned UNR and recognized it as a novel
member of the G protein-coupled P2 purinergic receptor family that
functionally behaves as a pyrimidinergic receptor.
GENE FUNCTION
Nguyen et al. (1995) found that, when expressed in a mammalian cell
line, UNR was activated specifically by UTP and UDP, but not by ATP and
ADP. Activation of UNR resulted in increased inositol phosphate
formation and calcium mobilization.
Adrian et al. (2000) analyzed the expression of several purinergic
receptors during differentiation in a promyelocytic leukemia cell line.
Granulocytic differentiation was induced by dimethylsulfoxide, and a
monocytic/macrophage phenotype was induced by phorbol esters. P2Y4 was
highly expressed in uninduced promyelocytes, and expression decreased
slightly following both granulocytic and monocytic differentiation.
MAPPING
By fluorescence in situ hybridization, Nguyen et al. (1995) demonstrated
that the UNR gene is located on chromosome Xq13.
PABPC1L2A
| dbSNP name | rs11093406(T,C) |
| cytoBand name | Xq13.2 |
| EntrezGene GeneID | 340529 |
| EntrezGene Description | poly(A) binding protein, cytoplasmic 1-like 2A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3531 |
NAP1L6
| dbSNP name | rs7888671(G,A); rs7888956(G,C) |
| cytoBand name | Xq13.2 |
| EntrezGene GeneID | 645996 |
| EntrezGene Description | nucleosome assembly protein 1-like 6 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3102 |
TSIX
| dbSNP name | rs7062816(T,C); rs798615(T,A); rs7061436(C,T); rs1076875(A,G); rs7060427(T,C); rs2184956(C,T); rs2152863(T,G); rs7892040(A,G); rs2156994(G,A); rs7051569(C,T); rs57266065(T,G); rs1088594(C,T); rs56068329(T,C); rs67761024(A,G); rs1088593(G,A); rs1088592(T,C); rs142417970(G,A); rs1088590(C,T); rs57319779(G,A); rs7051897(A,G); rs7062860(C,T); rs41449051(C,T); rs56009138(G,A); rs5981565(C,T); rs58000999(C,T); rs36008354(G,A); rs7058986(C,T); rs58546751(A,C); rs57234478(C,A); rs140177539(C,T); rs56325692(A,G); rs16992436(T,C); rs41306111(C,T); rs1620574(T,C); rs190234898(T,C); rs1794213(A,C); rs16992442(T,C); rs16992443(G,T); rs73486505(C,T) |
| cytoBand name | Xq13.2 |
| EntrezGene GeneID | 9383 |
| EntrezGene Description | TSIX transcript, XIST antisense RNA |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.07437 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Long, narrow face;
Long philtrum;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Microcornea;
Congenital cataract;
Microphthalmia;
Laterally curved eyebrows;
Thick eyebrows;
Vision loss;
Glaucoma, secondary;
Microcornea;
Persistent hyperplasia of primary vitreous;
Ptosis;
Blepharophimosis;
Exotropia;
[Nose];
Broad nasal tip;
High nasal bridge;
Bifid nasal tip;
[Mouth];
Cleft palate;
Submucous cleft palate;
Bifid uvula;
[Teeth];
Canine radiculomegaly;
Delayed dentition;
Persistent primary teeth;
Oligodontia;
Malocclusion;
Supernumerary teeth;
Fused teeth;
Root dilacerations (extension)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Mitral valve prolapse
GENITOURINARY:
[Internal genitalia, female];
Septate vagina
SKELETAL:
[Feet];
2-3 toe syndactyly;
Hammer toe (2-4 toes)
SKIN, NAILS, HAIR:
[Hair];
Laterally curved eyebrows;
Thick eyebrows
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
MOLECULAR BASIS:
Caused by mutations in the BCL6 corepressor gene (BCOR, 300485.0002)
OMIM Title
*300181 X INACTIVATION-SPECIFIC TRANSCRIPT-ANTISENSE; TSIX
;;XIST-ANTISENSE
OMIM Description
CLONING
In mammals, dosage compensation is achieved by X inactivation and is
regulated in cis by the X inactivation center (XIC) (see XIST; 314670).
The XIC controls X-chromosome counting, choice of X to inactivate, and
initiation of silencing. XIC activity culminates in a change in the
character of XIST RNA from an unstable, scarce RNA to a highly expressed
RNA that coats the future inactive X chromosome. Deleting a 65-kb region
downstream of XIST, which resides on Xq13.2, results in constitutive
XIST expression and X inactivation, suggesting the existence of a cis
regulatory element.
When examining Xist expression in embryonic stem (ES) cells by RNA FISH
using strand-specific probes, Lee et al. (1999) identified a gene
antisense to Xist. The antisense signal was pinpoint, localized to the
Xic, and found in male, female, and transgenic ES nuclei. Lee et al.
(1999) called the antisense gene 'Tsix.' Tsix is a 40-kb RNA originating
15 kb downstream of Xist with a CpG island identifying its 5-prime
start, and transcribed across the Xist locus. Tsix sequence is conserved
at the human XIC. The mouse Xist and human XIST genes are 63.5%
identical from bp 6200-10200 of Xist; the 5-prime third of Tsix has
regions that are 45.3 to 56.7% identical to the same region in the XIC.
Tsix RNA has no conserved open reading frames, is seen exclusively in
the nucleus, and is localized at the Xic. In mouse female ES cells,
before the onset of X inactivation, Tsix is expressed at low levels from
both X chromosomes. At the onset of X inactivation, Tsix expression
becomes monoallelic, is associated with the future active X, and
persists until Xist is turned off. Tsix is not found on the inactive X
once cells enter the X-inactivation pathway. Lee et al. (1999) concluded
that Tsix has features suggesting a role in regulating the early steps
of X inactivation, but not the silencing step.
Using murine ES cells carrying a transgene of human XIC and RT-PCR,
Migeon et al. (2001) identified human TSIX and subsequently detected its
expression in fibroblasts derived from human embryoid bodies. In silico
analysis, however, determined that TSIX has no open reading frame and
little homology to mouse Tsix. Five-prime RACE analysis suggested that
the transcription start site of TSIX may be analogous to Tsix exons 2
and 3, but that TSIX, unlike Tsix, lacks a proper CpG island at its
5-prime end, suggesting an evolutionary breakpoint. Migeon et al. (2001)
concluded that TSIX, like Tsix, is expressed only in embryo-derived
cells, initiates downstream of the 3-prime end of XIST, and produces an
untranslated RNA. This RNA is transcribed from the opposite strand as
XIST and is, in part, antisense to XIST. TSIX differs from Tsix in that
it is truncated at the 5-prime end, does not cover the XIST promoter,
and does not have the CpG island that is essential for the
X-inactivation function of mouse Tsix.
GENE FUNCTION
Chao et al. (2002) identified the insulator and transcription factor
CTCF (604167) as a candidate trans-acting factor for X chromosome
selection in mouse. The choice/imprinting center contains tandem CTCF
binding sites that function in an enhancer-blocking assay. In vitro
binding is reduced by CpG methylation and abolished by including non-CpG
methylation. Chao et al. (2002) postulated that Tsix and CTCF together
establish a regulatable epigenetic switch for X inactivation in the
mouse. Murine Tsix contains greater than 40 CTCF motifs and the human
sequence has greater than 10.
DXPas34 is made up of 34-bp repeats containing Ctcf motifs and is
located within a CpG-rich region in the 5-prime end of the mouse Tsix
gene. Cohen et al. (2007) showed that mouse Tsix acts in part through
DXPas34. DXPas34 had bidirectional promoter activity, produced
overlapping forward and reverse transcripts, and was necessary for both
random and imprinted X inactivation in mice. Phylogenetic analysis
showed a region similar to DXPas34 in the rat Xic. The human ortholog
contains a more distantly related 16-bp repeat that includes
CTCF-binding motifs. The human sequence also has a 14-kb insertion not
found in mouse Tsix. Cohen et al. (2007) believed that the repeats in
the 5-prime region mouse and human TSIX originated from an ancient
retrotransposon that introduced the CTCF recognition site.
Boumil and Lee (2001) reviewed the roles of Xist and Tsix in X
inactivation.
In the mouse placenta, where X inactivation is imprinted (the paternal X
chromosome is always inactive), the maternal Xist allele is repressed by
a cis-acting antisense transcript, encoded by the Tsix gene. Migeon et
al. (2001) showed that the human TSIX gene lacked key regulatory
elements needed for the imprinting function of murine Tsix. Migeon et
al. (2002), using RNA FISH for cellular localization of transcripts in
human fetal cells, showed that human TSIX antisense transcripts were
unable to repress XIST. TSIX was transcribed only from the inactive X
chromosome and was coexpressed with XIST. Also, TSIX was not maternally
imprinted in placental tissues, and its transcription persisted in
placenta and fetal tissues, throughout embryogenesis. Therefore, the
repression of Xist by mouse Tsix has no counterpart in humans, and TSIX
is not the gene that protects the active X chromosome from random
inactivation. Because human TSIX cannot imprint X inactivation in the
placenta, it serves as a mutant for mouse Tsix, providing insights into
features responsible for antisense activity in imprinted X inactivation.
Migeon (2003) suggested that the regulation of X-chromosome inactivation
differs considerably between mice and humans. Specifically, she
suggested that antisense regulation of Xist by Tsix occurs only in mice,
where the antisense Tsix blocks Xist expression during both imprinted
and random X inactivation. In reply, Lee (2003) concluded that it is too
soon to say whether Tsix-mediated regulation is shared by humans and
mice. In her view, the primary underpinnings of X inactivation appeared
to be identical in the 2 organisms.
Ogawa and Lee (2003) discovered a cis element in the mouse
X-inactivation center that regulates Tsix. They named this cis element
'X-inactivation intergenic transcription element,' or Xite. Xite harbors
intergenic transcription start sites and DNase I hypersensitive sites
with allelic differences. At the onset of X-chromosome inactivation
(XCI), deleting Xite downregulated Tsix in cis and skewed XCI ratios,
suggesting that Xite promotes Tsix persistence on the active X.
Truncating Xite RNA was inconsequential, indicating that Xite action
does not require intact transcripts. Xite is located 20 to 32 kb
downstream of Xist. Ogawa and Lee (2003) proposed that allele-specific
Xite action promotes Tsix asymmetry and generates X chromosome
inequality. Therefore, Xite is a candidate for the Xce, the classical
modifier of XCI ratios (see 300074).
Shibata and Lee (2003) reported that in undifferentiated murine
embryonic stem cells, Tsix RNA was present at 10- to 100-fold molar
excess over Xist RNA. Moreover, only 30 to 60% of Tsix RNA was spliced
at known exon-intron junctions. Tsix was spliced heterogeneously at the
5-prime end, and most detectable splice variants exhibited only a 1.9-kb
region of complementarity between sense and antisense RNAs.
Sado et al. (2005) and Navarro et al. (2005) independently determined
that mouse Tsix silences Xist by altering chromatin structure at the
Xist locus.
Xu et al. (2006) showed that in mouse embryonic stem cells
interchromosomal pairing mediates communication between X chromosomes to
regulate X inactivation and ensure mutually exclusive silencing. Pairing
occurs transiently at the onset of X inactivation and is specific to the
X inactivation center. Deleting Xite (300074) and Tsix perturbs pairing
and counting/choice, whereas their autosomal insertion induces de novo
X-autosome pairing. Ectopic X-autosome interactions inhibit endogenous
X-X pairing and block the initiation of X-chromosome inactivation. Thus,
Tsix and Xite function both in cis and in trans. Xu et al. (2006)
proposed that Tsix and Xite regulate counting and mutually exclusive
choice through X-X pairing.
Using 3-dimensional fluorescence in situ hybridization analysis, Bacher
et al. (2006) showed that the 2 X inactivation centers (Xics)
transiently colocalize, just before X inactivation, in differentiating
mouse female embryonic stem cells. Using Xic transgenes capable of
imprinted but not random X inactivation, and Xic deletions that disrupt
random X inactivation, Bacher et al. (2006) demonstrated that Xic
colocalization is linked to Xic function in random X inactivation. Both
long-range sequences and the Tsix element, which generates the antisense
transcript to Xist, are required for the transient interaction of Xics.
Bacher et al. (2006) proposed that transient colocalization of Xics may
be necessary for a cell to determine Xic number and to ensure the
correct initiation of X inactivation.
Ogawa et al. (2008) reported that murine Xist (314670) and Tsix form
duplexes in vivo. During X chromosome inactivation the duplexes are
processed to small RNAs, most likely on the active X chromosome in a
Dicer (606241)-dependent manner. Deleting Dicer compromised small RNA
production and derepressed Xist. Furthermore, without Dicer, Xist RNA
could not accumulate and histone H3 (see 602810) lysine-27
trimethylation was blocked in the inactive X. These defects were
partially rescued by truncating Tsix. Thus, Ogawa et al. (2008)
concluded that X chromosome inactivation and RNA interference intersect,
downregulating Xist on the active X chromosome and spreading silencing
on the inactive X chromosome.
Donohoe et al. (2009) demonstrated that OCT4 (164177) lies at the top of
the X chromosome inactivation (XCI) hierarchy, and regulates XCI by
triggering X chromosome pairing and counting. OCT4 directly binds TSIX
and XITE (300074), 2 regulatory noncoding RNA genes of the X
inactivation center, and also complexes with SCI transfactors CTCF
(604167) and YY1 (600013) through protein-protein interactions.
Depletion of Oct4 blocked homologous X chromosome pairing and resulted
in the inactivation of both X chromosomes in female mouse embryonic stem
cells. Donohoe et al. (2009) concluded that they identified the first
trans-factor that regulates counting and ascribed new functions to OCT4
during X chromosome reprogramming.
Navarro et al. (2010) demonstrated that Tsix upregulation in embryonic
stem cells depends on recruitment of the pluripotent marker Rex1 (ZFP42;
614572) and of the reprogramming-associated factors Klf4 (602253) and
Myc (190080), by the DXPas34 minisatellite associated with the Tsix
promoter. Upon depletion of DXPas34, binding of the 3 factors was
abrogated and the transcriptional machinery was no longer efficiently
recruited to the Tsix promoter. Additional analyses, including knockdown
experiments, further demonstrated that Rex1 is critically important for
efficient transcription elongation of Tsix. Hence, distinct embryonic
stem cell-specific complexes couple X-inactivation reprogramming and
pluripotency, with Nanog (607937), Oct4, and Sox2 (184429) repressing
Xist to facilitate the reactivation of the inactive X, and Klf4, Myc,
and Rex1 activating Tsix to remodel Xist chromatin and ensure random X
inactivation upon differentiation. The holistic pattern of Xist/Tsix
regulation by pluripotent factors that Navarro et al. (2010) identified
suggested a general direct governance of complex epigenetic processes by
the machinery dedicated to pluripotency.
ANIMAL MODEL
Lee and Lu (1999) created a targeted deletion of the Tsix gene in female
and male mouse cells. Despite a deficiency of Tsix RNA, X-chromosome
counting remained intact: female cells still inactivated 1 X, while male
cells blocked X inactivation. However, heterozygous female cells showed
skewed Xist expression and primary nonrandom inactivation of the mutant
X. The ability of the mutant X to block Xist accumulation was
compromised. The authors concluded that Tsix regulates Xist in cis and
determines X-chromosome choice without affecting silencing. Therefore,
counting, choice, and silencing are genetically separable. Contrasting
effects in XX and XY cells argued that negative and positive factors are
involved in choosing active and inactive X chromosomes.
Lee (2000) provided evidence that imprinting on the X chromosome is
controlled by the antisense Xist gene, Tsix. Tsix was maternally
expressed and mice carrying a Tsix deletion showed normal paternal but
impaired maternal transmission. Maternal inheritance occurred
infrequently, with surviving progeny showing intrauterine growth
retardation and reduced fertility. Transmission ratio distortion
resulted from disrupted imprinting and postimplantation loss of mutant
embryos. In contrast to effects in embryonic stem cells, deletion of
Tsix caused ectopic X inactivation in early male embryos and
inactivation of both X chromosomes in female embryos, indicating that
X-chromosome counting cannot override Tsix imprinting. These results
highlighted differences between imprinted and random X inactivation but
showed that Tsix regulates both. Lee (2000) proposed that an imprinting
center lies within Tsix.
Clerc and Avner (1998) targeted a 65-kb deletion to one of the 2 Xs in a
female ES cell line, which included both the end of the Xist gene and
the site of initiation of Tsix. This resulted in the exclusive
inactivation of the deleted X in differentiated ES cells. Morey et al.
(2001) reexamined the phenotype of the 65-kb deletion and targeted Tsix
and the terminal exons of Xist back to the deleted locus using a
cre/loxP site-specific reinsertion strategy. Prior to inactivation the
deleted X was associated in undifferentiated ES cells with both
increased Xist expression and diffusion of the Xist transcript away from
its site of synthesis. Restoration of Tsix repressed the steady-state
level of Xist expression and restricted Xist RNA to its transcription
site. At the onset of inactivation in differentiated ES cells,
restoration of Tsix failed to restore random X inactivation, even though
the levels of Xist RNA accumulation in cis were markedly reduced. The
authors proposed a dual function for Tsix as both a repressor of the
steady-state level of Xist expression and as a regulator of the
distribution of Xist RNA within the nucleus. They also hypothesized that
random inactivation requires mechanisms additional to the in cis
repression of Xist.
Deleting Tsix on one X chromosome of the mouse skews X chromosome
inactivation toward the mutated X chromosome in the female soma. Lee
(2002) generated homozygous Tsix-null mice to test how deletion of the
second allele affects the choice of X inactivation. Homozygosity led to
extremely low fertility and revealed 2 previously unknown nonmendelian
patterns of inheritance. First, the sex ratio was skewed against female
births so that one daughter was born for every 2 to 3 sons. The second,
the pattern of X inactivation unexpectedly returned to random in
surviving mice homozygous for the deletion. Thus, with respect to
choice, mutation of Tsix yields a phenotypic abnormality in
heterozygotes but not homozygotes. To reconcile the paradox of female
loss with apparent reversion to random choice, Lee (2002) proposed that
deleting both Tsix alleles resulted in chaotic choice and that
randomness in homozygous survivors reflects a fortuitous selection of
distinct X chromosomes as active and inactive.
Lee (2005) used mouse knockout and transgenic analysis to identify DNA
sequences within the noncoding Tsix and Xite genes as numerators of the
X chromosome. Homozygous deficiency of Tsix resulted in 'chaotic choice'
and a variable number of inactive X's, whereas overdosage of Tsix/Xite
inhibited X inactivation. Thus, counting was affected by specific
Tsix/Xite mutations, suggesting that counting is genetically separable
from but molecularly coupled to choice. The mutations affected XX and XY
mouse cells differently, demonstrating that counting and choice are
regulated not by one blocking factor, but by both a blocking and a
competence factor.
TTC3P1
| dbSNP name | rs6647813(A,G); rs5938183(G,A) |
| cytoBand name | Xq13.3 |
| EntrezGene GeneID | 286495 |
| EntrezGene Description | tetratricopeptide repeat domain 3 pseudogene 1 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | retrotransposed |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3742 |
| ExAC AF | 0.26 |
MAGEE2
| dbSNP name | rs151068350(A,G) |
| ccdsGene name | CCDS14431.1 |
| cytoBand name | Xq13.3 |
| EntrezGene GeneID | 139599 |
| EntrezGene Description | melanoma antigen family E, 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEE2:NM_138703:exon1:c.T732C:p.T244T, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.0 |
| ExAC AF | 1.626e-05 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GENITOURINARY:
[External genitalia, male];
Hypospadias, penoscrotal
MISCELLANEOUS:
See also autosomal form, 146450, and another X-linked form, 300633
MOLECULAR BASIS:
Caused by mutation in the mastermind-like domain containing 1 gene
(MAMLD1, 300120.0001)
OMIM Title
*300760 MELANOMA ANTIGEN, FAMILY E, 2; MAGEE2
OMIM Description
CLONING
By searching databases for sequences similar to MAGED2 (300470), Chomez
et al. (2001) identified human MAGEE2. The deduced protein has 2 MAGE
domains. RT-PCR detected MAGEE2 expression in normal adult human and
mouse tissues.
MAPPING
By genomic sequence analysis, Chomez et al. (2001) mapped the MAGEE gene
cluster to chromosome Xq13-q21.
EVOLUTION
Yngvadottir et al. (2009) genotyped 805 nonsense SNPs in 1,151
individuals from 56 worldwide populations. A nonsense SNP in the MAGEE2
gene, dbSNP rs1343879, displayed the highest Fst value, a measure of
population differentiation, due to a high frequency of the stop allele
in Asian and South American populations and its virtual absence from
European and African populations. The geographic distribution suggested
that the stop allele likely arose before the exit of humans from Africa
about 50 thousand years ago. The MAGEE2 transcript containing the
nonsense SNP was predicted to evade nonsense-mediated decay and encode a
protein truncated by about 77%. Resequencing the MAGEE2 gene in 91
individuals from African (YRI and LKW), European (CEU), and Asian (CHB)
HapMap populations and 1 chimpanzee revealed a total of 43 SNPs, and the
haplotypes carrying the stop allele were much less diverse than the
others. Further analysis suggested that positive selection favored the
truncated version of MAGEE2 in the CHB population. Yngvadottir et al.
(2009) concluded that the truncated version of MAGEE2 had a selective
advantage restricted to East Asia and the Americas.
MAGEE1
| dbSNP name | rs7051260(G,C) |
| ccdsGene name | CCDS14433.1 |
| cytoBand name | Xq13.3 |
| EntrezGene GeneID | 57692 |
| EntrezGene Description | melanoma antigen family E, 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEE1:NM_020932:exon1:c.G1017C:p.E339D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9HCI5 |
| dbNSFP Uniprot ID | MAGE1_HUMAN |
| dbNSFP KGp1 AF | 0.182037371911 |
| dbNSFP KGp1 Afr AF | 0.474285714286 |
| dbNSFP KGp1 Amr AF | 0.0730994152047 |
| dbNSFP KGp1 Asn AF | 0.0335689045936 |
| dbNSFP KGp1 Eur AF | 0.0079575596817 |
| dbSNP GMAF | 0.1826 |
| ESP Afr MAF | 0.448618 |
| ESP All MAF | 0.206955 |
| ESP Eur/Amr MAF | 0.010418 |
| ExAC AF | 0.064 |
OMIM Clinical Significance
Ears:
Congenital neurosensory deafness
Skin:
Patchy hypo- and hyper-pigmentation;
Piebald pigmentary variegation
Eyes:
No ocular albinism
Misc:
Hearing impairment in heterozygotes
Inheritance:
X-linked
OMIM Title
*300702 MELANOMA ANTIGEN, FAMILY D, 4; MAGED4
;;MAGEE1;;
KIAA1859
OMIM Description
CLONING
By serial analysis of gene expression (SAGE), Sasaki et al. (2001)
identified MAGED4, which they called MAGEE1, as a gene highly expressed
in glioblastoma relative to astrocytes. By PCR and 5-prime RACE, they
cloned 3 splice variants containing 741, 739, and 414 amino acids,
respectively, that share the N-terminal 348 amino acids. The 2 longer
isoforms are identical except for the last 2 C-terminal amino acids. The
414-amino acid isoform has a distinct 66-amino acid tail. The 2 long
isoforms share 78.3% acid identity with MAGED1 (300224) over amino acids
421 to 600. Northern blot analysis detected expression of a 3-kb
transcript in a human glioma cell line, primary glioblastoma, normal
brain, and ovary only, with no expression in testis or placenta. RT-PCR
analysis detected expression of the 2 long isoforms in glioma with the
short isoform expressed in all tumor samples examined.
By searching for sequences encoding large proteins expressed in fetal
brain, Nagase et al. (2001) identified a partial cDNA encoding MAGED4,
which they designated KIAA1859.
By RT-PCR analysis, Chomez et al. (2001) detected variable MAGED4
expression in all normal and tumor tissues examined. Database analysis
revealed 3 mouse MAGED genes, but no ortholog of MAGED4.
Using immunofluorescence microscopy, Ito et al. (2006) found that MAGED4
localized near cytoskeletal filaments in A549 lung cancer cells. From
telophase to postmitotic phase, MAGED4 was more intensively concentrated
in the central spindle and midbody relative to beta-tubulin (TUBB;
191130).
GENE FUNCTION
Using immunohistochemistry and RT-PCR, Ito et al. (2006) found that
expression of MAGED4 was upregulated in non-small cell lung cancers, but
MAGED4 was not expressed in normal lung tissue. However, there was no
significant difference in MAGED4 expression among different pathologic
stages. The proliferative activity of tumor cells was significantly
higher in tumors with high MAGED4 levels.
GENE STRUCTURE
Kawano et al. (2001) determined that the MAGED4 gene contains 13 exons.
Alternative splicing of exons 2, 3, and 12 produces at least 3 isoforms.
The promoter region contains transcription factor binding sites for Sp1
and AML1a (RUNX1; 151385). No conventional TATA box or CCAAT box could
be identified, but a CpG island centered around the transcription start
site was identified.
MAPPING
By radiation hybrid analysis, Kawano et al. (2001) mapped the MAGED4
gene to chromosome Xp11, at the same locus as MAGED2 (300470). An almost
exact duplication of the MAGED4 gene, designated MAGED4B (300765), is
also located on chromosome Xp11, and the 2 copies are separated by about
116 kb (Hartz, 2009).
ZCCHC5
| dbSNP name | rs4077512(G,A) |
| ccdsGene name | CCDS14440.1 |
| cytoBand name | Xq21.1 |
| EntrezGene GeneID | 203430 |
| EntrezGene Description | zinc finger, CCHC domain containing 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ZCCHC5:NM_152694:exon2:c.C349T:p.P117S, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8N8U3 |
| dbNSFP Uniprot ID | ZCHC5_HUMAN |
| dbNSFP KGp1 AF | 0.0886075949367 |
| dbNSFP KGp1 Afr AF | 0.0570175438596 |
| dbNSFP KGp1 Amr AF | 0.0491329479769 |
| dbNSFP KGp1 Asn AF | 0.00528169014085 |
| dbNSFP KGp1 Eur AF | 0.069014084507 |
| dbSNP GMAF | 0.08888 |
| ESP Afr MAF | 0.156193 |
| ESP All MAF | 0.153992 |
| ESP Eur/Amr MAF | 0.152736 |
| ExAC AF | 0.107 |
GPR174
| dbSNP name | rs3810712(C,T); rs3810711(T,C); rs3827440(T,C) |
| cytoBand name | Xq21.1 |
| EntrezGene GeneID | 84636 |
| EntrezGene Description | G protein-coupled receptor 174 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4873 |
| ESP Afr MAF | 0.419035 |
| ESP All MAF | 0.471741 |
| ESP Eur/Amr MAF | 0.409483 |
| ExAC AF | 0.503 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant;
Somatic mosaicism (in males)
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Dysmorphic features;
Coarse facies;
Maxillary prognathism;
[Eyes];
Nystagmus;
Retinitis pigmentosa;
Ocular flutter;
Thick eyebrows;
[Nose];
Broad nasal bridge;
[Mouth];
Open mouth;
Thick lips
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (1 patient)
GENITOURINARY:
[Kidneys];
Acute nephrotic syndrome (1 patient)
SKELETAL:
[Limbs];
Shortened extremities
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Epileptic encephalopathy;
Delayed psychomotor development, severe;
Hypotonia;
Seizures;
Hypsarrhythmia;
Small cerebellum;
Cerebral atrophy;
Thinning of the corpus callosum;
Delayed myelination
HEMATOLOGY:
Coagulation defects (1 patient)
IMMUNOLOGY:
Recurrent infections
LABORATORY ABNORMALITIES:
Abnormal serum transferrin pattern (in some patients);
Loss of galactose and sialic acid from multiple branches of complex
type N-glycans (in some patients)
MISCELLANEOUS:
Onset in infancy;
Males carry mutations in the somatic mosaic state;
Abnormal transferrin pattern tends to improve with age
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 35 (UDP-galactose
transporter), member 2 gene (SLC35A2, 314375.0001)
OMIM Title
*300903 G PROTEIN-COUPLED RECEPTOR 174; GPR174
;;GPCR17
OMIM Description
DESCRIPTION
G protein-coupled receptors (GPCRs), such as GPR174, are cell surface
integral membrane proteins that are activated by binding exogenous or
endogenous ligands. Ligand-activated GPCRs initiate cell signaling by
interacting with and activating trimeric forms of G proteins (see GNAS,
139320) in the intracellular space (summary by Takeda et al., 2002).
CLONING
By searching databases for intronless GPCRs, Takeda et al. (2002)
identified GPR174, which they designated GPCR17. The deduced protein
shares 50% homology with the putative purinergic receptor P2Y10 (P2RY10;
300529). RT-PCR detected ubiquitous GPR174 expression. Sugita et al.
(2013) reported that the GPR174 gene encodes a deduced 333-amino acid
protein with a calculated molecular mass of about 35 kD. By RT-PCR of 11
mouse tissues, Sugita et al. (2013) found that Gpr174 was expressed in
spleen and brain only.
GENE FUNCTION
Sugita et al. (2013) found that expression of human GPR174 caused
morphologic changes and slowed proliferation in Chinese hamster ovary
cells, concomitant with elevated intracellular cAMP and Erk (see MAPK1,
176948) phosphorylation. Screening of nucleotides and phospholipids for
possible GPR174 ligands revealed that lysophosphatidylserine stimulated
a dose-dependent increase in cAMP levels in GPR174-expressing cells.
GPR174 was fully activated by oleoyl or stearoyl acyl groups on
lysophosphatidylserine, but not by other phospholipids or nucleotides.
In GPR174-expressing cells, lysophosphatidylserine-dependent
intracellular cAMP elevation and Erk phosphorylation was abolished by
inhibition of the G protein G-alpha-S (GNAS). Sugita et al. (2013)
concluded that GPR174 is a lysophosphatidylserine receptor that
increases intracellular cAMP via G-alpha-S.
GENE STRUCTURE
Takeda et al. (2002) determined that the GPR174 gene has a single coding
exon.
MAPPING
By genomic sequence analysis, Sugita et al. (2013) mapped the GPR174
gene to chromosome Xq21.1. They mapped the mouse Gpr174 gene to a region
of chromosome XD that shares homology of synteny with human Xq21.1.
POU3F4
| dbSNP name | rs5921978(A,G); rs5921979(G,C) |
| ccdsGene name | CCDS14450.1 |
| cytoBand name | Xq21.1 |
| EntrezGene GeneID | 5456 |
| EntrezGene Description | POU class 3 homeobox 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | POU3F4:NM_000307:exon1:c.A708G:p.E236E, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.07557 |
| ExAC AF | 1.0 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Ears];
Deafness, profound;
Hearing loss, conductive;
Hearing loss, sensorineural, progressive;
Wide bulbous internal auditory meatus;
Deficient or absent bone between the lateral end of the meatus and
basal turn of the cochlea;
Abnormal communication between the subarachnoid space in the meatus
and the perilymph;
Stapes fixation;
[Eyes];
Choroideremia (degeneration of the choriocapillaris and retinal pigment
epithelium and finally retina);
Progressive vision loss (in males and some carrier females);
Choroidal sclerosis;
Choroidoretinal degeneration (starting in the midperiphery of the
fundus and progressing centrally and peripherally);
Reduced central vision (occurs last);
Constricted visual fields (occurs second);
Night blindness (occurs first);
Atrophy around the optic disc (in carrier females);
Irregular pigmentation of fundus (in carrier females)
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Mental retardation
MISCELLANEOUS:
Onset of choroideremia in second to third decade;
Leakage of fluid ('gusher') if the stapes is disturbed;
Female carriers may have mild hearing impairment and/or mild signs
of choroideremia;
Contiguous gene deletion syndrome
MOLECULAR BASIS:
Contiguous gene syndrome caused by deletion of chromosome Xq21 including
at least the Rab escort protein 1 gene (CHM, 300390) and the POU
domain, class 3, transcription factor 4 gene (POU3F4, 300039)
OMIM Title
#303110 CHOROIDEREMIA, DEAFNESS, AND MENTAL RETARDATION
;;CHROMOSOME Xq21 DELETION SYNDROME
OMIM Description
A number sign (#) is used with this entry because it represents a
contiguous gene deletion syndrome involving chromosome Xq21 and
including at least the CHM (300390) and POU3F4 (300039) genes.
CLINICAL FEATURES
Ayazi (1981) described a kindred in which 2 brothers and their maternal
uncle had choroideremia (CHM; 303100), congenital deafness, and mental
retardation. Female carriers had typical retinal changes indicative of
the choroideremia carrier state (Nussbaum et al., 1987). This family
(XL-45) was also reported by Cremers et al. (1989), Merry et al. (1989),
and Merry et al. (1992).
Nussbaum et al. (1987) reported a second family (XL-62) in which 2 first
cousins through their mothers had choroideremia, mental retardation,
deafness, and short stature. In a follow-up of this family, Merry et al.
(1989) noted that 1 of the patients had stapes fixation and
perilymphatic gusher on stapedectomy, consistent with DFN3 (304400). The
boys, both mothers, the maternal grandmother, and a sister were all
carriers of an Xq21 deletion. One of the mothers had mild high frequency
sensorineural hearing loss at age 41.
Song et al. (2010) reported a 3-year-old Korean boy who showed severe
bilateral hearing loss at 8 months of age. He also had central
hypotonia, developmental delay, mild mental retardation, and
vesicoureteral reflux. High-resolution temporal bone CT scan showed a
defective cochlear modiolus resulting in a fistulous connection between
the basal turn of the cochlea and the internal auditory canal, typical
of DFN3. His mother had mild high-tone hearing loss. Molecular analysis
identified a 16-Mb deletion of Xq21, including the POU3F4, RSK4
(300303), and CHM (300390) genes. Although he did not have symptoms of
choroideremia, Song et al. (2010) noted that choroideremia is a
progressive disorder that may become apparent with age. Multiplex
ligation-dependent probe analysis (MLPA) showed that the unaffected
mother also carried the deletion.
CYTOGENETICS
In affected members of a family (XL-62) in which 2 males had
choroideremia, mental retardation, and deafness, Nussbaum et al. (1987)
identified an interstitial deletion on chromosome Xq21; markers DXYS1
and DXS72 were deleted. Affected individuals in a second family (XL-45)
previously reported by Ayazi (1981) had a submicroscopic deletion of the
same region.
Schwartz et al. (1988) reported 2 brothers with mental retardation,
sensorineural deafness, and choroideremia associated with a small
interstitial deletion of Xq21.2-q31.31. The mother was found to be a
carrier of choroideremia. Cremers et al. (1989) performed fine mapping
of the deleted Xq21 region. Family XL-62 had a deletion between DXS72
and DXS214 and family XL-42 had a smaller deletion between DXS232 and
DXS95. Another patient (DM) reported by Schwartz et al. (1988) with
choroideremia, mental retardation, and deafness had a deletion between
DXS232 and DXYS5.
Merry et al. (1989) reported similar results as Cremers et al. (1989) in
deletion studies of families XL-62 and XL-42. The deletions involved not
only the choroideremia locus (303100), as proven at a molecular level,
but also the DFN3 locus for X-linked deafness and stapes fixation
(304400), which codes for X-linked deafness with stapes fixation. In
addition, Merry et al. (1989) reported a patient with choroideremia and
mental retardation but no deafness who had a partially overlapping
deletion between DXS233 and DXS3.
In a study of several overlapping deletions involving different parts of
Xq21 with DNA probes, Bach et al. (1992) assigned the DFN3 locus and a
locus for nonspecific X-linked mental retardation to an interval that
encompasses the marker DXS232 and that is flanked by DXS26 and DXS121. A
syndromic form of mental retardation has been mapped to the same area
(309605) but the associated clinical manifestations in those patients
were missing in the deletion patients with deafness and mental
retardation.
UBE2DNL
| dbSNP name | rs6623210(A,G) |
| cytoBand name | Xq21.1 |
| EntrezGene GeneID | 100131816 |
| snpEff Gene Name | RP1-215K18.1 |
| EntrezGene Description | ubiquitin-conjugating enzyme E2D N-terminal like (pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3682 |
| ExAC AF | 0.206 |
TGIF2LX
| dbSNP name | rs2290380(G,A) |
| ccdsGene name | CCDS14459.1 |
| cytoBand name | Xq21.31 |
| EntrezGene GeneID | 90316 |
| EntrezGene Description | TGFB-induced factor homeobox 2-like, X-linked |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TGIF2LX:NM_138960:exon2:c.G589A:p.V197I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8IUE1 |
| dbNSFP Uniprot ID | TF2LX_HUMAN |
| dbNSFP KGp1 AF | 0.742013261001 |
| dbNSFP KGp1 Afr AF | 0.823943661972 |
| dbNSFP KGp1 Amr AF | 0.672566371681 |
| dbNSFP KGp1 Asn AF | 0.525280898876 |
| dbNSFP KGp1 Eur AF | 0.498127340824 |
| dbSNP GMAF | 0.2588 |
| ESP Afr MAF | 0.101434 |
| ESP All MAF | 0.239421 |
| ESP Eur/Amr MAF | 0.318074 |
| ExAC AF | 0.69 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Mouth];
Oral thrush;
[Pharynx];
Absent tonsils
RESPIRATORY:
[Lung];
Pneumonia
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Chronic diarrhea
SKIN, NAILS, HAIR:
[Skin];
Candidal diaper rash;
Erythematous skin rashes
NEUROLOGIC:
[Central nervous system];
Recurrent bacterial meningitis
IMMUNOLOGY:
Frequent bacterial, fungal and viral infections;
Specific antibody production very poor;
Natural killer cells, reduced numbers and cytotoxicity;
Absent T lymphocytes;
Thymic hypoplasia;
Lymphoid depletion;
Lymph nodes are small and poorly developed
LABORATORY ABNORMALITIES:
Low absolute lymphocyte count;
Agammaglobulinemia
MISCELLANEOUS:
Death within first year of life
MOLECULAR BASIS:
Caused by mutation in the interleukin receptor gamma chain gene (IL2RG,
308380.0001)
OMIM Title
*300411 TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR 2-LIKE, X-LINKED; TGIF2LX
;;TGIFLX
OMIM Description
Yp11.2/Xq21.3 is a human-specific homology block that constitutes the
largest shared region among the sex chromosomes, spanning some 3.5 Mb.
Two transcribed sequences had been mapped to this segment: the
protocadherin genes PCDHX (300246) and PCDHY (400022), and the X-linked
poly(A)-binding protein PABPC5 gene (300407), whose Y-homolog was lost
during human evolution. Blanco-Arias et al. (2002) reported the genomic
structure, expression, and evolutionary conservation of a third (X-Y
homologous) transcribed sequence mapping to this region and designated
it TGIFLX/TGIFLY (400025) for TGIF-like X/Y. The genes contain
homeodomains related to the TALE (3-amino acid loop extension)
superclass gene family. Comparative DNA analysis indicated that TGIFLX
originated from retrotransposition of TGIF2 (607294), located on
20q11.2-q12, onto the X chromosome.
CLONING
RT-PCR analysis revealed that both X- and Y-linked TGIF-like genes are
specifically expressed in adult testis. By cloning and sequencing of
TGIFLX homologs in hominoids and Old World monkeys, Blanco-Arias et al.
(2002) found evidence for an open reading frame in the 8 species
studied. A single basepair deletion in the human TGIFLY (as compared
with TGIFLX) created a different reading frame, where the C-terminal
residues shared by TGIFLX and other TGIF proteins were missing. The
conservation, similarity to protein-encoding transcription factors, and
specific expression in testis pointed to a transcriptional role for
TGIFLX/Y in this tissue.
GENE STRUCTURE
Blanco-Arias et al. (2002) found that the TGIFLX/Y gene has a 2,666-bp
mRNA encoded by 2 exons separated by a 96-bp intron.
MAPPING
By amplification from X-linked YACs, Blanco-Arias et al. (2002) mapped
the TGIFLX gene to chromosome Xp21.3.
NAP1L3
| dbSNP name | rs1045686(G,C) |
| ccdsGene name | CCDS14465.1 |
| cytoBand name | Xq21.32 |
| EntrezGene GeneID | 4675 |
| EntrezGene Description | nucleosome assembly protein 1-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | NAP1L3:NM_004538:exon1:c.C670G:p.P224A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q99457 |
| dbNSFP Uniprot ID | NP1L3_HUMAN |
| dbNSFP KGp1 AF | 0.569620253165 |
| dbNSFP KGp1 Afr AF | 0.378947368421 |
| dbNSFP KGp1 Amr AF | 0.435606060606 |
| dbNSFP KGp1 Asn AF | 0.334146341463 |
| dbNSFP KGp1 Eur AF | 0.469581749049 |
| dbSNP GMAF | 0.4317 |
| ESP Afr MAF | 0.447979 |
| ESP All MAF | 0.388621 |
| ESP Eur/Amr MAF | 0.354786 |
| ExAC AF | 0.637 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Severe short-trunked dwarfism (identifiable in early childhood)
HEAD AND NECK:
[Face];
Normal facies
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum;
Posterior rib cupping;
Short clavicles
SKELETAL:
Spondyloepimetaphyseal dysplasia;
[Skull];
Mild maxillary hypoplasia;
[Spine];
Mild odontoid hypoplasia;
Platyspondyly;
Anterior vertebral tongue (infancy);
Wedge-shaped 11th or 12th thoracic vertebrae;
Kyphosis;
[Pelvis];
Narrow pelvis;
Hypoplastic iliac bones;
Horizontal acetabular roof;
Femoral neck hypoplasia;
Coxa valga;
[Limbs];
Moderate limitation of elbow extension;
Short, broad long bone diaphyses;
Disproportionately long ulnae;
Disproportionately long fibulae;
Prominent ulnar styloid process;
Irregular metaphyses;
Underossified epiphyses;
Cone-shaped epiphyses (distal radii);
Cone-shaped epiphyses fused within their metaphyses (distal femora,
proximal and distal tibiae);
[Hands];
Brachydactyly;
Radial deviation of hands;
Short hands;
Short, broad metacarpals and phalanges;
Cone-shaped epiphyses (metacarpals and proximal phalanges);
[Feet];
Short feet
NEUROLOGIC:
[Central nervous system];
Normal intelligence
MISCELLANEOUS:
Pectus carinatum present in obligate carrier mothers;
Dwarfism not detectable at birth
OMIM Title
*300117 NUCLEOSOME ASSEMBLY PROTEIN 1-LIKE 3; NAP1L3
OMIM Description
CLONING
The nucleosome, which is composed of DNA and histones, is a
characteristic feature of eukaryotic cells, constituting not only a
structural unit of the chromosome but a regulator of gene expression.
From a human fetal brain cDNA library, Watanabe et al. (1996) isolated a
novel gene sharing significant homology with the genes of nucleosome
assembly proteins (NAPs). This 2.6-kb cDNA clone, designated NAP1L3,
encodes a 506-amino acid protein. Its predicted amino acid sequence
shows 46% identity and 65% similarity to that of NAP1L (164060).
Northern blot analysis revealed strong expression of a 3-kb transcript
in human adult brain, weak expression in heart, and no detectable
transcript in other tissues tested.
MAPPING
By PCR amplification of radiation hybrid clones, Watanabe et al. (1996)
mapped the NAP1L3 gene to Xq21.3-q22.
LOC643486
| dbSNP name | rs10217873(C,T); rs17282164(A,G); rs180930705(G,C) |
| cytoBand name | Xq21.33 |
| EntrezGene GeneID | 643486 |
| EntrezGene Description | bromodomain, testis-specific pseudogene |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | intergenic |
| snpEff Functional Class | none |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2521 |
ARMCX4
| dbSNP name | rs5991904(G,A); rs5991935(G,A); rs12556314(T,C); rs186972650(T,C); rs4986644(A,G); rs58129309(T,C); rs112981763(C,A); rs7057885(G,A); rs62600821(G,T); rs113083426(T,C); rs2281307(T,C); rs1009457(T,A); rs2179669(A,G); rs2078204(G,C); rs2179670(T,C); rs7052093(T,C); rs376441134(C,T); rs5951260(G,A); rs183388196(G,C); rs190428741(C,A); rs182646373(A,C); rs112081267(G,A); rs147834922(G,A); rs140946033(A,G); rs5951315(G,T); rs59122732(G,A); rs4986645(C,T); rs4986639(G,C); rs140037054(G,T); rs189416741(C,T); rs2361009(T,C); rs5951316(T,C); rs5951317(A,G); rs145181008(C,T); rs6523498(G,A); rs3027567(C,T); rs5951318(A,G); rs3027566(G,C); rs4388621(T,C); rs6523499(C,G); rs56964548(C,T); rs2143596(T,C); rs2361011(T,C); rs5951263(C,T); rs5951320(C,T); rs184829994(C,A); rs5951322(A,G); rs5951323(A,T); rs5951324(A,G); rs6621070(C,A); rs5951325(T,C); rs5951326(C,T); rs5951264(G,A); rs5991938(T,C); rs150437072(T,C); rs5991906(C,T); rs5951265(G,C); rs78294786(G,A); rs113402053(G,A); rs5991907(A,G); rs7063823(A,G); rs5991908(A,G); rs7888475(T,C); rs5991940(A,T); rs142247943(A,G); rs149302835(T,C); rs56855359(A,T); rs148010138(T,C); rs145938777(G,C); rs139344539(A,G); rs6523504(A,G); rs143169075(C,T); rs2361297(A,G); rs138075790(G,A); rs4986648(A,T); rs113063413(A,C); rs112311329(G,C); rs183970129(C,A); rs6621074(T,C); rs145216578(C,T); rs4986649(T,G); rs5991910(C,A); rs11092309(G,A); rs3827421(A,G); rs149948598(G,A); rs2361298(G,A); rs963618(C,T); rs6621080(C,T); rs5951332(A,G); rs5951333(T,C); rs61736018(G,C); rs5991911(A,G); rs149021828(G,C); rs3174476(C,T); rs150629300(G,T); rs6523506(T,G); rs148442337(C,A); rs7060868(T,C); rs7060883(T,C); rs58775880(G,A); rs7060491(G,T); rs145409597(A,T); rs2157110(C,G); rs6621081(G,A); rs187102728(G,A); rs191489306(A,G); rs5951337(A,T); rs7887626(A,G); rs6616250(G,A); rs145665613(G,T); rs6621083(C,T); rs5951338(G,T); rs140640845(A,G); rs138687466(G,T); rs5951267(T,C); rs5951339(C,T); rs55917049(A,G); rs1114844(G,A); rs36017889(G,A); rs67235608(T,A); rs188624845(T,C); rs5951340(T,C); rs5951268(A,G); rs5951341(C,A); rs5951342(A,G); rs5951343(T,C); rs5951269(C,T); rs2057354(G,T); rs2057355(A,G); rs6523509(C,A); rs5951344(C,T); rs60684829(A,G); rs142498341(C,T); rs181923056(A,C); rs148078529(A,G); rs12833777(A,T); rs149733447(C,G); rs5951349(A,G); rs140900603(C,T); rs150474782(C,T); rs73564767(G,A); rs16984362(T,C) |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 100131755 |
| snpEff Gene Name | HNRNPH2 |
| EntrezGene Description | armadillo repeat containing, X-linked 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | intergenic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2823 |
ARMCX3
| dbSNP name | rs138397719(G,C); rs115179885(T,A); rs6995(A,G); rs115440192(A,T) |
| ccdsGene name | CCDS14489.1 |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 51566 |
| EntrezGene Description | armadillo repeat containing, X-linked 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ARMCX3:NM_177947:exon5:c.G136C:p.V46L,ARMCX3:NM_016607:exon5:c.G136C:p.V46L,ARMCX3:NM_177948:exon5:c.G136C:p.V46L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0271 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UH62 |
| dbNSFP Uniprot ID | ARMX3_HUMAN |
| ESP Afr MAF | 0.0 |
| ESP All MAF | 0.000473 |
| ESP Eur/Amr MAF | 0.000743 |
| ExAC AF | 0.0006425 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Coarse face;
[Ears];
Hypoplastic ear lobes;
[Eyes];
Small, downslanting palpebral fissures;
[Nose];
Large bulbous nose;
[Mouth];
Macrostomia
SKELETAL:
[Hands];
Brachydactyly;
[Feet];
Brachydactyly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe;
Lack of speech
OMIM Title
*300364 ARMADILLO REPEAT CONTAINING, X-LINKED 3; ARMCX3
;;ARM PROTEIN LOST IN EPITHELIAL CANCERS, X CHROMOSOME, 3; ALEX3
OMIM Description
Armadillo (arm) repeat proteins (e.g., beta-catenin; 116806), are
involved in development, maintenance of tissue integrity, and
tumorigenesis. Their common feature is a 42-amino acid motif, the arm
repeat.
CLONING
By searching sequence databases for homologs of ALEX1 (300362), followed
by screening a testis cDNA library, Kurochkin et al. (2001) obtained a
cDNA encoding ALEX3. Like ALEX2 (300363), the deduced 379-amino acid
ALEX3 protein contains a potential N-terminal transmembrane domain and a
single arm repeat. ALEX3 is identical to an alpha-fodrin SH3
domain-binding partner (GenBank GENBANK AF211175). EST database
searching of cDNA libraries detected ESTs matching ALEX3 in various
tissues, but not in liver, thymus, or leukocytes. The authors stated
that the coding region of ALEX3 is on a single exon.
MAPPING
By database searching, Kurochkin et al. (2001) determined that the ALEX1
gene maps to Xq21.33-q22.2.
TCEAL2
| dbSNP name | rs5944856(G,C); rs142560569(C,T) |
| ccdsGene name | CCDS14496.1 |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 140597 |
| EntrezGene Description | transcription elongation factor A (SII)-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCEAL2:NM_080390:exon3:c.G203C:p.G68A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9H3H9 |
| dbNSFP Uniprot ID | TCAL2_HUMAN |
| dbNSFP KGp1 AF | 0.129596142254 |
| dbNSFP KGp1 Afr AF | 0.107929515419 |
| dbNSFP KGp1 Amr AF | 0.0808383233533 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.101744186047 |
| dbSNP GMAF | 0.1294 |
| ESP Afr MAF | 0.166102 |
| ESP All MAF | 0.178453 |
| ESP Eur/Amr MAF | 0.185493 |
| ExAC AF | 0.134 |
BEX4
| dbSNP name | rs1064784(G,T); rs5987710(T,A) |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 56271 |
| EntrezGene Description | brain expressed, X-linked 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4117 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Tall, thin habitus
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Long, thin face;
Prominent forehead;
Maxillary hypoplasia;
Prominent jaw;
[Nose];
High nasal bridge;
[Mouth];
High-arched palate
CHEST:
[External features];
Pectus excavatum;
Pectus carinatum;
Narrow chest
SKELETAL:
[Spine];
Kyphosis;
Scoliosis;
[Hands];
Long hands;
Long fingers;
[Feet];
Long feet
MUSCLE, SOFT TISSUE:
Poor musculature
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild to severe;
[Behavioral/psychiatric manifestations];
Autistic features
VOICE:
Hypernasal voice
MOLECULAR BASIS:
Caused by mutation in the UPF3, B, yeast homolog gene (UPF3B, 300298.0001)
OMIM Title
*300692 BEX FAMILY MEMBER 4; BEX4
;;BRAIN-EXPRESSED X-LINKED GENE 4;;
BRAIN-EXPRESSED X-LINKED GENE-LIKE 1; BEXL1
OMIM Description
CLONING
Alvarez et al. (2005) performed subtractive hybridization and database
searches to identify genes involved in dopamine neuron differentiation.
Using rat embryonic day 10 ventral mesencephalic RNA as the tester and
RNA from mesencephalon and spinal cord as the driver, they identified a
novel Bex family member, which they designated Bex4. Human and mouse
homologs were identified through database searches. Using a multiple
human tissue array containing RNA from 75 human adult and fetal tissues
and cancer cell lines, Alvarez et al. (2005) found that BEX4 is
expressed at very high levels in heart, skeletal muscle, liver, and
kidney. Levels of BEX4 expression are uniform throughout the brain.
Using immunofluorescence to detect an epitope-tagged protein, Alvarez et
al. (2005) found that rat Bex4 localizes to the nucleus and cytoplasm of
HEK 293T cells. Based on this subcellular localization, Alvarez et al.
(2005) predicted that Bex4 passively diffuses across the nuclear pore
complex. By using proteasome inhibitor I, Alvarez et al. (2005) showed
that, like rat Bex3 (NGFRAP1; 300361), rat Bex4 is degraded by the
proteasome.
GENE STRUCTURE
Alvarez et al. (2005) stated that BEX4, like other members of the BEX
gene family, contains 3 exons, with the third exon containing the entire
open reading frame and the majority of the transcript.
MAPPING
By database analysis, Alvarez et al. (2005) mapped the BEX4 gene to
human chromosome Xq22.2, mouse chromosome XE3, and rat chromosome Xq34.
TCEAL5
| dbSNP name | rs6621640(C,G) |
| ccdsGene name | CCDS35356.1 |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 340543 |
| EntrezGene Description | transcription elongation factor A (SII)-like 5 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCEAL5:NM_001012979:exon3:c.G302C:p.R101P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q5H9L2 |
| dbNSFP Uniprot ID | TCAL5_HUMAN |
| dbNSFP KGp1 AF | 0.134418324292 |
| dbNSFP KGp1 Afr AF | 0.259708737864 |
| dbNSFP KGp1 Amr AF | 0.0402298850575 |
| dbNSFP KGp1 Asn AF | 0.0576208178439 |
| dbNSFP KGp1 Eur AF | 0.00663129973475 |
| dbSNP GMAF | 0.1336 |
| ESP Afr MAF | 0.340636 |
| ESP All MAF | 0.13132 |
| ESP Eur/Amr MAF | 0.012039 |
| ExAC AF | 0.060,6.652e-03,8.133e-06 |
TCEAL7
| dbSNP name | rs1045761(G,C) |
| cytoBand name | Xq22.1 |
| EntrezGene GeneID | 56849 |
| EntrezGene Description | transcription elongation factor A (SII)-like 7 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | intron |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3724 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GENITOURINARY:
[External genitalia, male];
Hypospadias, penoscrotal
MISCELLANEOUS:
See also autosomal form, 146450, and another X-linked form, 300633
MOLECULAR BASIS:
Caused by mutation in the mastermind-like domain containing 1 gene
(MAMLD1, 300120.0001)
OMIM Title
*300771 TRANSCRIPTION ELONGATION FACTOR A-LIKE 7; TCEAL7
OMIM Description
CLONING
By EST database analysis of a sequence previously identified as a
downregulated gene in 3 of 4 suppression subtraction libraries of
primary ovarian tumors against normal ovarian epithelial cell brushings,
followed by PCR, Chien et al. (2005) cloned TCEAL7. The deduced
100-amino acid protein has a coiled-coil domain. TCEAL7 shares amino
acid similarity with TCEAL1 (300237), TCEAL6, and NGFRAP1 (300361).
GENE FUNCTION
Chien et al. (2005) showed that overexpression of TCEAL7 in ovarian
cancer cells induced apoptosis. RT-PCR analysis detected expression in
normal ovarian epithelial cells but demonstrated loss of expression in
ovarian cancer cell lines and primary tumors, confirming downregulation
in ovarian tumors. Studies with 5-aza-2-prime-deoxycytidine demonstrated
a dose-dependent increase in TCEAL7 expression. The authors concluded
that methylation of a CpG SmaI site plays a role in controlling TCEAL7
expression and activation in primary ovarian tumors. Chien et al. (2005)
stated that there was no evidence for loss of heterozygosity, consistent
with the hypothesis that the TCEAL7 locus displays X inactivation and
that tumor-related epigenetic silencing inactivated the active allele.
GENE STRUCTURE
Chien et al. (2005) determined that the TCEAL7 gene contains 3 exons
with the entire open reading frame contained in exon 3.
MAPPING
By database analysis, Chien et al. (2005) mapped the TCEAL7 gene to
chromosome Xq22.1-q22.3, where it lies 24 kb and 42 kb proximal to
TCEAL6 and NGFRAP1, respectively.
NGFRAP1
| dbSNP name | rs140310852(C,T) |
| cytoBand name | Xq22.2 |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.007255 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Coarse face;
[Ears];
Hypoplastic ear lobes;
[Eyes];
Small, downslanting palpebral fissures;
[Nose];
Large bulbous nose;
[Mouth];
Macrostomia
SKELETAL:
[Hands];
Brachydactyly;
[Feet];
Brachydactyly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe;
Lack of speech
OMIM Title
*300361 NERVE GROWTH FACTOR RECEPTOR-ASSOCIATED PROTEIN 1; NGFRAP1
;;NGFR-ASSOCIATED PROTEIN 1;;
p75(NTR)-ASSOCIATED CELL DEATH EXECUTOR; NADE;;
BRAIN-EXPRESSED X-LINKED GENE 3; BEX3
OMIM Description
CLONING
The C-terminal cytoplasmic domain of p75(NTR) (NGFR; 162010) has a
type-2 death domain. However, TRAF (e.g., TRAF6; 602355)-like proteins
that interact with this domain do not affect NGF (162030)-dependent
apoptosis. Using a yeast 2-hybrid screen with the cytosolic domain of
p75(NTR) as bait, Mukai et al. (2000) obtained cDNAs encoding mouse and
human p75(NTR)-associated cell death executor, or NADE. Human NADE is
identical to the HGR74 cDNA cloned by Rapp et al. (1990) from an ovarian
granulosa cDNA library. HGR74 was expressed in testis, prostate, seminal
vesicle, and ovarian granulosa cells (Rapp et al., 1990). By sequence
analysis, Mukai et al. (2000) predicted that the 111-amino acid NADE
protein has a leucine-rich nuclear export signal (NES) and 2
ubiquitination sequence boxes. Western blot analysis showed expression
of mouse Nade only after proteasome inhibition, implying that native
Nade is modified by the ubiquitin conjugating system.
GENE FUNCTION
Using immunofluorescence microscopy, Rapp et al. (1990) demonstrated
expression of wildtype Nade, but not Nade carrying leu94-to-ala and
leu97-to-ala mutations in the NES, in the cytoplasm. GST pull-down
analysis indicated that the C terminus of Nade binds to the cytoplasmic
cell death domain of p75(NTR). Coimmunoprecipitation analysis showed
that NGF induces interaction of NADE and p75(NTR). Tunel analysis
determined that NGF, but not other neurotrophins, could induce apoptosis
in cells expressing NADE and p75(NTR). NGF-treated cells expressing NADE
and p75(NTR) processed CASP2 (600639) and CASP3 (600636) to their active
forms. Confocal microscopy established that most NGF-treated
oligodendrocytes underwent apoptosis and expressed NADE.
MAPPING
Scott (2001) mapped the NGFRAP1 gene to Xq22.1-q23 based on sequence
similarity between the NGFRAP1 sequence and the chromosome X clone
RP13-349O20 (GenBank GENBANK AL606763).
TCEAL4
| dbSNP name | rs11010(T,C) |
| ccdsGene name | CCDS14510.2 |
| CosmicCodingMuts gene | TCEAL4 |
| cytoBand name | Xq22.2 |
| EntrezGene GeneID | 79921 |
| EntrezGene Description | transcription elongation factor A (SII)-like 4 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TCEAL4:NM_024863:exon3:c.T438C:p.H146H,TCEAL4:NM_001006935:exon3:c.T438C:p.H146H,TCEAL4:NM_001006937:exon3:c.T438C:p.H146H, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.266 |
| ESP Afr MAF | 0.452934 |
| ESP All MAF | 0.397236 |
| ESP Eur/Amr MAF | 0.365488 |
| ExAC AF | 0.288 |
MORF4L2-AS1
| dbSNP name | rs12014141(C,G); rs1543384(C,T) |
| cytoBand name | Xq22.2 |
| EntrezGene GeneID | 340544 |
| snpEff Gene Name | MORF4L2 |
| EntrezGene Description | MORF4L2 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.008464 |
IRS4
| dbSNP name | rs1801164(G,C); rs80131334(T,A); rs41307415(C,T) |
| ccdsGene name | CCDS14544.1 |
| cytoBand name | Xq22.3 |
| EntrezGene GeneID | 8471 |
| EntrezGene Description | insulin receptor substrate 4 |
| EntrezGene Type of gene | protein-coding |
| ESP ClinicalLink | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=8471&%3Brs=1801164 |
| Annovar Function | IRS4:NM_003604:exon1:c.C2635G:p.H879D, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | O14654 |
| dbNSFP Uniprot ID | IRS4_HUMAN |
| DUPLICATE | http://www.ncbi.nlm.nih.gov/sites/varvu?gene=8471&%3Brs=1801164 |
| dbNSFP KGp1 AF | 0.48643761302 |
| dbNSFP KGp1 Afr AF | 0.48 |
| dbNSFP KGp1 Amr AF | 0.364341085271 |
| dbNSFP KGp1 Asn AF | 0.521621621622 |
| dbNSFP KGp1 Eur AF | 0.126488095238 |
| dbSNP GMAF | 0.4855 |
| ESP Afr MAF | 0.386441 |
| ESP All MAF | 0.356433 |
| ESP Eur/Amr MAF | 0.209869 |
| ExAC AF | 0.350,4.066e-05 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant;
Somatic mosaicism (in males)
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Dysmorphic features;
Coarse facies;
Maxillary prognathism;
[Eyes];
Nystagmus;
Retinitis pigmentosa;
Ocular flutter;
Thick eyebrows;
[Nose];
Broad nasal bridge;
[Mouth];
Open mouth;
Thick lips
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (1 patient)
GENITOURINARY:
[Kidneys];
Acute nephrotic syndrome (1 patient)
SKELETAL:
[Limbs];
Shortened extremities
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Epileptic encephalopathy;
Delayed psychomotor development, severe;
Hypotonia;
Seizures;
Hypsarrhythmia;
Small cerebellum;
Cerebral atrophy;
Thinning of the corpus callosum;
Delayed myelination
HEMATOLOGY:
Coagulation defects (1 patient)
IMMUNOLOGY:
Recurrent infections
LABORATORY ABNORMALITIES:
Abnormal serum transferrin pattern (in some patients);
Loss of galactose and sialic acid from multiple branches of complex
type N-glycans (in some patients)
MISCELLANEOUS:
Onset in infancy;
Males carry mutations in the somatic mosaic state;
Abnormal transferrin pattern tends to improve with age
MOLECULAR BASIS:
Caused by mutation in the solute carrier family 35 (UDP-galactose
transporter), member 2 gene (SLC35A2, 314375.0001)
OMIM Title
*300904 INSULIN RECEPTOR SUBSTRATE 4; IRS4
OMIM Description
CLONING
Insulin receptor (INSR; 147670) is a tyrosine kinase that phosphorylates
cellular substrates when it is activated by the binding of insulin (INS;
176730). Its most well-characterized substrates are 2 members of the
INSR substrate (IRS) family, IRS1 (147545) and IRS2 (600797). Lavan et
al. (1997) cloned cDNAs encoding IRS4, a 160-kD protein from human
embryonic kidney (HEK) 293 cells that undergoes rapid tyrosine
phosphorylation in response to insulin (Kuhne et al., 1995). The deduced
1,257-amino acid IRS4 protein has a structure similar to that of other
IRS family members, with a pleckstrin homology (PH) domain, a
phosphotyrosine-binding (PTB) domain, and 12 potential tyrosine
phosphorylation sites spread over the C-terminal portion. Overall, the
IRS4 protein shares only 27% and 29% identity with IRS1 and IRS2,
respectively; however, these proteins are highly similar in the PH and
PTB domains. Northern blot analysis of HEK 293 mRNA detected IRS4
transcripts of 6 kb and 10 kb.
Using in situ hybridization, Numan and Russell (1999) found that Irs4
had a restricted distribution in rat brain compared with other IRS
transcripts. Irs4 expression was widely detected throughout the
hypothalamus, with the most dense labeling observed in the medial
preoptic nucleus, ventromedial hypothalamus, and arcuate nucleus. Irs4
expression was much more restricted in other forebrain and midbrain
regions.
Schreyer et al. (2003) stated that IRS4 has a more restricted tissue
distribution than IRS1 and IRS2. Using Western blot analysis, they found
a prominent IRS4 band at an apparent molecular mass of 160 kD in HEK293
cells and in primary human skeletal muscle cells. A rat protein of 150
kD was detected in cardiac muscle and isolated cardiomyocytes, with
lower expression in red soleus muscle, and even lower expression in the
mixed fiber-type muscles quadriceps and gastrocnemius.
GENE FUNCTION
Fantin et al. (1998) characterized the IRS4 protein in HEK 293 cells. A
large portion of IRS4 was located at the cytoplasmic surface of the
plasma membrane in both the unstimulated and insulin-treated states.
Although the potential tyrosine phosphorylation sites of IRS4 are in
motifs that were expected to bind to the SH2 domain-containing proteins
phosphatidylinositol 3-kinase (PIK3), GRB2 (108355), tyrosine
phosphatase SHP2 (176876), and phospholipase C-gamma (Lavan et al.,
1997), Fantin et al. (1998) found IRS4 associated only with PIK3 and
GRB2. The authors determined that IRS4 is tyrosine phosphorylated in
response to both insulin and insulin-like growth factor I (IGF1;
147440), but not to epidermal growth factor (131530) or interleukin-4
(147780), which elicits tyrosine phosphorylation of IRS1.
Using Western blot analysis, Schreyer et al. (2003) found that
expression of Irs4 was moderately but significantly reduced in heart and
soleus muscle of Wistar Ottowa Karlsburg W (WOKW) rats, a model of
metabolic syndrome, compared with wildtype Wistar rats. Expression of
Irs1 was reduced in skeletal muscle only, and Irs2 expression was
unaffected. In HEK293 cells, IRS4 was prominently tyrosine
phosphorylated in response to insulin or IGF1 stimulation, but not in
response to osmotic stress. In contrast, in human myocytes, IRS4, but
not IRS1 or IRS2, was tyrosine phosphorylated in response to osmotic
stress, but not insulin stimulation.
Li et al. (2011) stated that Asb4 (605761) is downregulated by fasting
in rats and in genetically obese Zucker rats. Using double in situ
hybridization, they found that Irs4 colocalized with Asb4 in Pomc
(176830)- and Npy (162640)-expressing neurons in rat arcuate nucleus,
suggesting a role for Irs4 in regulation of food intake and metabolism.
Mouse Asb4 interacted with endogenous IRS4 and cotransfected mouse Irs4
in HEK293 cells, and Asb4 and Irs4 coimmunoprecipitated from rat
hypothalamic extracts. Expression of mouse Asb4 in HEK293 cells reduced
the level of endogenous and cotransfected IRS4 in a dose-dependent
manner. Asb4 increased ubiquitination of Irs4 following expression in
Chinese hamster ovary cells. Deletion of the SOCS box in Asb4 abrogated
binding of Asb4 to Irs4 and Asb4-dependent Irs4 ubiquitination.
MAPPING
Hartz (2013) mapped the IRS4 gene to chromosome Xq22.3 based on an
alignment of the IRS4 sequence (GenBank GENBANK AF007567) with the
genomic sequence (GRCh37).
ANIMAL MODEL
Bohni et al. (1999) showed that chico, a Drosophila homolog of the
vertebrate IRS gene family, plays an essential role in the control of
cell size and growth. Animals mutant for chico were less than half the
size of wildtype flies, owing to fewer and smaller cells. In mosaic
animals, chico homozygous cells grew slower than their heterozygous
sibs, showed an autonomous reduction in cell size, and formed organs of
reduced size. Although chico flies were smaller, they showed an almost
2-fold increase in lipid levels.
KCNE1L
| dbSNP name | rs697829(G,A) |
| cytoBand name | Xq23 |
| EntrezGene GeneID | 23630 |
| EntrezGene Description | KCNE1-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.214 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GENITOURINARY:
[Kidneys];
Nephrolithiasis;
Renal failure
SKELETAL:
[Feet];
Gout
LABORATORY ABNORMALITIES:
Hyperuricemia;
Hyperuricosuria
MISCELLANEOUS:
Partial deficiency of hypoxanthine phosphoribosyltransferase (HPRT,
78% activity)
MOLECULAR BASIS:
Caused by mutation in the hypoxanthine phosphoribosyltransferase gene
(HPRT1, 308000.0001)
OMIM Title
*300328 POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED FAMILY, MEMBER 1-LIKE;
KCNE1L
;;KCNE5
OMIM Description
CLONING
By database searching with an EST that mapped to the region commonly
deleted in the AMME (Alport syndrome, mental retardation, midface
hypoplasia, and elliptocytosis) contiguous gene syndrome (300194) on
Xq22.3, followed by 5-prime RACE and screening of an undifferentiated
NT2 neuron and a placenta cDNA library, Piccini et al. (1999) cloned a
novel full-length cDNA encoding a deduced 142-amino acid protein
designated KCNE1L. The protein contains a single transmembrane domain
surrounded by many charge residues and 2 potential N-glycosylation
sites. It shares 56% homology with the potassium channel KCNE1 (176271).
Northern blot analysis detected expression of a 1.5-kb KCNE1L transcript
predominantly in heart, skeletal muscle, brain, spinal cord, and
placenta. Piccini et al. (1999) also cloned the mouse homolog and found
that it shares 80% identity with the human protein. In situ
hybridization studies indicated that mouse Kcne1l is expressed in the
migrating neural crest cells of cranial nerves, in the somites, and in
the myoepicardial layer of the heart of the developing mouse embryo.
Piccini et al. (1999) suggested that the KCNE1L gene may be involved in
the cardiac and neurologic abnormalities found in the AMME contiguous
gene syndrome.
Meloni et al. (2002) also cloned the KCNE1L gene, which they designated
KCNE5.
MAPPING
Piccini et al. (1999) identified the KCNE1L gene within a region of
Xq22.3.
TDGF1P3
| dbSNP name | rs5942955(G,C); rs112201345(T,C) |
| cytoBand name | Xq23 |
| EntrezGene GeneID | 6998 |
| EntrezGene Description | teratocarcinoma-derived growth factor 1 pseudogene 3 |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3404 |
RBMXL3
| dbSNP name | rs191960604(G,A); rs12857270(G,A); rs191708687(C,T); rs73636269(C,T); rs4911809(C,T) |
| ccdsGene name | CCDS55478.1 |
| cytoBand name | Xq23 |
| EntrezGene GeneID | 139804 |
| EntrezGene Description | RNA binding motif protein, X-linked-like 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | RBMXL3:NM_001145346:exon1:c.G462A:p.P154P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.003023 |
| ExAC AF | 0.0008408 |
SLC25A5-AS1
| dbSNP name | rs1055287(T,C); rs1055285(T,C); rs12010266(T,C); rs392020(T,C); rs6603508(A,G); rs62599440(T,C) |
| cytoBand name | Xq24 |
| EntrezGene GeneID | 100303728 |
| snpEff Gene Name | SLC25A5 |
| EntrezGene Description | SLC25A5 antisense RNA 1 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | upstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4305 |
SLC25A5
| dbSNP name | rs371749(T,G); rs12390(T,C) |
| ccdsGene name | CCDS14578.1 |
| CosmicCodingMuts gene | SLC25A5 |
| cytoBand name | Xq24 |
| EntrezGene GeneID | 292 |
| EntrezGene Description | solute carrier family 25 (mitochondrial carrier |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | SLC25A5:NM_001152:exon2:c.T332G:p.L111R, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P05141 |
| dbNSFP Uniprot ID | ADT2_HUMAN |
| dbNSFP KGp1 AF | 0.767932489451 |
| dbNSFP KGp1 Afr AF | 0.937062937063 |
| dbNSFP KGp1 Amr AF | 0.635964912281 |
| dbNSFP KGp1 Asn AF | 0.484455958549 |
| dbNSFP KGp1 Eur AF | 0.599206349206 |
| dbSNP GMAF | 0.2328 |
| ExAC AF | 0.601 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Face];
Mild dysmorphic features;
Hypotonic midface;
Prominent jaw;
[Ears];
Thick ears;
Upturned lobes;
[Eyes];
Hypertelorism;
Upslanted palpebral fissures;
Synophrys;
[Nose];
Short nose;
Thickened alae nasi and columella;
[Mouth];
Open mouth;
Tented upper lip;
[Teeth];
Crowded dentition
SKELETAL:
Hyperextensible joints
NEUROLOGIC:
[Central nervous system];
Mental retardation, moderate;
Seizures (1 family);
[Behavioral/psychiatric manifestations];
Autistic features;
Hyperactivity
MISCELLANEOUS:
Carrier females may have mild features
MOLECULAR BASIS:
Caused by mutation in the IL1 receptor accessory protein-like 1 gene
(IL1RAPL, 300206.0001)
OMIM Title
*300150 SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ADENINE NUCLEOTIDE
TRANSLOCATOR), MEMBER A5; SLC25A5
;;ADENINE NUCLEOTIDE TRANSLOCATOR 2; ANT2;;
ADP/ATP TRANSLOCATOR OF FIBROBLASTS;;
ADP/ATP TRANSLOCASE 2;;
ADP/ATP CARRIER 2; AAC2
OMIM Description
DESCRIPTION
ADP/ATP translocase, the most abundant mitochondrial protein, is an
integral component of the inner mitochondrial membrane. It facilitates
exchange of ADP and ATP between the cytosol and the mitochondria,
thereby linking the subcellular compartment of ATP production to those
of ATP utilization. SLC25A5 is 1 of at least 3 transcriptionally active
ADP/ATP translocase genes in humans (Chen et al., 1990).
Battini et al. (1987) cloned an ADP/ATP translocase gene from an
Okayama-Berg library derived from SV40-transformed human fibroblasts.
Ku et al. (1990) cloned and sequenced the ANT2 gene.
Chen et al. (1990) isolated 7 ADP/ATP translocase pseudogenes from
recombinant human genomic libraries. Each pseudogene sequence had more
than 85% identity with the sequence of the translocase cDNA derived from
fibroblast mRNA, but each had mutations that precluded synthesis of a
functional protein.
GENE FUNCTION
Mitochondrial nucleoids are large complexes containing, on average, 5 to
7 mitochondrial DNA (mtDNA) genomes and several proteins involved in
mtDNA replication and transcription, as well as related processes.
Bogenhagen et al. (2008) had previously shown that ANT2 was associated
with native purified HeLa cell nucleoids. Using a formaldehyde
crosslinking technique, they found that ANT2 copurified with mtDNA and
was a core nucleoid protein.
Ito et al. (2010) showed that ANT2 coprecipitated with XPD (ERCC2;
126340), MIP18 (FAM96B; 614778), MMS19 (614777), and CIAO1 (604333) in a
protein complex that was required for chromosome segregation in human
cell lines.
GENE STRUCTURE
Ku et al. (1990) determined that, like the other 2 ANT genes (103220,
300151), ANT2 has 4 exons. They identified differences in the sequence
motif in the 5-prime-flanking regions of the 3 human translocase genes
that could account for differences in the cell-type-specific and
proliferation-associated expression.
Using an intron probe derived from a partial clone of the ANT2 gene,
Chen et al. (1990) localized the gene to chromosome Xq13-q26. The
assignment to the X chromosome and a particular region thereof was
performed by analysis of somatic cell hybrids. By study of somatic cell
hybrids containing different portions of the human X chromosome,
Schiebel et al. (1994) narrowed the assignment to chromosome Xq24-q25.
In connection with the previous assignment to Xq13-q26, the consensus
location can be said to be Xq24-q26.
ANIMAL MODEL
The mitochondrial permeability transition pore (mtPTP), a protein
complex that includes the ANTs, mediates the sudden increase in inner
mitochondrial membrane permeability that is a common feature of
apoptosis. Kokoszka et al. (2004) confirmed that the mouse genome
contains only 2 Ant genes, Ant1 and Ant2. They inactivated both Ant
genes in mouse liver and analyzed mtPTP activation in isolated
mitochondria and the induction of cell death in hepatocytes.
Mitochondria lacking Ant could still undergo inner membrane permeability
transition and release cytochrome c (123970). However, more Ca(2+) than
usual was required to activate mtPTP, and the pore could not be
regulated by Ant ligands, including adenine nucleotides. Hepatocytes
without Ant remained competent to respond to various initiators of cell
death. In addition, mutant mouse liver mitochondria showed respiration
rates that were almost twice that of controls and that were unresponsive
to the addition of ADP. The mitochondrial membrane potential was higher
than that of controls. The increased respiration rate was associated
with upregulated Cox1 (176805) protein levels.
RNF113A
| dbSNP name | rs1800823(T,C); rs708463(C,G) |
| cytoBand name | Xq24 |
| EntrezGene GeneID | 7737 |
| snpEff Gene Name | NDUFA1 |
| EntrezGene Description | ring finger protein 113A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | utr_5_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1125 |
| ESP Afr MAF | 0.13212 |
| ESP All MAF | 0.081266 |
| ESP Eur/Amr MAF | 0.052074 |
| ExAC AF | 0.081 |
CT47B1
| dbSNP name | rs871733(T,C) |
| ccdsGene name | CCDS48161.1 |
| cytoBand name | Xq24 |
| EntrezGene GeneID | 643311 |
| EntrezGene Description | cancer/testis antigen family 47, member B1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CT47B1:NM_001145718:exon1:c.A546G:p.P182P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3464 |
| ESP Afr MAF | 0.103391 |
| ESP All MAF | 0.373819 |
| ESP Eur/Amr MAF | 0.489326 |
| ExAC AF | 0.555 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
HEAD AND NECK:
[Eyes];
Corneal clouding, congenital;
Late subepithelial band keratopathy;
Endothelial changes resembling lunar craters (in carrier females and
some affected males);
Discontinuity and degeneration of the endothelial cell layer;
Marked thickening of Descemet membrane
OMIM Title
*300790 CANCER/TESTIS ANTIGEN FAMILY 47, MEMBER B1; CT47B1
;;CT47A13;;
CT47.13
OMIM Description
CLONING
Chen et al. (2006) identified 13 tandem copies of the CT47 gene,
including CT47B1, on chromosome Xq24.
Using an accession number provided by Strausberg et al. (2002) and
assigned to CT47A11 (300592), (GenBank GENBANK BC029540), Hartz (2009)
identified 12 copies of the CT47 gene on chromosome Xq24 (build 36.1).
Of these copies, 9 share 100% nucleotide identity, and 3 share over
90.0% nucleotide identity. All contain 3 exons.
See 300592 for further information.
MAPPING
Hartz (2009) mapped the duplications of the CT47 gene to chromosome Xq24
based on alignment of a sequence containing CT47A11 (GenBank GENBANK
AB097024) with the genomic sequence (build 36.1).
LOC100129520
| dbSNP name | rs3135237(A,G); rs3135238(T,C) |
| cytoBand name | Xq25 |
| EntrezGene GeneID | 100129520 |
| snpEff Gene Name | RP13-147D17.1 |
| EntrezGene Description | testis expressed sequence 13-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | LOC100129520:NM_001195272:exon1:c.A2431G:p.S811G, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1125 |
| ExAC AF | 0.11 |
DCAF12L2
| dbSNP name | rs3761552(G,A); rs61743114(G,A); rs12014937(T,G) |
| ccdsGene name | CCDS43991.1 |
| cytoBand name | Xq25 |
| EntrezGene GeneID | 340578 |
| EntrezGene Description | DDB1 and CUL4 associated factor 12-like 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | DCAF12L2:NM_001013628:exon1:c.C1218T:p.C406C, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4782 |
| ESP Afr MAF | 0.227901 |
| ESP All MAF | 0.469658 |
| ESP Eur/Amr MAF | 0.297265 |
| ExAC AF | 0.407 |
ACTRT1
| dbSNP name | rs61745544(A,T); rs61741364(C,A) |
| ccdsGene name | CCDS14611.1 |
| cytoBand name | Xq25 |
| EntrezGene GeneID | 139741 |
| EntrezGene Description | actin-related protein T1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | ACTRT1:NM_138289:exon1:c.T1033A:p.S345T, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.8461 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q8TDG2 |
| dbNSFP Uniprot ID | ACTT1_HUMAN |
| dbNSFP KGp1 AF | 0.0108499095841 |
| dbNSFP KGp1 Afr AF | 0.0208333333333 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0 |
| dbSNP GMAF | 0.01088 |
| ESP Afr MAF | 0.039635 |
| ESP All MAF | 0.014485 |
| ESP Eur/Amr MAF | 0.000149 |
| ExAC AF | 0.003571 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Prominent forehead;
Prominent supraorbital ridges;
Long face;
Short philtrum;
Upturned philtrum;
Marked infraorbital creases;
Prominent chin;
[Ears];
Large ears;
[Eyes];
Hypotelorism;
Deep-set eyes;
Strabismus;
Nystagmus;
[Nose];
Long, tubular nose;
[Mouth];
Thin upper lip
GENITOURINARY:
[External genitalia, male];
Hypoplastic scrotum;
Microphallus;
[Internal genitalia, male];
Cryptorchidism
NEUROLOGIC:
[Central nervous system];
Psychomotor delay;
Mental retardation, moderate to severe (IQ 40 to 60);
Mental retardation, mild, in most carrier females;
Hypotonia;
Speech delay;
Seizures;
Ataxic gait;
Spasticity;
Cerebellar signs;
Cerebellar hypoplasia;
Disorganization of the anterior cerebellar vermis;
Enlarged ventricles;
Enlarged cisterna magna;
Retrocerebellar cyst;
Decreased cerebral volume, especially of the frontal lobes;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Autistic features
MISCELLANEOUS:
Onset in infancy;
Most carrier females have mild mental retardation and subtle facial
changes
MOLECULAR BASIS:
Caused by mutation in the oligophrenin 1 gene (OPHN1, 300127.0001)
OMIM Title
*300487 ACTIN-RELATED PROTEIN T1; ACTRT1
;;ARPT1
OMIM Description
CLONING
Heid et al. (2002) purified bovine Arpt1 from the calyx fraction of
epididymal sperm heads. Using peptide sequences to search genomic and
EST databases, they identified human ARPT1. The deduced 376-amino acid
protein shares 49.3% amino acid identity with beta-actin (ACTB; 102630)
and 75.5% identity with ARPT2 (608535). Both ARPT1 and ARPT2 contain
several cysteine residues not found in beta-actin or other ARPs. Bovine
Arpt1 showed an apparent molecular mass of about 40 kD.
MAPPING
Heid et al. (2002) stated that the ACTRT1 gene maps to chromosome Xq25.
GPR119
| dbSNP name | rs73564074(G,A) |
| ccdsGene name | CCDS14625.1 |
| cytoBand name | Xq26.1 |
| EntrezGene GeneID | 139760 |
| EntrezGene Description | G protein-coupled receptor 119 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR119:NM_178471:exon1:c.C402T:p.Y134Y, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.03628 |
| ESP Afr MAF | 0.141069 |
| ESP All MAF | 0.051974 |
| ESP Eur/Amr MAF | 0.001189 |
| ExAC AF | 0.013 |
OMIM Clinical Significance
Eyes:
Albino pupillary reflex;
Depigmented fundus;
Prominent choroidal vessels;
Nystagmus;
Photophobia;
Impaired vision
Head:
Head nodding
Skin:
Normal pigmentation
Misc:
Mosaic fundal pigmentation in carrier females
Lab:
Macromelanosomes on EM
Inheritance:
X-linked
OMIM Title
*300513 G PROTEIN-COUPLED RECEPTOR 119; GPR119
;;G PROTEIN-COUPLED RECEPTOR 2; GPCR2
OMIM Description
DESCRIPTION
GPR119 is a member of the rhodopsin family of G protein-coupled
receptors (GPRs) (Fredriksson et al., 2003).
CLONING
By searching databases for GPRs containing no introns in the coding
region, Takeda et al. (2002) identified GPR119, which they designated
GPCR2. The deduced protein shares 27% homology with dopamine receptor-1
(see 126449). RT-PCR detected ubiquitous GPR119 expression.
By searching databases for sequences similar to rhodopsin-like GPRs,
Fredriksson et al. (2003) identified mouse and human GPR119. The deduced
335-amino acid proteins assume a classic 7-transmembrane (TM) topology
and share 82% amino acid identity. They contain the characteristic DRY
motif in the intracellular side of TM3 and an NSxxNPxxY motif in TM7.
GENE STRUCTURE
Takeda et al. (2002) and Fredriksson et al. (2003) determined that the
coding regions of the mouse and human GPR119 genes are derived from a
single exon.
MAPPING
By genomic sequence analysis, Fredriksson et al. (2003) mapped the
GPR119 gene to chromosome Xq26.1. They mapped the mouse Gpr119 gene to
the X chromosome.
OR13H1
| dbSNP name | rs499030(A,G); rs17316625(C,G); rs655415(A,C) |
| ccdsGene name | CCDS35396.1 |
| cytoBand name | Xq26.2 |
| EntrezGene GeneID | 347468 |
| EntrezGene Description | olfactory receptor, family 13, subfamily H, member 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | OR13H1:NM_001004486:exon1:c.A420G:p.V140V, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.3416 |
| ESP Afr MAF | 0.178618 |
| ESP All MAF | 0.300672 |
| ESP Eur/Amr MAF | 0.370244 |
| ExAC AF | 0.647 |
USP26
| dbSNP name | rs41299088(G,A); rs41304540(C,T); rs61741870(A,G) |
| ccdsGene name | CCDS14635.1 |
| cytoBand name | Xq26.2 |
| EntrezGene GeneID | 83844 |
| EntrezGene Description | ubiquitin specific peptidase 26 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | USP26:NM_031907:exon1:c.C1423T:p.H475Y, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0036 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BXU7 |
| dbNSFP Uniprot ID | UBP26_HUMAN |
| dbNSFP KGp1 AF | 0.0584689572031 |
| dbNSFP KGp1 Afr AF | 0.0460526315789 |
| dbNSFP KGp1 Amr AF | 0.00828729281768 |
| dbNSFP KGp1 Asn AF | 0.0729927007299 |
| dbNSFP KGp1 Eur AF | 0.0026455026455 |
| dbSNP GMAF | 0.05804 |
| ESP Afr MAF | 0.090222 |
| ESP All MAF | 0.035596 |
| ESP Eur/Amr MAF | 0.004459 |
| ExAC AF | 0.028 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
SKIN, NAILS, HAIR:
[Skin];
No eczema
HEMATOLOGY:
Severe congenital neutropenia;
Low to low-normal platelet count;
Normal mean platelet volume (MPV)
IMMUNOLOGY:
Increased activated CD8+ T cells;
Decreased CD4+/CD8+ ratio;
Recurrent major bacterial infections;
Decreased CD3(-)CD16/15(+) natural killer cells;
Low-normal IgA levels
MISCELLANEOUS:
Allelic to Wiskott-Aldrich syndrome (301000) and X-linked thrombocytopenia
(313900)
MOLECULAR BASIS:
Caused by mutation in the WAS gene (WAS, 300392.0012)
OMIM Title
*300309 UBIQUITIN-SPECIFIC PROTEASE 26; USP26
OMIM Description
CLONING
In a systematic search for genes expressed in mouse spermatogonia but
not in somatic tissues, Wang et al. (2001) identified 25 genes, 19 of
which were novel, that are expressed in only male germ cells. Of the 25
genes, 3 are Y-linked and 10 are X-linked, indicating that the X
chromosome has a predominant role in pre-meiotic stages of mammalian
spermatogenesis. One of the novel X-linked mouse genes identified was
ubiquitin-specific protease-26, which encodes a predicted protein
containing his and cys domains that are conserved among deubiquitinating
enzymes. Usp26 shows testis-specific expression. Wang et al. (2001)
identified an orthologous, full-length human USP26 cDNA sequence.
MOLECULAR GENETICS
USP26 is specifically expressed in testis tissue and is a potential
infertility gene. In 8 of 111 patients (7.2%) with Sertoli cell-only
syndrome (305700), Stouffs et al. (2005) found the same 3 changes of the
nucleotide sequence of USP26, all on the same allele: an insertion,
370-371insACA, resulting in the insertion of a threonine residue between
codon 123 and 124; a 494T-C transition resulting in a leu165-to-ser
substitution (L165S); and a 1423C-T transition resulting in a
his475-to-tyr substitution (H475Y). These changes were not found in 152
fertile controls or 32 patients with azoospermia with maturation arrest
(270960). DNA from other family members was not available for
segregation analysis, nor was testicular tissue available for expression
analysis. Stouffs et al. (2005) suggested that these changes might be
involved in male infertility or increase the risk of male infertility.
Using a restriction reaction to detect the 494T-C change in the USP26
gene, Stouffs et al. (2006) analyzed 146 Caucasian patients with
cryptozoospermia or oligozoospermia and 202 controls. The variant was
only detected in 1 man from the control group, who was diagnosed with
obstructive azoospermia but who had normal spermatogenesis on testicular
biopsy; sequencing confirmed the presence of the other 2 variants in
this individual. Stouffs et al. (2006) concluded that the previously
identified cluster of changes does not affect spermatogenesis per se.
Ravel et al. (2006) demonstrated that 2 of the changes identified by
Stouffs et al. (2006) in the USP26 gene, 494T-C and 370insACA,
correspond to the ancestral sequence of the gene, and that the USP26
haplotype is present in significant frequencies in sub-Saharan African
and South and East Asian populations, including in individuals with
known fertility. Ravel et al. (2006) concluded that the allele is not
associated with infertility.
MAPPING
By radiation hybrid analysis, Wang et al. (2001) mapped the human USP26
gene to the X chromosome. Stouffs et al. (2005) reported that the USP26
gene mapped to Xq26.2 (Genbank GENBANK NM_031907).
GENE STRUCTURE
Stouffs et al. (2005) noted that the USP26 gene mRNA sequence is 2,794
bp long and comprises 1 exon.
SMIM10
| dbSNP name | rs11739(C,G); rs2498769(G,A) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 644538 |
| snpEff Gene Name | Z83826.1 |
| EntrezGene Description | small integral membrane protein 10 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | utr_3_prime |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.4486 |
FAM127C
| dbSNP name | rs62599865(G,T); rs2475853(G,C); rs190970621(C,G) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 441518 |
| EntrezGene Description | family with sequence similarity 127, member C |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP KGp1 AF | 0.318264014467 |
| dbNSFP KGp1 Afr AF | 0.156542056075 |
| dbNSFP KGp1 Amr AF | 0.213286713287 |
| dbNSFP KGp1 Asn AF | 0.105577689243 |
| dbNSFP KGp1 Eur AF | 0.272425249169 |
| dbSNP GMAF | 0.318 |
| ExAC AF | 0.24 |
FAM127B
| dbSNP name | rs2498776(T,A) |
| ccdsGene name | CCDS43998.1 |
| CosmicCodingMuts gene | FAM127B |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 26071 |
| EntrezGene Description | family with sequence similarity 127, member B |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | FAM127B:NM_001134321:exon1:c.A142T:p.S48C,FAM127B:NM_001078172:exon1:c.A142T:p.S48C, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9BWD3 |
| dbNSFP Uniprot ID | F127B_HUMAN |
| dbNSFP KGp1 AF | 0.739602169982 |
| dbNSFP KGp1 Afr AF | 0.884892086331 |
| dbNSFP KGp1 Amr AF | 0.521551724138 |
| dbNSFP KGp1 Asn AF | 0.426020408163 |
| dbNSFP KGp1 Eur AF | 0.608606557377 |
| dbSNP GMAF | 0.2606 |
| ESP Afr MAF | 0.106216 |
| ESP All MAF | 0.203005 |
| ESP Eur/Amr MAF | 0.257143 |
| ExAC AF | 0.709,1.223e-04 |
LINC00087
| dbSNP name | rs1135844(T,C) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 644596 |
| snpEff Gene Name | NCRNA00087 |
| EntrezGene Description | long intergenic non-protein coding RNA 87 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3628 |
LOC100506790
| dbSNP name | rs2531370(A,G) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 100506790 |
| snpEff Gene Name | RP11-265D19.6 |
| EntrezGene Description | uncharacterized LOC100506790 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.004837 |
LINC00086
| dbSNP name | rs41312582(A,T); rs6635045(G,A); rs45601034(C,T) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 399668 |
| snpEff Gene Name | 5S_rRNA |
| EntrezGene Description | long intergenic non-protein coding RNA 86 |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | rRNA |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.0532 |
LOC101060211
| dbSNP name | rs5975573(C,T) |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 541466 |
| EntrezGene Symbol | CT45A1 |
| snpEff Gene Name | CT45A1 |
| EntrezGene Description | cancer/testis antigen family 45, member A1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1959 |
GPR101
| dbSNP name | rs5931046(A,G) |
| ccdsGene name | CCDS14662.1 |
| cytoBand name | Xq26.3 |
| EntrezGene GeneID | 83550 |
| EntrezGene Description | G protein-coupled receptor 101 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | GPR101:NM_054021:exon1:c.T1127C:p.L376P, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0002 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q96P66 |
| dbNSFP Uniprot ID | GP101_HUMAN |
| dbNSFP KGp1 AF | 0.158529234479 |
| dbNSFP KGp1 Afr AF | 0.159722222222 |
| dbNSFP KGp1 Amr AF | 0.0658682634731 |
| dbNSFP KGp1 Asn AF | 0.0537037037037 |
| dbNSFP KGp1 Eur AF | 0.0807365439093 |
| dbSNP GMAF | 0.159 |
| ESP Afr MAF | 0.21382 |
| ESP All MAF | 0.171637 |
| ESP Eur/Amr MAF | 0.147592 |
| ExAC AF | 0.174 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
NEUROLOGIC:
[Central nervous system];
Pseudobulbar palsy;
Cognitive deficits;
Facial, pharyngeal, and masticatory muscle diplegia;
Dysarthria;
Speech and language disorders;
Dyslexia;
Atypical absence, atonic/tonic, or tonic-clonic seizures;
Polymicrogyria;
Bilateral perisylvian cortical malformations on MRI
MISCELLANEOUS:
Extremely variable phenotype
OMIM Title
*300393 G PROTEIN-COUPLED RECEPTOR 101; GPR101
OMIM Description
DESCRIPTION
G protein-coupled receptors (GPCRs, or GPRs) contain 7 transmembrane
domains and transduce extracellular signals through heterotrimeric G
proteins.
CLONING
Lee et al. (2001) identified GPR101 within a genomic database using
sequences of the histamine receptor H1 (600167) as query. PCR primers
were designed to amplify and clone GPR101 from a genomic library.
Full-length GPR101 encodes a deduced 508-amino acid protein that shares
approximately 30% sequence identity in the transmembrane regions with
the G protein-coupled receptor RE2, the serotonin 5HT1A receptor (HTR1A;
109760), and the alpha-1A-adrenergic receptor (104221). Northern blot
analysis of human brain tissues revealed expression of 9.5- and 4.2-kb
transcripts in the caudate putamen and hypothalamus. No expression was
detected in cortex, thalamus, hippocampus and pons.
MAPPING
Lee et al. (2001) mapped the GPR101 gene to the X chromosome based on
sequence similarity between the GPR101 sequence and a genomic clone
(GenBank GENBANK AL390879) localized to the X chromosome.
SRD5A1P1
| dbSNP name | rs181936959(C,T) |
| cytoBand name | Xq27.1 |
| EntrezGene GeneID | 6719 |
| snpEff Gene Name | RP1-93C23.1 |
| EntrezGene Description | steroid-5-alpha-reductase, alpha polypeptide 1 pseudogene 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_pseudogene |
| snpEff Impact | modifier |
| dbSNP GMAF | 6.046E-4 |
CDR1
| dbSNP name | rs41299075(T,C) |
| ccdsGene name | CCDS14670.1 |
| cytoBand name | Xq27.1 |
| EntrezGene GeneID | 1038 |
| EntrezGene Description | cerebellar degeneration-related protein 1, 34kDa |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CDR1:NM_004065:exon1:c.A55G:p.I19V, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0004 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P51861 |
| dbNSFP Uniprot ID | CDR1_HUMAN |
| dbNSFP KGp1 AF | 0.0705244122966 |
| dbNSFP KGp1 Afr AF | 0.0643776824034 |
| dbNSFP KGp1 Amr AF | 0.0257142857143 |
| dbNSFP KGp1 Asn AF | 0.00880281690141 |
| dbNSFP KGp1 Eur AF | 0.0445682451253 |
| dbSNP GMAF | 0.07074 |
| ESP Afr MAF | 0.122034 |
| ESP All MAF | 0.102244 |
| ESP Eur/Amr MAF | 0.090963 |
| ExAC AF | 0.082,8.162e-06,8.162e-06 |
OMIM Clinical Significance
Neuro:
Cerebellar ataxia;
Late extrapyramidal signs
Inheritance:
X-linked
OMIM Title
*302650 CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN 1; CDR1
;;CDR;;
CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN, 34-KD; CDR34
OMIM Description
CLONING
Autoantibodies directed against neuronal proteins have been identified
in some patients with paraneoplastic cerebellar degeneration (PCD),
which occurs in association with small cell carcinoma of the lung,
neoplasms of the breast and ovary, and Hodgkin disease. The
corresponding antigen is designated cerebellar degeneration protein
(CDR). Using IgG from a PCD patient to screen a human cerebellum cDNA
library, then rescreening the library with the resultant cDNA fragment,
Dropcho et al. (1987) cloned CDR. The deduced 223-amino acid protein has
a calculated molecular mass of 27.0 kD. Over 90% of CDR is made up of 34
inexact tandem repeats of 6 amino acids that feature a nearly invariant
core of glutamine and aspartic acid residues. Possible splice variants
encoding variants that differ at the C-terminal end, outside of the
hexapeptide repeat region, were also identified. Northern blot analysis
detected 3 transcripts between 1.3 and 1.5 kb, with the 1.5-kb
transcript predominating, in cerebellum and SMS-KAN neuroblastoma cells.
RNA dot blot revealed high CDR expression in cerebellum and cerebrum,
but little expression in heart, lung, and kidney, and none in liver.
Among cancer cells lines, CDR expression was detected in all 10
neuroblastoma cell lines examined, as well as in a majority of renal
cell carcinoma cell lines and in some astrocytoma, melanoma, and lung
carcinoma cell lines.
Furneaux et al. (1990) demonstrated the selective expression of Purkinje
cell antigens in tumor tissue from PCD patients. The origins of the
cancers were breast (5 patients), ovary (3), endometrium (1), and
fallopian tube (1). These patients had a high titer of anti-Purkinje
cell autoantibody, called anti-Yo. Anti-Yo serum recognized 2 Purkinje
cell antigens, of 62 and 34 kD, known as CDR62 and CDR34. All samples of
anti-Yo serum seemed to recognize both antigens. CDR62 was the major
antigen; reactivity against CDR34 was typically an order of magnitude
less. Furneaux et al. (1990) suggested that this reaction be called
anti-onconeural. The fact that brain cells do not express major
histocompatibility antigens suggests that proteins specifically
expressed in neuronal cells, e.g., CDR34 and CDR62, may not have been
present in the immune system during the establishment of immune
tolerance. Thus, neuronal-specific proteins, although obviously 'self,'
may be regarded as 'foreign' by the immune system. In normal persons,
these 'foreign' neuronal proteins are not recognized by the immune
system, since they are expressed only in cells without MHC. Expression
of the neuronal-specific proteins in a tumor tissue that expresses MHC
is accompanied by a profound immune reaction.
Chen et al. (1990) cloned the human CDR34 gene. Examination of
corresponding mouse cDNA clones revealed similar hexapeptide repeating
units and a highly conserved glu-asp core in each repetitive unit.
GENE FUNCTION
Hansen et al. (2011) found that expression of endogenous CDR1 in HEK293
cells was controlled by its antisense transcript, CDR1AS (CIRS7;
300898), and microRNA-671 (MIR671; 615245). CDR1AS was spliced into a
circular noncoding RNA that appeared to stabilize the CDR1 transcript.
MIR671 destabilized both CDR1 and CDR1AS by directing ARGO2 (EIF2C2;
606229)-dependent degradation of CDR1AS.
GENE STRUCTURE
Chen et al. (1990) determined that the CDR1 gene is intronless.
MAPPING
Rettig et al. (1987) used Southern blot analysis of DNA extracted from
rodent-human somatic cell hybrids to assign the CDR gene to chromosome
Xq. By in situ hybridization, the CDR gene was located to region
Xq24-q27. Siniscalco et al. (1989) confirmed and refined the regional
localization of the CDR gene by linkage studies. They concluded that the
gene is located in the region Xq26-q27.2, the region of a
cytogenetically detectable deletion associated also with factor IX
deficiency (306900).
Using somatic cell hybrid analysis, Chen et al. (1990) mapped CDR34 to
both human and mouse X chromosomes. Regional localization of the human
gene to Xq24-q27 was accomplished by in situ hybridization. Hirst et al.
(1991) localized the CDR gene to a region proximal to the fragile site
close to DXS98 and DXS105. Siniscalco et al. (1991) reported similar
results.
LDOC1
| dbSNP name | rs710106(T,C) |
| cytoBand name | Xq27.1 |
| EntrezGene GeneID | 23641 |
| EntrezGene Description | leucine zipper, down-regulated in cancer 1 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.3543 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Mouth];
Oral thrush;
[Pharynx];
Absent tonsils
RESPIRATORY:
[Lung];
Pneumonia
ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Chronic diarrhea
SKIN, NAILS, HAIR:
[Skin];
Candidal diaper rash;
Erythematous skin rashes
NEUROLOGIC:
[Central nervous system];
Recurrent bacterial meningitis
IMMUNOLOGY:
Frequent bacterial, fungal and viral infections;
Specific antibody production very poor;
Natural killer cells, reduced numbers and cytotoxicity;
Absent T lymphocytes;
Thymic hypoplasia;
Lymphoid depletion;
Lymph nodes are small and poorly developed
LABORATORY ABNORMALITIES:
Low absolute lymphocyte count;
Agammaglobulinemia
MISCELLANEOUS:
Death within first year of life
MOLECULAR BASIS:
Caused by mutation in the interleukin receptor gamma chain gene (IL2RG,
308380.0001)
OMIM Title
*300402 LEUCINE ZIPPER, DOWNREGULATED IN CANCER 1; LDOC1
OMIM Description
CLONING
Using the RNA differential display technique, followed by screening a
human fetal brain cDNA library, Nagasaki et al. (1999) isolated a cDNA
encoding LDOC1. The predicted 146-amino acid LDOC1 protein has a
calculated molecular mass of approximately 17 kD and contains a leucine
zipper-like motif in its N-terminal region and a proline-rich region
that shares marked similarity to an SH3-binding domain. Northern blot
analysis detected ubiquitous expression of LDOC1 in normal tissues, with
high expression in brain and thyroid and low expression in placenta,
liver, and leukocytes. LDOC1 was expressed in 6 of 7 human breast cancer
cell lines examined, but, with only 1 exception, was not expressed in
any pancreatic or gastric cancer cell lines examined. Fluorescence
microscopy analysis demonstrated that the LDOC1 protein is located
predominantly in the nucleus.
MAPPING
By FISH, Nagasaki et al. (1999) mapped the LDOC1 gene to chromosome
Xq27.
MAGEC2
| dbSNP name | rs3765272(C,T); rs111821947(C,T); rs11095951(T,C) |
| ccdsGene name | CCDS14678.1 |
| cytoBand name | Xq27.2 |
| EntrezGene GeneID | 51438 |
| EntrezGene Description | melanoma antigen family C, 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEC2:NM_016249:exon3:c.G909A:p.P303P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.2703 |
| ESP Afr MAF | 0.401043 |
| ESP All MAF | 0.336647 |
| ESP Eur/Amr MAF | 0.299941 |
| ExAC AF | 0.7 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
HEAD AND NECK:
[Ears];
Hearing loss, sensorineural;
[Eyes];
Retinal degeneration;
Nystagmus
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Progressive neurodegeneration;
Hypotonia;
Choreoathetosis;
Seizures;
Loss of developmental milestones;
Speech delay;
Mental retardation;
Frontotemporal atrophy, mild, seen on MRI;
[Behavioral/psychiatric manifestations];
Restlessness
METABOLIC FEATURES:
Lactic acidosis (in some patients);
Metabolic acidosis (in some patients);
Hypoglycemia
LABORATORY ABNORMALITIES:
Patient cells show abnormal mitochondrial morphology;
Decreased activity of 2-methyl-3-hydroxybutyryl Co-A dehydrogenase;
Increased urinary 2-methyl-3 hydroxybutyrate;
Increased urinary tiglylglycine
MISCELLANEOUS:
Age at onset can range from infancy to childhood;
Variable phenotype and severity;
Less severe phenotype in females;
Severity of phenotype is not related to residual enzyme activity
MOLECULAR BASIS:
Caused by mutation in the 17-beta-hydroxysteroid dehydrogenase X gene
(HSD17B10, 300256.0001)
OMIM Title
*300468 MELANOMA ANTIGEN, FAMILY C, 2; MAGEC2
;;CANCER-TESTIS ANTIGEN 10; CT10;;
HCA587;;
MELANOMA ANTIGEN, FAMILY E, 1, FORMERLY; MAGEE1, FORMERLY
OMIM Description
CLONING
Genes of the MAGE family (see 300016) direct the expression of tumor
antigens that are recognized on human melanomas by autologous cytolytic
T lymphocytes. Using representational difference analysis (RDA) with a
melanoma cell line showing high expression of cancer-testis (CT)
antigens, Gure et al. (2000) identified cDNA fragments corresponding to
29 genes, including MAGEC2, which they designated CT10. They cloned
MAGEC2 from a human placenta genomic library. MAGEC2 encodes a deduced
373-amino acid protein that shares 56% homology with MAGEC1 (300223).
RT-PCR analysis of normal and tumor tissues showed expression in testis
and in 20 to 30% of various human cancers.
Lucas et al. (2000) also identified MAGEC2 by RDA with a different
melanoma cell line. By RT-PCR analysis, they also demonstrated
testis-specific expression of MAGEC2 in normal human tissues. Among
tumor tissues, they found that MAGEC2 was frequently expressed in
seminomas, melanomas, and bladder transitional cell carcinomas. It was
also expressed in a significant fraction of head and neck carcinomas,
breast carcinomas, nonsmall-cell lung carcinomas, and sarcomas.
Wang et al. (2002) identified MAGEC2, which they designated HCA587, by
serologic analysis of a recombinant cDNA expression library from a
hepatocellular carcinoma (HCC; 114550) patient.
GENE FUNCTION
By serologic survey, Gure et al. (2000) identified 2 melanoma patients
with anti-CT10 antibody, demonstrating the immunogenicity of CT10 in
humans.
Li et al. (2003) generated anti-HCA587 polyclonal antibody and assessed
the expression of HCA587 protein by immunohistochemical staining in a
panel of normal and tumor tissue sections. No protein was shown in
normal tissues except germ cells in testis and Purkinje cells in
cerebellum. In HCC specimens, the protein was expressed in either
cytoplasm or nucleus in 37.1% (26 of 70) of samples. There appeared to
be a correlation between the tumor differentiation of HCC and HCA587
protein expression, i.e., the lower the differentiation, the higher
percentage of expression. Seroreactivity showed that the antibody
specific to recombinant HCA587 protein was detected only in the sera of
3 patients with poorly differentiated HCCs. HCA587 antigen was also
expressed in different proportions in melanoma, lymphoma, pancreatic
cancer, and lung cancer.
GENE STRUCTURE
Gure et al. (2000) determined that the MAGEC2 gene contains 3 exons and
spans approximately 2.9 kb. The full ORF is contained within the last
exon.
MAPPING
By PCR analysis of somatic cell hybrids and FISH, Gure et al. (2000)
mapped the MAGEC2 gene to Xq27. Lucas et al. (2000) mapped the gene to
Xq26-q27 by radiation hybrid analysis.
See 300016 for a discussion of the high frequency of genes on the X
chromosome encoding proteins with the MAGE domain as well as other
cancer-testis antigen genes (Ross et al., 2005).
UBE2NL
| dbSNP name | rs237520(T,G); rs237521(A,C) |
| ccdsGene name | CCDS35420.1 |
| cytoBand name | Xq27.3 |
| EntrezGene GeneID | 389898 |
| EntrezGene Description | ubiquitin-conjugating enzyme E2N-like |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | UBE2NL:NM_001012989:exon1:c.T266G:p.L89X, |
| Annovar Mutation type | stopgain |
| Annovar Region type | exonic |
| snpEff Effect | stop_gained |
| snpEff Functional Class | nonsense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | high |
| dbNSFP KGp1 AF | 0.62326702833 |
| dbNSFP KGp1 Afr AF | 0.460227272727 |
| dbNSFP KGp1 Amr AF | 0.424812030075 |
| dbNSFP KGp1 Asn AF | 0.458937198068 |
| dbNSFP KGp1 Eur AF | 0.496183206107 |
| dbSNP GMAF | 0.3761 |
| ESP Afr MAF | 0.345241 |
| ESP All MAF | 0.333144 |
| ESP Eur/Amr MAF | 0.326249 |
| ExAC AF | 0.635 |
TMEM257
| dbSNP name | rs5919909(G,A); rs2474402(C,T) |
| cytoBand name | Xq27.3 |
| EntrezGene GeneID | 9142 |
| snpEff Gene Name | SLITRK2 |
| EntrezGene Description | transmembrane protein 257 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.474 |
CXorf40A
| dbSNP name | rs41302150(C,T); rs3747443(G,A); rs3747442(T,A) |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 91966 |
| EntrezGene Description | chromosome X open reading frame 40A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR5 |
| snpEff Effect | start_gained |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1143 |
MAGEA8
| dbSNP name | rs5983916(A,G) |
| ccdsGene name | CCDS14692.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 101410537 |
| EntrezGene Symbol | MAGEA8-AS1 |
| EntrezGene Description | MAGEA8 antisense RNA 1 (head to head) |
| EntrezGene Type of gene | miscRNA |
| Annovar Function | MAGEA8:NM_001166401:exon3:c.A681G:p.A227A,MAGEA8:NM_001166400:exon4:c.A681G:p.A227A,MAGEA8:NM_005364:exon3:c.A681G:p.A227A, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.1258 |
| ESP Afr MAF | 0.041982 |
| ESP All MAF | 0.145914 |
| ESP Eur/Amr MAF | 0.205174 |
| ExAC AF | 0.834 |
OMIM Clinical Significance
INHERITANCE:
Somatic mosaicism
HEAD AND NECK:
[Head];
Macrocephaly;
Microcephaly;
[Face];
Coarse facies;
[Eyes];
Iris coloboma;
Cataract;
Hypertelorism;
Epicanthal folds;
Strabismus;
[Mouth];
Thick lips;
[Teeth];
Irregularly spaced teeth
SKELETAL:
[Spine];
Kyphosis;
Scoliosis;
[Hands];
Clinodactyly;
Syndactyly;
Polydactyly
SKIN, NAILS, HAIR:
[Skin];
Macular hypopigmented whorls, streaks, and patches;
No inflammatory or bullous skin lesions;
[Hair];
Alopecia
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Cerebral atrophy;
Gray matter heterotopias
LABORATORY ABNORMALITIES:
Chromosomal mosaicism in fibroblast and/or peripheral lymphocytes
No consistent karyotypic finding
MISCELLANEOUS:
A nonspecific marker of somatic mosaicism;
Heterogeneous;
Skin abnormalities can be present at birth or appear later in infancy
or childhood;
Seventy percent of cases have associated anomalies;
Most cases sporadic
MOLECULAR BASIS:
Caused by chromosomal mosaicism
OMIM Title
*300341 MELANOMA ANTIGEN, FAMILY A, 8; MAGEA8
;;MAGE8
OMIM Description
The MAGEA family consists of 12 genes (MAGEA1 to MAGEA12), of which 6,
MAGEA1 (300016), MAGEA2 (300173), MAGEA3 (300174), MAGEA4 (300175),
MAGEA6 (300176), and MAGEA12 (300177), are expressed in melanomas and
other cancers. For further background information on the MAGEA family,
see 300016.
CLONING
De Plaen et al. (1994) identified the 12 MAGEA genes. MAGEA8 appeared to
be a weakly expressed member of the family. Rogner et al. (1995)
isolated a MAGEA8 cDNA from a fetal brain cDNA library.
MAPPING
By analysis of cell hybrids, ordered YACs, and cosmids, Rogner et al.
(1995) localized the MAGEA cluster to Xq28. They showed that the 12
genes are arranged in 3 clusters within 3.5 Mb. De Plaen et al. (1999)
mapped the mouse Mage8 gene to the X chromosome.
See 300016 for a discussion of the high frequency of genes on the X
chromosome encoding proteins with the MAGE domain as well as other
cancer-testis antigen genes (Ross et al., 2005).
CNGA2
| dbSNP name | rs5925018(G,A); rs112346801(C,T); rs5970100(C,A); rs184269859(C,T); rs7066992(T,C); rs28650278(C,T); rs5925020(T,G); rs733871(A,C); rs6627457(C,T); rs188591364(T,C); rs12013595(C,T); rs41289498(G,A); rs41289500(G,A); rs5969818(G,C); rs879372(C,T); rs879371(T,A) |
| ccdsGene name | CCDS14701.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 1260 |
| EntrezGene Description | cyclic nucleotide gated channel alpha 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CNGA2:NM_005140:exon7:c.G1081A:p.V361I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.9252 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q16280 |
| dbNSFP Uniprot ID | CNGA2_HUMAN |
| dbNSFP KGp1 AF | 0.00663050030139 |
| dbNSFP KGp1 Afr AF | 0.0 |
| dbNSFP KGp1 Amr AF | 0.00552486187845 |
| dbNSFP KGp1 Asn AF | 0.0 |
| dbNSFP KGp1 Eur AF | 0.0118733509235 |
| dbSNP GMAF | 0.006651 |
| ESP Afr MAF | 0.005997 |
| ESP All MAF | 0.011834 |
| ESP Eur/Amr MAF | 0.015161 |
| ExAC AF | 0.01 |
OMIM Clinical Significance
INHERITANCE:
Somatic mosaicism
HEAD AND NECK:
[Head];
Macrocephaly;
Microcephaly;
[Face];
Coarse facies;
[Eyes];
Iris coloboma;
Cataract;
Hypertelorism;
Epicanthal folds;
Strabismus;
[Mouth];
Thick lips;
[Teeth];
Irregularly spaced teeth
SKELETAL:
[Spine];
Kyphosis;
Scoliosis;
[Hands];
Clinodactyly;
Syndactyly;
Polydactyly
SKIN, NAILS, HAIR:
[Skin];
Macular hypopigmented whorls, streaks, and patches;
No inflammatory or bullous skin lesions;
[Hair];
Alopecia
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Cerebral atrophy;
Gray matter heterotopias
LABORATORY ABNORMALITIES:
Chromosomal mosaicism in fibroblast and/or peripheral lymphocytes
No consistent karyotypic finding
MISCELLANEOUS:
A nonspecific marker of somatic mosaicism;
Heterogeneous;
Skin abnormalities can be present at birth or appear later in infancy
or childhood;
Seventy percent of cases have associated anomalies;
Most cases sporadic
MOLECULAR BASIS:
Caused by chromosomal mosaicism
OMIM Title
*300338 CYCLIC NUCLEOTIDE-GATED CHANNEL, ALPHA-2; CNGA2
;;CYCLIC NUCLEOTIDE-GATED CHANNEL, OLFACTORY, 2; CNG2;;
OCNC1, MOUSE, HOMOLOG OF; OCNC1
OMIM Description
CLONING
Cyclic nucleotide-gated cation channels are essential in visual and
olfactory signal transduction. Two of these proteins, CNG1 (123825) and
CNG2, are encoded by 2 different genes. (An additional member of the
cGMP-gated channel family, termed CNG3, was cloned from bovine kidney;
see 600053.) Biel et al. (1993) characterized the gene for the olfactory
channel CNG2 and its protein product on the basis of the cDNA cloned
from a rabbit aorta cDNA library. The cDNA encodes a polypeptide that is
highly homologous to cloned olfactory channels, indicating that the
channels expressed in olfactory epithelium and aorta are derived from
the same primary transcript.
BIOCHEMICAL FEATURES
Zhong et al. (2002) reported the identification of a leucine zipper
homology domain named CLZ (carboxy-terminal leucine zipper) that is
present in the distal C terminus of CNG channel A subunits but is absent
from B subunits and mediates an intersubunit interaction. With
crosslinking, nondenaturing gel electrophoresis, and analytical
centrifugation, this CLZ domain was found to mediate a trimeric
interaction. In addition, a mutant cone CNG channel A subunit with its
CLZ domain replaced by a generic trimeric leucine zipper produced
channels that behaved much like the wildtype, but less so if replaced by
a dimeric or tetrameric leucine zipper. This A-subunit-only, trimeric
interaction suggested that heteromeric CNG channels actually adopt a
3A:1B stoichiometry. Biochemical analysis of the purified bovine rod CNG
channel confirmed this conclusion. Zhong et al. (2002) concluded that
this revised stoichiometry provides a new foundation for understanding
the structure and function of the CNG channel family.
Zheng and Zagotta (2004) found that when cRNA for 3 rat olfactory CNG
channel subunits, Cnga2, Cnga4 (609472), and Cngb1b (CNGB1; 600724),
were coinjected into Xenopus oocytes, functional channels in the surface
membrane contained a fixed ratio of Cnga2:Cnga4:Cngb1b of 2:1:1. When
expressed individually with Cnga2, the Cnga4 and Cngb1b subunits were
present as single copies, and when expressed alone, they did not
self-assemble.
Biskup et al. (2007) studied the action of homotetrameric olfactory-type
CNGA2 channels in inside-out membrane patches by simultaneously
determining channel activation and ligand binding, using a fluorescent
cGMP analog, 8-DY547-cGMP, as the ligand. At concentrations of
8-DY547-cGMP of less than 1 micromolar, steady-state binding was larger
than steady-state activation, whereas at higher concentrations it was
smaller, generating a crossover of the steady-state relationships.
Global analysis of these relationships together with multiple activation
time courses following cGMP jumps showed that 4 ligands bind to the
channels and that there is significant interaction between the binding
sites. Among the binding steps, the second is most critical for channel
opening: its association constant is 3 orders of magnitude smaller than
the others and it triggers a switch from a mostly closed to a maximally
open state.
MAPPING
Scott (2001) mapped the CNGA2 gene to chromosome Xq27 based on its
inclusion within a mapped genomic clone.
ANIMAL MODEL
Brunet et al. (1996) created knockout mice lacking functional olfactory
CNG channels to assess the roles of different second messenger pathways
in olfactory transduction. Using an electrophysiologic assay, they found
that excitatory responses to both cAMP- and IP3-producing odorants were
undetectable in knockout mice. These results provided direct evidence
that the CNG channel subserves excitatory olfactory signal transduction,
and further suggested that cAMP is the sole second messenger mediating
this process.
The organization of neuronal systems is often dependent on activity and
competition between cells. In olfaction, the X-linked murine Ocnc1
channel subunit is subject to random inactivation and is essential for
odorant-evoked activity. Reporter-tagged Ocnc1 mutant mice permitted
Zhao and Reed (2001) to visualize Ocnc1-deficient olfactory neurons and
their projections. In heterozygous females, X inactivation created a
mosaic with 2 populations of genetically distinct neurons.
Ocnc1-deficient neurons were slowly and specifically depleted from the
olfactory epithelium and displayed unusual patterns of projection to the
olfactory bulb. This depletion was dependent on odorant exposure and
could be reversed by odorant deprivation. The results suggested that
odorants and the activity they evoke are critical for neuronal survival
in a competitive environment, and implicated evoked activity in the
organization and maintenance of the olfactory system.
Mandiyan et al. (2005) found that Cnga2-null male mice failed to mate or
fight, suggesting a broad and essential role for the main olfactory
epithelium in regulating these behaviors. Compared to male wildtype
mice, the mutant mice had increased latency to first sniff the female
and did not display any mounting behavior. The mutant mice also showed a
reduction in sniffing and aggression toward other male mice, compared to
wildtype behavior. However, the mutant mice showed normal grooming
behavior towards other mice, suggesting that all social behaviors were
not disrupted.
MAGEA6
| dbSNP name | rs7056365(G,T) |
| ccdsGene name | CCDS14708.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 4105 |
| EntrezGene Description | melanoma antigen family A, 6 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEA6:NM_005363:exon3:c.G455T:p.S152I,MAGEA6:NM_175868:exon3:c.G455T:p.S152I, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0001 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | P43360 |
| dbNSFP Uniprot ID | MAGA6_HUMAN |
| dbNSFP KGp1 AF | 0.106690777577 |
| dbNSFP KGp1 Afr AF | 0.0747863247863 |
| dbNSFP KGp1 Amr AF | 0.045197740113 |
| dbNSFP KGp1 Asn AF | 0.0107142857143 |
| dbNSFP KGp1 Eur AF | 0.0968208092486 |
| dbSNP GMAF | 0.107 |
| ESP Afr MAF | 0.141106 |
| ESP All MAF | 0.152448 |
| ESP Eur/Amr MAF | 0.158912 |
| ExAC AF | 0.128 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Long, narrow face;
Long philtrum;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Microcornea;
Congenital cataract;
Microphthalmia;
Laterally curved eyebrows;
Thick eyebrows;
Vision loss;
Glaucoma, secondary;
Microcornea;
Persistent hyperplasia of primary vitreous;
Ptosis;
Blepharophimosis;
Exotropia;
[Nose];
Broad nasal tip;
High nasal bridge;
Bifid nasal tip;
[Mouth];
Cleft palate;
Submucous cleft palate;
Bifid uvula;
[Teeth];
Canine radiculomegaly;
Delayed dentition;
Persistent primary teeth;
Oligodontia;
Malocclusion;
Supernumerary teeth;
Fused teeth;
Root dilacerations (extension)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Mitral valve prolapse
GENITOURINARY:
[Internal genitalia, female];
Septate vagina
SKELETAL:
[Feet];
2-3 toe syndactyly;
Hammer toe (2-4 toes)
SKIN, NAILS, HAIR:
[Hair];
Laterally curved eyebrows;
Thick eyebrows
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
MOLECULAR BASIS:
Caused by mutations in the BCL6 corepressor gene (BCOR, 300485.0002)
OMIM Title
*300176 MELANOMA ANTIGEN, FAMILY A, 6; MAGEA6
;;MAGE6
OMIM Description
Genes of the MAGE family direct the expression of tumor antigens that
are recognized on a human melanoma by autologous cytolytic T
lymphocytes. Family A (see 300016) is clustered at Xq28 and family B is
clustered at Xp21.3 (see 300097).
CLONING
De Plaen et al. (1994) identified 12 family A MAGE genes. MAGE6 cDNA was
cloned from a melanoma cell cDNA library. The gene encodes a 314-amino
acid polypeptide that is 99% identical to MAGE3 (300174). RT-PCR
revealed that MAGE6 is expressed in a variety of cancer cell lines, but
among normal tissues only in testis.
GENE STRUCTURE
De Plaen et al. (1994) determined that the MAGEA6 gene comprises 3
exons, with the last exon containing the entire coding sequence.
MAPPING
De Plaen et al. (1994) used human/rodent cell hybrids to map the MAGE
family A cluster to Xq26-qter. Rogner et al. (1995) refined the mapping
of the MAGE family A cluster to Xq28. The 12 genes are arranged in 3
clusters within 3.5 Mb.
See 300016 for a discussion of the high frequency of genes on the X
chromosome encoding proteins with the MAGE domain as well as other
cancer-testis antigen genes (Ross et al., 2005).
MOLECULAR GENETICS
- Somatic Mutation in Pancreatic Cancer
Biankin et al. (2012) performed exome sequencing and copy number
analysis to define genomic aberrations in a prospectively accrued
clinical cohort of 142 patients with early (stage I and II) sporadic
pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative
tumors identified substantial heterogeneity with 2,016 nonsilent
mutations and 1,628 copy number variations. Biankin et al. (2012)
defined 16 significantly mutated genes, reaffirming known mutations and
uncovering novel mutated genes including additional genes involved in
chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage
repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4,
601335; NALCN, 611549; SLC16A4, 603878; and MAGEA6). Integrative
analysis with in vitro functional data and animal models provided
supportive evidence for potential roles for these genetic aberrations in
carcinogenesis. Pathway-based analysis of recurrently mutated genes
recapitulated clustering in core signaling pathways in pancreatic ductal
adenocarcinoma, and identified new mutated genes in each pathway.
Biankin et al. (2012) also identified frequent and diverse somatic
aberrations in genes described traditionally as embryonic regulators of
axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was
also evident in murine Sleeping Beauty transposon-mediated somatic
mutagenesis models of pancreatic cancer, providing further supportive
evidence for the potential involvement of axon guidance genes in
pancreatic carcinogenesis.
MAGEA3
| dbSNP name | rs61751891(G,A) |
| ccdsGene name | CCDS14715.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 4102 |
| EntrezGene Description | melanoma antigen family A, 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | MAGEA3:NM_005362:exon3:c.C879T:p.I293I, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.008464 |
| ESP Afr MAF | 0.015128 |
| ESP All MAF | 0.005494 |
| ESP Eur/Amr MAF | 0.0 |
| ExAC AF | 0.001596 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Face];
Long, narrow face;
Long philtrum;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Microcornea;
Congenital cataract;
Microphthalmia;
Laterally curved eyebrows;
Thick eyebrows;
Vision loss;
Glaucoma, secondary;
Microcornea;
Persistent hyperplasia of primary vitreous;
Ptosis;
Blepharophimosis;
Exotropia;
[Nose];
Broad nasal tip;
High nasal bridge;
Bifid nasal tip;
[Mouth];
Cleft palate;
Submucous cleft palate;
Bifid uvula;
[Teeth];
Canine radiculomegaly;
Delayed dentition;
Persistent primary teeth;
Oligodontia;
Malocclusion;
Supernumerary teeth;
Fused teeth;
Root dilacerations (extension)
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Mitral valve prolapse
GENITOURINARY:
[Internal genitalia, female];
Septate vagina
SKELETAL:
[Feet];
2-3 toe syndactyly;
Hammer toe (2-4 toes)
SKIN, NAILS, HAIR:
[Hair];
Laterally curved eyebrows;
Thick eyebrows
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
MOLECULAR BASIS:
Caused by mutations in the BCL6 corepressor gene (BCOR, 300485.0002)
OMIM Title
*300174 MELANOMA ANTIGEN, FAMILY A, 3; MAGEA3
;;MAGE3
OMIM Description
Genes of the MAGE family direct the expression of tumor antigens that
are recognized on a human melanoma by autologous cytolytic T
lymphocytes. Family A (see 300016) is clustered at Xq28 and family B is
clustered at Xp21.3 (see 300097).
CLONING
De Plaen et al. (1994) identified 12 family A MAGE genes. MAGE3 cDNA was
cloned from a melanoma cell cDNA library. The gene encodes a 314-amino
acid polypeptide. RT-PCR revealed that MAGE2 is expressed in a variety
of cancer cell lines, but among normal tissues only in testis and
placenta.
GENE STRUCTURE
De Plaen et al. (1994) determined that the MAGEA3 gene comprises 3
exons, with the last exon containing the entire coding sequence.
MAPPING
De Plaen et al. (1994) used human/rodent cell hybrids to map the MAGE
family A cluster to Xq26-qter. Rogner et al. (1995) refined the mapping
of the MAGE family A cluster to Xq28. The 12 genes are arranged in 3
clusters within 3.5 Mb.
See 300016 for a discussion of the high frequency of genes on the X
chromosome encoding proteins with the MAGE domain as well as other
cancer-testis antigen genes (Ross et al., 2005).
PNMA3
| dbSNP name | rs6526155(T,C); rs36042591(G,A); rs5970424(C,T); rs3830028(C,T); rs1045069(G,A); rs2301183(G,A); rs9035(T,C); rs7122(T,G) |
| ccdsGene name | CCDS35435.2 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 100287466 |
| EntrezGene Symbol | PNMA6D |
| EntrezGene Description | paraneoplastic Ma antigen family member 6D (pseudogene) |
| EntrezGene Type of gene | pseudo |
| Annovar Function | PNMA3:NM_013364:exon2:c.T1130C:p.V377A,PNMA3:NM_001282535:exon2:c.T1130C:p.V377A, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q9UL41 |
| dbNSFP Uniprot ID | PNMA3_HUMAN |
| dbNSFP KGp1 AF | 0.914406268837 |
| dbNSFP KGp1 Afr AF | 0.86231884058 |
| dbNSFP KGp1 Amr AF | 0.872448979592 |
| dbNSFP KGp1 Asn AF | 0.894039735099 |
| dbNSFP KGp1 Eur AF | 0.795555555556 |
| dbSNP GMAF | 0.08585 |
| ESP Afr MAF | 0.056614 |
| ESP All MAF | 0.111174 |
| ESP Eur/Amr MAF | 0.142263 |
| ExAC AF | 0.891,8.134e-06 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly, progressive
RESPIRATORY:
Respiratory insufficiency;
Apnea;
Central hypoventilation
ABDOMEN:
[Gastrointestinal];
Poor feeding;
Gastroesophageal reflux
NEUROLOGIC:
[Central nervous system];
Encephalopathy, severe, neonatal;
Developmental delay, severe;
Mental retardation, severe;
Seizures;
Axial hypotonia;
Hyperextension of the limbs;
Limb rigidity;
Hyperreflexia;
Dyskinetic movements;
Myoclonus;
EEG abnormalities;
Polymicrogyria (reported in 1 patient);
[Behavioral/psychiatric manifestations];
Stereotypical movements
MISCELLANEOUS:
Onset at birth;
Death usually within first 2 years of life;
MECP2 mutations are those found in females with Rett syndrome (312750)
MOLECULAR BASIS:
Caused by mutation in the methyl-CpG-binding protein 2 gene (MECP2,
300005.0003)
OMIM Title
*300675 PARANEOPLASTIC MA ANTIGEN 3; PNMA3
;;PARANEOPLASTIC ANTIGEN MA3; MA3
OMIM Description
DESCRIPTION
PNMA3 is a member of a family of genes, the paraneoplastic Ma genes,
whose protein products are the targets of immunity associated with
paraneoplastic disorders (see PNMA1, 604010) (Rosenfeld et al., 2001).
The PNMA3 gene contains a functional heptanucleotide shift sequence and
a classical H-type pseudoknot that promotes -1 frameshifting at
approximately 20% efficiency both in vitro and in vivo (Wills et al.,
2006).
CLONING
By immunoscreening a human brainstem lambda ZAP expression library using
sera from 2 patients with paraneoplastic disorder having immunity to Ma
proteins (see PNMA1, 604010 and PNMA2, 603970), Rosenfeld et al. (2001)
cloned PNMA3, which they called MA3. The deduced 470-amino acid protein
has a calculated molecular mass of 53.3 kD and shares regions of up to
75% amino acid identity with previously identified Ma proteins PNMA1 and
PNMA2 and with MAP1 (MOAP1; 609485). PNMA3 contains several potential
phosphorylation sites and a zinc finger C2HC domain near the 3-prime
terminus; the latter feature is unique to PNMA3. RT-PCR detected
expression in brain, testis, trachea, kidney, and, at lower levels, in
heart. Sera from 11 of 29 (38%) paraneoplastic disorder patients
displayed reactivity to PNMA3 by immunoblot analysis. Patient sera with
antibodies to both PNMA3 and PNMA1 displayed reactivity to rat brain
tissues, showing a number of discrete, reactive, speckled structures in
neurons, primarily in nuclei, and to rat germ cells from intermediate
stages of spermatogenesis. No Ma protein reactivities were detected in
200 control sera.
Using Northern blot analysis, Schuller et al. (2005) identified a major
4.4-kb and minor 3.5-kb PNMA3 transcript in brain and detected 5.5-,
4.4-, and 3.5-kb transcripts in testis. Much lower levels of expression
were detected in kidney and ovary.
GENE FUNCTION
Using bioinformatic analysis, Wills et al. (2006) identified the PNMA3
gene as a candidate for a putative -1 frameshift signal, a regulatory
mechanism in which a proportion of ribosomes shifts to an alternative
reading frame. This signal consists of a heptanucleotide shift sequence,
G GGA AAC, and a classical H-type pseudoknot structure, and involves
tRNAs in both the A and P sites (aminoacyl-tRNA and peptidyl-tRNA,
respectively) detaching from their codons and re-pairing to mRNA at the
2 overlapping -1 frame codons (in this case proposed shift to GGG AAA).
Wills et al. (2006) amplified the predicted frameshift site and showed
that this region promoted -1 frameshifting in an in vitro rabbit
reticulocyte lysate transcription/translation system. Mutations in the
proposed pseudoknot sequence greatly reduced the -1 frameshifting from
20% to 2 to 8%. Wills et al. (2006) showed -1 frameshifting in vivo, at
18% efficiency, by transfection into HEK293 cells of the pseudoknot
region with a luciferase reporter whose expression requires -1
frameshifting. Wills et al. (2006) concluded that the PNMA3 gene
contains a functional heptanucleotide shift sequence and a classical
H-type knot that promotes -1 frameshifting at approximately 20%
efficiency both in vitro and in vivo.
GENE STRUCTURE
Rosenfeld et al. (2001) determined that the PNMA3 gene has no introns.
MAPPING
By genomic sequence analysis, Rosenfeld et al. (2001) mapped the PNMA3
gene to the X chromosome.
Gross (2014) mapped the PNMA3 gene to chromosome Xq28 based on an
alignment of the PNMA3 sequence (GenBank GENBANK BC105096) with the
genomic sequence (GRCh37).
TMEM187
| dbSNP name | rs2266890(C,T); rs7350355(A,G) |
| ccdsGene name | CCDS14739.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 8269 |
| EntrezGene Description | transmembrane protein 187 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | TMEM187:NM_003492:exon2:c.C209T:p.S70L, |
| Annovar Mutation type | nonsynonymous SNV |
| Annovar Region type | exonic |
| dbNSFP LR score | 0.0 |
| snpEff Effect | non_synonymous_coding |
| snpEff Functional Class | missense |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | moderate |
| dbNSFP Uniprot Acc | Q14656 |
| dbNSFP Uniprot ID | TM187_HUMAN |
| dbNSFP KGp1 AF | 0.346594333936 |
| dbNSFP KGp1 Afr AF | 0.0622317596567 |
| dbNSFP KGp1 Amr AF | 0.26821192053 |
| dbNSFP KGp1 Asn AF | 0.568306010929 |
| dbNSFP KGp1 Eur AF | 0.115273775216 |
| dbSNP GMAF | 0.3476 |
| ESP Afr MAF | 0.107488 |
| ESP All MAF | 0.153198 |
| ESP Eur/Amr MAF | 0.179262 |
| ExAC AF | 0.305 |
OMIM Clinical Significance
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
Facial hypotonia;
[Ears];
Large ears;
[Mouth];
High-arched palate;
Sialorrhea;
[Teeth];
Bruxism;
[Neck];
Short neck
GENITOURINARY:
[External genitalia, male];
Macroorchidism (described in 1 family)
SKELETAL:
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Distal atrophy of the legs
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Delayed development;
Delayed speech;
Spasticity;
Tremor;
Ataxia;
Parkinsonism;
Shuffling gait;
Spastic gait;
Hyperreflexia;
Increased tone;
Extensor plantar responses;
Choreoathetosis (described in 1 patient);
Seizures;
EEG abnormalities;
[Behavioral/psychiatric manifestations];
Psychosis;
Mood instability;
Schizophrenic symptoms (reported in 1 patient)
MISCELLANEOUS:
Slowly progressive;
Highly variable phenotype with respect to facial dysmorphism and neurologic
features;
Female carriers may have mild mental retardation;
Allelic to Rett syndrome (312750)
MOLECULAR BASIS:
Caused by mutation in the methyl-CpG-binding protein 2 gene (MECP2,
300005.0009).
OMIM Title
*300059 TRANSMEMBRANE PROTEIN 187; TMEM187
;;CHROMOSOME X OPEN READING FRAME 12; CXORF12;;
DXS9878E;;
ITBA1 GENE
OMIM Description
CLONING
Faranda et al. (1996) isolated the ITBA1 gene, which has an open reading
frame encoding 261 amino acids and is ubiquitously expressed. See also
ITBA2 (300060).
MAPPING
Faranda et al. (1996) identified a ITBA1 gene about 2 kb downstream from
HCFC1 (300019), the host cell factor C1 gene located on Xq28. They
identified the gene by using an approach that coupled genomic sequencing
and EST database searching. Because the sequences came from CpG islands
in the proximity of HCFC1 and GDX (312070), ITBA1 was known to be
located in the interval between L1CAM (308840) and G6PD (305900).
NOMENCLATURE
Faranda (1996) stated that the designation of the ITBA gene was
arbitrarily chosen from the acronym of the institute where she works,
Istituto di Tecnologie Biomediche Avanzate, in Milan, Italy.
MIR6858
| dbSNP name | rs2070644(C,T) |
| ccdsGene name | CCDS14751.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 9130 |
| EntrezGene Symbol | FAM50A |
| snpEff Gene Name | FAM50A |
| EntrezGene Description | family with sequence similarity 50, member A |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.2025 |
| ESP Afr MAF | 0.477966 |
| ESP All MAF | 0.259301 |
| ESP Eur/Amr MAF | 0.109542 |
| ExAC AF | 0.154 |
LAGE3
| dbSNP name | rs6567(C,G) |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 8270 |
| snpEff Gene Name | PLXNA3 |
| EntrezGene Description | L antigen family, member 3 |
| EntrezGene Type of gene | protein-coding |
| Annovar Region type | UTR3 |
| snpEff Effect | downstream |
| snpEff Functional Class | none |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | modifier |
| dbSNP GMAF | 0.1862 |
| ESP Afr MAF | 0.434159 |
| ESP All MAF | 0.227966 |
| ESP Eur/Amr MAF | 0.110434 |
| ExAC AF | 0.177 |
CTAG2
| dbSNP name | rs4326559(A,C) |
| ccdsGene name | CCDS14759.1 |
| cytoBand name | Xq28 |
| EntrezGene GeneID | 30848 |
| EntrezGene Description | cancer/testis antigen 2 |
| EntrezGene Type of gene | protein-coding |
| Annovar Function | CTAG2:NM_020994:exon2:c.T345G:p.P115P,CTAG2:NM_172377:exon2:c.T345G:p.P115P, |
| Annovar Mutation type | synonymous SNV |
| Annovar Region type | exonic |
| snpEff Effect | synonymous_coding |
| snpEff Functional Class | silent |
| snpEff Gene Biotype | protein_coding |
| snpEff Impact | low |
| dbSNP GMAF | 0.4607 |
| ESP Afr MAF | 0.118644 |
| ESP All MAF | 0.438027 |
| ESP Eur/Amr MAF | 0.379869 |
| ExAC AF | 0.433 |
OMIM Clinical Significance
INHERITANCE:
X-linked dominant
NEUROLOGIC:
[Central nervous system];
Pseudobulbar palsy;
Cognitive deficits;
Facial, pharyngeal, and masticatory muscle diplegia;
Dysarthria;
Speech and language disorders;
Dyslexia;
Atypical absence, atonic/tonic, or tonic-clonic seizures;
Polymicrogyria;
Bilateral perisylvian cortical malformations on MRI
MISCELLANEOUS:
Extremely variable phenotype
OMIM Title
*300396 CANCER/TESTIS ANTIGEN 2; CTAG2
;;LAGE1;;
CTL-RECOGNIZED ANTIGEN ON MELANOMA; CAMEL
OMIM Description
CLONING
By representational difference analysis, Lethe et al. (1998) identified
and cloned CTAG2, which they called LAGE1, that is expressed in a human
melanoma cell line and not in normal melanocytes. The deduced 180-amino
acid protein shares 84% identity with CTAG1 and contains 2 glycine-rich
regions and a hydrophobic stretch near the C-terminus. An alternate
LAGE1 polypeptide contains 210 amino acids and lacks a hydrophobic
stretch in the C terminus. Northern blot analysis revealed expression of
both variants, showing 2 distinct bands of about 1000 and 750 bp in the
melanoma cell line, and in lung tumor and a sarcoma, but not in normal
lung. By PCR, LAGE1 was expressed in a significant fraction of
melanomas, sarcomas, breast, lung, head and neck, prostate, and bladder
cancers. Lethe et al. (1998) noted a correlation between the expression
of LAGE1 and NYESO1 (300156) in the tumor samples. A PCR screen of
normal tissues indicated strong expression in testis and weaker
expression in uterus and term placenta, but not in any other of the 16
normal tissues tested. Aarnoudse et al. (1999) identified 3 transcripts
of the CTAG2 gene by representational difference analysis of cytotoxic T
lymphocytes raised against IL2-transfected melanoma cells. One
transcript predicts a 180-amino acid protein of 18.2 kD and the second
is an unspliced variant that predicts a 210-amino acid protein of 21.1
kD. The third transcript, which they designated CAMEL, predicts a
109-amino acid protein with a molecular mass of 11.7 kD. CAMEL results
from the utilization of the second start codon and encodes a completely
different protein, with translation in a different reading frame.
GENE STRUCTURE
Lethe et al. (1998) determined that the CTAG2 gene contains 3 exons. The
promoter sequence does not display a TATA box, but shows 2 SP1 sites and
a CpG island.
MAPPING
By somatic cell hybrid mapping and by FISH, Lethe et al. (1998) mapped
the CTAG2 gene to chromosome Xq28. They noted that the somatic cell
hybrids positive for CTAG2 were also positive for NYESO1, and that
cohybridization with a cosmid containing MAGEA6 (300176) and MAGEA2
(300173) yielded superimposed signals.
GENE FUNCTION
Lethe et al. (1998) found that deoxyazacytidine induced expression of
LAGE1 in lymphoblastoid and tumor cells, indicating that methylation is
involved in the control of LAGE1 expression.
OTHER FEATURES
Aradhya et al. (2001) identified a duplicated region of the NEMO gene
(300248). The LAGE2 gene is located within this region, and a similar
but unique LAGE1 gene is located just distal to the duplicated loci.
Lethe et al. (1998) originally described the LAGE1 gene as a
tumor-specific transcript. By mapping and sequence information, Aradhya
et al. (2001) indicated that the duplicated regions are in opposite
orientation. Analysis of the great apes suggested that the NEMO/LAGE2
duplication occurred after divergence of the lineage leading to
present-day humans, chimpanzees, and gorillas 10 to 15 million years
ago. Despite this substantial evolutionary history, only 45
single-nucleotide differences exist between the 2 copies over the entire
35.5 kb, making the duplications more than 99% identical. This high
sequence identity and the inverted orientations of the 2 copies, along
with duplications of smaller internal sections within each copy,
predispose this region to various genomic alterations. Four
rearrangements were detected that involved NEMO, delta-NEMO, or LAGE1
and LAGE2. The authors hypothesized that the susceptibility of this
complex genomic region to various types of pathogenic and polymorphic
rearrangements may underlie the recurrent lethal deletion associated
with incontinentia pigmenti (308300).
TTTY12
| dbSNP name | rs374920063(G,A) |
| cytoBand name | Yp11.2 |
| EntrezGene GeneID | 83867 |
| snpEff Gene Name | AC007275.2 |
| EntrezGene Description | testis-specific transcript, Y-linked 12 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | processed_transcript |
| snpEff Impact | modifier |
TTTY22
| dbSNP name | rs72618768(T,C) |
| cytoBand name | Yp11.2 |
| EntrezGene GeneID | 252954 |
| EntrezGene Description | testis-specific transcript, Y-linked 22 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
TTTY5
| dbSNP name | rs28542474(T,G); rs112061226(T,C); rs7893048(T,C) |
| cytoBand name | Yq11.223 |
| EntrezGene GeneID | 83863 |
| EntrezGene Description | testis-specific transcript, Y-linked 5 (non-protein coding) |
| EntrezGene Type of gene | miscRNA |
| Annovar Region type | ncRNA_exonic |
| snpEff Effect | transcript |
| snpEff Functional Class | none |
| snpEff Gene Biotype | lincRNA |
| snpEff Impact | modifier |
OMIM Clinical Significance
Eyes:
Cataract;
Nystagmus
Inheritance:
? X-linked
OMIM Title
*400038 TESTIS-SPECIFIC TRANSCRIPT, Y-LINKED, 5; TTTY5
OMIM Description
CLONING
Skaletsky et al. (2003) stated that TTTY5 is transcribed, but it does
not appear to encode a protein.
MAPPING
Skaletsky et al. (2003) identified the TTTY5 gene on chromosome Yq. It
is located within the male-specific region of chromosome Y (MSY).
MOLECULAR GENETICS
Repping et al. (2004) identified the b2/b3 deletion within the AZFc
region (415000) of the Y chromosome, in which the TTTY5 gene is deleted.
The b2/b3 deletion has no obvious effect on fitness.